Real-world induction targeted therapy (TT) with immune checkpoint inhibitor (ICI) therapy switch in <i>BRAF</i> -mutant metastatic melanoma.

Abstract

e21525 Background: Induction BRAF/MEK inhibitor (TT) with a planned switch to doublet ICI has been evaluated in 2 clinical trials of patients (pts) with metastatic BRAF -mutant melanoma, with benefit noted in high-risk pts. In practice, this approach is typically reserved for highly symptomatic pts requiring rapid disease control. Reported outcomes from a real-world population, including those with brain metastases, are limited. Methods: In this retrospective study, all pts with metastatic BRAF V600-mutant melanoma that received induction TT with a planned ICI switch within 16 weeks were identified via chart review. Pts who did not initiate ICI as intended were included in analyses. Primary endpoint was overall survival (OS) with secondary endpoints of intracranial (IC) and extracranial (EC) progression-free survival (PFS) and time to strategy failure (TTSF; time to definitive progression requiring change in systemic treatment, or death). Survival analyses were performed using Kaplan-Meier estimates and Cox regression. Results: 17 pts met criteria (median age 53y [IQR 47-67], 7 [44%] male). In 12 (70%) with previous stage I-III melanoma, 1 (6%) had adjuvant therapy with TT and metastatic relapse occurred at a median of 3.8 years. 11 (65%) had brain metastases, 5 (29%) liver metastases, 7 (of 13 available; 54%) raised baseline LDH, 8 (47%) ECOG ≥2, and 6 (35%) had non-V600E mutation. 13 (76%) required corticosteroids (CS) for symptomatic disease. Of those with paired LDH pre and post TT (n = 9), 5 (56%) increased and 4 (44%) fell or remained normal. 4 pts (24%) did not proceed to ICI due to death (n = 2) or poor performance status (n = 2). 13 pts (76%) proceeded to combination ICI with ipilimumab (3mg/kg; median 3 cycles) + nivolumab (1mg/kg) at a median of 51 days (range 4-126) from TT initiation. All pts requiring CS that received ICI were weaned off prior to ICI initiation (n = 10). 6 (35%) received local therapy at any point after TT initiation. Following strategy failure (n = 9), all received an alternative second-line TT. At a median follow up of 23.8 months, median OS was 14.7mths (3.9–25.5) (secondary survival outcomes in Table 1). De novo metastatic disease (p = 0.005) and raised baseline LDH (p = 0.03) were associated with poor OS, however presence of brain metastases was not (p = 0.9). Conclusions: In this poor prognosis, real-world cohort, a TT-ICI switch strategy resulted in clinically meaningful median OS of over 14 months. Importantly, TT allowed all patients to cease steroids prior to ICI. De novo metastatic disease and elevated LDH portended poorer outcomes. Encouragingly, patients with and without brain metastases demonstrated similar benefit. Survival outcomes for TT-ICI switch strategy. Outcome Median (95% CI) PFS 4.1m (1.7-12.1) IC-PFS 5.6m (2.4-9.8) EC-PFS 6.4m (3.9-NR) TTSF 5.1m (1.7-12.1) OS 14.7m (3.9-25.5)