About half of patients who undergo tumor resection for early-stage non–small cell lung cancer (NSCLC), the most common type of lung cancer, experience recurrence and/or progression to metastatic disease. While immune checkpoint inhibitors have been shown to benefit some patients with metastatic NSCLC, it is not known whether giving such drugs before surgery can reduce the risk of recurrence and metastasis in patients with early-stage disease. In hopes of achieving such risk reduction, a new clinical trial at The University of Texas MD Anderson Cancer Center will offer preoperative therapy with checkpoint inhibitors to patients with early-stage NSCLC.
“In trial after trial, the checkpoint inhibitors have yielded more and longer responses than standard chemotherapy for metastatic NSCLC,” said William N. William Jr., M.D., an associate professor and chief of the Head and Neck Section in the Department of Thoracic/Head and Neck Medical Oncology. “But only about 20% of these patients have a durable response to the checkpoint inhibitors. We believe that the checkpoint inhibitors could be much more effective in patients with earlier stage NSCLC who have not yet developed metastatic disease.”
Dr. William is the principal investigator of the new trial (NEOSTAR), which will be among the first clinical studies of neoadjuvant checkpoint inhibitor therapy in patients with early-stage NSCLC. The trial is expected to begin enrolling patients in May/June 2017. Eligible patients are those with recently diagnosed, operable stage I–IIIA NSCLC. Patients who have received immunotherapy or chemo-radiation therapy are not eligible. In this trial, patients will receive one or two checkpoint inhibitors before resection. All patients will receive the PD-1 (programmed cell death protein 1) inhibitor nivolumab, and some will receive nivolumab plus the CTLA-4 (cytotoxic T lymphocyte antigen 4) inhibitor ipilimumab.
“We believe,” said Boris Sepesi, M.D., an assistant professor in the Department of Thoracic and Cardiovascular Surgery and lead surgeon in the NEOSTAR trial, “that checkpoint inhibitors given during the 6-week period before tumor resection can induce a major pathological response in a substantial proportion of patients. Moreover, our hope is that this treatment paradigm can train the patient’s immune system to recognize the tumor antigens while the tumor is still present and potentially induce a durable response.” Although the ability of neoadjuvant checkpoint inhibitor therapy to produce durable responses in NSCLC patients remains hypothetical, such responses could prevent recurrences that tend to occur even when a complete tumor resection is achieved.
Blood samples will be collected during checkpoint inhibitor treatment to monitor the immune response, and the tumor size will be monitored with imaging. As in all neoadjuvant therapy, the goals are to shrink the tumor before resection and to eliminate any existing micrometastatic disease, thus yielding a better outcome for the patient by reducing the risk of recurrence and metastasis.
The NEOSTAR trial will be available only at MD Anderson. However, the trial is designed to be as patient-friendly as possible by clustering treatments, doctor visits, and tests together so that only three visits, spaced 2 weeks apart, are required before resection. After surgery, patients will be offered standard therapy appropriate for their disease, if indicated.
In metastatic NSCLC and other cancers, checkpoint inhibitors are not effective in all patients. One aim of the NEOSTAR trial is to determine the characteristics of tumors that respond to the checkpoint inhibitors. Such knowledge could expand the numbers of patients who benefit from these agents while avoiding exposure for patients who are unlikely to benefit.
Tumor and tissue specimens and blood samples from patients in the NEOSTAR trial will be analyzed using methods modeled after the ongoing Immunogenomic Profiling of Non–Small Cell Lung Cancer (ICON) project. “In the ICON project, we are conducting an in-depth molecular analysis of resected tumors, surrounding tissues, and blood from patients with early-stage NSCLC and integrating those findings with clinical and outcome data to develop a comprehensive immunogenomic profile of these tumors,” said Dr. Sepesi, a co-leader of the project along with Don Gibbons, M.D., Ph.D., an associate professor in the Department of Thoracic/Head and Neck Medical Oncology. “This profile will generate a list of biomarkers—mutation or aberrant expression of specific genes and proteins—and an immune profile that can be used to learn more about how immunotherapy works in NSCLC.”
The ICON project and NEOSTAR trial aim to expand understanding of the immune response to NSCLC and how it could be harnessed to fight the disease. “The ICON project and NEOSTAR trial are efforts to thoroughly characterize immune cell activity in and around the tumor,” Dr. William said. “Armed with this information, we can develop novel therapies that narrowly target that activity. Eventually we hope to engineer T cell receptors that target specific tumor antigens, which will zero in on the tumor with minimal systemic effects or development of resistance.”
Dr. William continued, “The way we are looking at tumors in NEOSTAR goes beyond traditional staging and histologic criteria to develop new ways of identifying individuals who respond to specific therapies and of understanding what that response looks like.” And even as researchers use immunogenomic profiling to develop future treatments, the neoadjuvant immunotherapeutic approach offered by the NEOSTAR trial may give current patients with early-stage, operable NSCLC a better chance at long-term survival.
For more information, contact Dr. Boris Sepesi at 713-753-0131 or firstname.lastname@example.org or Dr. William N. William Jr at 713-792-6363 or email@example.com. For more information about clinical trials for patients with lung cancer, visit www.clinicaltrials.org. The NEOSTAR trial and ICON project are part of MD Anderson’s Lung Cancer Moon Shot program. For more information, visit http://bit.ly/2nKbOLF.
OncoLog, May-June 2017, Volume 62, Issue 5-6