📬 Melanoma Intelligence Digest — Week 2026-W34

FDA granted accelerated approval to RP1 (Tudriqev) plus nivolumab after anti-PD-1 progression with label ORR 24% and median duration of response 14.1 months, while COMBI-I reported median OS 61.5 vs 41.6 months, PIVOTAL updated neoadjuvant daromun RFS at 36.8 months, and axitinib plus nivolumab produced a 45% ORR in mucosal melanoma.

⚡ TL;DR

📄 Publications

Neoadjuvant Intralesional Daromun (L19IL2/L19TNF) in Resectable Locally Advanced Melanoma: An Update on the Efficacy and Safety Results of the PIVOTAL Phase III Trial. — PIVOTAL enrolled 256 patients and met its primary end point with a recurrence-free survival hazard ratio of 0.59 (P = .005) at a median follow-up of 21 months
Phase II trial of First-Line Axitinib Plus Nivolumab in Patients with Advanced Mucosal Melanoma. — Among 20 evaluable patients the ORR was 45%, including 4 complete responses (20%) and 5 partial responses (25%)

🐦 Twitter / 🦋 Bluesky

Update: RP1 (Tudriqev) plus nivolumab is approved, and the debate moves to the label's ORR 24% versus the sponsor's 33.6% — FDA granted accelerated approval to RP1 (Tudriqev) plus nivolumab for advanced melanoma after progression on anti-PD-1 therapy, after 2 prior FDA rejections and a 10-3 positive ODAC vote
Daraxonrasib in NRAS-mutant melanoma: a partial response after immunotherapy progression, plus preclinical cyclophilin A resistance mutations — A new Cancer Research (AACR) paper reports daraxonrasib in NRAS-mutant melanoma including a patient with partial response upon progression on immunotherapy
ctDNA in melanoma moves from webinar topic to prospective study, with a new Phase 1 monitoring trial in advanced skin cancers — Natera and Kupando launched a Phase 1 study to monitor ctDNA in advanced skin cancers

Full details below ↓

📄 What's Being Published

Manuscripts:

COMBI-I: Long-Term Overall Survival With Spartalizumab Plus Dabrafenib and Trametinib in BRAF V600-Mutant Advanced Melanoma. — Ribas Antoni et al., J Clin Oncol

COMBI-I randomized spartalizumab plus dabrafenib and trametinib (sparta-DabTram, n = 267) versus placebo plus dabrafenib and trametinib (placebo-DabTram, n = 265) in BRAF V600-mutant unresectable or metastatic melanoma, and failed to reach its primary end point of progression-free survival at 24 months. At a median follow-up of 76.9 months, median OS was 61.5 months with sparta-DabTram versus 41.6 months with placebo-DabTram (hazard ratio 0.760). Grade ≥3 treatment-related adverse events occurred in 57.3% of patients in the sparta-DabTram arm versus 36.7% in the placebo-DabTram arm, with pyrexia as the most common treatment-related adverse event (65.9% versus 46.2%).

Clinical bottom line: Adding spartalizumab to dabrafenib plus trametinib lengthened median overall survival by roughly 20 months despite missing the original PFS end point, at the cost of substantially more grade 3 or higher toxicity.

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Neoadjuvant Intralesional Daromun (L19IL2/L19TNF) in Resectable Locally Advanced Melanoma: An Update on the Efficacy and Safety Results of the PIVOTAL Phase III Trial. — Hauschild Axel et al., J Clin Oncol

PIVOTAL enrolled 256 patients and met its primary end point, demonstrating a statistically significant improvement in recurrence-free survival (hazard ratio 0.59; P = .005) for daromun followed by surgery versus up-front surgery at a median follow-up of 21 months. The trial included 34 patients (13%) with de novo diagnosed metastatic disease and 222 patients (87%) with recurrence after surgery. An updated analysis at a median follow-up of 36.8 months confirms clinically and statistically meaningful improvements in recurrence-free survival and distant metastasis-free survival, with no new safety signals of concern.

Clinical bottom line: With follow-up extended to 36.8 months, neoadjuvant intralesional daromun holds its recurrence-free and distant metastasis-free survival advantage over up-front surgery in fully resectable stage III melanoma, with event-free survival sensitivity analyses supporting the primary result.

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Circulating B cell and T cell activation states predict clinical outcomes in melanoma and reveal dynamic immune reinvigoration with checkpoint inhibitor immunotherapy. — Booth Lucy et al., J Immunother Cancer

Pretreatment elevated PD-1+ T cells predicted immune-related adverse events, whereas VEGF+TGF-β+ double-negative T cells were enriched in patients without subsequent toxicity. On-treatment, increased class-switched memory (IgG2+) B cells and activated T cells predicted improved survival, while persistent naive and double-negative B cells were associated with poorer outcomes. Anti-PD-1 monotherapy expanded naive (CD21hi) B cells and global T cells, while anti-PD-1/anti-LAG-3 combination contracted memory B cells.

Clinical bottom line: Peripheral B-cell and T-cell activation states, profiled by mass cytometry before and during checkpoint inhibitor therapy, separate patients by survival and by risk of immune-related adverse events, and distinguish the immune footprint of anti-PD-1 monotherapy from anti-PD-1/anti-LAG-3.

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ERK1/2 Inhibitor Ulixertinib in Pan-cancer Patients with BRAF Fusions or Non-V600E/K Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1L. — Subbiah Vivek et al., Clin Cancer Res

Among 34 eligible patients with BRAF fusions or non-V600E/K mutations, no patient achieved a complete or partial response, yielding an ORR of 0%. Median PFS was 1.7 months, the 6-month PFS rate was 5%, and median OS was 3.5 months. Twenty patients (57%) had grade 3 toxicities and one patient (3%) had grade 4 toxicity as their worst toxicity; there were no grade 5 toxicities.

Clinical bottom line: Single-agent ERK1/2 inhibition with ulixertinib produced no responses in heavily pretreated tumors with BRAF fusions or non-V600E/K mutations, so this genotype should not be treated with ulixertinib monotherapy outside of combination strategies.

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Phase II trial of First-Line Axitinib Plus Nivolumab in Patients with Advanced Mucosal Melanoma. — Lochrin Sarah E et al., Clin Cancer Res

Among 20 evaluable patients with advanced mucosal melanoma, first-line axitinib plus nivolumab produced an ORR of 45% (95% CI, 23–68), including 4 complete responses (20%) and 5 partial responses (25%), with a median duration of response of 21 months and median PFS of 6.4 months; median OS was not reached. Grade 3–5 treatment-related adverse events occurred in 67% of patients, including two treatment-related deaths. Seven patients received triplet therapy (n = 5 ipilimumab, n = 2 SBRT), with no unexpected toxicities observed.

Clinical bottom line: First-line nivolumab plus axitinib delivered a 45% response rate with durable responses in advanced mucosal melanoma, a subtype that responds poorly to standard immunotherapy, but the 67% grade 3–5 toxicity rate and two treatment-related deaths make the safety profile the limiting factor.

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🗣️ What People Were Discussing This Week

How these are chosen: filtered for clinical relevance, grouped by the new development discussed, then ordered by engagement (bookmarks and reposts).

Update: RP1 (Tudriqev) plus nivolumab is approved, and the debate moves to the label's ORR 24% versus the sponsor's 33.6%

The FDA granted accelerated approval to RP1 (Tudriqev) plus nivolumab for advanced melanoma after progression on anti-PD-1 therapy, following 2 prior FDA rejections and a July 30 10-3 vote by the Cellular, Tissue, and Gene Therapies Advisory Committee. The approved label reports a 24% response rate and median response duration of 14.1 months, whereas the IGNYTE trial dataset cited by others showed ORR 33.6% and duration of response greater than 35 months — a discrepancy traced to the FDA's exclusion of 25 patients whose target lesions were all injected, which shifted ORR from 34% to 24% and duration of response from 24 months to 14 months. Separately, one account summarized IGNYTE as ORR 33%, CR 15%, with activity in non-injected visceral lesions, noting the approval as a step while confirmatory randomized data are awaited. A melanoma clinician framed the label as a compromise and emphasized that patient access is what matters most.

Discussed by: @OncoAlert, @Melanoma_doctor, @Dr_ElvinaA, @twotreesthere, @CureMelanoma, @MelanomaReAlli, @VivekSubbiah, @OncoAlert, @OncoAlert, @OncLive, @ASCOPost, @CancerNetwrk, @AIMatMelanoma

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Daraxonrasib in NRAS-mutant melanoma: a partial response after immunotherapy progression, plus preclinical cyclophilin A resistance mutations

A new Cancer Research (AACR) paper on daraxonrasib in NRAS-mutant melanoma includes a patient with a partial response upon progression on immunotherapy. The paper also reports cyclophilin A mutations in preclinical samples that have not been observed in trials thus far, raising the question of how resistance monitoring should be structured if daraxonrasib advances into formal NRAS-mutant melanoma trials. Separate preclinical work proposes that BCL2 and MCL1 expression could identify treatment-resistant melanomas that may respond to specific drug combinations, with authors suggesting biomarker trials that match patients to treatment based on tumor BCL2 and MCL1 expression.

Discussed by: @Aiims1742, @smokinscientist

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ctDNA in melanoma moves from webinar topic to prospective study, with a new Phase 1 monitoring trial in advanced skin cancers

Natera and Kupando launched a Phase 1 study to monitor ctDNA in advanced skin cancers, while the August issue of Annals of Surgical Oncology addresses personalization of neoadjuvant immunotherapy in high-risk resectable melanoma and the utility of ctDNA as a biomarker of immunotherapy response. A melanoma expert webinar, led by Vincent Ma, MD, covered the science behind tumor-informed ctDNA testing and its use to monitor treatment response, detect recurrence earlier, and help guide clinical decision-making. The central question across these discussions is whether ctDNA is ready to personalize the duration of neoadjuvant immunotherapy in high-risk resectable melanoma, or whether prospective interventional data are still required.

Discussed by: @AnnSurgOncol, @SocSurgOnc, @CureMelanoma

→ View representative tweet

🔥 Top Ranked Tweets

OncoAlert @OncoAlert

RT @DrChoueiri: JUST IN: Big news in #melanoma today.

@US_FDA grants accelerated approval to RP1 (Tudriqev) + nivolumab for advanced melanoma after progression on anti–PD-1 therapy. Drug from @Replimune

An oncolytic immunotherapy injected directly into tumors—aiming to turn the tumor itself into an immune stimulus.

Quite a regulatory journey: 2 prior FDA rejections → 10–3 positive ODAC vote → approval.

Important new option for a difficult-to-treat population. And an important reminder that promising science sometimes takes a complicated road to patients.

Link: https://t.co/YB7n6gFzsw

Confirmatory Phase 3 ongoing.

@OncoAlert @OncBrothers @DanaFarber_GU @DanaFarber @harvardmed @OmidHamidMD @HTawbi_MDPhD @DrSapnaPatel

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