Mobocertinib Dose Rationale in Patients with Metastatic NSCLC with EGFR Exon 20 Insertions: Exposure-Response Analyses of a Pivotal Phase I/II Study.

Mobocertinib is an oral tyrosine kinase inhibitor approved for treatment of patients with locally advanced or metastatic non‐small cell lung cancer (mNSCLC) with epidermal growth factor receptor gene (EGFR) exon 20 insertion (ex20ins) mutations previously treated with platinum‐based chemotherapy. These exposure–response analyses assessed potential relationships between exposure and efficacy or safety outcomes in platinum‐pretreated patients with EGFRex20ins‐positive mNSCLC who received mobocertinib 160 mg once daily (q.d.) in a pivotal phase I/II study. A statistically significant relationship between the independent review committee‐assessed objective response rate and molar sum exposure to mobocertinib and its active metabolites (AP32960 and AP32914) was not discernable using a longitudinal model of clinical response driven by normalized dynamic molar sum exposure or a static model of best clinical response based on time‐averaged molar sum exposure. However, the longitudinal model suggested a trend for decreased probability of response with the change in mobocertinib molar sum exposure between the 160‐ and 120‐mg doses (odds ratio: 0.78; 95% confidence interval: 0.55–1.10; P = 0.156). Time‐averaged molar sum exposure was a significant predictor of the rate of grade ≥ 3 treatment‐emergent adverse events (AEs). Taken together, these exposure–efficacy and exposure–safety results support a favorable benefit‐risk profile for the approved mobocertinib 160‐mg q.d. dose and dose modification guidelines for patients experiencing AEs.