Phase II Efficacy Study of Repotrectinib in Frail and/or Elderly Patients With ROS1-rearranged Advanced NSCLC

Inclusion Criteria:

• Eligible patients are defined as patients with

• Eastern Cooperative Oncology Group (ECOG) PS ≥ 2 at the time of inclusionand/or

• Age ≥ 70 years

• Age ≥ 18 years

• Histologically or cytologically confirmed diagnosis of locally advanced ormetastatic NSCLC harboring an ROS1 gene rearrangement as by any nucleic acid-baseddiagnostic testing method (e.g., next-generation sequencing [NGS], Sangersequencing, reverse transcription-polymerase chain reaction), Break-apartfluorescence in situ hybridization (FISH) or Immunohistochemistry (IHC) (confirmedby NGS or qPCR test).

• Willing and able to provide written institutional review board (IRB)/institutionalethics committee-approved Informed Consent.

• At least 1 measurable target lesion according to RECIST (v1.1). CNS-only measurabledisease as defined by RECIST (v1.1) is allowed.

• Prior cytotoxic chemotherapy for advanced or metastatic disease is allowed. At thetime of starting treatment with repotrectinib, at least 14 days or 5 half-lives (whichever is shorter) must have elapsed after discontinuation of prior cytotoxicchemotherapy (or at least 42 days for prior nitrosoureas, mitomycin C, and liposomaldoxorubicin) and all side effects from prior treatments must have resolved to grade ≤ _1 (CTCAE Version 5.0 with the exception of alopecia.

• Prior immunotherapy (e.g., anti-PD-1, anti-PDL1, anti-TIM3, anti-OX40) is allowed.At the time of starting treatment with repotrectinib, at least 14 days must haveelapsed after discontinuation of prior immunotherapy treatment and allimmune-related side effects from prior treatments must have resolved to grade ≤ _1.

• No prior ROS1 TKI is allowed for the TKI naïve cohort.

• Prior ROS1 TKI is allowed for the TKI pretreated cohort (max 30% of patients). Atleast 7 days or 5 half-lives (whichever is shorter) must have elapsed sincecompletion of treatment with the last ROS1i prior to starting treatment withrepotrectinib for subjects enrolling into the TKI-pretreated expansion cohorts. Allside effects from prior treatments with ROS1i must have resolved to grade ≤ _1 priorto starting treatment with repotrectinib.

• Prior ROS1i allowed include crizotinib, ceritinib, lorlatinib, brigatinib,entrectinib, ensartinib, cabozantinib.

• Subjects with symptomatic CNS metastases and/or asymptomatic leptomeningealcarcinomatosis are eligible.

• Life expectancy ≥3 months

• Subject affiliated to an appropriate social security system

• Adequate hematologic and end-organ function, defined by the following laboratory

• ANC ≥ 1500 /mm3 without granulocyte colony-stimulating factor support

• Lymphocyte count ≥ 500/mm3

• Platelet count ≥ 100,000/mm3 without transfusion

• Hemoglobin ≥ 9.0 g/dL. Patients may be transfused to meet this criterion.

• INR or aPTT ≤ 1.5, upper limit of normal (ULN)

• This applies only to patients who are not receiving therapeuticanticoagulation; patients receiving therapeutic anticoagulation should bereceiving a stable dose.

• ASAT, ALAT, and alkaline phosphatase ≤ 2.5xULN, with the following exceptions:

• Patients with documented liver metastases: ASAT and/or ALAT ≤ 5xULN

• Patients with documented liver or bone metastases: alkaline phosphatase < 5xULN

• Serum bilirubin ≤1.25xULN

• Patients with known Gilbert disease who have serum bilirubin level ≤ 3xULN maybe enrolled.

• Calculated creatinine clearance (CRCL) ≥ 45 mL/min

• Adequate method of contraception during the treatment period

• For Females:

All women of childbearing potential (WOCBP) must agree to avoid pregnancy during the study and must use a highly effective method of contraception during study treatment with repotrectinib and for at least 2 months following the final dose.

Highly effective contraceptive methods consist of prior sterilization, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), injectable or implantable contraceptives and abstinence.

Hormonal contraception must begin 7 days prior to the first dose of study treatment.

Due to a potential loss of effectiveness of hormonal contraceptives caused by interaction with study intervention, if WOCBP use hormonal contraceptives (including oral hormonal contraceptives), they must use either another form of non-hormonal highly effective contraception or a reliable barrier method.

Female subjects must refrain from egg donation from screening through at least 2 months after the last dose of study drug.

• For Males:

Male participants with WOCBP partners must use latex condoms during treatment with repotrectinib and for 4 months following the final dose even if the participant has undergone a successful vasectomy or if the partner is pregnant or breastfeeding.

Male subjects must refrain from sperm donation from screening through at least 4 months after the last dose of study drug

Exclusion Criteria:

• Malignancies other than NSCLC within 2 years prior to inclusion, with the exceptionof those with a negligible risk of metastasis or death (e.g., expected 5-year OS ≥ 90%) treated with expected curative outcome (such as adequately treated carcinoma insitu of the cervix, basal or squamous-cell skin cancer, localized prostate cancertreated surgically with curative intent, ductal carcinoma in situ treated surgicallywith curative intent)

• Patients with active hepatitis B (chronic or acute; defined as having a positivehepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients withpast hepatitis B virus (HBV) infection or resolved HBV infection (defined as thepresence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligibleonly if they are negative for HBV DNA. Patients positive for hepatitis C virus (HCV)antibody are eligible only if PCR is negative for HCV RNA.

• Active tuberculosis

• Severe infections within 2 weeks prior to inclusion, including, but not limited to,hospitalization for complications of infection, bacteremia, or severe pneumonia

• Significant cardiovascular disease, such as New York Heart Association cardiacdisease (Class II or greater), myocardial infarction, or cerebrovascular accidentwithin 3 months prior to inclusion, unstable arrhythmias, or unstable angina

• Major surgical procedure other than for diagnosis within 28 days prior to inclusionor anticipation of need for a major surgical procedure during the course of thestudy

• Any other diseases, metabolic dysfunction, physical examination finding, or clinicallaboratory finding giving reasonable suspicion of a disease or condition thatcontraindicates the use of an investigational drug or that may affect theinterpretation of the results or renders the patient at high risk from treatmentcomplications.

• Patients with illnesses or conditions that interfere with their capacity tounderstand follow and/or comply with study procedures.

• Concurrent participation in any therapeutic clinical trial

• Patient deprived of liberty or placed under the authority of a tutor or a curator

• Assessed by the investigator to be unable or unwilling to comply with therequirements of the protocol