Melanoma Highlights: ASCO 2021

Melanoma is one of the most serious types of skin cancer and several pharma players are developing novel therapies, and trying combinations of existing ones. With ASCO 21 here, they presented results from their studies- some promising, others not that much! However, DelveInsight’s consultants have culled out a few, which are going to transform the treatment paradigm in the Melanoma therapy market. Read on to know more. 

Merck and AstraZeneca presents updated analysis from their respective phase II and phase I/II study respectively in the second-line setting for Melanoma

We already know that Checkpoint inhibitors can be lifesaving for many patients with advanced melanoma, however, a proportion of 40–60% of patients do not achieve any significant therapeutic response and a substantial proportion of responder experience tumor relapse within 2 years, therefore Key Pharma players are continuously trying to evaluate the best possible combination that can work out in a better way.

In the ongoing conference, Merck presented data spanning more than 20 cancer types from its oncology research program at the 2021 ASCO annual meeting along with covering phase II LEAP-004 study (NCT03776136) evaluating Keytruda (pembrolizumab) plus Lenvima (Lenvatinib) as a 2-L treatment for patients with melanoma who progressed on anti-PD-1/PD-L1 therapy.

Earlier in October 2020, the company reported that in the open-label, single-arm study, 21.4% of patients experienced an objective response by blinded independent review, and the median overall survival was 13.9 months. The response rate of 21% was quite impressive for this patient population. Moreover, the median overall survival of 13.9 months is about double that achieved with nivolumab or nivolumab plus ipilimumab in a similar patient population. According to the data presented at ASCO 2021, among 103 participants, ORR remained 21.4%, although Median DOR increased to 8.2 months. ORR was 33.3% in patients with PD on prior anti–PD-1 + anti–CTLA-4, 18.2% in patients whose only prior anti–PD-1/L1 was in the adjuvant setting, 22.6% in patients with primary resistance, and 22.7% in patients with secondary resistance. Median PFS and OS in the total population were 4.2 months (3.8-7.1) and 14 months; 12-months PFS and OS estimates were 17.8% and 54.5%. 

Expert Opinion: “With additional follow up, lenvatinib plus pembrolizumab continues to show clinically meaningful, durable responses in patients with advanced melanoma with confirmed progression on a PD-1 or PD-L1 inhibitor given alone, or in combination, with a confirmed ORR.”

Another key player AstraZeneca is investigating, ceralasertib (AZD6738), a potent and selective inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase in combination with durvalumab (MEDI4736). At ASCO 2021, the company presented updated findings from phase I/II study in patients with metastatic melanoma who failed prior anti-PD-1 therapy (NCT03780608). The company reported no complete response and 9 partial responses, 10 stable disease and 10 progressive disease. 30% ORR, DCR 63.3%, median PFS 7.1 months, and median OS was 14.2 months. Common adverse events of any grade were anorexia, nausea, constipation and others

According to the analysis, DelveInsight is optimistic for ceralasertib (AZD6738), in combination with durvalumab, as it offers a median OS of 14.2 months and 30% ORR compared to median OS of 14 months and 21.4% ORR offered by lenvatinib and pembrolizumab. Moreover, 7.8% led to discontinuation to discontinuation of the combination.


Abstract #9505: Lifileucel demonstrates promising long-term responses in heavily pre-treated patients with Advanced or Metastatic Melanoma 

Lifileucel is an autologous TIL therapy that uses tumour-tissue T cells capable of recognizing tumour antigens and being expanded ex vivo while maintaining the heterogeneous repertoire of T cells, using a centralized manufacturing process. At ASCO 2021, Iovance Biotherapeutics presented the 28-month follow-up data from a phase II multicentre study evaluating the efficacy and safety of lifileucel, in patients with advanced melanoma who have progressed on anti–PD-1 therapy and a BRAF inhibitor with or without a MEK inhibitor, if BRAFV600 positive. The objective response rate (ORR) of 36.4% was observed in 24 patients from the total of 66 patients analysed. It consisted of complete response (CR) in 4.5% and partial response (PR) in 31.8% of patients. Eighty-one percent of patients (50/62) had a reduction in tumour burden, and 11 patients (17.7%) had a deepening of response from an earlier data cutoff in April 2020. Interestingly, one patient had been converted from PR to CR at 24 months post lifileucel infusion. However, at 33.1 months follow-up with a data cutoff of April 22, 2021, the median duration of response (DOR) still had not been reached. Furthermore, treatment-related adverse events (TEAEs) were reported in all patients treated with lifileucel; grade 3/4 events were observed in 97.0%, but only 2 events were grade 5. 

Expert Views:

 “All newly diagnosed patients should be closely monitored for progression on anti–PD-1 therapy. Early intervention with lifileucel at the time of initial progression on anti–PD-1 agents may maximize the benefit”

“Anti-PD-1 therapy is a mainstay class of treatment offering several therapeutic options for metastatic melanoma. For patients who progress on anti-PD-1 therapy, there is an unfulfilled need for efficacious and durable treatment options. The latest results with lifileucel suggest that early intervention with lifileucel TIL therapy, immediately upon progression on anti-PD-1 therapy, may offer better outcomes and longer duration of response”

Abstract #9503: Much awaited results of LAG-3 Immunotherapy, Relatlimab in combination with nivolumab improving the PFS in Advanced Melanoma 

Bristol-Myers Squibb presented the interim analysis of the global phase II/III RELATIVITY-047 study. RELATIVITY-047 is the first randomized phase III trial to evaluate the antitumor activity of inhibiting LAG-3, and the first to demonstrate the potential clinical benefit of a checkpoint inhibitor that blocks a pathway other than PD-1 and CTLA-4. The PFS interim analysis of RELATIVITY-047 was based on a total of 714 patients with previously untreated, unresectable, or metastatic melanoma, with a median follow-up of 13.2 months. The PFS for patients who received relatlimab plus nivolumab was 10.1 months, compared with 4.6 months for patients who received nivolumab monotherapy, a statistically significant improvement. Moreover, the PFS benefit associated with combination therapy appeared at 12 months in the course of treatment, and the PFS rates were 47.7% and 36.0% in the combination therapy and monotherapy groups, respectively. Additionally, the combination of relatlimab plus nivolumab was found to have a manageable safety profile, with no unexpected safety signals observed during the course of the study. In the combination arm, 97.2% of patients experienced any grade of AE, while 40.3% experienced grade 3 or 4 AEs; in the monotherapy arm, these rates were 94.4% and 33.4%, respectively. Thereby, the study concluded that the addition of relatlimab to nivolumab more than doubled the median progression-free survival (PFS) compared with nivolumab alone in patients with previously untreated, unresectable or metastatic melanoma, based on the interim results from the study.

We must understand that the current standard of care for melanoma is mainly the combined dose of Opdivo-Yervoy and Opdivo monotherapy, and now relatlimab is the third distinct checkpoint inhibitor for the company with a promising opportunity to segment the melanoma treatment further and contribute to its growing share. 

Expert Views: 

“These findings suggest that LAG-3 expression alone does not predict benefit from relatlimab plus nivolumab, although there was a trend toward improved median PFS observed among LAG-3 expressors in both arms.”

“This combination is a new standard of care that I think should replace the anti–PD-1 antibody alone.”

“This drug gives us a third immune checkpoint inhibitor to add to the treatment toolkit which may be the difference between survival or not for melanoma patients around the world.

Discover more highlights from ASCO21 here. Feel free to drop us an email to discuss more about the happenings and ongoing clinical trials in the cancer market.