It's an absolute pleasure to be here to talk about unresectable stage, three, non small cell lung cancer. Um So I'm going to divide my talk into three different settings. Uh Where are we with radiation therapy? A lot has happened with systemic therapy and where are our next steps? Just to make note that this is truly patients who are unresectable. And we'll have a lively debate later about adjuvant versus new adjuvant for the ones who are resectable. So, a long time ago, we established that concurrent chemo radiation therapy is really standard of care. This is a paper from the early 20 tens that demonstrated in a meta analysis that we shouldn't really be doing sequential chemo radiation therapy for patients who can otherwise get concurrent. You can see minimal modest benefit but sustained benefit at five years with concurrent chemo radiation therapy. The other question is, what is the dose of radiation that should be used? The RT G 617 trial looked at whether or not escalating radiation dose will lead to survival advantage. Dr Jeff Bradley and colleagues demonstrated that actually higher is not better. So 60 gray, 60 to 66 gray should really be our standard for radiation therapy. So couple of takeaway points from uh radiation setting concurrent chemo radiation should be standard with about 60 gray. There are emerging trends that are different in radiation therapy should proton therapy really be employed. The RT ogo 318 trial which is listed here is looking at photons versus protons. This has completed accrual and then of course, uh SP RT can we consider that uh which is being evaluated on the luoo eight trial uh which is now open at our institution and probably at Fox shares as well. Looking at SP RT to the primary site followed by chemo radiation uh to the media stum compared to chemotherapy, uh che uh standard concurrent chemo radiation followed by maintenance immunotherapy. And I think this will be interesting to really as we start to explore novel radiation therapy techniques, coming to systemic therapy, a lot has changed in even just the last 45 years. And I wanna start with what's the choice for chemotherapy? First, we know from the proclaimed clinical study uh design that it really doesn't matter, right? This study looked at CISplatin and uh PEMEtrexed versus CISplatin and a topic which used to be our standard patients had a recovery period after three cycles of CM or two cycles of a topic side based therapy and went on to consolidation therapy um with either Petrey or investigator choice. And as you can see, there was no difference in outcomes. So the chemotherapy choice doesn't really matter. And at least for this trial, consolidation chemotherapy did not really uh pan out either. So our standard has been uh to use um either a CISplatin, more carboplatin with either pitre or Taxol without consolidation. But I think the biggest change that is uh really been noticeable in the stage three setting has been uh the use of immunotherapy in the consolidation setting. Almost everyone who's here is aware of the Pacific trial. This is five year updates from this large randomized trial that looked at um the rab after concurrent chemo radiation therapy for one year. And as you can see, five year overall survival hazard ratio is 0.72 with sustained benefit in PFS as well, really establishing Pacific as our standard. However, there is an unmet need in the Egfr mutant subset. Uh If we look at all patients, they do benefit. Uh But when you look at post talk analysis of just the EGFR mutant subset, there is really no benefit of giving immunotherapy to these patients compared to placebo. And that's where the Laura trial comes in. That was presented at this year's as o annual meeting. Very similar design to Pacific. You basically can insert egfr activating mutation uh Here instead of all comers patients after concurrent chemo radiation getting randomized to either oom ortin indefinitely or placebo. Primary end point for this trial was uh progression treat survivor. And this is a pretty significant, I think it crosses uh definitely passes the truck test. Uh that Doctor Royce talked about an eight X times improvement in median PFS from about five months to close to about 40 months. Uh benefits seen across all subgroups leading to an FDA approval recently for Laura. And as you can see and not unexpectedly, the most important difference that we can make for these patients is the reduction in brain mats. And then interim analysis of overall survival does seem to demonstrate an improvement despite 81% crossover. And I think this is one of the positive things about this trial that a great majority of the patients did get o or upon progression, which should really be standard of care. Um So in terms of systemic therapy for stage three, non small cell lung cancer, I think my takeaways are we can continue to use concurrent chemo radiation. There's no clear benefit of consolidation, chemotherapy, immunotherapy should be used for patients who are candidates and then personalizing treatment based on the molecular status. Of course, we have Laura now and we started to think about the same for, let's say our out positive patients. Um And how can we apply those findings there quickly in the last few minutes? I want to talk about the next steps. Where are we headed for unreceptable disease? There's a lot of exciting stuff on the horizon. Um So Pacific two was just reported um earlier, this year at um at ESMO. And really this question of, can you move immunotherapy even earlier, was asked on this trial. So patients with locally advanced unresectable non small cell lung cancer received concurrent chemo immunotherapy and radiation with Derval A or they received um concurrent chemo radiation. This was designed at a time when Pacific was not the standard of care. And as you can see, the control arm was just basically what we used to do Pre Pacific. And as you can see, there was no benefit of Pacific two in terms of PFS. Um So Dalma with concurrent chemo radiation actually had no um no improvement. But there is and also even in overall survival, you don't see an improvement. But I think what's really going to be a definitive trial in this setting will be a comparison of specific two versus specific one which is being led by the ECO group E 5181 which is comparing Pacific, which would be concurrent chemo radiation and then followed by consolidation of all to this investigational arm of Pacific two which is platinum doublet plus the vab plus radiation with the primary overall survival of primary end point of overall survival. Happy to report that this trial is fully accrued. And I I think this is going to be uh looked at extensively over the next several years. There are other trials that are looking at concurrent chemo radiation and immunotherapy um trials with the volume on the left and with Meliz A on the right, you can see there are different iterations of basically the same concept. Of course, there's also interest in looking at dual checkpoint blockade for many of these cohorts. And then I want to spend a little bit of time on how can we improve upon Pacific and we incorporate new immunotherapy agents. Coast is one such platform study that looked at addition of other immunotherapy agents with Derval A. So there were two agents electro as well as Mono Liz Aab that were evaluated on this phase two platform study both leading to an improvement in overall response rate over the val A alone um in this setting of Pacific. And here is uh some of the updated uh data from the study on the left, you can see PFS um data and on the right overall survival data, both the purple and the pink demonstrate the combination arms of the mab with these new investigational agents. Again, both of them looking really better than the mab. And this was a randomized phase two. This is now in a randomized phase three. This is specific nine again 1000 patient trial looking at how can we improve upon the standards of Pacific Dalom A is our control arm and we are using again these two agents, you know, one is to one is to one randomization with the primary end point for PFS. Um We just crossed our futility analysis So I think this is looking promising we're continuing enrollment about 3/4 of the way done. Uh Some other novel IO Agents uh TDT again, uh skyscraper three is listed on the left and then Key Vibe 006. These are trials again, thinking about how can we improve upon Dalum a in this post concurrent uh in this post chemo radiation setting and then target therapy. I wanna build upon what was discussed earlier in the adjuvant setting. I think it's the same idea that can, if Laura is giving us a pfs advantage, I think for these special subsets, we should be able to come in with something uh that's targeted, that's brain penetrate and can lead to improvements. So here are some of the trials that are evaluating uh horizon as well as bounce. So in summary, I think improvement in systemic therapy has improved outcomes and concurrent chemo radiation uh patient selection. I think biomarker testing is extremely important going to be crucial for personalization and the novel immunotherapy uh combinations as I discussed with you, novel targeted therapies are poised to further improve the landscape. Uh Thank you so much for your attention.
Related Presenters
