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Targeted Combo Fails in EGFR-Mutant NSCLC

(MedPage Today) Jan 7, 2021 - Adding a VEGF inhibitor to osimertinib (Tagrisso) failed to improve survival outcomes in previously treated patients with EGFR T790M-positive non-small cell lung cancer (NSCLC), a small randomized study from Japan showed. For the primary endpoint, the combination strategy of osimertinib plus bevacizumab (Avastin) led to a median progression-free survival (PFS) of 9.4 months, as compared to 13.5 months with osimertinib alone (adjusted HR 1.44, 80% CI 1.00-2.08, P=0.20), reported Hiroaki Akamatsu, MD, PhD, of Wakayama Medical University in Japan, and colleagues in JAMA Oncology.

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H. Jack West, MD (Posted: January 08, 2021)

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As I stated in the Editor's Note that accompanied this article, there is nothing about the research done thus far on the combination of osimertinib/bevacizumab that should lead us to have enthusiasm about phase III trials with this combination, or even lead us to proceed with them. This particular study was in the second line setting in patients with EGFR T790M mutation-positive acquired resistance to earlier generation EGFR TKIs, but a phase I/II trial by Yu and colleagues that was published in JAMA Oncology in 2020 was similarly disappointing, with a median PFS shorter than the median PFS in the phase III FLAURA trial with osimertinib monotherapy (Ramalingam, NEJM 2020).

As a nearly inviolable rule, phase III trials don't do exceptionally better than the preceding smaller trials of that approach. They almost always have a dilution of the signal seen in earlier, much smaller trials. We also have NO examples of an EGFR TKI/VEGF inhibitor combination that has translated to any significant improvement in overall survival in EGFR mutation-positive NSCLC, though we have multiple trials that have tested this, many far more encouraging in PFS findings than we're seeing with osimertinib + VEGF inhibitor therapy.

We have finite resources to run multimillion dollar phase III studies, not least of which are the limited opportunities for patients to enroll on trials that give them a meaningful probability of receiving a therapy that could demonstrate a significant improvement in outcomes. The fact that ECOG/ACRIN has developed a phase 3 trial propelled only by aspiration and a thought experiment, with no supporting evidence from preceding clinical data, is disappointing. It will be a shame to waste the money, time, and opportunity for these patients when the expected failure to demonstrate an overall survival difference is confirmed.

The onus should be on those developing the trials to prove a concept demonstrated as promising in early, smaller trials. We should not need to run phase 3 trials to counter the repeated negative results of phase I and II studies.

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