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Early recurrence after adjuvant anti-PD-1/L1 therapy for melanoma portended shorter survival, and these patients benefited more from non-PD-1-targeted systemic therapies, a subgroup analysis of a randomized trial showed.

Recurrence in the first 12 months after adjuvant nivolumab (Opdivo) was associated with a 4.7-month progression-free survival (PFS) on next-line systemic therapy versus 12.4 months with recurrence after 12 months. Median overall survival (OS) was 19.8 versus 42.8 months after early and late recurrence, respectively. The 24-month PFS and OS after next-line systemic therapy also showed a major difference favoring later recurrence.

The poorer outcomes after early recurrence were mitigated somewhat by next-line treatment with ipilimumab (Yervoy) or targeted therapy, whereas patients with later recurrence benefited from additional anti-PD-1 therapy, reported Jeffrey Weber, MD, PhD, of NYU Langone Medical Center in New York City, and co-authors in the .

"With the caveat that the interpretation of these data could have been affected by selection bias, data that show shorter time to recurrence following adjuvant anti-PD-1 appear to indicate a more biologically aggressive disease and a lower probability of benefit from subsequent anti-PD-1/L1 monotherapy rechallenge," the authors commented. "By contrast, patients had similar OS from subsequent ipilimumab-containing regimens and targeted therapy, regardless of timing of recurrence."

"These results emphasize both the continued need to develop novel therapeutics that can further reduce early recurrences in the adjuvant setting and treat patients effectively after recurrence and to develop predictive biomarkers to select patients for optimal adjuvant treatment."

The practical implications of the findings are "to avoid retreatment with adjuvant IO [immuno-oncology] if a relapse occurs within 6 months of starting therapy," Weber told 番茄社区app via email. "Give ipilimumab-nivolumab or nivolumab-LAG3 inhibition only in the face of early recurrence."

"I suspect early recurrence is a biological manifestation of poor immunogenicity and exhaustion and needs to be treated aggressively," he added.

Surgery remains the mainstay of treatment for cutaneous melanoma and for patients with locoregional disease. Prior to the advent of effective adjuvant therapy, recurrence rates for resected stage III melanoma ranged . Adjuvant treatment with IO agents or combination targeted therapies have reduced recurrence rates, but considerable room for improvement remains.

The phase III trial showed that adjuvant nivolumab improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) relative to adjuvant ipilimumab. The benefit persisted to 5 years, with RFS of 50% with nivolumab and 39% with ipilimumab and DMFS of 58% and 51%, respectively.

Among the CheckMate 238 patients who had recurrences, about 70% received subsequent systemic therapy. Data remain scarce for outcomes with post-recurrence systemic therapy, and CheckMate 238 afforded an opportunity to investigate the issue.

The trial involved a total of 906 patients, and 198 (44%) of those randomized to nivolumab versus 232 (51%) of those treated with ipilimumab had an unresectable recurrence. Median time to recurrence was 8.2 months with nivolumab and 6.6 months with ipilimumab.

Weber and colleagues evaluated patients according to the timing of recurrence (≤12 months vs >12 months). In the nivolumab arm, 122 patients had early recurrences and 76 had recurrences after 12 months. Corresponding numbers for the ipilimumab arm were 160 and 72.

Late recurrence was associated with better median PFS in both treatment groups (12.4 vs 4.7 months with nivolumab and 14.1 vs 7.2 months with ipilimumab). The 24-month PFS among patients who received subsequent systemic therapy was 21% with nivolumab and 22% with ipilimumab. Analyzed by timing of recurrence, PFS at 24 months was 16% vs 31% and 17% vs 34% for early and late recurrence in the nivolumab and ipilimumab groups, respectively. An analysis of early recurrence by intervals of 0-3 months and >3-12 months also showed better 24-month PFS with longer progression-free intervals.

Similarly, late recurrence was associated with better survival, including median OS (19.8 vs 42.8 months with nivolumab and 29.7 vs 45 months with ipilimumab) and 24-month OS (37% vs 73% with nivolumab and 59% vs 67% with ipilimumab).

Acknowledging dwindling patient numbers with the analyses, the authors found that late recurrence in the nivolumab group was associated with better 24-month OS when patients received additional anti-PD-1/L1 therapy (71% vs 17%). In contrast, 24-month PFS was similar for early and late recurrence in patients who received post-recurrence anti-CTLA-4 alone, anti-CTLA-4 plus anti-PD-1/L1, or combined targeted therapies.

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