Authors

  1. Nolen, Lindsey

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To improve oncological patient outcomes, researchers constantly seek new therapies and combination therapies to limit the risk of relapse. Two such therapies, relatlimab and nivolumab, were recently studied by a number of researchers to determine their effect on progression-free survival in patients with unresectable Stage III or metastatic melanoma. This study specifically looked at the neoadjuvant immunotherapy's impact on 30 patients with resectable clinical Stage III or oligometastatic Stage IV melanoma (Nature 2022; https://doi.org/10.1038/s41586-022-05368-8).

  
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One of the researchers, Rodabe Amaria, MD, Associate Professor in the Department of Melanoma Medical Oncology at the University of Texas MD Anderson Cancer Center, explained that this study followed her team's exploration of neoadjuvant therapy, which began in 2017 when they built up the critical mass to do trials. Her team wanted to study patients with high-risk cancer who seemed to have suboptimal outcomes with the standard approach of surgery and then postoperative therapy.

 

"The idea was to see if we could use some of the new drugs that have been developed for metastatic melanoma and use them in earlier lines of therapy, specifically for these patients with what we call clinical Stage III melanoma, and who had poor outcomes with upfront surgery and then postoperative therapy," Amaria explained. "This specific clinical trial was a continuation of an earlier trial using different kinds of immunotherapy options preoperatively."

 

She added that they conducted a prior trial testing use of either preoperative ipilimumab used with nivolumab or preoperative nivolumab alone. The prior study was a randomized, investigator-initiated clinical trial of either single-agent nivolumab (240 mg intravenously every 2 weeks up to four doses) or nivolumab 1 mg kg-1 with ipilimumab 3 mg g-1 (intravenously every 3 weeks up to three doses) in the neoadjuvant setting.

 

According to the researchers, this trial helped conclude that, although neoadjuvant single-agent nivolumab was safe (8% Grade 3/4 toxicities), the treatment's efficacy was modest (25% pCR rate). Further, the combination of nivolumab with ipilimumab was proven effective with a 45 percent pCR rate, with the toxicity being prohibitively high with 73 percent Grade 3/4 toxicities.

 

As the prior study showed neither regimen to be optimal, there was a need for one that balanced both efficacy and safety, which led to the idea of utilizing the combination of nivolumab and relatlimab. Researchers moved on with this combination since it was newly developed at the time and being tested in other clinical trials. Amaria said they were fortunate to have gotten access to the medication for this clinical trial.

 

"The early data suggest that this combination was well-tolerated, and so they launched into a variety of different clinical trials and this was one of them. The idea is that there's potentially synergy with these drugs since the two targeted checkpoints are distinct," she said. "The idea was that perhaps it was going to be synergistically beneficial to block both of those drugs as opposed to one drug or one target or the other."

 

During this most recent study, the patients involved received two neoadjuvant doses. The patients' data were accumulated from September 19, 2018, to September 23, 2020, with the median age of treated patients being 60 (range 35-79). Initially, 41 patients consented and 30 passed screening evaluations and were treated at MD Anderson Cancer Center and Memorial Sloan Kettering Cancer Center. However, nine of them were excluded for screen failure, stemming from a lack of resectable disease as determined by multidisciplinary review (n=4 patients) and laboratory values outside the specified criteria (n=3 patients).

 

"In terms of how we picked patients, basically, they just had to fit the criteria of the trial. Patients had to have what we call clinical Stage III melanoma disease that was able to be removed by surgery, be interested in this study, and have consented to it. They had to fulfill the basic criteria, having adequate labs, etc.," Amaria explained. "This was a study that we did predominantly in MD Anderson, but also collaborated with Memorial Sloan Kettering, as they contributed some patients as well."

 

Each patient received nivolumab 480 mg and relatlimab 160 mg intravenously every 4 weeks, followed by surgery, and then 10 doses of adjuvant combination therapy. The results demonstrated that of these patients, 29 underwent surgery (97%), 17 (57%; 95% CI, 37-75%) achieved pCR, two (7%) near PCR (defined as greater than 0% but less than or equal to 10% viable tumor), two (7%) partial pathologic response (defined as greater than 10% to less than or equal to 50% viable tumor), and eight (27%) no pathologic response (defined as greater than 50% viable tumor).

 

Upon treatment, patients were met with a median follow-up of 24.4 months (range 7.1-34.6 months) for the 30 treated patients, and their 1- and 2-year event-free survival rates (time from treatment initiation to recurrence in all patients) were 90 percent and 81 percent, respectively. The 1-year and 2-year RFS rates, which refer to the time from surgery to recurrence in patients that underwent surgery, were 97 percent and 82 percent, respectively.

 

Further, the 1-year and 2-year RFS rates were 100 percent and 91 percent for patients with pCR, compared to 92 percent and 69 percent for those without pCR (P=0.10). The 1-year and 2-year RFS rates were 100 percent and 92 percent for patients with any pathologic response, compared to 88 percent and 55 percent for those without a pathologic response (P=0.005). The 1-year and 2-year overall survival rates for all patients were 93 percent and 88 percent.

 

Ultimately, the major takeaways from researchers' findings were that the combination therapies resulted in 57 percent pCR rate and 70 percent overall pathologic response rate among patients treated. Additionally, the results demonstrated that a radiographic response rate using Response Evaluation Criteria in Solid Tumors 1.1 was 57 percent and no Grade 3-4 immune-related adverse events were observed in the neoadjuvant setting.

 

"So 57 percent of patients had a pathologic complete response, meaning that, [for the] 57 percent of patients who had the surgery, all of their tumors were dead at the time of the surgery, which is really what we hope," Amaria said. "An additional 7 percent had what we call a near pathologic complete response, so less than 10 percent viable tumor, and an additional 7 percent had between 10 and 50 percent viable tumor. That's how we describe the pathologic response, but again, I think the take home is the 57 percent with pathologic complete response."

 

Another significant finding was that 1- and 2-year recurrence-free survival rate was 100 percent and 92 percent for patients with any pathologic response, compared to 88 percent and 55 percent for patients who did not have a pathologic response (P=0.005). Along with an increased immune cell infiltration at baseline and a decrease in M2 macrophages during treatment associated with pathologic response, findings demonstrated that neoadjuvant relatlimab and nivolumab induce a high pCR rate.

 

From these results, the team of researchers was able to conclude that safety during neoadjuvant therapy is favorable as compared to other combination immunotherapy regimens. These data, combined with the results of a RELATIVITY-047 trial, confirmed the efficacy and safety of this immunotherapy regimen under review.

 

"I would say that the combination of nivolumab and relatlimab is both effective and safe. We definitely demonstrated that with this new neoadjuvant trial compared to our older version of the neoadjuvant trial where we have trouble with too much toxicity or not enough efficacy," Amaria said.

 

She noted that, during the prior version of this immunotherapy trial, they tested a couple of drugs, but didn't have the outcomes they wanted. They either had too much toxicity or inadequate efficacy. Amaria noted, they "kind of hit the sweet spot" where they balanced really good outcomes with reasonable toxicity with this clinical trial. For this reason, she believes this is a definite advantage in that this regimen really represents something that tends to be both effective and safe.

 

Moving forward, Amaria said that her team plans on conducting additional research on the collected blood and tumor samples to more deeply interrogate why some patients responded and others did not. She added that there's another global clinical trial using these drugs in the postoperative setting, so they will assess if that also works.

 

"That might be a new area for FDA approval. There are a number of ways this treatment could go in the future. It's already FDA-approved in metastatic melanoma, but we may see it become a proven Stage III melanoma [treatment as well] depending on results of the clinical trials in the postoperative setting that's currently ongoing," Amaria concluded.

 

Lindsey Nolen is a contributing writer.

 

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