Anti-PD-1 therapy induces durable long-term responses in advanced melanoma
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About three-quarters of patients with advanced melanoma who achieved complete responses to single-agent anti-PD-1 therapy remained in remission at 3 years, according to results of a single-center retrospective study published in Journal of Clinical Oncology.
However, researchers reported a 27% probability of treatment failure at 3 years. Responses to retreatment occurred infrequently.
In addition, the optimal duration of treatment after complete response remained unclear.
“There are two ways to interpret these data: You could be disappointed that the relapse rate is higher than previously reported, or you could find it reassuring that [most patients who achieve complete response] remain free of disease at 3 years after discontinuation of PD-1,” Allison Betof Warner, MD, PhD, assistant attending physician at Memorial Sloan Kettering Cancer Center, told Healio.
Most patients in the cohort (69.2%) who received the treatment at Memorial Sloan Kettering between 2009 and 2018 did so outside of a clinical trial.
“As we know, clinical trial populations are highly selected and often have better outcomes than those seen in the real world, so I find these data reassuring,” Betof Warner said. “That being said, it makes me very hesitant to use the word ‘cure’ with patients if we expect that about [one-quarter] will go on to have progressive disease. I generally tell patients that they have no evidence of melanoma in their body, which is wonderful, and we will monitor closely to ensure that it stays that way.”
The potential for durable responses with the anti-PD-1 agents pembrolizumab (Keytruda, Merck) and nivolumab (Opdivo, Bristol-Myers Squibb) — along with their costs and potential risks for toxicity — has fueled interest in understanding long-term outcomes after treatment discontinuation, as well as determining the optimal treatment duration after complete response.
Betof Warner and colleagues retrospectively analyzed long-term outcomes of 396 patients (median age at treatment, 67 years; range, 17-94; 64.4% men) with nonuveal, unresectable stage III or stage IV melanoma after discontinuation of single-agent anti-PD-1 therapy and at least 3 months of follow-up after discontinuation.
Researchers also assessed efficacy of retreatment with anti-PD-1 therapy after treatment failure.
All patients received single-agent pembrolizumab (85.9%) or nivolumab (14.1%).
Results showed 102 patients (25.8%) achieved complete response.
Nearly three-quarters (72.1%; 95% CI, 59.9-81.1) of patients who achieved complete response remained alive at 3 years with no need for additional melanoma therapy.
Median duration of treatment after complete response was zero months; some discontinued prior to complete response, and others discontinued as long as 26 months after complete response.
Researchers observed no significant association between treatment duration and relapse risk.
Seventy-eight patients underwent retreatment after disease progression, and 16 (20.5%) achieved responses. These included five of 34 patients retreated with a single-agent anti-PD-1 therapy, and 11 of 44 patients retreated with anti-PD-1 therapy in combination with ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-CTLA-4 monoclonal antibody.
“This was the largest series reported to date of patients treated with a second course of PD-1 [blockade] for progressive disease,” Betof Warner told Healio. “Unfortunately, the response rates to a second course are disappointing. Larger series and pooled analyses are needed to confirm these findings.”
A lack of assessment on tumor burden served as a limitation to this study.
“For those patients who go on to have progressive disease after discontinuing PD-1 [blockade], there are several potential options,” Betof Warner said. “The low response rates from our series suggest that going back to PD-1 is likely not an effective strategy, though a small number of patients did respond to the second course. In general, after progression we consider ipilimumab-based strategies, targeted therapy if the patient has an actionable mutation such as BRAF V600, or clinical trials.” – by John DeRosier
For more information:
Allison Betof Warner, MD, PhD, can be reached at betofa@mskcc.org.
Disclosures: Betof Warner reports honoraria from LG Chem Life Sciences Innovation Center and research funding from Leap Therapeutics. Please see the study for all other authors’ relevant financial disclosures.
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