Neoadjuvant Immunotherapy and Targeted Therapy in BRAF Mutant Resectable Stage III Melanoma

Researchers have found PFS enhanced in stage IV melanoma when anti-PD(L)1 is combined with BRAF/MEK-targeted therapy (TT). Recent evidence suggests that immunotherapy, rather than BRAF-TT, increases overall survival (OS) in stage IV melanoma and that induction TT provides no benefit. NeoTrio used the neoadjuvant therapy(NAT) platform to investigate the best way to combine BRAF-TT and anti-PD1 in patients with stage III melanoma (NCT02858921). A total of 60 patients with RECIST-evaluable stage III disease (no in-transit) Patients with BRAFV^V600-mutant melanoma were randomly assigned (1:1:1) to one of three groups receiving NAT for 6 weeks before undergoing complete lymph node dissection (CLND). Pembro ALONE (200mg Q3W x 2); SEQ – D+T (150mg bd + 2mg od) for 1 wk followed by pembro (200mg x 2; C) CON – D+T+pembro; D) D+T+pembro; E) CON (doses as SEQ). 46 weeks post-CLND pembro for the pts. Pathological response rate( pRR) and pathological complete response (pCR)at week 6 were the primary endpoints. Event-free survival (EFS), progression-free survival (PFS), overall survival (OS), adverse events (AE), and translational objectives were secondary measures. At the time of the data cutoff on January 2, 2022, the 20 patients in each arm shared similar demographics: 42% were female, the median age was 53, 82% were BRAF^V600E, and 62% were clinical N1b.

The median survival time was 20 months (95% CI 17-31). Rates of pCR and pRR were highest in the CON arm, whereas those in the ALONE and SEQ groups were comparable (Table). In this first review, the ALONE group fared worse regarding adverse outcomes (Table). Path response subtypes’ long-term viability in both groups is now being evaluated. Fatigue (65%, 70%, 70%, ALONE, SEQ, and CON correspondingly), fever (0%, 25%, 85%), and rash (50%, 35%, 35%) were the most prevalent Rx-related AEs. Pneumonia and hepatitis were the most common adverse events (AE) in CON during NAT, accounting for 30%, 25%, and 55%, respectively. In 1, 0, and 8 pts, respectively, Rx was temporarily interrupted during NAT, while in the remaining 19 pts, NAT was interrupted permanently. Eighty-one percent saw no change or improvement in surgical operability after NAT. Research on the microenvironment, microbiota, and temporal changes in melanoma tissue is ongoing. The highest pRR and pCR rate was attained with CON D+T+pembro, albeit at the cost of increased toxicity. Consistent with prior evidence of NAT with checkpoint inhibitors vs BRAF-TT, patients with pCR/near pCR experienced recurrences in the BRAF-TT arms but not in the pembro ALONE arms. Despite recent translational results demonstrating enhanced tumor-infiltrating T-cells early during treatment with D+T, a short course of D+T before PD1 did not improve route response. The process of following up with them is ongoing.

Source: https://meetings.asco.org/abstracts-presentations/208160

Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT02858921

Georgina V. Long, Matteo S. Carlino, George Au-Yeung, Andrew John Spillane, Kerwin Frank Shannon, David E. Gyorki, Julie R. Howle, Sydney Ch’ng, Maria Gonzalez, Robyn P.M. Saw, Thomas Pennington, Serigne N. Lo, Richard A. Scolyer, Alexander M. Menzies/NeoTrio: Randomized trial of neoadjuvant (NAT) pembrolizumab (Pembro) alone, in sequence (SEQ) with, or concurrent (CON) with dabrafenib plus trametinib (D+T) in resectable BRAF-mutant stage III melanoma to determine the optimal combination of therapy/J Clin Oncol 40, 2022 (suppl 16; abstr 9503)DOI10.1200/JCO.2022.40.16_suppl.9503