📬 Melanoma Intelligence Digest — Week 2026-W32

An FDA advisory committee voted 10-3 that IGNYTE data for RP1 plus nivolumab are evaluable and clinically meaningful in anti-PD-1-pretreated advanced melanoma, while darovasertib plus crizotinib showed PFS of 6.9 vs 3.1 months in HLA-A2-negative uveal melanoma, ctDNA-guided sequencing and surveillance data circulated, and COLUMBUS-AD reported its primary analysis in stage IIB/C BRAF V600E/K melanoma.

⚡ TL;DR

📄 Publications

primary analysis of the RANDOMIZED eortc-2139/columbus-ad trial: Adjuvant encorafenib and binimetinib versus placebo in high-risk stage II BRAF-V600E/K melanoma. — The trial planned to randomize 815 patients but only 110 were randomized after premature termination of accrual, with safety becoming the primary endpoint and RFS a secondary endpoint

🐦 Twitter / 🦋 Bluesky

Melanoma specialists on the adcomm panel push back on the FDA briefing document's framing of the RP1 response rate — A melanoma clinician argued the FDA briefing document was ill advised and that its extreme nature may have contributed to the 10-3 vote against that document
Update: CACTUS ctDNA-guided switching discussion widens to a broader case for adaptive treatment strategies — In the randomized phase II CACTUS trial (n=21), 100% of critical ctDNA results were available within 7 days and 100% achieved the prespecified ≥80% ctDNA reduction on targeted therapy
Immunologic determinants of response to TIL therapy in advanced melanoma — TIL therapy in advanced melanoma produced a durable ORR of 36%, CR of 14% and median PFS of 8 months
Longitudinal BRAF ctDNA monitoring after melanoma resection shows strong prognostic signal but limited sensitivity — In a prospective real-world cohort of 127 patients with 318 samples, ctDNA detection tracked disease status with OR 5.90 for locoregional and 7.21 for metastatic disease versus NED (both P<0.001)

Full details below ↓

📄 What's Being Published

Manuscripts:

Primary analysis of the randomized EORTC-2139/COLUMBUS-AD trial: Adjuvant encorafenib and binimetinib versus placebo in high-risk stage II BRAF-V600E/K melanoma — van Akkooi Alexander CJ et al., Eur J Cancer

The study planned to randomize 815 patients but accrual was terminated prematurely, leaving 110 patients randomized (339 screened for BRAF mutation), with safety amended to the primary endpoint and recurrence-free survival (RFS) as secondary. Among 54 patients who initiated encorafenib plus binimetinib, grade ≥3 treatment-related adverse events occurred in 13 (24%) patients and 18 (33%) had an adverse event leading to permanent treatment discontinuation. RFS at 12 months was 86% (95% CI: 65–95%) in the encorafenib/binimetinib arm versus 70% (95% CI: 46–85%) in the placebo arm; 12-month distant metastasis-free survival was 92% (95% CI: 77–97%) versus 82% (95% CI: 55–93%), with 87 of 110 randomized patients (79%) carrying a BRAF V600E mutation and median follow-up of 12 and 7 months in the encorafenib/binimetinib and placebo arms, respectively.

Clinical bottom line: With only 110 of 815 planned patients randomized and safety as the amended primary endpoint, COLUMBUS-AD can report a manageable toxicity profile and numerically higher 12-month RFS (86% vs 70%), but cannot establish adjuvant encorafenib/binimetinib as a standard of care in resected stage IIB/C BRAF V600E/K melanoma.

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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).

Melanoma specialists on the adcomm panel push back on the FDA briefing document's framing of the RP1 response rate

FDA reviewers questioned RP1 in advanced melanoma ahead of the advisory committee meeting, and shares fell sharply in anticipation; yet the adcomm returned a 10-3 vote that, in the words of one melanoma clinician, was in some ways a vote against the FDA briefing document itself, whose extreme nature may have contributed to that outcome. Observers noted that experienced melanoma specialists on the panel dismantled the FDA presentation on the basis of clinical knowledge and experience — correcting a numerator/denominator math error and providing clinical context on complete responses, duration of response, and systemic responses in uninjected tumors. A separate point of debate concerned whether tumor shrinkage in IGNYTE was attributable to RP1 or to nivolumab, with one clinician arguing that re-treating patients who failed active anti-PD-1 therapy with the same drug is illogical. The episode has prompted a direct question about whether disease-specific subject matter experts should be seated on adcomm panels — rather than only in the open public hearing — when a single-arm trial in a rare tumor is under review.

Discussed by: @Melanoma_doctor, @aVoice4ALS, @ThePharmaLetter, @Melanoma_doctor

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Update: CACTUS ctDNA-guided switching discussion widens to a broader case for adaptive treatment strategies

In the randomized phase II CACTUS trial (n=21), 100% of critical ctDNA results were available within 7 days and 100% of patients achieved the prespecified ≥80% ctDNA reduction on targeted therapy. Patients received targeted therapy or checkpoint inhibitor immunotherapy, with treatment switching based on progression or an 80% reduction in BRAF variant allele frequency; ctDNA results were delivered rapidly with no new safety concerns reported. Commentators framed CACTUS as a reminder of the potential of ctDNA to enable adaptive treatment strategies in melanoma, while the central clinical debate remains whether a ≥80% drop in BRAF variant allele frequency constitutes a sufficient trigger to switch from targeted therapy to immunotherapy before radiographic progression is documented.

Discussed by: @OncoAlert, @to_be_elizabeth, @OncoAlert

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Immunologic determinants of response to TIL therapy in advanced melanoma

TIL therapy in advanced melanoma produced a durable ORR of 36%, a CR of 14%, and a median PFS of 8 months; response was linked to CD8+ stem-like and LAG-3+ tumor-reactive TILs, and tertiary lymphoid structures were associated with increased response and PFS. Importantly, prior checkpoint inhibitor exposure was associated with reduced TIL fitness, a finding that sharpens the question of where in the treatment sequence TIL therapy should be positioned. Dr. Donia Marco of Copenhagen University Hospital reviewed the current role of TIL therapy alongside emerging modified TIL, TCR-T, and CAR-T strategies in an ASCO 2026 summary, situating the immunologic data within a broadening cell therapy landscape for advanced melanoma.

Discussed by: @OncoAlert, @VuMediHemOnc, @StephenVLiu

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Longitudinal BRAF ctDNA monitoring after melanoma resection shows strong prognostic signal but limited sensitivity

In a prospective real-world cohort of 127 patients with 318 samples, ctDNA detection tracked disease status with an OR of 5.90 for locoregional and 7.21 for metastatic disease versus no evidence of disease (both P<0.001). Detectable ctDNA carried an HR of 17.17 for relapse (P<0.001), and each ctDNA doubling carried an HR of 1.53 (P<0.001); however, sensitivity was noted to be limited. Patient-facing education is now being built around ctDNA for monitoring treatment response, detecting recurrence, and informing clinical decision-making in melanoma — yet the restricted sensitivity keeps open the question of whether a negative result can meaningfully change post-resection surveillance intervals, or whether the assay is clinically actionable only when positive.

Discussed by: @OncoAlert, @CureMelanoma

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🔥 Top Ranked Tweets

Eric D Whitman, MD @Melanoma_doctor

RT @adamfeuerstein: @docrodwong It was remarkable to watch the experienced melanoma doctors on the panel dismantle the FDA presentation, based on their clinical knowledge and experience. It's really why these adcomms are so valuable. The FDA needs to embrace them, schedule more.

Also, having panel participants who have subject matter expertise makes a huge difference. Melanoma doc debating melanoma data. And no, that's not putting a thumb on the scale bc the melanoma docs on the panel today expressed many of the concerns and agreed with the FDA on the study flaws. One melanoma doc / panelists voted no.

The FDA needs to liberalize its conflict of interest rules to allow smart, experienced clinicians to participate in adcomms.

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