OncoTargets and Therapy (Jul 2023)
Clinical Utility of Mobocertinib in the Treatment of NSCLC – Patient Selection and Reported Outcomes
Abstract
Abram Arnold,1 Apar Kishor Ganti2 1Department of Medicine, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; 2Division of Oncology/Hematology, Department of Internal Medicine, Veterans Affairs Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE, USACorrespondence: Apar Kishor Ganti, 986840 Nebraska Medical Center, Omaha, NE, 68198, USA, Tel +1 402 559-5622, Email [email protected]: Mobocertinib is an oral tyrosine kinase inhibitor (TKI) that selectively targets epidermal growth factor receptor exon 20 insertion (EGFRex20ins) mutations. It is a structural analog of the third-generation TKI osimertinib, which targets EGFR T790M mutant non-small cell lung cancer (NSCLC); however, mobocertinib gains selectivity for EGFRex20ins mutants over wild type (WT) by interacting with the C790 gatekeeper residue of EGFR. This is accomplished via a carboxylated isopropyl ester moiety at the C5-position of mobocertinib’s central pyrimidine core. In Phase 1/2 dose-escalation and dose-expansion studies, mobocertinib was found to have an investigator-confirmed overall response rate (ORR) of 56% (9/16; 95% CI: 30– 80%) and 25% (3/12; 95% CI: 5– 57%) in patients without and with baseline brain metastasis, respectively. Median investigator-assessed progression-free survival (mPFS) was 10.2 months (95% CI: 5.6 – not reached) and 3.7 months (95% CI: 1.8– 15.9) in patients without and with baseline brain metastasis, respectively. A third phase evaluated patients who had received pre-treatment with platinum-based chemotherapy (PPP) and included an extension cohort (EXCLAIM cohort) which evaluated patients treated previously with 1 or 2 lines of therapy. An Independent Review Committee (IRC) found both cohorts to have similar outcomes in terms of ORR, median time to response, mPFS, and disease progression or death. The treatment-emergent adverse events (TEAE) related to mobocertinib are similar to other EGFR inhibitors and are predominately gastrointestinal (eg diarrhea, nausea, vomiting) and cutaneous (eg rash). In September 2021, the FDA granted accelerated approval for mobocertinib in the treatment of patients with locally advanced or metastatic NSCLC with EGFRex20ins mutation whose disease progressed while on platinum-based chemotherapy. The present review describes data that led to the approval of mobocertinib.Keywords: mobocertinib, exon 20 insertion of EGFR, NSCLC, TKI
