Top advances of the year: Melanoma

INTRODUCTION

Malignant melanoma remains a significant global public health challenge with substantial morbidity and mortality. According to recent estimates, in the United States alone, the incidence of cutaneous melanoma reached nearly 100,000 new diagnoses in 2023, with approximately 8000 fatalities attributed to the disease.¹ Despite advancements in treatments, such as immune checkpoint inhibitors (ICIs) and BRAF-targeted therapy, the 5-year relative survival rate for metastatic melanoma remains at 32%.¹ Consequently, there is a pressing need for further research to enhance patient outcomes through the exploration of innovative therapeutic modalities, which could include novel combinations, personalized cancer vaccines, cell-based therapies, and the evaluation of existing agents in early stage melanoma, in both preoperative and postoperative settings. Here, we outline the recent progress made in the management of melanoma, with a particular emphasis on tumor-infiltrating lymphocytes (TILs) and bispecific antibodies. In addition, we provide insights from adjuvant studies in early stage melanoma, describe ongoing trials investigating combination immune-modulating therapies, and conclude by examining the rapidly evolving neoadjuvant landscape.

ADVANCED MELANOMA

Tumor-infiltrating lymphocytes

TILs have emerged as a promising therapeutic strategy for advanced melanoma because their polyclonal nature is capable of recognizing multiple tumor-associated antigens.² Lifileucel (LN-144) represents a notable advancement, being a one-time, autologous TIL cell therapy derived from a patient’s own tumor tissue.^3,4 The therapy involves the surgical extraction of TILs from resected tumor samples, yielding billions of polyclonal TILs specific to the patient’s tumor.³

Adoptive cell therapy with TILs has demonstrated promising antitumor activity in patients with advanced solid tumours.^3,5–8 The C-144–01 phase 2 study (ClinicalTrial.gov identifier NCT02360579) enrolled 153 patients who had disease-refractory melanoma before ICI or targeted therapy. Lifileucel demonstrated a promising objective response rate (ORR) of 31.4%, with significant responses observed across all subgroups analyzed. The median duration of response (DOR) was not reached at a median study follow-up of 27.6 months, with responses that lasted >18 months in approximately 40% of cases. The median overall survival (OS) was 13.9 months, with a 12-month OS rate of 54.0%, and the median progression-free survival (PFS) was 4.1 months, with a 12-month PFS rate of 28.3%.^3,7,8

In a post hoc analysis, lifileucel exhibited efficacy in patients who were refractory to prior anti–PD-1/PD-L1 therapy, with an ORR of 31.3%, whereas the ORR was 26.8% in patients who received a prior anti-PD-1 and anti–CTLA-4 combination.⁷ The DOR showed a positive correlation both with primary resistance to prior anti–PD-1 therapy and with shorter cumulative duration of prior anti–PD-1 therapy. According to the multivariate model, for each 6-month decrease in exposure to prior ICI therapy, the median DOR to lifileucel nearly doubled. Moreover, the DOR appeared to be influenced by the baseline lactate dehydrogenase level. Individuals with lactate dehydrogenase levels at or below the upper limit of normal demonstrated an improved DOR, with a hazard ratio (HR) of 0.39.

Toxicities associated with TIL cellular therapy were primarily linked to the nonmyeloablative lymphodepletion preconditioning regimen and post-TIL infusion interleukin-2 (IL-2) doses, with few infusion-related adverse reactions.⁸ Grade 3/4 treatment-emergent adverse events (TEAEs) included thrombocytopenia, anemia, and febrile neutropenia, consistent with the known safety profiles of the nonmyeloablative lymphodepletion and IL-2 regimens. Infusion-related reactions related to lifileucel were infrequent.^3,5,8 Adverse reactions, including anaphylactic and infusion-related events believed to be associated with lifileucel, were observed in two patients (1.3%; grade 3/4) and six patients (3.8%; grade 1/2), respectively. Grade 3/4 TEAEs that occurred in ≥30% of patients are summarized in Table 1.

TABLE 1.

Ongoing phase 2 and 3 clinical trials in the adjuvant setting.

Clinical trial (ClinicalTrials.gov identifier)	Phase	Disease stage (resected)	Treatment arms	Primary end point	Recruitment status
Relativity-098 (NCT05002569)	3	Stage III–IV	Relatlimab + nivolumab versus nivolumab	RFS	Completed
Keyvibe-010 (NCT05665595)	3	Stage II–IV	Vibostolimab + pembrolizumab versus pembrolizumab	RFS	Completed
INTerpath-01 (NCT05933577)	3	Stage II–IV	V940/pembrolizumab versus placebo/pembrolizumab	RFS	Ongoing
Regeneron (NCT05608291)	3	Stage II–IV	Cemiplimab/fianlimab versus pembrolizumab	RFS	Ongoing
COLUMBUS-AD (NCT05270044)	3	Stage IIB/C	Encorafenib + binimetinib versus placebo	RFS	Discontinued
Ansstas IIT (NCT03563716)	2	Stage II	Tiragolumab + atezolizumab versus atezolizumab in patients with positive ctDNA after resection	RRFS	Ongoing
NivoMela (NCT04309409)	3	Stage IIA/B/C	Nivolumab versus placebo informed by high-risk tumor gene expression profiling	RFS	Ongoing

Abbreviations: ctDNA, circulating tumor DNA; IIT, investigator-initiated trial; IITRFS, recurrence-free survival; RRFS, regional recurrence-free survival.

The Netherlands Cancer Institute recently published findings from a randomized phase 3 clinical trial investigating the efficacy of autologous, in vitro, expanded, noncryopreserved TILs versus ipilimumab in 168 patients who had previously treated, unresectable or metastatic melanoma.⁹ That study demonstrated a 6-month PFS rate of 53% in the TIL cell therapy group, in contrast to the rate of 21% observed in those receiving ipilimumab. Furthermore, the ORR was higher in the TIL group at 49% compared with 21% in the ipilimumab group. The median OS was 25.8 months in the TIL group and 18.9 months in the ipilimumab group (HR, 0.83; 95% confidence interval [CI], 0.54–1.27). Grade 3 or greater treatment-related adverse events were observed in all patients who received TILs and in 57% of those who received ipilimumab. These adverse events were primarily attributed to chemotherapy-related myelosuppression.

Based on the results described above, on February 16, 2024, the US Food and Drug Administration granted accelerated approval to lifileucel for adult patients who had unresectable or metastatic melanoma and were previously treated with an anti–PD-1 agent and targeted therapy if they were BRAF V600 mutation-positive.¹⁰ Recruitment commenced in late 2023 for a confirmatory phase 3 study investigating lifileucel in combination with pembrolizumab versus pembrolizumab alone in patients with untreated, unresectable, or metastatic melanoma in the front-line setting.¹¹

Despite apparent benefits, TIL therapy for solid cancers presents several challenges.¹² The initial step involves surgical resection to isolate TILs, which can be invasive and morbid. Not all tumors are accessible for resection, however, and radiologic interventions may be necessary, which are not universally available. Even after resection, only a portion of TILs can be successfully expanded, with approximately one third failing to do so in patients with melanoma. The need for specialized centers and technical expertise for TIL culture and expansion poses logistical hurdles. Moreover, the 6-week to 8-week period required for cell expansion may be too long considering the rapid progression of some of the tumors. Hence it is crucial to develop protocols aimed at reducing the production time of TILs.

Novel approaches to targeting preferentially expressed antigen in melanoma

IMC-F106C

Immune mobilizing monoclonal T-cell receptor (TCR) against cancer molecules, such as the gp100-directed molecule tebentafusp, represent a novel class of TCR/anti–CD3-bispecific fusion proteins. These agents are designed to target intracellularly derived peptides that are presented on the tumor cell surface in conjunction with human leukocyte antigen (HLA). Tebentafusp specifically has shown promising results, including an OS benefit, in a randomized phase 3 trial involving previously untreated patients with metastatic uveal melanoma and germline HLA-A*02:01 expression.¹³

IMC-F106C is a novel therapeutic agent designed to target cancers expressing preferentially expressed antigen in melanoma (PRAME), such as melanoma and lung, ovarian, and breast cancers, as established by Ikeda et al. in 1997.¹⁴ This unique construct comprises a soluble TCR domain fused to an anti-CD3 single-chain variable fragment. The TCR domain serves to recognize the PRAME peptide fragment when presented by HLA-A*02:01 on the cell surface, facilitating precise targeting of tumor cells expressing PRAME.

IMC-F106C as a weekly monotherapy demonstrated durable clinical efficacy in the IMC-F106C-101 phase 1 trial (ClinicalTrials.gov identifier NCT04262466), which was conducted in patients who were diagnosed with metastatic cutaneous and uveal melanoma as well as serous ovarian cancer.¹⁵ In that trial, 42 heavily pretreated patients were treated in nine cohorts during the dose-escalation phase. In the 13 tebentafusp-naive patients, none of 13 (69%) had tumor shrinkage, and five of 13 (38%) had a partial response, including two of three patients with cutaneous melanoma patients (all failed prior anti–PD-1 and anti–CTLA-4 treatments). Interestingly, a circulating tumor DNA response was observed across these multiple tumor types and included some cases with complete clearance.

The predominant TEAEs observed in greater than 40% of participants overall included pyrexia (57.3%), cytokine release syndrome (CRS; 52.8%), and rash (41.6%).¹⁵ Notably, most CRS events were of grade 1 severity, with no occurrences of grade 3 or greater CRS. Furthermore, CRS events predominantly transpired during the initial three doses, with a declining incidence and severity noted with each subsequent dose. These adverse events align with the proposed mechanism of action of IMC-F106C and are attributed to cytokine release stemming from rapid T-cell activation.

The combination of IMC-F106C with nivolumab is currently under investigation in a phase 3 clinical trial (PRISM-MEL-301; ClinicalTrials.gov identifier NCT06112314), in which treatment-naive patients with advanced melanoma who are positive for HLA-A*02:01 will undergo randomization in a 1:1:1 design.¹⁶ Participants will be assigned to receive either IMC-F106C at 40 mcg in combination with nivolumab (arm A), IMC-F106C at 160 mcg in combination with nivolumab (arm B), or a regimen comprising nivolumab alone or in combination with relatlimab. This trial aims to evaluate the efficacy and safety profile of these treatment regimens, with a focus on maximizing therapeutic outcomes for patients with advanced melanoma.

IMA203

Another approach to targeting PRAME is through TCR-engineered T cells (TCR-T), with which IMA203 has demonstrated early signals of robust and durable responses in patients who have treatment-refractory melanoma.¹⁷ In contrast with surgical TIL harvest, TCR-T cell production relies on T-cell collection from the blood followed by genetic modification with insertion of the exogenous TCR that recognizes a cancer antigen, and then reinfusion back to the patient as their treatment. Also different from TIL therapy, TCR-T cell therapy does not rely upon the administration of high-dose IL-2, potentially improving toxicity and simplifying the administration process.

In an ongoing phase 1 clinical trial, 16 heavily pre-treated patients received IMA203 T-cell therapy at escalating dose levels.¹⁷ All evaluable patients (N = 12) achieved disease control (stable disease or partial response), and six patients demonstrated partial responses. Updated results from the melanoma expansion cohort were presented at the International Congress of the Society for Melanoma Research in 2023.¹⁸ IM203 continued to be well tolerated, with a 50% confirmed ORR rate at the recommended phase 2 dose. Some of these responses were ongoing beyond 15 months, and the median DOR had not been reached at a median follow-up of 14.4 months. TEAEs after IMA203 infusion were believed to be transient and easily manageable.¹⁷ With the rapidly evolving landscape of cellular therapies and PRAME-targeted therapies and the associated risks of CRS, oncologists and other care providers would need to familiarize themselves with the management of CRS and incorporate it into their standard practice.

Germline HLA genotype has been previously evaluated for its prognostic and predictive value for response and immune adverse events in several cancer types.^19–22 HLA-A*02:01 status is routinely tested to determine eligibility for treatment with tebntafusp in the management of advanced uveal melanoma.¹³ With its routine use as an eligibility criterion for PRAME-targeting bispecific antibody trials, HLA-A*02:01 has the potential to become a new blood-based germline biomarker in the management of patients who have treatment-naive advanced cutaneous melanoma in addition to the somatic BRAF mutation testing.

Oncolytic viruses—RP1

RP1, an oncolytic virus with enhanced potency and replication potential, is generated from a novel clinical strain of herpes simplex virus-1 called RH018, chosen because of its superior oncolytic activity in vitro.²³ Early findings from the phase 1/2 IGNYTE clinical trial (ClinicalTrials.gov identifier NCT03767348) investigating RP1 in combination with nivolumab among patients with skin cancers indicate durable responses, with a median DOR reaching 13.3 months. Notably, there were responses in individuals with anti–PD-1 or anti–PD-1/anti–CTLA-4 therapy-refractory melanoma, with an ORR of 37.5%.²⁴ In addition, sustained antitumor activity was observed in patients with nonmelanoma skin cancers who were naive to anti–PD-1 treatment. That trial also included a registration-directed cohort (n = 125) focused on patients with advanced melanoma who failed on anti–PD-1 therapy. Preliminary data from the initial 91 patients with melanoma who failed on anti–PD-1 therapy (including 16 from the initial melanoma cohort and 75 from the registration-directed cohort) revealed an ORR of 37.4% (with a complete response rate of 18.7%), showcasing responses in both treated and untreated lesions. The combination is well tolerated, with mostly injection site pain or fever as TRAEs. Building upon these findings, a phase 3 study is planned with a two-arm, randomized trial with physician’s choice of treatment as a comparator arm versus the combination of RP1 plus nivolumab in ICI-refractory melanoma (ClinicalTrials.gov identifier NCT06264180).

Adjuvant therapy for resected stage II/III melanoma

Pembrolizumab and nivolumab have demonstrated relapse-free survival (RFS) and distant metastasis-free survival (DMFS) benefits in randomized clinical trials in patients with high-risk, completely resected, stage IIB/IIC and III melanoma, but OS data are not yet mature.^25–28 However, approximately 50% of patients with stage III melanoma still experience disease relapse despite curative-intent surgery and immunotherapy.²⁹

The phase 2 KEYNOTE-942 study (ClinicalTrials.gov identifier NCT03897881) evaluated the addition of messenger RNA individualized neoantigen therapy (V940) to pembrolizumab compared with pembrolizumab monotherapy in patients who had high-risk, resected, stage IIIB/IIIC/IIID and IV melanoma.³⁰ V940 is manufactured using whole-exome and transcriptome sequencing data generated from each patient’s tumor and blood to bioinformatically predict personalized neoantigens that will be expressed and bind to the patient’s germline HLA profile. In the study, up to 34 candidate neoantigens were predicted per patient and were subsequently encoded onto a single-stranded messenger RNA that was provided back for administration to the patient as a vaccination drug product. This phase 2 study demonstrated an additional 17% improvement in RFS (HR, 0.56; two-sided p = .053) and a 15% improvement in DMFS (HR, 0.34; two-sided p = .013) at 18 months of follow-up for the addition of V940 to pembrolizumab. An important point nuance here is the observation of an even larger benefit by HR for DMFS relative to RFS. In all prior adjuvant ICI trials in melanoma, these two measurements have been tightly correlated. Although preliminary, this observation for V940 may suggest a differentiated mechanistic effect and perhaps the potential for a more robust and obvious impact on OS compared with ICI alone.

No major safety concerns were seen with the combination of pembrolizumab and V940. Adverse events observed with V940 were like those reported with the coronavirus disease 2019 messenger RNA vaccines, including injection site erythema and swelling, flu-like symptoms, and headaches. Most of these were grade 1 or 2 and were self-limiting. Based on the promising results of this study, a phase 3 study has been initiated to evaluate the additional benefit of V940 to pembrolizumab.³¹

Several other combination adjuvant immunotherapy clinical trials have either recently completed recruitment or are ongoing. These trials are summarized in Table 1.

NEOADJUVANT IMMUNOTHERAPY

Neoadjuvant immunotherapy is a rapidly evolving treatment landscape in melanoma. It has been hypothesized that neoadjuvant treatment may facilitate a more robust and diverse T-cell response, as compared to adjuvant, due to intact neoantigen repertoire of the tumor.³² The phase 2 SWOG S1801 trial demonstrated a superior event-free survival (EFS) by giving three neoadjuvant cycles of pembrolizumab followed by 15 adjuvant cycles versus 18 cycles of adjuvant pembrolizumab with an estimated two year EFS 72% vs 49%, p = 0.004.³³ The OpACIN-neo and PRADO (ClinicalTrials.gov identifier NCT02977052) phase 2 trials of combination ipilimumab and nivolumab demonstrated an EFS rate at 12 months of about 85%, with a major pathologic response rate of approximately 60%.^34,35 Updated data from OpACIN-neo indicate that these outcomes are potentially durable (RFS rate at 3 years, 82%) and translate into a promising OS rate at 3 years of 92%.³⁶

Based on the findings from these combination trials, in the phase 3 NADINA trial (ClinicalTrials.gov identifier NCT04949113), patients with resectable, macroscopic, node-positive, stage III melanoma were randomized to receive either two cycles of neoadjuvant combination ipilimumab (80 mg) and nivolumab (240 mg) every 3 weeks followed by definitive surgery or upfront surgery followed by 12 cycles of adjuvant nivolumab (480 mg) every 4 weeks.³⁷ Patients who did not achieve a major pathologic response (defined as ≤10% residual viable tumor) in the neoadjuvant cohort were given adjuvant nivolumab or dabrafenib plus trametinib (if they were BRAF V600-mutation positive). The primary end point is EFS. Secondary end points included RFS, DMFS, OS, the pathologic response rate, safety, and quality of life. Results of this study are eagerly anticipated in 2024.

CONCLUSIONS

Significant progress has been made recently in advanced melanoma because of ICI combinations and the first approval of adoptive cell therapy in solid tumors. In addition, ICIs continue to expand their role in the perioperative and adjuvant settings for earlier stage disease. These advances are augmented by emerging next-generation therapeutics, such as individualized neoantigen therapy, PRAME-targeting strategies, oncolytic viruses, and more. Despite this success, a major unmet need remains to identify actionable biomarkers for patient selection across all stages of melanoma.