Switch to checkpoint inhibition after targeted therapy at time of progression or during ongoing response: A retrospective single‐centre experience in patients with BRAF‐mutated melanoma

Abstract

BRAF + MEK inhibition is preferentially applied as first‐line therapy in BRAF V600‐mutated melanoma patients with unfavourable prognostic features, due to the ability of targeted therapy (TT) to induce rapid symptom control, decrease tumour burden and normalize lactate dehydrogenase (LDH) levels. In addition, short‐term TT transiently increases tumour antigen presentation and tumour influx of T cells. Therefore, it might be favourable to switch TT to checkpoint inhibition (CPI) before progression (PD). We retrospectively analysed melanoma patients treated first line with TT (TT1) and who subsequently switched to CPI during response to TT (sDR group) or at progression upon TT (sPD group). We identified 74 patients (n = 37 sDR group and n = 37 sPD group). ORR to CPI was 27.0% in the sDR group versus 24.3% in the sPD group (p = .790). Median was PFS 2.5 months versus 1.2 months (p = .145), and median OS was 30.6 versus 14.1 months (p = .007). After adjusting for baseline differences and known prognostic factors, hazard ratios (HRs) favouring sDR were 0.89 for PFS upon CPI (p = .956) and 0.48 for OS (p = .055). Thus, patients switching to CPI during ongoing clinical benefit from TT do not have an inferior outcome. Due to baseline imbalances and small patient population, a favourable trend for the sDR group can be hypothesized only.

Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

“…Retrospective analyses of clinical data suggest that progression on MAPKi is associated with inferior responses to subsequent anti-PD-1 therapy and that any second-line therapy results in inferior outcomes versus the same therapy in the first-line setting (Ackerman et al, 2014;Johnson et al, 2017;Mason et al, 2020;Reijers et al, 2020;Simeone et al, 2017;Tetu et al, 2018). Whether treatment first with ICT until progression alters subsequent MAPKi responsiveness is still unclear.…”

Cytoskeletal Remodelling as an Achilles’ Heel for Therapy Resistance in Melanoma

“…This is supported by the transcriptional analyses of tumours from ICB non-responders, which showed alterations in similar invasion/metastasis pathways [31]. In fact, some retrospective studies suggest that the progression to MAPKi is associated with inferior responses to subsequent ICB treatment [32][33][34]. Mechanistically, BRAFi-resistant tumours are cross-resistant to ICB due to ERK reactivation and subsequently enhanced MAPK pathway transcriptional output, which establishes an immunosuppressive environment with dysfunctional dendritic cells [35].…”

The Great Debate at “Melanoma Bridge”, Naples, December 7th, 2019

“…In a retrospective analysis of patients with advanced BRAF-mutant melanoma, switching from targeted therapy to checkpoint inhibitors during ongoing response resulted in an OS benefit compared with switching at time of disease progression [38]. However, no significant correlation was seen between time of switching and PFS or response rates to checkpoint inhibitor therapy.…”