About four years ago Nasser K. Altorki, MD, Chief of Thoracic Surgery and Director, Neuberger Berman Lung Cancer Research Center, and Silvia C. Formenti, MD, Chair, Radiation Oncology, NewYork-Presbyterian/Weill Cornell Medical Center, initiated collaborative research to determine if combining sub-ablative doses of radiation with immune checkpoint inhibitors in patients with resectable non-small-cell lung cancer (NSCLC) have immunomodulating properties that produce potent local and systemic antitumor immune responses.
Dr. Nasser Altorki and Dr. Silvia Formenti
“Our primary objective was to determine whether preoperative anti-PDL-1 therapy with or without radiation leads to improvement in disease-free survival from a historical control rate of 75 percent at two years to 88 percent,” says Dr. Altorki. “The response rate for the 60 randomized patients recruited for the trial was far above what you would expect from other regimens using immune checkpoint inhibitors. More importantly, patients enrolled in this trial go to the operating room within six weeks, while patients who undergo immunotherapy with chemotherapy do not go to surgery for 12 weeks.”
The clinical protocol developed by Dr. Altorki and Dr. Formenti focuses on patients newly diagnosed with early resectable lung cancer – clinical stages I, II, and IIIA. “These are patients who despite being potentially curable by surgery, have a 30 to 70 percent chance of cancer recurrence,” says Dr. Formenti. “Instead of performing surgery first followed by immunotherapy, we are doing immunotherapy first – plus or minus radiation – then taking them to surgery. The results of adding radiation are quite promising, with data suggesting that radiation significantly increases the response rate. Our lab was the first to demonstrate the effects of radiation on the innate and adaptive immune system and this study translates to the clinic our preclinical results.”
The findings of Dr. Altorki, Dr. Formenti, and their colleagues at NewYork-Presbyterian/Weill Cornell, published in the June 2021 issue of The Lancet-Oncology, showed that “the preoperative combination of immune checkpoint blockade and radiotherapy to the primary tumor resulted in a significant and clinically meaningful increase in the proportion of patients with a major or complete pathological response.”
Specifically, major pathological response was observed in 16 of 30 patients in the durvalumab plus radiotherapy group compared to 2 of 30 in the durvalumab group. Of the 16 patients in the durvalumab plus radiotherapy group with major pathological response, 8 (50 percent) had a complete pathological response. No complete pathological responses were observed in the durvalumab group.
All 60 patients received at least one dose of durvalumab; all 30 patients in the durvalumab plus radiotherapy group received the assigned radiation dose; and 26 of the 30 in each group underwent the planned surgical resection.