A Decade of Transformation in Melanoma Treatments

Keith T. Flaherty, MD

When Keith T. Flaherty began treating patients with advanced melanoma 2 decades ago, his recommendation was simple: If you’re eligible, enroll in a clinical trial.

As late as 2010, only 2 FDA-approved therapies existed for the treatment of advanced melanoma: the chemotherapy dacarbazine and high-dose (HD) IL-2. A review of 3 dacarbazine trials reported response rates of 10% to 15% and overall survival (OS) of 8 months.¹ An analysis of HD IL-2 treatment reported a response rate of 16% and severe toxicity but also a durable response rate of just under 5% of patients.^2,3

“We would immediately follow discussions of the approved therapies by talking about investigational therapies. Essentially any investigational therapy was on the table, even ones that were absolutely brand new, just starting phase 1 trials, with or without rationale as to why they were a good fit for melanoma,” said Flaherty, director of the Henri and Belinda Termeer Center for Targeted Therapy and director of clinical research at Massachusetts General Hospital Cancer Center. “And this was widely considered the appropriate conversation to have with patients. Basically, any investigational therapy was considered a better option than pursuing approved treatments.”

The Start of the Immunotherapy Era

Things began to change in March 2011, when ipilimumab (Yervoy) was first approved for the condition. More than a dozen subsequent approvals have transformed the treatment of advanced melanoma and increased average survival by several years (TIMELINE).

Immunotherapy investigators were first attracted to melanoma for 2 reasons. The first was the enthusiasm that physicians like Flaherty had for directing patients away from approved treatments and toward trials. The second was the observation that melanoma is one of the most immunogenic tumor ypes. Indeed, analyses of resected melanomas had long detected the presence of tumor-infiltrating lymphocytes, and the occasional spontaneous regressions observed in patients with the condition indicated that the immune system attacked melanoma more frequently and effectively than it did other cancers.⁴

Ipilimumab, a recombinant human IgG1 monoclonal antibody that increases T-cell activity by blocking the expression of CTLA-4, was first approved by the FDA for previously treated advanced melanoma in March 2011. The trials that led to the approval showed an overall response rate (ORR) of just 10.9% in patients with previously treated advanced melanoma, but the toxicity was severe. Grade 3 or 4 immune-related adverse events (AEs) occurred in 10% to 15% of patients who received ipilimumab, and more than 2% of study patients suffered treatment-related deaths. However, ipilimumab was approved because durable responses in a small percentage of patients extended median OS by 4 months (median OS, 10.1 months vs 6.4 months with gp100 peptide vaccine; HR, 0.66; P = .003). At 1 year, the OS rate was 45.6%, 33.2% at 18 months, and 23.5% at 2 years.⁵

Neither that approval nor a subsequent expansion approving the medication for adjuvant treatment led to widespread adoption. This was mainly because the toxicity was so severe that patients and physicians hesitated to risk it for a small chance of durable response.

The true breakthrough for immunotherapy performance and adoption came with the approval of the PD-1 inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) in late 2014. Pembrolizumab’s accelerated approval was based on a 26% ORR in 173 patients with melanoma in the phase 1 KEYNOTE-001 study (NCT01295827). Response duration lasted from 6 weeks to more than 37 weeks, with no median duration reached.⁶ Results from the phase 3 KEYNOTE-006 study (NCT01866319) showed that after a median follow-up of 57.7 months (range, 56.7-59.2), median OS was 32.7 months (95% CI, 24.5-41.6) in patients receiving pembrolizumab and 15.9 months in patients receiving ipilimumab (95% CI, 13.3- 22.0; HR, 0.73; 95% CI, 0.61-0.88; P = .00049).⁷

Nivolumab’s accelerated approval was based on preliminary trial data from the phase 3 CheckMate 037 trial (NCT01721746) that showed a 32% ORR (95% CI, 23.5%- 40.8%) for patients treated with nivolumab.⁸ In the study, patients with unresectable or metastatic melanoma after progression on ipilimumab, plus a BRAF inhibitor in the case of a BRAF mutation, had a median duration of response that was not reached (range, 1.4+ to 10.0+ months) with nivolumab vs 3.5 months (range, 1.3+ to 3.5) with investigator’s choice of chemotherapy.⁹

The combination of higher rates of both overall and durable responses, along with a much lower incidence of serious AEs, quickly made PD-1 monotherapy the most common treatment, but subsequent studies found the combination of ipilimumab and nivolumab to be even more effective. Trials indicated the ORR for the combination was above 50%,¹⁰ and 6.5 years of follow-up data found that the median OS with the combination was 72.1 months vs 36.9 months with nivolumab alone (HR, 0.52; 95% CI, 0.43-0.64) and 19.9 months with ipilimumab alone.¹¹ A minority of patients who take such treatments experience complete remissions and may be cured.

Jeffrey S. Weber, MD, PhD

“Although those of us who were doing the trials were optimistic about immunotherapy for melanoma because we had seen the preclinical data on how immunogenic it was, there were plenty of skeptics who were surprised first by the trial data that showed PD-1 monotherapy had so many long-lasting responses and then by the fact that combination immunotherapy performed so much better,” said Jeffrey S. Weber, MD, PhD, deputy director of NYU Langone’s Perlmutter Cancer Center.

The extra efficacy came with a price, however. Grade 3 and 4 AEs, which are reported at 15% or less in most PD-1 monotherapy trials, often top 50% in trials of the ipilimmab-nivolumab combination.¹¹ According to Flaherty, this drawback has limited its use among community oncologists even as it has become common at academic cancer centers

Weber, a prolific melanoma researcher who has co-authored more than 4700 papers, was on the initial data safety monitoring committee for the initial trial of the ipilimumab-nivolumab combination. “We knew going in that it was going to be toxic, and man, was it toxic,” he said. “But there were also great responses right from the start. It produced responses in those brain metastases where previously there was no effective therapy in melanoma.”

A more recently approved immunotherapy combination may offer a better combination of efficacy and tolerability. Earlier this year, a trial (RELATIVITY-047; NCT03470922) of the LAG-3 inhibitor relatlimab, used in combination with nivolumab in previously treated patients with melanoma, found increased progression-free survival (PFS) over nivolumab alone (10.1 months vs 4.6 months; HR, 0.75; 95% CI, 0.62-0.92; P = .006). The PFS rate at 12 months was 47.7% in the co bination group vs 36.0% in the monotherapy group. Grade 3 or 4 treatment-related AEs occurred in 18.9% of patients in the relatlimab-nivolumab group and 9.7% of patients in the nivolumab group.12 Most recently, the FDA approved relatlimab in combination with nivolumab (Opdualag) for the treatment of patients 12 years or older with unresectable or metastatic melanoma in March.

Another potential type of immunological treatment that remains under investigation in melanoma is vaccine therapy. Potential treatments have induced responses but failed to extend lifespan. For example, a trial of talimogene laherparepvec (T-VEC; Imlygic) found durable responses in 16.3% of patients who received the treatment—far more than in the granulocyte macrophage colony-stimulating factor control group—but OS was comparable (23.3 months vs 18.9 months, respectively; HR, 0.79; 95% CI, 0.62-1.00; P = .051).¹³

Expanding Targeted Therapies

As investigators were testing immunotherapy treatments for melanoma, they were also testing targeted treatments for melanomas with BRAF mutations, which are present in roughly 45% of melanomas.

In 2011, vemurafenib (Zelboraf) became the first BRAF-targeted therapy approved for melanoma after a trial showed a 48% response rate and a 63% reduction in the 6-month risk of death over dacarbazine chemotherapy.¹⁴

Responses to vemurafenib monotherapy were not durable, however. Median PFS was only 5.3 months because tumors developed resistance to treatment through MAP kinase reactivation. Investigators countered by adding MEK inhibition to BRAF inhibition in trials that created a new targeted standard of care for patients with BRAF-mutated melanoma.

Treatment with dabrafenib (Tafinlar) and trametinib (Mekinist), vemurafenib and cobimetinib (Cotellic), and encorafenib (Braftovi) and binimetinib (Mektovi) combinations are all associated with longer OS than BRAF inhibitor monotherapy. Response rates exceed 60%, and complete response rates range from 10% to 18% in trials, though the regimens have never been tested against one another head to head.¹⁵

However, in 2020, a combination of the PD-L1 inhibitor atezolizumab (Tecentriq) plus vemurafenib and cobimetinib was found to be more effective than vemurafenib and cobimetinib alone in the phase 3 IMspire150 trial (NCT02908672). At a median follow-up of 18.9 months, PFS in the triplet combination group was significantly longer than in the doublet combination control arm (15.1 months vs 10.6 months; HR, 0.78; 95% CI, 0.63-0.97; P = .025).¹⁶ The FDA approved atezolizumab as part of the triplet regimen for patients with BRAF V600–mutated unresectable or metastatic melanoma several months later. (The drug was also later approved as first-line monotherapy in patients whose melanoma expresses high levels of PD-L1.¹⁷)

Other investigations found that mutations in KIT could also be targeted by treatment with tyrosine kinase inhibitors (TKIs) such as nilotinib (Tasigna). In 2017, the drug was found to be associated with a 26% response rate, a median PFS of 4.2 months, and a median OS of 18.0 months in patients with KIT-mutated melanoma.¹⁸

The overall advances in melanoma have been huge,” Weber said. “We’re the poster child for success in both immunotherapy and targeted therapy. The median survival for patients with a reasonable performance status going into treatment is now anywhere from 3 to 6 years. If you look at the Check-Mate 067 trial [NCT01844505] with the 72-month median survival, that’s amazing.¹¹ That beats non–small cell lung cancer. That beats colon cancer. That beats gastric cancer. That beats any other metastatic epithelial malignancy with the potential exception of prostate. Melanoma was once described as the tumor that gave oncology a bad name, and now we’ve beaten all the tumors that were thought to be untreatable.”

Further Advances in Melanoma

As new systemic treatments for melanoma have been introduced, innovations in melanoma diagnosis, staging, pathology, and genotyping have likewise been introduced. For example, the eighth edition of the American Joint Committee on Cancer (AJCC) melanoma staging system, which first appeared in 2018, differed in several key areas from the seventh edition, which was published in 2010.¹⁹

Surgical procedures have also evolved, as study investigators found benefits to procedures such as the immediate completion of lymph-node dissection in patients with sentinel-node metastases.²⁰ Thinking on the best relative timing of surgery and medical treatment in patients with melanoma receiving both has also continued to evolve with the publication of new study data, some of which suggest that immunotherapy may be more successful before surgery than afterward.²¹

The simultaneous advances in immunotherapy and targeted therapy have naturally led physicians to ask which treatment type should be used first in patients whose melanoma has targetable BRAF mutations. Preliminary results from the first large trial to study this question, the phase 3 DREAM-seq trial (NCT02224781), were presented and published in November 2021. Initial treatment with nivolumab plus ipilimumab was associated with a 20 percentage point improvement in the 2-year OS rate compared with initial treatment with the BRAF/ MEK inhibitor regimen of dabrafenib plus trametinib (log-rank P = .0095). The results triggered an early halt to the study.²²

Looking Ahead

Ongoing and proposed melanoma research will naturally continue to evaluate new treatment types. Results from a phase 2 study (NCT02360579) showed that lifileucel, an autologous tumor-infiltrating lymphocyte therapy, produced mostly long-lasting responses in 24 of 66 heavily pretreated patients, which may be enough to secure FDA approval.²³

Flaherty is just as excited by research designed to better predict which patients will respond well to existing treatments.

“Subsetting patients more effectively, figuring out what are the molecular biomarkers in tumors that predict complete or at least durable responses to BRAF-MEK or to PD-1 monotherapy, would be a major step,” said Flaherty, who has authored or co-authored more than 300 papers on melanoma. “Roughly 25% of patients outlive their diagnosis on PD-1 monotherapy, and we want to know who those patients are because we do not want to be giving combination immunotherapy with its far higher incidence of serious adverse events to people whose tumors have molecular signatures that indicate they will be cured by far milder PD-1 monotherapy.”

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