Peer Review: HER2+ Breast Cancer

PEER REVIEW: BREAST CANCER The importance of cancer clinical trials as illustrated by HER2+ breast cancer

Then and Now: Cumulative effects of 30 years of Research: Targeting HER2, Breast Cancer and Beyond

Written by Dr Claire Brady. Oncology Clinical Trials Registrar, Cork University Hospital

Cancer Clinical Trials

Clinical trials are fundamental to advances in healthcare. COVID 19 and the development of effective vaccines have helped shine an important spotlight on the importance of clinical trials. The recent ‘Just Ask 2022’ survey conducted by Cancer Trials Ireland (CTI) showed 78% of the the public surveyed agreed the pandemic has highlighted the importance of clinical trials. The oncology community was one of many groups that celebrated International Clinical Trials Day “Then and Now” on the 20th May 2022. International Clinical Trials Day (ICTD) is held on/ around the 20th May of each year to commemorate the day when James Lind started his clinical trial on scurvy in 1747. This laid the foundation for modern clinical research and is the bedrock on which clinical medicine advancements are made.

Why cancer trials are important

Clinical trials are the backbone of all progress seen in treatment of cancer. Medical oncology in particular, along with radiation oncology has helped to unite the disciplines of biology, basic research, genetics, immunology, pathology and pharmacology. The collective input of these diverse disciplines has seen the development of systemic treatments that has resulted in dramatically improved outcomes for patients. This is a dynamic and ever evolving field as shown by the recent ground breaking DESTINY 04 breast cancer trial results presented at the international American Society of Clinical Oncology (ASCO) annual meeting. The National Cancer Control Program (NCCP) was established by the HSE in 2007 to lead in the development and implementation of cancer policies with the aim of standardising and improving national cancer care and patient outcomes. In June 2022, the NCCP launched the Systemic Anti-Cancer Therapy (SACT) Model of Care. The report highlighted the growing incidence and prevalence of cancer in Ireland, with the number of cancers expected to double from 2015 to 2045. This will result in a projected 58-81% increase in the number of patients receiving SACT for cancer during this period. It has set out twenty five key recommendations to optimise SACT services.

One of its key recommendations is that ‘all patients should have access to a clinical trial where clinically appropriate’ and that ‘clinical trial services should be enhanced/developed in SACT services to support the availability of trials to all patients undergoing SACT.’ This recommendation is supported by the evidence that treatment on a clinical trial is regarded internationally as the gold standard of care. The report also notes there is evidence to suggest that outcomes for patients treated within the context of clinical trials are superior to those outside formal trials. The central role of clinical trials in cancer care has also being noted in the NCCP Cancer Strategy 2017-2026. One of its key performance indicators (KPI) is to increase patient participation in cancer therapeutic trials from 3% to 6% by 2020.

How cancer trials are conducted in Ireland

Cancer Trials Ireland (CTI), established in 1996 (formally known as ICORG) is the leading cancer research trials organisation in Ireland. More than 15,000 Irish patients have particiapted in over 350 cancer trials. It is a not for profit registered charity and is partly funded by the Health Research Board (HRB) and Irish Cancer Society. It has developed strong links with international cancer research groups and has facilitated Irish patients being able to participate in internationally, practice changing clinical trials. It serves as the key link for strategic and coordinated support for the dedicated on site cancer trials units in hospitals across Ireland and the recently formed six cancer clinical trials groups. In 2021, the HRB invested ¤22 million to support the delivery of high quality cancer care in these six cancer trials groups (Children’s Health Ireland Cancer Trials Group, Beaumont Hospital – RCSI University of Medicine and Health Sciences Cancer Trials Group, Irish Research Radiation Oncology Trials Group, UCC Cancer Trials Group, Ireland East Hospital Cancer Trials Group, Trinity Academic Cancer Trials Group.)

Regulation of Clinical Trials

The conduct of clinical trials is strictly regulated ensuring the fundamental importance of safety for all trial participants. All clinical trials must be conducted within strict national regulations and are underpinned by Good Clinial Practice (GCP). GCP is an international ethical and scientific quality standard for the designing, conducting and reporting of trials that involve human participants. Before a clinical trial can be conducted, it must receive approval by a national ethics committee and/or the Ethics Committee of the hospital in which it is taking place. The recent establishment of the National Ethics Committee aims to streamline this process. Furthermore, a clinical trial involving an investigational medicinal product (IMP) must be approved by the Health Products Regulatory Authority (HPRA). The HPRA ensures that trials are conducted in line with current Irish & EU legislation and standards for clinical research. Clinical trials are subject to continuous data monitoring with strict criteria for reporting serious adverse events. Pharmacovigilance compliance is monitored by HPRA.

Study personnel

All study personnel involved in the conduct of a study must have up to date GCP training and must receive specific training in relation to the particular study in which they are involved. Compliance with this standard provides public assurance that the rights, safety and wellbeing of people participating in cancer trials are protected and that the resulting clincal trial data is trustworthy.

Patient participation

Patient participation in clinical trials is entirely voluntarily. It involves a detailed consent process. This involves dicussing both standard of care options in addition to the clinical trial. Armed with this knowledge, a patient can determine what the best treatment plan is for them.

Why Cancer Trials are Important – review of 30 years of progress in treating HER2+ breast cancer

15-20% of breast cancers overexpress the HER2 protein and are referred to as HER2+ breast cancer. Before HER2 directed therapy, this subset of breast cancer was recognised

MYLOTARGTM is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33‑positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL)1,2

Add MYLOTARG™ to

REINFORCE YOUR AML TREATMENT

FOR LONGER REMISSION COMPARED WITH STANDARD OF CARE CHEMOTHERAPY1,2

MYLOTARG™ significantly extends EFS and RFS* for patients with previously untreated de novo AML compared with the standard of care, chemotherapy with DNR and AraC1,2

▼ MYLOTARG® (gemtuzumab ozogamicin)

PRESCRIBING INFORMATION

Please refer to the Summary of Product Characteristics (SmPC) before prescribing MYLOTARG 5 mg powder for concentrate for solution for infusion. Presentation: Each vial contains 5 mg gemtuzumab ozogamicin. After reconstitution the concentrated solution contains 1 mg/ mL gemtuzumab ozogamicin. Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the CD33-directed recombinant monoclonal antibody humanized hP67.6; recombinant humanised immunoglobulin [Ig] G4, kappa antibody covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin. Indications: MYLOTARG is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients aged 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL). Dosage: Administer under the supervision of a physician experienced in the use of cancer therapy and in an environment where full resuscitation facilities are immediately available. MYLOTARG should be used only in patients eligible to receive intensive induction chemotherapy. The recommended induction dose of MYLOTARG is 3 mg/m2/dose (up to a maximum of one 5 mg vial) infused over a 2 hour period on Days 1, 4, and 7 in combination with DNR 60 mg/m2/day infused over 30 minutes on Day 1 to Day 3, and AraC 200 mg/m2/day by continuous infusion on Day 1 to Day 7. If a second induction is required, DNR should be infused at a dose of 35 mg/m2/ day on Day 1 to Day 2 and AraC at a dose of 1 g/ m2/every 12 hours on Day 1 to Day 3. MYLOTARG should not be administered during a second induction. For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts in a normocellular marrow and an absolute neutrophil count (ANC) of more than 1.0 × 109 cells/L with a platelet count of 100 × 109/L or more in the peripheral blood in the absence of transfusion, up to 2 consolidation courses of intravenous DNR (60 mg/m2 for 1 day [first course] or 2 days [second course]) in combination with intravenous AraC (1 g/m2 every 12 hours, infused over 2 hours on Day 1 to Day 4) with intravenous MYLOTARG (3 mg/m2/dose infused over 2 hours up to a maximum dose of one 5 mg vial on Day 1) are recommended. Dose modification of MYLOTARG may be required based on individual safety and tolerability. Management of some adverse drug reactions may require dosing interruptions and/or dose reductions, or permanent discontinuation of MYLOTARG. See SmPC for dose modification guidelines for haematological and non haematological toxicities. Special populations: Hepatic impairment: No adjustment of the starting dose is required in patients with hepatic impairment defined by total bilirubin ≤ 2 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN. Postpone MYLOTARG until recovery of total bilirubin to ≤ 2 × ULN and AST and ALT to ≤ 2.5 × ULN prior to each dose. Renal impairment MYLOTARG has not been studied in patients with severe renal impairment. Paediatric population: The safety and efficacy of MYLOTARG in patients less than 15 years has not been established. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Premedication with acorticosteroid, antihistamine and acetaminophen (or paracetamol) is recommended 1 hour prior to MYLOTARG dosing due to the potential for infusion related reactions. In patients with hyperleukocytic AML, leukoreduction should be considered with hydroxyurea or leukapheresis to reduce the peripheral WBC count to below 30,000/mm3 prior to administration of MYLOTARG to reduce the risk of inducing tumour lysis syndrome. Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such as hydration, administration of antihyperuricemics (e.g., allopurinol) or other agents for treatment of hyperuricaemia (e.g., rasburicase) must be taken. Hepatotoxicity: Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic failure and VOD/SOS have been reported in patients treated with MYLOTARG. Adult patients who received MYLOTARG as monotherapy, either before or after a haematopoietic stem cell transplant (HSCT), and patients with moderate or severe hepatic impairment are at increased risk for developing VOD. Signs and symptoms of VOD/SOS should be monitored closely in all patients. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, close monitoring of liver tests is recommended during the post-HSCT period, as appropriate. Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of MYLOTARG (see section 4.2). In patients who experience VOD/SOS, MYLOTARG should be discontinued and patients treated according to standard medical practice. Myelosuppression/cytopenias: Neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some life-threatening and some with complications, were reported. Blood counts should be monitored prior to dosing and signs of myelosuppression should be monitored during treatment. Infusion related reactions: Infusion should be interrupted immediately for patients who develop evidence of severe reactions, especially dyspnoea, bronchospasm, or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of treatment should be strongly considered for patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension. The efficacy of MYLOTARG has been shown in AML patients with favourable- and intermediate-risk cytogenetics, with uncertainty regarding the size of the effect in patients with adverse cytogenetics (see smPC section 5.1). For patients being treated with MYLOTARG in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, when cytogenetics testing results become available it should be considered whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks for the individual patient (see smPC section 5.1) Fertility, pregnancy and lactation: Women of childbearing potential receiving this medicinal product, or treated male partners should use effective contraception during therapy and for at least 7 months or 4 months after completing therapy for females and males, respectively. There are no or limited amount of data from the use of MYLOTARG in pregnant women. Non-clinical studies have shown reproductive toxicity. MYLOTARG must not be used during pregnancy unless the potential benefit to the mother outweighs the potential risks. The potential hazard to the foetus of MYLOTARG treatment must be explained to pregnant women, patients becoming pregnant while receiving treatment, or treated male partners of pregnant women. Because of the potential for adverse reactions in breast-fed children, women must not breast-feed during treatment with MYLOTARG and for at least 1month after the final dose. Based on non-clinical findings, male and female fertility may be compromised by treatment with MYLOTARG. Driving and operating machinery: MYLOTARG may cause fatigue and patients should exercise caution when driving or using machines. Undesirable effects: The overall safety profile of MYLOTARG is based on data from patients with acute myeloid leukaemia from the combination therapy study ALFA-0701, monotherapy studies, and from post-marketing experience. In the combination therapy study, safety data consisting of selected treatment emergent adverse events (TEAEs) considered most important for understanding the safety profile of MYLOTARG consisted of all grades haemorrhages, all grades VOD, and severe infections. The most common adverse reactions (> 30%) in the combination therapy study were haemorrhage and infection. In patients who received MYLOTARG in the combination therapy study ALFA-0701, clinically relevant serious adverse reactions were hepatoxicity including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and tumour lysis syndrome (1.5%). See relevant SmPC (Table 5) for full details on specific comprehensive list of AEs for combination therapy.

Instructions for reconstitution and dilution:

Use appropriate aseptic technique for the reconstitution and dilution procedures. Following reconstitution and dilution, the solution should be protected from light and should be used immediately. If the product cannot be used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C–8°C) from the time of initial vial puncture with not more than 6 hours at room temperature (below 25°C). Legal Category: S1A. Marketing Authorisation Number: EU/1/18/1277/001 – 5mg 1 vial. The Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500. ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions. Last revised: 11/2020 Ref: ML 4_0

References

1. Pfizer MYLOTARG™ (gemtuzumab ozogamicin) Summary of Product Characteristics. 2. Pfizer Cytarabine Summary of Product Characteristics. *RFS is a secondary endpoint. Only EFS and RFS achieved significance in the ALFA-0701 study.1 AML, acute myeloid leukaemia; APL, acute promyelocytic leukaemia; AraC, Cytarabine; DNR, Daunorubicin; EFS, event-free survival; RFS, relapse-free survival.

PEER REVIEW: BREAST CANCER

for its aggressive biology and poorer outcomes in comparison to hormone sensitive breast cancer. Targeting HER2+ breast cancer has dramatically changed the natural history of this disease and is no longer associated with the dismal outcome of the past.

Identifying HER2 as an oncogene

The discovery of the protooncogene HER2 as a driver of cancer, is a prime example of how this sparked a revolution in the management of cancers which overexpress this protein. It highlights the essential ecosystem that is bench to bedside/clinical research. Understanding this process is important for all health professionals and is critical to be able to evaluate and critically appraise trial results.

Finding the Receptor: Cell signalling & Nomeclature

Neu refers to the oncogene that was isolated by Weinberg et al in rat neuroblastomas in 1984. It was noted to be similar in overall structure to EGF receptors. This was soon followed in 1985 by the cloning of the human neu counterpart by Ullrich’s group, which was called HER2 (Human E(GFR) Receptor 2) based on the similarity with EGFR receptor. ERBB2 refers to the gene across both human and rodent species. HER2 is one of the four members of the ERBB family of receptor tyrosine kinase inhibitors, which include EGFR (HER1), HER3 and HER4. HER2 mediates signalling pathways including PI3K/AKT/ mTOR and MAPK pathways, which regulate cellular processes of proliferation, motility and survival.

Discovering the role of HER2 in human cancer

In 1987, Dr Dennis Slamon, a physician/scientist at UCLA discovered that the HER2 gene was amplified in approximately 30% of breast cancers. This major breakthrough was achieved with the interrogation of tumour cells provided from a human breast cancer tumour bank rather than cell lines. The Slamon group furthermore, idenitifed HER2 as a prognositic biomarker showing that women with overpression of HER2 in their tumours had a more aggressive phenotype with a substantially worse progress. This provided strong evidence that HER2 was likely to play a role in driving tumorigenesis.

Defining HER2 positive breast cancer: IHC & ISH

Assessment of HER2 overexpression is with immunohistochemistry (IHC) and in situ hybridization (ISH) testing. Correct pathological assessment of HER2 status is of the utmost importance, as it is the sole predictive marker for response to HER2 directed therapy. Reporting of IHC and ISH results is in accordance with the updated 2018 ASCO/CAP guidelines. Since 2007, ASCO/CAP guidelines recommend initial assessment of HER2 status using IHC and a semi quantitative scoring system, followed by reflex ISH testing in all IHC score 2+ cases. Understanding the nuances of this testing has become even more important in the context of the recent DESTINY 04 trial publication. Prior to this trial, predictive HER status has been reported in a binary fashion (positive versus negative). DESTINY 04 results defined a new predictive group called HER2 low expression.

Hitting the bull’s-eye: HER2 as a predictive biomarker in breast cancer

Preclinical research by Drs' Shepard and Ullrich led to the development of HER2 mouse Current algorithm for defining monoclonal antibodies called ‘MoAb 4D5’ followed by the

HER2 humanised monoclonal antibody 4D5, now known as trastuzumab. In 2019, a New England of Medicine editorial by Professor + breast cancer* Current algorithm for defining Current algorithm for defining HER2+ breast cancer* HER testing by validated IHC assayHER2+ breast cancer*

Circumferential membrane staining that is complete, intense, and in >10% of tumour cells

Weak to moderate complete membrane staining observed in >10% of tumour cells

Incomplete membrane HER testing by validated IHC assay staining that is faint/barely perceptible and in >10% of tumour cells No staining is observed or Membrane staining that is incomplete and is faint/barely perceptible and in ≤10% of tumour cells

Circumferential membrane staining that is complete, intense, and in >10% of tumour cells IHC 3+ Positive

Weak to moderate complete membrane staining observed in >10% of tumour cells IHC 2+ Equivocal

Incomplete membrane staining that is faint/barely perceptible and in >10% of tumour cells IHC 1+ Negative

No staining is observed or

Membrane staining that is incomplete and is faint/barely perceptible and in ≤10% of tumour cells IHC 0 Negative

IHC 3+ Positive

IHC 2+ Equivocal

Must order reflex ISH testing

Must order reflex ISH testing

IHC 1+ Negative

IHC 0 Negative

ISH Positive HER2 Positive

ISH negative HER2 Negative

* Adapted from ASCO/CAP 2018 guidelines

Classes of HER2 Targeted Therapy

Monoclonal Monoclonal antibodies

antibodies Trastuzumab* Trastuzumab* (Herceptin & other (Herceptin & other brand names) brand names) Pertuzumab* Pertuzumab (Perjeta) * (Perjeta)

Margetuximab Margetuximab (Margenza) (Margenza)

Antibody drug Antibody drug conjugates (ADC)

conjugates (ADC) Ado-trastuzumab Ado-trastuzumabemtansine * emtansine (Kadcyla) * (Kadcyla)Fam-trastuzumab Fam-trastuzumabderuxtecan deruxtecan (Enhertu) (Enhertu)

Daniel Hayes stated – “the terms

‘game changer’ and ‘blockbuster’ are worn, but in this case the ingenuity, vision and persistence of these collaborators justify

these superlatives.” In 2019, Drs’ Slamon, Shepard and Ullrich were awarded the prestigious Lasker DeBakey Clinical Medical Research Award for their invention of Herceptin. The discovery of trastuzumab led to a flurry of clinical trials which demonstrated not only its dramatic benefit in the advanced setting but also in the neo/adjuvant setting. For instance, the HERA trial reported in 2005, showed the addition of adjuvant Herceptin in HER2+ breast cancers halved the risk of cancer returning when it was added to chemotherapy. Irish patients had the benefit of participating in this trial ensuring they had the earliest access to treatment which ultimately proved to dramatically improve survival. There is no better example of how access to clinical trials can be truly life changing for patients. Since those initial studies, the treatment landscape for HER2+ positive breast cancer has exploded, with 3 classes of HER2 targeted therapy now available.

Beyond HER2+ Breast Cancer:

In 2009, the TOGA (Trastuzumab for Gastric Cancer) Trial, showed a benefit of trastuzumab beyond breast cancer. The results of this phase III trial led to approval of trastuzumab for patients with HER2+ metastatic gastric or gastroesophageal cancer. HER2 also represents a potential opportunity for seeking tissue agnostic approval. These umbrella trials or basket trials enroll patients based on the genetic biomarkers of their tumours as determined with genomic sequencing, regardless of the pathological tissue of origin. Examples of these trials include the TAPUR (Targeted Agent and Profiling Utilisation Registry), MATCH and MyPathway.

Tyrosine kinase Tyrosine kinase inhibitors (TKI)

inhibitors (TKI) Lapatinib (Tykerb)* Lapatinib (Tykerb)*

Neratinib Neratinib (Nerlynx)* (Nerlynx)* Tucatinib (Tukysa) Tucatinib (Tukysa)

* Reimbursed by NCCP

2022 – HER2+ Low Breast Cancer: A new predictive biomarker & treatment paradigm

DESTINY 04 results which were presented at the plenary session at the annual ASCO congress in June 2022 were met with rapturous standing ovation by the packed audience. It is the first randomized trial to demonstrate that targeting HER2 for patients with metastatic HER2-low (IHC 1+ or IHC2+ and ISH negative) breast cancer had meaningful benefit. This phase three randomised trial, demonstrated that heavily pre-treated patients with advanced HER2 low expressing breast cancers as defined by conventional HER2 testing (previously defined as HER2 negative) had a 50% reduction in the risk of disease progression or death when treated with trastuzumab-deruxtecan as compared with treatment of physicians choice. With approximately 60% of HER2 negative breast cancers assessing low levels of HER2 expression; this represents a significant advancement for a large cohort

of patients. Further refinement and discussion regarding inter pathological variability in detecting HER2 low (IHC 1+) will be of even greater importance given this new therapeutic option, in addition to assessing risks and management of treatment related toxicities including pneumonitis. Clinical trials are integral to providing the very best care for patients. One in two people will develop cancer in their lifetime. It is imperative that we strive to cure * Reimbursed by NCCP as many people as possible. This can only be achieved with access to high quality clinical trials that is embedded in health care planning. Proposed algorithm for defining

HER2*See www.cancertrials.ie for more information. low breast cancer*

References available upon request

Proposed algorithm for defining HER2-low breast cancer*

HER testing by validated IHC assay

IHC 3+ POSITIVE

IHC 2+ Equivocal

IHC 1+ Negative

IHC 0 Negative

HER2 POSITIVE

ISH Positive HER2 POSTIVE ISH negative HER2 LOW HER2 LOW HER2 NEGATIVE

*Adapted from Tarantino et al. JCO 2020

HER 2+ Therapeutic Trials Open in Ireland (as of 1st July 2022)*

DESTINY- 12

• Disease site: breast • Indication: previously treated advanced HER2+ breast cancer, whose disease has progressed on prior HER2 based regimens • Phase: 3b/4, open-label, single arm • IMP: trastuzumab deruxtecan

DESTINY-05

• Disease site: breast • Indication: HER2+ primary breast cancer that do not achieve a complete pathological response after neoadjuvant chemotherapy and are at high risk of recurrence • Phase: 3, randomised, open label, active controlled study • IMP: trastuzumab deruxtecan vs trastuzumab emtansine

DESTINY DS8201-A-U306

• Disease site: Upper GI • Indication: HER2+ metastatic/and or unresectable gastric or GEJ cancer • Phase: 3, randomised, 2 arm, open label • IMP: trastuzumab deruxtecan vs ramucirumab + paclitaxel