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Novartis' MET Inhibitor Capmatinib Shows Activity in METex14 NSCLC Patients With Brain Metastasis

NEW YORK – At the American Association for Cancer Research's Virtual Annual Meeting on Monday, researchers presented data showing that Novartis' investigational lung cancer drug, the MET inhibitor capmatinib, was efficacious in patients with brain metastases.

In February, Novartis said that the US Food and Drug Administration had accepted its new drug application for capmatinib as a treatment for advanced or metastatic non-small cell lung cancer patients with MET exon 14 skipping mutations. As part of its application, the drugmaker had submitted results from the Phase II GEOMETRY mono-1 study, which had reported out an overall response rate of 67.9 percent in previously untreated patients and 40.6 percent in previously treated patients.

At the AACR meeting, Edward Garon from the University of California, Los Angeles, and a study investigator, presented the full data from the trial, including new data on capmatinib's activity in patients with brain metastases.

MET exon 14 skipping mutations (METex14) are reported in up to 4 percent of patients with NSCLC. Patients whose tumors harbor these mutations have poor outcomes to both cytotoxic chemotherapy and immunotherapy. In pre-clinical models of the disease, METex14 was validated as a driver alteration. Analysis of sample tissues from the TCGA database, as well as commercial testing labs, showed that METex14 alterations most predominantly occurred in lung cancers.

Capmatinib is a small ATP-competitive reversible inhibitor that is highly selective for MET.

The GEOMETRY mono-1 study was designed to evaluate capmatinib in MET-mutated cancer patients across seven cohorts. Garon's presentation focused on two cohorts: cohort 4 and cohort 5b, which examined the efficacy of the drug in METex14-mutated patients, who had to have their mutation status confirmed via centralized testing.

Novartis is working with Foundation Medicine to develop a companion diagnostic for capmatinib that can assess both tumor tissue and liquid biopsies. If capmatinib is approved for the METex14 NSCLC indication, this indication will be added to the FoundationOne CDx label and a new version of Foundation Medicine's liquid biopsy platform, which is also under review with the FDA.

Advanced NSCLC patients enrolled in the GEOMETRY mono-1 trial could not harbor genomic abnormalities in EGFR or ALK and had to have good performance status and measurable disease. Cohort 4 contained patients who had received at least one prior line of therapy for advanced disease, while cohort 5b consisted of treatment-naïve patients. More than 10 percent of patients in both cohorts had brain metastases at the time of enrollment.

Among the 69 patients in the previously treated cohort, objective responses were seen in more than 40 percent, and 75 percent had disease control on capmatinib. The median duration of response in this group was 9.72 months. In 28 patients in the treatment-naïve cohort, over 67 percent had an objective response, with nearly all patients achieving disease control. The median duration of response in this group was 11.14 months. Garon said that responses tended to occur early in the treatment course and many patients' responses in both cohorts lasted for more than a year.

In preclinical animal models, the drug had penetrated the central nervous system, which researchers thought could translate to a potential clinical benefit.

In the GEOMETRY mono-1 study, 14 patients had brain metastases at baseline, and there was evaluable disease in 13 patients. Of the 13, 54 percent experienced tumors shrinkage in the brain, as determined by central review. Four patients saw their brain lesions completely disappear, while others had some lesions completely resolve, and in some lesions stopped growing.

Garon noted that a small number of responders to capmatinib had prior brain radiation, but the majority of responders had either progressive brain metastases or new brain metastases at the time of study entry. Intracranial responses were rapid, and all responses were observed at the first radiographic evaluation. Intracranial disease control was observed in 12 of the 13 patients.

"The pre-clinical suggestion that efficacy in the central nervous system should be seen clinically has now been demonstrated among patients in the GEOMETRY mono-1 study, and it will be exciting to see further validation of this data," said Garon.

No treatment-related deaths were reported in the study. Serious treatment-related adverse events were seen in around 13 percent of patients, and 11 percent of patients discontinued treatment due to adverse events.

There are a number of drugs being developed for METex14-mutated NSCLC. In a Phase II trial of Merck KGaA's MET inhibitor tepotinib in METex14-mutated NSCLC, around 40 percent of patients had a confirmed partial response. This drug garnered breakthrough therapy designation from the FDA last year, and Japanese regulators approved the drug under the brand name Tepmetko, alongside ArcherDx's ArcherMET blood and tissue-based companion diagnostic to identify METex14-positive patients. 

Pfizer's crizotinib (Xalkori) also received breakthrough therapy designation from the FDA in 2018 based on initial data from the PROFILE 1001 study in previously treated metastatic NSCLC with METex14 alterations. However, earlier this year, researchers led by Paul Paik from Memorial Sloan Kettering reported that 32 percent of 65 evaluable patients in this trial saw their tumors shrink on the drug. They wrote in Nature Medicine that despite the activity seen in the study, it may not be an improvement upon other options being explored in this setting.