DEPARTMENT OF DEFENSE - CONGRESSIONALLY DIRECTED MEDICAL RESEARCH PROGRAMS

Posted November 1, 2019
Karen Kelly, M.D., University of California, Davis

LCRP
Dr. Karen Kelly

Nearly one in five patients diagnosed with early stage lung cancer (Stage I) are deemed unfit for surgical intervention due to age or comorbidity, an issue becoming more prevalent with an aging population – and one which is magnified among the nation’s Veterans. The standard of care for these patients consists of stereotactic ablative radiotherapy (SABR), highly focused beams of radiation delivered to the tumor under precise control; however, 30% of patients develop recurrent disease that is fatal within 3 years. Unfortunately for these patients, conventional chemotherapies are typically not well tolerated and are contraindicated due to the very same clinical features that preclude initial surgical resection. Novel, tolerable systemic therapies are needed to provide these patients with an opportunity for prolonged survival and to increase cure rates.   

One promising class of agents are immune checkpoint inhibitors (ICI) that target Programmed Death receptor (PD-1) or its cognate ligand (PD-L1), allowing CD8+ T cells to remain activated and exert their cytotoxic killing effect on cancer cells. These agents have already made a dramatic impact on prolonging survival in advanced lung cancer with the added benefit of being well tolerated. As a result, there is enthusiasm for their role in early stages of disease.  Heightening the enthusiasm is the knowledge that radiation is known to stimulate the local immune response within tumors and with minimal side effects that do not overlap with ICIs.   

Dr. Karen Kelly, at the University of California, Davis, was awarded a Lung Cancer Research Program (LCRP) Fiscal Year 2014 Clinical Exploration Award to test systemic delivery of MPDL3280A (atezolizumab), an anti-PD-L1 antibody, in combination with SABR in a first of its kind clinical trial focused in early stage lung cancer patients with inoperable disease. This study was pursued based on mouse studies combining radiation and ICI that were shown to be more effective in killing tumor cells than radiation or ICI alone.

Dr. Kelly’s team began enrolling patients in a small Phase I study to find the maximum tolerated dose of atezolizumab in combination with SABR. All patients received two doses of atezolizumab followed by concurrent atezolizumab plus SABR and 3 additional doses of atezolizumab. Early results indicate that the standard of care dose of atezolizumab is 1200 mg, in combination with SABR in this patient population produced no additional safety signals have been reported.

Two of ten patients experienced a partial response, one patient had a minor response and the other seven patients had stable disease after two doses of Atezolizumab. No patient progressed on treatment. Currently, Dr. Kelly is continuing completion of the Phase I trial and beginning to evaluate patient samples for clinical efficacy as well as the identification of potential biomarkers of patient response. The team reported on their Phase I study at the International Association for the Study of Lung Cancer 2019 World Conference on Lung Cancer in Barcelona, Spain in September of 2019. Remarkably, the exciting early results from this Phase I LCRP-funded study have spurred the National Cancer Institute’s sponsorship, through their National Clinical Trials Network, of a trial entitled, “A randomized phase III trial of SBRT with or without atezolizumab in early stage inoperable NSCLC patients.” This large Phase III trial is scheduled to begin enrollment late in early 2020. Dr. Kelly’s foundational work has an enormous potential for a population of lung cancer patients with inadequate current treatment options, and it may provide additional benefit to cohorts of patients burdened with other solid tumors that are deemed inoperable. 

Abstract:

A Phase I Trial of an Immune Checkpoint Inhibitor Plus Stereotactic Ablative Radiotherapy in Patients with Inoperable Stage I Non-Small Cell Lung Cancer

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Last updated Friday, November 1, 2019