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Despite the clinical benefits observed with first-line osimertinib in epidermal growth factor receptor-mutated non–small-cell lung cancer (EGFRm NSCLC), tumor progression occurs in most patients. While platinum-based chemotherapy remains the standard of care after progression on EGFR tyrosine kinase inhibitors (TKIs), several authors suggest continuing osimertinib beyond progression and adding other agents to target the putative mechanism of TKI resistance.

In parallel to expert recommendations, many second-line trials are investigating osimertinib or other third-generation EGFR TKIs in combination with a partner drug(s) as an attempt to overcome TKI resistance. Such trials tend to follow one of two designs: (1) a single or multicohort nonrandomized trial evaluating osimertinib or a third-generation EGFR TKI (hereafter referred to as "EGFR TKI" for brevity) plus a partner drug(s); and (2) a randomized trial comparing an EGFR TKI in combination with a partner drug(s) versus standard chemotherapy. These trial designs will yield results that are difficult to interpret, given that these study designs do not isolate contribution of effect of each component of the combination.

This article discusses the regulatory challenges related to the assessment of contribution of individual drugs to the observed treatment effect in trials evaluating EGFR TKIs in combination with partner drugs after progression on osimertinib and the potential trial design strategies to overcome these concerns. Of note, second-line trials investigating novel regimens without EGFR TKIs are outside the scope of this manuscript.

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