ESMO 2023 Lung Cancer Highlights – Keynote 671 | ALINA | TropionLung01 | Oncology Brothers

Unpacking ESMO 2023 Lung Highlights and KEYNOTE 671 OS Data Hello everyone I am Rahul goslain. And I'm Rohit Kissing and we are oncology brothers. Wow. ESMO 2023 was impressive to say the least. There was a lot of practice changing data that was presented just in lung cancer alone. And to cover this, while we've divided lung cancer highlights in two different segments today to focus on KEYNOTE 671 in resectable non small cell lung cancer then Alina trial in ALP positive patients followed by trope ion lung 01. We're joined by Doctor Joshua Royce from Georgetown Lombardi Cancer Center. Josh, thank you for joining us. Speaker 1 Thank you so much for having me back. You hit the nail on the head this. You probably could have called this conference the ESMO Lung 2023 conference with how much practice changing data there was. So excited to be here to unpack some of it. Speaker 3 I certainly agree with that Josh. Well, thank you so much for joining us. To get started, let's look at resectable non small cell lung cancer patient population here. Prior to ESMO 2023, Checkmate 816 was approved with neoadjuvant chemo IO combination with nivolumab. Now this is KEYNOTE 671, another phase three study looking at perioperative IO, chemo combination followed by surgery and then continuing IO that is pembrolizumab after. In a driven settings in the similar space, we have data for Adian with perioperative durvalumab and also Checkmate 770 with the volumab in perioperative setting. This space is getting crowded indeed. So what did Keynote 671 show? Speaker 1 Yes. So you know, obviously you hit the nail on the head. This is a rapidly expanding space you know first with. Actually our adjuvant studies, you know the EMPOWER 10 trial and pearls then the NEO adjuvant and now we're seeing multiple perioperative trials including the 1st results from the Checkmate 77 T study that were also presented at ESMO Lung 2023. But what was what you're showing here and what we were really excited to see at ESMO this year were the overall survival results for the KEYNOTE 671 study. So we already knew that from this trial with results presented at ASCO this year that the study met its event free survival endpoint with a hazard ratio of about .58 seen across strata, encouraging results there. But what the results we saw here were the much coveted overall survival results where we saw that the addition of pembrolizumab both before surgery in combination with a cisplatin based chemotherapy doublet followed by adjuvant pembrolizumab elicited an overall survival benefit with a hazard ratio of .72 favoring the IO chemo combination. Importantly, this benefit was seen regardless of disease, Histology, lymph node status, disease stage, perhaps a slightly more pronounced benefit in those with high PDL one expression, but absolutely practice changing These results came out in concert with an FDA approval for this regimen in patients with tumor size of 4 centimeters or greater or lymph node positive disease. And again, this was the first perioperative IO based. Trial to show an overall survival benefit, which means hopefully that we are actually curing more patients with the addition of immunotherapy perioperatively, which is very exciting. Speaker 2 Josh, thank you so much for touching on that that this is the first to have overall survival benefit with IO and Peri op space. Of course we had OS benefit with chemo in adjuvant settings. Comparing KEYNOTE 671 and Checkmate 816 for Patient Selection So this is very exciting, but coming back to the two options now we have in your clinic, who are you going to prescribe Checkmate 816 regimen versus who's going to get Keynote 671? Speaker 1 That's that's the real question, isn't it? And I will say it, it would be nice to see some additional data from the Keynote 671. You know, we know that pathologic complete response, The degree of response appears to potentially affect the event free survival benefit. But to see how that translates into an overall survival benefit I think will be helpful. In addition looking at things like CTDNA clearance as we hopefully see improvements in technology being able to accurately assess minimal residual disease and you know be able to see who may warrant de escalation versus escalation of therapy. It's hard to imagine already talking about de escalation of therapy for non small cell lung cancer when for so long we had so little in this space. I will say I think there are some subgroups that that might warrant us making a treatment decision at the onset. I think in the squamous population a lot of the perioperative studies showed a consistent benefit for a perioperative as opposed to a neoadjuvant approach alone. I think the same might be said about the PDL one negative population where those hazard ratios appear to be more consistent in benefit of a perioperative approach. But you know, as I alluded to, I think we need more information to see. Who could we stop potentially after a complete pathologic response is observed? That in and of itself is difficult, right, because if you start down a Pembroke chemo approach with KEYNOTE 671, the study really isn't designed to stop after a pathologic complete response. So I think that's where we need novel studies. We need some cooperative groups based trials on DE escalation and better biomarker strategies to look at minimal residual disease and look at really which patients need more therapy. Speaker 3 Totally agree with that and I believe another limitation which will play into action is the cisplatin eligibility as well. Now if the patient who's actually ineligible for a keynote 6711 could consider Checkmate 816. Now if this patient population has had partial response after Checkmate 816, are you going to consider adjuvant IO in this patient population? Speaker 1 Yeah, No, that's an excellent question and an excellent point that you know Keynote 671 did limit to a cisplatin based regimen. So does that mean these patients may have had less comorbidities, maybe we're more functional than your average patient. I think that's possible. I think one definitely, though could extrapolate and substitute in carboplatin with that caveat. But to your point, I think if one were to prescribe a neoadjuvant approach with 816, I definitely am kind of looking at a modified 816-O10 and 816 pearls and adding an adjuvant immunotherapy. There are some subgroups from earlier immunotherapy based trials, monotherapy studies that suggest continued adjuvant there is benefit there and the NCCN guidelines does not necessarily exclude adjuvant immunotherapy to those who give 8. 1/6, So I think that's a very reasonable strategy to consider. Speaker 2 Gosh, thank you for covering that. Alectinib's Role and Chemotherapy Considerations in ALK+ NSCLC Now switching gears, let's have a look at the Alina trial again. We're looking at resectable non small cell lung cancer who happens to have ALK positive mutation from the study we just covered. It is important to acknowledge that the patients with EGFR or ALK positive disease should not fall in this immunotherapy sandwich pre OP approach. Alena trial is a phase three study looking at electinib after surgery versus the current standard of care treatment of chemotherapy. Josh What did the study show? Speaker 1 Yeah, So this was definitely one of the studies that we were we were most excited to see and to your point we already had data for adjuvant Osumerton have been patients with resected EGFR mutation positive non small cell lung cancer. And I think a lot of us in the lung cancer community were really wondering given the tolerability of an ALC targeted therapy, you know would the same benefit apply to this population And in short, it absolutely did. So to your point, this was a phase three trial that randomized patients with resected stage 1B to 3A non small cell lung cancer by the AJCC 7th staging edition. To our second generation out the targeted therapy electinib which is the front line strategy that's commonly employed in those with metastatic disease, it often times is my targeted therapy of choice. And so patients were randomized to receive two years of the targeted therapy electinib or chemotherapy for cycles of platinum based chemotherapy, A noticeable difference from the ADORA study in which patients were randomized after receiving chemotherapy if indicated. But as the results are shown here, incredibly impressive disease free survival benefit with a hazard ratio of .24 in both the primary population of stage two to three A disease but also in the intention to treat population stage 1B to 3A. Notably, there was also significant benefit at the two year and three-year landmarks I think around. A 30% absolute disease free survival benefits, so really ground breaking and instantly practice changing. I think another notice notable point is that the CNS disease freezer hazard ratio of .22, meaning that there's nearly an 80% recurrence free survival in the CNS, meaning these patients had an almost 80% reduction in the likelihood of having this disease recurring, the CNS which we know. Is a problem and is quite common in those with ALK fusion positive lung cancer. Speaker 2 So again I think instantly practice changing Josh, thank you for covering that findings from Alina trial, you brought up the role of chemotherapy, who is going to get chemotherapy or all our patients are going to emit chemotherapy and move directly to lectinib. Speaker 1 Yeah, absolutely. I think this is an excellent question. So in my practice I. I probably would be hesitant to completely remove chemotherapy from this treatment approach in these patients. We do know that there is a survival benefit while small, you know maybe a 5 to 10% absolute survival benefit at five years for chemotherapy in patients with stage two and three resected non small cell lung cancer. So in my practice, I don't feel that electinib completely replaces chemotherapy in these patients, though obviously I'm not going to, you know, hold my patients down and force them to chemotherapy. I think we do know that electinib is a great therapy in in in this space. I think there are open questions. What's the optimal duration when you stop the electinib? Will we start to see the recurrences? Was that when we will start to see the recurrences take place, we'll need to monitor the CNS more closely. And then I think another important question because I think for a lot of us we were already deploying this strategy if we could get it approved with insurance. And I think it will be interesting to say, all right, well if you have a targeted therapy that's really well, well tolerated has great CNS penetrance for example, the right targeted therapies maybe emerging Ross one targeted therapies, can we replicate this approach in these populations And I think those are all important questions. Speaker 3 Thanks for addressing that very critical point that chemotherapy we cannot just completely subtract, but something a thought provoking question. Now we know that OC Mertinib was approved, posted or a trial and that is mainly an adjuvant setting for three years. Electinib here is for two years. It'll be interesting to see how as you stated Ross, targeted therapy and RED targeted therapy when you utilize an adjuvant setting, how that plays out. But again we have to wait for the trial data on that. Dato-DXd, Emerging ADCs, and ESMO Lung Cancer Takeaways Now switching gears, let's look at metastatic non small cell lung cancer disease that has progressed on first line treatment. Our current standard of care for years has been Dositaxel, Remu, Serumab combination. Intrapy on lung 01, we have a new antibody drug conjugate being looked at in phase three study to see if we can do better than our standard of care. That is again dositaxel and remyuserumab combination. Josh What did the study show? Speaker 1 Yeah, absolutely. So you know we are starting to see the emergence of this novel class of therapy, these novels of the lung cancer community. I think the the community based practitioners probably have more experience with this in Gu and breast. But this looked at a specific antibody drug conjugate called datapodumabderoxdecan or dado DXD. This is an antibody drug conjugate that targets the cell surface protein trope 2, which we know is is quite highly expressed across non small cell lung cancer and potentially has prognostic implications. And so this compound targets trope 2 conjugated to a dado DXD topoisomerase inhibitor warhead. And this study looked in the subsequent line space in patients with advanced non small cell lung cancer who had received up to two prior lines of therapy and were randomized 1 to 1 to dado DXD 6 milligrams per kilogram every three weeks versus dose Ataxel 75 milligrams per meter squared every three weeks with dual primary endpoints of progression free and overall survival. And as the results that you have up here, the study did meet its primary endpoint with a progression free survival advantage to data of DXD. Though I will say when looking at the numbers it is somewhat underwhelming a median progression free survival of 4.4 months compared to 3.7 months. When you do the math, that's probably around 3 weeks and a hazard ratio of .75. I will say the non squamous subgroup does look a little bit more promising. Potentially they are a progression free survival of four 5.6 months versus 3.7 months hazard ratio of .63. So perhaps that's a population where this benefit might be more pronounced. But I do think we need to wait for the overall survival data here. We need to see what's the depth and duration of these responses because this therapy, you know it's. It's not without toxicities. There's more stomatitis, there's the specter of ILD. While high high grade ILD is not common. I think knowing that we do see toxicities and and somewhat different toxicities and with that with then with dose of Taxol, we definitely need more data before this I think will become integrated commonly into practice. Speaker 2 Josh, thank you for touching on the Histology because when we're focusing on squamous the hazard ratio was actually greater than one. So most of the benefit was driven in non squam patients and particularly if anything we also saw data from Tropion lung 05 where at the same antibody drug conjugate seems to be active in actionable mutations like EGFR and ALC mutations, patients that have progressed on upfront TKI, is this the subset maybe we should look out for when using DADO DXD? Speaker 1 Yeah, I know that's a good point. I don't know if it's the only subgroup. I will commend, you know, the investigators for really singling out that subgroup and looking at it further. You know, obviously this is a really a different disease biology than patients without driver mutations. And I think it's it's promising, it's encouraging you know response rates probably on the order of around 30 to 40% progression free survival of six months, duration of response seven months that's in primarily the EGFR population where where was which was the largest subgroup there. I will say there is another ADC that's showing a lot of promise in that space. Patritramab directs TCAN. So same payload but targeting a different cell surface protein her three. And I would say the bulk of data while the numbers look very similar in terms of progression free duration of response, those things, there's definitely a lot more data for that compound. For her three DXD, the published data is over 200 patients. It's a population that's heavily pre treated responses observed across resistance mechanism. And at ESMO that this year we did see some data that her three DXD appears to penetrate the CNS and we see CNS responses. A small cohort, but maybe a response rate around 33% and really quite impressive of that a 30% complete CNS response rate. So I I think the data probably points more toward the her three DXD versus the DADO DXD. But it's great to see you know several promising compounds in this space and and that I know will be highlighted further on your Part 2 version of of this discussion. Speaker 3 Thank you so much for covering Josh. And that's exactly what's important that this just adds more treatment options for our patient population where this is a very dire unmet need data. DXD, yes, the data is underwhelming, but again just adding another treatment option with her three DXD is certainly very important. Josh, we've covered a lot of data here and we appreciate you joining us. Thank you so much for our listeners. Stay tuned for a quick wrap up. Speaker 1 Thank you. Speaker 3 Post asthma, we have covered three important studies in lung cancer with Doctor Joshua Royce in resectable non small cell lung cancer, chemo with nivolumab in neoadjuvant settings or cisplatin based chemotherapy with pembrolizumab are available treatment options. However, we only have oral survival data from Keynote 671 with pembrolizumab now. If a patient is a candidate for cispatin, this perhaps would be my go to for now. Speaker 2 Then another practice changing study was ALENA trial establishing the role of alactinib in adjuvant settings for resectable non small cell lung cancer without positive disease. This should now be our standard of care. Speaker 3 We have also covered the data for DADO DXD in second line non small cell lung cancer patient population. We await overall survival benefit here. Thanks for joining us. Please check out for our lung highlights covering everything with Amivantamab and Libretto 431 study in another segment. Also TuneIn for breast GI and Gu highlight for ESMO 2023, we are the oncology brothers.