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Improving Efficacy in First-Line Treatment of Advanced Melanoma: Focus on the Role of Immune Checkpoint Inhibitors

Optimal Treatment of Advanced Melanoma in the First-line Setting (Part 1 of a 2-Part Interactive Monograph Series)

Overview

Revolutionary advances have transformed the medical treatment of advanced melanoma over the last decade.¹ In 2022, it is estimated that there will be 99,780 new cases of melanoma diagnosed in the United States, with 7,650 melanoma-related deaths.² Advanced melanoma is a historically chemotherapy-resistant disease.³ The discovery of the immune checkpoints cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed cell death-1 (PD-1), which ultimately led to the development of immune checkpoint inhibitors (ICIs) that target these checkpoints, was a pivotal turning point. Wide adoption of these agents has ushered in the modern era of cancer immunotherapy, boasting the potential of durable responses and extended survival.

Advances in both immunotherapy and targeted therapy have resulted in a widening array of options in the first-line treatment of advanced melanoma, which makes informed treatment planning imperative for both patients and clinicians. Patient-specific factors including tumor burden, sites of metastases, and comorbidities must be considered given recent findings from clinical trials.^4-6 In this monograph, we will focus on ICI–containing first-line treatment options for advanced melanoma in the context of clinical data and patient-specific factors to help select the most appropriate therapy for varied patient cases (Table).¹

Common Targets in the Treatment of Metastatic Melanoma

Immune Checkpoints

CTLA-4

The first immune checkpoint, the T-cell surface protein CTLA-4, was discovered in the 1990s, and serves as a natural brake system for the priming phase of the cell-mediated immune response by indirectly reducing signaling through the co-stimulatory receptor CD28.⁷ Efforts were undertaken by James P. Allison to develop an antibody to bind to the CTLA-4 receptor and block its function, thereby weighing the balance toward T-cell activation.⁸ It was discovered that CTLA-4 blockade with ipilimumab stimulated T-cell activation and restored exhausted T cells, resulting in durable responses in patients with advanced melanoma.⁹ Ipilimumab is the only US Food and Drug Administration (FDA)-approved CTLA-4 inhibitor.

PD-1/PD-L1

Another T-cell surface protein, PD-1, was discovered in 1992 by Tasuku Honjo. PD-1 was found to be another checkpoint receptor located on the T-cell which, when activated by the ligand PD-L1, directly suppresses T-cell activation via suppression of the effector phase of the cell-mediated immune response.⁷ The antibodies nivolumab and pembrolizumab were developed to block the PD-1 receptor and were found to result in profound T-cell activation and subsequent cytotoxic activity against the tumor.⁷ In 2018, James P. Allison and Tasuku Honjo were jointly awarded The Nobel Prize in Physiology or Medicine for the discovery of the CTLA-4 and PD-1 receptors, in recognition of the tremendous improvement in cancer mortality that has resulted from blockage of these immune checkpoints.⁸ Apart from nivolumab and pembrolizumab (anti–PD-1), atezolizumab (anti–PD-L1) is the only other PD-1/PD-L1 ICI FDA approved for use in a first-line treatment regimen for advanced melanoma, namely atezolizumab, vemurafenib, and cobimetinib.⁶

LAG-3

The third and newest targetable immune checkpoint, lymphocyte-activation gene 3 (LAG-3), is a cell surface molecule expressed on T-cells which directly inhibits T-cell activation and effector T-cell function.¹⁰ LAG-3 is also expressed on tumor-infiltrating lymphocytes and contributes to tumor-mediated T-cell exhaustion. Dual inhibition of both LAG-3 and PD-1 reverses effector T-cell exhaustion, stimulating the immune response against the tumor. Relatlimab is the only FDA-approved LAG-3 inhibitor, indicated for use in combination with the PD-1 ICI nivolumab for metastatic melanoma.^5,6

Mutational Targets

BRAF plus MEK

Activating BRAF mutations are present in approximately 50% of all cutaneous melanoma.¹¹ In patients with the common BRAF V600E and V600K mutations, BRAF inhibitors have been shown to have a rapid, potent antitumor effect by blocking the RAS-RAF-MEK-ERK mitogen-activated protein kinase signaling pathway in melanoma, particularly when used in combination with MEK inhibitors. Three combination therapy options have been approved by the FDA for the treatment of BRAF V600-mutated advanced melanoma: dabrafenib plus trametinib (2014), vemurafenib plus cobimetinib (2015), and encorafenib plus binimetinib (2018).⁶

Preferred First-line ICI Treatment Regimens and Pivotal Clinical Trial Data

The 5-year relative survival for advanced melanoma in the United States increased from 15% in 2004 to 30% for patients diagnosed during 2011 through 2017.² Recent landmark clinical trial updates from the use of combination ICIs indicate that 5-year overall survival (OS) of more than 50% is well within reach.¹² Below is a summary of key clinical trial data that led to these improved clinical outcomes.

Metastatic Melanoma

Anti–CTLA-4 or anti–PD-1 ICI monotherapy

Ipilimumab was the first ICI to be approved by the FDA in March 2011 for the treatment of metastatic melanoma, and remains the only FDA-approved anti–CTLA-4 ICI.⁹ In late 2014, nivolumab and pembrolizumab were each granted accelerated approval by the FDA as the first PD-1 inhibitor monotherapies for the treatment of advanced melanoma.¹³ Each agent was later shown to be more effective at prolonging survival for ICI-naive metastatic melanoma than anti–CTLA-4 monotherapy with ipilimumab based on results from the KEYNOTE-006 and CheckMate 067 trials.^14-16 In the current treatment landscape, ipilimumab is no longer used as monotherapy in the first-line or adjuvant settings due to the superiority of PD-1 blockade.⁶

Combination PD-1 and CTLA-4 blockade

The predominant use of ipilimumab now stems from the CheckMate 067 trial and subsequent approval by the FDA in 2015 for use with the PD-1 inhibitor nivolumab for treatment of metastatic melanoma—the first ICI combination therapy, via combined CTLA-4 and PD-1 blockade.^12,16 CheckMate 067 showed improved progression-free survival (PFS) and OS with combination nivolumab plus ipilimumab versus nivolumab or ipilimumab alone at 5-year and 6.5-year follow-up.^12,16 While toxic (59% rate of grade 3 or 4 treatment-related adverse events [AEs], otherwise known as immune-related adverse events [irAEs]), the combination is also effective in a variety of high-risk populations, including those with high tumor burden and visceral metastases.¹⁶ Furthermore, although patients with brain metastases have generally been excluded from ICI trials, the phase 2 CheckMate 204 trial showed that patients with untreated, asymptomatic melanoma metastases to the brain have similar benefit from combination nivolumab plus ipilimumab as compared to patients without brain metastasis from the CheckMate 067 trial.¹⁷

Combination PD-1 and LAG-3 blockade

New results from the RELATIVITY-047 trial published in January 2022 show that first-line relatlimab plus nivolumab doubled PFS compared with nivolumab alone in patients with metastatic melanoma.⁵ While long-term survival outcomes are yet to be determined, relatlimab was approved by the FDA in March 2022 for use in combination with the PD-1 inhibitor nivolumab for the treatment of unresectable or metastatic melanoma.⁵ In the melanoma treatment landscape, the efficacy of relatlimab plus nivolumab appears similar to that of ipilimumab and nivolumab, whereas the toxicity profile of relatlimab plus nivolumab (18.9% risk of grade 3-5 treatment-related AEs) falls somewhere between the high-risk profile of nivolumab plus ipilimumab (59%) and the low-risk profile of anti–PD-1 monotherapy (approximately 10%-15%).^15,18

Combination PD-L1 and BRAF/MEK blockade

In 2020, the PD-L1 inhibitor atezolizumab was approved by the FDA for use in combination with vemurafenib plus cobimetinib for advanced BRAF V600-mutated melanoma based on improved PFS versus vemurafenib and cobimetinib alone in the IMspire150 trial.¹⁹ However, recently published results from the phase 3 DREAMseq trial comparing first-line nivolumab plus ipilimumab to first-line dabrafenib plus trametinib showed that ICI combination therapy resulted in improved OS at 2 years (72%) as compared with BRAF/MEK inhibition (52%).⁴ This would suggest that starting with an ICI combination first, rather than targeted therapy, may matter more than previously thought. Thus, the place of the triplet combination in the current treatment landscape is unclear due to these results, and its toxicity profile. Patients with the need for rapid response due to fast disease progression are more commonly treated with doublet BRAF/MEK therapy alone.^1,6

Adjuvant Therapy for High-Risk Resected Patients

Anti–PD-1 ICI monotherapy

Anti–PD-1 monotherapy is the current standard for treatment of high-risk resected melanoma.⁶ Nivolumab was approved by the FDA in December 2017 for the adjuvant treatment of melanoma, based on the results of CheckMate 238 showing extended PFS with use of nivolumab as compared with high-dose ipilimumab for patients with stage III or IV resected disease.²⁰ In February 2019, pembrolizumab also was approved by the FDA for the adjuvant treatment of stage III melanoma following complete resection based on the results of KEYNOTE-054; then in December 2021, pembrolizumab received approval for adjuvant use in stage IIB or IIC melanoma after resection based on KEYNOTE-716.^21,22 While dabrafenib plus trametinib also was approved in 2018 for use in the adjuvant setting for stage III melanoma, 41% of patients in the COMBI-AD trial experienced grade 3 or 4 treatment-related toxicity.²³ Furthermore, results from DREAMseq called into question whether starting with BRAF/MEK blockade may be suboptimal in the adjuvant setting.⁴

Treatment of Patients With BRAF Wild-Type Unresectable or Metastatic Melanoma

For patients with BRAF wild-type tumors and stable clinical status, combination ICI with PD-1 and CTLA-4 blockade is the most efficacious choice for first-line therapy based on long-term outcomes of the CheckMate 067 trial.^12,16,24 However, relatlimab plus nivolumab may be preferable in cases where mid-range risk of immune toxicity is more acceptable. Patients who opt for combination ICI must be willing to accept the increased risk of irAEs over anti–PD-1 monotherapy in favor of improved survival outcomes. Combination ICI is strongly preferred for any patient with high tumor burden or visceral metastases.^12,16 For patients with metastasis to the brain, the combination of nivolumab plus ipilimumab is the preferred first-line treatment choice based on CheckMate 204.¹⁷ Anti–PD-1 monotherapy may be necessary in cases of poor performance status or other clinical need for the lowest risk of irAEs.

Treatment of Patients With BRAF V600-Mutated Unresectable or Metastatic Melanoma

As mentioned, results from the DREAMseq trial have helped identify the best treatment order for BRAF V600-mutated advanced melanoma.⁴ First-line treatment with BRAF V600-mutated melanoma should now follow the same pattern as that for BRAF wild-type tumors, starting with combination ICI treatment—preferably PD-1 and CTLA-4 blockade—whenever possible.¹ However, for patients with fast progression or high tumor burden in need of a rapid response, a BRAF/MEK inhibitor doublet or, rarely, the combination of atezolizumab, vemurafenib, and cobimetinib, may be the most appropriate option.

Emerging Data on First-line ICI Therapies

Ongoing Clinical Trials of Interest Plus Novel Combinations and Agents Under Investigation

Although multiple novel ICI combinations have failed to show clinical benefit in later phase trials, many trials of interest with novel ICI combinations are still ongoing. Vascular endothelial growth factor inhibitor and ICI combinations have shown promise from interim results of the LEAP-004 phase 2 trial, with phase 3 efforts including the LEAP-003 trial in the first-line setting for melanoma ongoing.²⁵ In addition, the phase 2 PIVOT-02 trial of the interleukin-2 agonist bempegaldesleukin in combination with nivolumab in the first-line setting for patients with advanced melanoma recently published encouraging results, with a response rate of 52.6% and median PFS of 30.9 months at 29-month follow-up, with good tolerability; phase 3 efforts are enrolling.²⁶ Other novel agents and ICI combinations are actively being investigated in earlier phase trials.¹

Summary

Clinical outcomes from the medical treatment of advanced melanoma continue to improve. Results from the recent DREAMseq and RELATIVITY-047 trials help give new clarity to first-line treatment options for advanced melanoma, despite a widening array of options in this setting. Combination ICIs offer the potential for improved outcomes, albeit with increased risk of toxicity as compared with anti–PD-1 ICI monotherapy. Shared decision-making with patients can help clinicians balance the risk of toxicity against the potential clinical benefit to make the most appropriate choice based on each patient’s case.

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