Melanoma Matters

Melanoma Matters: Why Adjuvant Doublet Immunotherapy Fell Short

Hobbies - James wishes he was surfing more

This episode breaks down three negative adjuvant melanoma trials testing combination immunotherapy against anti PD 1 monotherapy. The discussion focuses on why toxicity rises without clear efficacy gains, and what these results mean for adjuvant and neoadjuvant strategy going forward.

James Larkin and Sapna Patel also dig into a bigger question: if combination therapy helps in metastatic disease, why does it seem to lose its edge in microscopic or adjuvant disease?

Key topics

In this episode, the hosts review three adjuvant trials:

• CheckMate 915
• Relativity 098
• KeyVibe 010

• The bottom line across all three studies is negative efficacy for combination therapy versus monotherapy in the adjuvant setting.
• The conversation emphasizes toxicity and discontinuation as a major issue with combination arms, especially when patients stop early because of adverse effects rather than progression.
• They revisit the CheckMate 915 dosing question, noting that the ipilimumab exposure in that study was much lower than the classic EORTC adjuvant regimen.
• The hosts compare dosing intensity and cumulative dose across adjuvant and metastatic settings, including the idea that dose density may matter as much as total dose.

• The episode raises a larger strategic question for melanoma care:
• Should adjuvant therapy remain monotherapy?
• Should neoadjuvant treatment replace some adjuvant use?
• Should patients receive both?

James asks the big question

In this episode, Sapna and James discuss the INTerpath-001 press release describing primary endpoint (RFS) and key secondary endpoint (DMFS) findings from the randomized phase 3 study of individualized neoantigen therapy plus pembrolizumab for resected stage IIB to IV melanoma. No data were shared, only descriptive findings of "statistically signficant" and "clinically meaningful" results. As James puts it, one of these is binary, the other is subjective.

In this episode, James and Sapna debate how to pronounce the newest FDA approved treatment for melanoma: T-U-D-R-I-Q-E-V

They discuss the FDA Cell and Gene Therapy Advisory Committee's review of the single-arm IGNYTE data and key issues around if this represents a local or systemic therapy, the maths around calculating response rate, and importantly how to identify optimal tumor characteristics for this treatment - what Sapna calls "Larkin-izing" the data.

It's a long episode with a short fact check and lots of shoutouts to Kevin Harrington for his work in this space.

In this episode, Sapna and James talk tv shows - The Gambler and His Cowboys, Brassic...

They discuss the paper from NKI on surgical considerations for TIL harvest published in BJS in 2025. Topics of interest include optimal anatomic site(s), size (is bigger always better?), number of lesions and which of these components comprise a successful ex vivo expansion of TIL

In this episode, the chin dimple is front and center. James explains the wizarding home of Tintagel in Cornwall to Sapna, situated on a lovely promontory. This episode explores the latest evidence on gene expression profile tests—Merlin 001 study of CP-GEP and Castle i31-SLNB —used to predict sentinel lymph node positivity in melanoma. James and Sapna discuss the study designs, clinical utility, and implications for clinical management.

James and Sapna welcome Megan Othus, Professor of Biostatistics at the Fred Hutch Cancer Center and one of the key statisticians at SWOG.

Megan talks about growing up in the PNW and going East to get back West. She helps us digest the time of day analyses and some of the missing analyses that should have been shown in the papers published to date. She teaches us about confounders, accounting for multiple comparisons, and guarantee time bias.

In this episode, James & Sapna tease the size of ASCO and ESMO and number of simultaneous publications.

They review the most impactful melanoma and Merkel cell carcinoma presentations from ASCO 2026, focusing on practice-changing trials and innovative strategies that could shape future treatment landscapes.

Studies discussed include:

• OptimUM-02 phase 2/3 trial for metastatic uveal melanoma
• ADAM phase 3 trial for MCC
• 5yr update of the phase 2 Keynote 942 trial (adjuvant melanoma)
• Pilot neoadjuvant studies (NeoReNi, NeoINR)
• Time of day of infusion and immunotherapy efficacy

James & Sapna sent a brief message from ASCO 2026 about what they are looking forward to hearing at the meeting.

OptimUM-02

ADAM

KN-942

Neoadjuvant pilot studies

... and more

SummaryThe conversation covers the published data from the IGNYTE study - RP1 + nivolumab: response rate and safety profile, RNA-seq analysis, and toxicity. The key takeaways include insights into clinical trial interpretation and treatment efficacy (and incorrect graphs).Takeaways

• Clinical Trial Data
• Treatment Efficacy

Chapters

• 00:00 Introduction to IGNYTE Study
• 14:04 Response Rate and Safety Profile
• 25:17 RNA-seq Analysis and Toxicity