If, at the 5-year analysis, survival data indicate that the combination therapy confers a superior treatment benefit vs immediate surgery, Dr In said that the results would justify neoadjuvant T-VEC as a standard therapy for patients with resectable disease. “These results certainly suggest that some patients will benefit from this approach. The most important question that I would like to see answered by the end of the trial is whether there is a continued overall survival benefit; if so, then this would argue that the treatment should be considered as a standard option,” Dr In said, pointing out that the OS benefit has reduced between the 2- and 3-year analyses of the trial.
However, in this trial, as in numerous others involving T-VEC, some patients did not respond to the therapy. These patients were subsequently removed from the trial and directed to surgery. Combining T-VEC with other immunotherapy agents, such as immune checkpoint inhibitors, might be an effective strategy for inducing responses in this subpopulation, Dr Dummer noted.
“T-VEC is immunotherapy and we know that individual tumors maybe inaccessible for immune cells. In this situation, immunotherapy will not work. We also have translational data that show that the induction of a T cell influx is essential for a beneficial outcome,” said Reinhard Dummer MD, lead investigator of the trial and vice chair Department of Dermatology in the Skin Cancer Center at the University Hospital Zurich, Switzerland. “I am convinced that T-VEC is a perfect combination partner for other immunotherapy approaches,” added Dr Dummer.
Several trials evaluating this approach are ongoing, including the MASTERKEY-265/KEYNOTE-034 study (ClinicalTrials.gov identifier: NCT02263508), for which Dr Dummer serves a co-investigator. The trial combines T-VEC and pembrolizumab for patients with unresectable advanced melanoma. The study previously reported a 3-year progression-free survival rate and OS rate of 53.6% and 71.0%, respectively.
“Increasing evidence, including the phase 1b data from the MASTERKEY-265 trial, suggests that combining anti-PD-1-based immunotherapy with T-VEC will achieve important synergy through complementary pathways. Both PD-1 and T-VEC are reasonably well-tolerated and also have efficacy as individual therapies in the treatment of melanoma,” said Dr In, who is a principal investigator on a trial (ClinicalTrials.gov identifier: NCT02965716) currently testing the combination in patients whose disease progressed after initial anti-PD-1/L1-based monotherapy.
Updated results from just under 5 years of follow-up from the MASTERKEY-265 trial were also presented at SITC, and showed that of the 13 of the trial’s 21 patients who initially responded to the combination, 12 of them were still responding. This included nine complete responses. The phase 1b/3 trial MASTERKEY-265/KEYNOTE-034 to further investigate the combination has finished enrollment of over 700 patients and is ongoing.2
“I think this is another bit of a scaffold that we need to build upon with T-VEC, indicating that the therapy is going to become part of the normal treatment regimen for malignant melanoma. Its steady progress in a more real-world clinical setting—not selected patients—shows good promise that it will continue to develop as a frontline therapy,” said Daschner.
“T-VEC is an exceptional and important new treatment for melanoma, and unfortunately, I just don’t think enough people are aware of it yet. Although it is FDA approved since 2015, and now in all the melanoma guidelines, I still see that is rarely being considered. I hope that this will change, because it is an effective and well-tolerated treatment, and it can help many patients with melanoma,” said Dr In.
R Dummer has intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dohme (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen Inc, Takeda, Pierre Fabre, Sun Pharma, Sanofi, and CatalYm outside the submitted work.
- Dummer R, Gyorki DE, Berger AC, et al. 3-year results of the phase 2 randomized trial for talimogene laherparepvec (T-VEC) neoadjuvant treatment plus surgery vs surgery in patients with resectable stage IIIB-IVM1a melanoma. Poster presented at: Society of Immunotherapy for Cancer (SITC) Annual Meeting; November 11-14, 2020. Poster 432.
- Long GV, Dummer R, Johnson DB, et al. Long-term analysis of MASTERKEY-265 phase 1b trial of talimogene laherparepvec (T-VEC) plus pembrolizumab in patients with unresectable stage IIIB-IVM1c melanoma. Poster presented at: Society of Immunotherapy for Cancer (SITC) Annual Meeting; November 11-14, 2020. Poster 429.