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Clinical Trial
. 2024 Oct 14;15(1):8851.
doi: 10.1038/s41467-024-53145-0.

Prospective assessment of circulating tumor DNA in patients with metastatic uveal melanoma treated with tebentafusp

Manuel Rodrigues  1   2 , Toulsie Ramtohul  3 , Aurore Rampanou  4 , José Luis Sandoval  4 , Alexandre Houy  2 , Vincent Servois  3 , Léah Mailly-Giacchetti  2 , Gaelle Pierron  5 , Anne Vincent-Salomon  6 , Nathalie Cassoux  7 , Pascale Mariani  7 , Caroline Dutriaux  8 , Marc Pracht  9 , Thomas Ryckewaert  10 , Jean-Emmanuel Kurtz  11 , Sergio Roman-Roman  2   12 , Sophie Piperno-Neumann  1 , François-Clément Bidard  1   4   13 , Marc-Henri Stern  14 , Shufang Renault  15
Affiliations
Clinical Trial

Prospective assessment of circulating tumor DNA in patients with metastatic uveal melanoma treated with tebentafusp

Manuel Rodrigues et al. Nat Commun. .

Abstract

Tebentafusp, a bispecific immune therapy, is the only drug that demonstrated an overall survival benefit in patients with metastatic uveal melanoma (MUM). Circulating tumor DNA (ctDNA) has emerged as a potential prognostic and predictive marker in the phase 3 IMCgp100-202 trial using multiplex PCR-based next-generation sequencing (NGS). In this study (NCT02866149), ctDNA dynamics were assessed using droplet digital PCR (ddPCR) in 69 MUM patients undergoing tebentafusp treatment. Notably, 61% of patients exhibited detectable ctDNA before treatment initiation, which was associated with shorter overall survival (median 12.9 months versus 40.5 months for patients with undetectable ctDNA; p < 0.001). Patients manifesting a 90% or greater reduction in ctDNA levels at 12 weeks demonstrated markedly prolonged overall survival (median 21.2 months versus 12.9 months; p = 0.02). Our findings highlight the potential of ddPCR-based ctDNA monitoring as an economical, pragmatic and informative approach in MUM management, offering valuable insights into treatment response and prognosis.

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Conflict of interest statement

M.R. reports personal fees for serving as an advisor from Merck Sharp & Dohme, AstraZeneca, GlaxoSmithKline, Immunocore; travel support from AstraZeneca; funds to his institution to support research from Merck Sharp & Dohme, Janssen-Cilag, Daiichi-Sankyo. F-C.B. received advisory board fees from Pfizer, AstraZeneca, Daiichi-Sankyo, Lilly, Novartis, Menarini, Caris Life Science, GE Healthcare, Exact Sciences, Gilead, Roche, SAGA Diagnostics; research support from AstraZeneca, Novartis, Pfizer, Prolynx, Merck KGAa, GE Healthcare, SAGA Diagnostics, Personalis; travel support from AstraZeneca, Novartis, Pfizer, Daiichi-Sankyo. A.V-S. received research grant from AstraZeneca, Daiichi-Sankyo, Ibex, Owkin, Primaa; travel support from AstraZeneca, Roche; conference fees from Daiichi-Sankyo, Exactsciences, Amgen; honoraria for conferences or lectures from AstraZeneca, Roche, MSD, Exactsciences; advisory board or consultant fees from Ibex, Primaa. M.P. received advisory board fees and travel support from AstraZeneca. J-E.K. reports personal fees for serving as an advisor from GlaxoSmithKline, Clovis Oncology, Tesaro, AstraZeneca, and Dragonfly Therapeutics; funds to his institution to support research from Merck Sharp & Dohme; travel support from Roche, PharmaMar, Tesaro. S.P-N reports personal fees for serving as an advisor from Immunocore and Pierre Fabre and travel support from Immunocore, Novartis. M-H.S. and S.R. received research support from Immunocore. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Progression-free survival (PFS) and overall survival (OS) in the whole cohort (A) and workflow (B).
Patients in the PFS curve are censored at the date of last news if not in progression, while patients in the OS curve are censored at the date of last news if alive. NR: not reached; UM: uveal melanoma; 3w: 3 weeks; 12w: 12 weeks. Source data are provided as a Source Data file.
Fig. 2
Fig. 2. ctDNA detection before and on treatment.
A levels of ctDNA detection at baseline in patients with ctDNA detected (n = 39, median = 31.0, IQR [9.0-557.0]). Errors bars are presented as median +/- IQR. B, C correlation between baseline ctDNA levels with serum LDH level (Pearson coefficient; (B); n = 63, exact p-value:3.10−8) and with diameter of the largest metastasis according to TNM (Wilcoxon test; (C); M1a: n = 36; M1b: n = 22 and M1c: n = 6). Error bars are presented as median +/- IQR. M1a: median = 0.1, IQR [0.1-9.0]; M1b: median = 18.0, IQR [8.5-499.3]; M1c: median = 431.0, IQR [146.8-1570]. Two-sided statistical tests were used. Exact p-value for comparison between M1a and M1b is 9.6.10−5. D Sankey plot showing the dynamic changes of ctDNA detection in patients under tebentafusp. E swimmer plot showing the dynamic changes of ctDNA levels in each patient. Top panel E presents the patients with ctDNA detected at baseline while bottom panel presents patients without ctDNA detected at baseline or patients with no available ctDNA analysis at baseline. Symbols in black and white represent the samples with positive and negative ctDNA detection. Red, yellow and green bars represent the duration of treatment (with colors representing the best response in each patient) while gray bars represent the follow-up after tebentafusp discontinuation. ND: not detected; LDH: lactate dehydrogenase; MAF: mutant allele frequency; NA: not available; TNM: tumor node metastasis classification. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Prognostic values of ctDNA, LDH and TNM classification.
Prognostic values of markers on PFS (left panels) and OS (right panels) at baseline. A Prognostic value of ctDNA detection. Exact p-value for OS: 7.10−6. B Prognostic value of LDH. Exact p-value for OS: 10−5. C Prognostic value of TNM. Exact p-value for OS: 7.10-4. N: normal range; H: higher than normal range; PFS: Progression Free Survival; OS: Overall Survival. Kaplan–Meier plots were used for survival analysis, with significance assessed using the two-sided log-rank test. Source data are provided as a Source Data file.
Fig. 4
Fig. 4. Predictive value of ctDNA variations on tebentafusp.
According to variation at 12 weeks (A) 3 weeks (B) and 12 weeks in patients with progressive disease at first assessment (C). OS: overall survival. Clearance of ctDNA is defined as the absence of detectable ctDNA at 3 weeks or 12 weeks after treatment, following an initial detection of ctDNA at baseline. Kaplan–Meier plots were used for survival analysis, with significance assessed using the two-sided log-rank test. Source data are provided as a Source Data file.
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References

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