Anti-PD1 plus BRAF/MEK inhibitors (triplet therapy) after failure of standard therapy in patients (pts) with advanced melanoma.
Authors: Zimmer Lisa , Dimitriou Florentia , Grover Piyush , Hassel Jessica Cecile , Erdmann Michael , Forschner Andrea , Johnson Douglas Buckner , Livingstone Elisabeth , Roesch Alexander , Ugurel Selma , Schulz Carsten , Berking Carola , Menzies Alexander M. , Long Georgina V. , Dummer Reinhard , Schadendorf Dirk , Albrecht Lea Jessica 
Published: June 2023

9528

Background: Preclinical models support the combination of immune checkpoint inhibitors (ICI) with targeted therapy (TT), suggesting a synergistic effect; however, clinical trials evaluating the efficacy of triplet combination in first-line setting showed limited advantage compared to TT only. Early data from the phase II TRIDeNT (NCT02910700) study showed promising clinical activity in anti-PD1 refractory pts. We sought to evaluate the efficacy of combined TT plus anti-PD1 after the failure of standard therapy in pts with advanced melanoma. Methods: This retrospective, multicenter study included pts with advanced melanoma who were treated with a BRAF inhibitor and a MEK inhibitor in combination with a PD1 inhibitor after failure of a minimum of one standard therapy in seven major melanoma centers between February 2016 and July 2022. Demographics, disease characteristics, therapy details, and outcome data were evaluated. Results: 59 pts were identified; med age was 48 yrs (range, 24-80), 32 pts (54.2%) were males, 20 pts (33.9%) had ECOG PS 1, 46 pts (78%) had 3 or more metastatic sites, 40 pts (67.8%) had brain metastases, and 25 (42.2%) had LDH levels above the upper limit of normal before initiation of triple therapy. Median follow-up time was 16.2 months (IQR, 6.02-20.81). Median number of previous treatment lines was 2 (range, 1-6); 40 pts (67.8%) were pretreated with at least one line of ICI and TT in any sequence. Of 55 pts who received ICI (n = 41 CTLA4 plus PD1; n = 9 PD1 mono; n = 2 CTLA4 mono; n = 3 PD1-based therapy) prior to triplet therapy, 44 pts (80%) were primary resistant (progressive disease (PD); stable disease (SD) for < 6 months), and 11 pts (20%) secondary resistant (complete response (CR), partial response (PR), SD for > 6 months) to the ICI therapy. Treatment with triplet therapy resulted in an overall response rate (ORR) of 44.1% (n = 26) and a disease control rate (DCR) of 55.9% (n = 33) with a median duration of response of 13.7 months (range, 5.4-33.2). Median PFS for the entire cohort was 6 months (95% CI, 3.88-8.08), with a 12-month PFS of 29.4% (95% CI, 17.8-42.1) and a 24-month PFS of 20.2% (95% CI, 11.0-32.8). Median OS was 15.7 months (95% CI, 8.1-23.3 months), with a 12-month OS of 52.7% (95% CI, 39.1-65.7) and a 24-month OS of 43.2% (95% CI, 29.6-55.9). Pts with extracerebral PD prior to triplet therapy (40.7%, n = 24) showed an ORR of 50%, pts with intracerebral PD (32.2%, n = 19) of 47.4%, and pts with global PD (27.1%, N = 16) of 31.3%. Treatment-related adverse events (TRAE) of grade ≥3 occurred in 17 of 59 pts (28.8%), of which cytokine release syndrome (n = 7) and hepatitis (n = 3) were the most common. In 16.9% (n = 10) of pts, TRAEs led to treatment discontinuation. Conclusions: Triple therapy has shown promising efficacy in heavily pretreated pts with advanced melanoma and may represent a treatment option after failure of standard therapy with ICI and TT.