FDA Approval Summary: Capmatinib and Tepotinib for the Treatment of Metastatic NSCLC Harboring MET Exon 14 Skipping Mutations or Alterations

Mutations in the mesenchymal–epithelial transition (MET) gene leading to exon 14 skipping are estimated to occur in 2%–4% of non–small cell lung cancers (1–3). Prior to the approval of capmatinib and tepotinib, there were no FDA-approved therapies specific for MET-altered lung cancers. The standard of care for treating such patients was platinum-based combination chemotherapy with or without immunotherapy or immunotherapy alone (for PD-L1 positive NSCLC). Patients with metastatic NSCLC with MET exon 14 skipping represent a population of patients with a serious condition and an unmet clinical need.

Capmatinib and tepotinib are orally administered tyrosine kinase inhibitors that target the MET tyrosine kinase receptor, including variants resulting from exon 14 skipping. On May 6, 2020, capmatinib (TABRECTA; Novartis) was granted accelerated approval by the U.S. Food and Drug Administration (FDA) for the treatment of adults with metastatic NSCLC whose tumors have a mutation that leads to MET exon 14 skipping as detected by an FDA-approved test. On February 3, 2021, tepotinib (TEPMETKO; EMD Serono) was granted accelerated approval by the FDA for the treatment of adults with metastatic NSCLC harboring MET exon 14 skipping alterations. The accelerated approvals do not extend to the MET amplified NSCLC population. Herein, we summarize key findings and discuss regulatory insights that supported the accelerated approvals of capmatinib and tepotinib.

Both capmatinib and tepotinib are kinase inhibitors that target MET, including the isoform produced by exon 14 skipping. Direct comparisons of potencies are difficult given differences in assay formats and differences in clinical pharmacokinetic properties for different drugs taken at different doses. Both drugs inhibited MET with IC₅₀s of less than 2 nmol/L and demonstrate in vitro and in vivo inhibition of MET-dependent cancer cell lines, including cells driven by a MET exon 14-associated skipping mutation. Screening assays also identified melatonin 2 and imidazoline receptors as additional potential targets for tepotinib inhibition.

Toxicology studies conducted for both drugs used rats as the rodent species, but tepotinib utilized dogs as the non-rodent species, while capmatinib used monkeys. Consistent with clinical findings, the major target organs in animal studies based on changes in clinical pathology or histopathologic changes associated with both tepotinib and capmatinib included the liver, lung, and GI tract as well as occasional findings of edema in some organs; capmatinib also showed mild pancreatic toxicity. For tepotinib, the liver findings in dogs included significant bile duct hyperplasia. Other notable findings in tepotinib-treated dogs not noted in capmatinib-treated animals included decreased cortical vacuolation of adrenal glands and milky retention in mammary glands in females treated at all dose levels.

Capmatinib administration also resulted in vacuolation of white matter of the brain in both 4-and 13-week rat studies at doses ≥ 2.2 times the human exposure (AUC) at the 400 mg twice daily clinical dose. In some cases, the brain lesions were associated with early death and/or convulsions or tremors. Concentration of capmatinib in the brain tissue of rats was approximately 9% of the corresponding concentrations in plasma. The capmatinib label includes a description of these findings.

Neither drug was mutagenic nor clastogenic. Developmental studies showed malformations at doses resulting in exposures significantly lower than the human exposures for both drugs. In vitro photosensitivity studies suggested a potential risk for phototoxicity for both capmatinib and tepotinib; however, follow-up in vivo animal studies for capmatinib, but not tepotinib, suggested a potential risk of photosensitivity at exposures ≥ 3 times the human exposure (C_max), resulting in an additional warning in the capmatinib product label for taking precautions against ultraviolet light.

The FDA reviewed subject-level data collected from healthy participants and cancer patients to characterize the pharmacokinetics (PK) of capmatinib (Table 1). Dosing of capmatinib tablets at 400 mg twice daily taken with or without food is supported by results from the dose-escalation trial (Study X2102), in whichit was shown to have comparable PK and safety with the originally-established recommended phase 2 dose (RP2D) of capmatinib capsule 600 mg twice daily. The product label recommends monitoring patients closely for toxicities during concomitant use of capmatinib with strong CYP3A inhibitors, as capmatinib exposure increases (4). Coadministration of capmatinib with a strong or moderate CYP3A inducer may decrease capmatinib antitumor activity and concomitant use should be avoided. Where concomitant use of capmatinib with sensitive CYP1A2, P-gp, and BCRP substrate drugs cannot be avoided, and minimal changes in the concentrations of these substrate drugs may lead to serious adverse reactions, the dosages of such drugs should be reduced in accordance with their approved prescribing information.

For tepotinib, the proposed dosing regimen of 450 mg QD (free base form, corresponding to 500 mg tepotinib hydrochloride hydrate) was selected based on results from the dose-finding study, in which the maximum tolerated dose (MTD) was not reached up to a dosage of 1,400 mg QD, and dose-limiting toxicities (DLT) were only observed at dose levels of 1000 mg and 1,400 mg once daily (Table 1). The clinical pharmacology review focused on the drug-drug interaction potential for tepotinib as a victim. Metabolism and in vitro data showed that tepotinib was a substrate of CYP3A4, CYP2C8 and P-gp. However, the fractions metabolized by individual major CYP isozymes could not be reliably quantified. The product label recommends patients to avoid concomitant use of tepotinib with strong CYP3A4 inducers, dual strong CYP3A inhibitors or P-gp, and strong CYP3A inducers (5).

The main efficacy outcome measure in GEOMETRY mono-1 and VISION was confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) as evaluated by a Blinded Independent Review Committee (BIRC). An additional efficacy outcome measure was duration of response (DOR) by BIRC. In both GEOMETRY mono-1 and VISION, patients were required have epidermal growth factor receptor (EGFR) wild-type, anaplastic lymphoma kinase (ALK) rearrangement negative NSCLC and at least one measurable lesion as defined by RECIST v1.1.

The GEOMETRY mono-1 trial (Study A2201; NCT02414139), is a single-arm, open-label, international, multicenter, multi-cohort trial in patients with advanced/metastatic NSCLC with mutations leading to MET exon 14 skipping or MET amplification. MET exon 14 skipping mutations were prospectively confirmed by central laboratory testing using an RNA-based clinical trial assay. Mandatory blood samples were collected from all patients at Cycle 1 Day 1 for the development of a potential circulating tumor deoxyribonucleic acid (ctDNA)-based companion diagnostic. Eligible patients received capmatinib 400 mg orally twice daily.

VISION (Study MS200095–0022; NCT02864992), is a single-arm, open-label, multicenter, multicohort study in patients with advanced/metastatic NSCLC with MET exon 14 skipping alterations or MET amplification. Identification of MET exon 14 skipping alterations was prospectively determined using central laboratories employing either a PCR-based or next-generation sequencing-based clinical trial assays using tissue (58%) and/or plasma (65%) samples. Eligible patients received tepotinib 450 mg orally once daily.

The efficacy analysis population for this application included 69 previously treated patients and 28 treatment-naïve patients with MET exon 14 skipping NSCLC. The safety population included 334 patients with advanced NSCLC who received capmatinib 400 mg orally twice daily in GEOMERTY-mono-01. Key baseline characteristics for the efficacy population are presented in Table 2. Compared to the safety population, the efficacy population had a higher proportion of older patients (median age 71 years with 36% of patients 75 years or older vs. median age 66 years with 16% of patients 75 years or older), females (60% vs. 41%), and patients who had never smoked (60% vs. 31%). Efficacy results for capmatinib are summarized in Table 3.

In the GEOMETRY mono-1 trial, 334 patients received at least one dose of capmatinib 400 mg twice daily and the median duration of treatment was 15 weeks (range: 0.4 to 177 weeks). Thirty-one percent of patients were exposed to capmatinib for at least 6 months and 16% were exposed for at least one year. In the GEOMETRY mono-1 trial, 66% of patients experienced treatment emergent adverse event (TEAE) of Grade 3 or higher severity. Serious adverse reactions occurred in 51% of patients in the GEOMETRY mono-1 trial, with the most frequent dyspnea (7%), pneumonia (4.8%), and pleural effusion (3.6%). A fatal adverse reaction occurred in one patient (0.3%) due to pneumonitis. Capmatinib was permanently discontinued due to an adverse reaction in 16% of patients, with peripheral edema (1.8%), pneumonitis (1.8%) and fatigue (1.5%) the most frequent adverse reactions leading to discontinuation. Dose interruptions due to an adverse reaction occurred in 54% of patients, while dose reductions due to an adverse reaction occurred in 23% of patients. Adverse reactions requiring dose reduction in > 2% of patients included peripheral edema, increased ALT, increased blood creatinine, and nausea. The most common TEAEs of any grade (incidence ≥ 20%) in the safety population were peripheral edema, nausea, fatigue, vomiting, dyspnea, and decreased appetite. Interstitial lung disease (ILD)/pneumonitis occurred in 4.5% of patients treated with capmatinib in GEOMETRY mono-1, with 1.8% of patients experiencing Grade 3 ILD/pneumonitis. Hepatoxicity was observed in GEOMETRY mono-1, with Grade 3 or 4 increases in ALT/AST in 6% of patients.

The efficacy analysis population for this application included 83 previously treated patients 69 treatment-naive patients with MET exon 14 skipping NSCLC. The safety population included 255 patients with advanced NSCLC harboring METex14 skipping alteration who received tepotinib 450 mg orally once daily in VISION. Key baseline characteristics of patients enrolled on VISION are noted in Table 2. Baseline characteristics were similar between the efficacy and safety populations. Efficacy results for tepotinib are summarized in Table 4.

In the VISION trial, the primary safety population included 255 patients with NSCLC harboring MET exon 14 skipping alterations who received at least one dose of tepotinib 450 mg once daily; the median duration of treatment was 22 weeks (range: 0 to 188 weeks). Forty-two percent of patients were exposed to tepotinib for at least 6 months and 18% were exposed for at least one year. Fifty-three percent of patients experienced TEAE of grade 3 or higher severity. Serious adverse events occurred in 45% of patients, with the most frequent pleural effusion (7%), pneumonia (5%), edema (3.9%) and dyspnea (3.9%). Fatal adverse reactions of pneumonitis, hepatic failure, and dyspnea from fluid overload occurred in one patient (0.4%) each. Tepotinib was permanently discontinued due to an adverse reaction in 20% of patients with edema (5%), pleural effusion (2%), dyspnea (1.6%), general health deterioration (1.6%), and pneumonitis (1.2%) the most frequent adverse reactions leading to discontinuation. Dose interruptions due to an adverse reaction occurred in 44% of patients, while dose reductions due to an adverse reaction occurred in 30% of patients. Adverse reactions requiring dose reductions in > 2% of patients included edema, pleural effusion, and increased blood creatinine. The most common TEAEs of any grade (incidence ≥ 20%) in were edema, fatigue, nausea, and diarrhea. In the safety population, the incidence of ILD/pneumonitis was 3.1%, with 0.4% of patients experiencing Grade 3 ILD/pneumonitis. Hepatotoxicity was observed in VISION, with Grade 3 or 4 increases in ALT/AST in 6.5% of 255 patients.

Based on FDA review of the results of GEOMETRY mono-1 and VISION, FDA determined that capmatinib and tepotinib demonstrated substantial evidence of effectiveness based on the magnitude and duration of responses and had a favorable benefit–risk profile (Table 5) in the treatment of patients with metastatic NSCLC with MET exon 14 skipping. The accelerated approvals do not extend to the MET amplified NSCLC population. Efficacy results in the previously treated setting were similar in both trials with ORR 41% (95% CI: 29, 53) for capmatinib and 43% (95% CI: 33, 55) for tepotinib. In the first-line setting, the ORR for capmatinib in 28 patients (ORR = 68%) was higher than that reported with available therapy of an anti-PD-(L)1 antibody in combination with chemotherapy. While the point estimate of ORR for tepotinib (43%) is in the range of ORR observed with FDA-approved available therapies, the differing safety profile and option for treatment with a single agent administered orally make this a valuable treatment option for treatment-naïve patients.

During the assessment of these applications, FDA reviewed reports of real-world data (RWD) from retrospective studies submitted by the Applicants regarding response to conventional therapy (platinum-based chemotherapy and/or immunotherapy) in patients with MET exon 14 skipping NSCLC. These reports contained minimal data for patients receiving immunotherapy, especially as part of first-line treatment. FDA also reviewed the available literature, in which reports are similarly limited by small numbers of patients receiving immunotherapy alone. In both the literature and the RWD submitted by the Applicants, there was a paucity of data for patients receiving anti-PD-(L)1 antibody in combination with chemotherapy as first-line treatment. Taken together, little is known regarding how patients with MET exon 14 skipping NSCLC may respond to currently available conventional therapy.

Safety signals identified for both capmatinib and tepotinib were interstitial lung disease and hepatotoxicity, with risk of photosensitivity based on animal studies included in the labeling for capmatinib. The overall safety profiles were similar, with edema, nausea, and fatigue the most common adverse reactions reported for both capmatinib and tepotinib. The observed safety profiles of both capmatinib and tepotinib are considered acceptable when assessed in the context of the treatment of a life-threatening disease.

To confirm clinical benefit, neither Applicant will be conducting a randomized trial, but instead both Applicants were asked to provide additional single arm ORR and DOR data in the indicated population, with all responders in the treatment-naïve population followed for at least 12 months after initial response and all responders in the previously treated population followed for at least 6 months after initial response. This was deemed acceptable given the rarity of the population, making conduct of a randomized trial impractical, and the demonstration of efficacy in both the previously treated and the first-line setting. Contemporaneous with the approval of capmatinib, the FDA's Center for Devices and Radiological Health reviewed and approved a supplemental premarket approval application for FoundationOneCDx (F1CDx) as a companion diagnostic (CDx) device for the detection of mutations that lead to MET exon 14 skipping. Contemporaneous approval of the CDx for tepotinib could not be accomplished. FDA guidance states, “FDA generally will not approve the therapeutic product or new therapeutic product indication if the IVD companion diagnostic device is not approved or cleared for that indication” but indicates exceptions can be made such as this case when the therapeutic product is intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists and benefits outweigh risks (6). Approval of tepotinib included a post-market commitment to provide adequate analytical and clinical validation results from clinical trial data to support labeling of a companion diagnostic test. The expectation is that therapeutic product labeling will be revised to stipulate the use of the IVD companion diagnostic device once approved.

The magnitude and durability of responses observed with capmatinib and tepotinib in GEOMETRY mono-1 and VISION, respectively, in treatment-naïve and previously treated patients with metastatic NSCLC with MET exon 14 skipping demonstrate an effect on an early clinical endpoint reasonably likely to predict clinical benefit for a life-threatening condition. These results, along with the observed safety profiles, provided favorable benefit-risk evaluations for capmatinib and tepotinib for the approved indications above that of available therapies. The approvals of capmatinib and tepotinib represent the first FDA-approved therapies specific to this patient population. Capmatinib and tepotinib provide new therapeutic options for the treatment of a rare subset of NSCLC.

No disclosures were reported.

The Editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose.