Immunotherapy after progression to double immunotherapy: Pembrolizumab and Lenvatinib versus conventional chemotherapy for patients with metastatic melanoma after failure of PD-1/CTLA-4 inhibition

BackgroundPD-1 inhibition as monotherapy following by CTLA-4 inhibition in progressive disease or as upfront co-inhibition have drastically improved the prognosis of metastatic melanoma. Still many patients develop primary/acquired resistance to both agents, relapse soon and survive less. For many years, conventional chemotherapy (CC)was the standard of care for these patients. Recently the phase II LEAP004 trial supported that pembrolizumab/lenvatinib could overcome anti-PD-1/anti-CTLA-4 refractoriness.MethodsIn absence of any prospective comparison in this frail population, we retrospectively debate here the LEAP004 proposed combination (pembrolizumab 200mg with lenvatinib, at a dose of 10mg, due to its known toxicity) with CC (carboplatin 4AUC and dacarbazine 850mg/m2 Q3W) in real-world melanoma patients who relapsed to both ICIs, either in combinatorial or sequential setting, between July 2022 and January 2024. Patient and disease characteristics as well as treatment and safety outcomes were recorded. Survival analyses were performed using the Kaplan-Meier method.Results84 patients were included in the final analysis (pembro/lenva, n=39 vs CC, n=45; males: 33.3% vs 46.7%, respectively). Median age was 67(45-87) and 64(34-87) years. The distribution of their metastatic sites was comparable, including 12.8% and 20% with brain involvement. Most patients had a PS<2 (69.9% vs 56.5%), increased LDH (71.8% vs 84.4%), BRAF-wild status (82.1% vs 84.8%) and received>=2 previous therapies (61.5% vs 53.3%). Median follow-up was 18 months. ORR was 23.1% and 11.1% in pembro/lenva and CC groups (P<0.0001). mPFS was 4.8 and 3.8 months (HR[95%CI]: 0.57 [0.36-0.92]; P=0.017) and mOS was 14.2 and 7.8 months(HR[95%CI]:0.39 [0.22-0.69]; P=0.0009), for pembro/lenva and CC arms, respectively. Grade 3-5 TRAEs were documented in 48.7% and 75.6% of patients (P=0.034), leading to discontinuation in 10.3% and 17.8% of cases, respectively.ConclusionsThis is the first comparative study in patients with metastatic melanoma refractory to PD-1/CTLA-4 inhibition and showed significantly longer outcomes in cases treated with pembro/lenva versus CC.Legal entity responsible for the studyThe authors.FundingHas not received any funding.DisclosureD.C. Ziogas: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, BMS, Ipsen, Pierre Fabre, Gilead, Amgen; Financial Interests, Personal, Advisory Board: Roche. H. Gogas: Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre, Sanofi; Financial Interests, Personal, Invited Speaker: MSD, BMS, Novartis, Pierre Fabre, Sanofi; Financial Interests, Steering Committee Member: Amgen, Replimmune; Financial Interests, Institutional, Local PI: Amgen, MSD, BMS, Replimmune, Iovance, Bayer; Financial Interests, Institutional, Research Grant: BMS, Pfizer, Lilly, Pierre Fabre, AstraZeneca. All other authors have declared no conflicts of interest.