Dr. Riess: So， previous to just a few weeks ago the management strategy was to start patients off with EGFR activating mutations， in the United States either on erlotin， afatinib， gefitinib， they are first or second-generation EGFR-TKI inhibitors， and they have been studied in multiple clinical trials compared to chemotherapy， and in those trials there was a substantial progression free-survival benefit to the EGFR-TKI patients whose tumors had EGFR activated mutations. And then when they progress， you would do a biopsy and if they were positive to the T790M mutation， which was about 50 to 60% of EGFR mutant non-small cell lung cancer， osimertinib is approved for that indication. and that for T790M positive had about a 60% response rate in a 10-month progression free-survival， so that was the optimal choice. If they were negative for T790M they would either go on a clinical trial or be treated with standard of care chemotherapy， but that’s changed with the new FLAURA study that shows about a PFS benefit of 19 months and a signal of a potential overall survival benefit， so I think many people will adopt first-line osimertinib as the new standard of care for EGFR lung cancer and then the question is what comes after that? Because the resistance mechanisms will shift and will unlikely be T790M. I think Dr. Gainor has some additional thoughts on this as well.

 

Dr. Gainor: I tend to agree. I think historically we made our decisions based on activity and safety profile. And so， historically all of our first and second generations inhibitors were always compared against chemotherapy and we were always doing cross trial comparisons. We’ve now started doing clinical trials comparing EGFR inhibitors and I think that started to uncover what the proper sequence should be. I agree， I think in light of the FLAURA data showing profound improvement in PFS on top of a very favorable side effect profile with osimertinib that will immerge as a new standard of care， at least in first line. And then future questions are going to be what comes next after that.

 

Dr. Gainor: I think it depends on the oncogene. So for example KRAS lung cancer， KRAS is the most common oncogene in non-small cell lung cancer. We’ve known about it for the longest， yet it is something that we really have been unable to target today with effective targeted therapy. And so for KRAS lung cancer we’ve been stuck with our standard therapies， either chemotherapy or more recently immunotherapy. What we found though for anther oncogenic drivers， EGFR， ALK， ROS1 and BRAF， those are on the oncogenes where we have good targeted therapies that have shown high response rates in either single or even randomized studies depending on oncogene. And for those subsets I think the standard of care right now is to start with targeted therapy. And then for patients who don’t have those specific alterations our current standard of care， at least at my institution， is to perform broad based next generation sequencing to identify additional potential targets. We recognize that most of these oncogenic drivers are mutually exclusive， so if you have one you don’t have the other. And we are trying to carve out smaller and smaller pieces of the pie of the oncogenic drivers in lung cancer.

Dr. Riess: I generally agree with that， with what Dr. Gainor said. My philosophy is if the response rate is more than 50%， I give the front-line targeted therapy. I think in the US， EGFR， ROS1 and ALK， and now BRAF approved and I think I fit that mold.  KRAS fusions have a response rate of targeted therapy as for lung have 30% or so range， HER2 mutations have a response rate at a 15 to 30% to certain targeted therapies; so those types of mutations where we don’t have a targeted therapy that has quite the response rate of an EGFR or ROS1， TKI， I do chemotherapy first. 

 

 

Dr. Gainor: So I think it goes back to again what is the oncogene that we are talking about. For EGFR and ALK-positive lung cancers I think in general， immunotherapy should be de-prioritized compared to the targeted therapies， and patients should really should try to maximize and optimize targeted therapy in those patients first， before exploring immuno checkpoint inhibitors. Because today immune checkpoint inhibitors have shown relatively low response rates at no specific molecular subsets. Moving forward we need to do better and try to understand that there are still some patients who derive benefit even among EGFR patients. The frequency is low but we need to identify what is about those patients in order to guide our therapies while also exploring potential combinations to try to improve the response rates in those subsets.

 

Dr. Riess: I think that Dr. Gainor gave a great summary. I would just amplify that for oncogene driven non-small cell lung cancer， my preference is to give immunotherapy later in the course of treatment and to maximize targeted therapy， chemotherapy. Even when I’ve given immunotherapy， I am generally looking for clinical trials with combination therapies. I think single agent PD-1， PD-L1 in the absence of something compelling like very high PD-L1 status， something unusual like a high mutation in EGFR mutant patient which is pretty much non-existent. I think that trials of combinations are the best.

 

 

Dr. Riess: That is a great question， but a very broad question. To be concise about it， I talked a little bit about in the talk I think targeted therapy， now that we have advances with lung cancer with alectinib， osimertinib and EGFR mutant lung cancer， I think not just bring them up front， but bring them upfront in combination as those drugs tend to be better tolerated than some of the older generation TKI inhibitors. And coming up with those schemes in combination we are heading to bypass tract as well as the on target in innovation and doing it first-line to prevent resistance， I think that will be the next step and you can envision trials that even do something like serial plasma moderate resistance mutations， almost like they do in chronic myeloid leukemia， and the finding the resistance mutations early. But I think that is going to take years of trial to sort out any benefit. But I think that is what he future is going to hold. In terms of immunotherapy I think combination strategy is once again targeting potential resistance mechanisms， maximizing treatment of the patients that hat don’t seem to benefit as much from single agent PD-1 therapy.

Dr. Gainor: Yes， I will agree with that. That one of the major challenges is going to be that we have so many different potential combinations in lung cancer right now， especially around immunotherapies based where we are seeing basically every agent that we have combine with PD-1 inhibitor， and it is up to us to develop more rational clinical trials， to develop novel clinical trial designs where we can rapidly evaluate combinations， move combinations that are promising for faster while also eliminating futile combinations. And I think that is going to be only way to evaluate all of these combinations that reach futility. And I think that is going to be the only way， that we are going to actually be evaluate all these combinations， in parallel with doing so with rigorous translational science so that to understand why certain combinations fail while other are of benefit.

 

Dr. Gainor: Personally， I think that the best data that we have so far is with the ALEXs data showing an upfront treatment with alectinib was superior to crizotinib producing a very impressive progression free-survival around 26 months， and that was similar to what was observe in the ALKs data. So， for me I think that treatment with a more potent penetrant ALK inhibitor， alectinib， first-line looks superior to using sequential crizotinib followed by a second-generation inhibitor. And so that to me， once it achieves regulatory approval， I think should be the new standard of care.   

 

Dr. Riess: I agree， what I presented today I stand by. I was pretty firm that I think alectinib based on magnitude of PFS benefit the CNS activity and tolerability as the first sign standard of care. The details are going to be sorting out what comes next. But I think 26 months vs 11 eleven-month is pretty substantial and I think patients tolerated better and they don’t get， almost 43% of patients on crizotinib had and in the IALSC study had CNS progression within a year and that is devastating for patients. So the longer you can delay that， the better. 

 

Thank you!