Multicenter, Phase II, Neoadjuvant and Adjuvant Study of Alectinib, Entrectinib, or Vemurafenib Plus Cobimetinib in Patients with Stages I-III Non-Small Cell Lung Cancer with ALK, ROS1, NTRK, or BRAF V600E Molecular Alterations
This trial will evaluate the efficacy and safety of targeted therapies in participants with resectable Stage IIA, IIB, IIIA, and select IIIB (T3N2) resectable and untreated non-small cell lung cancer (NSCLC) tumors with selected molecular alterations.
The primary efficacy objective for this study is to evaluate the efficacy of each study treatment on the basis of the following endpoint:
Determination of major pathologic response (MPR), (defined as less than or equal to 10% residual viable tumor cells) scored by a local pathologist, based on surgical resection as defined by Hellmann et al. 2014 and further outlines in the pathology standard operating procedure (SOP)
Pathological regression based on % viable tumor cell assessment (see pathology
Investigator-assessed response ORR per RECIST v1.1
Pathological complete response (pCR), defined as the absence of residual invasive in situ cancer and all sampled regional lymph nodes (i.e., ypT0 ypN0 in the current AJCC staging system), as assessed by the investigator site pathology laboratory
Disease-free survival (DFS), defined as the time from the first date of no disease (e.g., date of surgery or date of CR prior surgery) to local or distant recurrence or death due to any cause, whichever occurs first, as determined by the investigator during the adjuvant treatment and observation follow-up
Event-free Survival (EFS), defined as the time from first dose to the first
documented disease progression, per RECIST v1.1, or local or distant disease
recurrence, as determined by the investigator, or death from any cause, whichever occurs first
Overall survival (OS), defined as the time from first dose to death from any cause
Evaluate the change in blood ctDNA from baseline to pre-surgery and the
correlation with clinical outcome measures
Evaluate the blood ctDNA status post-surgery and the correlation with clinical
Monitoring of ctDNA status and profiles in blood post-surgery over time and
correlation with clinical outcome measures
Incidence and severity of adverse events, with severity determined according to
National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0)
Pathologically documented NSCLC: Stage IIA, IIB, IIIA, or selected IIIB, including T3N2, or T4 (by size criteria, not by mediastinal invasion) NSCLC (based on the 8th edition of the American Joint Committee on Cancer [AJCC] Non-Small Cell Lung Cancer Staging system
Molecular testing results from CLIA-certified laboratories and showing at least one of the following abnormalities: ALK fusion, ROS1 fusion, NTRK1/2/3 fusion; BRAF V600 mutation; RET fusion
Measurable disease, as defined by RECIST v1.1
Evaluated by the attending surgeon prior to study enrollment to verify that the primary tumor and any involved lymph nodes are technically completely resectable and verify that the participant is medically operable
Adequate pulmonary function to be eligible for surgical resection with curative intent
Adequate cardiac function to be eligible for surgical resection with curative intent
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Male participants must be willing to use acceptable methods of contraception
Female participants of childbearing potential must agree to use acceptable methods of contraception
NSCLC that is clinically T4 by virtue of mediastinal organ invasion or Stage IIIB by virtue of N3 disease
Any prior therapy for lung cancer, including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, within 2 years
Participants with prior lung cancer that have been in remission for > Major surgical procedure within 28 days prior to Cycle 1, Day 1
Participants known to be positive for HIV are excluded if they meet any of the following criteria: CD4+ T-cell count of > Severe infection within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infections, or any active infection that, in the opinion of the investigator, could impact participant safety
Pregnant or lactating, or intending to become pregnant during the study
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