Design of a phase II trial comparing tepotinib + gefitinib with cisplatin + pemetrexed in EGFR inhibitor-resistant, c-Met+ NSCLC

Abstract

Background: The phase Ib part of this trial established a recommended phase II dose for tepotinib of 500 mg/day for use in combination with gefitinib for the treatment of patients ( pts) with gefitinib-resistant, locally advanced/metastatic c-Met+ NSCLC. The combination was well tolerated with evidence of antitumor activity, particularly in patients with c-Met+ tumors. The current design of the ongoing phase II part of the trial (NCT01982955) is described. Trial design: As previously described, eligible pts are adults of ECOG PS 0 or 1 with locally advanced/metastatic NSCLC bearing an EGFR-activating mutation and high levels of c-Met (2 + /3+ expression determined by IHC or MET amplification determined by ISH). In the randomized part, 136 pts with confirmed EGFR T790M- tumors are randomized to tepotinib 500 mg/day + gefitinib 250 mg/day PO or pemetrexed 500 mg/m2 IV + cisplatin 75 mg/m2 IV administered on day 1 of a 21-day cycle. In the non-randomized part, pts with EGFR T790M+ tumors receive tepotinib + gefitinib. Protocol updates have extended recruitment from Asia to include Europe and the USA, as well as making pts with acquired resistance to any approved first-line EGFR TKI, including erlotinib or afatinib as well as gefitinib, eligible. Pts with acquired resistance to any of these EGFR TKIs are expected to be resistant to gefitinib monotherapy. The primary objective is to evaluate whether progression-free survival of second-line tepotinib in combination with gefitinib is superior to pemetrexed + cisplatin in pts with T790M-, c-Met+ locally advanced or metastatic NSCLC with acquired resistance to first-line EGFR TKIs. Secondary objectives are to evaluate the safety and tolerability of tepotinib in combination with gefitinib, the efficacy of tepotinib in combination with gefitinib in T790M-, c-Met+ pts, the antitumor activity of tepotinib in combination with gefitinib in T790M + , c-Met+ pts, and quality of life. This trial will establish whether the use of tepotinib in the treatment of patients with EGFR TKI-resistant, c-Met+ NSCLC merits further investigation.