Treatment Outcomes and Safety of Mobocertinib in Platinum-Pretreated Patients With EGFR Exon 20 Insertion–Positive Metastatic Non–Small Cell Lung Cancer

Abstract

IMPORTANCEMetastatic non-small cell lung cancer (mNSCLC) with EGFR exon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively target EGFRex20ins mutations.OBJECTIVE To evaluate treatment outcomes and safety of mobocertinib in patients with previously treated EGFRex20ins-positive mNSCLC.DESIGN, SETTING, AND PARTICIPANTS This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreated EGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treated EGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort). INTERVENTIONS Mobocertinib 160 mg once daily. MAIN OUTCOMES AND MEASURESThe primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety. RESULTS Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash. CONCLUSIONS AND RELEVANCEIn this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treated EGFRex20ins-positive mNSCLC, with a manageable safety profile.

EGFR Exon 20 Insertion Mutations in Sinonasal Squamous Cell Carcinoma

“…Unlike previously approved reversible and irreversible inhibitors, mobocertinib has shown the ability to bind and inactivate the compact ATP-binding site of EGFR Ex20ins mutants that was shown to be inaccessible to most compounds [ 75 ]. Approval was based on results from an international, non-randomized, open-label, multicohort EXCLAIM clinical trial (NCT02716116), which evaluated mobocertinib efficacy in a cohort of 114 NSCLC patients carrying EGFR Ex20ins mutations that have progressed on or after platinum-based chemotherapy [ 76 , 77 , 78 ]. Patients were administered with mobocertinib 160 mg orally daily until disease progression or intolerable toxicity.…”

Therapeutic advances in non‐small cell lung cancer: Focus on clinical development of targeted therapy and immunotherapy

“… 140 Later, in September, the approval of mobocertinib (TAK‐788) was based on Study 101, in which mobocertinib showed an ORR of 28% with a median response duration of 17.5 months. 68 …”

“…Mobocertinib is granted a BTD from the U.S. FDA for NSCLC with EGFR or HER2 exon 20 insertion mutations, based on the data from a phase II trial. 68 Despite the approval of fam‐trastuzumab deruxtecan‐nxki (Enhertu), other inhibitor targeting HER2 showed promising effects on NSCLC. Poziotinib, an oral irreversible pan‐HER TKI, demonstrated a promising ORR of 35.1% in HER2‐ mutated NSCLC in a phase II trial, ZENTITH20‐2.…”

HER2 Aberrations in Non-Small Cell Lung Cancer: From Pathophysiology to Targeted Therapy

“…The most common treatment-related AEs were QTc prolongation, rash, and diarrhea occurring in 60.9%, 43.5%, and 21.7%, respectively. Mobocertinib is a novel small-molecule TKI designed against exon 20 insertions; in a phase I/II clinical trial, mobocertinib showed promising antitumor activity in previously treated NSCLC patients with EGFR exon 20 insertions, resulting in "breakthrough therapy designation" by the U.S. Food and Drug Administration (FDA) [76,77]. Preclinical data indicate that mobocertinib is highly selective, as it possesses the lowest HER2 exon 20 insertion/wild-type EGFR IC50 ratio.…”