The Holmium Platform: Three integrated products delivering individualised SIRT at its full potential

December 2021 | Educational Supplement

interventionalnews.com

This educational supplement has been sponsored by Terumo Interventional Systems

Introduction to technology Contents:

2 I ntroduction to technology

3 The setup

4-5 C urrent trials and future directions

Introduction to The Holmium Platform

Selective internal radiation therapy (SIRT) is a loco-regional therapy, which is currently recommended by the international guidelines for selected patients with primary and secondary unresectable liver diseases: hepatocellular carcinoma (HCC), metastatic colorectal cancer (mCRC) in the liver and metastatic neuroendocrine tumours (mNET) in the liver.

THE HOLMIUM PLATFORM (166Ho-SIRT) fits with the paradigm shift from a one-size-fits-all towards a patientspecific and therefore individualised approach to SIRT. Dose-to-tumour and dose-to-healthy-tissue (dosimetry) are key concepts for tailoring the therapy to a specific patient’s tumour characteristics.

The Holmium Platform is an end-toend comprehensive SIRT platform, which allows for individualised dosimetry by using an innovative scout dose (QuiremScout™ Holmium-166 Microspheres) for the pretreatment diagnostic or "work-up"

procedure, and a treatment planning and dose verification software (Q-Suite™ Imaging Software). This is the first fully integrated and individualised SIRT platform, which is currently available in the field of SIRT. QuiremScout is the first SIRT work-up product utilising the same particle (polyL-lactic acid microspheres loaded with 166 Ho) as the therapeutic microspheres (QuiremSpheres™ Holmium-166 Microspheres).

The isotope 166Ho-SIRT has unique imaging capabilities. It emits gamma radiation and has paramagnetic properties, and can therefore Dose simulation & planning can be performed with accuracy using a dedicated software

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6-7 Clinical

roadmap

be used to perform visualisation and dose quantification using single photon emission computed tomography (SPECT) and/or high-resolution magnetic resonance (MR) imaging and reconstructions. In addition, 166 Ho-SIRT is a beta emitter with a high initial dose rate (90% of radiotherapy dose delivered within four days). One reported case experience saw a rapid clinical response, which the investigators attributed to this higher dose rate.1 Published clinical data have demonstrated that QuiremScout (Holmium-166 Microspheres) is a safe2 and effective3 work-up product. Not only is it a safe alternative to the currently used 99m-technetium macroaggregates, it also predicts dose distribution to the lungs and within the liver (tumour vs. normal liver tissue) more accurately, enabling better SIRT patient selection.3 Using Q-Suite Imaging Software, a fully integrated 166Ho-SIRT dosimetry software, each treatment can then be planned based on the 166Ho scout dose (Holmium-166 Microspheres) distribution by considering patient-specific tumour characteristics. This enables clinicians to make an informed patient selection decision regarding whether SIRT will be safe prior to performing the procedure. In addition, this dosimetry software also allows for an accurate posttreatment dose verification based on SPECT and/or MR imaging.

References: 1. Depalo, T., Boni, G., Ghinolfi, D. et al. Potential benefits of 166 Ho-SIRT radioembolization as a neoadjuvant treatment of intrahepatic cholangiocarcinoma. Cardiovasc Intervent Radiol.

2021 Feb;44(2):345–7.

2. Braat, A., Prince, J., van Rooij, R. et al. Safety analysis of 166Ho-SIRT microsphere scout dose imaging during radioembolization work-up: A cohort study. Eur Radiol. 2018 Mar;28(3):920–8.

3. Chiesa, C., Maccauro, M. 166Ho-SIRT microsphere scout dose for more accurate radioembolization treatment planning. Eur J Nucl Med Mol Imaging. 47, 744–7 (2020).

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The setup

The Holmium Platform

Multidisciplinary teams and seamless implementation aid adoption of The Holmium Platform Ana Oliveira (Centro Hospitalar Universitário de São João, Porto, Portugal) discusses her experience setting up and using The Holmium Platform to treat patients with liver tumours.

WE EMBARKED ON OUR ADOPTION of The Holmium Platform by initially discussing the selection of the first patients with our tumour board at Centro Hospitalar Universitário de São João. In this conversation, we focused on presenting Holmium microspheres’ unique capabilities during the evaluation of unresectable liver tumours.

Specifically, we outlined the role this technology can play in relation to its direct alternatives, highlighting the possibility of expanding the therapy to patients who had previously been considered ineligible for selective internal radiation therapy (SIRT) due to their high lung-shunt values. We also decided to refer patients in whom an excessive lung shunt would be expected—for example, those with voluminous tumours.

A paradigmatic case of ours was a patient who had been diagnosed with cholangiocarcinoma and whose calculated lung shunt with macroaggregated albuminTc-99m (99m-Tc-MAA) was approximately 30%. She was therefore not a SIRT candidate.

As there were no other therapeutic options, we decided to evaluate her with the 166Ho-

Holmium is highly paramagnetic and can be visualised with high-resolution MRI

Ho decays under emission of beta radiation and a primary gamma photon (81 keV) 166

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SIRT scout dose, which revealed a lung shunt of under 10%, allowing us to proceed with treating her.

Ease of implementation

We have more than 10 years of experience using SIRT with the same dedicated team, so it was fairly easy for us to implement this technique. An important consideration was the fact that the internal procedures regarding patient stay and radiation safety— during the work-up with QuiremScout (Holmium-166 Microspheres) and treatment via QuiremSpheres (Holmium-166 Microspheres)—were the same as those with SIRT procedures using Yttrium-90 (Y-90) microspheres.

Notwithstanding, Terumo gave us all the support we needed throughout, and since, our adoption of this technology. This began with an initial training period in Utrecht, The Netherlands. Then, before starting the technique and for the first procedures, there was onsite medical, technical and IT support—which included calibrating the equipment, selecting the patients, calculating the doses, and administering the spheres.

Since then, there has been continuous online assistance on request as well.

Setting up for success

In terms of the ideal setup for performing the first cases using The Holmium Platform, in our opinion, there should be a multidisciplinary team designed to evaluate patients and select the right candidate for SIRT. In our hospital, this includes surgery, gastroenterology, oncology, radio-oncology, radiology, interventional radiology, nuclear medicine, and pathology.

Treatment-wise, there should also be a team dedicated to performing the therapeutic procedures—including radiology, interventional radiology, nuclear medicine, and medical physics. It is this team that makes all the key decisions on administering the treatment. Logistically, the Nuclear Medicine Department had to obtain a licence for using 166Ho, which took us about one month.

Finally, we would like to highlight the training period and all the subsequent support from the Quirem specialist, which is particularly important when using the Q-Suite Imaging Software application and calculating the doses.

Ana Oliveira

Isotope

166

Ho

Yttrium-90

Beta radiation (MeV)

1.77 (48.7%) / 1.85 (50.0%)

2.28

Gamma radiation (keV)

81 (6.7%)

–

Visible on MRI

Yes

No

Half-life (h)

26.8

64.1

Material

PLLA

Resin (r)

Glass (g)

Diameter (µm)

25-35

r:20-60

g:15-30

Density (g/cm3)

1.4

r:1.6

g:3.3

Work-up product

“Scout” Holmium-166 microspheres

99mTc-MAA (protein)

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Current trials and future directions

The iHEPAR study: A key step forward in HCC treatment

Irene Bargellini (Pisa University Hospital, Pisa, Italy) outlines the intentions of the iHEPAR study, which will assess the use of personalised dosimetry via The Holmium Platform to treat patients with hepatocellular carcinoma (HCC), and the impact its results may have on how this disease is treated in the future.

Could you please briefly explain the design, setup and primary objectives of the iHEPAR study for treatment of HCC Irene Bargellini with The Holmium Platform?

The iHEPAR study is a multicentre, nonrandomised, open-label study assessing the potential of personalised dosimetry in patients with HCC, who are excluded from curative treatments, using The Holmium Platform. The study will enrol 30 patients from University Medical Centre (UMC) Utrecht and Erasmus MC Rotterdam in The Netherlands, and Pisa University Hospital in Italy. The primary endpoint will be safety of this personalised approach, expressed as the rate of unacceptable toxicity. Besides this, there are a number of secondary endpoints— including the evaluation of radiological and biochemical tumour response, and impact on liver function and quality of life.

Compared to previous studies investigating the outcomes of personalised dosimetry in HCC, this study has the advantage of working with The Holmium Platform. That means using Holmium Scout Dose for dosimetry planning, which has been demonstrated to be more accurate and reproducible compared to

the standard planning using Tc99m-labelled macroaggregated albumin (MAA). This means that the results could be more reliable and reproducible when assessing dosimetry to the tumour, as well as to the surrounding healthy liver.

Why is individualised dosimetry important in HCC, and why is this study essential for potential improvement of HCC treatment with SIRT? Over the past few years, we have learned that accurate and personalised dosimetry has a strong impact on the outcome of SIRT in both primary and secondary liver tumours, and that one of the main reasons for failure of previous large randomised studies investigating the role of selective internal radiation therapy (SIRT) in intermediate-to-advanced HCC was poor dosimetry. The recent DOSISPHERE study using MAA and glass microspheres has shown impressive differences in response and survival when comparing patients treated with standardised versus personalised dosimetry.

As such, these studies are absolutely necessary to improve SIRT outcomes as a first step to re-evaluate the role of SIRT in different stages of HCC disease—including early stage as curative intent, intermediate stage for downstaging, advanced stage for improvement of survival, and quality of life.

Combining Holmium-166 SIRT and immunotherapy with the HOLM-Brave study By combining established immunotherapy with The Holmium Platform, the upcoming HOLM-Brave study will set out to evaluate the use of individualised selective internal radiation therapy (SIRT) in the treatment of hepatocellular carcinoma (HCC). Principal investigator Lambros Tselikas and Thierry De Baere (Institut Gustave Roussy Cancer Campus, Villejuif, France) discuss the importance of the study in establishing the role this novel approach can play moving forward.

Could you please briefly explain the design and primary objectives of this study?

This is a very ambitious study aiming to bring together the best from both the

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interventional oncology and immunooncology worlds for patients with nonresectable HCC. The design is very simple.

It is a single-arm, multicentre, phase II

More specifically, how can the results of the iHEPAR study make a significant impact to SIRT treatment in HCC? Holmium radioembolization is the new kid on the block and dosimetry studies with it are currently lacking. However, 166Ho-SIRT microspheres have some peculiar features that make them highly appealing as a means to improve SIRT results. The aforementioned Holmium Scout Dose represents a step forward in radioembolization planning, while the 166Ho radionuclide has some specific features—for instance, faster decay compared to Yttrium-90—that could potentially allow for faster tumour response. All this needs to be investigated, and could impact the chance for controlling, downstaging and curing the tumour using SIRT in HCC patients.

How may the results change the treatment landscape for HCC? This study is focused on the safety of personalised dosimetry. It would represent the first step for future randomised studies reassessing the role of SIRT as a monotherapy or in combination with systemic treatments, in comparison with other treatment options in different stages of the disease. In fact, in clinical practice, we acknowledge the value of SIRT as a safe, well-tolerated, affordable and efficient treatment modality, but past mistakes have not allowed us to receive the same recognition in most of the international guidelines. We have learned that, to succeed with SIRT, we need to have an in-depth knowledge of clinical indications and contraindications, technique and dosimetry.

This study represents an essential step for the future of Holmium SIRT in the complex landscape of HCC.

study evaluating the added value of The Holmium Platform to the standard of care—atezolizumab in combination with bevacizumab—for this population of patients with advanced HCC. We are convinced that The Holmium Platform will allow for customised SIRT and, as such, the primary endpoint is to obtain a 50% objective response rate at six months, without significantly increasing the treatment-related adverse events.

Could you comment on patient selection for this combination therapy?

The targeted population is very similar to that of the IMbrave150 study. Liver function should be preserved, active intra-hepatic HCC should be present, and sufficient liver remnant should be available. Furthermore, December 2021

The Holmium Platform

The CAIRO7 study: Positive results may trigger shift in mCRC standard of care The CAIRO7 study of the Dutch Colorectal Cancer Group (DCCG) will assess the treatment of metastatic colorectal cancer (mCRC) using The Holmium Platform, and could help to shed more light on the role radioembolization can play in treating fragile or elderly mCRC patients with liver-only metastases. Co-prinicipal investigator Kees Punt (Julius Center UMC Utrecht, Utrecht, The Netherlands) discusses the study and the wider implications its results may have.

What are your key considerations when treating a fragile or elderly patient with mCRC? In the case of elderly or fragile patients, who often have more comorbidities, intensive systemic treatment regimens or major surgery are usually not an option. As such, the standard, first-line treatment protocol for these patients is one chemotherapeutic drug—capecitabine—plus an antibody against the vascular endothelial growth factor (VEGF)—bevacizumab or a biosimilar. This has been shown in several prospective studies to be safe and effective.

The main consideration here is weighing up what you have to gain versus the possible downsides of this approach—with the latter including increased toxicity over time, leading to side-effects like hand-foot syndrome that negatively impact quality of life (QoL) and daily living in elderly patients especially, as well as a greater treatment burden due to regular hospital visits.

Could you briefly explain the design and primary objectives of the CAIRO7 study?

The CAIRO7 study will compare the

the pretreatment planning will allow selection of the patients to be included in the study.

Do you expect the combination of SIRT and immunotherapy to result in a greater benefit than that seen in each therapy separately?

There are many reasons to be enthusiastic and expect synergy between these two therapies. First of all, one could palliate to the insufficiencies of the other. Holmium has proved to be highly effective for intra-hepatic disease, while immunotherapy may face challenges in bulky liver disease—including portal vein invasion. On the other hand, atezolizumab plus bevacizumab will allow the Thierry De Baere

December 2021

outcomes of a control group, in which patients receive the standard treatment, with an experimental arm using radioembolization as a single treatment modality. We were quite certain that a formal, prospective, noninferiority phase III study would not be feasible, as it would require too many patients, so we designed a multicentre, comparative, open-label, randomised phase II study.

We are enrolling 220 elderly and/or fragile patients with liver-limited, unresectable mCRC within the DCCG network.

These patients will be followed up with computed tomography (CT) scans and QoL questionnaires. The primary endpoint of CAIRO7—and the best endpoint to reflect the efficacy of a first-line treatment such as this—is progression-free survival (PFS).

We aim to demonstrate that this outcome falls within the range of the 95% confidence interval of PFS that has been observed in previous prospective studies of capecitabine plus anti-VEGF as a first-line treatment. A control arm is included to prevent selection bias. The secondary endpoints are safety/ toxicity, cost-effectiveness, QoL and overall survival.

control of extra-hepatic disease, if it is present.

Furthermore, preclinical data and early clinical data support the immune-stimulating potential of SIRT by enhancing the presentation of tumour antigens, and inducing both local and systemic immune activation.

Why is this study essential in establishing potential future therapies?

This study is crucial as it will help to position SIRT, performed with optimal dosimetry, for this specific population. What is also very important is the translational research programme that was built on this study, which will, hopefully, bring a lot of answers on the mechanisms of action of this novel combination—and may even highlight some biomarkers to better predict patient outcomes, and then improve treatment allocation.

How do you expect The Holmium Platform to contribute to the preservation of QoL and safety in this fragile patient category?

Kees Punt What we hope to demonstrate is that this single, first-line radioembolization approach is at least as effective in terms of PFS, but is also associated with less toxicity, lower costs and a better QoL with fewer hospital visits compared to the standard of care.

With The Holmium Platform, you have the advantage over Yttrium radioembolization of being able to use a pre-treatment scouting dose in order to see exactly how these microspheres are distributing in the liver, which may vary considerably between patients. This scouting dose allows calculation of the optimal treatment dose per individual patient.

If the results are positive, what worldwide impact could they have to further optimise treatments for this subgroup of mCRC patients?

Radioembolization has been shown to be a safe procedure but, as a single modality, has only been studied in late-line treatment. In first-line treatment, it has only been tested in combination with combination chemotherapy.

So, using radioembolization as a single, firstline treatment is quite novel in this space.

We have to prove it in the CAIRO7 trial but, based on published data, we are quite confident that this will result in a better QoL for patients compared to standard treatments. And, if the trial’s results do find non-inferiority in terms of PFS, I think that Holmium radioembolization should be considered as the preferred firstline treatment in this group of patients.

What insights will this study bring us?

If this study is positive—although a randomised controlled trial will probably be needed—it will pave the way to the new standard as a first-line treatment for advanced/nonresectable HCC patients, and interventional oncology will be part of it as well.

What are the next steps in combining SIRT with immunotherapy?

Many future directions are foreseen. Other populations could be targeted, namely stage B patients on the Barcelona Clinic Liver Cancer (BCLC) system. Other systemic regimens (immunotherapy combinations like anti-CTLA4 antibodies with anti-PD-L1 +/- targeted therapies) could be evaluated, as well as novel administration routes for the immunotherapy drug itself.

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Clinical roadmap Evidence generation roadmap of The Holmium Platform

Phase II=HEPAR PLuS N=30 pts Safety and effectiveness in bulky liver disease after PRRT

Published evidence:

Phase II: HEPAR II / N=38 pts / Efficacy and safety

mNET (1) • Safe and effective after PRRT at three months (N=30) • Tumour response (CR+PR) 43% at three months and 47% at six months • Disease control (CR+PR+SD): 93% • 77% of symptomatic patients improve the symptomatology related to mNET

Ho-SIRT for liver metastases

166

Future directions:

CAIRO7 Can Ho-SIRT delay first-line chemotherapy in fragile mCRC patients?

166

TARE in LMBC (in design phase) Adding 166Ho-SIRT to systemic therapy in liver metastatic breast cancer

Liver metastases (2, 3) • 60 Gy whole-liver absorbed dose (N=15) • Safe and effective at three months (N=38) • 73% disease control

Improved dosimetry and individualised 166Ho-SIRT iHEPAR Validation of dosimetry with QuiremScout Holmium-166 Microspheres, move away from 'one size fits all' approach

Ho-SIRT evidence generation

166

Patients have been treated with 166Ho-SIRT in the framework of clinical trials for almost a decade, with early studies conducted at Utrecht University in The Netherlands. Currently, four clinical trials with 166Ho-SIRT have been completed: a phase I safety study (HEPAR I),2 a phase II efficacy study (HEPAR II),3 a phase I/II safety and efficacy study in liver metastatic disease from neuroendocrine tumours (HEPAR PluS),1 and a phase I/II study in patients with HCC (HEPAR Primary).

THE HEPAR I AND HEPAR II STUDIES correspondingly assessed safety and efficacy and toxicity of 166Ho-SIRT in patients with unresectable liver metastases who had chemotherapy refractory disease or were unable to undergo systemic treatment.2,3 In the HEPAR PLuS study, 166Ho-SIRT was used in patients with neuroendocrine tumour

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Phase II: SIM N=24 Improving T/N activity concentration ratio

Phase I: HEPAR I / N=15 pts / Dose escalation

liver metastases who underwent four cycles of PRRT, with tumour response rate at three months being the primary outcome. In general, the results obtained in these studies demonstrated that 166Ho-SIRT had good safety and efficacy outcomes in the included patients and encouraged further research.

The recently completed phase I/II study

RETOUCH Individualised dosimetry, high tumour dose treatment

conducted by the investigators at University Medical Centre (UMC) Utrecht in The Netherlands, HEPAR Primary, evaluated 166 Ho-SIRT for treatment of patients with HCC. The results were available for a total of 31 patients (BCLC stage B and C, 87% with multifocal disease, and with the largest tumour diameter ranging from 15mm to 195mm). The study was focused on treatment toxicity in these patients and demonstrated promising outcomes, with unacceptable toxicity related to study treatment recorded in three patients (one case of cholangitis and two cases of bacterial peritonitis). No cases of REILD (total bilirubin increase grade 3 or higher in combination with ascites and low albumin) were reported. New or worsened toxicity was mostly grade 1 and included December 2021

The Holmium Platform

Abbreviations: mNET = metastatic neuroendocrine tumour, HCC = hepatocellular carcinoma, PRRT = peptide receptor radionuclide therapy, T/N = tumour/non-tumour, CR = complete response, PR = partial response, SD = stable disease, MAA = macroaggregated albumin, OS = overall survival, mCRC = metastatic colorectal cancer, LMBC = liver metastasis from breast cancer, RFA = radiofrequency ablation.

mNET HEPAR Primary N=31 pts Safety and efficacy

Dosimetry and treatment planning studies

Mixed/other liver metastases All tumours HCC

Scout dose (4,5,6) • Safe alternative to 99mTc-MAA (N=86) • Reliable pretreatment imaging • It can lead to improved individualised treatment planning

HCC (7) • Median OS: 14.9 months • Safe and effective • Tumour response: CR+PR (mRECIST): 54% at three months and 84% at six months • Disease control (CR+PR+SD): 96% at three months

Ho-SIRT as adjuvant or in combination

166

HOLM-Brave Combination of 166 Ho-SIRT with immunotherapy for HCC

RALLY Phase I/II study to investigate use of 166 Ho-SIRT to downsize to resection, while maintaining tumour control

HORA EST I Treating hyperaemic area after RFA with 166Ho-SIRT to prevent recurrence

DISCLAIMER: Investigator-initiated studies TARE in LMBC, iHEPAR, RETOUCH, HOLM-Brave, RALLY are receiving grants from Terumo/Quirem Medical, while SIM, Primary and HORA EST have been supported by microspheres and/or financial support.

fatigue, back pain, ascites, dyspnoea, nausea, and abdominal pain.

The follow-up at three and six months showed complete or partial tumour response in target lesions in 54% and 84% of cases, respectively. Median overall survival was 14.9 months [95% confidence interval: 10.4 months; not reached]. Moreover, the study did not reveal any significant decline in quality of life. These encouraging first results, demonstrating safety of 166Ho-SIRT in patients with intermediate and advanced HCC, were first presented at ECIO 2021.

Future evidence generation for 166Ho-SIRT will be based on several planned and ongoing investigator-initiated studies (IISs). It includes evaluation of potential clinical benefits of 166 Ho-SIRT in patients with HCC or metastatic December 2021

liver disease, such as mCRC and metastatic breast cancer (mBC). An IIS in patients with mBC, which is currently in the design stage, intends to evaluate whether 166Ho-SIRT can improve outcomes when used in addition to systemic therapy. Several future studies will focus on improving the dosimetry and treatment planning with QuiremScout (Holmium-166 Microspheres) and establishing a truly individualised approach to patients with primary or metastatic disease. In recent years, a lot of emphasis has been placed on the potential combination of loco-regional treatments, including selective internal radiation therapy (SIRT), with immunotherapy to achieve a synergistic effect. Furthermore, the use of SIRT as a neo-adjuvant treatment before ablation or resection appears to be

promising. Such combination treatments will be evaluated in several planned and ongoing IISs with 166Ho-SIRT. The results of these studies will hopefully demonstrate the benefits of individualised 166Ho-SIRT treatment and make it available for a growing range of patients with primary and metastatic liver tumours.

References: 1. Braat et al. 2020. https://pubmed.ncbi.nlm.nih.gov/32112737/ 2. Smits et al. 2012 https://pubmed.ncbi.nlm.nih.gov/22920685/ 3. Prince et al. 2018 https://pubmed.ncbi.nlm.nih. gov/28916623/ 4. Smits et al. 2020 https://pubmed.ncbi.nlm.nih.gov/31399801/ 5. Braat et al. 2020 https://pubmed.ncbi.nlm.nih.gov/32112737/ 6. Chiesa et al. 2020 https://pubmed.ncbi.nlm.nih. gov/31875243/ 7. M.T. Reinders-Hut et al. Safety and efficacy of 166HoSIRT radioembolization in hepatocellular carcinoma: the HEPAR Primary study. ECIO2021 https://www.ecio.org/ wp-content/uploads/sites/2/2021/04/ECIO-2021-Book-ofAbstracts.pdf, manuscript submitted

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