Capmatinib Continues to Show Significant Antitumor Activity in METex14+ NSCLC

Capmatinib continued to elicit a significant, durable responses in patients with metastatic non–small cell lung cancer whose tumors harbor a MET exon14 skipping mutation.

Capmatinib (Tabrecta) continued to elicit a significant, durable responses in patients with metastatic non–small cell lung cancer (NSCLC) whose tumors harbor a MET exon14 skipping (METex14) mutation, according to data from the pivotal phase 2 GEOMETRY mono-1 trial (NCT02414139) published in the New England Journal of Medicine.1

Updated data showed that treatment with the MET inhibitor led to a confirmed overall response rate (ORR) of 68% (95% CI, 48-84) per blinded independent radiology committee (BIRC) in those with METex14-mutant disease (n = 97) who were treatment naïve (n = 28), and 41% (95% CI, 29-53) in those who received 1 or 2 lines of prior treatment (n = 69).

Among responders, the median duration of response (DOR) per independent review committee (IRC) assessment was 12.6 months (95% CI, 5.6-not estimable [NE]) in those who received previous treatment and 9.7 months (95% CI, 5.6-13.0) in those who had not. Responses occurred rapidly, with 82% and 68% of patients, respectively, experiencing a tumor response at the time of the first tumor assessment following the initiation of treatment with the MEK inhibitor.

Notably, a total of 14 of these patients had brain metastases at baseline; 10 of these patients had received prior treatment, while 3 had not. Of the 14 patients, 13 had available data for independent neuroradiologic review committee (INRC) evaluation. Per INRC, 12 of 13 patients achieved intracranial disease control with capmatinib. A total of 7 patients experienced an intracranial response to treatment; 4 of these patients achieved a complete response.

“The pivotal data published today not only confirm the positive results we’ve seen previously with [capmatinib] treatment in NSCLC, but also underscore the value of early and broad molecular testing of patients’ tumors to guide treatment decisions for both first-line and previously treated patients,” Jeff Logos, senior vice president and head of Oncology Drug Development at Novartis Oncology, stated in a press release.2

A total of 364 patients with advanced NSCLC were enrolled to GEOMETRY mono-1, and across cohorts 1-5, 97 patients harbored a METex14 mutation and 210 had MET amplified–disease. Patients who had received prior treatment were enrolled to cohorts 1-4, while those who were treatment naïve were enrolled to cohorts 5a and 5b.

In the cohorts comprised of patients with METex14-mutant disease, the median age was slightly higher, at 71 years, compared with the cohorts that included those with MET-amplified disease, which ranged from 60 to 70 years. Moreover, patients with METex14-mutated disease were more likely to be women and to have never smoked compared with those with MET amplifications.

Cohort 6 of the study included a total of 34 patients; of these patients, 3 had MET-amplified disease with a gene copy number of at least 10, while 31 had METex14-mutated disease and had received 1 prior line of treatment. At the time of data cutoff, January 6, 2020, 23 patients with METex14-mutated disease who had not received previous treatment were enrolled to cohort 7 of the trial. No efficacy data are available for this patient cohort, noted the study investigators.

The primary end point of the trial was overall response evaluated under blinded conditions to be performed by an IRC in accordance with RECIST v1.1 criteria. An important secondary end point of the trial was DOR under blinded conditions per IRC assessment. Other secondary end points included investigator-evaluated response and DOR, investigator- and IRC-assessed time to response, disease control, progression-free survival (PFS), and safety.

Additional results from an analysis on 73 patients were reported; 53 of these patients had received previous treatment and 20 were treatment naïve. Results showed a 99% concordance between next-generation sequencing and reverse transcription polymerase chain reaction analyses was reported. No considerable variances in response to the MET inhibitor were reported with regard to the type of genetic alteration causing METex14 or MET amplification. Moreover, the tumor mutational burden was found to be low in those whose tumors harbored a METex14 mutation.

Additionally, the median PFS per IRC was 5.4 months (95% CI, 4.2-7.0) in those who had received previous treatment versus 12.4 months (95% CI, 8.2-NE) in those who had not. PFS benefit per investigator assessment proved to be comparable to that of IRC evaluation.

Data from the expansion cohort 6, which was comprised of 31 patients with METex14-mutated who had received 1 prior line of treatment, proved to be consistent with the efficacy data observed in cohort 4, which included those with METex14-mutated who had received previous treatment. In cohort 6, the ORR with capmatinib was 48% (95% CI, 30-67).

With regard to safety, the most commonly experienced all-grade adverse effects (AEs) across all cohorts in the trial included peripheral edema, nausea, and vomiting. Toxicities that were grade 3 or 4 in severity were observed in 67% of patients. The most frequently reported AEs associated with treatment (TRAEs) included peripheral edema, nausea, vomiting, and increased blood creatinine level.

Serious TRAEs reported with capmatinib were experienced by 13% of patients (n = 48/364), with lower incidences reported in cohorts 1b, 2, and 3, which were comprised of patients who received shorter durations of treatment with the MET inhibitor.

Toxicities that resulted in discontinuation of capmatinib occurred in 11% of patients (n = 39). Specifically, treatment-related peripheral edema resulted in the discontinuation of 2% of patients (n = 6), with an event of grade 3 or 4 experienced by 1% of patients (n = 2). Overall,

23% of patients (n = 83) experienced at least 1 toxicity that resulted in a dose reduction of the agent.

Moreover, death from other causes beyond advanced disease occurred during treatment in 4% of patients (n = 13), with reported causes including atrial fibrillation, hepatitis, pneumonia, organizing pneumonia, bacterial pneumonia, pneumonitis, respiratory distress, sepsis, septic shock, sudden death, assisted suicide, and cardiac arrest. Only 1 death was thought to potentially be related to capmatinib following investigator and medical review.

“Capmatinib therapy showed efficacy in patients with NSCLC with a METex14 mutation,” the study authors concluded. “These results and the safety profile, involving mainly low-grade and reversible AEs, suggest that capmatinib may be a new therapeutic option in patients with advanced NSCLC with a METex14 mutation.”

In May 2020, the FDA granted an accelerated approval to capmatinib for use in this patient population based on primary findings from GEOMETRY mono-1. At that time, the MET inhibitor had demonstrated a ORR of 67.9% (95% CI, 47.6%-84.1%) per independent review in treatment-naïve patients with METex14-mutated disease.

References:

  1. Wolf J, Seto T, Han J-Y, et al. Capmatinib in MET exon 14–mutated or MET-amplified non–small-cell lung cancer. N Engl J Med. Published online September 3, 2020. doi:10.1056/NEJMoa2002787
  2. Novartis announces NEJM publication of pivotal study of Tabrecta in patients with METex14 metastatic non-small cell lung cancer. News release. Novartis. September 2, 2020. Accessed September 3, 2020. https://bit.ly/3br66Ug.
  3. Novartis announces FDA approval of MET inhibitor Tabrecta for metastatic non-small cell lung cancer with METex14. News release. Novartis. Published May 6, 2020. Accessed September 3, 2020. https://bit.ly/2SIEmTc.
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