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Making a Case for Second-Line TKI in EGFR-Mutated NSCLC

*September 2023*

“Insanity is doing the same thing over and over again and expecting different results.” While there’s some debate as to who actually said that off-quoted comment, there’s less uncertainty about the kernel of truth it contains. When it comes to treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), the idiom could apply to the continued use of osimertinib (Tagrisso) as second-line treatment even after first-line tyrosine kinase inhibitor (TKI) resistance has set in, FDA officials argued.

First-line osimertinib has “clinical benefits,” conceded Bernardo H.L. Goulart, MD, MS, of the FDA Office of Oncologic Diseases in Silver Spring, Maryland, and colleagues in a “Comments and Controversies” article in the Journal of Clinical Oncology.

And “platinum-based chemotherapy remains the standard of care after progression on EGFR [TKIs],” the authors said. But they also noted that many experts advise “continuing osimertinib beyond progression and adding other agents to target the putative mechanism of TKI resistance.” Justifications for this approach include:

  • Avoiding a “tumor flare” after stopping an EGFR TKI
  • Maintaining central nervous system disease control
  • Prolonging TKI clinical benefits especially in oligometastatic or oligoprogressive disease
  • “When the available evidence suggests that targeting the putative mechanism of resistance and the original EGFR mutation concomitantly is necessary to induce an antitumor effect. However, the evidence supporting this practice is limited and derives mostly from nonrandomized clinical data.”
    The article outlined the regulatory considerations that come into play when the FDA considers ongoing third-generation TKIs in second-line trials of EGFR-mutated NSCLC. These include adequate demonstration of the contribution of individual drug components to a combination regimen and the possibility that in the setting of high toxicity, it may just be the one drug that has the most benefit, Goulart and co-authors said.

    For instance, the ongoing randomized controlled COMPEL trial is testing osimertinib in combination with platinum chemotherapy and pemetrexed versus placebo plus platinum chemotherapy and pemetrexed in the post-osimertinib setting (estimated completion date is Dec. 2024).

    “With a primary end point of progression-free survival (PFS) and a projected sample size of 204 patients, COMPEL is expected to generate relevant evidence regarding the efficacy and safety of continuing osimertinib post-progression,” the authors wrote. “While the data from COMPEL may provide evidence of the benefit of continuing osimertinib when administering platinum-based chemotherapy, such results cannot necessarily be extrapolated to other potential partner drug(s) with differing mechanisms of action. The design of trials evaluating second-line, osimertinib containing combinations may need to be revisited to address individual contribution of drug component.”  Read more.