Article: Transcript: MASTERKEY-115: A Complete (But Concise) Update for Melanoma Treatment - Brian Gastman, MD @BrianGastmanMD @GastmanLab @CleClinicLCM #ASCO22 #OncoTwitter
Transcript: The FDA 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 intra-tumoral oncolytic virus t-vec 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 the data for its use in patients who had never had immunotherapy with immunotherapy specifically anti-pd1 from pembrolizumab was an ongoing face retrial after a run-in phase one trial which was published in the high impact journal and there was a lot of hope that it would be successful around let's just say two-thirds approximately the way into that trial the concept of starting another trial where we are using the same regimen that
is TVAC plus Anti-PD-1 which is parabolizumab in patients who had failed immunotherapy came out because really that was a major unmet needed 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 four cohorts but essentially two cohorts were patients who were failing immunotherapy with progressing unrespectable stage four disease to begin with and we were converting them over to combination of of this TVAC plus Anti-PD-1 monotherapy the other group which was a group which is an emergent merging unmet need group as well are groups that had had surgical high-risk disease who post-operatively received immunotherapy in what we call adjuvant therapy and recurred and depending on when they recurred very early on or later on they went into different the two the two different chords and what we found was in the first two cohorts which was the progressing patients with you know volume disease etc there really wasn't much of a response when we added t back to pembrolizumab and that was a little bit surprising to me because in practice i still use TVAC to some degree in these patient populations especially as a bridge to another therapy and we've 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 however there were significant responses seen in the other two cohorts now could that be because in the first two chords we're dealing with even more aggressive disease than the last two 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 hair genetic 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 you know consequential and thus TVAC 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 milieu as soon as you fail there's a myriad of other clinical trial options and so on and every one of them may 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 agile therapy and specifically immunotherapy it does appear that if they do occur with injectable tumors for intra-tumor therapy that one should consider adding TVAC to just Anti-PD-1 myotherapy and perhaps even more aggressive immunotherapy like it being evo we don't know but it's possible and the reason why i bring that up is 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 emergents emerging therapies having another you know another part of our armamentarium to at least stretch out these patients 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 as of today so that's the the overall gestalt of of what that of what this trial is and what it has done to the field
Question - Common Questions from Your Colleagues?
Yeah the most common question really is in part related to the fact that the immunotherapy naive group was which was not part of the study but it was essentially a very similar study did not was not positive it 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 when I see any results in fact the fact of the minimal responses seen in the first two cohorts was not shocking to them because they would just say well if it doesn't work in the immunotherapy naive setting why would it work in the immunotherapy refractory setting and you know i think what we're learning is there are subsets of patients that do benefit from these combinations you know maybe a biomarker is you know post-surgery I I don't know what it is yet it's still to be determined but and what's interesting I also remind them that if you look at at least the presented data for the immunotherapy naive population the actual the smaller group that was treating the United States actually was positive versus the larger group outside the United States so it could be who's treating the patients who which patients are being picked because each you know country even could have a difference in opinion of who goes on which trials and all that might be why in for example in the iona population it was positive in the US and there was a fair number of US sites on this newer trial it was heavily US so I I think ultimately the TVAC in combination with a checkpoint inhibitor is still alive it's it's lost some of its luster but I think this should reinvigorate people to not only rethink TVAC just to find the right patients but also to stem perhaps what could have been a an overall dampening of enthusiasm for intra-tumor therapies and specifically oncolytic viral therapies
Question - Will This Affect Clinicians Today?
So I do think that if you have a patient who has intra-tumoral therapies intra-chemotherapy 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 three randomized control trial does point to a reasonable option of combining pembrolizumab with TVAC 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 that they have with these therapies since they are 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 have to be smart about it because we don't want to to do this even if we do believe that this will help patients that we then leave them with financial toxicity so but I do think there's enough there in this particular setting to warrant its use and the warrant to go after that even though there could be a financial toxicity but i think you need the 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
Question - What Are the Next Steps?
It's a very good question you know industry is driven by various motivations that groups in academia are not and there's probably gonna be some meeting somewhere that will include people whose names don't end with md after them that will make major decisions it may be that the TVAC 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 TVAC with epinevo is going to add a lot of toxicities but we know that for example rella nevo is a is a much less toxic but still slightly more efficacious option than his anti-p1 model therapy and perhaps combining that with TVAC would be a really interesting option in this cohort and you could even do a randomized control trial combining rel and evo versus you know you know user's choice of nevo pembro plus TVAC to see if we can even do better than that in this group I would love for that to happen ultimately though TVAC been around for a while I would call it a first generation intra-tumor once therapy and second third generations are coming out with a lot more excitement with new payloads more viral replication tumeral societal activities and so the field might be moving a little bit too quickly for us to re-examine 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 intra-tumor therapy groups to consider this population because adjuvant therapy for melanoma which really hit the scene heavily in 2017 and 18 is is is here to stay it's really important but we're seeing five-year data of up to four out of 10 patients failing that therapy so that means surgery plus adjuvant anti-pd1 is failing and adding additional therapies like epinevo was not shown to be additive in in the 915 study and so how we can do how are we going to do better one is to come up with maybe new adjuvant strategies maybe new azure strategies but also having a catcher's mitt 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 feedback and I was specifically interested in the failed adjuvant population I think we got the first major trial of of a positive 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 I hope this helps that population it's a population I deal with increasingly and I'm very concerned about
Question – Final Thoughts
Well 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 antibiotic it's it's out there in the in the blogosphere it's out there in the oncology sphere and I think the use of TVAC has taken a reduction in enthusiasm hit and I I do hope that my colleagues re-um investigate why we were all excited about it in the first place and and not the as they say throw the baby out the bath water because there is something there 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 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 TVAC will be you know it could be stopping produced if we just all stop using it you