# Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée)

Perrine Rousset, Charlée Nardin, Eve Maubec, Valentine Heidelberger,

Alexandra Picard, Laura Troin, Emilie Gerard, Nora Kramkimel, Maud

Steff-Naud, Gaëlle Quéreux, et al.

► To cite this version:

Perrine Rousset, Charlée Nardin, Eve Maubec, Valentine Heidelberger, Alexandra Picard, et al. Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée). Oncologist, 2024, 29 (10), pp.e1364-e1372. 10.1093/oncolo/ovae145. hal-05084358

HAL Id: hal-05084358

https://nantes-universite.hal.science/hal-05084358v1

Submitted on 26 May 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: the Lenvamel study, a multicenter retrospective study of the French Group of Skin Cancers (Groupe de Cancérologie Cutanée)

Perrine Rousset<fnref n="1" />, Charlée Nardin<fnref n="2" />, Eve Maubec<fnref n="3" />, Valentine Heidelberger<fnref n="3" />, Alexandra Picard<fnref n="1" />, Laura Troin<fnref n="1" />, Emilie Gerard<fnref n="4" />, Nora Kramkimel<fnref n="5" />, Maud Steff-Naud<fnref n="6" />, Gaëlle Quéreux<fnref n="7" />, Caroline Gaudy-Marqueste<fnref n="8" />, Candice Lesage<fnref n="9" />, Claire Mignard<fnref n="10" />, Géraldine Jeudy<fnref n="11" />, Thomas Jouary<fnref n="12" />, Mélanie Saint-Jean<fnref n="13" />, Barouyr Baroudjian<fnref n="14" />, Elodie Archier<fnref n="15" />, Laurent Mortier<fnref n="16" />, Céleste Lebbe<fnref n="14" />, Henri Montaudié<fnref n="1" />,<fnref n="17" />,*

## Abstract

**Background:** Currently, treatment options for patients with advanced melanoma who experience failed immunotherapy or targeted therapy are lacking. Recent studies suggest the antitumor activity of combined pembrolizumab and lenvatinib in patients with advanced melanoma progressing on immunotherapy. Herein, we report the clinical outcomes of combined lenvatinib and a programmed cell death protein-1 inhibitor (PD-1) in this population.

**Materials and Methods:** This French multicenter real-world study was conducted between September 2020 and July 2023. The primary endpoint was the objective response rate (ORR) according to the Response Evaluation Criteria in Solid Tumours (version 1.1). Secondary variables were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS), and duration of response (DOR).

**Results:** Of the 67 patients included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV-M1c or M1d disease. The overall ORR was 28.4% (95% CI, 18%-41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. Median DOR was 3.1 (interquartile range, 1.3-4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5-3.7) and 9.8 (95% CI, 5.6-13.9) months, respectively. Grades 3-5 TRAEs occurred in 16 (24%) patients; common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). No treatment-related deaths occurred.

**Conclusion:** Our real-world study demonstrates an interesting response rate and acceptable safety profile in a population with poor prognostic factors. Our data support this treatment option for refractory melanoma, as it is not approved by the Food and Drug Administration or European Medicines Agency, and highlight the need for new strategies.

**Key words:** advanced melanoma; lenvatinib; immunotherapy; anti-PD-1; real-world.

<footnote n="1">¹Dermatology Department, University Hospital of Nice, Nice, France,</footnote>

<footnote n="2">²Dermatology Department, University Hospital of Besançon, Université de Franche-Comté, Besançon, France,</footnote>

<footnote n="3">³AP-HP, Dermatology Department, Avicenne Hospital, Bobigny, France,</footnote>

<footnote n="4">⁴Dermatology Department, University Hospital of Bordeaux, Bordeaux, France,</footnote>

<footnote n="5">⁵AP-HP, Dermatology Department, Cochin Hospital, Paris, France,</footnote>

<footnote n="6">⁶Dermatology Department, CHI Aulnay-Sous-Bois, Aulnay-Sous-Bois, France,</footnote>

<footnote n="7">⁷Dermatology Department, University Hospital of Nantes, Nantes, France,</footnote>

<footnote n="8">⁸AP-HM, Dermatology and skin cancer Department, Hôpital Timone, Marseille, France,</footnote>

<footnote n="9">⁹Dermatology Department, University Hospital of Montpellier, Montpellier, France,</footnote>

<footnote n="10">¹⁰Dermatology Department, University Hospital of Rouen, Rouen, France,</footnote>

<footnote n="11">¹¹Dermatology Department, University Hospital of Dijon, Dijon, France,</footnote>

<footnote n="12">¹²Dermatology Department, University Hospital of Pau, Pau, France,</footnote>

<footnote n="13">¹³Oncology Department, Institut de Cancérologie de l'Ouest, Saint-Herblain, France,</footnote>

<footnote n="14">¹⁴AP-HP, Oncodermatology Department, Saint-Louis Hospital, Université de Paris, Paris, France,</footnote>

<footnote n="15">¹⁵AP-HM, Dermatology Department, Hôpital Saint-Joseph, Marseille, France,</footnote>

<footnote n="16">¹⁶Dermatology Department, Lille University, Lille, France</footnote>

<footnote n="17">¹⁷INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, Nice, France</footnote>

<footnote>*Corresponding author: Henri Montaudié, MD, PhD, Dermatology Department, University Hospital of Nice, 151 Route Saint-Antoine de Ginestière, 06200 Nice, France (montaudie.h@chu-nice.fr); INSERM U1065, Centre Méditerranéen de Médecine Moléculaire, Université Côte d'Azur, Nice, France.</footnote>
## Implications for Practice

The Lenvamel study findings consolidate the encouraging results of phase 2 LEAP-004 study by showing an interesting response rate and acceptable safety profile in an immuno-refractory and heavily pretreated population with poor prognostic factors. As it is not approved by the Food and Drug Administration or European Medicines Agency, this treatment may be an option for refractory melanoma, when there is no study available after failure of standard therapies. Patients pretreated with anti-PD-1 plus anti-CTLA-4 and those with *BRAF* wild-type melanoma seemed to benefit more from this strategy. Our study provides promising but limited data on patients with advanced mucosal melanoma.

## Introduction

Over the past decade, the advent of targeted therapy (TT; *BRAF* and *MEK* inhibitors), immune checkpoint inhibitors (ICIs), and inhibitors of programmed cell death protein-1 (PD-1) or its ligand (PD-L1) alone or combined with cytotoxic T-lymphocyte-associated antigen-4 inhibitors (CTLA-4) has considerably improved the survival of patients with unresectable stage III-IV melanoma. Response rates significantly exceed those of chemotherapy, ranging from 40% to 60%–70% in the case of combination therapies, with prolonged responses over time.<sup>1-5</sup>

However, a substantial proportion of patients do not respond to these therapies because of innate or acquired resistance, necessitating additional treatments.<sup>6,7</sup> Currently, the treatment options for these patients are limited, and new strategies need to be developed.

Some authors have suggested that the multikinase inhibitor, lenvatinib, mainly used in combination with programmed cell death protein (PD)-1 inhibitors, potentiates antitumor activity and overcomes resistance to ICI by inhibiting vascular endothelial growth factor (VEGF) and fibroblast growth factor receptors and shifting the tumor microenvironment to an immune-stimulatory state.<sup>8-13</sup>

Recent studies have suggested antitumor activity of combined pembrolizumab and lenvatinib in advanced melanoma,<sup>14,15</sup> while lenvatinib monotherapy has demonstrated a poor objective response rate (ORR) of 9%.<sup>16</sup>

In particular, the phase II LEAP-004 study, evaluating combined lenvatinib and pembrolizumab in 103 patients with advanced melanoma progressing on ICI, showed an ORR of 21.4%, reaching up to 33.3% in patients previously treated with anti-PD-1 and anti-CTLA-4 combination therapy. The median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) were 8.3, 4.2, and 14 months, respectively. The safety profile was 46% for grades 3-5 treatment-related adverse events (TRAEs).<sup>14</sup>

The Lenvamel study aimed to investigate the efficacy and safety of lenvatinib combined with anti-PD-1 in a French multicenter real-world patient cohort with advanced melanoma refractory to prior treatment with anti-PD-1 with or without anti-CTLA-4.

## Materials and methods

### Study design and population

This retrospective multicenter study enrolled patients from 16 participating French centers and was conducted between September 2020 and July 2023.

Inclusion criteria were: age > 18 years, diagnosis of unresectable stage III or IV melanoma, treatment with combined lenvatinib and anti-PD-1, and resistance to prior anti-PD-1 therapy (monotherapy or in combination). Patients previously

treated with adjuvant immunotherapy were included. Those with primary uveal melanoma were excluded.

We collected the following patient data: age, sex (male or female), disease stage (III or IV according to the American Joint Committee on Cancer [AJCC], 8th edition), melanoma type (cutaneous, mucosal, and unknown), Eastern Cooperative Oncology Group (ECOG) performance status (0, 1, or ≥2), serum lactate dehydrogenase (LDH) level (≤upper limit of normal [ULN], >ULN, <2ULN, or ≥2ULN), *BRAF* V600 status (wild type or mutated), *NRAS* and *CKIT* status (wild type or mutated), number of metastatic sites (≤3 or >3), stereotactic radiosurgery (SRS) for active brain metastasis (progressive and/or symptomatic brain metastasis at the initiation of anti-PD-1 plus lenvatinib), number of previous treatments (including ICI, TT, chemotherapy, or others, in adjuvant and/or metastatic setting; 1, 2, or ≥3), and resistance to anti-PD-1 therapy. Primary resistance in the adjuvant setting was defined as follows: (1) progressive disease (PD) within 12 weeks after the last anti-PD-1 therapy dose used in the adjuvant setting, versus primary resistance in the metastatic setting; (2) best stable disease (SD) or PD response to anti-PD-1 (metastatic setting) versus secondary resistance in the metastatic setting; and (3) PD after a previous best complete response (CR) or partial response (PR) to anti-PD-1.

We also collected data on combined treatment with lenvatinib and anti-PD-1, including treatment duration, regimen dose, dose reduction and/or interruption, and toxicity.

In order to ensure replicability, data were collected using a uniform and standardized case report form (CRF). Investigators at each site, reviewed, completed, and validated relevant anonymized patient data in the CRF.

### Treatment regimen

All patients received lenvatinib orally at doses of 20, 14, 10, or 8 mg, once daily. The choice of initial dose and ICI regimen was at the discretion of the physicians at each participating center. Lenvatinib treatment could be interrupted or the dose reduced to manage toxicity.

The concomitant SRS usage data were collected for patients with brain metastasis.

### Assessments

All patients at baseline or just before initiating anti-PD-1 plus lenvatinib were subjected to staging with a thoraco-abdominopelvic computed tomography (CT) or positron emission tomography-CT. Brain imaging and other imaging modalities, such as magnetic resonance imaging, were performed based on clinical indication at the discretion of the treating physician. Then, radiographic assessment was performed every 12 weeks. The response was assessed per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, by investigator assessment.<sup>17</sup> Adverse events (AEs)
and laboratory abnormalities were collected regularly during study treatment and graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Adverse events and immune-related adverse advents (irAE) of clinical significance were defined as any immune-breakthrough adverse event that was grade 3 or higher or any event that caused discontinuation or resulted in permanent organ dysfunction. TRAEs and irAE were categorized by symptoms into cutaneous, cardiovascular, endocrinologic, rheumatologic, gastrointestinal, hepatic, pulmonary, hematological, ophthalmological, renal, general, and musculoskeletal.

## Outcomes

The primary endpoint was ORR, defined by radiologists from each participating institution as the proportion of patients with CR or PR according to RECIST v1.1.¹⁷

Secondary endpoints were PFS, OS, DOR, and safety. PFS was defined as the time from the start of treatment to the date of PD or death, whichever occurred first. Patients who remained alive without PD were censored on the date of their last assessment. OS was defined as the time from the start of treatment to death. Patients who remained alive were censored on the date of last contact. DOR was defined as the time from the first evidence of CR or PR to PD or death in responsive patients. Patients who maintained CR or PR were censored on the date of their last visit. For PD, we collected data regarding the next therapeutic line (continuation of lenvatinib plus anti-PD-1, ICI, TT, CT, palliative care, or others).

## Statistical analysis

Baseline patient characteristics are presented as numbers and percentages for categorical variables, and as mean (standard deviation), median (interquartile range, [IQR]), and range for continuous variables, as appropriate. The Clopper-Pearson method was used to calculate 95% exact binomial CIs for ORR. Patients without response assessments were considered nonresponders. DOR, duration of SD, PFS, and OS were estimated using the Kaplan-Meier method. Patients lost to follow-up were censored at their last visit. Missing data were not replaced.

## Results

### Population characteristics

The 67 included patients had a median age of 69 (IQR, 27-88) years and follow-up duration of 5.0 (IQR, 3.3-9.8) months.

Fifty-seven (85%), 42 (63%), 26 (39%), and 58 (86%) patients had stage IV M1c or M1d disease, ≥3 metastatic sites, elevated LDH levels, and ECOG <2, respectively. Twenty (30%) patients had active brain metastasis. Thirteen (19%) and 20 (30%) patients had *BRAF* V600 mutations and *NRAS*-mutant melanoma, respectively.

Most patients had received ≥3 prior lines of therapy (45%), whereas 58 (87%) had experienced progression on prior anti-PD-1 and anti-CTLA-4 therapy. All patients with *BRAF* V600 mutations were pretreated with targeted therapy.

The anti-PD-1 resistance phenotype showed primary resistance in the adjuvant setting in 8 (12%) patients, and primary and secondary resistance in a metastatic setting in 29 (43%) and 30 (45%) patients, respectively.

All patients received >1 dose of lenvatinib combined with anti-PD-1 (pembrolizumab (200 mg every 3 weeks) for 55 (82%) or nivolumab (480 mg every 4 weeks) for 12

(18%) patients). One patient received concurrent intrathecal nivolumab therapy. Fourteen of the 20 patients (70%) with active brain metastasis received concomitant brain SRS. At data cutoff, 53 (79%) patients had discontinued all treatments, most commonly for radiographic PD in 32 (60%) patients, followed by toxicity in 14 (21%) patients. All demographic and disease characteristics are presented in Table 1.

## Efficacy

Table 2 shows the response rates. The best ORR was 28.4% (95% CI, 18%-41%), with 3 (4.5%) and 16 (23.9%) patients achieving CR and PR, respectively. The median DOR and SD duration were 3.1 (IQR, 1.3-4.3) and 2.3 months, respectively. Estimated SD duration of ≥6 months was seen in 12.5% of participants.

Among the 19 patients who achieved initial PR or CR, 11 (58%) experienced PD. At data cutoff, 13 (19%) patients remained on treatment, and 1 patient had a maximum follow-up of 18.8 months.

Among the remaining 51 patients who discontinued the treatment for toxicity or PD, 23 (45%) received exclusive palliative care, while 28 (55%) received a new antitumoral therapy: 16 (31%) received CT; 5 (10%), TT; 5 (10%), ICI; and 2 (4%), combined anti-PD-1 and TT.

Regarding prior therapy, ORR was 32.8% (95% CI, 22%-46%) in patients progressing on prior anti-PD-1 and anti-CTLA-4 combination therapy, regardless of the line, and 38.5% (95% CI, 22-57) in those treated with first-line anti-PD-1 and anti-CTLA-4 therapy. ORR was 33.3% (95% CI, 13-59) for patients who received 2 prior lines of therapy and 20% (95% CI, 8-39) for patients who received 3 and more prior lines of therapy. None of the 5 patients who received targeted therapy, nor any of the 2 patients who received adjuvant anti-PD-1 immediately prior to pembrolizumab plus lenvatinib experienced objective response. By resistance phenotype, ORR was 12.5% (95% CI, 2%-47%) for primary resistance in the adjuvant setting, 34.5% (95% CI, 20%-53%) for primary resistance in the metastatic setting, and 26.7% (95% CI, 14%-44%) for secondary resistance in the metastatic setting. By tumor characteristics, ORR was 71.4% (95% CI, 29%-96%) for primary mucosal melanoma versus 24.1% (95% CI, 14%-38%) for primary cutaneous melanoma, and ORR was 31.5% (95% CI, 20%-46%) for *BRAF* wild-type melanoma versus 15.4% (95% CI, 2%-45%) for *BRAF*-mutant melanoma.

By prognostic factors, ORR was 45.0% (95% CI, 23%-68%) for patients with active brain metastasis, 19.0% (95% CI, 10%-33%) for >3 metastatic sites versus 44% (95% CI, 24-65) for <3 metastatic sites, and 30.8% (95% CI, 17%-50%) for LDH levels >ULN.

Supplementary Table S1 shows the response patterns by subgroups.

With 55 (82.1%) PD or death events in the total population, the median PFS was 3.1 (95% CI, 2.5-3.7) months, with estimated 6- and 12-month PFS rates of 14.9% and 4.5%, respectively (Figure 1A). With 29 (43.4%) deaths, the median OS was 9.77 (95% CI, 5.6-13.9) months, with estimated 6- and 12-month OS rates of 40.3% and 17.9%, respectively (Figure 1B).

## Tolerance data

The median lenvatinib treatment duration was 2.9 months (range 4 days–22.9 months), with a mean dose intensity of
<table><caption>**Table 1.** Baseline demographic and disease characteristics.</caption><thead><tr><th>Baseline characteristics</th><th>All patients (N = 67)</th></tr></thead><tbody><tr><td>Age (years)</td><td></td></tr><tr><td>Mean</td><td>64</td></tr><tr><td>Median (range)</td><td>69 (27-88)</td></tr><tr><td>≥65, N (%)</td><td>38 (57)</td></tr><tr><td>Sex, N (%)</td><td></td></tr><tr><td>Men</td><td>33 (49)</td></tr><tr><td>Women</td><td>34 (51)</td></tr><tr><td>Primary melanoma, N (%)</td><td></td></tr><tr><td>Cutaneous</td><td>54 (81)</td></tr><tr><td>Mucosal</td><td>7 (10)</td></tr><tr><td>Unknown</td><td>6 (9)</td></tr><tr><td>AJCC 8th edition, N (%)</td><td></td></tr><tr><td>III</td><td>2 (3)</td></tr><tr><td>IV</td><td>65 (97)</td></tr><tr><td>M1a</td><td>1 (2)</td></tr><tr><td>M1b</td><td>7 (10)</td></tr><tr><td>M1c</td><td>28 (42)</td></tr><tr><td>M1d</td><td>29 (43)</td></tr><tr><td>Active brain metastasis, N (%)</td><td></td></tr><tr><td>With concomitant brain stereotactic radio-surgery</td><td>14 (70)</td></tr><tr><td>Without concomitant brain stereotactic radiosurgery</td><td>6 (30)</td></tr><tr><td>Number of disease sites, N (%)</td><td></td></tr><tr><td>≤3</td><td>25 (37)</td></tr><tr><td>>3</td><td>42 (63)</td></tr><tr><td>ECOG PS, N (%)</td><td></td></tr><tr><td>0</td><td>23 (34)</td></tr><tr><td>1</td><td>35 (52)</td></tr><tr><td>≥2</td><td>9 (14)</td></tr><tr><td>Mutations status, N (%)</td><td></td></tr><tr><td>BRAF V600</td><td>13 (19)</td></tr><tr><td>NRAS</td><td>20 (30)</td></tr><tr><td>CKIT</td><td>4 (6)</td></tr><tr><td>LDH, N (%) > ULN; IC (95%)</td><td></td></tr><tr><td>Normal</td><td>33 (49)</td></tr><tr><td>N > ULN and <2ULN</td><td>20 (30)</td></tr><tr><td>N ≥ 2ULN</td><td>6 (9)</td></tr><tr><td>Unknown</td><td>8 (12)</td></tr><tr><td>Number of prior lines of therapy, N (%)</td><td></td></tr><tr><td>1</td><td>19 (28)</td></tr><tr><td>2</td><td>18 (27)</td></tr><tr><td>≥3</td><td>30 (45)</td></tr><tr><td>Prior line with Ipilimumab + Nivolumab, N (%)</td><td>58 (87)</td></tr><tr><td>First-line treatment, N (%)</td><td></td></tr><tr><td>Immune checkpoint inhibitors</td><td>63 (94)</td></tr><tr><td>Anti-PD-1 in adjuvant setting</td><td>13 (19)</td></tr><tr><td>Anti-PD-1 in metastatic setting</td><td>24 (36)</td></tr><tr><td>Ipilimumab + Nivolumab</td><td>26 (39)</td></tr><tr><td>Targeted therapy</td><td></td></tr><tr><td>BRAFi + MEKi in adjuvant setting</td><td>1 (1)</td></tr><tr><td>BRAFi + MEKi in metastatic setting</td><td>2 (3)</td></tr></tbody></table>

<table><caption>**Table 1.** Continued</caption><thead><tr><th>Baseline characteristics</th><th>All patients (N = 67)</th></tr></thead><tbody><tr><td>Triplet therapy (Anti-PD-1 + BRAFi + MEKi)<sup>a</sup></td><td>1 (1)</td></tr><tr><td>Chemotherapy</td><td>0 (0)</td></tr><tr><td>Previous line before starting anti-PD-1 and lenvatinib, N (%)</td><td></td></tr><tr><td>Immune checkpoint inhibitors</td><td>50 (75)</td></tr><tr><td>Anti-PD-1 in adjuvant setting</td><td>2 (3)</td></tr><tr><td>Anti-PD-1 in metastatic setting</td><td>18 (27)</td></tr><tr><td>Ipilimumab + Nivolumab</td><td>30 (45)</td></tr><tr><td>Targeted therapy</td><td>6 (9)</td></tr><tr><td>BRAFi + MEKi in adjuvant setting</td><td>0 (0)</td></tr><tr><td>BRAFi + MEKi in metastatic setting</td><td>5 (7)</td></tr><tr><td>MEKi alone</td><td>1 (1)</td></tr><tr><td>Triplet therapy (Anti-PD-1 + BRAFi + MEKi)</td><td>1 (1)</td></tr><tr><td>Chemotherapy</td><td>6 (9)</td></tr><tr><td>Others<sup>b</sup></td><td>4 (6)</td></tr><tr><td>Resistance to anti-PD-1, N (%)</td><td></td></tr><tr><td>Primary resistance in the adjuvant setting</td><td>8 (12)</td></tr><tr><td>Primary resistance in the metastatic setting</td><td>29 (43)</td></tr><tr><td>Secondary resistance in the metastatic setting</td><td>30 (45)</td></tr><tr><td>Follow-up (months)</td><td></td></tr><tr><td>Mean</td><td>7.5</td></tr><tr><td>Median [IQR]</td><td>5.0 [3.3-9.8]</td></tr></tbody></table>

15.8 mg daily. Eighteen (26.9%) patients underwent at least 1 lenvatinib dose reduction. The median duration of pembrolizumab treatment duration was 3.3 months (range 4 days-22.9 months; Supplementary Table S2).

Fifty-four (81%) patients experienced a total of 183 TRAEs of any grade, and 16 (24%) experienced 25 grade 3-4 AEs (Table 3). At data cutoff, 14 (21%) patients had discontinued all treatments for toxicity.

Most common TRAEs of any grade were fatigue (43.3%), nausea and vomiting (26.8%), hypertension (20.9%), diarrhea (20.9%), and hypothyroidism (13.4%). Other TRAEs of any grade that occurred in ≥5 patients were anorexia (11.9%), weight loss (11.9%), proteinuria (11.9%), abdominal pain (10.4%), stomatitis (9.0%), liver test abnormalities (9.0%), arthralgia (9.0%), dysphonia (7.5%), and thrombocytopenia (7.5%). No treatment-related deaths occurred during the follow-up. The occurrence of AEs of any grade, by the different organs/systems involved, is presented in Supplementary Table S3.

Discussion

Despite therapeutic advances in the management of advanced melanoma owing to immunotherapy and TT, a substantial proportion of patients experience innate or acquired resistance. Currently, the treatment options for these patients are limited, and new strategies need to be developed. In a phase

<footnote><sup>a</sup>Clinical trial Combi-I: NCT02967692.</footnote>

<footnote><sup>b</sup>Other therapies were pembrolizumab plus trametinib (N = 2), nivolumab plus relatlimab (N = 1), sorafenib (N = 1).</footnote>

<footnote>Abbreviations: AJCC, American Joint Committee on Cancer; IQR, interquartile range; ECOG, Eastern Cooperative Oncology Group; LDH, lactate dehydrogenase.</footnote>
<table><caption>**Table 2.** Response rates.</caption><thead><tr><th></th><th></th></tr></thead><tbody><tr><td>Total population (N = 67)</td><td></td></tr><tr><td>Best overall response, no. (%)</td><td></td></tr><tr><td>Complete response</td><td>3 (4.5)</td></tr><tr><td>Partial response</td><td>16 (23.9)</td></tr><tr><td>Stable disease</td><td>8 (11.9)</td></tr><tr><td>Progressive disease</td><td>32 (47.8)</td></tr><tr><td>Not evaluated</td><td>8 (11.9)</td></tr><tr><td>Objective response, no. (%) [95% CI]</td><td></td></tr><tr><td>No. of patients</td><td>19 (28.4) [18-41]</td></tr><tr><td>Disease control</td><td></td></tr><tr><td>No. of patients</td><td>27 (40.3)</td></tr><tr><td>Duration of response</td><td></td></tr><tr><td>No. of patients</td><td>19</td></tr><tr><td>Median (months)</td><td>3.1</td></tr><tr><td>Range (months)</td><td>0.6-20.8</td></tr></tbody></table>

Ib/II study cohort of 21 patients with metastatic melanoma who received ≤2 previous systemic therapies (62% were treatment-naïve), combined lenvatinib and pembrolizumab showed an ORR of 48%, 12.5-month median DOR, and 5.5-month median PFS.¹⁵ The phase II LEAP-004 study showed, in a cohort of 103 patients previously treated with anti-PD-1 with or without anti-CTLA-4, that the ORR was 21%, with a median DOR of 8.3 months.

The outcomes in our real-world cohort are similar. Our population showed an ORR of 28.4%. This is a clinically significant rate considering the substantial proportion of patients displaying poor prognostic factors (eg, 43%, 63%, and 39% had stage M1d disease, >3 metastatic sites, and elevated LDH levels, respectively) and heavily pretreated melanoma (including 45% and 87% patients with ≥3 prior therapy lines and anti-CTLA-4 and anti-PD-1 combination pretreatment, respectively). Responses were observed in most subgroups except in patients with LDH levels >2ULN. In patients with active brain metastases, ORR was 45%. This impressive result could be explained in part by the finding of Tran et al, who suggested that lenvatinib may modify brain endothelial permeability and promote trans-endothelial migration of immune cells.¹³ It is noteworthy that 14 (70%) patients underwent concomitant brain SRS. In a recently published smaller cohort, overall ORR was 28% and 31% for patients with brain metastasis. In this study, all the patients with brain metastasis received SRS.¹⁸

Unexpectedly, no response was observed for patients with stages III and IV-M1a melanoma; however, the sample size was small, with 2 and 1 patient, respectively. In contrast to the LEAP-004 study which suggested a similar likelihood of response across clinical resistance phenotypes, patients with primary anti-PD-1 resistance in the adjuvant setting in our cohort seemed to benefit less from this strategy. However, our results must be interpreted with caution given the small sample size. A deeper understanding of mechanisms underlying resistance phenotypes would allow us to adjust strategies and develop more effective treatments.

Interestingly, ORR was higher in patients who previously received first-line combined anti-CTLA-4 and anti-PD-1 therapy (38.5%), compared to those treated with anti-PD-1 alone (8.3%), similar to the LEAP study results. Response

rates were lower in patients with BRAF-mutant tumors (15.4%) compared to those with BRAF wild-type tumors (31.5%). This lower benefit in patients with BRAF mutations has already been reported¹⁴,¹⁸ without specifying whether a link occurred by the cross-pathway resistance mechanisms.¹⁹

An impressive response was also observed for mucosal melanoma with an ORR of 71.4%. Literature on this subject is limited, but recent studies have highlighted the promising efficacy of a combination of anti-PD-1 and anti-angiogenic agents in patients with advanced mucosal melanoma. The efficacy of this combination could be explained not only by an additive antitumor effect but also by the remodeling of the immuno-suppressive tumor microenvironment to an immuno-stimulatory state by inhibiting VEGF.²⁰,²¹ We could also hypothesize an effect through the KIT pathway, targeted by lenvatinib,²²,²³ but we need further investigations to better understand the mechanisms involved in mucosal melanoma pathogenesis. Our observations, based on a small number of cases (n = 7), need to be supported by Supplementary Data. Currently, combined lenvatinib and pembrolizumab is being evaluated for the treatment of mucosal melanoma in a neoadjuvant setting.²⁴

However, this substantial response rate must be weighed against the short-response duration. Indeed, our study showed a lower median DOR (3.1 months) than that observed in the LEAP-004 and phase Ib/II studies (8.3 and 12.5 months, respectively).¹⁴,¹⁵ This difference may be explained by a shorter median follow-up in our study (5.0 months versus 15.3 months in the LEAP-004 study). Nevertheless, we cannot rule out an immune effect of the combination either, as we observed some long responders (DOR ranges from 0.6 to 20.8 months).

The safety profile in the Lenvamel study was consistent with those previously reported for other neoplasms, with the following most common AEs; fatigue, nausea and vomiting hypertension, diarrhea, and hypothyroidism.¹⁴,¹⁵,²⁵⁻²⁸ However, in our cohort, 81% of patients experienced TRAEs of any grade, and 24% experienced grades 3-4 TRAEs, which is a lower rate than that previously reported.¹⁴,¹⁵,²⁵⁻²⁸ This lower incidence of TRAEs could be explained by a different regimen dose. Indeed, the starting dose of lenvatinib was 20 mg daily in other studies, even though the mean doses in the LEAP-004 study and our cohort were similar (15 mg vs 15.8 mg daily, respectively). Moreover, we can hypothesize that a substantial proportion of patients already experienced side effects related to prior immunotherapy or other treatments, which may reduce the report of adverse events with this combination. Finally, it is interesting to highlight that no TRAE-related deaths occurred during the follow-up. At data cutoff, 14 (21%) patients had discontinued all treatments because of TRAEs, suggesting that toxicity may be manageable, although requiring a close follow-up. Indeed, previous trials recommended that lenvatinib be commenced at a high dose while managing toxicities by reducing and/or interrupting the dose to maintain lenvatinib efficacy.

This study had some limitations in particular the small number of patients in subgroups and the short follow-up, which may constrain the generalizability of the data. Further research with larger cohorts is needed to provide more robust data. A longer follow-up duration would also offer more comprehensive insights into the long-term efficacy and safety of
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Survival endpoints. Kaplan-Meier estimate of PFS (A) and OS (B). Abbreviations: OS, overall survival; PFS, progression-free survival.</figcaption></figure>

the treatment. Some other limitations were inherently related to its retrospective design, such as the completeness of safety reporting or the risk of missing data. But, in this multicenter study, all the data were collected using a uniform and standardized CRF across all participating centers. Furthermore, as the proportion of missing data was small, the accuracy of

our analyses was high. Thus, these results must be interpreted with caution. Nevertheless, these findings remain interesting in a population where there is a severe lack of therapeutic options.

As anti-PD-1 plus lenvatinib is not approved by the Food and Drug Administration or European Medicines Agency,
<table><caption>**Table 3.** Rate and severity of AEs.</caption><thead><tr><th rowspan="2">Population</th><th rowspan="2">Patient No.</th><th colspan="3">Adverse events</th></tr><tr><th>All grades, No. patients (%)</th><th>Grade I-II (%)</th><th>Grade III-IV (%)</th></tr></thead><tbody><tr><td>Total</td><td>67</td><td>54 (81%)</td><td>38 (57%)</td><td>16 (24%)</td></tr><tr><td>Total TRAEs leading to interruption of lenvatinib, anti-PD-1, or both</td><td>67</td><td>23 (34%)</td><td>10 (15%)</td><td>13 (19%)</td></tr><tr><td>Total TRAEs leading to discontinuation of lenvatinib, anti-PD-1, or both</td><td>67</td><td>14 (21%)</td><td>8 (12%)</td><td>6 (9%)</td></tr></tbody></table>

Most frequent TRAEs (all cohort N = 67 patients)

<table><thead><tr><th>AEs</th><th>Any grade, No.(%)</th><th>Grade III-IV, No.(%)</th></tr></thead><tbody><tr><td>Fatigue</td><td>29 (43.3%)</td><td>5 (7.5%)</td></tr><tr><td>Nausea and vomiting</td><td>18 (26.8%)</td><td>2 (3.0%)</td></tr><tr><td>Hypertension</td><td>14 (20.9%)</td><td>4 (6.0%)</td></tr><tr><td>Diarrhea</td><td>14 (20.9%)</td><td>1 (1.5%)</td></tr><tr><td>Hypothyroidism</td><td>9 (13.4%)</td><td>0 (0%)</td></tr><tr><td>Anorexia</td><td>8 (11.9%)</td><td>0 (0%)</td></tr><tr><td>Proteinuria</td><td>8 (11.9%)</td><td>4 (6.0%)</td></tr><tr><td>Weight loss</td><td>7 (10.4%)</td><td>1 (1.5%)</td></tr><tr><td>Abdominal pain</td><td>7 (10.4%)</td><td>1 (1.5%)</td></tr><tr><td>Arthralgia</td><td>6 (9.0%)</td><td>2 (3.0%)</td></tr><tr><td>Liver test abnormalities</td><td>6 (9.0%)</td><td>1 (1.5%)</td></tr><tr><td>Stomatitis</td><td>6 (9.0%)</td><td>0 (0%)</td></tr><tr><td>Dysphonia</td><td>5 (7.5%)</td><td>0 (0%)</td></tr><tr><td>Thrombocytopenia</td><td>5 (7.5%)</td><td>1 (1.5%)</td></tr><tr><td>Hemorrhage</td><td>2 (3.0%)</td><td>0 (0%)</td></tr></tbody></table>

our data support this treatment option for refractory melanoma, when no study is available after the failure of standard therapies. We also have to keep in mind the negative results of the LEAP-003 study, although not published yet.²⁹ Indeed, this study aimed to compare lenvatinib and pembrolizumab versus pembrolizumab as first-line therapy for advanced melanoma. The combination therapy provided no added clinical benefit compared with pembrolizumab alone, justifying that it cannot be a first-line option, and highlighting the need for further investigations to understand resistance mechanisms.

Thus, our study highlights the need for new efficient strategies, particularly in the era of cellular therapies, such as TILs, whose data are promising in melanoma refractory to anti-PD-1.³⁰

## Conclusion

The Lenvamel cohort study findings consolidate the encouraging results of the phase II LEAP-004 study by showing an interesting response rate and acceptable safety profile with manageable toxicities in an immuno-refractory and heavily pretreated population with poor prognostic factors. Patients

previously treated with the anti-PD-1 and anti-CTLA-4 combination and those with BRAF wild-type melanoma seemed to benefit more from this second-line strategy. Our study also provides promising but limited data on patients with advanced mucosal melanoma. All these findings support this strategy for refractory melanoma but also highlight the need for new strategies. However, the resistance mechanisms require further investigation.

## Acknowledgments

The authors thank Elsevier Language Editing Services for copyediting.

## Author contributions

Perrine Rousset and Henri Montaudié: study design, data collection, data analysis and interpretation of results, manuscript writing, final approval of manuscript. Charlée Nardin, Eve Maubec, Valentine Heidelberger, Alexandra Picard, Laura Troin, Emilie Gerard, Nora Kramkimel, Maud Steff-Naud, Gaëlle Quéreux, Caroline Gaudy-Marqueste, Candice Lesage, Claire Mignard, Géraldine Jeudy, Thomas Jouary, Mélanie
Saint-Jean, Barouyr Baroudjian, Elodie Archier, Laurent Mortier and Céleste Lebbe: data interpretation, approval of final manuscript. All authors contributed to the publication according to the ICMJE guidelines for the authorship. All authors read and approved the manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

## Funding

No funding to report.

## Conflicts of interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: P.R.: declares no competing interest. C.N.: reports Honoraria from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre; Participated in clinical trials with Bristol Myers Squibb, Checkpoint Therapeutics, MSD, Novartis, Pierre Fabre, Regeneron, Replimmune; Travel grants from Bristol Myers Squibb, Pierre Fabre, and Novartis. E.M.: declares no competing interest. V.H.: declares no competing interest. A.P.: declares no competing interest. L.T.: declares no competing interest. E.G.: reports Honoraria from Bristol Myers Squibb, Novartis, MSD and Pierre Fabre; Participated in clinical trials with Bristol Myers Squibb, MSD, Pierre Fabre, Novartis. Travel grants from Bristol Myers Squibb, Pierre Fabre and Novartis. N.K.: declares no competing interest. M.S.-N.: declares no competing interest. G.Q.: declares no competing interest. C.G.-M.: reports Honoraria from Bristol Myers Squibb and Pierre Fabre; Participated in clinical trials with Bristol Myers Squibb, Pfizer, Amgen, GSK, Roche, Novartis, Pierre Fabre, MSD, Janssen, Kartos, IFX, Huyabio, Astex, Regeneron, IO Biotech, Philogen, Sotio, Kinnate, Astra Zeneca Replimmune; Travel grants from MSD, Bristol Myers Squibb and Pierre Fabre. C.L.: declares no competing interest. C.M.: declares no competing interest. G.J.: reports honoraria from Bristol Myers Squibb, MSD, Novartis, Pierre Fabre; and participated in clinical trials with Bristol Myers Squibb, Huyabioscience, MSD, Novartis, Pierre Fabre, Regeneron; Travel grants from MSD, Pierre Fabre, Novartis. T.J.: declares no competing interest. M.S.-J.: declares no competing interest. B.B.: declares no competing interest. E.A.: declares no competing interest. L.M.: declares no competing interest. C.L.: declares no competing interest. H.M.: reports Honoraria from Bristol Myers Squibb, Merck Serono, MSD, Novartis, Pierre Fabre; Institutional support from Bristol Myers Squibb, Leo Pharma; Participated in clinical trials with Bristol Myers Squibb, Checkpoint Therapeutics, Huyabioscience, Incyte, Merck Serono, MSD, Nektar Pharmaceuticals, Novartis, Pierre Fabre, Regeneron, Replimmune; Travel grants from Bristol Myers Squibb, Pierre Fabre, Novartis

## Data availability

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

## Supplementary material

Supplementary material is available at *The Oncologist* online.

## References

1. Ugurel S, Röhmel J, Ascierto PA, et al. Survival of patients with advanced metastatic melanoma: the impact of MAP kinase pathway inhibition and immune checkpoint inhibition - update 2019. *Eur J Cancer*. 2020;130(7):126-138. https://doi.org/10.1016/j.ejca.2020.02.021

2. Ascierto PA, Flaherty K, Goff S. Melanoma. *Am Soc Clin Oncol Educ Book*. 2018;38(1):751-758. https://doi.org/10.1200/EDBK_199047

3. Robert C, Grob JJ, Stroyakovskiy D, et al. Five-year outcomes with dabrafenib plus trametinib in metastatic melanoma. *N Engl J Med*. 2019;381(7):626-636. https://doi.org/10.1056/NEJMoa1904059

4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma [published correction appears in N Engl J Med. 2018 Nov 29;379(22):2185]. *N Engl J Med*. 2015;373(1):23-34. https://doi.org/10.1056/NEJMoa1504030

5. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-term outcomes with nivolumab plus ipilimumab or nivolumab alone versus ipilimumab in patients with advanced melanoma. *J Clin Oncol*. 2022;40(2):127-137. https://doi.org/10.1200/JCO.21.02229

6. Bai R, Chen N, Li L, et al. Mechanisms of cancer resistance to immunotherapy. *Front Oncol*. 2020;10(1):1290. https://doi.org/10.3389/fonc.2020.01290

7. Kluger HM, Tawbi HA, Ascierto ML, et al. Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce. *J ImmunoTher Cancer*. 2020;8(1):e000398. https://doi.org/10.1136/jitc-2019-000398

8. Kimura T, Kato Y, Ozawa Y, et al. Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1-6 hepatocellular carcinoma model. *Cancer Sci*. 2018;109(12):3993-4002. https://doi.org/10.1111/cas.13806

9. Kato Y, Tabata K, Kimura T, et al. Lenvatinib plus anti-PD-1 antibody combination treatment activates CD81 T cells through reduction of tumor-associated macrophage and activation of the interferon pathway. *PLoS One*. 2019;14(2):e0212513. https://doi.org/10.1371/journal.pone.0212513

10. Deng H, Kan A, Lyu N, et al. Dual vascular endothelial growth factor receptor and fibroblast growth factor receptor inhibition elicits antitumor immunity and enhances programmed cell death-1 checkpoint blockade in hepatocellular carcinoma. *Liver Cancer*. 2020;9(3):338-357. https://doi.org/10.1159/000505695

11. Yi C, Chen L, Lin Z, et al. Lenvatinib targets FGF receptor 4 to enhance antitumor immune response of anti-programmed cell death-1 in HCC. *Hepatology*. 2021;74(5):2544-2560. https://doi.org/10.1002/hep.31921

12. Adachi Y, Kamiyama H, Ichikawa K, et al. Inhibition of FGFR reactivates IFNgamma signaling in tumor cells to enhance the combined antitumor activity of lenvatinib with anti-PD-1 antibodies. *Cancer Res*. 2022;82(2):292-306. https://doi.org/10.1158/0008-5472.CAN-20-2426

13. Tran TT, Caulfield J, Zhang L, et al. Lenvatinib or anti-VEGF in combination with anti-PD-1 differentially augments antitumor activity in melanoma. *JCI Insight*. 2023;8(7):e157247. https://doi.org/10.1172/jci.insight.157347

14. Arance A, de la Cruz-Merino L, Petrella TM, et al. Phase II LEAP-004 study of lenvatinib plus pembrolizumab for melanoma with confirmed progression on a programmed cell death protein-1 or programmed death ligand 1 inhibitor given as monotherapy or in combination. *J Clin Oncol*. 2023;41(1):75-85. https://doi.org/10.1200/JCO.22.00221

15. Taylor MH, Lee CH, Makker V, et al. Phase IB/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. *J Clin Oncol*. 2020;38(11):1154-1163. https://doi.org/10.1200/JCO.19.01598

16. O'Day S, Gonzalez R, Kim K, et al. A phase II study of the multitargeted kinase inhibitor lenvatinib in patients with advanced BRAF
wild-type melanoma. *J Clin Oncol.* 2013;31(15_suppl):9026-9026.
https://doi.org/10.1200/jco.2013.31.15_suppl.9026

17. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). *Eur J Cancer.* 2009;45(2):228-247. https://doi.org/10.1016/j.ejca.2008.10.026

18. Stoff R, Asher N, Laks S, et al. Real world evidence of Lenvatinib + anti PD-1 as an advanced line for metastatic melanoma. *Front Oncol.* 2023;13(2):1180988. https://doi.org/10.3389/fonc.2023.1180988

19. Hugo W, Shi H, Sun L, et al. Non-genomic and immune evolution of melanoma acquiring MAPKi resistance. *Cell*. 2015;162(6):1271-1285. https://doi.org/10.1016/j.cell.2015.07.061

20. Mao L, Fang M, Chen Y, et al. Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: a multicenter, open-label, single-arm phase II Study. *Clin Cancer Res.* 2022;28(21):4642-4648. https://doi.org/10.1158/1078-0432.CCR-22-1528

21. Sheng X, Yan X, Chi Z, et al. Axitinib in combination with toripalimab, a humanized immunoglobulin G₄ monoclonal antibody against programmed cell death-1, in patients with metastatic mucosal melanoma: an open-label phase IB trial. *J Clin Oncol.* 2019;37(32):2987-2999. https://doi.org/10.1200/JCO.19.00210

22. Matsui J, Yamamoto Y, Funahashi Y, et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. *Int J Cancer.* 2008;122(3):664-671. https://doi.org/10.1002/ijc.23131

23. Tohyama O, Matsui J, Kodama K, et al. Antitumor activity of lenvatinib (E7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. *J Thyroid Res.* 2014;2014(1):638747. https://doi.org/10.1155/2014/638747

24. Mao L, Si L, Jie D, et al. NeoPlus: a phase II study of neoadjuvant Lenvatinib and pembrolizumab in resectable mucosal melanoma.NeoPlus: a phase II study of neoadjuvant lenvatinib and pembrolizumab in resectable mucosal melanoma. *J Clin Oncol.* 2023;41(16_suppl):9514-9514. https://doi.org/10.1200/JCO.2023.41.16_suppl.9514

25. Finn RS, Ikeda M, Zhu AX, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepatocellular carcinoma. *J Clin Oncol.* 2020;38(26):2960-2970. https://doi.org/10.1200/JCO.20.00808

26. Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. *J Clin Oncol.* 2020;38(26):2981-2992. https://doi.org/10.1200/JCO.19.02627

27. Lee CH, Shah AY, Rasco D, et al. Lenvatinib plus pembrolizumab in patients with either treatment-naive or previously treated metastatic renal cell carcinoma (Study 111/KEYNOTE-146): A phase 1b/2 study. *Lancet Oncol.* 2021;22(7):946-958. https://doi.org/10.1016/S1470-2045(21)00241-2

28. Mo DC, Luo PH, Huang SX, Wang HL, Huang JF. Safety and efficacy of pembrolizumab plus lenvatinib versus pembrolizumab and lenvatinib monotherapies in cancers: a systematic review. *Int Immunopharmacol.* 2021;91(1):107281. https://doi.org/10.1016/j.intimp.2020.107281

29. Arance A, Berciano-Guerrero MA, Guo J et al. Lenvatinib plus pembrolizumab (len + pembro) versus pembro alone for unresectable or metastatic melanoma (MEL): results of LEAP-003. The 20th International Congress of the Society For Melanoma Research; 2023.

30. Rohaan MW, Borch TH, van den Berg JH, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. *N Engl J Med.* 2022;387(23):2113-2125. https://doi.org/10.1056/NEJMoa2210233