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. 2024 Sep 6;29(9):e1180-e1188.
doi: 10.1093/oncolo/oyae085.

Molecularly matched targeted therapy: a promising approach for refractory metastatic melanoma

Emily Connell  1   2 , Émilie Gerard  3 , Bénédicte Oules  4 , Florence Brunet-Possenti  5 , Anouck Lamoureux  6 , Hugo Bonnefille  7 , Sorilla Mary-Prey  3 , Ana Carrasquilla  8 , Stéphane Mouret  9 , Nora Kramkimel  4 , Candice Lesage  10 , Pierre-Emmanuel Stoebner  7 , Axel Bartoli  11 , Sandrine Monestier  1   2 , Florian Correard  12 , Audrey Gros  13 , Arnaud Jeanson  2   14 , L'Houcine Ouafik  15 , Caroline Gaudy-Marqueste  1   2 , Pascale Tomasini  2   14 , Julie Charles  9 , Mona Amini-Adle  8 , Nausicaa Malissen  1   2
Affiliations

Molecularly matched targeted therapy: a promising approach for refractory metastatic melanoma

Emily Connell et al. Oncologist. .

Abstract

Background: Only a fraction of patients with metastatic melanoma derive durable benefit from approved treatments. The clinical impact of personalized medicine strategies for melanoma, apart from BRAF, NRAS, or CKIT targeting, has rarely been reported.

Materials and methods: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all patients with advanced melanoma aged 18 years and older for whom molecular testing identified one or more actionable molecular alterations and who accordingly received molecularly matched therapy. We excluded patients with only BRAF, NRAS, or CKIT alterations and patients who received molecularly matched therapy for less than 15 days.

Results: We included 26 patients with a median follow-up of 8 months (1-54), a median age of 63 years (24-89), and a sex ratio of 2.7. These patients had been heavily pretreated, and 64% had elevated LDH levels. The disease control rate was 38%, with 4 cases of partial response (overall response rate: 15%) and 6 of stable disease for at least 6 months. The median duration of treatment was 3.1 months (0.9-13.5). Among patients with disease control, the median duration of control was 6.6 months (2.6-13.5) and 3 cases were ongoing at the end of the study. Patients with controlled disease had GNA11, MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1, MDM2/CDK4, and CDKN2A/NRAS alterations.

Conclusions: High-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments.

Keywords: actionable molecular alteration; melanoma; molecularly matched therapy; precision medicine; refractory melanoma; targeted therapy.

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Conflict of interest statement

E.C. has no conflict of interest. E.G. has received fees from MSD, BMS, Pierre Fabre, Sanofi (speaker honoraria, financial support for congress participation). B.O. declares having received meeting invitations from Novartis, Abbvie, and Bristol Myers Squibb. F.B.P. declares having received advisory fees from Bristol Myers Squibb, Merck and Novartis. A.L. has received fees from Novartis, BMS, MSD, Pierre Fabre, SANOFI (speaker honoraria, boards participation, or financial support for congress participation). H.B. has received fees from Novartis (financial support for congress participation). S.M.P declares being investigator and having received meeting invitations from Bristol Myers Squibb, and MSD. A.C. has no conflict of interest. S.M. has no conflict of interest. N.K. has no conflict of interest. C.L. has received grants for boards or congresses from BMS, MSD, Novartis, Pierre Fabre Oncology, Sanofi. P.E.S. and A.B have no conflict of interest. S.M. received advisory fee from BMS and Sanofi, payment for lectures or meeting invitations from Novartis, BMS, Sanofi, Pierre Fabre Oncology and MSD. FC reports personal fees from Novartis, BMS, MSD and Pierre Fabre outside the submitted work. A.G. has no conflict of interest. A.J. has no conflict of interest. L.O. declares having received advisory fees from AMGEN SAS, Janssen Cilag, Astrazeneca, GlaxoSmithKline, Lilly France, payment for lectures and meeting invitations from Myriads Genetics SAS, Janssen Cilag, Astrazeneca. C.G. has received honoraria from BMS France, Blue Print, MSD Oncology, Pierre Fabre, Consulting or advisory role for Pierre Fabre and travel and accommodations expenses for Pierre Fabre, BMS France and MSD Oncology. P.T. had a consulting or advisory role for Roche, AZ, BMS, Takeda, Amgen and travel and accommodations expenses for BMS and Amgen. J.C. has no conflict of interest. M.A.A. has received fees from BMS, Pierre Fabre, Sanofi (consultant and speaker honoraria, financial support for congress participation). N.M. declares having received advisory fees from Abbvie, Bristol Myers Squibb, Janssen Cilag and Novartis, payment for lectures and meeting invitations from Pierre Fabre Oncology, Novartis, Bristol Myers Squibb, Sanofi, Abbvie, Leo Pharma, L’Oréal and MSD.

Figures

Figure 1.
Figure 1.
Matched targeted therapy outcomes. (A) Duration of matched targeted therapy received. In this swimmer plot, each bar represents 1 of the 26 patients with metastatic melanoma. The dotted line split patients with disease control (above) and patients without disease control (under). Among the 10 patients with disease control: 4 had a partial response (patients 6, 8, 9, and 10) and 6 had a stable disease of at least 6 months. (B) Radiological response of patient number 6 at baseline (on the left images) and at 3 months of treatment (on the right images) on adrenal (upper pictures) and retroperitoneal localizations (lower pictures). (C) Metabolic response of patient number 8 at baseline (upper picture) and at 3 months of treatment (lower picture). (D) Clinical response of patient number 9 on cutaneous and subcutaneous metastases at baseline (a and b) and at 1.5 months of treatment (c and d).
Figure 2.
Figure 2.
Molecular coalterations among our patients with metastatic melanoma who received matched targeted therapy. Each column represents one patient (P).
See this image and copyright information in PMC

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