After 18 months of no real collaborative interaction there was a need to return to some semblance of normalcy and ESMO 2021 did just that. It was, as current President Solange Peters said, “a return to the feeling of community”. In the place of tens of thousands of attendees, roughly 240 committee members and presenters came to Paris to take the first steps towards normalcy, doing their best in small groups and, for the first time in a long time, behind the podium. The melanoma sessions did not disappoint, setting some new standards and offering breakthroughs in adjuvant and metastatic therapy.
The Presidential Session highlighted the recent positive trial of adjuvant PD1 blockade for resected high-risk stage II (IIB, IIC) melanoma. KEYNOTE-716 randomized 976 patients in a 1:1 fashion comparing pembrolizumab and placebo. Recurrence free survival, the primary objective of the study, was significant 90.5% vs 83.1 % at 12 months (HR = 0.65). The treatment was tolerable and subgroup analysis favored all groups. Upon review of patterns of recurrence, the risk of distant recurrence was nearly halved 4.7 % vs 7.8%. Concerns with the incidence of endocrine toxicity and a 15% early discontinuation led to agreement that better biomarkers would be needed to identify appropriate patients.
With the approval of single agent PD1 therapy in stage III resected melanoma and an upcoming approval for stage II adjuvant, there was a need to identify combination therapies with tolerability and efficacy. Based on Phase 2/3 RELATIVITY-047 trial, in which the relatlimab (antiLAG-3 antibody) and nivolumab fixed-dose combination demonstrated a statistically significant and clinically meaningful progression-free survival benefit over Nivolumab monotherapy the FDA has assigned a Prescription Drug User Fee Act (PDUFA) date of March 19, 2022. This trial met its endpoint of a statistical superior PFS (10.12 vs 4.63 mo ) . Grade 3/4 toxicities were significantly less than the combination with Ipilimumab and Nivolumab combination. This approval may fit a need for patients who have progressed on adjuvant PD1 therapy looking for an option without significant toxicity risk. Patients on Rela/Nivo combination demonstrated a superior progression free survival or death (HR = 0.77) after the next line of therapy (PFS2)). PFS2 will likely have a greater role for therapeutic evaluation of regimens in the adjuvant and metastatic space. We await further data in relation to response rates of the Rela/Nivo combination and overall survival benefit in upcoming presentations.
The combination of Ipilimumab and Nivolumab remains a mainstay in therapy for metastatic and unresectable melanoma. Dr. Jeff Weber presented the triplet combination of flipped dose Ipilimumab and Nivolumab with the addition of IL-6 inhibitor Tocilizumab in unresectable and metastatic melanoma. He noted that patients with high IL-6 levels have shown poorer prognosis with Immunotherapy. The initial data on 41 patients showed a trend towards a lower grade 3/4 toxicity, 17% compared to 34%. A response rate of 58% was seen. Serum cytokines at baseline and week 7 were associated with toxicity (TNF-alpha) and response (IL-8) with IPI/NIVO/TOCI. The combination of standard doses of Ipilimumab and Nivolumab remained the treatment of choice in brain metastases as an update of Checkmate-204, a trial run by the Cytokine Working Group, continued to show stellar Intracranial PFS of 52% with a response rate of 54%.
The most interesting data relating to BRAF therapy was presented by Dr. Paulo Ascierto on the update of the randomized phase 2 SECOMBIT trial looking at sequencing (1) initial combination braf targeted therapy with combination immunotherapy at progression versus (2) combination immunotherapy to targeted therapy at progression versus (3) 2 months targeted therapy with switch to immunotherapy with return to targeted therapy upon progression. As the first evaluation of such regimens the 3 year over survival trend favoring initial immunotherapy. We eagerly await biomarker data to clarify the predictive markers for benefit.
I left ESMO 2021 energized to return to patient care and utilize this information, knowing that there is more to learn upon review of the abstracts and posters. As the pioneer in immunotherapy with checkpoint inhibition and BRAF targeted therapy I know that this valuable information will ultimately be utilized for the benefit of patients with other solid tumors.
Dr. Hamid is on Consulting/Advisory Boards for Aduro, Akeso, Amgen, Beigene, Bioatla, BMS, Roche Genentech, GSK, Immunocore, Idera, Incyte, Janssen, Merck, Nextcure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Tempus, and Zelluna. He is involved in the speaker bureau for BMS, Novartis, Pfizer, and Sanofi/Regeneron. He is also involved in contracted research for Arcus, Aduro, Akeso, Amgen, Bioatla, BMS, CytomX, Exelixis, Roche Genentech, GSK, Immunocore, Idera, Incyte, Iovance, Merck, Moderna, Merck-Serono, NextCure, Novartis, Pfizer, Sanofi/Regeneron, Seattle Genetics, Torque, and Zelluna.
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