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Capmatinib effective in MET-mutated, advanced NSCLC

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SAN DIEGO — Phase 2 data from the GEOMETRY mono-1 trial showed that capmatinib was effective and well tolerated in patients with advanced non-small cell lung cancer who harbored MET exon 14 skipping mutations.

Capmatinib (INC280; Incyte, Novartis) also demonstrated “considerable efficacy” against brain metastases, according to Juergen Wolf, MD, medical director of the Center for Integrated Oncology at the University Hospital Cologne in Germany.

“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 MET exon 14 mutations,” Wolf said during a presentation at the ASCO Annual Meeting. “Orphan drug designation and breakthrough therapy designation has been granted to capmatinib.”

Approximately 3% to 4% of patients with NSCLC harbor MET exon 14 skipping mutations, which are associated with a poor prognosis and poor response to standard treatment, including immunotherapy, according to Wolf. Capmatinib previously showed in vitro and in vivo activity in preclinical cancer models. It is the “most potent inhibitor against MET,” surpassing the activity of savolitinib (HMPL-504/AZD6094; AstraZeneca, Chi-Med), tepotinib (Merck), cabozantinib (Cabometyx, Exelixis) and crizotinib (Xalkori, Pfizer), Wolf said.

GEOMETRY mono-1 is a multicohort trial. The current analysis exclusively focused on 69 pretreated patients and 28 treatment-naive patients with stage 3b or 4 NSCLC who harbored MET exon 14 skipping mutations. Enrollment criteria required that patients have ALK-negative, EGFR wildtype tumors and at least one measurable lesion.

The primary endpoint was the overall response rate (ORR) to 400 mg of capmatinib twice daily. The main secondary endpoints included duration of response, PFS, OS and safety. Efficacy was determined through investigator assessment as well as a blinded independent central review committee (BIRC).

Data from the pretreated and treatment-naive cohorts were analyzed separately. In the pretreated group, 73.9% of patients received one prior line of therapy, 23.2% received two prior lines of therapy and 2.9% received three prior lines of therapy. Most patients received platinum-based chemotherapy (88.4%). Other treatments included immunotherapy (26.1%), single-agent chemotherapy (13%) and targeted therapy (4.3%).

Among the pretreated patients, the ORR was 40.6% (95% CI, 28.9-53.1) in the BIRC assessment and 42% (95% CI, 30.2-54.5) in the investigator assessment. The median duration of response in this group was 9.72 months (95% CI, 5.55-12.98) per BIRC and 8.31 months (95% CI, 4.34-12.06) per investigator. Median PFS was 5.42 months (95% CI, 4.17-6.97) per BIRC and 4.8 months (95% CI, 4.11-7.75) per investigator.

Responses were higher among treatment-naive patients. In this group, the ORR was 67.9% (95% CI, 47.6-84.1) in the BIRC assessment and 60.7% (95% CI, 40.6-78.5) in the investigator assessment. Meanwhile, the median duration of response was 11.14 months (95% CI, 5.5 to non-estimable [NE]) per BIRC and 13.96 months (95% CI, 4.27-NE) per investigator. Median PFS was 9.69 months (95% CI, 5.52-13.86) per BIRC and 11.14 months (95% CI, 5.52-15.24) per investigator.

The onset of response began within the first 7 weeks of treatment among 82.1% of patients in the pretreated group and 68.4% in the treatment-naive group. A neuro-radiologist review confirmed the activity of capmatinib against brain metastases. Of the 13 evaluable patients with brain metastases, seven (54%) had an intracranial response. Among these patients, four had complete resolution of all brain lesions.

There was no association between efficacy and MET mutation type or co-occurring MET amplication, Wolf said.

Capmatinib had a “favorable and manageable safety profile,” according to the researchers. Approximately 35% of patients experienced a grade 3 or 4 adverse event, most commonly peripheral edema (7.5%). Nearly 22% of patients had a dose adjustment and slightly more 11% discontinued treatment due to treatment-related adverse events.

“Capmatinib has demonstrated, in this trial, clinically meaningful efficacy in advanced NSCLC harboring MET exon 14 mutations,” Wolf concluded. “The responses were rapid [and] deep with a meaningful duration, regardless of the line of therapy. The higher overall response in the treatment-naive patients highlights the importance of early molecular testing.” – by Stephanie Viguers

Reference:

Wolf J, et al. Abstract 9004. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.

Disclosure: Wolf reports serving on advisory boards and receiving lecture fees from AbbVie, Amgen, AstraZeneca, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Chugai Pharmaceutical, Eli Lilly and Company, Ignyta, Merck, Novartis, Pfizer, Roche and Takeda. He also reports receiving research support on behalf of his institution from Bristol-Myers Squibb, Johnson and Johnson, Merck, Novartis and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.