Spotlight Trial: A Phase II Study Examines the Potential of Immune Checkpoint Inhibitor Combination Therapies for Patients with Oncogene-Driven Lung Cancer

March, 2018

Trial PI, Alice T. Shaw,  MD, PhD (MGH)

Trial PI, Alice T. Shaw, MD, PhD (MGH)

A phase II trial open at Beth Israel Deaconess Medical Center, Dana-Farber Cancer Institute, and Massachusetts General Hospital led by principal investigator Alice Shaw, MD, PhD (MGH), draws on recent advances in immunotherapy that have transformed the landscape of treatment for advanced non-small cell lung cancer (NSCLC), which historically has carried a poor prognosis. Immune checkpoint inhibitors targeting the pathways involved in tumor-induced immunosuppression look especially promising. Nivolumab activates the immune system by inhibiting the programmed death receptor-1 (PD-1), which downregulates the immune system and is thought to facilitate tumor cells’ escape from immune detection.

The phase II study is testing the effectiveness, safety, and tolerability of nivolumab in combination with standard-of-care chemotherapies or in combination with ipilimumab, another immune checkpoint inhibitor that activates the immune system by targeting the receptor CTLA-4. Investigators are hopeful that such combination therapies will synergize to allow the body’s immune system to more effectively work against tumor cells.

The study is enrolling patients whose NSCLC tumor cells express mutant epidermal growth factor receptor (EGFR) or harbor anaplastic lymphoma kinase (ALK) gene rearrangements, and whose malignancy has progressed despite prior treatment with EGFR or ALK inhibitors.  

The US Food and Drug Administration (FDA) has approved nivolumab and ipilimumab as treatments for several types of cancers; however, the combination of nivolumab with other drugs has not been approved by the FDA as a treatment for NSCLC. Elsewhere in this issue of eNews, a second Spotlight on Clinical Trials feature reports on testing these drugs for treatment of genitourinary tumors.

“One of the key questions that needs to be answered is the role for immune checkpoint inhibitors in the treatment of patients with EGFR-mutant or ALK-rearranged NSCLC, where targeted therapy very much remains the cornerstone of therapy,” said study investigator Jessica Jiyeong Lin, MD, a postdoctoral and oncology fellow at Massachusetts General Hospital. “What we have learned so far from retrospective analyses and pooled analyses of prior randomized studies is that PD-1 or PD-ligand 1 (PD-L1) antibodies, when used as a single agent in these patients, are not very effective.  However, more recently emerging data suggests that combination immunotherapy regimens may have a potential role.”

The study is comprised of four groups or cohorts. In Cohorts A and B, investigators are studying the efficacy of nivolumab combined with carboplatin and pemetrexed chemotherapy in advanced NSCLC with mutant EGFR (Cohort A) or ALK rearrangements (Cohort B). Patients in these cohorts must not have received prior chemotherapy, but must have been treated with at least one third-generation EGFR inhibitor (for Cohort A) or at least one next-generation ALK inhibitor (for Cohort B), which is the standard of care. In Cohorts C and D, the team is studying the efficacy of nivolumab combined with ipilimumab in EGFR-mutant (Cohort C) or ALK-rearranged (Cohort D) advanced NSCLC.  These patients similarly must have received available EGFR or ALK inhibitors and they must also have had one or two lines of combination chemotherapy. 

In this trial, patients will not be taking agents targeting EGFR and ALK in addition to the study drugs. “Typically, when a patient’s cancer progresses on one of these agents and the patient transitions to chemotherapy, our current conventional approach has been to discontinue the EGFR or ALK inhibitor,” said Dr. Lin. “This is based on prior studies suggesting that continuation in such settings confers minimal benefit; however, this is an area of active investigation and is also individualized to each patient.” Investigators are also concerned that adding an EGFR or ALK inhibitor to the study’s immunotherapy regimens will increase the potential for toxicity, which has been demonstrated in other studies.  

If the phase II trial generates promising results, a larger, randomized study will be warranted with the goal of validating and expanding on the findings. Another key next step will be to study potential markers of response to checkpoint inhibitor combinations among patients with NSCLC. Such information will help clinicians determine which patients are most likely to benefit.

Study Design
Patients will be grouped into the four cohorts, with an estimated enrollment of 100 participants. The trial began enrolling patients in November 2017. The estimated primary completion date is October 2020, and the estimated study completion date is October 2024. The primary endpoint of the trial is objective response rate (complete response and partial response).

Phase II Trial
Nivolumab in Combination with Chemotherapy, or Nivolumab in Combination with Ipilimumab, in Advanced EGFR-Mutant or ALK-Rearranged NSCLC
DF/HCC Principal Investigator: Alice Shaw, MD, PhD (MGH)
NIH Trial Number: NCT03256136
DF/HCC Protocol Number: 17-011

The trial is recruiting patients. Find more information at

-Tracy Hampton, PhD