
==== Front
Oncologist
Oncologist
oncolo
The Oncologist
1083-7159
1549-490X
Oxford University Press US

38761384
10.1093/oncolo/oyae085
oyae085
Melanoma and Cutaneous Malignancies
AcademicSubjects/MED00010
Oncolo/20
Molecularly matched targeted therapy: a promising approach for refractory metastatic melanoma
Connell Emily Dermatology and Skin Cancer Department, Aix Marseille University, APHM, CRCM Inserm U1068, CNRS U7258, Marseille, France
Department of Early Phase Cancer Trial Center (CEPCM) “CLIP2,” Aix Marseille University, APHM, Marseille, France

Gerard Émilie Dermatology Department, CHU de Bordeaux, Bordeaux, France

Oules Bénédicte Dermatology Department, Cochin Hospital, Paris, France

https://orcid.org/0000-0003-2100-2913
Brunet-Possenti Florence Dermatology Department, Bichat Claude-Bernard Hospital, Paris, France

Lamoureux Anouck Dermatology Department, Montpellier Cancer Institute, Montpellier, France

Bonnefille Hugo Dermatology Department, CHU de Nîmes, Nîmes, France

Mary-Prey Sorilla Dermatology Department, CHU de Bordeaux, Bordeaux, France

Carrasquilla Ana Dermatology Department, Leon Bérard Cancer Center, Lyon, France

Mouret Stéphane Dermatology Department, CHU Grenoble Alpes, University Grenoble Alpes, INSERM U 1209, CNRS UMR 5309, Institut for Advanced Biosciences, Grenoble, France

Kramkimel Nora Dermatology Department, Cochin Hospital, Paris, France

Lesage Candice Dermatology Department, CHU de Montpellier, Montpellier, France

Stoebner Pierre-Emmanuel Dermatology Department, CHU de Nîmes, Nîmes, France

Bartoli Axel Radiology Department, Aix Marseille University, APHM, CERIMED, Marseille, France

Monestier Sandrine Dermatology and Skin Cancer Department, Aix Marseille University, APHM, CRCM Inserm U1068, CNRS U7258, Marseille, France
Department of Early Phase Cancer Trial Center (CEPCM) “CLIP2,” Aix Marseille University, APHM, Marseille, France

Correard Florian Pharmacy Department, Aix Marseille University, APHM, Marseille, France

Gros Audrey Tumor Biology and Tumor Bank Department, University Hospital of Bordeaux, Bordeaux, France

Jeanson Arnaud Department of Early Phase Cancer Trial Center (CEPCM) “CLIP2,” Aix Marseille University, APHM, Marseille, France
Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France

Ouafik L’Houcine Oncobiology Department, Aix Marseille University, APHM, CNRS, INP, Inst Neurophysiopathol, Marseille, France

Gaudy-Marqueste Caroline Dermatology and Skin Cancer Department, Aix Marseille University, APHM, CRCM Inserm U1068, CNRS U7258, Marseille, France
Department of Early Phase Cancer Trial Center (CEPCM) “CLIP2,” Aix Marseille University, APHM, Marseille, France

Tomasini Pascale Department of Early Phase Cancer Trial Center (CEPCM) “CLIP2,” Aix Marseille University, APHM, Marseille, France
Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University, CNRS, INSERM, CRCM, APHM, Marseille, France

Charles Julie Dermatology Department, CHU Grenoble Alpes, University Grenoble Alpes, INSERM U 1209, CNRS UMR 5309, Institut for Advanced Biosciences, Grenoble, France

Amini-Adle Mona Dermatology Department, Leon Bérard Cancer Center, Lyon, France

https://orcid.org/0000-0001-7211-9658
Malissen Nausicaa Dermatology and Skin Cancer Department, Aix Marseille University, APHM, CRCM Inserm U1068, CNRS U7258, Marseille, France
Department of Early Phase Cancer Trial Center (CEPCM) “CLIP2,” Aix Marseille University, APHM, Marseille, France

The Group of Cutaneous Oncology of the French Society of Dermatology
Corresponding author: Nausicaa Malissen, Service de Dermatologie et Cancérologie Cutanée, Aix Marseille University, Hôpital La Timone, 264 Rue de Saint Pierre, 13385 Marseille, France (nausicaa.malissen@ap-hm.fr).
9 2024
18 5 2024
18 5 2024
29 9 e1180e1188
20 9 2023
26 3 2024
© The Author(s) 2024. Published by Oxford University Press.
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

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.

Considering those who benefit from the approved treatments, there is still an unmet medical need for patients with metastatic melanoma. This article evaluates the clinical benefit of personalized medicine strategies, excluding those targeting only BRAF , NRAS , or CKIT alterations, in patients with advanced melanoma.

melanoma
precision medicine
targeted therapy
refractory melanoma
molecularly matched therapy
actionable molecular alteration
==== Body
pmcImplications for Practice

There is still an unmet medical need for most patients with metastatic melanoma since only a fraction benefit from approved treatments. The objective of this study was to evaluate the clinical benefit of personalized medicine strategies, excluding those targeting only BRAF, NRAS, or CKIT alterations, in advanced melanoma patients. In this heavily pretreated population, molecularly matched strategies achieved a 38% disease control rate. This study suggests that high-throughput sequencing followed by matched targeted therapy is a promising approach for patients with advanced melanoma refractory to approved treatments.

Introduction

The prognosis of patients with metastatic melanoma has dramatically improved in recent years with the introduction of 2 therapeutic strategies. BRAF and MEK inhibitors are small molecules that block the mitogen-activated protein kinase pathway, which is constitutively activated by recurrent BRAF V600 mutations in 45% of patients with melanoma.1 In addition, monoclonal antibodies against the immune checkpoints cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and programmed death 1 (PD-1) can restore an efficient and durable antitumor immunity, even following treatment discontinuation.

In the metastatic setting, BRAF and MEK inhibitors have been shown to lead to a rapid and strong response, but the benefit is often limited by a high rate of secondary resistance, with a 5-year progression-free survival (PFS) of 19% for the dabrafenib plus trametinib combination.2 The combination of ipilimumab and nivolumab (2 immune checkpoint blockade) reached a 36% 5-year PFS in one study.3 Therefore, only a fraction of patients derive durable benefit, and there is still an unmet medical need for most patients with metastatic melanoma.

Cancer precision medicine is an emerging strategy enabled by the increased accessibility to tumor genomic sequencing technologies. International and European pantumor recommendations have been published about next-generation sequencing (NGS)-based results interpretation in cancer.4,5 For melanoma, in addition to BRAF, NRAS, and CKIT, molecular testing is performed using melanoma-specific panels6,7 or nonmelanoma-specific large genomic panels, tissue DNA, or circulating tumor DNA. Whole-exome sequencing studies have demonstrated that among all cancers, melanoma has one of the highest rates of somatic mutations.8 Different large series using NGS custom melanoma-specific panels of 35-64 genes have revealed at least one alteration in 85%-87% of samples.6,9 The clinical impact of targeting actionable molecular alterations outside of BRAF, NRAS, and CKIT, has rarely been reported in melanoma, either in basket trials10 or small retrospective cohorts.6,11,12

Our objective was to evaluate the clinical benefit of molecularly matched therapy following a molecular test identifying one or more actionable molecular alterations (and excluding only BRAF, NRAS, or CKIT alterations) in patients with advanced melanoma.

Materials and methods

Study design

MELtarget was a French national multicentric retrospective study conducted in France through the Group of Cutaneous Oncology of the French Society of Dermatology. This study was approved by the local IRB (PADS22-184). Informed consent was obtained from each surviving participant. For deceased patients, the investigators checked whether the patients had expressed their opposition in writing during their lifetime.

We retrospectively included all metastatic or unresectable melanoma patients aged 18 years and older for whom a molecular test identified 1 or more actionable molecular alterations and who received molecularly matched therapy between 2018 and 2022. We excluded patients with only BRAF, NRAS, or CKIT alterations and patients who received molecularly matched therapy for less than 15 days.

The collected data included age, sex, primary melanoma characteristics, number and type of previous systemic treatments received, and prognostic factors at treatment initiation. We also collected molecular test results, including the type of sample used (tumor DNA or circulating tumor DNA), exact gene panel performed, type of alteration identified, variant allele frequency, and tumor mutational burden (TMB), when available. The following data were collected up to the end of the study: matched targeted therapy introduced, treatment plan, tumor board or molecular tumor board validation, tolerance according to CTCAE v5.0, treatment duration and dose adaptations, imaging results before and during treatment, reasons for treatment cessation, ensuing lines received, and status and date of latest follow-up.

Actionable molecular alterations

A gene alteration was defined as molecularly actionable if it had been defined as targetable by a tumor board or a molecular tumor board.

Accessibility of matched targeted therapies

Treatments approved for other indications were given using French exceptional access measures. Nonapproved therapeutics were accessed as follows: tipifarnib access was temporarily possible through an exceptional measure named “Accès Précoce” by the French national agency called ANSM (Agence Nationale de Sécurité du Médicament et des Produits de Santé); for siremaldin, patients were treated in the MEGAMOST phase 2 study, as promoted by the Centre Leon Berard, Lyon, France.

Response criteria

Response was evaluated using RECIST 1.1 criteria.13

Treatment duration was calculated from the date of molecularly matched therapy introduction to the date of treatment cessation.

Follow-up of patients was calculated from the date of molecularly matched therapy introduction to the date of death or loss to follow-up.

Progression-free survival (PFS) was defined as the time from the initiation of molecularly matched therapy introduction to disease progression or death from any cause.

Overall survival (OS) was defined as the time from the initiation of molecularly matched therapy introduction to death from any cause.

The disease control rate (DCR) was defined as the proportion of patients who achieved a partial response, complete response, or stable disease for at least 6 months.

The overall response rate (ORR) was defined as the proportion of patients who achieved a partial response or complete response.

Statistical analysis

Statistical analyses were performed using GraphPad Prism v9. Survival curves were generated using the Kaplan-Meier method to estimate the probability of survival.

The Mann-Whitney test was used to compare the TMB between patients with disease control and patients without disease control. A P-value <.05 was considered to indicate statistical significance, and P values were computed by default using 2-tailed tests.

Results

Our multicentric cohort was composed of 26 heavily pretreated patients with metastatic melanoma

We included 26 patients from 8 French oncodermatology centers with an 8-month (1-54) median follow-up. Table 1 summarizes the clinical characteristics of the patients. The median age at inclusion was 63 years (24-89), with 19 men (73%) and 7 women (27%). The primary melanoma type was cutaneous for 18/26 patients (70%); 2 patients had primary uveal melanoma, 3 had mucosal melanomas, and 3 had melanomas of unknown origin. Only 12% of patients had the BRAFV600E mutation, and 19% had NRAS mutation; no CKIT alterations were found. At treatment initiation, 27% of patients had Eastern Cooperative Oncology Group (ECOG)—Performances Status 2 or above, and lactate dehydrogenase (LDH) levels were above the upper limit in 64% of the patients (Table 1).

Table 1. Clinical characteristics of our cohort of patients with metastatic melanoma that received matched targeted therapy.

Variables	Number of patients (%)	
Cohort	26 (100%)	
Median age at inclusion (range)	63 (24-89)	
Sex	
 Male	19 (73%)	
 Women	7 (27%)	
Primary melanoma type	
 Cutaneous	18/26 (70%)	
 Uveal	2/26 (8%)	
 Mucosal	3/26 (11%)	
 Unknown	3/26 (11%)	
Presence of a classical melanoma alteration	
 BRAF	3/26 (12%)	
 NRAS	5/26 (19%)	
 CKIT	0/26 (0%)	
Previous lines of systemic treatments received	
 None	1 (4%)	
 1	1 (4%)	
 2	9 (34%)	
 ≥3	15 (58%)	
Previous line of treatment received including at least a regimen based on	
 Anti-PD-(L)1	25/26 (96%)	
 Anti-CTLA4	20/26 (73%)	
 BRAF/MEK inhibitors	3/26 (12%)	
 Chemotherapy	8/26 (31%)	
 Developmental agents	14/26 (54%)	
ECOG (PS) at inclusion	
 0 or 1	18 (69%)	
 ≥2	7 (27%)	
 Unknown	1 (4%)	
Number of metastatic sites at inclusion	
 <3	6/26 (23%)	
 ≥3	20/26 (77%)	
Metastatic specific localizations history	
 Brain metastases	11/26 (42%)	
 Liver metastases	10/26 (38%)	
LDH levels at treatment initiation	
 Normal	9/25 (36%)	
 Abnormal	16/25 (64%)	
 <2N	11/15 (73%)	
 ≥2N	5/15 (33%)	
 Unavailable	1/26 (4%)	
Matched targeted therapy selected by a molecular tumor board	
 Yes	23/26 (92%)	
Abbreviations: LDH: lactate dehydrogenase, ECOG (PS): Eastern Cooperative Oncology Group (Performance Status).

Most patients (24/26, 92%) received 2 or more previous lines of systemic treatment. Apart from patient 14 (Figure 1; Table 2) who did not receive any previous line of treatment due to the severity of brain involvement and who required a salvage-targeted therapy strategy, all other patients had at least received a regimen based on anti-PD-(L)1 (only 1/25 received atezolizumab, an anti-PD-L1) and 73% an anti-CTLA4 treatment. All patients who carried the BRAFV600E mutation had received a BRAF/MEK inhibitor combination, which failed. In addition, more than half of the patients had received at least one line of treatment with an investigational agent within a clinical trial, which failed (Table 1).

Table 2. Detailed molecular alterations, molecular matched therapy introduced accordingly, and responses to treatment.

Patients	Genetic alterations	Variant allele frequency (%)	Treatment received	Best RECIST 1.1 response obtained	Treatment duration (months)	
1	GNA11 Q209L	E	Trametinib + pembrolizumab	SD	13.5	
2	ATM (deletion exons 39-46);
BRAFV600E	22; 75	Olaparib + dabrafenib + trametinib	SD	11.0	
3	Fusion FYCO1-RAF1	E	Ttrametinib + nivolumab	SD	9.7	
4	CDK4-MDM2 amplification	NA	Siremadlin + ribociclib	SD	7.4	
5	GNA11 R183C	E	Trametinib + deticene	SD	6.7	
6	CDKN2A loss; NRASQ61R	NA; 8	Ribociclib + binimetinib	PR	6.4	
7	HRAS Q61R	8	Tipifarnib	SD	6.3	
8	CCND1 amplification	NA	Palbociclib	PR	4.8	
9	MAP2K1 E203K	31	Trametinib	PR	4.6	
10	CDKN2A loss; NRASQ61R	NA; 37	Ribociclib + binimetinib	PR	2.6	
11	CCND1 amplification	NA	Siremadlin + ribociclib	SD	5.1	
12	GNA11 Q209L	E	Trametinib + fotemustine	PD	4.8	
13	PIK3CA E545K	28	Alpelisib	PD	3.3	
14	MET Exon 14	E	Cabozantinib	PD	3.1	
15	MAP2K1 l103_K104del	48	Trametinib + dabrafenib (RD)	PD	3.1	
16	EMSY amplification	NA	Olaparib	PD	3.0	
17	NF1 loss exon 1-8	NA	Trametinib + pembrolizumab	PD	2.8	
18	CDKN2A/B-p16INK4a W15*	7	Abemaciclib	PD	2.3	
19	KRAS amplification	NA	Trametinib + pembrolizumab	PD	2.3	
20	GNA11 Q209L	1	Trametinib	PD	1.8	
21	CBL R540; CBLR559	1; 1	Sunitib	PD	1.8	
22	MAP2K E102_l103del	31	Trametinib + dabrafenib (RD)	PD	1.8	
23	PTEN G127	31	Everolimus	PD	1.4	
24	ALK R1120W	23	Alectinib	PD	1.4	
25	EGFR V765M	E	Afatinib	PD	1.1	
26	CDKN2A loss, BRAFV600E	NA; 75	Palbociclib + dabrafenib + trametinib	PD	1.0	
Abbreviations: NA: not applicable, E: equivocal, PD: progressive disease, PR: partial response, SD: stable disease; dabrafenib RD: dabrafenib at reduced dosage to prevent skin adverse events.

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).

The MAP kinase pathway was the top targeted pathway, followed by the cell cycle pathway

Due to the different availability of molecular tests across centers, molecular testing was performed on tissue DNA for most patients (16/26) and on circulating tumor DNA for 7/26 patients; 3 patients had both (Figure 2). The median number of genes covered by the molecular test used to identify actionable molecular alterations was 324 (22-324), including 4 tests (15%) using a restricted and nondedicated panel of less than 40 genes.

Figure 2. Molecular coalterations among our patients with metastatic melanoma who received matched targeted therapy. Each column represents one patient (P).

Four patients (P2, P6, P10, and P26) had 2 concurrent targetable molecular alterations. Overall, 30 targetable alterations were detected: 17/30 (57%) affected the MAP kinase pathway, 6/30 (20%) affected the cell cycle pathway, 3/30 (10%) affected the receptor tyrosine kinase pathway (RTK), 2/30 (6.5%) affected the PIK3CA pathway, and 2/30 (6.5%) affected the BRCA spectrum (Figure 2).

MAP kinase pathway alterations were targeted using trametinib for 10 patients with GNA11 mutation (n = 4), MAP2K1 mutation (n = 3), NF1 loss (n = 1), FYCO1-RAF1 fusion (n = 1), and KRAS amplification (n = 1), while tipifarnib was given for an HRAS mutation (n = 1) and sunitinib for a CBL mutation (n = 1). For cell cycle pathway alterations, abemaciclib was given for patients with a CDKN2A/B mutation (n = 1), palbociclib for patients with a CDKN2A deletion (n = 1), a combination of ribociclib and binimetinib for patients with concurrent loss of CDKN2A and NRAS mutations (n = 2), and siremaldin and ribociclib for patients with CCND1 amplification (n = 1) or MDM2/CDK4 amplification (n = 1). EGFR, ALK, and MET mutations were targeted using afatinib (n = 1), alectinib (n = 1), and cabozantinib (n = 1), respectively. A PIK3CA mutation was targeted with alpelisib (n = 1) and a PTEN mutation was targeted with everolimus (n = 1). Finally, the BRCA spectrum (ATM deletion and EMSY amplification) was targeted with olaparib in 2 patients, in combination with dabrafenib and trametinib in one patient who had just experienced relapse after rechallenge with this therapy (Table 2).

Sequencing-based matched targeted therapy was selected by a molecular tumor board for 23/26 patients (88%) and by a tumor board for all patients (100%). For 6 of the 26 patients (23%) from 1 center, the tumor board decided to add molecularly matched treatment while continuing the previous line of treatment as a strategy to overcome confirmed resistance to anti-PD-1 treatment (n = 4) or chemotherapy with dacarbazine (n = 1) or fotemustine (n = 1; Figure 1A).

This personalized strategy elicited a DCR of 38%

The DCR was 38%, with 4 cases of partial response 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 (Figure 1A). Images of the radiological, metabolic, and clinical responses of patients 6, 8, and 9 are presented in Figure 1B-1D. The median progression-free survival was 3.2 months and the median overall survival was 9.1 months (Supplementary Figure S1). Patients with controlled disease (patients 1-10) had GNA11 (n = 2); MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1, and MDM2/CDK4 or CDKN2A/NRAS (n = 2) alterations (Table 2).

Most patients reported mild adverse events related to their molecularly matched therapy

No side effects were reported for 5/26 patients (19%), and CTCAE grade 1 and 2 adverse events were reported for 11/26 patients (42%). They included cutaneous toxicity (n = 10), digestive tract toxicity (n = 5), and hematologic toxicity (n = 3), as well as drug-induced hepatitis for 1 patient and pulmonary toxicity for 1 patient. Three patients (12%) experienced severe grade 3 adverse events, namely, dropped head syndrome under trametinib, pancytopenia under palbociclib, and drug-induced diabetes and cardiac left ventricular ejection fraction deterioration leading to treatment cessation under alpelisib.

Disease control was observed even in patients with poor prognosis

With caution due to the small number of patients included in our study, we observed disease control in 2 patients with an ECOG performance status greater than or equal to 2 and in 4 patients with elevated LDH levels, including 2 patients with LDH levels 2 times the upper reference limit (Supplementary Tables S1 and S2).

No significant differences were found between patients with disease control and patients without disease control regarding the existence of molecular coalterations and tumor mutational burden levels.

Most patients (81%) had 1 or more molecular coalterations in addition to those targeted by the molecularly matched therapy. Among the 5 patients for whom only 1 molecular alteration was identified and targeted, 4 did not derive any benefit (Figure 2).

Similarly, we wondered whether the tumor mutational burden (TMB) affects therapeutic response and observed no significant difference in the TMB between patients with disease control (mean = 7.1 mutations/Mb) and patients without disease control (mean = 14 mutations/Mb; P = .3639).

Discussion

In our multicentric and retrospective cohort, we observed an unexpected 38% DCR using a personalized medicine strategy to target tumor actionable molecular alterations in 26 heavily pretreated patients with unresectable metastatic melanoma.

The cohort characteristics were representative of patients refractory to available therapies except for the sex ratio in favor of men (2.7), which is usually balanced in melanoma, and for the low number of BRAF-mutant patients (12%), for whom we made the assumption that broad tumor sequencing is less common. Patients with poor prognosis included 2 with primary uveal melanoma and 3 with primary mucosal melanoma, both of which are known to be associated with poor outcomes.

The 38% DCRs and 15% ORRs indicate that 60% of the patients who benefited from the strategy had a stable outcome of at least 6 months.

This DCR is in line with the 30% clinical benefit lasting ≥6 months reported by Shoushtari et al,12 who analyzed clinical and treatment data from 27 patients with rare targetable drivers who prospectively underwent sequencing in the Memorial Sloan Kettering MSK-Impact project and received genomically matched therapies. Most of the treatments received were mostly MEK and ERK inhibitors for RAS alterations and BRAF class II alterations and TRK inhibitors for NTRK fusions.

These numbers are also in line with those of a retrospective cohort of 33 patients treated with trametinib for pretreated NRAS-mutated melanoma which reported an 18% ORR and 49% DCR with a 6.8 months median duration of response.14 In the Shoushtari study and in our cohort of patients, the clinical outcomes of rare targetable drivers are of interest despite the small number of patients included and treated.

The durable disease control obtained with the combination of olaparib, dabrafenib, and trametinib in a patient with concurrent ATM deletion and the BRAFV600E mutation is striking. The 11 months of stable disease achieved were unlikely due to dabrafenib and trametinib rechallenge since this patient had just experienced failure of a 3-month rechallenge with BRAF and MEK inhibitors before olaparib introduction. A few recently published case reports also showed high response rates to olaparib in patients with homologous recombination deficiency. Interestingly, this was the case for mutations involving the DNA damage response pathway (DDR)15,16 or despite the absence of mutations in DDR genes.17

In addition, 2 remarkable partial responses were described for 2 patients with concurrent CDKN2A loss and the NRASQ61R mutation who received ribociclib combined with cobimetinib combination which is in line with a recently published phase Ib/II trial reporting a 32.5% response rate in this specific population.18

Finally, 1 of our 3 patients with MAP2K1 (MEK1) mutation achieved a partial response to trametinib. One explanation is that MEK1E203K, which was also successfully targeted in the Shoushtari et al cohort,12 is sensitive to feedback inhibition of RAF, in contrast to insertion-deletion mutations in the MAP2K1 inhibitory domain from amino acids 98-113.19

Despite these encouraging results, our study has numerous limitations due to its retrospective nature, the small number of patients included and the heterogeneity of available NGS panels and sequencing strategies between centers. Since personalized medicine is not a standard of care for patients with melanoma, despite the inclusion of patients through a national network of skin cancer specialists, the number of included patients was low. It was therefore impossible to obtain homogenous profiling strategies to assess broad tumor sequencing output in refractory metastatic melanoma. Finally, we chose to exclude patients treated for less than 15 days to avoid patients who did not receive treatment for a long enough time to be evaluated, even though some targeted therapies are able to provide rapid and strong responses.

In conclusion, personalized strategies are a promising approach for treating patients with refractory metastatic melanoma because of the importance of improving access to molecular testing, molecular tumor boards, and matched targeted therapies. In the future, prospective cohorts are needed to better define these strategy outcomes among upcoming metastatic melanoma strategies.

Supplementary material.

Supplementary material is available at The Oncologist online.

oyae085_suppl_Supplementary_Figure

oyae085_suppl_Supplementary_Table_S1

oyae085_suppl_Supplementary_Table_S2

Author contributions

Emily Connell: collection of data, data analysis and interpretation, manuscript writing. Émilie Gerard: provision of study material or patients, final approval of manuscript. Bénédicte Oules: provision of study material or patients, final approval of manuscript. Florence Brunet-Possenti: provision of study material or patients, final approval of manuscript. Anouck Lamoureux: provision of study material or patients, final approval of manuscript. Hugo Bonnefille: provision of study material or patients, final approval of manuscript. Sorilla Mary-Prey: provision of study material or patients, final approval of manuscript. Ana Carrasquilla: provision of study material or patients, final approval of manuscript. Stéphane Mouret: provision of study material or patients, final approval of manuscript. Nora Kramkimel: provision of study material or patients, final approval of manuscript. Candice Lesage: provision of study material or patients, final approval of manuscript. Pierre-Emmanuel Stoebner: provision of study material or patients, final approval of manuscript. Axel Bartoli: provision of study material or patients, final approval of manuscript. Sandrine Monestier: data analysis and interpretation, final approval of manuscript. Florian Correard: data analysis and interpretation, final approval of manuscript. Audrey Gros: provision of study material or patients, final approval of manuscript. Arnaud Jeanson: conception and design, data analysis and interpretation, final approval of manuscript. L’Houcine Ouafik: data analysis and interpretation, final approval of manuscript. Caroline Gaudy-Marqueste: conception and design, data analysis and interpretation, final approval of manuscript. Pascale Tomasini: conception and design, data analysis and interpretation, final approval of manuscript. Julie Charles: conception and design, provision of study material or patients, data analysis and interpretation, final approval of manuscript. Mona Amini-Adle: conception and design, provision of study material or patients, data analysis and interpretation, final approval of manuscript. Nausicaa Malissen: conception and design, provision of study material or patients, collection of data, data analysis and interpretation, manuscript writing, final approval of manuscript.

Funding

The authors declare no funding.

Conflicts of interest

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.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.
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