Mobocertinib (Exkivity): A Comprehensive Monograph on a Targeted Tyrosine Kinase Inhibitor for EGFR Exon 20 Insertion-Positive NSCLC

I. Executive Summary

Mobocertinib, marketed under the brand name Exkivity, is a first-in-class, orally administered, irreversible tyrosine kinase inhibitor (TKI) developed by Takeda Pharmaceuticals.[1] It was specifically engineered to address a significant unmet medical need: the treatment of non-small cell lung cancer (NSCLC) driven by epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations. This molecular subtype, representing approximately 6-12% of all EGFR-mutated NSCLC cases, has historically been associated with a poor prognosis and intrinsic resistance to first-, second-, and third-generation EGFR TKIs.[3]

The clinical development of mobocertinib culminated in an accelerated approval from the U.S. Food and Drug Administration (FDA) in September 2021. This decision was based on compelling data from a single-arm Phase 1/2 clinical trial, which demonstrated a clinically meaningful overall response rate (ORR) of 28% and a notably durable median duration of response (DoR) of 17.5 months in patients with advanced disease who had progressed on or after platinum-based chemotherapy.[6] For a brief period, mobocertinib represented the only approved oral targeted therapy for this patient population.

However, the drug's trajectory was ultimately defined by the results of its mandatory Phase 3 confirmatory trial, EXCLAIM-2. This randomized study, which compared mobocertinib to standard platinum-based chemotherapy in the first-line setting, failed to meet its primary endpoint of demonstrating a superior progression-free survival (PFS).[5] This outcome, coupled with a challenging safety profile dominated by gastrointestinal and dermatologic toxicities, led Takeda to initiate a voluntary global withdrawal of the drug in October 2023.[8]