Capmatinib Snags Full FDA Approval for MET Exon 14 Skipping NSCLC

The FDA has granted capmatinib regular approval for patients with metastatic non–small cell lung cancer (NSCLC) whose tumors have a mutation leading to MET exon 14 skipping. The drug comes with warning for pneumonitis, hepatotoxicity, and pancreatic toxicity.

Following data from a 22-month extended follow-up, the FDA has granted capmatinib (Tabrecta) full approval for patients with metastatic non–small cell lung cancer (NSCLC) whose tumors harbor a MET exon 14 skipping, as detected by an FDA-approved test.1

In May 2020, capmatinib received accelerated approval on the same indication based on initial overall and duration of response (DOR) rates observed in the GEOMETRY mono-1 trial (NCT02414139), a multicenter, non-randomized, open-label, multi-cohort study. Patients with metastatic disease (n = 160) and a mutation leading to MET exon skipping received 400 mg of oral capmatinib twice daily until disease progression or unacceptable toxicity.

Data supporting the 2020 accelerated approval included the overall response rate (ORR), which was 68% (95% CI, 55%-80%) among the treatment-naïve subgroup (n = 60) and 44% (95% CI, 34%-54%) in the pretreated group (n = 100). The DOR was 16.6 months (95% CI, 8.4-22.1) and 9.7 months (95% CI, 5.6-13), respectively.

The recommended dose for capmatinib is 400 mg orally twice daily with or without food. Patients should be instructed to swallow the tablets whole.2 They should not be broken, crushed, or chewed. If a patient misses or vomits a dose, they should not attempt to make up the dose, but instead wait and take the next dose at the scheduled time.

In the event of adverse reactions, providers should reduce the dose to 300 mg twice daily. At second adverse event (AE), the dose should be further reduced to 200 mg twice daily. Patients who are unable to tolerate 200 mg twice daily should permanently discontinue the drug.

The drug comes with warnings for interstitial lung disease (ILD) and pneumonitis, hepatotoxicity, and pancreatic toxicity. Patients should be educated for their increased risks of these events and taught to monitor and report the appropriate symptoms.

Approximately 4.8% of patients enrolled in GEOMETRY mon-1 experienced ILD or pneumonitis, and 1.9% of these cases were graded as grade 3. One patient died as a result of ILD/pneumonitis and 9 patients discontinued treatment because of ILD/pneumonitis complications.

Any signs of pulmonary symptoms, including dyspnea, cough, and fever should be monitored and reported immediately. The median time-to-onset time for grade 3 or worse events was 1.8 months (0.2 months – 1.7 years). Capmatinib should immediately be withheld if this AE is suspected and discontinued if it is positively identified.

An increased in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) was observed in 15% of patients who received capmatinib, of which 7% became grade 3 or 4. Three patients discontinued treatment because of hepatotoxicity.

Liver function should be tested at baseline and monitor every 2 weeks throughout the first months of treatment. These tests should include ALT, AST, and total bilirubin. After 3 months, la should be collected once a month, or as clinically indicated, with more frequent routine assessment for those who develop increased transaminases or bilirubin. If severe AEs begin to develop, it may be appropriate to withhold, dose reduce, or permanently discontinue capmatinib.

Fourteen patients experienced elevations in amylase and lipase levels, 7% and 1.9% of whom experienced grade 3 and 4 severity, respectively. Three patients discontinued because of pancreatic toxicity. One patient permanently discontinued treatment because of grade 3 pancreatitis.

Amylase and lipase levels should be assessed at baseline and regularly monitored throughout treatment. If severe AEs begin to develop, it may be appropriate to withhold, dose reduce, or permanently discontinue the agent.

Overall, the most common serious AEs included dyspnea (7%), pneumonia (7%), pleural effusion (4.3%), musculoskeletal pain (3.8%), general physical health deterioration (2.9%), ILD/pneumonitis (2.7%), and vomiting (2.4%). Fatal AEs occurred in 0.5% of treated patients, with pneumonitis representing the leading specified cause (0.3%).

Seventeen patients needed to discontinue because of an AE. The AEs most commonly associated with discontinuation included ILD/pneumonitis (2.4%), edema (2.4%), fatigue (1.3%), and pneumonia (1.1%).

Dose interruptions occurred in approximately 57% of patients on the trial. The AEs most likely to require a dose interruption included edema, increased blood creatinine, nausea, increased lipase, vomiting, increased ALT, dyspnea, pneumonia, fatigue, increased amylase, increased AST, musculoskeletal pain, abdominal pain, and increased blood bilirubin. The AEs most likely to require a dose reduction were edema, increased ALT, and increased blood creatinine.

According to a news release, nearly 70% of patients with NSCLC have a genomic mutation, and 3% to 4% of patients with NSCLC have MET exon 12 skipping.3 The approval of this agent represents another targeted therapy for those 4000 to 5000 patients with this oncogenic driver mutation.

References

  1. FDA approves capmatinib for metastatic non-small cell lung cancer. FDA. August 10, 2022. Accessed August 11, 2022. https://bit.ly/3C7HIX8
  2. Capmatinib. Prescribing information. Novartis Pharmaceuticals Corp; 2022. Accessed August 11, 2022. https://bit.ly/3JLN2kQ
  3. Novartis announces FDA approval of MET inhibitor Tabrecta for metastatic non-small cell lung cancer with METex14. May 6, 2020. Accessed August 11, 2022. https://bit.ly/2SIEmTc