V940 Plus Pembrolizumab in Melanoma: Mechanism, Data, and Safety

CancerNetwork® spoke with Matteo S. Carlino, MD, PhD, FRACP, a medical oncologist at Westmead and Blacktown Hospitals, a faculty member at Melanoma Institute Australia, and a clinical senior lecturer at The University of Sydney in Australia, about intismeran autogene (V940), an individualized mRNA-based neoantigen therapy being evaluated with pembrolizumab (Keytruda) in resected melanoma. The conversation covered V940’s mechanism of action, efficacy and safety findings from the randomized and the phase 3 INTerpath-001 trial (NCT05933577) and phase 2b KEYNOTE-942 study (NCT03897881), and which patients may benefit most from the combination.^1,2

CancerNetwork: To begin, can you briefly explain the mechanism of action of V940?

Carlino: V940 is a personalized mRNA based individualized neoantigen therapy. Some people refer to it as a personalized vaccine. Essentially, individual patients have their tumor sequenced and are HLA-typed to characterize their immune system. Bioinformatics is then used to design a product with up to 34 neoantigens individualized to that patient. That product is injected intramuscularly, leading to antigen presentation of these 34 neoantigens, with the goal of generating an immune response directed toward antigens specific to the tumor.

Looking at the INTerpath-001 trial, it met its primary end point of relapse-free survival and secondary end point of distant-metastasis-free survival at the interim analysis. What was the magnitude of effect seen with V940 plus pembrolizumab vs pembrolizumab alone across these end points?

It’s exciting to see the announcement that the INTerpath-001 study is a positive study. The results are not yet known publicly but will be presented later this year at the ESMO [European Society for Medical Oncology] meeting. The smaller randomized phase 2 study, I presented updated results from at ASCO [the American Society of Clinical Oncology Annual meeting] this year. That was a study with the same compound. It was a randomized trial with patients [randomly assigned] to pembrolizumab plus V940 or pembrolizumab alone, and we saw a benefit in terms of relapse-free survival of 49%, so a relative risk reduction of 49%, and that translated to an absolute benefit at 5 years of over 20%. We’ll see in the coming months if that benefit we saw in the smaller randomized phase 2 trial is repeated or confirmed in the phase 3 study.

The press release noted that there were no new safety signals observed. For clinicians managing real-world patients, how does the addition of an intramuscular mRNA neoantigen vaccine impact the incidence or severity of immune-related adverse events [AEs] compared with single-agent pembrolizumab?

That was one of the exciting results from the phase 2 study. Typically, when we combine drugs, we get an incremental increase in toxicity, and for immunotherapy the worry is that we see an increased rate of immune-related [AEs]. We see that when we add ipilimumab [Yervoy] to nivolumab [Opdivo] or relatlimab [Opdulag] to nivolumab. In the randomized phase 2 study, we saw no change in the rate of immune-related adverse events for the toxicities that we know are associated with pembrolizumab and similar drugs.² We did see the [AEs] typically associated with mRNA-based vaccines, and these were relatively minor: arm pain at the site of injection, occasional fevers, and rigors, very similar to what patients would typically remember if they’ve had an mRNA vaccine for other indications.

Are you able to review some of the most common toxicities associated specifically with V940 administration? Do these interfere with the scheduled dosing of pembrolizumab at all?

Typically not. The toxicities of the combination are largely driven by the pembrolizumab, and clinicians are aware of the pembrolizumab safety profile, given it’s been available for well over a decade for melanoma and other indications. As I said, the V940 product had [AEs] that included occasional fevers and occasional rigors and also arm pain at the site of injection. This is usually transient, lasting anywhere from a few hours to a day or so, and for most patients these were easily manageable. Very few patients needed to stop the V940 product for toxicity.

Pembrolizumab was already approved in stage IIB/IIC and stage III/IV resected melanoma. Which subset of patients stands to gain the greatest incremental benefit from adding V940?³

If we look at the randomized phase 2 trial, that data was only in a high-risk population, which was largely stage IIIC and above.³ We’ll be interested to see if the incremental additional benefit is seen across that wider population from the INTerpath-001 study. I predict it would be seen across that wider population, so we hope the additional benefit is seen across that whole population. The patient population where it may be of greatest benefit is the patients who have microscopic nodal disease and stage II melanoma, because the patients with macroscopic nodal disease are now largely treated with neoadjuvant therapy. It will be those slightly lower-risk patients, the stage II patients and the microscopic stage III patients, who probably have the most to gain from the addition of V940.

Is there anything else that you’d like to highlight?

The main thing is we’re all excited to see the data available publicly later this year, and hope to see this treatment translate and become available to patients around the world, hopefully in short order.

References

1. Merck and Moderna announce phase 3 INTerpath-001 trial of intismeran autogene plus KEYTRUDA® met endpoints of recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with completely resected stage IIB-IV melanoma. News release. August 19, 2026. Accessed August 25, 2026. https://tinyurl.com/yxe3d24n
2. Carlino MS, Khattak A, Meniawy T, et al. Individualized neoantigen therapy intismeran autogene (intismeran) plus pembrolizumab (pembro) in resected melanoma: 5-year update of the KEYNOTE-942 study. J Clin Oncol. 2026;44(suppl 16):9500. doi:10.1200/JCO.2026.44.16_suppl.9500
3. FDA approves Merck’s KEYTRUDA® (pembrolizumab) as adjuvant treatment for adult and pediatric (≥12 years of age) patients with stage IIB or IIC melanoma following complete resection. News release. Merck. December 3, 2021. Accessed August 25, 2026. https://tinyurl.com/svj9nymr