Expert Point of View: Olivier Michielin, MS, MD, PhD

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The findings of the EORTC 18071 trial are a new landmark in our quest for the optimal treatment of melanoma in the adjuvant setting.
— Olivier Michielin, MS, MD, PhD

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The paper’s invited discussant was Olivier Michielin, MS, MD, PhD, Head of Personalized Analytical Oncology and the Melanoma Clinic at Lausanne University Hospital in Switzerland. He called the findings of the European Organisation for Research and Treatment (EORTC) 18071 trial a “new landmark in our quest for the optimal treatment of melanoma in the adjuvant setting” and commented on the lessons learned in terms of clinical and immunologic science.

Jeffrey Weber, MD, PhD, Deputy Director of the Laura and Isaac Perlmutter Cancer Center at New York University Langone Medical Center and a pioneer in checkpoint inhibitor therapy, also commented on these findings. In an interview with The ASCO Post, Dr. Weber said the results “reinforce the desire to use” ipilimumab as adjuvant therapy in a “risk-adapted” manner.

Shedding Light on Checkpoint Blockade

Dr. Michielin said that EORTC 18071 showed the benefit of cytotoxic T-lymphocyte–associated protein 4 (CTLA4) blockade observed in the metastatic setting can be translated into the adjuvant setting and that a T-cell response can be raised in the setting of residual disease. Unlike the metastatic setting, the adjuvant setting might not be marked by continuous antigen release, T-cell infiltration, and other hallmarks of immune activity, he pointed out.

If you are going to use adjuvant ipilimumab, give it in the right population and in a risk-adjusted manner.
— Jeffrey Weber, MD, PhD

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Efficacy in the setting of microscopic disease raises important questions: What is the exact nature of this residual disease? What are the relevant rejection antigens? What is the composition of the metastatic niche? What is the role of the PD-1/PD-L1 (programmed cell death protein 1/ligand 1) axis in the absence of T-cell infiltration?

“In this context, the activity of checkpoint blockade is more difficult to work out, and there are big questions to be answered. The trial today sheds important light,” Dr. Michielin said.

EORTC 18071 is but one of several important phase III adjuvant trials of single agents that will produce data within the next few years, including the following:

  • ECOG 1609 (n = 1,500): ipilimu­mab (Yervoy) at 10 mg/kg vs ipilimumab at 3 mg/kg in patients with stages IIIB/C and IV M1a/b disease. Accrual is completed.
  • CheckMate 238 (n = 800): ipilimumab at 10 mg/kg vs nivolumab (Opdivo) at 3 mg/kg in patients with stages IIIA–C disease. Accrual is completed.
  • EORTC 1325 (n = 900) in patients with stages IIIA–C disease: pembrolizumab (Keytruda) at 200 mg vs placebo. Accrual is ongoing.

“This constellation of trials will teach us a lot about treating melanoma in the adjuvant setting with checkpoint blockade,” Dr. Michielin predicted. In addition, smaller phase I/II trials are evaluating various doses and combinations of ipilimumab and nivolumab. Trials of neoadjuvant checkpoint blockade are also beginning to produce data, he added.

“All these [combinations] are now being moved into the adjuvant setting, and we are eagerly waiting to see how this landscape is going to evolve,” he commented.

More on Toxicity

Dr. Michielin also addressed the issue of ipilimumab toxicity, noting the profile is comparable to that seen with ipilimumab/nivolumab combination in the metastatic setting and the risk/benefit is actually similar to what has been accepted for some other treatments in other tumors. “The EORTC data, both in terms of absolute gain (11% difference in survival at year 5) and toxicity compare favorably to historical data in other disease types like lung cancer. The number needed to treat [for survival gain] is 9.1, vs 35 for interferon. This is a signature of the much higher efficacy of ipilimu­mab in this setting,” he offered. CTLA-4 inhibitors of the next generation are in development that could be more active or less toxic, he added.

Risk-Adjusted Use

Dr. Weber acknowledged that in spite of the proven efficacy of ipilimumab in preventing recurrences, toxicity can be an issue with the 10-mg/kg dose. “You are not going to put an 85-year-old with comorbidities on 10 mg/kg of adjuvant ipilimumab,” he admitted. “You are probably also not going to give this to a stage IIIA patient, who has an 80% chance of cure—the patient with 0.1-mm tumor in one lymph node with a thin nonulcerated primary and no mitoses.”

He continued: “But yes, you may treat the patient with multiple recurrences with multiple positive nodes and locally resected lesions. These are huge-risk patients. This is a risk-adjusted maneuver,” he added.

Dr. Weber agreed with Dr. ­Eggermont that the toxicity concerns are not resolved by using the lower dose of 3 mg/kg. “It’s not the labeled indication, and it’s not proven. We saw data at ESMO comparing these doses in the metastatic setting, and the hazard ratio was 0.82 favoring 10 mg/kg. It looks like we are better off giving the higher dose, and this will probably translate into the adjuvant setting, so I would not change the dose,” he said.

“If you are going to use adjuvant ipilimumab,” he advised, “give it in the right population and in a risk-adjusted manner.” ■

Disclosure: Dr. Weber is a consultant for Merck, Genentech, AstraZeneca, GlaxoSmithKline, Novartis, Nektar, Medivation, Roche, Celldex, Incyte, and EMD Serono; he is on the advisory boards of Bristol-Myers Squibb, Lion Bioscience, Celldex, CytoMx, Incyte, and cCam; he holds equity in Celldex, Cytomx, and Altor, his institution received research support from Bristol-Myers Squibb, Merck, GlaxoSmithKline, Novartis, and AstraZeneca; and his laboratory receives support from Mirati and Acetylon. Dr. Michielin reported no potential conflicts of interest.

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