NEW YORK – Merck and Moderna's bespoke neoantigen vaccine generated encouraging immune responses in patients with both melanoma and non-small cell lung cancer, according to new data from the Phase I KEYNOTE-603 clinical trial published Thursday in Cancer Discovery.
First author Justin Gainor, program director of the Center for Thoracic Cancers at Massachusetts General Hospital, and his colleagues at other cancer centers and Moderna evaluated the patient-specific vaccine, dubbed mRNA-4157 or V940, in 16 patients with either resected NSCLC or cutaneous melanoma. Using baseline and posttreatment blood samples, the researchers noted multiple forms of T-cell proliferation, which lasted 30 weeks after treatment.
The Cancer Discovery paper isn't the first set of promising data supporting Merck and Moderna's personalized vaccine. In June, the drugmakers — which jointly develop mRNA-4157 — presented three-year follow-up data from the melanoma-specific KEYNOTE-942 clinical trial in which patients with high-risk melanoma were still benefiting from adjuvant treatment with the personalized vaccine plus Merck's Keytruda (pembrolizumab) versus Keytruda alone. In that trial, patients who received adjuvant mRNA-4157 plus the immune checkpoint inhibitor saw a 49 percent reduction in the risk of disease recurrence or death versus patients who received Keytruda alone.
The Phase I KEYNOTE-603 data in Cancer Discovery focuses on a smaller patient population — ultimately, just three NSCLC patients and nine melanoma patients were included in the analysis — and the study wasn't randomized like the Phase II KEYNOTE-942 melanoma study. But according to Gainor, the analyses from KEYNOTE-603 offer a close-up look at patients' immune responses. This was possible, in part, because the researchers harvested patients' blood cells through leukapheresis before and after treatment.
"We were able to collect large amounts of blood [and] many more immune cells to get a sense of which neoantigens patients were responding to," he said.
Three of the NSCLC patients and two of the melanoma patients had received prior adjuvant systemic therapy. The patients with melanoma, of note, all received Keytruda in combination with their personalized neoantigen vaccines.
Merck and Moderna's patient-specific vaccine involves analyzing patients' resected tumor samples and normal tissue samples using tumor-normal sequencing, then using an algorithm to identify up to 34 specific neoantigens, which Merck and Moderna encode into an mRNA strand. Then, the drugmakers pack that strand into an injectable lipid nanoparticle, and patients receive injections of these personalized vaccines.
"Results of this study further support the validity and performance of the algorithm for mRNA-4157, which can predict and select neoantigens with preexisting reactivities with high accuracy," Gainor and coauthors wrote in their paper.
According to Gainor, KEYNOTE-603 investigators were encouraged to see both CD4 and CD8 T-cell responses. The researchers noted that adjuvant treatment with mRNA-4157, either as a monotherapy or in combination with Keytruda, generated de novo T-cell responses as well as expanded preexisting neoantigen-specific T-cell responses, both in NSCLC and in melanoma.
"Although the [NSCLC patient] sample size was small, it is worth noting that all three patients showed mRNA-4157-specific T-cell responses," wrote Gainor and coauthors. "Administration of mRNA-4157 alone or with pembrolizumab induced both CD3 and CD8 T cells, and longitudinal immunogenicity analyses showed sustained T-cell response in vitro to targeted neoantigens collected 30 weeks after treatment initiation."
In other words, the immune responses appeared to last.
Additionally, Gainor said the study helped researchers begin to understand which of the 34 neoantigens included in mRNA-4157 were driving patient responses. "A fundamental question in immunotherapy is how many neoantigens are necessary to produce anti-tumor responses," he said.
Here, they found that 22.7 percent and 29.8 percent of the total number of neoantigens included in mRNA-4157 could generate immune responses as monotherapy and combination therapy, respectively. The median number of neoantigens that individual patients responded to was four, but the range spanned one to 20 responses to individual neoantigens. Five patients had responses to at least five individual neoantigens.
Merck and Moderna have previously shared preliminary safety data for mRNA-4157 in both NSCLC and melanoma, but according to Gainor, the present data offers further evidence that the toxicity profile of this type of therapy is manageable — which is a particularly important consideration for patients diagnosed with earlier-stage disease like those in the KEYNOTE-603. Treatment-emergent adverse events were mostly grade 1 or grade 2, he said, and there were no dose-limiting toxicities or grade 4 or 5 toxicities.
Beyond the immunogenicity information and the encouraging toxicity report, Gainor said the KEYNOTE-603 trial was, perhaps more than anything, a proof-of-concept study showing just how feasible a personalized cancer vaccine can be. Although the average turnaround time that it took to manufacture and administer patients' bespoke vaccines isn't public information, Gainor said the timing was reasonable and that the whole process was manageable for patients and their oncologists.
Merck and Moderna's recent push to move mRNA-4157 into registration-directed studies — and in expanded tumor types — reflects this same enthusiasm on the part of the drugmakers.
The partners, for instance, are already running a Phase III trial, dubbed INTerpath-001, in high-risk melanoma and a Phase III trial dubbed INTerpath-002 in stage II, IIA, or IIIB resected NSCLC.
Beyond that, Merck and Moderna are studying mRNA-4157 as treatment in certain squamous cell carcinoma, renal cell carcinoma, and urothelial carcinoma patients, among other tumor types.