Magellan Rx Report

2 Managed Care Newsstand

4 Tumor DNA Tests and Cancer Monitoring

8 Accelerated Approvals Update: Full Approval of Cancer Therapies

16 Prostate Cancer: Treatments for Advanced Disease and Management

Published By Magellan Rx Management 4801 E. Washington St., Ste. 100 Phoenix, AZ 85034

Tel: 401-344-1000

Fax: 401-619-5215 magellanrx.com

Editor Lindsay Speicher, J.D. Project Manager, Specialty lspeicher@magellanhealth.com

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Carole Kallas ckallas@magellanhealth.com 401-344-1132

The content of Magellan Rx™ Report — including text, graphics, images, and information obtained from third parties, licensors, and other material (“content”) — is for informational purposes only. The content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Magellan Rx™ Report does not verify any claims or other information appearing in any of the advertisements contained in the publication and cannot take responsibility for any losses or other damages incurred by readers in reliance on such content. Developed by D Custom.

Contributors

22 Multiple Myeloma: CAR-T Advances and Management Impact

28 Oncology Supportive Care and Telemedicine

32 Oncology Biosimilar Update: Stakeholder Impact

37

Steve Cutts, Pharm.D. SVP, Market General Manager, MRx Specialty

Haita Makanji, Pharm.D. VP, Clinical Strategy and Innovation, Specialty

Amy E. Edquist Senior Manager, Marketing

Joe Tavares

SVP, Sales and Business Development, Specialty

Carole Kallas

Project Manager

Brian MacDonald, Pharm.D. Director, Specialty Clinical Strategy

Erin Ventura, Pharm.D. Manager, Specialty Clinical Programs

Brian Kinsella, Esq.

Senior Legal Counsel

Alina Young

Associate Legal Counsel

Simone Ndujiuba, Pharm.D., BCOP Director, Clinical Strategy and Innovation, Oncology

Pipeline

Editorial Advisory Board

Mona M. Chitre, Pharm.D., CGP

Chief Pharmacy Officer & VP Clinical Analytics, Strategy & Innovation, Excellus BlueCross BlueShield

Dennis Bourdette, M.D., FAAN, FANA Chair and Roy and Eulalia Swank Family Research Professor, Department of Neurology, Oregon Health & Science University

Yousaf Ali, M.D., FACR

Chief, Division of Rheumatology, Mount Sinai West; Professor of Medicine, Icahn School of Medicine at Mount Sinai

Steven L. D’Amato, B.S.Pharm. Executive Director, New England Cancer Specialists

Joseph Mikhael, M.D., M.Ed., FRCPC, FACP

Chief Medical Officer, International Myeloma Foundation

Steve Marciniak, R.Ph.

Director II, Medical Benefit Drug Management, BlueCross BlueShield of Michigan

Saira A. Jan, M.S., Pharm.D.

Director of Pharmacy Strategy and Clinical Integration, Horizon BlueCross BlueShield of New Jersey

A NOTE FROM OUR CEO

Dear Managed Care Colleagues,

Welcome to our fall 2023 issue of the Magellan Rx Report! It has been a busy year so far, with 38 novel drug approvals as of October. As always, we work diligently to bring our audience valuable and timely managed care trends and updates. For this issue, we are excited to provide insights across the oncology space with the help of our oncology expert, Simone Ndujiuba, Pharm.D., BCOP.

Our cover story (page 28) for this special oncology-focused issue highlights the utilization of telemedicine in the oncology space, specifically for supportive care. Telemedicine has been an important asset in post-COVID healthcare; in this article, we look at some ways it can be best used in oncology treatment and management.

Another article focuses on updates in prostate cancer (page 16) — specifically, a new oral treatment approval in the space. Addressing adherence issues may be key to improved outcomes for patients with prostate cancer.

In our accelerated approvals update article (page 8), we highlight oncology drugs that received accelerated approval, noting those that have now been granted full approval as well as those that have been withdrawn. Accelerated approvals can be tricky for payers to manage, and tracking clinical benefit is critical in determining the appropriate patients and their access to treatment.

Other topics in this issue include a discussion of tumor DNA testing and monitoring (page 4), an article focusing on the CAR-T advances in multiple myeloma treatment (page 22), and an update on oncology biosimilars and the effect on average sales price (ASP) (page 32). As always, we’ve rounded out the issue with our pipeline update (page 37) and managed care newsstand (page 2).

To learn more about our support for payer initiatives of the future, please feel free to contact us at MagellanRxReport@ magellanhealth.com. As always, we value any feedback you may have. I hope you enjoy the report!

Sincerely,

Mostafa Kamal Chief Executive Officer Magellan Rx Management

SUBSCRIBE TODAY!

Stay on top of managed care trends and become a Magellan Rx Report subscriber. Email us at MagellanRxReport@magellanhealth.com to subscribe today. Magellan Rx Report provides pharmacy and medical management solutions for managed care executives and clinicians. We hope you enjoy the issue; thank you for reading.

MANAGED CARE

NEWSSTAND

Lawmakers are considering various strategies to advance PBM reform or gain bipartisan support, including combining smaller PBM bills into a larger package.

PBM Reform Efforts

Congressional action to reform pharmacy benefit managers (PBMs) has significantly intensified, with multiple committees of jurisdiction in the House and Senate working to pass PBM reforms. Lawmakers are considering various strategies to advance PBM reform or gain bipartisan support, including combining smaller PBM bills into a larger package.

Most bills making their way through Congress would affect how PBMs bid and contract with plans, including reporting requirements, pricing models, benefit offerings, and compensation within Medicare, Medicaid, and the commercial market.

It is yet to be determined which PBM reforms will be enacted, if any, since the pressure to pass appropriations bills and other must-pass legislation will make finding floor time challenging. However, broad bipartisan support for PBM reform increases the likelihood that the bills will be brought to the House or Senate floor for a vote later this year or incorporated into a larger must-pass package.

Requirements Related to the Mental Health Parity and Addiction Equity Act, Proposed Rule

In July, the Biden administration released a new proposed rule to reinforce elements of the 2008 Mental Health Parity and Addiction Equity Act (MHPAEA). The law requires group health plans and health insurance issuers that provide mental health and substance use disorder benefits to maintain parity between those benefits and the medical or surgical benefits they provide. In 2013, the final parity rule for commercial plans was issued, and in 2016, the final Medicaid/CHIP parity rule was issued.

The new proposed rule clarifies how insurers should evaluate whether their plans comply with the law. The proposed rule, if finalized, would codify the requirement that plans and issuers conduct meaningful comparative analyses to measure the impact of “nonquantitative” treatment limitations (NQTLs). These include prescription drug formularies, tiered network design, step or fail-first policies, and limitations based on medical necessity, appropriateness, or experimental nature. This analysis evaluates standards related to network composition, out-of-network reimbursement rates, and prior authorization NQTLs.

FDA Approves OTC Birth Control Pill

In July, the FDA approved Opill, a brand version of the oral contraceptive medication norgestrel for over-the-counter sale. The Opill is expected to be available in early 2024. Many questions related to cost and coverage remain. Under the Affordable Care Act (ACA), insurers must cover prescribed contraceptives, but the act does not currently require coverage for over-thecounter medications.

On June 23, 2023, the Biden administration issued an “Executive Order on Strengthening Access to Affordable, HighQuality Contraception and Family Planning Services,” directing the U.S. Secretaries of Treasury, Labor, and Health and Human Services to expand access to and reduce the cost of birth control in America. Among the directives, the order encourages federal entities to: 1) Improve contraception affordability for women with private insurance; 2) Promote increased access to over-the-counter contraceptives, including emergency birth control; and 3) Improve coverage of birth control through Medicare.

Medicare Advantage and Prescription Drug Programs: Part C and Part D Explanation of Benefits PRA

In June, CMS published a notice in the Federal Register requesting to renew the currently approved Part D Explanation of Benefits (EOB), which proposed updates to comply with the Part D Redesign provisions of the Inflation Reduction Act (IRA), including smoothing. Under the IRA, a new monthly cost-sharing cap policy ($2,000) will allow people to choose to spread (a.k.a. “smooth”) their out-of-pocket costs throughout the year starting in 2025.

CMS Revised Guidance for Historic Medicare Drug Price Negotiation Program

On June 30, 2023, CMS released a revised guidance specifying requirements and procedures for implementation of the Medicare Prescription Drug Inflation Rebate Program for Medicare Parts B and D. CMS maintained many of its proposals from the initial guidance. According to the revised guidance, CMS intends for Part D plans to include all dosages and strengths of each covered Part D drug that is a selected drug

on Part D formularies during contract year 2026 and all subsequent years for which the MFP of the selected drug is in effect.

Notably, the revised guidance provides that for contract year 2026, CMS is not implementing explicit tier placement requirements for selected drugs. However, CMS will use its formulary review process to assess any instances where Part D sponsors place selected drugs on non-preferred tiers; or on a higher tier than non-selected drugs in the same class; or require utilization of an alternative brand drug prior to a selected drug with an MFP (i.e., step therapy); or impose more restrictive utilization management for a selected drug.

Proposed Legislation of Interest

Transparency in Coverage Act (H.R. 4507): Introduced in January 2023, the bill would amend the Employee Retirement Income Security Act (ERISA) to codify a Trump administration rule of the same name and require PBMs and health plans to be more transparent about cost-sharing responsibilities and other metrics of pricing information with their enrollees. It cleared the House Commitee on Education and the Workforce during its July 12 markup.

Transparent Prices Required to Inform Consumer and Employers Act (PRICE Act) (H.R. 3281): The bill would require both hospitals and insurers to make price information publicly available. This bill became the primary vehicle for the inclusion of two PBM bills: The Fairness for Patient Medication Act (H.R. 3285) and the PBM Accountability Act (H.R. 2679). The Transparent Price Act cleared the House Committee on Energy and Commerce in May.

Promoting Access to Treatments and Increasing Extremely Needed Transparency Act (PATIENT Act) of 2023 (H.R. 3561): The bill

would require PBMs to provide annual reports to employers with detailed information on prescription drug spending, acquisition costs, out-of-pocket expenses, formulary placement, and rebates. It cleared the House Committee on Energy and Commerce.

Medicaid VBPs for Patients (H.R. 2666): This bill would codify value-based purchasing arrangements under Medicaid. It cleared the House Committee on Energy and Commerce in May.

Hidden Fee Disclosure Act (H.R. 4508): This would amend ERISA to clarify that PBMs must disclose information related to the compensation received for their services to group health plans. It cleared the House Committee on Education and the Workforce on July 12.

Health Data and Access and Transparency Act (DATA) (H.R. 4527): This bill would require plan fiduciaries to have access to deidentified health claims information from PBMs. It cleared the House Committee on Education and the Workforce on July 12.

Health Care Price Transparency Act of 2023 (H.R. 4822): This bill would require PBMs to submit detailed reports to plan sponsors that include, among other data, the total amount of copay assistance received and drug spending, as well as rebate amounts, fees, and any other remuneration from manufacturers. It would also limit Part D beneficiary cost-sharing to the net price amount and authorize the Government Accountability Office to report and analyze the cost-sharing limits and compliance enforcement. The bill cleared the House Committee on Ways and Means on July 26.

Providers and Payers COMPETE Act (H.R. 3284): This bill would mandate the Secretary of the Department of Health and Human Services (HHS) to assess the

impact of regulatory changes on Medicare payment systems, specifically regarding the consolidation of healthcare providers and payers, during the annual rulemaking process. It cleared the House Committee on Ways and Means on July 26.

Modernizing and Ensuring PBM

Accountability Act: This bill would delink PBM compensation from prescription drug prices under Medicare Part D, ban spread pricing in Medicaid, require PBMs to report pricing data to HHS, require the HHS Secretary to institute standard Part D measures for assessing network pharmacy performance, and require the HHS Office of Inspector General to investigate the impact of vertical integration between Part D plans, PBMs, and pharmacies. It cleared the Senate Committee on Finance on July 26.

Pharmacy Benefit Manager Transparency

Accountability Act (S. 127): This bill would ban spread pricing; prohibit “clawback” payments; require extensive disclosure of fees, rebates, and payments; and give the FTC new powers to enforce the bill. It is included in the Modernizing and Ensuring PBM Accountability Act the Senate Committee on Finance passed on July 26.

Pharmacy Benefit Manager Reform Act (S. 1339): A bipartisan proposal that limits spread pricing and requires full rebate passthroughs and broad reporting requirements for PBMs and their affiliates. It cleared the Senate HELP Committee and was sent to the full Senate for consideration.

Biosimilar Red Tape Elimination Act: The bill would amend the federal code to state that all biosimilars that receive FDA approval are, by definition, interchangeable. The interchangeability designation allows pharmacies to substitute the reference product for the biosimilar without requiring physician permission.

Tumor DNA Test and Cancer Monitoring

Certain characteristics of ctDNA, such as its rapid clearance from circulation, can make obtaining reliable test results a challenge.

Martin Burruano, R.Ph.

Vice President, Pharmacy Services Independent Health

Circulating tumor DNA (ctDNA) is a specific type of cell-free DNA (cfDNA) originating from cancerous cells and tumors — either a primary tumor, circulating tumor cells, or metastasized cells.1, 2 ctDNA is the portion of cell-free DNA released from tumor cells via apoptosis, necrosis, or active release found in the blood of cancer patients.3 Fewer than 200 nucleotides comprise ctDNA, making them small pieces of DNA.

The presence of ctDNA may indicate the presence of a tumor, cancer spread or progression, or used to detect a gene mutation in the tumor.4 Testing for ctDNA occurs via liquid biopsy, during which a patient’s blood is examined to detect DNA fragments from cancer cells.4

Guidelines

Certain characteristics of ctDNA, such as rapid clearance from circulation due to a short half-life of 16 minutes to 2.5 hours, can make obtaining reliable results a challenge.3 Standardized clinical validation guidelines are necessary to ensure effective ctDNA testing.3

Because ctDNA is not an exact match to the patient’s DNA, the presence of DNA with genetic differences, or ctDNA, signifies the potential presence of a tumor.1 Once a tumor is detected, ctDNA can be used to diagnose the type of tumor, which reduces the need for a tumor biopsy.

The 2022 National Comprehensive Cancer Network (NCCN) guidelines specific to non-small cell lung cancer (NSCLC) recommend against using ctDNA testing in lieu of histologic tissue diagnosis, but support its consideration in specific clinical circumstances.5 Further, the NCCN reports have shown high specificity but compromised sensitivity for detecting molecular biomarkers that guide therapeutic interventions, so data supports complementary testing of ctDNA and histologic tissue diagnosis to reduce turnaround time and increased alteration detection yield.5

A clinical guideline from the College of American Pathologists, International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology, which has been endorsed by the American Society of Clinical Oncology and multiple national professional organizations, highlights the role of ctDNA testing specifically in lung cancer management.6-8 The guideline includes recommendations for standalone ROS1 testing with additional confirmation testing in all patients with advanced lung adenocarcinoma, as well as RET, ERBB2 (HER2), KRAS, and MET testing as part of larger panels.6-8

Further recommendations were for standalone BRAF testing in patients with advanced adenocarcinoma, as well as ctDNA testing methods for lung cancers with non-adenocarcinoma NSCLC component in patients with targetable mutations who relapsed on targeted therapy.6-8 The IASLC reported that liquid biopsies of ctDNA have significant potential to improve patient care, and immediate implementation is justified in a number of therapeutic settings relevant to NSCLC.9

The Centers for Medicare & Medicaid Services (CMS) has approved coverage for liquid biopsy for patients with lung cancer, as well as NSCLC, colorectal, breast, and other solid tumors, under specific clinical scenarios.2 A CMS coverage determination was approved for liquid biopsy as a follow-up to a sample taken from baseline tumor diagnostic material as part of minimal residual disease (MRD) testing for cancer.2

Clinical Considerations

The detection of ctDNA can be clinically helpful in several ways. Because ctDNA is not an exact match to the patient’s DNA, the presence of DNA with genetic differences, or ctDNA, signifies the potential presence of a tumor.1 Once a tumor is detected, ctDNA can be used to diagnose the type of tumor, which reduces the need for a tumor biopsy.1

Monitoring treatment or testing for minimal residual disease (MRD) and remission using ctDNA can be a valuable resource for care providers. A decrease in ctDNA quantity suggests the tumor is shrinking and treatment is working, while a lack of ctDNA in the bloodstream indicates cancer has not returned.1 In some cases, ctDNA may be helpful in guiding tumor-specific treatment. However, the U.S. Food and Drug Administration (FDA) has limited approval for ctDNA testing to personalize cancer treatment.1

Clinical utilization of liquid biopsy of ctDNA is increasing in patients with advanced lung cancer.10 Advancing technologies may offer significant potential benefits for patients, providers, and healthcare systems.10 Despite the potential for clinical benefit, there are some challenges associated with ctDNA testing, including sensitivity and specificity, quantity of ctDNA, detection of a small versus a large panel of genes, and clonal hematopoiesis of indeterminate potential.10

Analyses show this testing may be most useful in certain patient populations, such as those who are unable to undergo biopsy or whose detected mutations may be more representative of the predominant tumor burden than for tissue-based assays. The testing may also be valuable in screening, primary diagnosis, residual disease, local recurrence, therapy selection, or early therapy response and resistance monitoring.10

Payer Coverage and Implications

In 2021, a final CMS rule established a pathway to expedite access to innovative devices for Medicare beneficiaries called the “Medicare Coverage of Innovative Technology (MCIT)” pathway.11 The implementation was delayed, and ultimately, the rule was rescinded in November 2021. However, if implemented, the rule would have granted immediate nationwide Medicare coverage

of the two ctDNA tests currently available, Guardant360 CDx and FoundationOne Liquid CDx, which were approved as FDA Breakthrough Devices.11-13

There were concerns associated with the bill related to incentives for device manufacturers to conduct additional studies on devices, which would ensure that CMS would have access to robust information to make informed coverage decisions.11 While no final rule has been issued since, there are other mechanisms to support expedited coverage of new devices in Medicare. These include a parallel review program in which manufacturers may opt to have CMS and FDA simultaneously review a new product and the coverage with evidence development pathway. This would allow Medicare to cover a new product conditionally by collecting additional evidence on the benefits and risk of the product in the Medicare population.11, 14

Despite the absence of regulatory coverage requirements, a 2022 analysis of payer coverage found that coverage for ctDNA test has been increasing in both the Medicare program and among private payers. In October 2022, 100% of Medicare local coverage decisions and 70% of private payers’ policies provided coverage for at least one of the ctDNA testing indications studied.15, 16 Compared to ctDNA testing rates from 2015 to 2019, these coverage rates indicate an increase and expansion in covered cancer indications.15

Expanded coverage policies increase patient access to ctDNA tests, which may lead to improved outcomes and better patient management.15 Increased access may also generate greater realworld evidence to demonstrate the benefit and safety profile of these tests.15 The cost burden of these tests may increase as testing and targeted therapy utilization and indications expand. Real-world evidence may serve as an important tool for testing cost-benefit assessments and cost implications.16

The 2022 analysis demonstrated that 25% of ctDNA coverage policies were co-branded with laboratory benefit managers (LBMs), who are contracted with insurers to determine covered tests, patient eligibility, and qualifications for ordering and servicing providers.15, 16 For the private sector, LBMs play a significant role in establishing coverage policies and negotiating prices.15, 16

As genomic testing continues drive spend, increasing from 5% a decade ago to 20% today, access to data, understanding of the specific clinical benefit, and knowledge of effective management strategies will be critical.17 Standardized guidelines, mature realworld evidence, and increased data will help clarify the optimal clinical setting, patient population, and utilization of these tests moving forward.

References

1. “What is circulating tumor DNA and how is it used to diagnose and manage cancer?” MedlinePlus, https://medlineplus.gov/genetics/ understanding/testing/circulatingtumordna/.

2. Clyne, Mindy, et al. “The Use of Cell-free DNA in Clinical Practice: Work in Progress.” Centers for Disease Control and Prevention, 14 Dec. 2022, https://blogs.cdc.gov/genomics/2022/12/14/the-useof-cell-free-dna/.

3. Kim, Hyunji, et al. “Clinical Circulating Tumor DNA Testing for Precision Oncology.” Cancer Research and Treatment, 13 Mar. 2023, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10101787/.

4. Carter, Devon. “Liquid biopsies: Understanding ctDNA and circulating tumor cells.” The University of Texas MD Anderson Cancer Center, 23 Aug. 2021, https://www.mdanderson.org/cancerwise/ liquid-biopsies--understanding-ctdna-and-circulating-tumor-cells. h00-159463212.html.

5. “NCCN Non-Small Cell Lung Cancer v.1.2022 - Meeting - July 9, 2021.” National Comprehensive Cancer Network, 9 Jul. 2021, https:// www.nccn.org/guidelines/guidelines-process/transparency-processand-recommendations/GetFileFromFileManagerGuid?FileManagerG uidId=cb4c31f6-f3b0-4d10-9b43-8ead08007d8c.

6. Kalemkerin, GP, et al. “Molecular Testing Guideline for the Selection of Patients with Lung Cancer for Treatment with Targeted Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/ International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update.” Journal of Clinical Oncology, 20 Mar. 2018, https://pubmed.ncbi.nlm.nih. gov/29401004/.

7. Lindeman, NI, et al. “Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association of Molecular Pathology.” Journal of Thoracic Oncology, Mar. 2018, https://pubmed.ncbi.nlm.nih. gov/29396253/.

8. Lindeman, NI, et al. “Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors: Guideline From the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.” Archives of Pathology and Laboratory Medicine, Mar. 2018, https://pubmed.ncbi. nlm.nih.gov/29355391/.

9. Rolfo, Christian, et al. “Liquid Biopsy for Advanced Non-Small Cell Lung Cancer (NSCLC): A Statement Paper from the IASLC.” Journal of Thoracic Oncology, Sept. 2018, https://pubmed.ncbi.nlm.nih. gov/29885479/.

10. Krebs, Matthew G., et al. “Practical Considerations for the Use of Circulating Tumor DNA in the Treatment of Patients with Cancer.” Journals of the American Medical Oncology, 20 Oct. 2022, https://jamanetwork.com/journals/jamaoncology/articleabstract/2797725.

11. “Medicare program: Medicare coverage of innovative technology (MCIT) and definition of ‘reasonable and necessary.’” Centers for Medicare & Medicaid Services, 14 Jan. 2021, https://www. federalregister.gov/documents/2021/01/14/2021-00707/ medicare-program-medicare-coverage-of-innovative-technologymcit-and-definition-of-reasonable-and.

12. “Foundation Medicine’s ctDNA monitoring assay, FoundationOne® Tracker, granted breakthrough devices designation by U.S. Food and Drug Administration.” Foundation Medicine, 15 Feb. 2022, https:// www.foundationmedicine.com/press-releases/af7bb7df-2dcf-411fbc7d-ebb8ab90d788.

13. “The Guardant360® Assay Receives Expedited Access Pathway Designation for Breakthrough Devices from FDA.” Guardant, 15 Feb. 2018, https://investors.guardanthealth.com/press-releases/ press-releases/2018/The-Guardant360-Assay-Receives-ExpeditedAccess-Pathway-Designation-for-Breakthrough-Devices-fromFDA/default.aspx#:~:text=Guardant360%20has%20been%20 extensively%20validated,that%20serve%20unmet%20 medical%20needs.

14. Tunis, SR, et al. “Improving Medicare coverage of innovative technologies.” Health Affairs Forefront, 14 Oct. 2022, https://www. healthaffairs.org/content/forefront/improving-medicare-coverageinnovative-technologies.

15. Douglas, Michael P., et al. “Private Payer and Medicare Coverage Policies for Use of Circulating Tumor DNA Tests in Cancer Diagnostics and Treatment.” Journal of the National Comprehensive Cancer Network, June 2023, https://pubmed.ncbi.nlm.nih. gov/37308126/.

16. Socal, Mariana P., et al. “Increasing Private Payer and Medicare Coverage of Circulating Tumor DNA Tests: What’s at Stake?” Journal of the National Comprehensive Cancer Network, June 2023, https://jnccn.org/view/journals/jnccn/21/6/article-p685. xml?ArticleBodyColorStyles=contributor%20notes.

17. “Optum releases new lab benefit management system.” APS, 5 Oct. 2022, https://apsmedbill.com/whitepapers/optum-releases-newlab-benefit-management-system.

Accelerated Approvals Update:

Full Approval of Cancer Therapies

The key to managing accelerated approvals is timely confirmatory results, verifying the clinical benefit, and providing access to the most clinically beneficial therapies.

Carly Rodriguez, Pharm.D., FAMCP Vice President & Chief Pharmacy Officer Moda Health

In our summer issue, we discussed the U.S. Food and Drug Administration’s (FDA) Accelerated Approval process, some associated challenges, and the process for full approval. Currently, there are 69 oncology drugs approved via accelerated approval and awaiting full approval (See Table 1).1

Approval through this pathway is conditional, meaning there must be a confirmatory trial to demonstrate actual clinical benefit.2 In March 2023, the FDA issued a draft guidance, “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics.”3 The guidance outlines recommendations for the design of clinical trials and potential ways to improve the data available at the time the accelerated approval is granted.3 Further, the guidance addresses how to reduce clinical uncertainty for patients by initiating post-marketing confirmatory studies in a timely manner.3

The guidance outlines the potential design, conduct, and analysis of data through two randomized clinical trial approaches — either by conducting two separate randomized controlled clinical trials or using one trial for both accelerated approval and to verify clinical benefit.3 Notably, the guidance mentions a potential advantage of randomized clinical trials compared to single-arm trials.3 Specifically, the use of the one-trial approach, where appropriate, may not require separate clinical trials because longer term follow-up in the same trial could fulfill the post-marketing requirement.3

The FDA also notes that when confirmatory trials are in progress at the time of accelerated approval, they are more likely to result in timely verification of clinical benefit, possibly minimizing the period of uncertainty for patients and other stakeholders.3

Elranatamab-bcmm (ELREXFIO™)

Talquetamab-tgvs (TALVEY™)

Glofitamab-gxbm (COLUMVI™)

Epcoritamab-bysp (EPKINLY™)

Pembrolizumab (KEYTRUDA®)

Enfortumab vedotinefjv (PADCEV®)

adults with R/R MM who have received > four prior lines of therapy, including a PTI, an immunomodulatory agent, and an anti-CD38 antibody

adults with R/R MM who have received > four prior lines of therapy, including a PTI, an immunomodulatory agent, and an anti-CD38 antibody

DLBCL, not otherwise specified or LBCL arising from follicular lymphoma, after two or more lines of systemic therapy

adult patients with R/R DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after two or more lines of systemic therapy

in combination with enfortumab vedotin-ejfv for treatment of adult patients with locally advanced or metastatic UC who are not eligible for cisplatin-containing chemotherapy 4/3/2023

in combination with pembrolizumab for treatment of adult patients with locally advanced or metastatic UC who are not eligible for cisplatin-containing chemotherapy

patients with metastatic or recurrent locally advanced MCC

Tucatinib (TUKYSA®)

Mirvetuximab soravtansine-gynx

in combination with trastuzumab for the treatment of adult patients with RAS wildtype, HER2-positive, unresectable or metastatic CRC that has progressed following treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy

with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy

folate receptor-alpha positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer, who have received one to three prior systemic treatment regimens, selected for therapy based on an FDA-approved test

with R/R MM who have received at least four prior lines of therapy, including a PTI, an immunomodulatory agent, and an anti-CD38 monoclonal antibody

advanced or metastatic solid tumors with a RET gene fusion who

progressed during or following prior systemic treatment or who have no satisfactory alternative treatment options

who have received a prior systemic therapy

for adult and

6 and up with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options

and up with unresectable or metastatic solid tumors with BRAF V600E mutation who have progressed following prior treatment and have no satisfactory alternative treatment options

Table 1. Current Oncology Accelerated Approvals Awaiting Full Approval1

ACCELERATED APPROVALS UPDATE

Dostarlimab-gxly (JEMPERLI)

Infigratinib (TRUSELTIQ)

Sotorasib (LUMAKRAS™)

Amivantamab-vmjw (RYBREVANT®)

patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy

treatment for adult patients with dMMR recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed during or following prior treatment and who have no satisfactory alternative treatment options

treatment of adult patients with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or other rearrangements, as detected by an FDA-approved test

treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic NSCLC, as determined by an FDA-approved test, who have received at least one prior systemic therapy

treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA approved test, whose disease has progressed during or after platinum-based chemotherapy

in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy, for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive GEJ adenocarcinoma

Loncastuximab

Melphalan flufenamide (Pepaxto®)

treatment of adult patients with R/R/ LBCL after two or more lines of systemic therapy, including DLBCL not otherwise specified, DLBCL arising from low-grade lymphoma, and high-grade B-cell lymphoma

treatment

adult patients with locally advanced or metastatic UC who have

in combination with dexamethasone for the treatment of adult patients with R/R MM who have received > four prior lines of therapy and whose disease is refractory to at least one PTI, one immunomodulatory agent, and one anti-CD23 antibody

Daratumumab and hyaluronidase-fihj (DARZALEX FASPRO®)

treatment of patients with AL amyloidosis in combination with bortezomib, cyclophosphamide, and dexamethasone in newly diagnosed patients

Abbreviations: AL = light chain; BTK = bruton tyrosine kinase; CRC = colorectal cancer; DLBCL = diffuse large B-cell lymphoma; dMMR = mismatch repair deficient; EGFR = epidermal growth factor receptor; FGFR2 = fibroblast growth factor receptor 2; GEJ = gastric or gastroesophageal junction; LBCL = large B-cell lymphoma; MCC = Merkel cell carcinoma; MCL = mantle cell lymphoma; MET = mesenchymal-epithelial transition; MM = multiple myeloma; MZL = marginal zone lymphoma; NSCLC = non-small cell lung cancer; PROS = PIK3CA-related overgrowth spectrum; PTI = proteasome inhibitor; R/R = relapsed or refractory; UC = urothelial cancer

Table 1. Current Oncology Accelerated Approvals Awaiting Full Approval1 (Cont.)

Recent Traditional Approvals

A total of 94 oncology therapies that received accelerated approvals have been verified and received traditional approval through the FDA (See Table 2).4 In 2023 alone, six cancer therapies have received traditional approval thus far.4

Pralsetinib (GAVRETO®)

In August 2023, the FDA granted regular approval to pralsetinib (GAVRETO®) for the treatment of adult patients with metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) as detected by an FDA-approved test.5 Efficacy was demonstrated in the ARROW trial, a multicenter, open-label, multi-cohort trial.6 A total of 237 patients with locally advanced or metastatic RET fusion-positive NSCLC received pralsetinib until disease progression or unacceptable toxicity occurred.6 Overall response rate (ORR) was 78% with a median duration of response (DOR) of 13.4 among 107 treatment-naïve patients.6 Patients treated previously with platinum-based chemotherapy had an ORR of 63% with a median DOR of 38.8 months.6

Adverse reactions associated with pralsetinib included musculoskeletal pain, constipation, hypertension, diarrhea, fatigue, edema, pyrexia, and cough.5

Blinatumomab (BLINCYTO®)

In June 2023, the FDA granted full approval to blinatumomab (BLINCYTO®) for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (B-ALL) in first or second complete remission with minimal residual disease (MRD) of 0.1% or more.7 Approval was based on results from the phase 3 ALL1331 trial of 255 patients with low-risk ALL who were randomly assigned to either the 2/block 2/2 continuation cycles of chemotherapy followed by maintenance, or two cycles of continuation chemotherapy with three blocks of blinatumomab and maintenance.7 The blinatumomab arm had a four-year disease-free survival rate of 61.2% + 5.0% compared to 49.5% + 5.2% in the chemotherapy arm.8 The overall survival was 90.4% + 3.0% in the blinatumomab arm compared to 79.6% + 4.3% in the chemotherapy arm.8

Cemiplimab-rwlc (LIBTAYO®)

In April 2023, the FDA granted Cemiplimab-rwlc (LIBTAYO®) full approval for the treatment of patients with metastatic basal cell carcinoma (mBCC) who previously received a hedgehog inhibitor

In 2023 alone, six cancer therapies have received traditional approval thus far.

(HHI) or for whom a HHI is not appropriate.9 Approval was based on results from a phase 2 trial of 138 patients with locally advanced or metastatic, nodal or distant, basal cell carcinoma who had progressed on a HHI, had not responded after nine months of treatment with a HHI, or who proved to be intolerant to previous HHI treatment.10 Cemiplimab achieved an ORR of 24% in those with mBCC and 32% in those with locally advanced BCC.10 The median DOR in the metastatic group was 16.7 months, with 92% experiencing a DOR that lasted for at least six months. In the locally advanced groups, DOR was not yet reached and 85% of patients responded for at least six months.10

The most common adverse events associated with cemiplimab included fatigue, musculoskeletal pain, diarrhea, rash, upper respiratory tract infection, pruritus, hemorrhage, and hypertension.9

Polatuzumab vedotin-piiq (POLIVY®)

The FDA granted full approval to polatuzumab vedotinpiiq (POLIVY®) in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone for adult patients with previously untreated diffuse large B-cell lymphoma (DLBCL), not otherwise specified, or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater.11

Results from the POLARIX trial informed approval and evaluated the superiority of substituting polatuzumab vedotin for vincristine, in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone regimen.12 In the trial, 879 patients with previously untreated large B-cell lymphoma (LBCL) and an International Prognostic Index score of 2-5 were randomized to receive either polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone for six 21-day cycles followed by two additional cycles of rituximab alone in both arms.12

In the polatuzumab vedotin arm, progression-free survival (PFS) was significantly longer statistically, with a hazard ratio of 0.73.12 This arm also showed a statistically significant improvement in modified event-free survival.12

ACCELERATED APPROVALS UPDATE

Adverse reactions associated with polatuzumab vedotin include peripheral neuropathy, nausea, fatigue, diarrhea, constipation, alopecia, and mucositis, as well as laboratory abnormalities, including lymphopenia, neutropenia, hyperuricemia, and anemia.11 In 53% of the patients, peripheral neuropathy either developed or worsened, with 58% reporting resolution after a median of four months.11

Pembrolizumab (KEYTRUDA®)

In March 2023, the FDA granted full approval to pembrolizumab (KEYTRUDA®) for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.13 Patients are determined to be eligible for treatment using an FDA-approved test.13

The full approval was based on results from the phase 2

KEYNOTE-158, KEYNOTE-164, and KEYNOTE-051 trials.13

KEYNOTE-158 was a study of 373 patients with advanced MSI-H/ dMMR non-colorectal cancers who had disease progression following prior therapy.14, 15 KEYNOTE-164 was a study of 124 patients with advanced MSI-H/dMMR colorectal cancer that progressed following treatment with fluoropyrimidine and either oxaliplatin or irinotecan with or without anti-VEGF/EGFR monoclonal antibody-based therapy.14, 16 KEYNOTE-051 was a study

of seven pediatric patients with MSI-H/dMMR cancers.14, 17 Patients with autoimmune disease or a medical condition that required immunosuppression were excluded from all trials, and MSI or MMR tumor status was determined using polymerase chain reaction or immunohistochemistry, respectively.14-17

An aggregate analysis of the three trials showed that pembrolizumab demonstrated an ORR of 33.3%, including a complete response rate of 10.3% and a partial response rate of 23.0%; the median follow-up time was 20.1 months.14-17 The ORR in patients with MSI-H/dMMR colorectal cancer was 34% with a DOR ranging from 4.4 to 58.5+ months.16 Patients with MSI-H/dMMR non-colorectal solid tumors had an ORR of 33%, with a duration of response ranging from 1.9 to 63.9+ months.15

Dostarlimab-gxly (JEMPERLI)

After granting accelerated approval in April 2021, the FDA approved dostarlimab-gxly (JEMPERLI) for adults with dMMR recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed during or following a prior platinumcontaining regimen in any setting and who are not candidates for curative surgery or radiation.18

GARNET, a multicenter, multicohort, open-label trial conducted in patients with advanced solid tumors, underscored its clinical

benefit.18 The study population included 141 patients with dMMR recurrent or advanced endometrial cancer who had progressed during or after a platinum-containing regimen.19 Patients were excluded if they were treated with prior PD-1/PD-L1-blocking antibodies or other immune checkpoint inhibitors, or had autoimmune diseases requiring systemic immunosuppressant agents within two years.19

Confirmed ORR was 45.4% with a 15.6% complete response rate and a 29.8% partial response rate.19 The median DOR was not reached; 85.9% of patients had durations of more than 12 months and 54.7% had durations of more than 24 months.19

Adverse reactions associated with dostarlimab-gxly occurring in more than 20% of patients include fatigue/asthenia, anemia, rash,

nausea, diarrhea, constipation, and vomiting.18 Immune-mediated potential adverse reactions include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis with renal dysfunction, and adverse skin adverse reactions.18

Withdrawals

When confirmation trials for drugs with accelerated approval fail to demonstrate actual clinical benefit, the drug or approved indication may be withdrawn from the market.20 As the number of accelerated approvals increased, so did the number of withdrawals and traditional approvals.20 Six withdrawals occurred between 1992 and 2001.20 So far in 2023, there have already been four withdrawals of cancer therapies with accelerated approvals (See Table 3).21

Blinatumomab (BLINCYTO®)

Cemiplimab-rwlc (LIBTAYO®)

Polatuzumab vedotinpiiq (POLIVY®)

Pembrolizumab (KEYTRUDA®)

of CD-19 positive B-cell precursor ALL in first or second complete remission with MRD greater than or equal to 0.1% in adults and children

patients with metastatic BCC previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate

in combination with bendamustine and a rituximab product for adult patients with R/R DLBCL, not otherwise specified, after at least two prior therapies

treatment of adult patients with unresectable or metastatic MSI-H or dMMR solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or metastatic MSI-H or dMMR CRC that have progressed following a treatment with fluropyrimidine, oxaliplatin, and irinotecan

Dostarlimab-gxly (JEMPERLI) treatment of adult patients with dMMR recurrent or advanced EC, as determined by an FDA-approved test, that has progressed on or following prior treatment with a platinumcontaining regimen

Capmatinib (TABRECTA®) treatment of adult patients with metastatic NSCLC whose tumors have a mutation test that leads to MET exon 14 skipping as detected by an FDA-approved test

ages 1 to 21 with R/R acute lymphocytic leukemia after at least two prior regimens

Fam-trastuzumab deruxtecan-nxki (ENHERTU®)

of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting

Abbreviations: ALL = acute lymphoblastic leukemia; CP = chronic phase; DLBCL = diffuse large B-cell lymphoma; dMMR = mismatch repair deficient; EC = endometrial cancer; MRD = minimal residual disease; MSI-H = microsatellite instability-high; NSCLC = non-small cell lung cancer; Ph+ CML = Philadelphia chromosome-positive chronic myeloid leukemia; R/R = relapsed or refractory; TKIs = tyrosine kinase inhibitors

Table 2. Recent Traditional Approvals — Accelerated Approval Oncology Drugs4

ACCELERATED APPROVALS UPDATE

Management Implications

Payer spending in settings with unconfirmed clinical benefit can be a challenge associated with accelerated approvals. A pilot project found that a single health insurance payer — the U.S. Medicare Program — spent nearly $50 million over a two-year period on an accelerated approval drug administrated in a clinical setting where clinical benefit was not confirmed.22 Another research group evaluated estimated Medicare spending across 10 oncology drug indications that lacked clinical benefit after receiving FDA accelerated approval. Their research found that Medicare spending increased to an estimated inflation-adjusted $569 million, of which $171 million corresponded to indications voluntarily withdrawn, and $398 million corresponded to indications reevaluated by the FDA.23 Payers can incur exorbitant costs for drugs without a confirmed clinical benefit and that may eventually be withdrawn.

The traditional approval or withdrawal of drugs with accelerated approvals can help payers effectively manage these therapies. Traditional approval provides further clarity and confirmation that the drug should be accessible to the appropriate patients with the appropriate indication that an accelerated approval does not always carry. Since accelerated approvals launch new treatment options without definitive proof of clinical benefit, traditional approval helps boost payer confidence in the drug, as well as provide clearer parameters for coverage.

Withdrawals can be more of a challenge for payers in terms of managing the costs associated with market withdrawals. The key to best managing these accelerated approvals is timely confirmatory results, verifying the clinical benefit, and ensuring payers and providers can provide access to the most appropriate and clinically beneficial therapies for patients.

Idelalisib (ZYDELIG®)

Pembrolizumab (KEYTRUDA®)

with BTZ and DEX for the treatment of patients with MM who have received at least two prior regimens, including BTZ and an immunomodulatory agent

received at least two prior systemic therapies and relapsed SLL in patients who

prior systemic therapies

treatment of patients with recurrent or locally advanced or metastatic gastric or GEJ adenocarcinoma whose tumors express PD-L1 as determined by an FDA-approved test, with disease progression on/after two or more prior lines of therapy, including fluoropyrimidine and platinum-containing chemotherapy and, if appropriate, HER2/NEU targeted therapy

Abbreviations: BTZ = bortezomib; DEX = dexamethasone; FL = follicular lymphoma; MCL = mantle cell lymphoma; MM = multiple myeloma; MTC = medullary thyroid cancer; MZL = marginal zone lymphoma; PH- = Philadelphia chromosome negative; PTI = proteasome inhibitor; RET = rearranged during transfection; R/R = relapsed or refractory; SLL = small lymphocytic lymphoma

Table 3. Recent Withdrawals for Cancer Therapies with Accelerated Approval — 2022 and 202321

References

1. “Ongoing | Cancer Accelerated Approvals.” U.S. Food and Drug Administration, 17 Aug. 2023, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/ongoing-cancer-acceleratedapprovals.

2. “Accelerated Approval Program.” U.S. Food and Drug Administration, 30 May 2023, https://www.fda.gov/drugs/nda-and-bla-approvals/ accelerated-approval-program.

3. “FDA Issues Draft Guidance Aimed at Improving Oncology Clinical Trials for Accelerated Approval.” U.S. Food and Drug Administration, 24 Mar. 2023, https://www.fda.gov/news-events/ press-announcements/fda-issues-draft-guidance-aimed-improvingoncology-clinical-trials-accelerated-approval.

4. “Verified Clinical Benefit | Cancer Accelerated Approvals.” U.S. Food and Drug Administration, 10 Aug. 2023, https://www.fda.gov/drugs/ resources-information-approved-drugs/verified-clinical-benefitcancer-accelerated-approvals.

5. “FDA approves pralsetinib for non-small cell lung cancer with RET gene fusions.” U.S. Food and Drug Administrations, 9 Aug. 2023, https://www.fda.gov/drugs/drug-approvals-and-databases/fdaapproves-pralsetinib-non-small-cell-lung-cancer-ret-gene-fusions.

6. Griesinger, F., et al. “Safety and efficacy of pralsetinib in RET fusionpositive non-small-cell lung cancer including as first-line therapy: update from the ARROW trial.” Annals of Oncology, 13 Aug. 2022, https://www.annalsofoncology.org/article/S0923-7534(22)038662/fulltext.

7. Pelosci, Ariana. “FDA Gives Full Approval to Blinatumomab in MRDPositive B-Cell ALL.” Cancer Network, 21 Jun. 2023, https://www. cancernetwork.com/view/fda-gives-full-approval-to-blinatumomabin-mrd-positive-b-cell-all.

8. Hogan, Laura E., et al. “Children's Oncology Group AALL1331: Phase III Trial of Blinatumomab in Children, Adolescents, and Young Adults with Low-Risk B-Cell ALL in First Relapse.” Journal of Clinical Oncology, 31 May 2023, https://pubmed.ncbi.nlm.nih. gov/37257143/.

9. Rosa, Kristi. “FDA Grants Regular Approval to Cemiplimab for Metastatic Basal Cell Carcinoma.” OncLive, 1 May 2023, https:// www.onclive.com/view/fda-grants-regular-approval-to-cemiplimabfor-metastatic-basal-cell-carcinoma.

10. Davis, Christina M., et al. “Brief overview: cemiplimab for the treatment of advanced basal cell carcinoma: PD-1 strikes again.” Therapeutic Advances in Medical Oncology, 19 Jan. 2022, https:// journals.sagepub.com/doi/10.1177/17588359211066147.

11. “FDA D.I.S.C.O. Burst Edition: FDA approval of Polivy (polatuzumab vedotin-piiq) for previously untreated diffuse large B-cell lymphoma, not otherwise specified, and high-grade B-cell lymphoma.” U.S. Food and Drug Administration, 7 June 2023, https:// www.fda.gov/drugs/resources-information-approved-drugs/fdadisco-burst-edition-fda-approval-polivy-polatuzumab-vedotin-piiqpreviously-untreated-diffuse.

12. Tilly, Herve, et al. “Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.” The New England Journal of Medicine, 27 Jan. 2022, https://www.nejm.org/doi/full/10.1056/ NEJMoa2115304.

13. Pelosci, Ariana. “FDA Gives Full Approval to Pembrolizumab in dMMR/MSI-H Solid Tumors.” Cancer Network, 29 Mar. 2023, https://www.cancernetwork.com/view/fda-gives-full-approval-topembrolizumab-in-dmmr-msi-h-solid-tumors.

14. “FDA Grants Full Approval to Pembrolizumab for Certain Adult and Pediatric Patients with Advanced MSI-H or dMMR Solid Tumors.” ASCO Post, 30 Mar. 2023, https://ascopost.com/news/march-2023/ fda-grants-full-approval-to-pembrolizumab-for-certain-adult-andpediatric-patients-with-advanced-msi-h-or-dmmr-solid-tumors/.

15. Marabell, Aurelien, et al. “Efficacy of Pembrolizumab in Patients with Noncolorectal High Microsatellite Instability/Mismatch RepairDeficient Cancer: Results From the Phase II KEYNOTE-158 Study.” Journal of Clinical Oncology, 1 Jan. 2020, https://pubmed.ncbi.nlm. nih.gov/31682550/.

16. Le, Dung T., et al. “Phase II Open-Label Study of Pembrolizumab in Treatment-Refractory, Microsatellite Instability-High/Mismatch Repair-Deficiency Metastatic Colorectal Cancer: KEYNOTE-164.” Journal of Clinical Oncology, 1 Jan. 2020, https://pubmed.ncbi.nlm. nih.gov/31725351/.

17. Geoerger, Birgit, et al. “Pembrolizumab in paediatric patients with advanced melanoma or a PD-L1-positive, advanced, relapsed, or refractory solid tumor or lymphoma (KEYNOTE-051): interim analysis of an open-label, single-arm, phase 1-2 trial.” The Lancet Oncology, Jan. 2020, https://pubmed.ncbi.nlm.nih.gov/31812554/.

18. “FDA D.I.S.C.O. Burst Edition: FDA approval of Jemperli (dostarlimabgxly) for dMMR endometrial cancer.” U.S. Food and Drug Administration, 7 Mar. 2023, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-disco-burst-edition-fda-approvaljemperli-dostarlimab-gxly-dmmr-endometrial-cancer.

19. Oaknin, Ana, et al. “Safety and antitumor activity of dostarlimab in patients with advanced or recurrent DNA mismatch repair deficient/ microsatellite instability-high (dMMR/MSI-H) or proficient/stable (MMRp/MSS) endometrial cancer: interim results from GARNET - a phase 1 single-arm study.” Journal for ImmunoTherapy of Cancer, 2022, https://jitc.bmj.com/content/10/1/e003777.

20. Beakes-Read, Ginny, et al. “Analysis of FDA’s Accelerated approval Program Performance December 1992-December 2021.” Therapeutic Innovation and Regulatory Science, Sept. 2022, https:// pubmed.ncbi.nlm.nih.gov/35900722/.

21. “Withdrawn | Cancer Accelerated Approvals.” U.S. Food and Drug Administration, 25 Jul. 2023, https://www.fda.gov/drugs/resourcesinformation-approved-drugs/withdrawn-cancer-acceleratedapprovals.

22. Ballreich, J., et al. “Medicare expenditures of atezolizumab for a withdrawn accelerated approved indication.” JAMA Oncology, 1 Nov. 2021, https://pubmed.ncbi.nlm.nih.gov/34554196/.

23. Shahzad, M., et al. “Estimated Medicare spending on cancer drug indications with a confirmed lack of clinical benefit after US Food and Drug Administration accelerated approval.” Journal of the American Medical Association Internal Medicine, 1 Dec. 2021, https:// pubmed.ncbi.nlm.nih.gov/34661616/.

Prostate Cancer: Treatments for Advanced Disease and Management

Prostate cancer is typically slow growing, so early diagnosis and treatment are key to effective management.

Mona Chitre, Pharm.D. Chief Pharmacy Officer & VP, Integrated Clinical Strategy

The most common cancer in the U.S., prostate cancer is the second leading cause of cancer deaths among men in the U.S.1 In 2023, there are 288,300 estimated new cases, comprising 14.7% of all new cancer cases.2 Approximately 13% of the male population will be diagnosed with prostate cancer at some point in their lifetime, and in 2020, there were an estimated 3.3 million men in the U.S. living with prostate cancer.1, 2

Prostate cancer is typically slow growing, so early diagnosis and treatment are key to effective management.1 Among prostate cancer patients, there is a 97.1% five-year survival rate.2 Prostate cancer occurs more often and with a higher mortality rate in black men versus white men.3 Risk factors associated with prostate cancer include age, family history of prostate cancer, race, hormones, and deficiencies in vitamin E, folic acid, and dairy and calcium.3

While there are no standard or routine screening tests for prostate cancer, digital rectal exams are often employed to feel for any prostate abnormalities.3 Notably, the American Urology Association and Society of Urologic Oncology (AUA/SUO) have defined screening recommendations; these guidelines recommend clinicians discuss prostate cancer screening with patients where appropriate, engage in prostate-specific antigen (PSA) testing as a first screening test, and start offering screenings beginning at age 45 to 50 in general and age 40 to 45 for those with increased risk.4 PSA tests can be taken to measure PSA levels in the blood; PSA is a substance made by the prostate that may be elevated in individuals with prostate cancer.5 However, these tests are not conclusive, as PSA levels may be elevated in those with an infection or inflammation of the prostate or who have benign prostatic hyperplasia.3 These screening measures are useful in detecting prostate cancer in its early stages.3

The U.S. Preventive Services Task Force (USPSTF) issued a recommendation against PSA screening in 2012 based on data from two trials to evaluate the impact of this screening. Results of both trials showed zero to minimal risk reduction associated with screening.5 Following the USPSTF recommendations, there was a substantial reduction in PSA screening.5

An analysis of data from 2004 to 2018 revealed that incidence rates of metastatic prostate cancer (mPC) increased from 2011 to 2018, coinciding with the recommendations across screenings.5 According to National Comprehensive Cancer Network guidelines, after a baseline evaluation of family history, medications, personal history, and race, clinicians should discuss risks and benefits of a baseline PSA test. The American Cancer Society guidelines do not recommend routine screening in any age group, but individuals should be given information and discuss screening with providers if they are age 50 and at average risk, at age 45 and at high risk, or at age 40 and at higher risk.6

Treatment

Prostate cancer treatment varies on the stage of cancer (See Table 1).

Stage Treatment Option

Surveillance

Radical prostatectomy

EBRT

I

II

III

IV

Recurrent (or metastatic)

Interstitial implantation of radioisotopes

Photodynamic therapy*

Bicalutamide*

Surveillance

Radical prostatectomy

EBRT with or without hormonal therapy

Interstitial implantation of radioisotopes

Cryosurgery*

Proton-beam therapy*

Photodynamic therapy*

Neoadjuvant hormonal therapy*

Bicalutamide*

EBRT with or without hormonal therapy

Hormonal manipulations with or without radiation therapy

Radical prostatectomy with or without EBRT

Surveillance

Cryosurgery*

Proton-beam therapy*

Bicalutamide*

Hormonal manipulations

Bisphosphonates

EBRT with or without hormonal therapy

Palliative radiation therapy

Palliative surgery with TURP

Surveillance

Hormone therapy

Chemotherapy for hormone-resistant prostate cancer

Immunotherapy

Radiopharmaceutical therapy/alpha emitter radiation

PARP inhibitors for BRCA1, BRCA2, and/or ATM mutations

Cryosurgery*

*Under clinical evaluation

Abbreviations: EBRT = external-beam radiation therapy; TURP = transurethral resection of the prostate

Hormonal therapies are often administered in advanced prostate cancer and include bilateral orchiectomy (the surgical removal of both testicles), luteinizing hormone-releasing hormone (LHRH) agonists, gonadotropin-releasing hormone (GnRH) antagonists, androgen receptor (AR) inhibitors), androgen synthesis inhibitors, combined androgen blockade, and intermittent androgen deprivation therapy (ADT).8

Chemotherapy may be used in patients with advanced or castration-resistant prostate cancer (CRPC), as well as those with newly diagnosed or castration-sensitive metastatic prostate cancer.8 Standard chemotherapy for prostate cancer begins with docetaxel combined with prednisone. Some research suggests adding docetaxel to ADT in newly diagnosed or castration-

Standard chemotherapy for prostate cancer begins with docetaxel combined with prednisone. Some research suggests adding docetaxel to ADT in newly diagnosed or castration-sensitive mPC can help stop disease progression and improve survival rates.

sensitive mPC can help stop disease progression and improve survival rates.8

Targeted therapies may be used to target the cancer’s specific genes or proteins; for prostate cancer, these include rucaparib (Rubraca®) and two newly approved therapies, olaparib (LYNPARZA®) and talazoparib (TALZENNA®).8 Testing must be completed to identify appropriate patients for these therapies, including testing for the inherited mutation, genomic sequencing of tumor tissue, and genomic sequencing of the tumor DNA in the blood.8

Recent Approvals

Olaparib (LYNPARZA®)

In May 2023, the U.S. Food and Drug Administration (FDA) approved olaparib (LYNPARZA®, AstraZeneca Pharmaceuticals) with abiraterone and prednisone or prednisolone for adult patients with deleterious or suspected deleterious BRCA-mutated metastatic CRPC (mCRPC), as determined by an FDA-approved companion diagnostic test.9

The PROpel trial of 796 patients with mCRPC evaluated efficacy.9 Patients with prior systemic therapy for mCRPC were excluded and all patients were required to have a prior orchiectomy or have received gonadotropin-releasing hormone (GnRH) analogs.10 Enrolled patients were randomized to receive either olaparib with abiraterone or placebo with abiraterone and also received prednisone or prednisolone; randomization was stratified by site of metastases and prior docetaxel.10 The primary efficacy measure was investigator-assessed radiological progression-free survival with

Table 1. General Treatment Options by Stage7

overall survival (OS) as an additional endpoint.10 The olaparib with abiraterone group showed statistically significant improvement in radiographic progression-free survival (rPFS) compared to placebo with abiraterone in the intent-to-treat (ITT) population.10

Common adverse reactions associated with olaparib plus abiraterone included anemia, fatigue, nausea, diarrhea, decreased appetite, lymphopenia, dizziness, and abdominal pain.9 Of patients receiving olaparib plus abiraterone, 18% required at least one blood transfusion and 12% required multiple transfusions.9

Talazoparib (TALZENNA®) and Enzalutamide (XTANDI®)

The FDA approved talazoparib (TALZENNA®, Pfizer) with enzalutamide (XTANDI®) for homologous recombination repair (HRR) gene-mutated mCRPC in June 2023.11 The TALAPRO-2 is a randomized, double-blind, placebo-controlled, multi-cohort trial that evaluated efficacy.12 The trial enrolled 399 patients with HRR gene-mutated mCRPC who were randomized to receive enzalutamide 160 mg plus either talazoparib 0.5 mg or placebo daily.12 Enrolled patients were required to have a prior orchiectomy, and if not, must have received GnRH analogs.12 Those with prior systemic therapy for mCRPC were excluded, though prior CYP17 inhibitors or docetaxel for metastatic castration-sensitive prostate cancer (mCSPC) were permitted.12 HRR genes were assessed prospectively using tumor tissue and/

or circulating tumor DNA-based next generation sequencing assays.12 In the HRR gene-mutated population, there was a statistically significant improvement in rPFS for talazoparib with enzalutamide compared to placebo with enzalutamide.12

Common adverse reactions included decreased hemoglobin, neutrophils, lymphocytes, platelets, calcium, sodium, phosphate, magnesium, and potassium; fatigue; fractures; dizziness; decrease in appetite; dysgeusia; and increased bilirubin.11

Niraparib and Abiraterone Acetate with Prednisone (AKEEGA™)

In August 2023, the FDA approved a fixed dose combination of niraparib and abiraterone acetate (AKEEGA™, Janssen Biotech) with prednisone for adult patients with deleterious or suspected deleterious BRCA-mutated mCRPC.13 Cohort 1 of MAGNITUDE, a randomized, double-blind, placebo-controlled trial, evaluated the efficacy of the fixed dose.14 The trial included 423 patients with HRR gene-mutated mCRPC who were randomized to receive niraparib 200 mg and abiraterone acetate 1,000 mg plus prednisone 10 mg daily or placebo and abiraterone acetate plus prednisone daily.14

To participate, patients were required to have a prior orchiectomy or be receiving GnRH analogues.14 Patients were eligible if they

Prostate Cancer Pipeline

Drug Manufacturer Route of Administration Mechanism of Action Status

denosumab (GP2411)

denosumab (ENZ215)

abiraterone acetate (TAVT-45)

ipatasertib (GDC-0068)

fluzoparib (SHR3162)

abemaciclib (Verzenio®)

Sandoz; Hexal SC RANKL inhibitor Pending (12/2023)

Enzene Biosciences; Alkem Laboratories SC RANKL inhibitor Phase 3

Tavanta Therapeutics oral androgen biosynthesis inhibitor Phase 3

Roche; Genentech oral AKT inhibitor Phase 3

Jiangsu Hengrui Pharmaceuticals oral PARP inhibitor Phase 3

Eli Lilly; Boehringer Ingelheim oral CDK4/6 dual inhibitor Phase 3

pembrolizumab (KEYTRUDA®) Merck IV PD-1 inhibitor Phase 3

lutetium (177Lu) zadavotide POINT Biopharma IV radiotherapy Phase 3

lutetium Lu 177 PSMA I&T (Lu 177 PSMA I&T) Curium Pharma IV radiotherapy Phase 3

triptorelin pamoate (Triptodur® Kit) Debiopharm injectable GnRH/LHRH agonists Phase 3

stapuldencel-T (DCVAC/PCa)

SOTIO® SC DCT Phase 3

vobramitamab duocarmazine (MGC018) MacroGenics IV cytotoxic agent; anti B7-H3 antibody Phase 3

senaparib (IMP4297)

IMPACT Therapeutics oral PARP inhibitor Phase 2

abivertinib (FUJOVEE™) ACEA Therapeutics; Sorrento oral tyrosine kinase inhibitor Phase 2

docetaxel; ritonavir (ModraDoc006/r) Modra Pharmaceuticals oral protease inhibitor; mitotic inhibitor Phase 2

Abbreviation: DCT = dendritic cell therapy; IV = intravenous; PARP = poly (ADP-ribose) polymerase; PD-1 = programmed cell death 1; RANKL = RANK ligand; SC = subcutaneous

have mCRPC and had not received prior systemic therapy in the mCRPC setting except for a short duration of prior abiraterone acetate plus prednisone and ongoing ADT. Further, they could have received prior docetaxel or androgen-receptor targeted therapies in earlier disease settings.14 BRCA gene mutations were identified in 53% (225) of the patients.14

BRCA patients receiving niraparib and abiraterone acetate plus prednisone showed a statistically significant improvement in rPFS compared to placebo (16.6 months versus 10.9 months, respectively).14 OS was 30.4 months versus 28.6 months for BRCA patients receiving niraparib and abiraterone acetate plus prednisone compared to placebo, respectively.14 Results from the subgroup of 198 patients with non-BRCA HRR mutations indicate that the improvement in the ITT HRR gene-mutated population was primarily attributed to the results seen in the subgroup of patients with BRCA mutations.14

Adverse reactions associated with treatment included laboratory abnormalities: decreased hemoglobin, lymphocytes, white

blood cells, platelets, neutrophils, and potassium, and increased alkaline phosphatase, creatinine, potassium, and AST. Additional reactions included musculoskeletal pain, fatigue, constipation, hypertension, and nausea.13, 14 About 27% of patients receiving treatments required a blood transfusion, including 11% who required multiple.13, 14

Recommended dosing of the treatment is 200 mg niraparib and 1,000 mg abiraterone acetate taken orally once daily in combination with 10 mg of prednisone daily, until disease progression or unacceptable toxicity results.13 Those receiving treatment should receive a GnRH analog concurrently or should have had a bilateral orchiectomy.13

Adherence to Oral Cancer Therapy and Payer Impact

The approval of a new oral combination therapy for prostate cancer may raise concerns regarding adherence to oral cancer therapies overall.15 Unlike traditional infusion oncology treatment, oral

The approval of a new oral combination therapy for prostate cancer may raise concerns regarding adherence to oral cancer therapies overall.

cancer treatment requires correct patient administration of the drug without provider oversight.15 As many of these treatments are very toxic with myriad side effects and dosed accordingly, the regimen is essential with scheduled breaks. However, following the proper regimen and administering the dose correctly can present a challenge.15

Various factors contribute to nonadherence, including adverse effects, confusion, lack of treatment understanding, and cost.15 The immediate and long-term adverse effects accompanying many cancer therapies, including fatigue, decreased blood cell counts, neuropathy, mouth sores, and other complications, can create a disincentive for patient adherence.15 Oral therapies also have different adverse effects than infusion therapies, including dermatological reactions, as well as some kidney

and liver complications.15 Patients will often forego reporting adverse reactions and discontinue use of the therapy on their own. Nausea is one of the most common adverse effects and one that can be proactively managed in a clinical setting. In the home administration setting, however, patients may avoid taking their dose to prevent further nausea when they feel unwell.15

A study from 2014 to 2016 of patients prescribed oral targeted therapy or chemotherapy evaluated adherence via electronic pill caps.16 The study showed patients reporting greater cancer-related symptom severity (fatigue, drowsiness, disturbed sleep, memory problems, and emotional distress) had lower treatment adherence overall.16 These results underscore the need for adherence to be addressed in the oral oncology treatment setting.16

Research suggests multicomponent interventions may be effective in promoting patient adherence to oral anticancer medicines.17 Integrating digital solutions with direct clinical contacts from providers or pharmacists may be effective in encouraging adherence and improving outcomes.17

With a new combination oral therapy for prostate cancer, as well as other new treatment options, payers may benefit from management in the space, including patient adherence programs for oral therapies. To achieve the best outcomes, treatment compliance is crucial. Oral therapies often require clinical intervention to ensure patients continue proper administration.

References

1. “Prostate Cancer.” National Cancer Institute, https://www.cancer.gov/ types/prostate.

2. “Cancer Stat Facts: Prostate Cancer.” National Cancer Institute, 2023, https://seer.cancer.gov/statfacts/html/prost.html.

3. “Prostate Cancer Prevention (PDQ®) - Patient Version.” National Cancer Institute, 6 May 2022, https://www.cancer.gov/types/ prostate/patient/prostate-prevention-pdq.

4. Wei, John T., et al. “Early Detection of Prostate Cancer: AUA/ SUO Guideline Part I: Prostate Cancer Screening.” The Journal of Urology, 1 Jul. 2023, https://www.auajournals.org/doi/10.1097/ JU.0000000000003491#F1.

5. Desai, Mihir M., et al. “Trends in Incidence of Metastatic Prostate Cancer in the US.” Journal of the American Medical Association Network Open, 14 Mar. 2022, https://jamanetwork.com/journals/ jamanetworkopen/fullarticle/2790041#248271102.

6. “Prostate Cancer Guidelines.” MedScape, 31 May 2023, https:// emedicine.medscape.com/article/2259453-overview.

7. “Prostate Cancer Treatment (PDQ®) - Health Professional Version.” National Cancer Institute, 13 Feb. 2023, https://www.cancer.gov/ types/prostate/hp/prostate-treatment-pdq#_62.

8. “Prostate Cancer: Types of Treatment.” Cancer.Net Editorial Board, Dec. 2022, https://www.cancer.net/cancer-types/prostate-cancer/ types-treatment.

9. “FDA approves olaparib with abiraterone and prednisone (or prednisolone) for BRCA-mutated metastatic castration-resistant prostate cancer.” U.S. Food and Drug Administration, 31 May 2023, https://www.fda.gov/drugs/drug-approvals-and-databases/fdaapproves-olaparib-abiraterone-and-prednisone-or-prednisolonebrca-mutated-metastatic-castration.

10. Goodman, Alice. “PROpel Trial: Improvement in Progression-Free Survival with First-Line Olaparib Plus Abiraterone in Metastatic Prostate Cancer.” The American Society of Clinical Oncology Post, 10 Apr. 2023, https://ascopost.com/issues/april-10-2023/ improvement-in-progression-free-survival-with-first-line-olaparibplus-abiraterone-in-metastatic-prostate-cancer.

11. “FDA approves talazoparib with enzalutamide for HRR gene-mutated metastatic castration-resistant prostate cancer.” U.S. Food and Drug Administration, 20 June 2023, https://www.fda.gov/drugs/drugapprovals-and-databases/fda-approves-talazoparib-enzalutamidehrr-gene-mutated-metastatic-castration-resistant-prostate.

12. Agarwal, Neeraj. “TALAPRO-2 Supports First-Line Talazoparib/ Enzalutamide in All-Comers with mCRPC.” 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium, 16 Feb. 2023, https://dailynews.ascopubs.org/do/talapro-2-supports-first-linetalazoparib-enzalutamide-all-comers-mcrpc.

13. “FDA approves niraparib and abiraterone acetate plus prednisone for BRCA-mutated metastatic castration-resistant prostate cancer.” U.S. Food and Drug Administration, 11 Aug. 2023, https://www.fda. gov/drugs/resources-information-approved-drugs/fda-approvesniraparib-and-abiraterone-acetate-plus-prednisone-brca-mutatedmetastatic-castration.

14. Chi, Kim N., et al. “Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castrationresistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations.” Journal of Clinical Oncology, 2022, https://ascopubs.org/doi/abs/10.1200/ JCO.2022.40.6_suppl.012.

15. Wimbiscus, Bill. “Patient Adherence, a Challenge of Oral Chemotherapy.” Targeted Oncology, 21 Jan. 2019, https://www. targetedonc.com/view/patient-adherence-a-challenge-of-oralchemotherapy.

16. Jacobs, Jamie M., et al. “Patient Experiences with Oral Chemotherapy: Adherence, Symptoms, and Quality of Life.” Journal of the National Comprehensive Cancer Network, 1 Mar. 2019, https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC6626621/.

17. Dang, Thu Ha, et al. “Investigation of Intervention Solutions to Enhance Adherence to Oral Anticancer Medicines in Adults: Overview of Reviews.” Journal of Medical Internet Research Cancer, 2022, https://cancer.jmir.org/2022/2/e34833.

Multiple Myeloma:

CAR-T Advances and Management Impact

The introduction of CAR-T as an alternative treatment for the multiple myeloma population represents a promising opportunity for improved outcomes.

Michael Harvey, Pharm.D. Director of Pharmacy AultCare

Multiple myeloma is a blood cancer that affects the plasma cells found in bone marrow.1, 2 These cells produce antibodies that play a key role in helping the immune systems fight off infection.1, 2 Multiple myeloma causes these plasma cells to mutate and grow uncontrollably, producing an abnormal antibody called M protein.1, 2 The multiplication of these cells causes a decrease in red blood cells, white blood cells, and platelets, often leading to anemia, excessive bleeding, and a compromised immune system.1, 2 Multiple myeloma is associated with other complications, including bone damage, hypercalcemia, and kidney damage.1, 2

This cancer is relatively uncommon in the U.S. — a person’s lifetime risk of contracting multiple myeloma is 1 in 132 (0.76%).3 Novel agents have led to increased rates of deep, long-lasting remission. However, because nearly all patients become resistant to therapy, multiple myeloma is considered an incurable disease.4 In 2023, there will be an estimated 35,730 new multiple myeloma case diagnoses with 12,590 expected deaths.3

Standard of Care

The standard of care for multiple myeloma patients is predicated on whether the patient is eligible for stem cell transplant.4 Certain drugs can cause severe damage to healthy cells in bone marrow, which makes it more challenging to harvest stem cells for transplant.

According to the National Comprehensive Cancer Network (NCCN) Guidelines from 2022, the preferred primary multiple myeloma therapy regimen for transplant candidates is bortezomib/ lenalidomide/dexamethasone, with lenalidomide preferred as maintenance therapy.5 For patients ineligible for transplant, preferred primary therapies include bortezomib/lenalidomide/ dexamethasone or daratumumab/lenalidomide/dexamethasone, with lenalidomide preferred as maintenance therapy.5

For early relapses (after one to three prior therapies) in patients with previously treated multiple myeloma, preferred regimens include: bortezomib/lenalidomide/dexamethasone, carfilzomib/lenalidomide/dexamethasone, daratumumab/ (bortezomib or carfilzomib or lenalidomide)/dexamethasone, ixazomib/lenalidomide/dexamethasone, and isatuximab-irfc/ carfilzomib/dexamethasone. 5

For late relapses (after more than three prior therapies), NCCN 3.2022 guidelines recommended belantamab mafodotin-blmf or idecabtagene vicleucel.5

CAR-T Treatment for Multiple Myeloma

Currently, there are two CAR-T therapies available for multiple myeloma. Idecabtagene vicleucel (ide-cel) (ABECMA®), approved by the U.S. Food and Drug Administration (FDA) in 2021, was the first, followed in 2022 by the approval of ciltacabtagene autoleucel (cilta-cel) (CARVYKTI®).

New Cilta-Cel Data

More recent data on cilta-cel show the benefit of cilta-cel in lenalidomide for the treatment of multiple myeloma. In the CARTITUDE-4 study, the first phase 3 study designed to evaluate the efficacy and safety of CAR-T therapy for patients with lenalidomide-refractory multiple myeloma, a single infusion of cilta-cel was associated with a significant improvement in progression-free survival (PFS) in patients with lenalidomiderefractory multiple myeloma after first relapse, when compared with the standard of care.6, 7

Because lenalidomide-based therapies are used extensively as first-line treatments, patients with lenalidomide-refractory disease need effective disease therapies that can be employed early in treatment.

In the study, 419 patients with lenalidomide-refractory multiple myeloma who had previously received between one and three lines of therapy, including a proteasome inhibitor and immunomodulatory agent, were assigned to receive either cilta-cel or standard of care.6, 7

The 12-month PFS rates were 75.9% and 48.6% for cilta-cel and standard of care, respectively.6, 7 Cilta-cel also significantly improved overall response rate (ORR), the rate of increased complete response, and the overall measurable residual disease negativity rate compared to standard of care. In the cilta-cel population, there was a positive trend toward improved overall survival.6, 7

Grade 3 or 4 adverse events were reported in 97% of patients who received cilta-cel and 94% standard of care, including infections and cytopenias.6, 7 Of patients receiving cilta-cel, 76% experienced cytokine release syndrome (CRS) and 5% experienced immune effector cell-associated neurotoxicity syndrome (ICANS).6, 7 The rates of CRS and ICANS were reportedly lower in CARTITUDE-4 than CARTITUDE-1, which may suggest that cilta-cel has an improved safety profile when used earlier in treatment.6, 7

The results of CARTITUDE-4 suggest the potential for cilta-cel to be an earlier line treatment option for patients with lenalidomide-refractory multiple myeloma after a first relapse.6, 7 Because lenalidomide-based therapies are used extensively as first-line treatments, patients with lenalidomide-refractory disease need effective disease therapies that can be employed early in treatment.6, 7

Allogeneic Versus Autologous

Conventionally, CAR-T therapy is autologous, meaning cells must be drawn from a patient, genetically modified, and multiplied

into large quantities, at which point they are reintroduced to the patient to attack the cancer cells.8 Since this process can be lengthy and require time unafforded to patients with later stage multiple myeloma, some studies are investigating an allogeneic CAR-T approach.8 Allogeneic CAR-T would use cells taken from healthy donors, which are genetically modified and stored in larger batches, ready to be used off the shelf.8 Providers will use a patient’s tissue type to identify the best match among donor cells, saving time in the treatment process.8

Researchers conducted a phase 1 clinical trial at Memorial Sloan Kettering Cancer Center in which patients were given donor CAR-T cells (allogeneic) rather than autologous CAR-T therapy.9 The initial results of this trial showed that allogeneic CAR-T therapy can be safe and effective.9

However, there are challenges associated with allogeneic CAR-T cells. When donor cells are used, graft-versus-host disease (GVHD) can develop; this occurs when the transplanted donor cells attack a patient’s normal cells. In some cases, the reverse can occur and a patient’s immune cells can attack donor cells.8

Phase 1 study researchers treated patients with an immunesuppressing treatment before the transplant. In modifying the donor CAR-T cells, researchers removed a T cell protein called TRAC.8 This procedure helped prevent GVHD while still allowing

the cells to effectively attack the BCMA protein on the cancer cells.8 Study results showed these modifications and manipulations helped overcome the anticipated challenges of off-the-shelf CAR-T therapy.8 No study participants experienced GVHD and the transplanted cells survived and multiplied after infusion.8

Recent Approvals

Teclistamab-cqyv (TECVAYLI®)

In October 2022, the U.S. Food and Drug Administration (FDA) granted teclistamab-cqvy (TECVAYLI®, Janssen Biotech) accelerated approval for the treatment of adult patients with relapsed or refractory (R/R) multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.10

Teclistamab is the first bispecific B-cell maturation antigen (BCMA)-directed CD3 T-cell engager.10 The recommended dose for teclistamab-cqyv is 0.06 mg/kg via subcutaneous injection on Day 1, 0.3 mg/kg on Day 4, and 1.5 mg on Day 7, followed by 1.5 mg/kg once weekly until disease progression or unacceptable toxicity.10

In MajesTEC-1, a single-arm, multi-cohort, open-label, multicenter study, the efficacy of teclistamab was evaluated in a population of 110 patients who had previously received at least three prior therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, and had not received prior BCMA-targeted therapy.10 ORR was 61.8% with a median follow-up of 7.4 months among responders, and the estimated duration of response (DOR) rate was 90.6% at six months and 66.5% at nine months.11

Teclistamab carries a Boxed Warning for life-threatening or fatal CRS and neurologic toxicity, including ICANS.10 CRS occurred in 72% of patients who received teclistamab at the recommended dose, while neurologic toxicity occurred in 57% and ICANS in 6%.10 Due to these risks, teclistamab is available only through a Risk Evaluation and Mitigation Strategy (REMS) program.10

Adverse reactions associated with teclistamab included pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea.10 Grade 3 to 4 laboratory abnormalities associated with treatment included decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin, and decreased platelets.10

Talquetamab-tgvs (TALVEY™)

In August 2023, the FDA granted accelerated approval to talquetamab-tgvs (TAVLVEY™, Janssen Biotech) for the treatment of adults with R/R multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.12 Approval was based on efficacy results from MMY1001, a single-arm, open-label, multicenter study of 187 patients who previously received at least four prior systemic therapies.12

In the study, patients received talquetamab-tgvs 0.4 mg/kg subcutaneously weekly, following two step-up doses in the first week of therapy, or talquetemab-tgvs 0.8 mg/kg subcutaneously biweekly following three step-up doses until disease progression or unacceptable toxicity.13 In the patients who received the 0.4 mg/kg dosage, ORR was 73% and median DOR was 9.5 months, while patients who received the 0.8 mg/kg dosage had an estimated ORR of 73.6% and the DOR was not estimable.13 Response was maintained for at least nine months in an estimated 85% of responders.13

Talquetamab-tgvs comes with a Boxed Warning for life-threatening or fatal CRS and neurologic toxicity, including ICANS.12 Due to these risks, talquetamab-tgvs is only available through a REMS program.12

Adverse reactions associated with talquetamab-tgvs were CRS, dysgeusia, nail disorder, musculoskeletal pain, skin disorder, rash,

Pipeline

fatigue, decreased weight, dry mouth, pyrexia, xerosis, dysphagia, upper respiratory tract infection, and diarrhea.12

Elranatamab (ELREXFIO™)

In August 2023, the FDA approved elranatamab (ELREXFIO™, Pfizer), a BCMA CD-3 targeted bispecific antibody, for the treatment of patients with R/R multiple myeloma.14 The recommended dose of elranatamab is as follows: “step-up dose 1” of 12 mg on Day 1, “step-up dose 2” of 32 mg on Day 4, followed by the first treatment of 76 mg on Day 8 and 76 mg weekly, thereafter, through week 24.14 Patients who have received at least 24 weeks of treatment and have achieved partial response or better and maintained response for at least two months will transition to an every two-week schedule.14 Approval was based on data from the MagnetisMM-3 study of 123 BCMA-naïve patients with R/R multiple myeloma.14 Participants were previously treated with at least three classes of therapies, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.15 Results showed patients who received elranatamab as their first BCMA-targeted therapy achieved a high ORR of 61%.15 Among patients receiving the recommended dose of elranatamab, the ORR was 57.7%.15 The DOR rate at six months was 90.4% and at nine months was 82.3%.15

Elranatamab prescription information includes a Boxed Warning for life-threatening or fatal CRS and neurologic toxicity, including ICANS.14 Of patients who received the recommended dose, 58%

Drug Manufacturer Route of Administration Mechanism of Action Status

CAR-T

ALLO-605

zevorcabtagene autoleucel (CT053)

Others

elranatamab (PF-06863135)

talquetamab (JNJ-64407564)

Allogene Therapeutics; Pfizer injectable CAR-T immunotherapy Phase 2

CARsgen Therapeutics IV autologous cellular product Phase 2

Pfizer SC BCMA antibody Pending (3Q 2023)

Janssen Biotech; Genmab SC anti-CD3 antibody; anti-GPRC5D Pending (2H 2023)

denosumab (GP2411) Sandoz; Hexal SC RANKL inhibitor Pending (12/2023)

iberdomide (CC-220)

REGN5459

nirogacestat

Celgene; Bristol Myers Squibb oral cereblon E3 ligase modulator Phase 2

Regeneron Pharmaceuticals IV anti-D3 antibody; BCMA Phase 2

SpringWorks Therapeutics; Pfizer oral gamma secretase inhibitor Phase 2

Abbreviations: BCMA = anti-B-cell maturation antigen; IV = intravenous; RANKL = RANK ligand; SC = subcutaneous

MULTIPLE MYELOMA |

experienced CRS, 59% experienced neurologic toxicity, and 3.3% experienced ICANS.14 Adverse reactions occurring in at least 20% of patients who received elranatamab included CRS, fatigue, injection site reaction, diarrhea, upper respiratory tract infection, musculoskeletal pain, pneumonia, decreased appetite, rash, cough, nausea, and pyrexia.14 Common Grade 3 and 4 laboratory abnormalities included decreased lymphocytes, neutrophils, hemoglobin, white blood cells, and platelets.14

Motixafortide (APHEXDA®)

In September, the FDA approved motixafortide (APHEXDA®, BioLineRx) in combination with filgrastim (G-CSF), a compound therapy intended to mobilize hematopoietic stem cells (HSC) to the peripheral blood for collection and subsequent autologous transplantation in patients with multiple myeloma.16 Approval was supported by results from the GENESIS phase 3 trial of motixafortide on top of G-CSF compared to placebo plus G-CSF in stem cell mobilization for autologous transplantation in multiple myeloma patients.17 Results showed that 67.5% of patients in the motixafortide plus G-CSF arm achieved stem cell collection goal of >6 x 106 CD34+ cells/kg within two sessions compared to 9.5% of the placebo plus G-CS arm.17 Also, 92.5% of patients in the motixafortide arm reached stem cell collection goal in up to two apheresis sessions compared to 21.4% in the placebo arm.17

Of patients receiving motixafortide plus G-CSF, 5.4% experienced serious adverse events, including vomiting, injection site reaction, hypersensitivity reaction, injection site cellulitis, hypokalemia, and hypoxia.16 Common adverse events were injection site reactions like pain, erythema, pruritis, flushing, and back pain.16

Drug Removed from Market

In November 2022, GSK announced it would be removing belantamab mafodotin (BLENREP) from the U.S. market.18 In 2020, belantamab was approved via accelerated approval pathway for the treatment of patients with R/R multiple myeloma who have received at least four prior therapies, including an antiCD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.18

Ultimately, the confirmatory trial failed to show a benefit in delaying disease progression in comparison to standard therapy.18 The confirmatory trial showed no benefit in preventing deaths and was not greatly successful at shrinking tumors. Further, trial patients treated with belantamab had a 14% higher risk of death.18

CAR-T Impact on Payers and Management Strategies

According to a recent analysis of Medicare claims, CAR-T therapy claims have been doubling every six months.19 The use of innovative CAR-T therapies available for multiple myeloma will continue to increase, creating a trend in the coming years.

The introduction of CAR-T as an alternative treatment in the multiple myeloma population represents a promising opportunity for improved outcomes. Historically, multiple myeloma has a fiveyear survival rate of 54%, and many patients do not respond effectively to standard multiple myeloma therapies or relapse after treatment.20 Patients with R/R multiple myeloma may now have access to a later line treatment option in CAR-T therapies.

Now that recently released data show some clinical benefit to the utilization of CAR-T in earlier line multiple myeloma treatment, standard of care recommendations and guidelines may adjust to account for these findings.6, 7 Considering the myriad of treatment options for different lines of multiple myeloma treatment, providers will need to determine the most appropriate treatment for each individual patient. Meanwhile, payers will have to actively manage the category to ensure patients have access to the treatment most suited to their needs. While not curative, CAR-T therapies may have a major impact on multiple myeloma patients, especially later stage patients who have few or no other treatment options.

Costs of treating multiple myeloma can be high, with a range of $220,000 to $300,000 per treatment, and treatment often consists of a combination of multiple drug therapies.21 The price of CAR-T therapies may present a financial burden for both patients and payers. However, considering the high costs of the standard of care for multiple myeloma, cost-effectiveness analyses suggest that CAR-T therapies for multiple myeloma could have significant value at their current price as well as small-to-substantial net health benefits over standard of care.

An Institute for Clinical and Economic Review (ICER) report evaluating clinical and cost-effectiveness of both ide-cel and cilta-cel concluded that both demonstrated a net health benefit superior to usual care, with positive effects on the patient’s and caregiver’s quality of life and the patient’s ability to manage and sustain treatment.22 Payers must still consider certain criteria for eligibility to balance providing access to these medications for appropriate patients with managing costs. Payers should also be cognizant of the budget impact of these products expanding to earlier line settings and explore opportunities for innovative contracting models (e.g., global case rates) to manage the cost of CAR-T.

References

1. “What is Multiple Myeloma?” American Cancer Society, 2018, https://www.cancer.org/cancer/multiple-myeloma/about/what-ismultiple-myeloma.html.

2. “Understanding Multiple Myeloma.” Multiple Myeloma Research Foundation, https://themmrf.org/multiple-myeloma/.

3. “Key Statistics About Multiple Myeloma.” American Cancer Society, 12 Jan. 2023, https://www.cancer.org/cancer/types/multiplemyeloma/about/key-statistics.html.

4. Fischer, L., et al. “CAR T cell therapy in multiple myeloma, where are we now and where are we heading for?” European Journal of Haematology, 2023 Aug. 7, doi: 10.1111/ejh.14051.

5. Callander, Natalie, et al. “NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022.” Journal of the National Comprehensive Cancer Network, Jan. 2022, https://jnccn.org/view/journals/ jnccn/20/1/article-p8.xml.

6. Dhakal, Binod, et al. “First phase 3 results from CARTITUDE-4: Ciltacel versus standard of care (PVd or DPd) in lenalidomide-refractroy multiple myeloma.” American Society of Clinical Oncology, 2023, https://meetings.asco.org/abstracts-presentations/220015.

7. Dhakal, Binod. “CARTITUDE-4 Shows Benefit with Ciltacabtagene Autoleucel in Lenalidomide-Refractory Multiple Myeloma.” American Society of Clinical Oncology, 5 June 2023, https://dailynews.ascopubs. org/do/cartitude-4-shows-benefit-ciltacabtagene-autoleucellenalidomide-refractory-multiple.

8. “Off-the-Shelf CAR T Cell Therapy for Multiple Myeloma Shows Promise,” Memorial Sloan Kettering Cancer Center, 23 Jan. 2023, https://www.mskcc.org/news/shelf-car-cell-therapy-multiplemyeloma-shows-promise.

9. Mailankody, Sham, et al. “Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results.” Nature Medicine, 23 Jan. 2023, https://www.nature. com/articles/s41591-022-02182-7.

10. “FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma.” U.S. Food and Drug Administration, 25 Oct. 2022, https:// www.fda.gov/drugs/resources-information-approved-drugs/fdaapproves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma.

11. Moreau, Philippe, et al. “Teclistamab in Relapsed or Refractory Multiple Myeloma,” New England Journal of Medicine. 11 Aug. 2022, https://pubmed.ncbi.nlm.nih.gov/35661166/.

12. “FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma.” U.S. Food and Drug Administration, 10 Aug. 2023, https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-grants-accelerated-approval-talquetamabtgvs-relapsed-or-refractory-multiple-myeloma.

13. “TALVEY - MonumenTAL-1 (MMY1001) Study.” Janssen Science, 14 Aug. 2023, https://www.janssenscience.com/products/talvey/ medical-content/talvey-monumental1-mmy1001-study.

14. ”FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma.” U.S. Food and Drug Administration, 14 Aug. 2023, https://www.fda.gov/drugs/resources-information-approveddrugs/fda-grants-accelerated-approval-elranatamab-bcmmmultiple-myeloma#:~:text=On%20August%2014%2C%20 2023%2C%20the,four%20prior%20lines%20of%20therapy%2C.

15. Helwick, Caroline. “Elranatamab Induces Responses in Many Patients with Resistant Multiple Myeloma in Phase II Trial.” The American Society of Clinical Oncology Post, 25 Feb. 2023, https:// ascopost.com/issues/february-25-2023-supplement-conferencehighlights-ash-2022/elranatamab-induces-responses-in-manypatients-with-resistant-multiple-myeloma-in-phase-ii-trial.

16. Tucker, Nicole. “FDA Approves Aphexda to Aid in HST Mobilization in Patients with Multiple Myeloma.” Targeted Oncology, 11 Sept. 2023, https://www.targetedonc.com/view/fda-approves-aphexda-to-aidin-hst-mobilization-in-patients-with-multiple-myeloma.

17. Crees, Zachary D., et al. “Motixafortide and G-CSF to mobilize hematopoietic stem cells for autologous transplantation in multiple myeloma: a randomized phase 3 trial.” Nature Medicine, 17 Apr. 2023, https://www.nature.com/articles/s41591-023-02273-zv.

18. “Withdrawal of Blenrep from the US Market.” International Myeloma Foundation, 23 Nov. 2022, https://www.myeloma.org/news-events/ withdrawal-blenrep-us-market.

19. Caffrey, Mary. “Real-world data offers good news for CAR-T cell therapy.” American Journal of Managed Care, 15 Dec. 2020, add https://www.ajmc.com/view/real-world-data-offers-good-news-forcar-t-cell-therapy.

20. “Multiple Myeloma: Statistics.” Cancer.Net, Feb. 2020, https://www. cancer.net/cancer-types/multiple-myeloma/statistics.

21. “Can We Afford the Cost of Myeloma Therapy?” Medscape, 25 June 2018, http://www.medscape.com/viewarticle/898450.

22. “Anti B-Cell Maturation Antigen CAR T-cell and Antibody Drug Conjugate Therapy for Heavily Pre-Treated Relapsed and Refractory Multiple Myeloma.” Institute for Clinical and Economic Review, 11 May 2021, https://icer.org/wp-content/uploads/2020/10/ICER_ Multiple-Myeloma_Final-Report_Update_09102021.pdf.

Oncology Supportive Care and Telemedicine

Telehealth can be useful — and in some cases preferred — for the maintenance and management of ongoing oncology treatment.

Lindsay Speicher, J.D. Project Manager, Specialty Magellan Rx Management

Telemedicine, or telehealth, is healthcare provided by doctors and other health providers via electronic means, typically phone or video.1 Email or text message between a patient and a provider may also be employed where appropriate.1 Remotely monitoring patients’ symptoms may complement telehealth by electronically collecting symptoms data using devices such as wearable activity trackers.1

The COVID-19 pandemic created a surge in telehealth utilization. During the first peak in April 2020, telehealth visits numbered more than 2,600 in a single day.2 Telehealth was a preferred method of care delivery during the pandemic and experienced a 135% increase in visits from March to April 2020.3

While telehealth seemed to grow slightly slower in some oncology settings, some cancer centers have witnessed steady growth.4 The medical director at the Center for Telehealth at Dartmouth-Hitchcock Health noted that in 2022, about 12% of outpatient center oncology visits were conducted via telehealth.1

The American Society of Clinical Oncology (ASCO) published a report on care during the pandemic, identifying visits for non-urgent, high-risk patient populations and symptom management as eligible for telehealth visits.3 Overall, according to the ASCO data, by December 2021, 5-6% of the volume of oncology visits were being conducted via telehealth, but this varied from practice to practice.5

Policy measures that loosened telehealth restrictions during the pandemic encouraged widespread adoption. Additionally, many states waived licensure requirements for clinicians to provide care remotely. Recent federal legislation authorized an extension through 2024 of Medicare telehealth flexibilities established during the COVID-19 public health emergency.6

Value of Telemedicine in Oncology Care

Patient and Provider Satisfaction

Cancer patients receiving telehealth visits have reported high rates of satisfaction. A survey of oncology patients utilizing telehealth reported satisfaction among 80% of survey participants.7 Satisfaction increased from the baseline to the follow-up, which could indicate increased familiarity and comfort with using the technology-based care method.7

Additional data from more than 30,000 patients who received in-person visits and nearly 6,000 patients with telemedicine visits showed that telehealth visits had a higher rate of high satisfaction among patients than in-person visits (75.8% versus 62.5%, respectively).8 Of patients receiving telehealth services, 90.7% reported high satisfaction with the response and concern demonstrated by their care provider compared to 84.2% of those who received in-person care.8

According to results from a survey of oncologists, there is a high satisfaction rate among providers who provide telehealth services. Nearly 60% of the 200 oncologists surveyed believed video visits were sufficient in managing most patient care, such as discussion of treatment plans and review of lab results.9 Clinicians reported interest in continuing to utilize telehealth in the future.9

There are obvious restrictions to telehealth, especially for diagnostic screenings such as mammography, colonoscopy, and computerized tomography (CT) scans for lung cancer screenings.1 Notably, clinicians reported that in-person visits were preferable for promoting a connection with the patient. Additionally, certain discussions are better handled in person, such as new diagnoses and end-of-life decision-making.1 However, for the maintenance and management of ongoing treatments, telehealth can be useful, and in some cases, preferred, for many patients.1

Improved Access and Cost for Patients

Telehealth can provide an opportunity for improved access to quality care for patients who may not live near care centers. Patients with limited access, lack of transportation, or without proximity to treatment centers and practitioners alike can benefit from telehealth by connecting with providers who may otherwise be out of reach.

According to an analysis of 25,500 telehealth visits by more than 11,600 adults with cancer during the COVID-19 pandemic, the use of telehealth was associated with an average cost savings of between $147 and $186 per visit for patients.10 Estimated patient savings were associated with indirect costs, including travel

Telemedicine can provide a means to alleviate the costs associated with transportation, as well as the parking and housing arrangements often required, especially for longterm cancer care.

expenses and lost income from missing work for appointments and travel time.10 Cost models suggest that telehealth was associated with savings of nearly $1.2 million in otherwise lost income due to driving time and $467,000 savings in lost income due to appointment time. Combined, there was an estimated savings in lost income of $1.6 million for the participants in the study.

Lack of or inadequate transportation is the highest reported out-of-pocket nonmedical cost for patients receiving cancer treatment leading to missed appointments and reliance on emergency department care.8 Telemedicine can provide a means to alleviate the costs associated with transportation, as well as the parking and housing arrangements often required, especially for long-term cancer care.8

Improved Outcomes

Telehealth presents an opportunity for more regular and convenient follow-up management. After or throughout treatment, patients can consult with their providers virtually to monitor treatment progress, manage side effects and address patient concerns. With provider communication readily available via telehealth, patients may be more likely to divulge information about side effects and address concerns with treatment.11

Patients can also receive educational materials and resources using telehealth, which may lead to better understanding of their diagnosis and treatment journey.11 Supportive care services, including nutrition counseling, physical therapy, and mental health support, are more accessible remotely using telehealth.11 Telehealth also has the potential to reduce the mental health burden patients experience due to concerns about direct access to a healthcare professional, alleviating the need to wait for an in-person visit if they experience an adverse event or reaction associated with treatment.

Remote monitoring, which tracks patients’ symptoms via smartphones or other devices, is becomingly increasingly attractive in cancer treatment. A study at the Huntsman Cancer Institute at the University of Utah evaluated patients using a remote monitoring system to report any cancer and treatment-related symptoms. The system provided guidance on how to best manage side effects, including direct follow-up for any ongoing symptoms.1 Patients who used remote monitoring experienced symptom improvement and were better able to manage side effects at home than patients who were not monitored remotely.1

Other innovative technologies, including artificial intelligence and virtual reality, may expand telehealth’s possibilities. In a current National Cancer Institute study, virtual reality technology is implemented remotely to assess its ability to reduce stress and improve mood in adults treated for brain tumors. Participants in the study will utilize the virtual reality technology to view relaxing scenes.1

Challenges

Telehealth is not without challenges; healthcare providers have cited several concerns, including inadequate patient interactions and acquisition of medical data, increased potential for missing significant clinical findings, decreased quality of care, and potential medical liability.12

Additionally, challenges surrounding the equitable delivery of telehealth must be addressed as this care modality moves forward.12 Vulnerable patients who are older, lower-income, and uninsured or underinsured may not have equal access to the technology necessary to receive this type of care.12 Accordingly, the shift to telehealth services has the potential to widen existing healthcare disparities.3 Notably, low-income individuals report lower rates of smartphone ownership (71%), home broadband access (59%), internet use (82%), and basic digital literacy (53%).3 Digital literacy can be a major impediment to the delivery of quality care via telehealth. Many patients may be most comfortable with telephone-only visits.

Addressing potential barriers and limitations to telehealth is important as the healthcare community moves forward with widespread implementation of this care delivery method.

Payer Perspective

Many payers continue to invest in virtual care options and support and reimburse telemedicine across primary care and specialties.5 Across all specialties, post-pandemic telehealth utilization remains

Payers prioritize effective, affordable, and accessible cancer care; telehealth presents an opportunity to expand patient access to high-quality oncologists.

around 10%, which is well above pre-pandemic utilization. Payers prioritize effective, affordable, and accessible cancer care; telehealth presents an opportunity to expand patient access to high-quality oncologists.5

Additionally, telemedicine support may be of value to payers in promoting effective disease management by identifying patients at higher risk for adverse outcomes, providing patients with tools, enabling direct interaction between patients and oncologists, and providing patient education materials.5 Payers can support patient utilization of telehealth via services provided by the Virtual Centers of Excellence, where patients can access second opinion consultations and be directed to real-time telehealth services, telehealth for cancer patients represents a significant opportunity to achieve improved patient outcomes.5

References

1. Wang, Linda. “Telehealth-Based Cancer Care Surged during COVID. Will It Continue?” National Cancer Institute, 9 Mar. 2022, https:// www.cancer.gov/news-events/cancer-currents-blog/2022/ pandemic-telehealth-surge-cancer-care.

2. Thomson, Andrew J., et al. “Outpatient Virtual Visits and the ‘Right’ Amount of Telehealth Going Forward.” Telemedicine and e-Health, 13 Dec. 2021, https://www.liebertpub.com/doi/abs/10.1089/ tmj.2020.0468?journalCode=tmj.

3. Nguyen, Ryan, et al. “Telehealth Is Here to Stay: Opportunities and Challenges for Cancer Care.” OncologyLive, 20 Oct. 2020, https:// www.onclive.com/view/telehealth-is-here-to-stay-opportunitiesand-challenges-for-cancer-care.

4. Curtis, Kevin, et al. “Pandemic Use of Telehealth by Oncology at a Rural Academic Medical Center.” Telemedicine Journal and E-Health, Apr. 2022, https://pubmed.ncbi.nlm.nih.gov/34287089/.

5. Langer, Lucy R., et al. “The Future of Telemedicine in Oncology.” Journal of the National Comprehensive Cancer Network, 2 Jun. 2022, https://jnccn.org/view/journals/jnccn/20/5.5/article-p1_3. xml?ArticleBodyColorStyles=contributor%20notes.

6. “Telehealth policy changes after the COVID-19 public health emergency.” Department of Health and Human Services, 17 Jul. 2023, https://telehealth.hhs.gov/providers/telehealth-policy/ policy-changes-after-the-covid-19-public-health-emergency.

7. Natesan, Divya, et al. “Cancer patient satisfaction with telehealth: Survey results from a large NCI-designed cancer institute.” American Society of Clinical Oncology, 2021, https://ascopubs.org/doi/ abs/10.1200/JCO.2021.39.15_suppl.1579.

8. Patel, Krupal B., et al. “Telemedicine Adoption in an NCI-Designated Cancer Center During the COVID-19 Pandemic: A Report on Patient Experience of Care.” Journal of the National Cancer Care Network, May 2023, https://jnccn.org/view/journals/jnccn/21/5/ article-p496.xml?ArticleBodyColorStyles=inline%20pdf.

9. Neeman, Elad, et al. “Attitudes and Perceptions of Multidisciplinary Cancer Care Clinicians Toward Telehealth and Secure Messages.” Journal of the American Medical Association Network Open, 24 Nov. 2021, https://jamanetwork.com/journals/jamanetworkopen/ fullarticle/2786551.

10. Patel, Krupal B., et al. “Estimated Indirect Cost Savings of Using Telehealth Among Nonelderly Patients with Cancer.” Journal of the American Medical Association Network Open, 10 Jan. 2023, https:// jamanetwork.com/journals/jamanetworkopen/fullarticle/2800164.

11. Khan, Aziz. “Enhancing cancer patients’ health outcomes with telehealth.” Southern Illinois University School of Medicine, 27 Mar. 2023, https://www.siumed.edu/blog/enhancing-cancer-patientshealth-outcomes-telehealth#:~:text=Telehealth%2C%20also%20 known%20as%20telemedicine,health%20care%20facility%20 in%20person.

12. Darcourt, Jorge G., et al. “Analysis of the Implementation of Telehealth Visits for Care of Patients with Cancer in Houston During the COVID-19 Pandemic.” Journal of Clinical Oncology Oncology Practice, 1 Jan. 2021, https://ascopubs.org/doi/full/10.1200/ OP.20.00572.

Oncology Biosimilar Update: Stakeholder Impact

Daniel Uting, Pharm.D., MBA Senior Director, Medical Formulary Management Prime Therapeutics

The U.S. Food and Drug Administration began approving oncology biosimilars in 2015, with the majority approved in 2019. Biosimilars have been created for a range of oncology products, including trastuzumab, bevacizumab, rituximab, pegfilgrastim, and filgrastim.

Currently, there are 22 biosimilars on the market for the oncology reference drugs with more in the pipeline (Table 1).

Payer Strategy and Impact

According to a payer survey reported in the 2022 Magellan Rx Management Medical Pharmacy Trend Report, 68% of responders indicated that oncology is their top concern for medical pharmacy management.1 The oncology market is experiencing increasing competition, with 22 approved oncology biosimilars across five originator products and more in the pipeline. After five years, the average biosimilar share in the oncology treatment market and pegfilgrastim was 75%.2 Of these products, bevacizumab had the greatest biosimilar market share at 85%, with trastuzumab following at 83%.2

Biosimilar Drug Manufacturer Phase Potential Approval Date

Reference

(Neulasta®)

Lupifil-P on-body injector

Reference Product - Bevacizumab (Avastin®) BAT1706

SB8

Reference Product - Rituximab (RITUXAN®)

Healthcare, Apotex, Intas Pharmaceuticals

Pharmaceuticals

Solutions; Sandoz

approval 2023

Bioepis; Organon Pending approval N/A

The Magellan Rx 2020 Trend Report stated that 59% of payers surveyed had implemented a specific oncology biosimilars strategy. Another 44% reported that the strategy was for new starts, while 15% reported that the strategy was for new starts and current utilizers.3 Utilization management with step therapy has been a popular strategy for payers — it encourages the initial use of preferred biosimilar products with the goal of driving utilization to the least costly alternative product.3 Strategies that

prefer biosimilars may be key to offsetting growing oncology costs in other areas.

Oncology spend grew at a slower pace from 2020-2021, according to the 2022 Magellan Rx Report, and the use of biosimilars was a major contributing factor to this trend.1 Oncology drugs were notable trend drivers across all lines of business, and biosimilars fueled most of the utilization trend.1

The oncology market is experiencing increasing competition, with 22 approved oncology biosimilars across five originator products and more in the pipeline.

A new report from Samsung Bioepis indicates that oncology biosimilars are more price-sensitive on the market than other biosimilar categories, with lower biosimilar prices leading to higher market share.4 Since 2019, oncology biosimilars have contributed to an estimated 7% reduction in total oncology spend per member per month (PMPM) for the commercial market; biosimilars have contributed to an estimated 1.6% and 0.5% reduction in total oncology PMPM spend in Medicare and Medicaid, respectively.1

While the wholesale acquisition cost (WAC) for oncology products has remained steady, increased competition has led to an erosion of average sales price (ASP) in varying degrees across

Table 1. Oncology Biosimilar Pipeline

ONCOLOGY BIOSIMILAR UPDATE |

all originator products. Biosimilar launches have resulted in an overall ASP decline of 41% on average after the first biosimilar launch; the steepest decline in ASP has occurred among oncology biosimilars.2 The decrease in ASP across oncology originator products is shown in Table 2.

Pegfilgrastim (Neulasta®) experienced the most dramatic decrease in ASP for the brand reference drug at 78%, while trastuzumab (Herceptin®) followed at 24%. ASPs are only expected to continue their decline as more biosimilar options enter the market, increasing competition. ASPs across biosimilars for each oncology originator product are eroding as well. Figures 1-3 show the notable decrease in ASP for rituximabs,

trastuzumabs, and pegfilgrastims. Payers can realize potential savings while ensuring their patient population has access to clinically appropriate therapies.

Internal Magellan data noted several key savings areas associated with oncology biosimilars.3, 5 The utilization of bevacizumab biosimilars increased 71% in less than two years — from 9% in the first quarter of 2020 to 80% in the third quarter of 2021 — and resulted in a one-year net savings of approximately $41 million.3, 5 Similarly, a 76% increase in trastuzumab biosimilar utilization resulted in a one-year net savings of $45 million.3 An 68% increase of rituximab biosimilar utilization achieved a oneyear net savings of $38 million, while a 10% uptick in filgrastim biosimilar utilization contributed to a one-year net savings of $13 million.3, 5 These savings illustrate the market opportunities biosimilar preference presents.

Further Impact

While there is significant potential for payer savings, it remains to be seen how these dropping ASPs will impact other stakeholders.

Patients

As savings potential increases, questions arise regarding who these savings will ultimately benefit. Increased market competition creates lower barriers to access to these therapies for the appropriate patients. Biosimilars’ competitive prices and cost savings have the potential to directly benefit patients; for example, patients could see lower out-of-pocket costs that would further increase access to treatment.6

A study by the Bloomberg School of Public Health at Johns Hopkins University focused on cost savings associated with biosimilars at

Biosimilar launches have resulted in an overall ASP decline of 41% on average after the first biosimilar launch; the steepest decline in ASP has occurred among oncology biosimilars.

large employer plans and found that increased utilization of just one biosimilar saved large employers an average of $1.53 million.7 However, the savings did not end with employers. Data showed that members also experienced savings; those who took the biosimilar paid 12% and 45% less out of pocket than those who took the reference drugs for infliximab and filgrastim, respectively.7

Providers

A drop in ASP may impact providers depending upon payer reimbursement strategies. Reimbursement based on ASP may yield different results for providers than reimbursement based on WAC. The Department of Health and Human Services (HHS) has a provider reimbursement strategy based on a formula set at 106% of the ASP for drugs covered under Medicare Part B.8

The Inflation Reduction Act (IRA) required a temporary five-year increase in the Medicare Part B payment for certain qualifying biosimilars with an ASP equal to or lower than the ASP of the reference product.9 Providers will be reimbursed for these biosimilars at a rate of ASP plus 8%, rather than plus 6% of the reference product’s ASP.9 This change implemented by the IRA is intended to increase access to and utilization of biosimilars in the marketplace.9

Pharmaceutical Manufacturers

Increased competition and the emergence of biosimilars has put pressure on manufacturers to launch their products at lower prices and/or provide market access discounts to providers and payers. This has resulted in decreased drug costs and increased affordability. As ASP declines continue, manufacturers may begin evaluating ways to prevent further erosion of their ASPs.

Figure 1. Rituximab ASP Decline

Figure 2. Trastuzumab ASP Decline

Figure 3. Pegfilgrastim ASP Decline

ONCOLOGY BIOSIMILAR UPDATE

References

1. “Magellan Rx Management Medical Pharmacy Trend Report 2022 Twelfth Edition.” Magellan Rx Management, 2022, https:// issuu.com/magellanrx/docs/medical_pharmacy_trend_ report_2022?fr=sNWIwNzU2MDk5ODQ.

2. Joszt, Laura. “Price Discounts Have Driven Higher Biosimilar Usage, Especially in Oncology.” American Journal of Managed Care, 13 Jul. 2023, https://www.ajmc.com/view/price-discounts-have-drivenhigher-biosimilar-usage-especially-in-oncology.

3. “Magellan Rx Management Medical Pharmacy Trend Report 2020 Eleventh Edition.” Magellan Rx Management, 2020, https://issuu.com/magellanrx/docs/mptr20_050421_ weboptimizedwithlinks?fr=sOGUyMTM2MDc3MDU.

4. “Biosimilar Market Report: 2nd edition, Q3 2023.” Samsung Bioepis, 11 July 2023, https://www.samsungbioepis.com/upload/attach/ SB+Biosimilar+Market+Report+Q3+2023.pdf.

5. Joszt, Laura. “Biosimilar Competition and Utilization Uptake Have Driven Down Costs in the Oncology Space.” American Journal of Managed Care, 1 Apr. 2022, https://www.centerforbiosimilars.com/ view/biosimilar-competition-and-utilization-uptake-have-drivendown-costs-in-the-oncology-space.

6. Kvien, Tore K., et al. “The cost savings of biosimilars can help increase patient access and lift the financial burden of health care systems.” Seminars in Arthritis and Rheumatism, Feb. 2022, https:// www.sciencedirect.com/science/article/pii/S0049017221002171.

7. Socal, Mariana, et al. “Biosimilar Medications - Savings Opportunities for Large Employers.” Johns Hopkins University Center for Hospital Finance and Management, Mar. 2020, https://www.eric. org/wp-content/uploads/2020/03/JHU-Savings-Opportunities-forLarge-Employers.pdf.

8. “Medicare Part B Drug Average Sales Price.” Centers for Medicare & Medicaid Services, 21 Aug. 2023, https://www.cms.gov/medicare/ medicare-fee-for-service-part-b-drugs/mcrpartbdrugavgsalesprice.

9. “Frequently Asked Questions: Inflation Reduction Act Biosimilars Temporary Payment Increase.” Centers for Medicare & Medicaid Services, https://www.cms.gov/files/document/biosimilar-faqs.pdf.

live attenuated

maralixibat (LIVMARLI®)

familial intrahepatic cholestasis-related pruritus (ages > 2 months)

sNDA; breakthrough therapy; orphan drug 12/14/2023

trastuzumab (biosimilar to Genentech’s Herceptin®)

Biotech;

breast cancer; gastric or gastroesophageal junction adenocarcinoma

BLA

pembrolizumab (KEYTRUDA®)

gastric and gastroesophageal

adenocarcinoma (locally advanced unresectable or metastatic, 1st-line; in combination with chemotherapy)

eplontersen

PIPELINE DRUG LIST CONT.

hepatitis B vaccine, recombinant adjuvanted (Heplisav-B®)

Dynavax Technologies hepatitis B vaccine (adults with hemodialysis) IM sBLA

clobetasol propionate

February 2024

Formosa Biomedical Technology ocular pain and/or inflammation ophthalmic 505(b)(2) NDA 3/4/2024

glatiramer depot Viatris multiple sclerosis IM 505(b)(2) NDA 3/8/2024

exagamglogene autotemcel

immune globulin/ hyaluronidase (HyQvia)

beta-thalassemia (transfusiondependent)

Novo Nordisk T1DM; T2DM

zanubrutinib (BRUKINSA®) BeiGene follicular lymphoma (R/R, > third-line, in combination with obinutuzumab)

coagulation factor IX, recombinant (IXINITY)

Medexus Pharmaceuticals

COVID-19 vaccine, monovalent (Omicron XBB.1.5) mRNA

BLA; fast track; orphan drug; RMAT; RPD 3/30/3024

October

SC

infusion sBLA; orphan drug

SC

oral

IV

SC

SC

sBLA February-March 2024

BLA 4/1/2024

BLA

STADA Arzneimittel AG; Xbrane Biopharma DME; DR; macular edema following RVO; MCN; wet AMD intravitreal BLA 4/21/2024

BioNTech COVID-19 prevention (ages > 6 months) IM sBLA; Fast Track 4/24/2024

Abbreviations: ALS = amyotrophic lateral sclerosis; AMD = age-related macular degeneration; BLA = biologics license application; CD = Crohn’s disease; CKD = chronic kidney disease; CRBSI = catheter-related bloodstream infections; CV = cardiovascular; DED = dry eye disease; DMD = Duchenne muscular dystrophy; DME = diabetic macular edema; DR = diabetic retinopathy; GERD = gastroesophageal reflux disease; IM = intramuscular; IV = intravenous; JIA = juvenile idiopathic arthritis; MCN = myopic choroidal neovascularization; NDA = new drug application; NSCLC = non-small cell lung cancer; PsA = psoriatic arthritis; QIDP = qualified infectious disease product; RA = rheumatoid arthritis; RMAT = regenerative medicine advanced therapy; RPD = rare pediatric disease; R/R = refractory or relapsed; RVO = retinal vein occlusion; sBLA = supplemental biologics license application; SC = subcutaneous; sNDA = supplemental new drug application; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; UC = ulcerative colitis