Tepotinib Approved in Japan for MET-Positive NSCLC

The Japanese Ministry of Health, Labour and Welfare (MHLW) has approved tepotinib (Tepmetko) for the treatment of patients with unresectable, advanced or recurrent non—small cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations.¹

The MHLW based its decision on data from the ongoing, single-arm phase II VISION study (NCT02864992), in which the MET inhibitor tepotinib induced an overall response rate (ORR) of 42.4% (95% CI, 32.5-52.8) in patients with METex14-altered NSCLC. The median duration of response was 12.4 months, regardless of whether patients had their MET status determined by liquid (95% CI, 8.4 — not evaluable [NE]) or tissue (95% CI, 9.7–NE) biopsy.

The MHLW also approved the ArcherMET companion diagnostic to identify patients with NSCLC whose tumors harbor METex14 skipping alterations.² ArcherMET can be used with either blood or tissue samples.

"Identifying oncogenic drivers in order to guide the course of treatment for lung cancer patients is a clinical best practice; however, there previously was no approved therapy that specifically targeted MET alterations in metastatic NSCLC," Hiroshi Sakai, MD, director, Division of Thoracic Oncology, Saitama Cancer Center, Saitama, Japan, said in a press release. "With the approval of Tepmetko, we now have a new treatment option that addresses this need, offering clinical benefit and duration of response with convenient once-daily oral dosing, representing real progress for patients with this aggressive type of lung cancer."

The phase II VISION study comprises 2 cohorts: cohort A includes patients with METex14 skipping mutations and cohort B includes those with MET amplification. In both groups, tepotinib is administered at 500 mg daily. The approved dose in Japan is 500 mg once daily administered as two 250 mg tablets. The data the MHLW reviewed was for 99 patients with NSCLC with METex14 skipping alterations, 15 of whom were Japanese.

The safety cohort the MHLW reviewed included 130 patients. Overall, the drug was considered to be well tolerated. Permanent treatment discontinuation due to adverse events occurred in 11 (8.5%) patients. The most common treatment-related adverse events (TRAEs) across all grades were peripheral edema (53.8%), nausea (23.8%), and diarrhea (20.8%).

Tepotinib previously received SAKIGAKE fast track designation in Japan for patients with advanced NSCLC harboring METex14 mutations.

In the United States, the FDA granted a breakthrough therapy designation in September 2019 to tepotinib for use as a treatment for patients with metastatic NSCLC with METex14 alterations who have progressed on prior platinum-based chemotherapy.

The designation was based on earlier data from the VISION trial than was used for the Japanese approval. The data the FDA reviewed showed an ORR of 50.0%, as assessed by an independent review committee (IRC), and an investigator-assessed ORR of 55.3%, in patients with METex14-altered NSCLC, which was identified by liquid biopsy.³ For patients who were identified to have METex14 alterations via tissue biopsy, the IRC- and investigator-assessed ORRs were 45.1% and 54.9%, respectively.

The findings the FDA considered included 87 evaluable patients from cohort A. The median age of patients was 74 years, and most patients (74.7%) had an ECOG performance status of 1. Brain metastases were present in 9.2% of patients. Overall, 33 patients had received no prior treatment, and 54 were treated in the second-line or beyond setting.

Results showed that the median progression-free survival was 9.5 months by IRC in liquid biopsy—assessed tumors and was 10.8 months in standard biopsy–identified tumors.

Additionally, the IRC- and investigator-assessed median duration of response (DOR) was 12.4 months and 17.1 months, respectively, among patients whose tumors were evaluated via liquid biopsy. Among patients with tissue-assessed tumors, the IRC- and investigator-assessed median DOR was 15.7 and 14.3 months, respectively.

Regarding safety, the majority of TRAEs were of grade 1/2, and no grade 4/5 TRAEs were observed. All-grade TRAEs reported by ≥10% of 87 patients who were evaluable for safety included peripheral edema (48.3%), nausea (23.0%), diarrhea (20.7%), and increased blood creatinine (12.6%). Additional relevant TRAEs, the company stated, included increased lipase (4.6%), fatigue (3.4%), and vomiting (3.4%). Four patients had to permanently discontinue treatment due to TRAEs; these included peripheral edema (n = 2), interstitial lung disease (n = 1), and diarrhea and nausea (n = 1).

References

1. TEPMETKO® (Tepotinib) Approved in Japan for Advanced NSCLC with METex14 Skipping Alterations. Published online March 25, 2019. https://prn.to/2UDtB4v. Accessed March 25, 2019.
2. ArcherDX Receives Approval for Archer®MET Companion Diagnostic for TEPMETKO® (Tepotinib) in Advanced Non-Small Cell Lung Cancer in Japan. Published online March 25, 2019 https://prn.to/3ajadR9. Accessed March 25, 2019.
3. Pain PK, Veillon R, Cortot AB, et al. Phase II study of tepotinib in NSCLC patients with METex14 mutations. J Clin Oncol. 2019;37 (suppl; abstr 9005). doi: 10.1200/JCO.2019.37.15_suppl.9005