Abstract 79TiP
Background
Osimertinib has robust efficacy as first-line treatment for advanced EGFR mutant non-small cell lung cancer (NSCLC). Osimertinib with repotrectinib inhibited Src/FAC/Janus kinase 2 (JAK2), STAT3 and YAP1 signaling, abrogating tumor growth, and having efficacy with no substantial toxicity in patients (pts) with EGFR-mut tumors. Based on this evidence, we designed the current trial. The TOTEM trial will evaluate the tolerability/safety, preliminary efficacy, the pharmacokinetic (PK) and pharmacodynamic (PD) profile of repotrectinib and osimertinib.
Trial design
Eligible pts are ≥ 18 years, diagnosed with locally advanced, unresectable or metastatic NSCLC harboring EGFR exon 18, exon 19, exon 21, or T790M mut, ECOG 0-1, either without brain metastasis (BM) or asymptomatic BM, and creatinine clearance >50 mL/min. Treatment with previous chemotherapy, immunotherapy, and tyrosine kinase inhibitors (TKIs), including osimertinib, is allowed. The study includes an initial dose escalation phase following a 3+3 design to determine the recommended phase II dose (RP2D). Pts receive osimertinib monotherapy for 14 days at 80 mg per day (QD), followed by osimertinib in combination with repotrectinib at the assigned dose level (80 mg QD, 160 QD, or 160 mg twice a day [bid]); The expansion phase will enroll 20–30 pts who have progressed to osimertinib or first /second-generation TKIs, who will receive the combination at the RP2D. Treatment will continue until progression, or unacceptable toxicity. Tolerability is evaluated by the incidence of dose-limiting toxicities (DLTs). The RP2D is defined as the dose level with less than 33% of pts experiencing a DLT. Safety is assessed by frequency and severity of adverse events. Secondary endpoints include objective response rate, intracranial response (for pts with BM), PFS, and OS. As of Jan 2023, 11 pts are accrued. No DLT was reported at 80 mg QD of repotrectinib, while 1/6 pts had a DLT consisting of renal toxicity at 160 mg QD. Preliminary PKs results showed no significant interaction that required dose adjustments. The third dose level (160 mg bid repotrectinib/80 mg osimertinib) is currently open to recruitment and 2 pts have already initiated study treatment.
Clinical trial identification
NCT04772235, EudraCT 2020-005151-20.
Editorial acknowledgement
We acknowledge MFAR Clinical Research staff for their assistance in the development of this abstract.
Legal entity responsible for the study
Instituto Oncológico Dr. Rosell (IOR).
Funding
IOR though industry partner Bristol-Myers Squibb (BMS).
Disclosure
All authors have declared no conflicts of interest.