The 18th international congress of the Society for Melanoma Research (SMR) was held recently at the end of October 2021. It has been almost two years of getting used to virtual meetings since the initial COVID-19 outbreak. The convenience of the well-organized virtual meeting of SMR 2021 seemed to have nearly approximated the expectations from an in-person experience. With more than 150 poster presentations and over 50 oral presentations, it was a great experience learning about the advancement in melanoma research from around the world. The rapidly progressing research in melanoma is evident from the phenomenal improvement in survival of patients with advanced melanoma: what was 10 years ago a median survival of 6-9 months, with only 25% alive at one year and less than 10% alive at five years is now a 5-year survival that has gone up to 66% in patients with local metastasis and 27% in those with distant metastasis in recent years (1,2). SMR proved to be a great source of latest exclusive research in melanoma.
Immunotherapy in melanoma was one of the most discussed topics among the presentations at SMR 2021. Various late-breaking updates included KEYNOTE-587, which is an extended follow-up from KEYNOTE-006, the pivotal trial that supported use of pembrolizumab in advanced melanoma (3). The KEYNOTE-587 results represent the longest follow-up from a phase 3 trial of anti-PD-1/L1 therapy for advanced melanoma available so far. This 7-year follow-up data from the KEYNOTE-006 showed median overall survival (OS) of 32.7 months for pembrolizumab and 15.9 months for that of ipilimumab, with 7-year OS rates being 37.8% vs 25.3% for pembrolizumab and ipilimumab, respectively. Further exploratory analysis showed improved clinical outcomes regardless of BRAF status, prior BRAF inhibitor therapy, and poor prognostic characteristics such as high LDH level, larger tumor size, or presence of brain metastases.
Another major update in SMR included the second interim analysis at 18 months of the KEYNOTE-716 trial (4); a phase 3 placebo-controlled study of adjuvant pembrolizumab in patients with surgically resected high risk stage 2 melanoma. The results showed that median relapse free survival (RFS) has not yet been reached in either of the arms. At the second interim analysis, 14.8% patients treated with pembrolizumab and 23.5% of those in the control arm experienced recurrence. The analysis showed an improvement in hazard ratio of RFS since first interim analysis at 12 months, thus pembrolizumab showed a continued association with reduction in the risk of disease recurrence and death compared to placebo in patients with resected high-risk stage 2 melanoma.
The five-year outcomes of CheckMate 238 trial (5), adjuvant nivolumab versus ipilimumab in resected stage IIIB-C or IV melanoma, a phase 3, double blind trial were presented with some interesting biomarker data. The five-year RFS data showed that the median has been reached, with a supporting hazard ratio of 0.72 (95% CI 0.60-0.86) which is also maintained across the stage IIIB-C and IV subgroups. The distance metastasis free survival (DMFS) also continues to have a 7% difference at five years in favor of nivolumab with a HR of 0.79 (95% CI 0.63-0.99). The biomarker analyses showed that higher levels of tumor IFN-γ gene expression profile, tumor PD-L1, CD8 and TMB, and lower levels of CRP were associated with favorable RFS and OS in both arms; however, these biomarkers were analyzed to have minimal clinical predictive value. It is reassuring that the study continued to show superior RFS and DMFS activity of nivolumab as compared with ipilimumab.
Long term follow-up of KEYNOTE-029, part 1B and 1C arms looking at standard dose pembrolizumab with alternate-dose ipilimumab in advanced melanoma were presented with their safety profiles. The data, though immature, suggested that the standard dose pembrolizumab plus alternate-dose ipilimumab continues to show robust antitumor activity, good long-term survival, and manageable safety in advanced melanoma. Combination of standard dose pembrolizumab with 50mg Q6W dose of ipilimumab led to fewer grade 3-5 treatment related adverse events than the combination with 100mg Q12W dose of ipilimumab.
Among other updates, a phase 2 study of alrizomadlin (APG-115), a novel small-molecule MDM2 inhibitor with pembrolizumab in patients with melanoma failing immunotherapy, suggested that the combination was well tolerated and is efficacious in patients with immunotherapy relapsed/refractory metastatic melanoma. In another update, a phase 1b trial of intermittent MEK inhibition by selumetinib for treatment of metastatic uveal melanoma failed to show clinical efficacy, which further supported the findings from phase 3 SUMIT trial (6) that selumetinib is not an effective therapy in metastatic melanoma.
The exciting updates on melanoma research and the enthusiastic participation of clinicians and researchers alike, despite the virtual mode of meeting, sets higher aims for future of melanoma research. The next SMR annual congress planned to be held at Edinburgh, Scotland. Hopefully the melanoma research community will be able to finally meet in person!
Dr. Behera has no conflicts of interest to report.
References:
1. Bhatia, S., Tykodi, S. S. & Thompson, J. A. Treatment of metastatic melanoma: an overview. Oncol Williston Park N Y 23, 488–96 (2009).
2. Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer Statistics, 2021. Ca Cancer J Clin 71, 7–33 (2021).
3. Robert, C. et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. New Engl J Medicine 372, 2521–2532 (2015).
4. Luke, J. J. et al. KEYNOTE-716: Phase III study of adjuvant pembrolizumab versus placebo in resected high-risk stage II melanoma. Future Oncol 16, 4429–4438 (2020).
5. Weber, J. et al. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. New Engl J Medicine 377, 1824–1835 (2017).
6. Carvajal, R. D. et al. Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT). J Clin Oncol 36, 1232–1239 (2018).
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