Repotrectinib Plus Osimertinib Under Study in EGFR-Mutant NSCLC


Investigators are evaluating the combination of repotrectinib and osimertinib for the treatment of patients with advanced or metastatic EGFR-mutant non–small cell lung cancer in the phase 1 TOTEM trial.

Investigators are evaluating the combination of repotrectinib (TPX-0005) and osimertinib (Tagrisso) for the treatment of patients with advanced or metastatic EGFR-mutant non–small cell lung cancer (NSCLC) in the phase 1 TOTEM trial (NCT04772235). The study design was presented at the 2022 World Conference on Lung Cancer. 

TOTEM is a single-arm, multicenter trial evaluating repotrectinib in combination with osimertinib in patients with advanced or metastatic EGFR-mutant NSCLC.

The study has been initiated and will be conducted across 4 hospitals in Spain.

“Osimertinib has robust efficacy and is the standard first-line treatment for advanced EGFR-mutant NSCLC. [But] lung cancer cells generate resistance to osimertinib through activation of other TKI signaling pathways,” study authors wrote in the poster.

Repotrectinib is a receptor TKI of ROS1 and TRK that directly competes with ATP binding and inhibits wild-type fusion proteins and fusion proteins harboring resistance. In preclinical assays, the agent has shown potent multi-kinase inhibition against a range of resistance mechanisms including JAK2, SRC, and FAK at clinically relevant concentrations.

“The combination of osimertinib with repotrectinib inhibited Src/FAC/JAK2 in EGFR-mutant cell lines and abrogated STAT3 and YAP1 signaling with tumor growth inhibition in vitro and in vivo. There was no substantial toxicity in nude mice models,” study authors added. “Based on this evidence and repotrectinib’s unique inhibition affinity for Src, FAC and JAK2, we designed the current trial.”

To be eligible for enrollment, patients must be at least 18 years of age with a diagnosis of locally advanced, unresectable or metastatic NSCLC with local or central determination of EGFR exon 18, exon 19, exon 21, or T790M mutation. Patients must have an ECOG performance of 0 or 1 and a creatinine clearance of more than 50 mL/min. Patients with asymptomatic brain metastases are eligible, and treatment with prior chemotherapy, immunotherapy, and TKIs, including osimertinib, is allowed.

The primary objective of the study is to establish the safety and tolerability of repotrectinib across several doses in combination with osimertinib; determine the first cycle of dose-limiting toxicities (DLTs) and the maximum tolerated dose of repotrectinib given in combination with osimertinib; and identify the recommended phase 2 dose (RP2D) of repotrectinib given in combination with osimertinib. The RP2D will be defined as the dose level with less than 33% of patients experiencing a DLT.

Secondary end points include evaluating repotrectinib’s effect on the pharmacokinetics of osimertinib, establishing the pharmacokinetics of the combination, and determining the preliminary efficacy of the combination defined by the objective response rate (ORR), intracranial ORR, duration of response, clinical benefit rate, progression-free survival, and overall survival.

All radiographic efficacy end points will be based on investigator assessment using RECIST v1.1 criteria. Intracranial responses will also be evaluated by RECIST v1.1 criteria.

Investigators will evaluate pharmacodynamic effects and potential predictive biomarkers of response for the combination using serial tumor biopsy and/or blood samples as an exploratory objective. 

The study includes 2 parts: part A is a dose-escalation phase following a 3+3 design including 6 to 18 patients to determine the RP2D. Patients in part A will receive osimertinib monotherapy for 14 days at 80 mg per day, followed by osimertinib in combination with repotrectinib at the assigned dose level of 80 mg or 160 mg once daily, or 160 mg twice daily.

Part B is an expansion phase enrolling 20 to 30 patients who have progressed on osimertinib or first-/second-generation TKIs. Patients in part B will receive the combination at the RP2D. Treatment will continue until confirmed radiographic disease progression according to RECIST v1.1 criteria confirmed by blinded independent central review, or unacceptable toxicity.

Six of 38 expected patients have enrolled to the first (80 mg once daily; n = 3) and second (160 mg once daily; n = 3) dose levels since accrual begin in March 2022. Recruitment is expected to be completed by March 2023.


  1. Aguilar A, Cobo M, Azkarate A, et al. Design of a phase I trial (TOTEM) to test repotrectinib in combination with Osimertinib in advanced, metastatic EGFR mutant NSCLC. Presented at: 2022 World Conference on Lung Cancer. August 6-9, 2022; Vienna, Austria. Abstract EP08.02-011.
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