Osimertinib plus gefitinib for treatment of EGFR-mutated non-small cell lung cancer

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Published: 12 Jun 2020
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Dr Julia Rotow - Dana Farber Cancer Institute, Boston, USA

Dr Julia Rotow talks to ecancer in an online interview for the ASCO 2020 virtual meeting about using concurrent osimertinib plus gefitinib for treating EGFR-mutated NSCLC.

The EGFR TKI osimertinib is active against the acquired gefitinib-resistant mutation EGFR T790M, as is gefitinib against the osimertinib-resistant EGFR C797S. Preclinical evidence suggests dual EGFR inhibition with gefitinib osimertinib may delay emergence of acquired resistance.

Dr Rotow outlines the trial design and results, and how this regimen will impact clinical practice.

This programme has been supported by an unrestricted educational grant from Bristol Myers Squibb.


 

I’m happy to speak with you today about our abstract evaluating the role of a combination of osimertinib plus gefitinib for treatment of patients with EGFR mutated non-small cell lung cancer in the first line setting. This study was based on existing data which we know looking at mechanisms of resistance to EGFR TKI therapy, both third generation TKIs like osimertinib and first generation TKIs like gefitinib, and particularly their existing knowledge regarding acquisition of EGFR second site mutations add acquire resistance to these therapies. Certainly the emergence of the T790M gatekeeper mutation for patients treated with earlier generation TKIs like gefitinib is well established and we’ve also seen this EGFR C797S mutation emerging in a smaller fraction but still present in patients who receive osimertinib in the first line setting.

This study evaluated combining both agents for intent to evaluate their ability to inhibit the development of these second site mutations and by doing so improve patient response to therapy outcomes. This is a phase I/II study which enrolled at time of data cut-off 27 patients who were evaluable and included in this particular abstract presentation. Overall the combination was well tolerated and certainly tolerability and feasibility was the primary endpoint both in the dose escalation and dose expansion phases of this study.

From a tolerability perspective we actually saw no new safety signals compared to our current understanding of the side effect profile of earlier generation and third generation TKIs given as monotherapy with GI side effects and skin toxicities like rash and dry skin being seen most commonly. However, our overall rate of grade 3 adverse events was quite comparable to those seen for third generation EGFR TKIs given in monotherapy, for example in the first line FLAURA study.

Our primary endpoint in dose expansion was feasibility which we defined as completion of at least six one-month cycles of combination therapy. We did find that 82% of patients were able to complete at least six cycles so that was promising and reassuring in terms of tolerability of this regimen. The overall entire course of follow-up approximately 30% of patients needed to discontinue their gefitinib for side effects, again mostly for skin and GI toxicity. Only one patient needed to discontinue osimertinib for concern for reduction in LVEF.

Response rates were similar to those seen for osimertinib monotherapy in this preliminary analysis with 89% of patients experiencing objective response and 100% of patients experiencing disease control. However, we believe that a longer term follow up with mature data regarding progression free survival may provide us with additional information regarding the ultimate clinical applicability of this combination in the first line setting.

We found also of great interest was the evaluation of cfDNA clearance of the EGFR mutation from the plasma following initiation of combination therapy. There are some data from osimertinib monotherapy where rapid clearance of the EGFR mutation was associated with better patient outcomes as measured by progression free survival. Here we do see a quite rapid and robust clearance of the EGFR mutation with 88% of the patients with a pre-assigned detectable EGFR within the plasma clearing by two weeks of therapy. We will continue to follow this as data maturity progresses.