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Poster Display session

79TiP - Progress of a phase I trial (TOTEM) of repotrectinib in combination with osimertinib in advanced, metastatic EGFR mutant NSCLC


31 Mar 2023


Poster Display session


Andres Aguilar Hernandez


Journal of Thoracic Oncology (2023) 18 (4S): S35-S88.


A. Aguilar Hernandez1, M.A. Cobo2, A. Azkarate3, A. Calles4, M. Gonzalez Cao5, A. Cantero6, J. Terrasa3, R. Alvarez4, M.Á. Molina5, R. Rosell7

Author affiliations

  • 1 Barcelona/ES
  • 2 Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, Málaga/ES
  • 3 Hospital Universitario Son Espases, Mallorca/ES
  • 4 Hospital General Universitario Gregorio Marañón, Madrid/ES
  • 5 Quirón-Dexeus University Institute, Barcelona/ES
  • 6 Hospitales Universitarios Regional y Virgen de la Victoria, IBIMA, 29010 - Málaga/ES
  • 7 Germans Trias i Pujol Research Institute and Hospital (IGTP), 8916 - Badalona/ES


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Abstract 79TiP


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).


IOR though industry partner Bristol-Myers Squibb (BMS).


All authors have declared no conflicts of interest.

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