Combining chemotherapy with checkpoint inhibitor immunotherapy is standard for patients with operable or resected stage II and III non-small cell lung cancer (NSCLC). However, not all patients can tolerate chemotherapy, and immunotherapy alone is ineffective in most patients. A new study by NewYork-Presbyterian/Weill Cornell Medicine thoracic surgeons recently found that patients with stage I-III NSCLC who received stereotactic body radiation therapy (SBRT) in addition to durvalumab immunotherapy before cancer surgery experienced better progression-free survival (PFS) compared with patients who received durvalumab alone. The study was published in the December 19, 2023, issue of Nature Communications.
"To my knowledge, this is the first study showing the effectiveness of adding low-dose radiation therapy to immunotherapy before surgery for early-stage lung cancer," says Nasser Altorki, MD, Chief of Thoracic Surgery at NewYork-Presbyterian/Weill Cornell Medicine and the paper's lead author. "Patients need options. Not everyone can receive chemotherapy. They may be older or have underlying conditions such as kidney disease that preclude them from receiving the appropriate doses of chemotherapy. We want to provide patients with as many options as possible for their treatment."
Low-dose radiation therapy enhances the efficacy of immunotherapy leading to more frequent tumor eradication and possibly better cancer-free survival.
— Dr. Nasser Altorki
A Pioneering Study
Dr. Nasser and his colleagues at-NewYork-Presbyterian/Weill Cornell Medicine initiated a randomized phase II trial that began in 2017. Sixty patients with stage I-III NSCLC were randomized to receive two preoperative cycles of durvalumab immunotherapy with or without three daily fractions of 8 Gy SBRT. The primary purpose of the radiation was to augment the immune response, rather than to kill the tumor.
In an initial report published in Lancet Oncology in 2021, the authors demonstrated that the combination treatment eradicated significantly more tumors than immunotherapy alone, invoking a “major pathological response” (MPR) — one that kills more than 90% of the cells in resected tumors. MPR was achieved in 53.3% of patients who received the dual therapy versus 6.7% of those in the monotherapy group.
The investigators continued to follow the patients to analyze disease-free survival (DFS) and PFS at two and three years. DFS at three years was similar but slightly better in the combination therapy group (67%) compared with durvalumab alone (63%). In an unplanned post-hoc analysis, two- and three-year PFS trended toward better outcomes for the dual therapy group: 92% and 83%, respectively, for the combination therapy group versus 69% and 69%, respectively, for the monotherapy group. The PFS curves separated at 12 months and maintained a 20% relative difference in PFS at 24 months and beyond, particularly for patients with stage III disease.
Six patients who received immunotherapy alone died of cancer. However, in the dual therapy arm, there was only one death from cancer and five deaths unrelated to cancer recurrence.
Modulating the Tumor Microenvironment
There are multiple mechanisms through which radiation therapy might enhance the immune response, including induction of immunogenic cell death, enhanced antigen presentation, activation of dendritic cells, and increased infiltration of T cells into a tumor. “Low-dose radiation therapy renders immune cells within the tumor to be more receptive to the effects of chemotherapy and enhances the efficacy of immunotherapy,” Dr. Altorki explains.
In a collaboration NewYork-Presbyterian/Columbia medical oncologist Benjamin Izar, MD, PhD, and NewYork-Presbyterian/Columbia MD/PhD candidate Zachary Walsh, analysis of patients' peripheral blood, the team found that MPR was accompanied by heightened immune activity. Individuals who received immunotherapy plus radiation and had achieved MPR had more activated T cells in their blood than those who did not have an MPR. In fact, patients who mounted an MPR harbored CD103-expressing T cells in their blood even before treatment had begun.
"A pre-existing immune response before treatment may not have been an effective enough on its own to eradicate the cancer, but these patients were more likely to have a good result to the combination treatment," Dr. Altorki notes. "It indicates that in some people, the immune system is trying to fight the cancer and the treatment gives it a leg up. This is a hypothesis-generating finding that we would like to explore in a larger clinical trial." A patient's pretreatment T-cell repertoire could potentially be used as a biomarker to identify individuals who would benefit from radiation therapy and immunotherapy and indicate which patients might be better off with other therapies.
Working with additional NewYork-Presbyterian/Weill Cornell Medicine colleagues Timothy McGraw, PhD, Professor of Biochemistry, and Olivier Elemento, PhD, Director of the Englander Institute of Precision Medicine, the investigators performed gene expression profiling showing that patients who did not experience cancer recurrence had evidence of genes associated with an activated immune response, compared with patients whose tumors did recur. CD103 gene expression was higher in tumor samples from patients who remained disease-free versus those with disease recurrence, independent of MPR. "We believe that in some patients immunotherapy activates enough of an immune response to prevent recurrence. That is another important concept we would like to investigate further," adds Dr. Altorki.
Patients need options. Not everyone can receive chemotherapy. We want to provide patients with as many options as possible for their treatment.
— Dr. Nasser Altorki
Designing a Larger Study
The investigators are finalizing the design of a larger phase 2 study that would include twice as many participants and compare the SBRT-immunotherapy combination with the standard treatment, chemotherapy plus immunotherapy. It is hoped that the study will begin by mid-2024. NewYork-Presbyterian/Weill Cornell Medicine will be the lead center for the study. "We're trying to engage other hospitals in this clinical trial. If we can all work together, we can reach our goals more quickly. I am hoping our colleagues will help us bring these ideas to the finish line. And if another hospital comes up with another good idea, we will be happy to jump on board," Dr. Altorki concludes. "In the end, we care about what's best for the patient. If we can advance the field just a little bit at a time, that would be great."
