New Therapy on Horizon for Rare Lung Cancer Subtype

Juergen Wolf, MD

The highly selective and potent MET inhibitor capmatinib (INC280) showed intriguing signs of clinical efficacy in a rare subtype of patients with non­—small cell lung cancer identified by a MET exon 14 (METex14) skipping mutation, according to findings presented at the American Society of Clinical Oncology (ASCO) 2019 Annual Meeting in Chicago, IL.

In the phase 2 GEOMETRY study that was presented at the meeting, capmatinib showed an objective response rate (ORR), indicating at least a 30% reduction in tumor size by independent review (IR), of 67.9% (95% CI: 47.6-84.1) in treatment-naive patients with METex14-altered NSCLC. MET exon 14 skipping mutations have been identified in approximately 3% to 4% of NSCLC cases and are associated with a poor response to currently available therapies.

“Capmatinib is a potent and selective MET Inhibitor that represents a new potential treatment option in this rare but challenging patient population of advanced NSCLC harboring METexl4 mutations,” lead investigator Juergen Wolf, MD, from the Center for Integrated Oncology, University Hospital Cologne, said during a presentation of the findings at ASCO. “Capmatinib has demonstrated clinically meaningful efficacy in advanced NSCLC patients harboring METex14 mutations, and also demonstrated efficacy in patients with brain metastases.”

The GEOMETRY trial is examining capmatinib across several cohorts, with cohort 4 and 5b selected for presentation at ASCO. Cohort 4 contained pretreated patients with METex14 alterations in the second- or third-line setting (n= 69) while cohort 5b included treatment-naive patients (n= 28). The median age across both cohorts was 71 years, and approximately three-fourths had an ECOG status of 1. In cohort 4, 15.9% of patients had brain metastases compared with 10.7% in cohort 5b. The most common prior therapy used was platinum-based chemotherapy (88.4%).

In pretreated patients, the ORR by IR was 40.6% (95% CI: 28.9-53.1). The disease control rate (DCR; ORR plus stable disease) was 78.3% (95% CI: 66.7-87.3). In the frontline setting, the ORR by IR was 67.9% (95% CI: 47.6-84.1) and the DCR was 96.4% (95% CI, 81.7-99.9).

“Deep responses were observed in a majority of patients across both cohorts,” said Wolf.

The median duration of response (DOR) by IR was 9.72 months in pretreated patients and 11.14 months in those receiving capmatinib in the frontline setting. The median time without progression of disease or death was 5.42 months in the pretreated group and 9.69 months for those treated in the frontline setting.

Approximately half of the patients with brain metastases at baseline experienced an intracranial response with capmatinib (7 of 13 [54%]). Of these patients, 4 had a complete resolution of brain lesions (31%). The intracranial DCR was 92.3% (12 of 13).

“Deep responses and duration of response were observed independently of type of MET mutation leading to METex14 or co-occurrence of MET amplification,” said Wolf. “There was high concordance between next generation sequencing [NGS] and RT-PCR in detection of METex14 in tumor tissue.”

Capmatinib has received an orphan drug designation and a breakthrough therapy designation for METex14 skipping mutation positive metastatic NSCLC following platinum-based chemotherapy. As these therapies move toward the clinic, it emphasizes the need to make genetic sequencing a standard of care for patients with NSCLC.

Safety was assessed across all cohorts examined in the study, which each included patients with MET dysregulated NSCLC (N = 334). Grade 3 treatment-related adverse events (AEs) occurred in 31.1% of patients and a grade 4 event was seen in 4.5% of patients. Peripheral edema was the most common grade 3/4 event (7.5%) followed by fatigue (3.0%). The most common treatment-related AE of any grade was peripheral edema (41.6%), nausea (33.2%), increased blood creatinine (19.5%), and vomiting (18.9%).Wolf J, Setons T, Han J-Y, et al. Capmatinib (INC280) in METΔex14-mutated advanced non-small cell lung cancer (NSCLC): Efficacy data from the phase II GEOMETRY mono-1 study. J Clin Oncol. 2019;37 (suppl; abstr 9004).