Mobocertinib for previously treated EGFR exon 20 insertion mutant non-small cell lung cancer: updated results of the phase I EXCLAIM trial
Advanced NSCLC with epidermal growth factor receptor exon 20 insertion mutations (EGFRex20ins) remains to be an unmet medical need. Updated results of the phase I EXCLAIM trial demonstrate that the tyrosine kinase inhibitor (TKI) mobocertinib induces a response in a quarter of relapsed or recurrent advanced NSCLC EGFRex20ins patients, with high rates of disease control and an encouraging progression-free survival (PFS). Moreover, mobocertinib had a positive impact on the symptom burden of patients and came with a tolerable safety profile.
Introduction
EGFRex20ins mutations are found in approximately 5-12% of all EGFR-mutated NSCLC patients. The success of 1st and 2nd generation EGFR tyrosine kinase inhibitors in patients harbouring EGFRex20ins mutations is limited with response rates of 10-15% and a median progression free survival (PFS) of only 3-5 months. Mobocertinib is a first-in-class TKI that specifically targets EGFRex20ins. Based on the initial results of the phase I EXCLAIM study, the drug obtained a breakthrough therapy designation in the United States and China for EGFRex20ins positive NSCLC patients who failed on chemotherapy. In this study, 114 locally advanced/metastatic NSCLC patients with EGFRex20ins, who had progressed on at least one prior line of therapy received mobocertinib 160 mg orally, 4 times a day. A detailed study design is depicted in slide 1. At WCLC 2020, the study reported the results of an extended study cohort and zoomed in on the results obtained in a cohort of patients who previously received platinum-based chemotherapy (PPP cohort).
Disease control in three quarters of patients
The median age in both the extended EXCLAIM and the PPP cohorts was 60 years, two thirds of patients was female and approximately 70% had an ECOG performance status 1. In the PPP cohort, 41% of patients received mobocertinib in 2nd line, while 32% and 27% received in third line or beyond third line, respectively. In the extended EXCLAIM cohort these rates were 51%, 31% and 18%. Respectively 25% and 31% of patients received prior TKI therapy and 43% and 34% of patients had prior immunotherapy exposure. The independent review committee (IRC) confirmed objective response rate (ORR) was similar between the PPP and extended ECLAIM cohort at 26% and 23%, respectively. Responses were durable, with 78% and 84% of patients had having a duration of response of more than 6 months in PPP and extended EXCLAIM cohorts. In both cohorts, the median PFS was reported at 7.3 months. Overall, 82% of patients in the PPP cohort and 80% in the extended EXCLAIM cohort had a tumour volume reduction following mobocertinib. Response rates were similar in all investigated subgroups, irrespective of prior TKI or immunotherapy use and regardless of the presence of brain metastases.
The mobocertinib safety profile was consistent with what is known from other TKIs. The most common all-grade treatment-related adverse events were diarrhoea (~90%), rash (45%), paronychia (34%), decreased appetite (32%), nausea (both 32%), dry skin (30%) and vomiting (30%). Grade ≥3 diarrhea was reported in 21% and 16% of patients in the PPP and extended EXCLAIM cohort, respectively. Overall, 17% of patients in the PPP group and 10% in the extended cohort experienced adverse events that resulted in treatment discontinuation. In both cohorts, 1 treatment-related death was observed. Interestingly, treatment with mobocertinib lead to clinically meaningful improvements in symptoms of dyspnoea (54.4% of patients), coughing (44.4%) and chest pain (37.8%).
Conclusion
In this phase I study, mobocertinib demonstrated a clear clinical benefit in advanced NSCLC patients with exon 20 insertion mutations inducing a response in a quarter of patients and three quarters of patients experiencing disease control. In addition, mobocertinib was associated with clinically meaningful improvements in the symptom burden of patients. The safety profile observed in this study was comparable to the known safety profile of other EGFR TKIs.
Reference
Zhou C et al., Mobocertinib in NSCLC With EGFR Exon 20 Insertions: Results from EXCLAIM and Platinum-Pretreated Patient Populations. Presented at WCLC 2020; Abstract OA04.03.
