Mobocertinib is a tolerable and possible treatment option for patients with EGFR exon 20 insertion mutated advanced non-small-cell lung cancer

1. Overall response rate was 28% and 35% in the platinum pretreated cohort (PPP) and 25% and 32% in the EXCLAIM cohort (independent review committee and investigator assessment percentages, respectively).

2. Progression free survival was 7.3 months in both the PPP and EXCLAIM cohort, while overall survival was 2 years in the PPP group and not reached in the EXCLAIM group.

Evidence Rating Level: 2 (Good)

Study Rundown: EGFR exon 20 insertion (EGFRex20ins) mutations are a rare form of non-small cell lung cancer (NSCLC). First line treatment is platinum-based chemotherapy, but the disease progresses for most patients within 6 months. The use of non-specific EGFR tyrosine kinase inhibitors (TKIs) has minimal effectivity on this particular mutation of NSCLC. However, mobocertinib, a TKI targeting the EGFRex20ins mutation, has shown encouraging results in previous phase 1/2 clinical trials. This report details the outcomes of daily mobocertinib on objective response rate (ORR; assessed via computed tomography (CT) or magnetic resonance imaging (MRI)), progression free survival (PFS), overall survival (OS), and safety in patients with EGFRex20ins mutated NSCLC. Results are presented for two cohorts: those who had been pretreated with platinum-based chemotherapy (PPP cohort) and those previously treated with systemic therapy (EXCLAIM cohort). In the PPP cohort, ORR was 28% and 35% by independent review committee (IRC) and investigator assessment, respectively. PFS was 7.3 months and median OS was 2 years. ORR in the EXCLAIM cohort was 25% and 32% by IRC and investigator assessment, respectively. PFS was 7.3 months, while median OS was not reached. Safety was assessed by the extent and tolerability of adverse effects (AEs) and the most common of any severity in both groups were rash and diarrhea. Diarrhea was the most common severe AE. Skin and gastrointestinal AEs were mainly mild, and all AE were adequately managed by supportive treatment, modifying dosage, or discontinuing mobocertinib. Only 17% of the PPP cohort and 10% of the EXCLAIM cohort stopped mobocertinib due to AEs. Limitations of this study include its status as a non-randomized trial with no control arm. As well, not all tumour tissues obtained were adequate samples for assessment and not all EGFRex20ins mutations were detectable. Finally, this study may not be applicable to evaluate response rates in patient populations with active brain metastases as they were excluded. Overall, mobocertinib appears to be a potential treatment option with a decent safety profile for use in patients with EGFRex20ins mutated NSCLCs.

Click to read the study in JAMA Oncology

Relevant Reading: Mobocertinib (TAK-788): A Targeted Inhibitor of EGFR Exon 20 Insertion Mutants in Non–Small Cell Lung Cancer

In-Depth [prospective cohort]: This cohort expansion from the phase 1/2 nonrandomized clinical trial included 114 patients who were pretreated with platinum therapy (PPP cohort) and 96 patients who had been previously treated with 160 mg daily mobocertinib (EXCLAIM cohort) for EGFRex20ins mutated NSCLC. The effect of 160 mg mobocertinib administration once daily on objective response rate (ORR), progression free survival (PFS), overall survival (OS), and safety was reported. Treatment cycles were 28 days, and patients received 160 mg of oral mobocertinib daily until the disease progressed, they experienced severe adverse events (AEs), or met other specified study-cessation criteria. Response to treatment was assessed via CT or MRI of the brain, chest, abdomen, and pelvis. In the PPP cohort, the ORR was 28% (95% confidence interval (CI), 20-37%) and 35% (95% CI, 26-45%) by IRC and investigator assessment, respectively. PFS was 7.3 months (95% CI, 5.5-9.2 months) and median OS was 2 years (24 months) (95% CI, 14.6-28.8 months). In the EXCLAIM cohort, the ORR was 25% (95% CI, 17-35%) and 32% (95% CI, 23-43%) by IRC and investigator assessment. PFS was 7.3 months (95% CI, 5.5-9.1 months), while median OS was not reached. Within both groups, the most common AEs of any severity were rash and diarrhea. The most common severe AE was diarrhea, and most of the skin and gastrointestinal (GI) AEs were relatively mild. All AEs were manageable either by supportive treatment, and modifying or discontinuing mobocertinib. Treatment was discontinued due to AEs in 17% of the PPP cohort and in 10% of the EXCLAIM cohort.

Image: PD

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