Tepotinib Plus an EGFR TKI in Patients with EGFR-mutant NSCLC and Resistance to EGFR TKIs Due to MET Amplification (METamp)

초록

Introduction METamp is a mechanism of acquired resistance to tyrosine kinase inhibitors (TKIs) and is reported to occur in ∼30% of patients treated with EGFR TKIs; there is a high unmet need for effective treatment options in these patients. Combination treatment with a MET TKI plus an EGFR TKI may overcome MET-related EGFR TKI resistance. We report clinical activity of tepotinib plus an EGFR TKI in this population. Methods Tepotinib plus an EGFR TKI has been investigated in the Phase (P) Ib/II INSIGHT study (NCT01982955). In PIb, patients received oral tepotinib (300 mg or 500 mg) plus 250 mg gefitinib once daily. In PII, patients received tepotinib 500 mg plus gefitinib or chemotherapy. METamp was determined using FISH (gene copy number ≥5 and/or MET/CEP7 ratio ≥2). The combination of tepotinib plus an EGFR TKI has also been explored in clinical practice, including compassionate use. Results In the INSIGHT study, 18 patients with METamp received tepotinib plus gefitinib (PIb, n=6; PII, n=12). Median (range) treatment duration for the combination was 6.9 (1.7–13.8) months in PIb and 11.3 (1.4–22.7) months in PII; three patients are still ongoing treatment (≥4 years). A total of 12/18 (67%) patients had a response; 4/6 in PIb with a duration of response (DOR) of 5.5, 5.6, 11.7, and 12.5 months, respectively, and 8/12 patients in PII with a median (m) DOR of 19.9 months (90% CI: 7.0, NE). In PII, mPFS was 16.6 months (8.3, NE) and mOS was 37.3 months (NE, NE); both greatly improved versus chemotherapy (PFS HR 0.13 [0.04, 0.43], OS HR 0.08 [0.01, 0.51]). The table shows information on patients with duration of treatment >12 months (8/18 patients). Outside clinical trials, several patients have received tepotinib plus an EGFR TKI in clinical practice; information on two patients receiving this combination >6 months is shown (Table). A 62-year-old female is currently benefitting from tepotinib plus osimertinib after receiving chemotherapy, afatinib, osimertinib, and immunotherapy. A 79-year-old male, who received prior gefitinib and osimertinib, is currently benefitting from tepotinib plus osimertinib. Conclusion The combination of tepotinib with an EGFR TKI, including osimertinib, shows clinical activity in the treatment of patients with EGFR TKI-resistant NSCLC due to METamp. Tepotinib plus osimertinib is currently being investigated in the INSIGHT 2 study (NCT03940703) in patients with METamp EGFR-mutant NSCLC with acquired resistance to first-line osimertinib. Enrollment is ongoing in 125 sites in 17 countries; encouraging preliminary activity has been observed.