ROS1 rearrangements are rare, accounting for only 1-2% of NSCLC cases, but have been associated with response to ROS1 inhibitors, such as crizotinib and entrectinib. However, many patients develop resistance to the tyrosine-kinase inhibitors (TKIs), creating a need for new treatments.
Repotrectinib is a new-generation TKI designed against ROS1 or NTRK rearranged malignancies (Drilon 2018). Early phase clinical data support activity of repotrectinib in patients with NSCLC harboring such gene rearrangements (TRIDENT-1 study), but there are limited evidence in frail populations, such as poor performance status patients and/or elderly patients, who are classically excluded from clinical trials or underrepresented.
The present study aims to assess the activity and tolerability of repotrectinib in frail (PS ≥2) and/or elderly patients with ROS1-rearranged advanced NSCLC.
Eligible patients are defined as patients with
Eastern Cooperative Oncology Group (ECOG) PS ≥ 2 at the time of inclusion and/or
Age ≥ 70 years
Age ≥ 18 years
Malignancies other than NSCLC within 2 years prior to inclusion, with the exception of 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 in situ of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
Patients with active hepatitis B (chronic or acute; defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody [HBcAb] and absence of HBsAg) are eligible only 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
Single group
Repotrectinib
DrugRepotrectinib 160 mg BID, until progression or unacceptable toxicity
Objective response rate (ORR) according to RECIST v1.1.
ORR defined as the proportion of patients who achieved a complete or partial response according to RECIST v1.1 from the date of first treatment administration until disease progression or death if patient died before progression or the introduction of a new treatment assessed by blinded independent central review. Tumor assessments will be performed at Screening, every 2 Months during the first year then every 3 months thereafter until documented progression, death or the introduction of a new treatment. Patients who discontinue treatment for reasons other than radiographic disease progression per RECIST v1.1 (toxicity, symptomatic deterioration) will continue scheduled tumor assessments until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the co-Sponsors, whichever occurs first
Progression free survival (PFS) by masked, independent central review
Independent central review of progression free survival (PFS) from Repotrectinib initiation, defined as the time from first dose of Repotrectinib to first documentation of objective disease progression (RECIST v1.1) or to death from any cause. Patients lost to follow-up will be censored as the last date of radiological assessment without progression. Tumor assessments will be performed at Screening, every 2 Months during the first year then every 3 months thereafter until documented progression, death or the introduction of a new treatment. Patients who discontinue treatment for reasons other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor assessments until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the co-Sponsors, whichever occurs first.
Disease control rate (DCR) by masked, independent central review
DCR, defined as the proportion of patients who achieved a complete response (CR) or partial response (PR) or stable disease (SD) according to RECIST v1.1 assessed by BICR. Tumor assessments will be performed at Screening, every 2 Months during the first year then every 3 months thereafter until documented progression, death or the introduction of a new treatment. Patients who discontinue treatment for reasons other than radiographic disease progression per RECIST v1.1 (e.g., toxicity, symptomatic deterioration) will continue scheduled tumor assessments until radiographic disease progression per RECIST v1.1, withdrawal of consent, death, or study termination by the co-Sponsors, whichever occurs first.
Intracranial ORR (ic-ORR) by masked, independent central review
ic-ORR, defined as the proportion of patients who achieved CR or PR in measurable brain metastases based on RECIST 1.1 criteria
Overall survival (OS)
OS, defined as the time from first dose of Repotrectinib until death from any cause. Patients lost to follow-up will be censored at the last date known to be alive. OS will be evaluated every 3 months (until death or lost to follow-up) in patients who: * Discontinue the study treatment due to disease progression * Discontinue the study treatment due to an unacceptable toxicity or any other reason, and who start a new therapy * Reach the End-of-study Time Point.
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Centre Hospitalier Intercommunal de Toulon La Seyne sur Mer
Lead sponsor
Groupe Francais De Pneumo-Cancerologie
Collaborator
Hospices Civils de Lyon
Collaborator
