Osimertinib plus repotrectinib phase I trial in TKI-resistant non-small cell lung cancer (NSCLC) with EGFR mutations.

8604 Background: NSCLC patients with EGFR mutations develop resistance when treated with EGFR TKI. We previously reported that osimertinib combined with TPX-0005 (repotrectinib) ablated STAT3, paxillin, and YAP1 phosphorylation in a preclinical model. Osimertinib-induced Src and FAK phosphorylation was abrogated with TPX-0005 alone or in combination with osimertinib in H1975 (EGFR L858 and T790M) cell line. TPX-0005 potentiated the effect of osimertinib in PC9 and H1975 tumor xenografts without substantial toxicity (Karachaliou et al. eBioMedicine 2017). The findings prompted us to carry out the current study with osimertinib plus TPX-0005, which inhibit Src/FAK/JAK2, in addition to ALK, ROS1 and NTRKs. Methods: TOTEM (NCT04772235) is a phase I, two-part study to assess safety, tolerability, pharmacokinetics, and antitumor activity of repotrectinib plus osimertinib in EGFR-mutant patients resistant to previous lines of treatment. Phase Ia was a dose escalation (3+3). Treatment naïve patients were treated with osimertinib 80mg QD plus: repotrectinib 80mg QD, 160mg QD and 160mg BID. In part Ib, patients should have received osimertinib or osimertinib plus chemotherapy as first line treatment. Results from part Ia are presented in this abstract. Results: Phase Ia included 15 patients with a median age of 61 yrs (34-71). Of these patients:10 were female (66.7%), 9 had PS1 (60%), and 7 had brain metastasis (48.7%). At the time of starting treatment, two patients had exon 18 (G719X) mutations (p.E709_T710delinsD and p.G719A), 5 had exon 21 (4 p.L858R, 1 p.L861Q) and 8 had exon 19 deletion. Eight patients had p53 co-mutations, other co-alterations included PIK3CA, RET, FAT1, FGFR3 and MYC mutations, CDK4 and EGFR amplification, and MET, ROS1, EGFR and FGFR3 over-expression. Six patients were treatment-naive, four were osimertinib progressors, and five had received two or more previous lines of treatment. With repotrectinib plus osimertinib, intracranial complete response was attained in 3 of the seven patients with brain metastasis (42.85%). The overall objective response rate (ORR) was noted in 5 patients (33.3%), and stable disease in 8 patients (53.3%). Median PFS was 4.4 mo. (95% CI 2.9-NR). Among the adverse events, transient, manageable dizziness was observed in 76% of the patients, and dysgeusia occurred in 48% of cases. Most side effects were grade 1-2, including anemia, diarrhea, fatigue, and liver enzyme elevation. Pharmacokinetic analysis indicated a favorable profile of the combination. Dose level 3 (160mg BID) was safe, therefore, part Ib continued with repotrectinib 160mg BID plus osimertinib 80mg QD in 15 patients enrolled. Conclusions: In Part Ia osimertinib + repotrectinib showed impressive intracranial ORR with a manageable safety profile. Part Ib with repotrectinib 160 mg BID plus osimertinib 80 mg is ongoing. Updated results will be presented. Clinical trial information: NCT04772235 .