The waiting room is filling up, as it does most weekday mornings. One patient warmly greets another. They chat about their day, their families, and how they have been doing since they last crossed paths at a follow-up visit. They’ve had the chance to get to know each other a bit after being diagnosed with advanced melanoma.

That didn’t used to happen, Jedd D. Wolchok, MD, PhD, told Medscape Medical News.

For Wolchok, such interactions between patients provide a welcome reminder of how far the field has come.

Advanced melanoma once carried a likely death sentence. Now the word “cure” comes up on a regular basis in conversations among these patients.

“There are more patients who recognize each other in the waiting room because honestly, they’re not dying nearly as often,” said Wolchok, the Meyer Director of the Sandra and Edward Meyer Cancer Center and professor of medicine at Weill Cornell Medicine, New York City.

“With immunotherapy, there is so much more hope,” he said.

The Melanoma Revolution

Before the advent of immune checkpoint inhibitors, treatment for advanced melanoma involved chemotherapy and early immunotherapy drugs like interleukin (IL)-2.

Chemotherapy response rates were low and generally nondurable. Some patients received high-dose IL-2, which provided slightly better responses, but still, only about 2%-5% of patients experienced a complete response, Wolchok noted. The treatment was also “quite toxic and couldn’t be offered to everybody.”

However, early successes with immunotherapy hinted at the potential for harnessing the immune system to fight cancer and paved the way for major breakthroughs.

In 2011, the FDA approved the anti-CTLA-4 drug ipilimumab, the first immune checkpoint inhibitor for unresectable or metastatic melanoma. The approval was based on 2010 findings showing improved overall survival of about 3.6 months.

But the drug came with a big caveat: immune-related adverse events were common, often debilitating, and sometimes deadly. 

Anti-PD-1 therapies followed, with FDA approvals in the second-line advanced melanoma setting, starting in September 2014 with pembrolizumab, followed shortly after by nivolumab in December 2014. These agents showed better efficacy and safety than ipilimumab. Response rates nearly doubled with these new agents, and many patients experienced durable responses.

The benefits are extended to the first-line setting as well. Even phase 1 data showed that treatment-naive patients receiving pembrolizumab experienced 5-year survival rates just over 40%. 

Combining these agents seemed to be even better Wolchok, soon found. 

Over a decade ago, Wolchok and his colleagues embarked on the pivotal CheckMate 067 trial, which compared first-line nivolumab plus ipilimumab to monotherapy with both drugs in patients with unresectable or metastatic melanoma.

Recently, Wolchok’s team unveiled the final 10-year survival results from the trial, which underscored the big immunotherapy-related strides in melanoma care over the past 15 years.

At a minimum 10-year follow-up, the median overall survival was 71.9 months among patients who received nivolumab plus ipilimumab — nearly double the 36.9 months seen with nivolumab monotherapy and more than triple the 19.9 months observed with ipilimumab monotherapy. At 10 years, 43% of patients receiving the combination were alive vs 37% with nivolumab and 19% with ipilimumab.

What was striking, Wolchok noted, was the median melanoma-specific survival extended beyond 120 months among patients receiving the combination. By contrast, median melanoma-specific survival was 49.4 months with nivolumab and 21.9 months with ipilimumab. Overall, melanoma-specific survival at 10 years was 52% with nivolumab plus ipilimumab, 44% with nivolumab, and 23% with ipilimumab.

This combination, however, came with an increased risk for immune-related adverse events. Almost 63% of patients in the combination group experienced a grade 3 or 4 adverse event, including diarrhea, colitis, and fatigue compared with 24.6% in the nivolumab group and 29.6% in the ipilimumab group. And having a treatment-related adverse event within the first 6 months of follow-up did appear to affect overall survival: from 6 months through 10 years, overall survival was 49% with nivolumab plus ipilimumab, 62% with nivolumab, and 26% with ipilimumab.

Overall, though, Wolchok and colleagues concluded that “compared with ipilimumab monotherapy, nivolumab-containing therapies have continued to show a prolonged survival benefit in patients with advanced melanoma.” More broadly, the researchers emphasized how these 10-year data “highlight the potential for a cure in patients who have a response to this type of treatment.”

Nivolumab or pembrolizumab monotherapy, as well as combination immunotherapy, are now standard first-line options in this setting, according to National Comprehensive Cancer Network guidelines.

Other first-line options include combination targeted therapy if the tumor contains a BRAF V600 activating mutation, which occurs in 40%-50% of cutaneous melanomas. These combinations include dabrafenib plus trametinib, vemurafenib plus cobimetinib, and encorafenib plus binimetinib.

Over the past 15 years, Teresa Amaral, MD, PhD, has watched the field transform in real time with immune checkpoint therapy.

“It has been a really fantastic time to work in this area,” said Amaral, head of the Skin Cancer Clinical Trials Center at the University of Tϋbingen, Tϋbingen, Germany.

“Before immune checkpoint therapy, all of my patients died,” she recalled. But now, many patients are surviving for years and are effectively cured. 

After 5 years of follow-up, those patients are released and have the chance to live a normal life, which is “empowering for patients and very rewarding from my side,” Amaral said. “I think it’s really a revolution.”

The Latest and Next Frontiers

Even with major wins, the work continues to further improve patient outcomes.

In 2022, the FDA approved a new first-line immunotherapy option for unresectable or metastatic melanoma — relatlimab — alongside nivolumab.

Relatlimab, the first FDA-approved LAG-3 blocker, was approved based on findings from the phase 3 RELATIVITY-047 trial, which found a significant improvement in progression-free survival vs nivolumab monotherapy in patients with previously untreated metastatic or unresectable stage III or IV melanoma (median 10.1 vs 4.6 months; hazard ratio, 0.75).

This fixed-dose combination of relatlimab (Opdualag, Bristol Myers Squibb) and nivolumab is a “game changer that we have been waiting 10 years for,” Hussein Tawbi, MD, PhD, University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News back in 2022 when the phase 2/3 trial findings were published. “We were always excited about the relatlimab-nivolumab combination…but I didn’t expect it to be this effective.”

But there are still gaps in care. Some patients, for instance, don’t respond to immune checkpoint inhibition, and researchers don’t really know why.

“We are trying to understand who will and will not benefit from immune checkpoint therapy,” Amaral said. “We are trying to address the patients who are not benefiting. We do have some second-line therapies, but we are still far away from having a lot of success.”

One newer and promising second-line option is the cellular therapy lifileucel. In 2024, after nearly 30 years of research, the FDA approved lifileucel for adults with unresectable or metastatic melanoma whose disease had progressed on certain immunotherapies or targeted therapies. This marked the first cellular therapy approval in the solid tumor setting, based on an open-label single-arm study that reported an objective response rate of 31.5%.

Vaccines for melanoma are also emerging, including a few in phase 3 trials, Wolchok noted. “One is based on a personalized neoantigen vaccine, and that is a triumph of modern science — to sequence tumor DNA in a few weeks and create a customized vaccine.” However, he added, “Whether that adds significantly to checkpoint blockade is a question in current phase 3 trials.”

Another key area of research is understanding the optimal duration of immunotherapy, Wolchok noted.

In CheckMate 067, treatment with nivolumab alone or with ipilimumab continued until disease progression, unacceptable toxicity, or withdrawal of consent, resulting in variable treatment durations. 

But the optimal treatment duration has not been firmly established. Guidelines recommend continuing until progression, unacceptable toxicity, or up to 2 years in patients with no evidence of progression, but recent data suggest 1 year is “both necessary and sufficient,” while treatment beyond 2 years does not appear to prolong survival and could cause harm.

“Perhaps we don’t need to treat as long as we currently do,” Wolchok said, explaining that reducing the side effects of immunotherapy without affecting the benefit. “We are looking at shorter periods of time for treatment.”

Overall, the strides made in the melanoma space have been a game changer for patient care, and it’s critical to understand not only what has been accomplished in melanoma care but also how we got here, Wolchok said.

While industry support was essential to be able to conduct the pivotal clinical trials that got these drugs approved, “the science that led us to those trials was the result of federally funded research,” he emphasized.

“It’s a huge part of my personal motivation — seeing something that was considered speculative science 15 years ago is now a standard pillar of not only melanoma care, but also the care of other types of cancers,” he said.

Wolchok and Amaral each disclosed having relationships with numerous pharmaceutical companies, including Bristol Myers Squibb, the maker of ipilimumab and nivolumab and a sponsor of the CheckMate 067 trial.

Sharon Worcester, MA, is an award-winning medical journalist based in Birmingham, Alabama, writing for Medscape Medical News, MDedge, and other affiliate sites. She currently covers oncology, but she has also written on a variety of other medical specialties and healthcare topics. She can be reached at sworcester@mdedge.com or on Twitter: @SW_MedReporter.