Tabrecta (Capmatinib) First FDA-Approved Drug for Metastatic NSCLC with MET Exon 14 Skipping Mutation

December 2021 Twelfth Annual Payers' Guide - FDA Approvals
Loretta Fala
Medical Writer

Lung and bronchus cancer is the second most prevalent form of cancer in the United States.1 Representing 12.4% of all new cancer cases in 2021, lung cancer is estimated to be diagnosed in 235,760 individuals in 2021 in the United States, and 131,880 will die of the disease.1 Lung cancer remains the leading cause of cancer mortality in men and in women, accounting for an estimated 21.7% of all cancer deaths.1 The estimated relative 5-year survival rate of lung cancer is 21.7% in 2021.

Of the 2 main types of lung cancer, non–small-cell lung cancer (NSCLC) accounts for approximately 85% of all cases, and small-cell lung cancer accounts for approximately 15%.2 NSCLC includes 3 main subtypes: adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma.2

The 5-year relative survival rate for patients with metastatic NSCLC is only 7%, based on data from 2010-2016.3 Common symptoms observed in patients with NSCLC include dyspnea, cough, fatigue, distress, and pain—symptoms that can have a significant impact on the patient’s daily function and quality of life.4

The treatment of metastatic NSCLC can include chemotherapy, radiation therapy, chemoradiation, immunotherapy, targeted therapy, or a combination of these therapies.5 NSCLC is associated with a wide range of genomic mutations. Approximately 3% to 4% of NSCLC tumors harbor a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping.6-8 Patients with NSCLC and the MET exon 14 skipping mutation are likely to have aggressive forms of NSCLC with a poor prognosis and limited treatment options.6,9 The first treatment for this patient population was approved by the US Food and Drug Administration (FDA) in 2020.10

Tabrecta Approved for Metastatic NSCLC with MET Exon 14 Mutation

On May 6, 2020, the FDA approved capmatinib (Tabrecta; Novartis), an oral kinase inhibitor, for the treatment of adults with metastatic NSCLC associated with the MET exon 14 skipping mutation, as detected by an FDA-approved test.10 Capmatinib was the first agent to be approved by the FDA for the treatment of any tumor with MET exon 14 mutation. Capmatinib was granted an accelerated approval and received breakthrough therapy and orphan drug designations by the FDA for this indication.10

“Lung cancer is increasingly being divided into multiple subsets of molecularly defined populations with drugs being developed to target these specific groups,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Tabrecta is the first approval specifically for the treatment of patients with non–small-cell lung cancer whose tumors have mutations that lead to MET exon 14 skipping. This patient population now has an option for a targeted therapy, which they didn’t have prior to today,” Dr Pazdur noted.10

Mechanism of Action

Capmatinib is an oral kinase inhibitor that targets and blocks the activity of MET, including the variant mutation produced by exon 14 skipping. In preclinical studies, capmatinib inhibited cancer-cell growth driven by the mutated MET variant lacking exon 14. The drug showed antitumor activity in tumors with the MET exon 14 skipping mutation or MET amplification.11

Capmatinib inhibits MET phosphorylation and MET-mediated downstream-signaling proteins and blocks the proliferation and survival of MET-dependent cancer cells.11

Dosing and Administration

Capmatinib is available in 2 doses, 150-mg and 200-mg tablets. The recommended dose of capmatinib for this indication is 400 mg, taken orally twice daily with or without food.11 Patients should be selected for capmatinib therapy based on results of an FDA-approved test showing the presence of the MET exon 14 skipping mutation.

Pivotal Clinical Trial: GEOMETRY Mono-1

The GEOMETRY Mono-1 study, a nonrandomized, open-label, multicenter, phase 2 clinical trial included 364 patients with NSCLC, of whom 97 patients (median age, 71 years; range, 49-90 years) had NSCLC and MET exon 14 skipping, as detected by local tests and confirmed by an FDA-approved test.6 Of these 97 patients, the majority were female (60%), white (75%), and had an Eastern Cooperative Oncology Group performance status of 0 (24%) or 1 (75%).6

The efficacy of capmatinib in patients with NSCLC and the MET exon 14 skipping mutation was evaluated in the cohort of the 97 patients with this mutation. In all, 28 of these patients received capmatinib as first-line therapy and 69 patients received capmatinib after previous therapy; 88% of the latter group had previously received platinum-based chemotherapy.6 All 97 patients received capmatinib 400 mg orally twice daily until disease progression or unacceptable adverse events.6

The primary end point was the overall response rate, which was 68% in 28 treatment-naïve patients and 41% in the 69 patients who had received previous treatment before receiving capmatinib (Table).6,11 Among the patients who had a response to capmatinib therapy, the median duration of response was 12.6 months in the treatment-naïve group and 9.7 months in the previously treated group.6

Table

Adverse Reactions

The most common (≥20%) adverse reactions of any grade with capmatinib were peripheral edema (52%), nausea (44%), fatigue (32%), vomiting (28%), dyspnea (24%), and decreased appetite (21%).11

Serious adverse reactions were reported in 51% of patients who received capmatinib. In addition, 16% of the patients discontinued capmatinib permanently because of adverse reactions, including peripheral edema (1.8%), pneumonitis (1.8%), and fatigue (1.5%). A fatal case of pneumonitis was reported in 1 patient who received capmatinib.11

Capmatinib has no contraindications.11

Drug Interactions

Co-administration of capmatinib with a strong cytochrome (CY) P3A inhibitor increases the exposure of capmatinib, which may increase the incidence and severity of capmatinib-related adverse reactions. Conversely, co-administration of capmatinib with a strong or moderate CYP3A inducer can decrease the exposure of capmatinib, which may reduce the antitumor activity of capmatinib. Co-administration of capmatinib with strong and moderate CYP3A inducers should be avoided.11

The co-administration of capmatinib with CYP1A2 substrates, P-glycoprotein substrate, breast cancer resistance protein substrate, and MATE1 and MATE2K substrates may increase the adverse reactions of these substrates.11

Use in Specific Populations

There are no data regarding the use of capmatinib in pregnant women. Capmatinib can cause fetal harm when administered to a pregnant woman.11 Similarly, there are no data about the impact of capmatinib or its metabolites on the breastfed child or on milk production. Women should be advised not to breastfeed during capmatinib treatment and for 1 week after the last dose of capmatinib.11

No dosage adjustment of capmatinib is required for patients with moderate renal impairment. The impact of capmatinib on patients with severe renal impairment is not known.11

Capmatinib was not associated with differences in safety or effectiveness between patients aged 65 years or older and patients younger than 65 years.11

Warnings and Precautions

Interstitial lung disease or pneumonitis, a potentially fatal condition, occurred in patients receiving capmatinib. Patients should be monitored for new or worsening pulmonary symptoms indicative of interstitial lung disease or pneumonitis (ie, dyspnea, cough, and fever). Capmatinib should be withheld if the patient has interstitial lung disease or pneumonitis, and the drug should be withheld if interstitial lung disease or pneumonitis is suspected.11

Hepatotoxicity has occurred in patients receiving capmatinib. Liver function tests should be done before initiating capmatinib therapy, then every 2 weeks during the first 3 months of treatment, and then once a month or as clinically appropriate, with more frequent testing in patients who have increased levels of transaminases or bilirubin. Capmatinib may require a dose reduction, or temporary or permanent discontinuation, depending on the severity of the adverse reaction.11

Photosensitivity may occur during treatment with capmatinib. Patients receiving capmatinib should be advised to limit direct ultraviolet exposure and take precautionary measures (ie, sunscreen or protective clothing).11

Pregnant women should be advised about the potential risk for fetal harm during treatment with capmatinib.11 Women of reproductive potential should be advised to use effective contraception during capmatinib treatment and for 1 week after the last dose. Men with female partners of reproductive potential should be advised to use effective contraception during capmatinib treatment and for 1 week after the last dose.11

Conclusion

Patients with metastatic NSCLC whose tumors harbor a MET exon 14 skipping mutation have limited treatment options. Capmatinib, a kinase inhibitor, is the first therapy to receive FDA approval for the treatment of this patient population. In the GEOMETRY Mono-1 study, treatment with capmatinib showed an overall response rate of 68% in treatment-naïve patients and 41% in previously treated patients; 47% and 32% of patients in these 2 groups, respectively, sustained their response for ≥12 months.11 The approval of capmatinib provides the first targeted therapy designed specifically for patients with metastatic NSCLC and the MET exon 14 skipping mutation.

References

  1. National Cancer Institute SEER Program. Cancer stat facts: lung and bronchus cancer. https://seer.cancer.gov/statfacts/html/lungb.html. Accessed June 10, 2021.
  2. American Cancer Society. What is lung cancer? Revised October 1, 2019. www.cancer.org/cancer/lung-cancer/about/what-is.html. Accessed June 10, 2021.
  3. American Cancer Society. Lung cancer survival rates. Updated January 29, 2021. www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/survival-rates.html. Accessed June 10, 2021.
  4. Whisenant MS, Williams LA, Garcia Gonzalez A, et al. What do patients with non–small-cell lung cancer experience? Content domain for the MD Anderson symptom inventory for lung cancer. JCO Oncol Pract. 2020;16:e1151-e1160.
  5. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Non-Small Cell Lung Cancer. Version 4.2021. March 3, 2021. www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed June 10, 2021.
  6. Wolf J, Seto T, Han JY, et al; for the GEOMETRY mono-1 investigators. Capmatinib in MET exon 14–mutated or MET-amplified non–small-cell lung cancer. N Engl J Med. 2020;383:944-957.
  7. Awad MM, Oxnard GR, Jackman DM, et al. MET exon 14 mutations in non–small-cell lung cancer are associated with advanced age and stage-dependent MET genomic amplification and c-Met overexpression. J Clin Oncol. 2016;34:721-730.
  8. König D, Prince SS, Rothschild SI. Targeted therapy in advanced and metastatic non-small cell lung cancer. An update on treatment of the most important actionable oncogenic driver alterations. Cancers (Basel). 2021;13:804. DOI: 10.3390/cancers13040804.
  9. Tong JH, Yeung SF, Chan AWH, et al. MET amplification and exon 14 splice site mutation define unique molecular subgroups of non-small cell lung carcinoma with poor prognosis. Clin Cancer Res. 2016;22:3048-3056.
  10. US Food and Drug Administration. FDA approves first targeted therapy to treat aggressive form of lung cancer. May 6, 2020. www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-treat-aggressive-form-lung-cancer. Accessed March 10, 2021.
  11. Tabrecta (capmatinib) tablets, for oral use [prescribing information]. Novartis Pharmaceuticals Corporation; May 2020. www.novartis.us/sites/www.novartis.us/files/tabrecta.pdf. Accessed June 10, 2021.
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