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Medicine Matters oncology

I'm Julia Rotow. I'm here from the Dana-Farber Cancer Institute. And thank you for the opportunity to talk with you today. I'll be discussing the abstract of myself and my group, where we discuss the use of osimertinib plus gefitinib for a first-line treatment of EGFR-mutated non-small-cell lung cancer. And the rationale behind the study was an ongoing effort across the lung cancer research community to try to improve upon the response rates we see to EGFR TKI therapy in the first line setting for lung cancer, which has certainly been a revolutionary development.



For osimertinib, most recent data suggests a little over a year and a half progression-free survival for patients who received this first line. But as we've understood better the resistance mechanisms to these earlier generation drugs, there's been a lot of efforts towards developing novel combination therapy strategies for these patients, either as a personalized therapy strategy at the point of acquired resistance or upfront as a combination therapy based on what we know and predict potential resistance mechanisms to be.



In this study, the intent was to target the known propensity for the development of acquired EGFR second-site mutations at resistance and trying to inhibit that particular resistance mechanism, in the hopes of improving patient outcomes on therapy. Specifically for-- in this study, we evaluated combination of gefitinib, which is an earlier-generation EGFR TKI, and osimertinib, which is a third-generation EGFR TKI. For gefitinib, patients who develop resistance most commonly develop an acquired gatekeeper T790M mutation, which is well demonstrated in the literature. And osimertinib has good activity against this mutation.



In contrast, patients who receive Osimertinib first line, the most commonly seen acquired EGFR mutation is the C797S mutation. This is not seen as frequently as the gatekeeper mutation in numbers ranging from about 7% of patients to about a quarter of patients, depending on the case series, but does offer a potential therapeutic target as gefitinib and other earlier-generation EGFR TKIs are been shown to have activity against this mutation. So in this study, we did evaluate combination of both drugs helping to eliminate these two common resistance mechanisms.



This is a phase 1/2 study for patients with EGFR activating mutations who had not previously received therapy for metastatic disease. In this study, we evaluated both safety of the combination in the phase 1 dose escalation portion as well as some preliminary efficacy outcomes for patients who continued on the and were treated on the expansion phase. At time of our analysis for ASCO, there were 27 patients who are evaluable and were included in this preliminary analysis.



We did find, first and very importantly, that this combination was tolerable and did not have any new safety signals compared to what we know about these two drugs as monotherapy. Most common side effects were common EGFR TKI side effects, including findings like rash, dry skin, and diarrhea, the most commonly seen adverse events. So the primary endpoint was feasibility in the expansion phase, which we defined as an ability to continue at least six months of combination therapy.



And the majority of patients were able to achieve this. Approximately 81% did at least six months of therapy. This is a very important consideration when considering adding a combination therapy to an approved monotherapy which is well tolerated and active.



So on the efficacy outcomes, we did evaluate objective response rates in this preliminary analysis. And we did find an objective response rate of approximately 89% for patients who received treatment. That will continue to be updated as we reach a full enrollment and a more mature data analysis.



A second very interesting outcome on this study was the evaluation of plasma cfDNA clearance of the EGFR activating mutation. This is something that has been gaining interest in recent years as we've had the ability to monitor the driver mutation within the cfDNA DNA. And we know for patients who receive osimertinib-- that there's some data that treating rapid clearance with EGFR treatment may correlate to better survival outcomes.



So here we did evaluate that with serial plasma DNA starting at two weeks of therapy and continuing onwards. And for the approximately two-thirds of our patients who did have detectable plasma DNA at baseline saw very high and rapid clearance of the EGFR mutation from the plasma. And by two weeks, that mutation had cleared in 88% of patients.



It's difficult to compare directly to prior studies. But certainly, in other preliminary reports using different methods and different assays, there was approximately two-thirds rate of clearance. So we feel optimistic that that may be a good signal for outcomes for these patients, pending further confirmation down the line.



What are your next steps?

Key interest is understanding and being sure of tolerability and safety of the combination. These drugs are good as monotherapy as well. And we hope to expand upon that. And if things go well, we want patients on therapy for many, many-- a good long period of time. People are on osimertinib sometimes for years at first-line therapy.



So it needs to be a tolerable combination that patients can continue on with good safety outcomes. So that's, of course, the chief concern of these sorts of combination studies in the initial setting. Down the line, to better understand how this might impact treatment, there are two key considerations.



One, of course, is survival outcomes. And when you discuss adding potential toxicity by adding second drugs, you want to see improvements in progression-free survival that make that combination meaningful for patients. So looking down the line as we have additional mature progression-free survival data, I think that will help to clarify where this might stand as a dual TKI therapy up front for patients. And we're looking forward to additional data as we reach full enrollment.



In our preliminary data set, we saw progression-free survival of 22.5 months. But the data was immature with only one-third of patients having had progression events. So we'll continue to monitor that as we go forward in the study.



The other important point for how this may fit into future therapy options will be understanding the effect that combination therapy upfront has on the development of resistance. And we'll be evaluating that when patients do develop disease progression and be evaluating for mechanisms of acquired resistance at the genomic level. Thus far, for the smaller subset of patients who've experienced progression, we haven't seen any acquired known pathogenic EGFR second-site mutations. And I think it will be important to see going forward to what extent this might impact subsequent resistance mechanisms and treatment options for patients.