Real-world efficacy and safety of mobocertinib in EGFR exon 20 insertion-mutated lung cancer

Abstract

BackgroundNon-small cell lung cancer (NSCLC) harboring EGFR exon 20 insertions (EGFRex20ins) is relatively resistant to the existing EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is a novel TKI that selectively targets EGFRex20ins and has demonstrated therapeutic efficacy in pretreated patients with tumors harboring these mutations.MethodsThis is a retrospective, non-interventional, multicenter real-world study aimed at assessing the efficacy and safety of mobocertinib in patients with EGFRexon20ins who received 160 mg QD monotherapy as part of expanded access. Data collection was based on patients’ records. PET-CT or CT scans were used to measure systemic response, while brain MRIs were used to examine intracranial response as part of the follow-up.Results16 patients were included in this report. Mobocertinib was administered to 31.3% (5) of patients as first-line, 50% (8) as second-line, and 18.7% (3) as a later-line therapy. The median age was 65 years (range, 38-83), 75% (12/16) were female, and 50% (8/16) had brain metastases at baseline before mobocertinib treatment. The objective response rate (ORR) to mobocertinib was 25% (4/16) (1/5 for first line and 3/11 for other lines), disease control rate (DCR) was 75% (12/16) with a follow-up period of 11 months. The median duration of treatment (mDoT) was 5.6 months across all patients, and 8.6 months in responders. Based on the presence or absence of brain metastasis, the mDoT was 14.8 and 5.4 months (p=0.01), respectively. Mobocertinib Grade ≥3 treatment-related adverse events (TRAEs) included diarrhea (19%), nausea (6%) and renal failure (6%). Dose reduction was reported in 25% of cases to 80 mg.ConclusionMobocertinib in compassionate use exhibited an ORR of 25%, which is very similar to that of the phase 2 EXCLAIM study and clearly better than historical data of monochemotherapy or conventional EGFR inhibitors. The greatest benefit was noted in patients without brain metastases, who showed durable effects with mDoT 14.8 months, while intracranial activity was limited. These findings may assist therapeutic considerations, inasmuch as results from the EXCLAIM cohort-3 dedicated to brain lesions are not available yet.

EGFR exon 20 insertion mutations and ERBB2 mutations in lung cancer: a narrative review on approved targeted therapies from oral kinase inhibitors to antibody-drug conjugates

“…Investigators have since published proposals for proactive management of both dermatologic and gastrointestinal toxicities to minimize the need for mobocertinib dose reductions/interruptions ( 133 ). Real-world experience with mobocertinib has mirrored that seen in these initial clinical studies ( 134 ).…”

Glioblastoma with novel EGFR mutations (T790M and exon 20 insertion) yet unresponsive to osimertinib: A case report

“…Treatment of NSCLC patients with osimertinib has shown promising results, achieving partial response or stable disease, including brain metastases due to the ability of osimertinib to cross the blood–brain barrier, a feature lacking in first and second generation EGFR TKIs, 7,8,13,15,35,36 although not all studies have shown such efficacy 37 . Other novel TKIs specifically targeting EGFR Ex20Ins such as mobocertinib and poziotinib have shown promise in early‐stage clinical trials in lung cancer patients 38 . Poziotinib has also been shown to possess meaningful CNS activity.…”

“…37 Other novel TKIs specifically targeting EGFR Ex20Ins such as mobocertinib and poziotinib have shown promise in early-stage clinical trials in lung cancer patients. 38 Poziotinib has also been shown to possess meaningful CNS activity. In a phase II trial of poziotinib, patients with CNS metastases of NSCLC showed a 28% objective response rate, including one patient with complete CNS response after treatment.…”

Clinical Utility of Mobocertinib in the Treatment of NSCLC – Patient Selection and Reported Outcomes

“…This includes the formation of an irreversible covalent bond with the cysteine 797 residue in EGFR. 4 , 8 , 11 Additionally, the C5-carboxylate isopropyl ester moiety on mobocertinib’s middle pyrimidine ring interacts with the C790 gatekeeper residue in the ATP binding pocket of EGFR, therefore selectively targeting EGFRex20ins oncogenic variants. 5 , 6 , 10 …”

“…The study population was similar to the PPP cohort of EXCLAIM study; however, it also included patients receiving mobocertinib as first-line treatment (5/16) as part of the compassionate use program (CUP) who were otherwise not suitable candidates for chemotherapy. 4 …”