Background: Combination anti-PD(L)1 and BRAF/MEK-targeted therapy (TT) improves PFS in stage IV melanoma vs TT. In stage IV melanoma recent data suggest immunotherapy 1st until progression, rather than BRAF-TT, improves OS, and induction TT upfront adds little benefit. NeoTrio explored the optimal combination of BRAF-TT and anti-PD1 using the NAT platform in pts with stage III melanoma (NCT02858921). Methods: 60 pts with resectable, RECIST measurable stage III (no in-transit) BRAF^V600-mutant melanoma were randomized 1:1:1 to 3 arms of 6 wks of NAT followed by complete lymph node dissection (CLND): A) Pembro ALONE (200mg Q3W x 2); B) SEQ - D+T (150mg bd + 2mg od) for 1 wk followed by pembro (200mg x 2); C) CON – D+T+pembro (doses as SEQ). Pts had 46 wks pembro post-CLND. Primary endpoint was the pathological response rate (pRR) and pathological complete response (pCR) at wk 6. Secondary endpoints; RECIST RR at wk 6, event-free survival (EFS), RFS, OS, adverse events (AE) and translational endpoints. Results: At data cutoff 2 Jan 2022, 20 pts per arm had similar baseline characteristics; overall 42% female, med age 53 yrs, 82% BRAF V600E, 62% clinical N1b. Med f/u was 20 months (95% CI 17-31). The pCR rate and pRR were highest in CON arm, and similar in ALONE and SEQ arms (Table). Events (progression before surgery, recurrence after surgery or death) were highest in ALONE arm at this 1st analysis (Table). Assessment of the durability of path response subtypes in each arm is ongoing. Most common Rx related AE were fatigue (65%, 70%, 70%, ALONE, SEQ and CON respectively), pyrexia (0%, 25%, 85%) and rash (50%, 35%, 35%). Gd 3/4 AE occurred in 30%, 25% and 55%, respectively; pyrexia and hepatitis were common in CON during NAT. Rx interruptions during NAT occurred in 0, 3 and 19 pts, respectively; 1, 0 and 8 pts permanently discontinued. Post NAT surgical operability was the same or improved in 81%. Longitudinal analysis of melanoma tissue, microenvironment and microbiome is ongoing. Conclusions: CON D+T+pembro achieved the highest pRR, pCR rate, but with greater toxicity. Recurrences were seen in those with pCR/near pCR in BRAF-TT containing arms, but not in pembro ALONE, in keeping with previous data of NAT with checkpoint inhibitors vs BRAF-TT. Short course of D+T prior to PD1 did not improve path response, despite previous translational data showing increased tumour infiltrating T-cells early-during treatment with D+T. Follow up is ongoing. Clinical trial information: NCT02858921.

*2 pts and ̂1 pt progressed prior to surgery; no CLND was performed.