Ahmad Tarhini, MD, PhD, on Ipilimumab and High-Dose IF in High-Risk Melanoma

First evidence that adjuvant low-dose ipi3 extended overall survival vs standard-of-care high-dose interferon

  • by Mark L. Fuerst
    Contributing Writer, MedPage Today

    Medpage Today

Recent advances have greatly improved the outcomes for patients with unresectable metastatic melanoma: for example, phase III adjuvant trials have reported benefits in relapse-free survival (RFS) with six FDA-approved regimens and in overall survival (OS) with use of high-dose interferon alfa-2b and ipilimumab at 10 mg/kg (ipi10), which was approved as adjuvant therapy for stage III melanoma in 2015. The significant risk of immune-related toxicities has limited the use of ipi10 as adjuvant therapy; for unresectable metastatic melanoma, ipilimumab at 3 mg/kg (ipi3) was FDA approved in 2011.

Now, the Intergroup trial E1609, led by Ahmad A. Tarhini, MD, PhD, director of Cutaneous Clinical and Translational Research at Moffitt Cancer Center in Tampa, Florida, and published in the Journal of Clinical Oncology, compared the relative safety and efficacy of ipilimumab at the two dose levels versus high-dose interferon (HDI).

In the following interview, Tarhini elaborated on the team's findings.

What does your study add to the literature about the role of adjuvant ipilimumab for high-risk melanoma?

Tarhini: This is the first time a study has shown that ipilimumab improved OS against an active control regimen. Adjuvant ipi3 had significant OS versus HDI, which has been the standard of care since 1995. Ipi10 was more toxic and not superior to HDI or ipi3. HDI is no longer an acceptable form of therapy for high-risk melanoma; ipi3 may represent an option for patients who have progressed on adjuvant anti-programmed death-1 (PD-1) therapy and still have resectable disease.

Were there any surprises?

Tarhini: This is the largest adjuvant trial in melanoma, which was conducted at 850 sites across the U.S. and Canada -- a North American effort that demonstrates significant improvement in OS with an immune checkpoint inhibitor against an active regimen. Surprisingly, OS and RFS with ipi10 was not superior to HDI. The increased toxicity with ipi10 may have affected efficacy. Patients had less treatment exposure to ipi10 and higher discontinuation rates compared with ipi3.

A smaller percentage of patients received any salvage therapy after ipi10 compared with the other two arms. If we consider the salvage use of anti-PD-1, anti-PD-1 ligand, BRAF inhibitors, MEK inhibitors, ipilimumab, and combinations of these agents, the overall post-recurrence use was 69.7% after ipi3, 86.2% after HDI, and 51.6% after ipi10. Again, toxicity could have inhibited the ability for salvage therapy.

Why does ipi3 seem to lead to more durable results, leading to survival benefit?

Tarhini: Ipi3 improved survival in stage IV melanoma, which prompted us to test ipi3 and ipi10 in the adjuvant setting. We felt the benefit of ipi3 may derive from less toxicity. It was important to evaluate the two doses, and our hypothesis was proved correct.

How does the toxicity of these regimens in the adjuvant setting compare with the metastatic setting?

Tarhini: There is more toxicity in the adjuvant setting, which may be due to a more active immune response and therefore a more sustainable response to immunotherapy interventions. Immune-related adverse events are related to the activity of the drugs, which leads to a higher rate of immune toxicity.

For which patients would you recommend ipi3, and what about the other regimens?

Tarhini: The standard of care is an anti-PD-1 agent, pembrolizumab or ipilimumab, as adjuvant therapy. If the patient is BRAF-mutated, then the clinician could use a BRAF-MET inhibitor combination. I would choose ipi3 over ipi10 for those who have received prior anti-PD-1 therapy and have progressed and remain resectable.

What is the next step in this research?

Tarhini: This study has given us a trove of data. At the 2020 ASCO-Society for Immunotherapy of Cancer Clinical Immuno-Oncology Symposium, we presented data that showed an association between the development of autoimmune toxicity and survival benefit. We are looking for biomarkers to predict clinical benefit and the risk of toxicity. At the 2020 ASCO Virtual Scientific Program we will present a quality-of-life analysis based on the data.

What is the take-home message for practicing oncologists?

Tarhini: Ipi3 has demonstrated an OS advantage in the adjuvant setting compared with an active control, HDI. For patients who have failed on anti-PD-1 therapy and have resectable disease, ipi3 has an advantage over ipi10.

Read the study abstract here and expert commentary about the clinical implications here.

Tarhini reported consulting/advisory roles with Bristol-Myers Squibb (BMS), Merck, Genentech/Roche, Incyte, Newlink Genetics, Array BioPharma, Novartis, OncoSec, HUYA Bioscience, Immunocore, Pfizer/EMD Serono, Sanofi/Regeneron, and BioNTech; and institutional research funding from Incyte, Prometheus Laboratories, BMS, Amgen, Incyte, Novartis, GreenPeptide, and Merck.