ORLANDO – Patients with high-risk melanoma, including those with lower tumor mutational burden, benefited from combination treatment with Moderna's investigational personalized cancer vaccine and Merck's checkpoint inhibitor Keytruda (pembrolizumab), researchers reported at the American Association for Cancer Research's (AACR) annual meeting on Sunday.
In December 2022, Merck and Moderna attracted much public fanfare over the announcement that high-risk melanoma patients had benefited more from Keytruda plus Moderna's messenger RNA personalized neoantigen vaccine, mRNA-4157/V940, than with Keytruda alone in a randomized Phase II study. The combination treatment strategy was novel: From patients' resected tumor samples, Moderna would perform tumor-normal next-generation sequencing, RNA sequencing, and human leukocyte antigen (HLA) subtyping, and from that data select 34 neoantigens specific to each patient's cancer to target with a personalized vaccine.
Back in December, the drugmakers had only teased that the Phase II results had shown that patients receiving the combination regimen experienced a 44 percent reduction in the risk of disease progression or death versus those on Keytruda. They said they would launch a Phase III trial to further investigate the findings. At this meeting, however, Merck and Moderna shared the much-anticipated full dataset from the Phase II Keynote-942 trial including a key biomarker analysis.
Patients with stage III and IV melanoma who'd just undergone surgical tumor resection got either the combination or single-agent Keytruda, and researchers followed them for a year, until their melanoma recurred, or they died. Of the 107 patients on mRNA-4157/V940 plus Keytruda, 78.6 percent were still alive without disease progression after 18 months versus 62.2 percent of 50 patients who got Keytruda.
"No one is more of a cancer vaccine skeptic than I am," said Jeffrey Weber, the deputy director of NYU Langone Perlmutter Cancer Center, in presenting the results at the meeting. "I've been involved in multiple cancer vaccine trials, and virtually none of them have been successful." But now, he said he sees genuine promise in personalized cancer vaccines, because the technology exists to single out tumor-specific neoantigens most likely to induce a T-cell response in patients.
The safety and tolerability across the treatment arms was comparable, according to Weber, with patients receiving the combination regimen experiencing slightly more of what he described as "typical mRNA vaccine-related side effects," similar to what's been seen with COVID-19 mRNA vaccines but slightly exaggerated. "Myalgias, fevers, chills, night sweats, fatigue … all the classic things that you would expect from the vaccine," he said, adding that on the whole the regimen was well tolerated.
In an exploratory analysis, Merck and Moderna analyzed patients' melanoma tumors at baseline across three key biomarkers: tumor mutational burden (TMB), PD-L1 expression, and a tumor inflammation score (TIS) calculated using RNA sequencing of the tumor transcriptome. "Interestingly, we have TMB and TIS [data] on everybody, which is rare for a study," Ryan Sullivan, associate director of Mass General Cancer Center's melanoma program, said during a presentation to members of the press on Sunday. "But, obviously, the trial itself required those two pieces of data to make the drug."
For TMB, researchers used the cutoff of 10 mutations per megabase, which the US Food and Drug Administration approved alongside Keytruda's tumor-agnostic solid tumor indication using that biomarker. Here, researchers reported that although the patients with high TMB levels had better outcomes versus TMB-low patients in both treatment arms, the degree to which the personalized vaccine improved outcomes was comparable across the high- and low-biomarker groups. In the high-TMB group, adding mRNA-4157/V940 to Keytruda reduced the risk of disease progression or death by 35 percent, and in the low-TMB group, it reduced the risk of disease progression or death by 41 percent.
During a discussion about Keynote-942, Margaret Callahan, a melanoma oncologist and research director of Memorial Sloan Kettering's immunotherapies program, pointed out that there were more TMB-high patients in the Keytruda-vaccine combination arm than in the Keytruda arm and that this imbalance may have been a confounding factor. However, she acknowledged that this can only be confirmed once data from a larger Phase III trial are available.
For the PD-L1 biomarker analysis, researchers defined patients as having PD-L1-positive tumors if they had a combined positive score of at least one via immunohistochemistry testing. Here, too, adding Moderna's vaccine to Keytruda benefited patients regardless of PD-L1 expression scores.
"The trend is reassuring," Callahan said of the analysis showing a benefit regardless of patients' biomarker status. "But the data only stretches so far, and we need to be mindful that larger studies are going to be needed to adequately address these questions."
Such analyses will be part of future trials, confirmed Eric Rubin, Merck's senior VP of oncology early development. Merck and Moderna hope to begin enrolling patients as early as this summer in the upcoming Phase III randomized trial of the vaccine, though Rubin declined to provide details on the study design.
Since cancer vaccines have historically yielded questionable benefit, the latest data from Merck and Moderna stirred up excitement among attendees at the AACR annual meeting. Still, experts tried to temper expectations by noting that the study was too small to draw definitive conclusions. "There are some caveats and quid pro quos to any randomized Phase II approach," Weber told the press on Sunday. "Phase II studies are of moderate size, and the follow-up wasn't five years, it was two years. You have to be a little cautious."
Moreover, in taking a closer look at the relapse-free survival data over time, experts pointed out that patients' outcomes across the two treatment arms were fairly similar for about the first nine months of the study, and only after that time did patients in the combination arm begin to experience improved outcomes versus those on the monotherapy. To Weber, this reflected the fact that it took multiple vaccinations to generate a sufficient quality and quantity of T cells to mediate clinical benefit. In this trial, patients received up to nine doses of the vaccine.
Given the time it took for the vaccine's benefits to kick in and the fact that there's a roughly six-week turnaround time to create a personalized vaccine, Weber said he was "a little skeptical about the utility of this sort of approach in metastatic disease," where patients would be at risk of relapsing before they experience clinical benefits.
Sullivan, for his part, expressed concerns about the utility of this approach in even earlier disease settings than Phase III, mainly due to biopsy limitations. To actually make the vaccine, Moderna needs to have access to sufficient tissue samples, which many patients, especially those with earlier-stage disease, might not have available. These early-stage patients likely aren't at the point where their tumors are shedding too much circulating tumor DNA, so it could be tough to attempt a blood-based approach to manufacturing these.
"The biggest limitation in general for the development of vaccines in the adjuvant setting is the lack of tissue," Sullivan said. "Patients with stage II and stage III melanoma have a relatively small amount of cancer available to do whole-exome sequencing and RNA sequencing, and that's not going to change."
But this "technology limitation" may not be a problem in the future, Sullivan said, as test developers get better at performing these analyses on smaller samples and at detecting even lower amounts of circulating tumor DNA.
Merck, meanwhile, has been consistently pushing for Keytruda's expansion into earlier treatment settings. "Our understanding of Keytruda's use in earlier-stage cancer is driving where we think individualized neoantigen therapies fit into the treatment paradigm and have the potential to provide the most benefit to patients," Rubin said.
Looking ahead, Rubin said Merck and Moderna are eager to test out the vaccine in other immunogenic solid tumor types including non-small cell lung cancer.
"I have every confidence that this strategy will be expanded to other histologies that are PD-1 sensitive, such as non-small cell lung cancer, renal cancer, [and] gastroesophageal cancer," Weber agreed. In the meantime, he said he's looking forward to beginning to enroll patients into the larger, Phase III trial this summer and to seeing additional analyses from this trial, including a BRAF mutation biomarker analysis and distant metastases-free survival outcome analysis at the American Society of Clinical Oncology's annual meeting in June.