With incredibly paced approvals and clinical advancements in the systemic therapy of cutaneous melanoma, the efficacy of immunotherapy in this disease is clear. However, many important questions remain regarding timing and dosing—in other words, which drug (or drugs) makes the most sense and in which clinical context. The phase II adjuvant IMMUNED trial, reported by Zimmer et al¹ and reviewed in this issue of The ASCO Post, adds to a growing body of evidence supporting a higher clinical efficacy of combination immunotherapy over monotherapy as well as deepening our understanding of the benefits of adjuvant therapy.

Pauline Funchain, MD

‘Impressive Differences’ in Recurrence-Free Survival

Zimmer et al investigated the efficacy of adjuvant immunotherapy in stage IV melanoma with no evidence of disease. In fully resected or radiated stage IV disease, this randomized, double-blind study compared 1 year of adjuvant nivolumab monotherapy, combination ipilimumab and nivolumab, and placebo. Impressive differences in recurrence-free survival were observed, with combination immunotherapy consistently better than nivolumab monotherapy (75% vs 52% at 1 year and 70% vs 42% at 2 years). Both combination immunotherapy and nivolumab monotherapy showed longer recurrence-free survival vs placebo (32% at 1 year and 14% at 2 years). The hazard ratios (HRs) for combination and single-agent immunotherapy vs placebo were 0.23 (P < .0001) and 0.56 (P = .011), respectively.

Overall, these data suggest that adjuvant immunotherapy, whether in combination or as monotherapy, results in an objective and striking decrease in recurrence in the context of completely resected or radiated stage IV disease. This study strongly indicates that adjuvant immunotherapy should be used in all patients with stage IV disease who have been rendered free of disease by local therapies. Given the poor recurrence-free survival observed in the placebo group, surveillance in this patient group should not be considered a viable option for patients able to undergo immunotherapy.

Combination Immunotherapy vs Monotherapy

In considering the question of whether combination immunotherapy represents a clinically meaningful benefit over PD-1 monotherapy, the clear and wide separation of recurrence-free survival curves is thought provoking, to say the least. These curves suggest dramatically higher clinical efficacy of combination immunotherapy over anti–PD-1 monotherapy.

As in CheckMate 067, which compared combination immunotherapy and nivolumab monotherapy with ipilimumab monotherapy, this adjuvant three-arm study was not designed to compare combination immunotherapy with nivolumab monotherapy. However, the recurrence-free survival curves widen dramatically after 6 months and demonstrate a nearly 30-point drop in 2-year recurrence-free survival moving from combination therapy to nivolumab monotherapy and another nearly 30-point drop from nivolumab monotherapy to placebo. An exploratory analysis between combination and single-agent immunotherapy resulted in a hazard ratio of 0.40 (97.5% confidence interval = 0.020–0.79), implying a benefit for the combination over monotherapy. Overall survival data are not yet mature, but it is difficult to imagine that overall survival curves will not in some way follow suit.

Toxicity

Treatment-related toxicity from the immunotherapy arms was as expected. In the combination-therapy arm, 71% experienced grade 3 or 4 toxicities, and in the nivolumab-monotherapy arm, 27%. Combination ipilimumab and nivolumab represents a high burden of toxicity, with more than 62% discontinuing treatment due to toxicity, as opposed to 13% with nivolumab. However, the price of toxicity may not only be balanced, but even possibly outweighed by increased efficacy and interestingly a much shorter median time on treatment. On the combination immunotherapy arm, median time on treatment was 6.5 weeks, as compared with 21.9 weeks on nivolumab.

Ultimately, the relative values of toxicity, time on treatment, and recurrence-free survival need to be properly quantified and described by the oncology community. Then, relative weights can be assigned to each of these factors in selecting between combination and single-agent adjuvant therapy.

Subgroup Analysis

Preplanned subgroup analysis was done to identify patient groups that might accrue greater benefit from combination therapy. In almost every analysis, hazard ratios suggested a benefit with combination therapy, yet more than half of the same subgroups did not with nivolumab. That said, two subgroups appeared to derive a differential benefit from combination immunotherapy: those with BRAF-mutant melanoma and those with treated brain metastases. Although both patients with BRAF-mutant and BRAF wild-type melanomas experienced benefit with combination immunotherapy (HRs = 0.07 and 0.44, respectively), the benefit for those with BRAF-mutant melanomas over BRAF wild-type melanomas was significantly larger (P = .0089) and was the only prespecified subgroup to demonstrate a statistically significant difference.

This finding echoed prior trials suggesting a greater benefit in BRAF-mutant melanomas with ipilimumab-containing regimens. In CheckMate 238, patients with BRAF-mutant melanoma had a higher median recurrence-free survival (25.8 months) than did those with BRAF wild-type melanoma (16.8 months) when treated with adjuvant ipilimumab. Although the numbers were much smaller in the subgroup with cerebral metastases, combination immunotherapy also appeared to show a greater benefit in this group. In contrast, all patients with cerebral metastases who received either nivolumab or placebo experienced recurrence.

Similarly, an Australian phase II study of combination and single-agent immunotherapy in brain metastases showed doubling of the objective intracranial response rate in those who received combination immunotherapy over those who received single-agent anti–PD-1 (46% vs 20%). This study also supports the idea that the addition of ipilimumab may enhance clinical efficacy with intracranial disease.

Closing Thoughts

The phase II IMMUNED study makes a strong argument for adjuvant immunotherapy for resected or radiated stage IV melanoma. Clinical outcomes on the placebo arm in this trial underscore a poor prognosis for patients with stage IV melanoma despite definitive local therapies and a lack of radiologic evidence of disease. Systemic immunotherapy was shown to be effective in reducing recurrence in this context, and the recurrence-free survival data presented are compelling, even without mature overall survival data.

Of note, this trial is the first to show a strong benefit in the adjuvant setting for combination ipilimumab plus nivolumab and suggests a role for the combination in resected stage IV melanoma. Adjuvant nivolumab monotherapy is also an effective option in this context, with considerably shorter recurrence-free survival in comparison to combination therapy but also substantially reduced toxicity. Both combination immunotherapy and nivolumab monotherapy should be considered in the adjuvant treatment of resected stage IV melanoma, as well as careful discussion with patients regarding the differences between the two regimens in terms of clinical efficacy and toxicity. 

Dr. Funchain is an oncologist in the Department of Hematology and Medical Oncology at the Cleveland Clinic.

DISCLOSURE: Dr. Funchain has served as a consultant or advisor to Eisai and has received institutional research funding from Pfizer.

REFERENCE

1. Zimmer L, Livingstone E, Hassel JC, et al: Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy vs placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): A randomised, double-blind, placebo-controlled, phase II trial. Lancet 395:1558-1568, 2020.