May 6, 2020

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213591s000lbl.pdf.

On May 6, 2020, the Food and Drug Administration granted accelerated approval to Capmatinib (TABRECTA, Novartis) for adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.

Today, FDA also approved the FoundationOne CDx assay (Foundation Medicine, Inc.) as a companion diagnostic for capmatinib.

Efficacy was demonstrated in the GEOMETRY mono-1 trial (NCT02414139), a multicenter, non-randomized, open-label, multicohort study enrolling 97 patients with metastatic NSCLC with confirmed MET exon 14 skipping. Patients received capmatinib 400 mg orally twice daily until disease progression or unacceptable toxicity.

The main efficacy outcome measures were overall response rate (ORR) determined by a blinded independent review committee using RECIST 1.1 and response duration. Among the 28 treatment-naïve patients, the ORR was 68% (95% CI: 48, 84) with a response duration of 12.6 months (95% CI: 5.5, 25.3). Among the 69 previously treated patients, the ORR was 41% (95% CI: 29, 53) with a response duration of 9.7 months (95% CI: 5.5, 13.0).

The most common adverse reactions (≥ 20% of patients) were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. Capmatinib can also cause interstitial lung disease, hepatotoxicity, photosensitivity, and embryo-fetal toxicity.  Based on a clear positive signal for phototoxicity in early laboratory studies in cells, patients may be more sensitive to sunlight and should be advised to take precautions to cover their skin, use sunscreen, and not tan while taking capmatinib.

The recommended capmatinib dose is 400 mg orally twice daily with or without food.

View full prescribing information for TABRECTA.

This indication is approved under accelerated approval based on overall response rate and response duration. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

This review used the Assessment Aid, a voluntary submission from the applicant to facilitate FDA’s assessment. The FDA approved this application 3 months ahead of the FDA goal date.

FDA granted capmatinib orphan drug and breakthrough therapy designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

For information on the COVID-19 pandemic, see the following resources:

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Pharmacist’s Applications to Practice

Capmatinib for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with specific mutations leading to mesenchymal-epithelial transition (MET) exon 14 skipping

Author: Jessica N. LeClair, PharmD, MBA
Clinical Oncology Pharmacist
Smilow Cancer Hospital at Yale New Haven Health
New Haven, CT

What is the potential role for capmatinib in the treatment of NSCLC?

  • Capmatinib is a targeted tyrosine kinase inhibitor (TKI) that selectively inhibits MET genomic mutations and the only therapy approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with metastatic NSCLC whose tumors have a mutation leading to MET exon 14 skipping.2
  • Oncogenic driver genomic alterations in MET include MET exon 14 skipping mutations, MET gene copy number (GCN) gain or amplification, and MET overexpression and have been linked to a variety of cancers.3
  • In patients with NSCLC, therapy targeting MET overexpression has not shown significant benefit. However, MET exon 14 skipping mutations and high-level MET amplification are two potential predictive biomarkers.4
    • Mutations leading to MET exon 14 skipping occur in 3-4% of patients with NSCLC, are generally mutually exclusive of other driver mutations, and associated with a poor prognosis.
    • MET amplification occurs in 1-6% of patients with NSCLC.
  • Per the National Comprehensive Cancer Network (NCCN) guidelines, capmatinib is the preferred therapy option for patients with metastatic NSCLC found to have MET exon 14 skipping mutations as first-line therapy. Capmatinib is also recommended as subsequent therapy for patients who have completed, are currently receiving, or have experienced progression of disease while on another systemic therapy, as long as capmatinib or crizotinib were not previously used for treatment. Platinum doublets are subsequent therapy options if progression occurs while on capmatinib or crizotinib. Interestingly, patients found to have MET exon 14 skipping mutations and high programmed death-ligand 1 (PD-L1) expression, do not respond to immunotherapy.3
  • The GEOMETRY mono-1 study was a multiple-cohort, phase 2 study evaluating capmatinib in patients with MET-dysregulated advanced NSCLC. Patients were assigned to cohorts based on previous lines of therapy and MET status, either MET exon 14 skipping mutation or MET amplification according to GCN in tumor tissue. Patients in this study had stage IIIB or IV NSCLC, wild-type epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) rearrangement negative, Eastern Cooperative Oncology Group (ECOG) performance-status score 0-1, at least one measurable tumor, according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and if present, brain metastases were asymptomatic or neurologically stable.4
    • Overall response in patients with a MET exon 14 skipping mutation was 41% in previously treated patients and 68% in treatment-naive patients. The median duration of response was 9.7 months and 12.6 months, respectively. Overall response with MET amplification and GCN ≥10 was 29% for previously treated patients and 40% for treatment naïve patients, which was substantially improved compared to previously treated patients with MET amplification who had a GCN <10 found="" to="" have="" overall="" response="" of="" 7-12="" sup="">4
  • Crizotinib is an oral TKI that inhibits MET high-level amplification and MET exon 14 skipping mutation, as well as ALK and ROS1 fusions. It is the only other TKI recommended by NCCN for patients with metastatic NSCLC positive for MET exon 14 skipping mutation, deemed useful in certain circumstances.3
    • Crizotinib was studied in a phase 2 trial of 69 patients with advanced NSCLC, positive for MET exon 14 skipping mutations. The objective response rate was 32%, the median duration of response was 9.1 months, and the median progression free survival was 7.3 months.5
    • Capmatinib was selected as the preferred therapy over crizotinib, attributable to the higher response rates and longer duration of response with capmatinib.
  • Capmatinib continues to be studied in clinical trials, including a phase 3 study comparing capmatinib to single agent docetaxel in previously treated NSCLC patients with MET exon 14 skipping mutation, as well as a phase 2 study comparing capmatinib plus pembrolizumab versus pembrolizumab alone as first-line therapy in locally advanced or metastatic NSCLC with PD-L1≥ 50%. Capmatinib is also being studied in other solid tumors, including hepatocellular carcinoma, renal cell carcinoma, glioblastoma multiforme, melanoma, triple negative breast cancer, among others.6

What role can the pharmacist play in the management of patients on capmatinib?

  • Capmatinib is dosed 400 mg orally twice daily and can be taken with or without food.2
    • There are no renal or hepatic dose adjustments provided for capmatinib.2
    • The recommended dose reductions for adverse events (AEs) are 300 mg orally twice daily for the first occurrence and 200 mg orally twice daily for the second occurrence.2
  • Interstitial lung disease (ILD)/pneumonitis occurred in 4.5% of patients treated with capmatinib in GEMOETRY mono-1, with 1.8% grade 3 severity and 1 patient (0.3%) grade 5 severity, resulting in death. Patients need to be monitored closely for new or worsening pulmonary symptoms such as dyspnea, cough, and fever that may be indicative of ILD/pneumonitis.2,4
    • Capmatinib should be permanently discontinued in patients experiencing any grade ILD/pneumonitis.2
  • Hepatotoxicity with increased alanine aminotransferase (ALT)/aspartate aminotransferase (AST) occurred in 13% of patients treated with capmatinib in GEMOETRY mono-1, with 6% grade 3 and 4 severity, and three patients (0.9%) requiring permanent discontinuation. Patients need to have liver function tests (LFTs) monitoring prior to starting capmatinib, every 2 weeks during the first 3 months of treatment, then once monthly or as clinically indicated, with more frequent monitoring in patients who have experienced transaminitis or elevated bilirubin.2,4
    • Hepatotoxicity dose reductions depend on the severity of LFTs and total bilirubin elevations, included below2:
      • Grade 3 ALT/AST elevations without increased bilirubin: hold capmatinib until recovery to baseline ALT/AST. If recovery occurs within 7 days, resume at same dose level; otherwise resume at reduced dose.
      • Grade 4 ALT/AST elevations without increased bilirubin: permanently discontinue.
      • ALT/AST elevations >3 times the upper limit of normal (ULN) with total bilirubin >2 times ULN: permanently discontinue.
      • Grade 2 or 3 total bilirubin elevations without increased ALT/AST: hold capmatinib until recovery to baseline bilirubin. If recovery occurs for grade 2 reaction within 7 days, resume at the same dose level; otherwise resume at reduced dose. If recovery occurs for grade 3 reaction within 7 days, resume at reduced dose level; otherwise permanently discontinue.
      • Grade 4 bilirubin elevations without increased ALT or AST: permanently discontinue.
  • There is a potential risk of photosensitivity reactions associated with capmatinib use in animal studies. Patients should be advised to minimize ultraviolet (UV) exposure and use precautionary measures such as sunscreen and protective clothing.2
  • Grade 3 and 4 AEs occurring in >2% of patients on capmatinib in GEMOETRY mono-1 included peripheral edema (9%), fatigue (8%), non-cardiac chest pain (2.1%), nausea (2.7%), vomiting (2.4%), dyspnea (7%); laboratory AEs included elevated amylase (4.4%), GGT (7%), lipase (7%), and AST (4.9%), hyponatremia (6%), hypophosphatemia (4.6%), and hyperkalemia (3.1%); hematologic AEs included decreased lymphocytes (14%) and decreased hemoglobin (2.8%).2
    • Dose reductions for AEs not previously defined are included below:2
      • Grade 2 reaction: maintain dose level. If intolerable, consider holding capmatinib until resolution of AE and resume at reduced dose.
      • Grade 3 reaction: hold capmatinib until resolution of AE and resume at reduced dose.
      • Grade 4 reaction: permanently discontinue capmatinib.
  • CYP3A4 inhibitors increase capmatinib exposure, which may increase toxicities, while strong/moderate CYP3A4 inducers decrease capmatinib exposure, which may decrease efficacy. Therefore, co-administration of CYP3A4 inhibitors or strong/moderate CYP3A4 inducers should be avoided.2
  • Co-administration of capmatinib led to increase exposure of CYP1A2, P-glycoprotein (P-gp), Breast Cancer Resistance Protein (BCRP), MATE1, and MATE2K substrates, which may increase the AEs of these substrates.2

Clinical Pearls

  • Along with capmatinib, the FDA also approved the FoundationOne CDx assay (F1CDx) as a companion diagnostic for the drug. F1CDx is a next-generation sequencing based in vitro diagnostic device capable of detecting several mutations, including mutations that lead to MET exon 14 skipping.1
  • Capmatinib is available as 200 mg and 150 mg tablets, stable at room temperature and packaged with a desiccant cartridge to protect from moisture. Unused tablets should be discarded after 6 weeks from opening the original bottle. 2
  • Capmatinib is considered teratogenic based on findings from animal studies and its mechanism of action. Oral administration of capmatinib in pregnant rats and rabbits during organogenesis resulted in malformations. Pregnant females should avoid taking or handling this medication. Females and males of reproductive age should use effective contraception during and for one week following the last dose of capmatinib.2
  • There is no data on the presence of capmatinib in human or animal milk or its effects on a breastfed child or lactation; therefore, women should not breastfeed during treatment and for one week following the last dose of capmatinib.2
  • Patients with symptomatic CNS metastases, clinically significant uncontrolled cardiac disease, or who received treatment with any MET or hepatocyte growth factor (HGF) inhibitor were not eligible for the GEMOETRY mono-1 study.2,4
  • Patient Assistance Now Oncology (PANO) is a support center consisting of insurance specialists and case managers who assist patients in need of Novartis pharmaceuticals, such as capmatinib. The Novartis Oncology Universal Co-pay Program allows for immediate co-pay savings on prescriptions of capmatinib in eligible patients with private insurance, where Novartis will pay the remaining co-pay, up to $15,000 per calendar year. Full terms and conditions can be found by visiting Copay.NovartisOncology.com or calling 1-877-577-7756.7

References

  1. FDA Approves First Targeted Therapy to Treat Aggressive Form of Lung Cancer. US FDA website. Available at: https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-treat-aggressive-form-lung-cancer. Accessed September 26, 2020.
  2. Tabrecta [package insert]. East Hanover, NJ: Novartis; 2020.
  3. Non-small cell lung cancer. Version 8.2020. National Comprehensive Cancer Network. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed September 26, 2020.
  4. Wolf J, Seto T, Han JY, et al. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med. 2020 Sep 3;383(10):944-957.
  5. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020 Jan;26(1):47-51.
  6. Clinicaltrials.gov Registry. National Institutes of Health. Available at: www.clinicaltrials.gov. Accessed September 26, 2020.
  7. Trabecta Access. Novartis website. Available at: https://www.hcp.novartis.com/products/tabrecta/met-exon-14-skipping-mutation-nsclc/access/. Accessed September 28, 2020.