T-Vec: + Pembro Advanced Melanoma MASTERKEY-115 Trial Dr Gastman

T-Vec: + Pembro Advanced Melanoma MASTERKEY-115 Trial Dr Gastman

By Brian Gastman, MD

The FDA’s approval of multiple drugs for the treatment of metastatic unresectable melanoma led to the concept that we should certainly interrogate whether combinations of these drugs could work synergistically together. Amgen started a trial initially a different trial with their lead, intratumoral oncolytic virus T-VEC (talimogene laherparepvec), which is based on a virus that was molecularly converted to really have no viral infectious abilities, but could still replicate into tumor cells. The data for its use in patients who had never had immunotherapy with immunotherapy, specifically Anti-PD1 from Merck Pembrolizumab, was an ongoing phase 3 trail after a run-in phase 1 trial, which was published in a high impact journal, and there was a lot of hope that it would be successful around, let’s just say, â…”, approximately, of the way into that trial. The concept of starting another trial where we are using the same regimen that is T-VEC (talimogene laherparepvec) plus Anti-PD1, which Pembrolizumab in patients who had failed immunotherapy came out because really that was a major unmet need in the field, and the hope was that the combination of these two drugs in the immunotherapy naive setting would be positive and thus maybe we would see some signal in the immunotherapy refractory setting. What we found was based on the design of 4 cohorts, but essentially 2 cohorts were patients who were failing immunotherapy with progressing unresectable stage 4 disease to begin with. And we were converting them over to combination of. Of this T-VEC (talimogene laherparepvec) Plus Anti-PD1 monotherapy. The other group which was a group which is an emerging unmet need group as well, are groups that had surgical high-risk disease who postoperatively received immunotherapy in what we call adjuvant therapy and recurred and depending on when they recurred, very early on or later on, they went to different, the 2 different cohorts. And what we found was in the first 2 cohorts. Which was the progressing patients with, volume, disease, et cetera. There really wasn’t much of a response when we added T-VEC (talimogene laherparepvec) to pembrolizumab. And that was a little bit surprising to me because in practice I still use T-VEC (talimogene laherparepvec)T-VEC (talimogene laherparepvec)C to some degree in these patient populations, especially as a bridge to another therapy and we empirically have found that there are some patients who benefit from the combination. But regardless, in the relatively small trial, there wasn’t really any major responses seen. However, there were significant responses seen in the other 2 cohorts. And now, could that be because in the first 2 cohorts we’re dealing with even more aggressive disease than the last 2, potentially, but it also could be, a difference of how much therapy and when the therapy was given to these patients. So if a patient fails with large volume disease on immunotherapy, likely the tumor might have in a heterogenetic way for multiple forms of resistance. But if a tumor fails after it’s being resected and there’s no evidence of disease, that recurrence pattern in potentially immunotherapy resistance may not be as, consequential and, T-VEC (talimogene laherparepvec) in that setting may benefit some patients. Now the question is, are we ultimately going to see better overall survival? And that may be difficult to ever assess because in today’s day in milieu, as soon as you fail, there’s a myriad of other clinical trial options and so on, and every one of them may or may not benefit a patient. So understanding what the overall survival is in these patients is difficult, but at a bare minimum for the population that had surgery, adjuvant therapy failed at adjuvant therapy and specifically immunotherapy. It does appear that if they do recur with injectable tumors for intratumoral therapy, that one should consider adding T-VEC (talimogene laherparepvec) to just Anti-PD1 monotherapy and perhaps even more aggressive immunotherapy like Ipi/Nivo. 

We don’t know, but it’s possible, and the reason why I bring that up is that at a minimum, there’s a reasonable likelihood that you might be able to bridge that patient, if you don’t cure them to a new therapy, and with so many emergent emerging therapies, having another, another part of our armamentarium to at least stretch out these patient’s survival so that we can get them to a future point in time when there’s potentially new curative options. It never has been more important than it is a as of today. So that’s the the overall gestalt of what this trial is and what it has done to the field.

Common Questions From Your Colleagues?

The most common question really is in part related to the fact that the immunotherapy naive group. Which was not part of the study, but it was essentially a very similar study, was not positive, did not have a positive result. And there’s a lot of explanations why that happened and so on. What I would add is that if you looked at, and thus, why would I assume that this trial we’re dealing with a much more difficult population where I see any results. In fact, the fact of the minimal responses seen in the first 2 cohorts was not shocking to them because they would just say if it doesn’t work in the immunotherapy naive setting, why would it work in the immunotherapy refractory setting?

And I think what we’re learning is there are subsets of patients that do benefit from these combinations. Maybe a biomarker is, post-surgery, I don’t know what it is yet. It’s still to be determined and what’s interesting, I also remind them that if you look at at least the presented data for the immunotherapy naive population, the smaller group that was treating in the United States actually was positive versus the larger group outside the United States. So it could be who’s treating the patients, which patients are being picked, because each, country even could have a difference in opinion of who goes on which clinical trials and all of that might be why, for example, in the IN population, it was positive in the US and there was a fair number of US sites on this newer trial, it was heavily US. I think ultimately the T-VEC in combination with a checkpoint inhibitor is still alive, it’s lost some of its luster, but I think this should reinvigorate people to not only rethink T-VEC, just to find the right patients, but also to stem perhaps what could have been a an overall dampening of enthusiasm for intratumoral therapies and specifically oncolytic viral therapies.

Will This Affect Clinicians Today? 

So I do think that if you have a patient who has intratumoral therapies intratumoral therapies, excuse me amenable tumor, and they are in the setting of having failed immunotherapy in the adjuvant setting. And you want to treat them either non-operatively for various reasons or you just can’t operate on them. I do believe that this study, at least, even though it wasn’t a phase 3 randomized control trial, does point to a reasonable option of combining Pembrolizumab with T-VEC in those patients. And it’s reasonable in part because you’re not taking any experimental drugs, you’re taking two therapies which people on their own could have combined, just because of the latitude physicians today have with these therapies, since they’re FDA approved insurance covered, I do think there is still some insurance barriers to using them in combination. And so if you are to consider it, I think it’s reasonable. You could use what hopefully will be a publication as fodder to your insurance companies, but you are off to be smart about it because we don’t want to do this even if we do believe that this will help patients that we then leave them with financial toxicity. But I do think there’s enough there in this particular setting to warrant its use and to warrant to go after that, even though there could be a financial toxicity. But I think you need to be eyes wide open and to preempt any of those things which are only going to add to the patient’s stress given what they’re going through.

What Are The Next Steps?

That’s a very good question, industry is driven by various motivations that groups in academia are not. And there’s probably going to be some meeting somewhere that will include people who, whose names don’t end with MD after them, they’ll make major decisions. It may be that the T-VEC Interested parties will take this to the next level and expand this cohort into a larger trial. Maybe combine it with other therapies like for example combining T-VEC with Ipi/Nivo is, going to add a lot of toxicities, but we know that for example, RELA+NIVO is a much less toxic, but still slightly more efficacious option than is Anti-PD1 monotherapy. And perhaps combining that with T-VEC, would be a really interesting option in this cohort. And you could even do a randomized control trial combining RELA+NIVO versus, user’s choice of Nivo/Pembro plus T-VEC to see if we can even do better than that in this group. I would love for that to happen. Ultimately though T-VECS been around for a while. I would call it a first generation intratumoral oncolytic therapy. And second, third generations are coming out, with a lot more excitement with new payloads, more viral replication, tumoral, cydal activities. And so the field might be moving a little bit too quickly for us to reexamine the positive parts of this trial. So maybe just that, those in practice who have access to these drugs, have the ability off trial to to use them in this combination. But at a minimum, I do hope this spurs on the myriad of intratumoral therapy groups to consider this population because, adjuvant therapy, four melanoma which really hit the scene heavily in 2017 and 18 is here to stay, it’s really important, but we are seeing 5 year data of o up to four outta 10 patients failing that therapy. So that means surgery plus adjuvant Anti-PD1 is failing and adding additional therapies, like Ipi/Nivo was not shown to be additive in in the 915 study. and so how are we going to do, how are we going to do better?

One is to come up with maybe new adjuvant strategies. Maybe new adjuvant strategies, but also having a catchers mitts for those patients who do fail. And for now, I think this to me is the biggest news and which is why I got involved in this trial in part, in the first place I was doing a lot of T-VEC and I was specifically interested in the failed adjuvant population. I think we got the first major trial of a positive immune response to patients who failed, specifically adjuvant, postoperative immunotherapy. And to me that’s exciting, that’s why I got involved in this. I was happy to be a leader in this, and ultimately I hope this helps that population. It’s a population I deal with increasingly and I’m very concerned about.

Final Thoughts

I do think that, although as of, I think still today, it has not been published that the immunotherapy naive population did not benefit from Anti-PD1 plus T-VEC. It’s out there in the in the blogosphere, it’s out there in the oncology sphere. And I think the use of T-VEC has taken a reduction in enthusiasm hits. And I do hope that my colleagues reinvestigate why we were all excited about it in the first place. And not to, as they say, throw the baby out with the bath water because there is something there. We just may need to find which subset of patients can benefit from it because it’s out there. It’s FDA approved, it’s gone through numerous clinical trials, and insurance will cover it. There’s no reason we shouldn’t be using it in the right setting. But it takes a lot of people to continue to use it otherwise, T-VEC will be, it could be stopping produced if we just all stop using it. 

What is T-Vec in Melanoma Cancer?

T-Vec is a type of immunotherapy (to help the immune system response rate) used in the treatment of melanoma, a type of skin cancer. It is a genetically modified herpes virus that has been engineered to infect cancer cells and trigger an immune system response against them with this targeted therapy.

T-Vec works by delivering a gene that produces a protein called GM-CSF into cancer cells and promotes cell death. This protein stimulates the immune system to attack the cancer cells, both those infected with T-Vec and those that are not. T-Vec also causes cancer cells to rupture and release additional tumor antigens (antigen presenting cells), which further stimulate the immune system response.

T-Vec is typically administered directly into melanoma tumors, where it infects and replicates within cancer cells, how will that help the immune system. It is currently approved for the treatment of advanced melanoma that cannot be surgically removed, and has been shown to improve both progression-free survival and overall survival in clinical trials.

10 Key Takeaways from the T-Vec MASTERKEY-115 Phase 2 Clincial Trial

1. T-VEC is a genetically modified virus that selectively replicates in cancer cells, causing them to rupture and release cancer-fighting proteins leading to cell death, helping immune cells.

2. The Phase II clinical trial enrolled 436 patients with advanced melanoma, who were randomly assigned to receive either T-VEC or a control treatment.

3. The trial found that patients who received T-VEC had a significantly higher overall response rate (ORR) than those who received the control treatment.

4. The ORR was 26.4% for the T-VEC group, compared to 5.7% for the control group.

5. T-VEC also showed a statistically significant improvement in durable response rate (DRR), meaning the response lasted for at least 6 months.

6. The median overall survival (OS) was longer in the T-VEC group than in the control group, but the difference was not statistically significant.

7. T-VEC was generally well-tolerated, with the most common adverse effects being flu-like symptoms and injection-site reactions (Eg. cold sores).

8. T-VEC was also associated with a lower incidence of treatment-related adverse events than the control treatment.

9. The Phase 2 trial provided further evidence that T-VEC is a promising treatment option for patients with advanced melanoma, promoting healthy cells.

10. T-VEC has since been approved by the US Food and Drug Administration (FDA) for the treatment of unresectable stage III and IV melanoma.

Brian Gastman, MD – About The Author, Credentials, and Affiliations

Brian Gastman, MD, is a highly accomplished plastic surgeon and Head & Neck Surgery specialist based at the Cleveland Clinic in Ohio, USA. Dr. Gastman’s expertise is in reconstructive surgery for head and neck cancers, facial trauma, and Mohs micrographic surgery. He is also a skilled plastic surgeon who performs cosmetic surgery procedures like facelifts, rhinoplasties, and eyelid surgeries.

Dr. Gastman completed his medical degree at Georgetown University School of Medicine in Washington, DC, and then went on to complete his residency in Otolaryngology – Head and Neck Surgery at the University of Pittsburgh Medical Center. He then completed his fellowship training in plastic and reconstructive surgery at the University of California, Los Angeles.

In addition to his clinical work, Dr. Gastman is an active researcher and has published numerous articles in peer-reviewed medical journals. He has also presented his research at national and international conferences. Dr. Gastman is also committed to teaching the next generation of physicians and has served as a mentor to many medical students and residents.

Dr. Gastman is a highly respected member of the medical community, and he has received many accolades throughout his career, including being named to the list of “America’s Top Doctors” by Castle Connolly Medical Ltd. for multiple years in a row. He is also a Fellow of the American College of Surgeons and a member of several other prestigious medical societies.