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Laura and Isaac Perlmutter Cancer Center
NYU Langone Health
Professor of Medicine
NYU Grossman School of Medicine
New York, New York
Jeffrey S. Weber, MD, PhD, has disclosed that he has received consulting fees from AstraZeneca, Bristol-Myers Squibb, Genentech, GlaxoSmithKline, Merck, Moderna, Novartis, and Pfizer.
First, let me set the stage with some background on adjuvant therapy in melanoma. The modern era of adjuvant therapy for melanoma began with the EORTC 18071 trial, the first randomized phase III trial in the modern era that showed a clear benefit of adjuvant therapy in terms of relapse-free survival (RFS) and overall survival (OS) for patients with high-risk resected melanoma. The study enrolled 951 patients with resected stage IIIA, B, and C melanoma and compared adjuvant ipilimumab vs placebo. Placebo was justified at this time because there was no consistent evidence that any agent prolonged survival as adjuvant therapy in melanoma. Interferon was available but not widely used, and there was concern over its toxicity and whether it really prolonged survival in randomized studies. At 5 years of follow-up, the EORTC 18071 trial data showed a clear survival benefit with adjuvant ipilimumab vs placebo.
Following this, 2 trials examined adjuvant anti–PD-1 therapy: the CheckMate 238 trial of nivolumab and the KEYNOTE-054 (EORTC 1325) trial of pembrolizumab. CheckMate 238 compared nivolumab with ipilimumab, an active control arm, and found that nivolumab improved RFS with lower toxicity. At 4 years, the RFS difference is highly significant with an HR of 0.71 (95% CI: 0.60-0.86; P = .0003). In the KEYNOTE-054 trial of pembrolizumab, the comparator arm was placebo. This trial was mostly enrolled in Europe where there was not an approved adjuvant therapy at that time. In the United States, ipilimumab was approved, although it was not widely used due to toxicity. Pembrolizumab improved RFS vs placebo, which remains significant at 3.5 years of follow-up (HR: 0.59; 95% CI: 0.49-0.70). Together, those are great data compared with historical controls or with placebo where, at 5 years, fewer than 30% of the patients who had stage IIIB and IIIC disease were alive and free of relapse. OS data from KEYNOTE-054 is not yet available, and recent OS data for CheckMate 238 did not show a significant difference in OS, likely due to crossover between arms. This commentary focuses on immunotherapy, but I note that the combination of the BRAF inhibitor dabrafenib plus the MEK inhibitor trametinib appears to be equally effective as single agent anti–PD-1 therapy in BRAF V600–mutated melanoma for resected, stage III disease over a 4-year or 5-year span.
The idea is that if these agents work as adjuvant therapies, perhaps they work as neoadjuvant therapies given prior to surgery. What would the outcome be if one used the most effective immunotherapy, which for melanoma is the combination of ipilimumab and nivolumab, and gave it prior to lymph node resection in a patient who had measurable, palpable lymph nodes, mostly stage IIIC disease? The other advantage of neoadjuvant therapy is for a patient who is borderline resectable, who has matted lymph nodes (stage IIID), or invasion of a vital structure—neoadjuvant therapy might make them operable, whereas they might not have been operable beforehand. The OpACIN study (N = 20) compared neoadjuvant vs adjuvant ipilimumab plus nivolumab. Although effective, using the standard adjuvant dosing for ipilimumab of 3 mg/kg plus nivolumab 1 mg/kg, the resulting toxicity was high. Because one third of patients with stage III disease will likely be cured with surgery alone, it was deemed inappropriate to use those high doses with their corresponding toxicity. Of importance, at a 4-year follow-up, none of the 7 patients in that trial with any pathologic response after neoadjuvant therapy had relapsed.
The larger OpACIN-neo trial (N = 86) compared 3 different neoadjuvant dosing regimens. Investigators gave either 2 doses of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg, 2 doses of “flipped dose” ipilimumab (1 mg/kg) plus nivolumab (3 mg/kg), or consecutive ipilimumab and nivolumab (both at 3 mg/kg, 2 doses each). More than one half of patients (57%) receiving flipped dose ipilimumab plus nivolumab experienced a pathologic complete response (pCR) and the RFS at 2 years was estimated to be 84%. That is pretty impressive because, remember, most of these patients had to have palpable disease, which means they tend to have worse outcomes. The rate of grade ≥3 immune-related adverse events was lower with flipped dosing (20%) vs standard dosing (40%). In the flipped dose arm, the proportion of patients who had a pCR or near pCR was more than 60%. Adding patients who had 50% necrosis or more, a partial pathologic response, the number of the patients who had evidence of benefit increases to 77%. Of interest, the pCR rate was not necessarily reflected in CT scan imaging at Week 6. The radiographic Response Evaluation Criteria in Solid Tumors complete response rate was 10%, but the actual pCR rate was much higher. This generated the interesting idea that what is visualized under the microscope was not reflected on the CT scan. This is an important concept, suggesting that one must actually examine the tissue pathologically to decide how much benefit the patient has experienced. Although promising, we do not have long-term data, we do not have much survival data, and this was a small number of patients.
A recent compilation of neoadjuvant studies, including both immunotherapy and targeted therapy, published by Alex Menzies, found that for patients with a pCR at 2 years, the RFS was 89% and OS was 95%. That is quite impressive! For patients with a pCR, near pCR, or partial pathologic response with immunotherapy, the 2-year RFS was 96%. I think that there is probably value in neoadjuvant immunotherapy. With targeted therapy, the 2-year RFS was lower at 79% among patients with pCR and OS was 91%.
Ongoing and Planned Studies of Neoadjuvant Therapy
There is an ongoing study of neoadjuvant pembrolizumab plus adjuvant therapy after surgery vs surgery and adjuvant therapy alone (planned enrollment of 500). The primary outcome is event-free survival and the trial is approximately 50% enrolled (NCT03698019).
I am more excited about ipilimumab/nivolumab neoadjuvant treatment, and a large, randomized trial is planned. I cannot overemphasize the need for a large, randomized study. Perhaps a total of 100 patients across several small trials have received flipped dose ipilimumab/nivolumab as neoadjuvant therapy. I do not think that you should base a practice-changing maneuver on 100 patients in melanoma. What is needed is a 500-patient randomized study of patients with palpable and measurable disease. The planned study will give 2 doses of flipped dose ipilimumab/nivolumab as neoadjuvant therapy followed by surgery. The comparator arm will not receive neoadjuvant therapy, but after surgery, adjuvant nivolumab, pembrolizumab, or dabrafenib plus trametinib will be administered. Pathologic complete, near complete, and partial responses will be monitored for patients in the neoadjuvant arm and used to inform subsequent therapy. If a patient does not have a pCR or a pathologic significant response, meaning less than 50% necrosis, I believe patients will receive physician’s choice of nivolumab, pembrolizumab, or dabrafenib plus trametinib as adjuvant therapy. Outcomes will be RFS and distant metastasis–free survival. If neoadjuvant therapy results in a significant prolongation of RFS and distant metastasis–free survival at 2 or more years, it will become standard of care. If it turns out that it does not matter whether treatment is given prior to surgery or later as adjuvant therapy, in my opinion, few healthcare professionals will use neoadjuvant therapy.
I like the idea of neoadjuvant therapy, and there is both a scientific and a clinical rationale. I look forward to seeing data from an international, randomized phase III trial of neoadjuvant ipilimumab/nivolumab vs adjuvant therapy. Until we see those data, I am going to hold off judgement of whether I truly believe it is advantageous to give neoadjuvant therapy, but I have high hopes.
What are your questions on neoadjuvant therapy? Have you used neoadjuvant therapy in your clinical practice? Do you currently consider neoadjuvant therapy clinical trials for your patients with melanoma? Answer the polling question below and join the discussion by posting a comment in the discussion section.