Novel Combinations Highlight Treatment Advances in Melanoma

James W. Smithy, MD, MHS

Melanoma Medical Oncologist and Cellular Therapist

Assistant Attending Physician

Memorial Sloan Kettering Cancer Center

New York, NY

Melanoma remains a formidable challenge in oncology, particularly in its advanced stages. Over the past decade, however, the treatment landscape has transformed with immune checkpoint inhibitors (ICIs) and targeted therapies. The emergence of CTLA-4, PD-1, and PD-L1 inhibitors, along with BRAF and MEK inhibitors, has significantly improved outcomes.¹

“The key question in melanoma today is how to extend these therapies to maximize their benefit,” James W. Smithy, MD, MHS, a melanoma medical oncologist and assistant attending physician at Memorial Sloan Kettering Cancer Center, New York, New York, told Targeted Therapies in Oncology in an interview.

Smithy addressed the challenges facing clinicians and patients, especially regarding overcoming resistance, optimal sequencing strategies, exploring the potential role of tumor-infiltrating lymphocytes (TILs), and details about adjuvant and neoadjuvant approaches.

“Despite these advances, resistance remains a hurdle. Approximately half of patients have long-term benefit from existing combination immunotherapies,” Smithy said, “but for patients who don’t benefit, we need strategies that augment responses and overcome resistance.”

Wolchok et al² showed that after a 10-year follow-up, the median overall survival (OS) was 71.9 months with nivolumab (Opdivo) plus ipilimumab (Yervoy), 36.9 months with nivolumab, and 19.9 months with ipilimumab.

The HR for death was 0.53 (95% CI, 0.44-0.65) for nivolumab plus ipilimumab as compared with ipilimumab and was 0.63 (95% CI, 0.52-0.76) for nivolumab as compared with ipilimumab.² Overall, among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab, according to investigators.²

Smithy noted there are several ways to augment this benefit. One encouraging method is to leverage a vaccine approach through immunomodulatory vaccines or the development of personalized vaccines.

“Vaccines have recently come to the fore as potential partners to immunotherapies to enhance their efficacy,” Smithy said.

Immunomodulatory Vaccines

“[ICIs] enhance the T-cell response against melanoma, but there are other immune cells in the tumor microenvironment that can also deter the antitumor effect,” Smithy said. Data from studies evaluating the safety and effects of an immunomodulatory peptide vaccine that targets these inhibitory immune cell populations have shown promise.

A phase 1/2 trial (NCT03047928) evaluating IO102-IO103 in combination with nivolumab in 30 patients with metastatic melanoma led to an objective response rate (ORR) of 80% (95% CI, 62.7%-90.5%), with 43% of patients (CI, 27.4%60.8%) achieving a complete response (CR) and 37% (95% CI, 20.9%-54.5%) reaching a partial response (PR) as the best overall response. Further, investigators reported a median progression-free survival (PFS) of 26 months (95% CI, 15.4-69 months).³

Early-onset response was frequent, with 22 of 30 patients having an ORR at the first evaluation (after 12 weeks on treatment). Median times to PR and CR were 75 days (range, 54-256) and 327 days (range, 73-490), respectively.³ Evaluating the subset of patients with PD-L1–positive disease (n = 17) revealed an ORR of 94.1% (95% CI, 73.0%-99.7%), and those who were PD-L1 negative (n = 13) had an ORR of 61.5% (95% CI, 35.5%-82.3%).³ “This could be an exciting potential strategy for overcoming ICI resistance,” Smithy said.

A phase 2 trial (NCT05912244) evaluating nivolumab and relatlimab-rmbw (Opdualag) in combination with the vaccine IO102-IO103 is underway in patients with untreated, unresectable stage III/IV melanoma.⁴ The vaccine is administered subcutaneously every 2 weeks for the initial 8 weeks and then every 4 weeks for up to 2 years. An interim efficacy analysis will follow after response data are available for 21 patients.

Phanie - Sipa Press / Alamy Stock Photo

The primary end point is ORR by RECIST 1.1, weighted by PD-L1 expression. Secondary end points include safety assessed by Common Terminology Criteria for Adverse Events v5.0, PFS by RECIST 1.1, duration of disease response, and disease control rate.⁴

Personalized Vaccines

Another way to enhance the immune response is the use of personalized vaccines, according to Smithy. The rationale for developing such vaccines is based on the fact that each patient has a different set of mutations, and melanoma has many mutations. Investigators hypothesized that these mutations can be used to prime the immune response against the disease. The pivotal phase 3 randomized V940-001 clinical trial (NCT05933577) is evaluating V940, an investigational individualized neoantigen therapy, in combination with pembrolizumab (Keytruda) as an adjuvant treatment in patients with resected high-risk (stage IIB-IV) melanoma.⁵

The trial is evaluating the efficacy and safety of adjuvant pembrolizumab plus V940 compared with pembrolizumab plus placebo.

Approximately 1089 patients will be randomly assigned 2:1 to receive 400 mg of pembrolizumab plus 1 mg of V940 or 400 mg of pembrolizumab with placebo.

Pembrolizumab will be administered intravenously every 6 weeks, and v940 or placebo will be administered intramuscularly every 3 weeks. Treatment will continue for up to 9 doses or until disease recurrence, unacceptable toxicity, or patient withdrawal.

The primary end point is recurrence-free survival by investigator review. Secondary end points are distant metastasis–free survival by investigator review, OS, safety and tolerability, and quality of life.

“The trial pairs a standard ICI with a personalized vaccine that is mRNA based to determine if that combination can help overcome resistance or prevent recurrence [compared with] just ICI alone,” said Smithy.

Targeted Therapies

Targeted therapies focusing on BRAF-mutated melanoma have met with success, with vemurafenib (Zelboraf) and dabrafenib (Tafinlar) demonstrating response rates of approximately 50%.^6,7 Over time, however, these monotherapies met with resistance But BRAF/MEK inhibitor combinations of dabrafenib/trametinib (Mekinist) and vemurafenib/cobimetinib (Cotellic) achieved a median PFS of about 1 year.

Sequencing

In advanced disease, the optimal sequence of targeted therapy vs immunotherapy for patients is widely debated. But findings from the phase 3 DREAMseq trial (NCT02224781) may have settled the question.⁹

In the trial, patients with treatment-naive BRAF V600–mutant metastatic melanoma were randomly assigned to receive either the combination of nivolumab/ipilimumab (arm A) or dabrafenib/trametinib (arm B) in step 1. At disease progression, they were enrolled in step 2 to receive the alternate therapy, dabrafenib/trametinib (arm C) or nivolumab/ipilimumab (arm D).⁹

Investigators enrolled 265 patients in the trial, with 73 going on to step 2 (27 in arm C and 46 in arm D). The study was stopped early because a clinically significant end point had been achieved. The 2-year OS for those starting in arm A was 71.8% (95% CI, 62.5%-79.1%) and 51.5% in arm B (95% CI, 41.7%-60.4%).

Step 1 PFS favored arm A (P = .054). The ORRs for arms A through D were 46.0%, 43.0%, 47.8%, and 29.6%, respectively. The median duration of response (DOR) was not reached for arm A and was 12.7 months for arm B (P < .001).⁹

The investigators concluded that the preferred treatment sequence for most patients should be the combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary.

Smithy highlighted key takeaways: “If possible, consider using immunotherapy first before targeted therapy tomize long-term benefit. For patients with heavy disease burden, targeted therapy offers quicker responses and a higher chance of initial response. If you need to get the disease under control urgently, targeted therapy is a useful tool [to] address that,” he said.

The SECOMBIT 3-arm trial (NCT02631447) evaluated treatment-naive patients with metastatic BRAF V600 mutation melanoma who were randomly assigned to receive either targeted therapy followed by immunotherapy (arm A), immunotherapy followed by targeted therapy (arm B), or targeted therapy and immunotherapy followed by additional targeted therapy (arm C).¹⁰

Findings demonstrated that sequential immunotherapy of ipilimumab (Yervoy) plus nivolumab (Opdivo) followed by the targeted therapy combination of encorafenib (Braftovi) plus binimetinib (Mektovi) provides OS benefit in patients with untreated BRAF-mutated metastatic melanoma.¹⁰

“What was interesting was the third arm, where patients started with 8 weeks of targeted therapy and then switched before progression to immunotherapy. Those patients seemed to do about as well as those that started with immunotherapy up front. We sometimes adopt that approach if we need to get a quick onset of action,” Smithy said. “Based on the trials’ [data], it appears that once a melanoma has developed resistance to targeted therapy, the responsiveness to immune checkpoint inhibitors seems to be lower,” Smithy added. “The tumor biology seems to have changed, and this informs our clinical practice. More work is needed to better understand this phenomenon.”

Tumor-Infiltrating Lymphocyte Therapy

TIL therapy has emerged as a breakthrough for resistant melanoma. The tumor-derived T-cell immunotherapy, lifileucel (Amtagvi), was approved by the FDA in 2024.¹¹ The agent was indicated in patients with unresectable or metastatic melanoma previously treated with a PD-1–blocking antibody, and, if they are BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor.

The main efficacy outcome measures were ORR and DOR, as reported in the C-144-01 trial (NCT02360579).¹²

The median time to initial response to lifileucel was 1.5 months. The ORR was based on 73 participants who received lifileucel within the recommended dosing range of 7.5 × 10⁹ to 72 × 10⁹ viable cells.

The ORR was 31.5% (95% CI, 21.1%-43.4%), and the median DOR was not reached (NR; 95% CI, 4.1-NR).¹²

Smithy noted that although the T-cell therapy was recently approved, efforts to maximize its benefit are underway. Notably, TILVANCE-301 (NCT05727904) is investigating the efficacy and safety of the agent in combination with pembrolizumab in the frontline setting.¹³ In the study, 670 patients have been randomly assigned to arm A (lifileucel plus pembrolizumab) or arm B (pembrolizumab alone).

“The trial will give us an understanding of how these immunotherapies work synergistically and at an earlier point in the disease course,” Smithy said.

Other TIL therapies undergoing evaluation include IOV-4001 in a phase 1/2 trial (NCT05361174) assessing the agent’s safety and effectiveness in patients with unresectable or metastatic melanoma, and OBX-115, in a phase 1 study (NCT05470283) in patients with ICI-resistant melanoma.

Smithy pointed out that TIL therapies are sometimes perceived as a last line of treatment.

“In our experience, the best outcomes have been observed in patients with lower disease burden and excellent functional status. In many cases, it’s considerably safer to give cellular therapy in that setting,” Smithy said.

As research continues, the focus remains on optimizing combinations, sequencing, and cellular therapies to extend survival. With each advancement, melanoma gets closer to becoming a manageable disease.

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