Targeted Therapy in Treating Patients With Incurable Non-Small Cell Lung Cancer With Genetic Mutations

Phase II Pilot Study Evaluating Strategies to Overcome Resistance at the Time of Progression for Patients With Non-small Cell Lung Cancers Harboring Major Oncogenic Drivers

This phase II trial studies how well targeted therapy works in treating patients with incurable non-small cell lung cancer with a genetic mutation. Giving drugs that target other genetic mutations or other specific proteins may work better when a patient has cancer caused by a driver mutation and the treatment that targets that mutation stops working.

Study Overview

• Status: Terminated
• Conditions: Recurrent Non-Small Cell Lung Carcinoma; Stage IV Non-Small Cell Lung Cancer; EGFR Activating Mutation
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Biological: Nivolumab; Biological: Pembrolizumab; Drug: Chemotherapy; Biological: Immunotherapy; Drug: Tyrosine Kinase Inhibitor; Drug: Targeted Molecular Therapy

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the objective response rate among patients with high PD-L1 expressing cancers after failure of targeted therapy.

SECONDARY OBJECTIVES:

I. To compare the overall survival for patients receiving treatment targeting primary mutations, secondary mutations, or immunotherapy at the time of progression on tyrosine kinase inhibitor therapy.

II. To assess the incidence of secondary mutations in this population according to smoking status.

III. To evaluate the response rates of patients treated using these different approaches.

IV. To correlate outcomes with specific secondary genetic changes.

OUTLINE: Patients are assigned to 1 of 3 treatment arms.

ARM I (PD-L1 >= 50%): Patients receive nivolumab intravenously (IV) over 60 minutes every 2 weeks or pembrolizumab IV every 3 weeks in the absence of disease progression or unacceptable toxicity.

ARM II (PD-L1 < 50% without secondary oncogenic driver): Patients receive tyrosine kinase inhibitor therapy orally (PO) targeting the initial oncogenic driver or other treatment for about 3 weeks.

ARM III (PD-L1 < 50% with secondary oncogenic driver): Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.

After completion of study treatment, patients are followed up for a minimum of 30 days.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Comprehensive Cancer Center of Wake Forest University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed incurable non-small cell lung cancer that harbors an activating mutation in EGFR, MET, BRAF, V600E, RET, HER2, translocation in Alk, or translocation in ROS-1
• Patients must be receiving treatment or planning to start treatment with a tyrosine kinase inhibitor targeting the activated gene
• Patients may not be receiving the treatment targeting the activated gene as part of a clinical treatment trial other than the Precision Oncology Trial
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-3
• Total bilirubin =< 1.5 X institutional upper limit of normal
• Aspartate transaminase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine transaminase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X institutional upper limit of normal
• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
• Ability to understand and the willingness to sign an Institutional Review Board (IRB)-approved informed consent document

Exclusion Criteria:

• Emergent need for palliative radiation
• Patients may not be receiving any other investigational agents for the treatment of non-small cell lung cancer
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded; breastfeeding should be discontinued

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (nivolumab, pembrolizumab); Patients receive nivolumab IV over 60 minutes every 2 weeks or pembrolizumab IV every 3 weeks in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Biological: Nivolumab; Given IV; Other Names: BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo; Biological: Pembrolizumab; Given IV; Other Names: Keytruda; MK-3475; Lambrolizumab; SCH 900475
Experimental: Arm II (kinase inhibitor, chemotherapy, immunotherapy); Patients receive tyrosine kinase inhibitor therapy PO targeting the initial oncogenic driver or other treatment for about 3 weeks.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Chemotherapy; Receive other treatment; Other Names: Chemo; Chemotherapy (NOS); Chemotherapy, Cancer, General; Biological: Immunotherapy; Receive other treatment; Other Names: Immunologically Directed Therapy; Drug: Tyrosine Kinase Inhibitor; Given PO; Other Names: Protein Tyrosine Kinase Inhibitors; PTK Inhibitors; TK Inhibitors
Experimental: Arm III (kinase inhibitor, targeted therapy, other treatment); Patients receive tyrosine kinase inhibitor therapy PO targeting initial oncogenic driver, a drug targeting the secondary mutation, or other treatment for about 3 weeks.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Chemotherapy; Receive other treatment; Other Names: Chemo; Chemotherapy (NOS); Chemotherapy, Cancer, General; Biological: Immunotherapy; Receive other treatment; Other Names: Immunologically Directed Therapy; Drug: Tyrosine Kinase Inhibitor; Given PO; Other Names: Protein Tyrosine Kinase Inhibitors; PTK Inhibitors; TK Inhibitors; Drug: Targeted Molecular Therapy; Receive drug targeting secondary mutation; Other Names: molecularly targeted therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate in patients with high PD-L1 expressing cancers after failure of targeted therapy defined as complete or partial response according to the investigator's assessment	A Simon's two-stage design will be used.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events measured using Common Terminology Criteria for Adverse Events version 4.0	Toxicities for each group will be estimated and described using counts and frequencies by grade, location and relatedness.	Up to 30 days after the last dose of study treatment
Incidence of mutations in secondary genes for patients with PD-L1 expression < 50%		Up to 3 years
Objective response rates for patients without high PD-L1 expressing cancers	Objective response rates will be estimates in the two PD-L1 expression < 50% arms. Confidence intervals for each of these rates will be estimated. An exploratory comparison will be made among the three groups comparing complete response/partial response versus stable disease/progressive disease among the groups using a Fisher's exact test (for the 2x3 table).	Up to 3 years
Objective response rates for the combined population to historical controls receiving second or third line targeted agents	Objective response rates will be estimates in the two PD-L1 expression < 50% arms. Confidence intervals for each of these rates will be estimated. An exploratory comparison will be made among the three groups comparing complete response/partial response versus stable disease/progressive disease among the groups using a Fisher's exact test (for the 2x3 table).	Up to 3 years
Overall survival	Estimated using Kaplan-Meier methods and survival rates will be compared using log-rank tests.	From date of progression on primary targeted treatment to death, assessed up to 3 years
Rate of tobacco use and mutation burden based on PD-L1 expression at time of progression		Up to 3 years
Smoking status defined as current, former, never	Whether smoking status is related to the prevalence of any mutations identified (present/absent) will be examined using Cochran-Maentel Haenzel tests. These tests will be performed overall and then separately in the three arms.	At baseline

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start (Actual): March 10, 2017
• Primary Completion (Actual): January 8, 2018
• Study Completion (Actual): January 12, 2021

Study Registration Dates

• First Submitted: October 27, 2016
• First Submitted That Met QC Criteria: October 27, 2016
• First Posted (Estimate): October 31, 2016

Study Record Updates

• Last Update Posted (Actual): January 29, 2021
• Last Update Submitted That Met QC Criteria: January 28, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Pembrolizumab
• Other Study ID Numbers: IRB00041150; P30CA012197 (U.S. NIH Grant/Contract); NCI-2016-01589 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CCCWFU 62716 (Other Identifier: Comprehensive Cancer Center of Wake Forest University)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No