Early findings from a phase II efficacy and safety study may be the first step in developing a definitive rationale for sequencing targeted therapies and immunotherapies in patients with metastatic melanoma.
Early findings from a phase II efficacy and safety study (NCT02631447) may be the first step in developing a definitive rationale for sequencing targeted therapies and immunotherapies in patients with metastatic melanoma. In this first report, the use of a short course of targeted therapies followed by a switch to immunotherapy resulted in higher progression-free survival. Further, at 1 and 2 years, objective response rate (ORR) and median PFS were consistent with those reported in pivotal studies, according to Paolo Ascierto, MD, at the 2020 European Society of Medical Oncology (ESMO) Virtual Congress.
Although targeted therapies and immunotherapies have revolutionized the treatment of metastatic melanoma, there is no consensus on the optimal sequence of these therapies because only retrospective analyses have been carried out. Currently, treatment choice is based on patients’ characteristics rather than data generated from randomized controlled trials.
Two-hundred thirty patients with metastatic melanoma with a BRAF V600 mutation were randomized to 3 treatment arms. Patients in arm A (n = 69) were given encorafenib (Braftovi; 450 mg) and binimetinib (Mektovi; 45 mg), patients in arm B (n = 71) were given ipilimumab (Yervoy; 3 mg/kg) and nivolumab (Opdivo; 1 mg/kg), and patients in arm C (n = 69) were given encorafenib and binimetinib for 8 weeks. At disease progression, patients in arm A received the ipilimumab/nivolumab combination, patients in arm B received the encorafenib/binimetinib combination, and patients in arm C received ipilimumab/nivolumab followed by encorafenib/binimetinib. The primary end point was overall survival (OS) and secondary end points were PFS, total PFS, best ORR, duration of response, toxicity of the investigational medicinal products, and EORTC QLQ-C30- assessed quality of life and general health status.
“We screened 251 patients because the drop-out rate was more than 10%,” Ascierto, director of the Unit of Melanoma, Cancer Immunotherapy, and Innovative Therapy at the National Tumour Institute “Fondazione G. Pascale” in Naples, Italy, said. Eventually, 36 patients remained on treatment in arm A, 31 remained on arm B, and 42 remained on arm C.
The median age across all 3 arms was 55.0 (range, 19-77), 55.0 (18-81), and 51.0 (28-80) in arms A, B, and C, respectively. Lactate dehydrogenase (LDH) levels >1 x upper limit normal (ULN) were 40.6%, 47.9%, and 36.2% in arms A, B, and C, respectively.
“In regard to lesion site involvement with more than 3 sites, arm B had a higher percentage at 40.9%, compared with arm A and arm C, both of which were 36.2%,” Ascierto said. Due to stratification criteria, Ascierto noted a slight imbalance in terms of elevated LDH and the number of metastatic organs among the 3 arms.
Median PFS was 15.8 months (95% CI, 9.5-22.2) for arm A, 7.2 months (95% CI, 3.2-11.3) in arm B, and 11.4 months (95% CI, 7.2-15.5) in arm C. Ascierto suggested these differences were due to the lactate dehydrogenase levels.
Looking at PFS rates, he said, “It’s interesting that 2-year PFS rates are similar across the arms [arm A, 35 months; arm B, 38 months; arm C, 39 months].”
Best ORR was 82.6% (95% CI, 73.7%-91.6%) in arm A, 45.1% (95% CI, 33.5%-53.6%) in arm B, and 78.3% (95% CI, 68.5%-88.0%) in arm C. Complete responses in arm A was 21%, 15.5% in arm B, and 29.0% in arm C.
Regarding safety, treatment-related adverse effects (TRAEs) for any grade was 77% in arm A, 83% in arm B, and 81% in arm C. Grade 3/4 TRAEs were 28%, 54%, and 32% respectively. Ten percent of patients discontinued treatment in arm A, 11% in arm B, and 4% in arm C.
Ascierto reported no new safety signals were observed as compared with data from historical clinical trials evaluating the ipilimumab/nivolumab and encorafenib/binimetinib combinations. Although no new signals were reported, Ascierto did highlight the occurrence of fever. Any grade fever was 10% in arm A, 13% in arm B, and 29% in arm C. Zero patients reported grade 3/4 fever in arms A and B, but 3% of patients in arm C experienced the adverse effect.
Investigators observed that the 2-year PFS was 48% (95% CI, 33%-63%) in arm A, 58% (95% CI, 45%-71%) in arm B, and 62% (95% CI, 50%-75%) in arm C, although Ascierto cautioned that these were preliminary findings.
Ascierto expects additional data about total PFS and the first report of OS to be available during the second half of 2021 and he’s looking forward to an ongoing biomarkers parallel study that will provide additional information about responders and resistance mechanisms.
Ascierto PA, Mandela M, Ferrucci PF, et al. First report of efficacy and safety from the phase II study SECOMBIT (Sequential COMBo Immuno and Targeted therapy study). Presented at: 2020 ESMO Virtual Congress. September 19-21, 2020. Abstract LBA45.