The US FDA has approved the targeted anticancer drug Tabrecta (capmatinib, formerly known as INC280, carmatinib) for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) harboring MET exon 14 skipping (METex14) mutations, including both first-line (treatment-naïve) and previously treated (treatment-experienced) patients.
Based on the results of the phase 2 GEOMETRY mono-1 trial (NCT02414139), in the group of patients receiving second-line carmatinib (n=31), the overall response rate (ORR) was 51.6% (95% CI, 33.1%–69.8%); this included a 51.6% partial response rate (PR) and a 35.5% stable disease rate. The median duration of response (DOR) was 8.4 months (95% CI, 4.2–not evaluable), and the disease control rate (DCR) for this subset was 90.3% (95% CI, 74.2%–98.0%). The median progression-free survival (PFS) was 6.9 months (95% CI, 4.2–13.3).
In all previously treated patients (n=100), carmatinib generated an ORR of 44.0% (95% CI, 34.1%–54.3%), with a PR rate of 44.0% and a disease stabilization rate of 36.0%. The median DOR for carmatinib in this population was 9.7 months (95% CI, 5.6–13.0), and the DCR was 82.0% (95% CI, 73.1%–89.0%). The median PFS for these patients was 5.5 months (95% CI, 4.2–8.1).
"A positive CHMP result for carmatinib provides patients with a treatment option targeting their tumors," said Dr. Juergen Wolf, principal investigator of the GEOMETRY mono-1 trial at the Center for Integrative Oncology, University Hospital of Cologne, in a press release. "If approved by the European Commission, new targeted therapies, such as carmatinib—supported by early and extensive molecular testing of a patient's tumor—could better guide treatment decisions and ensure patients receive appropriate cancer care."
Patients with stage IIIB/IV non-small cell lung cancer carrying METex14 and at least 18 years of age were enrolled in the study. Patients' ECOG performance status had to be 0 or 1, with at least one measurable lesion per RECIST V1.1. EGFR wild-type disease and ALK rearrangement criteria had to be negative. Notably, patients with neurologically stable or asymptomatic brain metastases were permitted. Study participants received a dose of carmatinib 400mg twice daily. The trial administered mg of medication and divided patients into several cohorts based on their prior treatment regimen and MET status. Cohort 4 included patients who had received pretreatment and second- or third-line therapy (n=69); Cohort 5b included treatment-naïve patients who received carmatinib as first-line therapy (n=28); Cohort 6 included patients who received drug pretreatment in second-line therapy (n=31); and Cohort 7 included patients who had not received treatment in first-line therapy (n=32).
The primary endpoint of the trial was the ORR assessed by each blinded independent review committee (BIRC), and the secondary endpoint was the DOR assessed by each BIRC. Other secondary endpoints included DCR assessed by the BIRC and investigator, DOR and ORR assessed by the investigator, response time and PFS assessed by the BIRC and investigator, overall survival, safety, and pharmacokinetics. As of September 1, 2020 As of the data cutoff date on the 8th, a total of 160 patients were included in the four cohorts; 60 patients were treatment-naïve and 100 patients received pretreatment. Furthermore, 31.7% of treatment-naïve patients and 14.0% of pretreatment patients were still receiving carmatinib. The most common reason for discontinuation was disease progression. The median age of the 160 patients was 71 years (range 48–90 years). The majority of patients were female (60.6%), Caucasian (76.9%), had ≥1 ECOG presentation (75.0%), were non-smokers (60.6%), and had adenocarcinoma (82.5%). Additionally, 16.3% of patients had brain metastases. Regarding safety, carmatinib has been found to have an acceptable toxicity profile, with no new signals reported. Of the 373 patients included in all cohorts, 98.4% experienced any level of toxicity.
The most common adverse events (AEs) included peripheral edema (54.2%), nausea (45.0%), vomiting (28.2%), elevated serum creatinine (26.5%), dyspnea (23.3%), fatigue (22.3%), and decreased appetite (21.2%). In addition, 86.9% of patients experienced treatment-related adverse events, the most common being peripheral edema (46.1%) and nausea (34.3%). 50.9% of patients experienced serious adverse events (SAEs) of any grade, of which 13.1% were expected to be related to carmatinib. Approximately 16% (16.1%) of patients experienced adverse events leading to treatment discontinuation. Four patients experienced fatal serious adverse events, including cardiac arrest (0.3%), hepatitis (0.3%), organizing pneumonia (0.3%), and pneumonia (0.3%).
