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Neoadjuvant durvalumab (Imfinzi) combined with stereotactic body radiotherapy (SBRT) significantly improved major pathologic response rates in non-small cell lung cancer (NSCLC), according to results from a phase II trial.

Researchers observed a major pathologic response in more than 50% of patients who received the PD-L1 inhibitor and SBRT compared with less than 10% of patients who received durvalumab monotherapy.

"We found that the combination is safe, well-tolerated, and associated with a significant enhancement of major pathological response, the primary endpoint of the trial," wrote Nasser K. Altorki, MD, of Weill Cornell Medicine/New York-Presbyterian Hospital in New York City, and colleagues in .

They noted that the use of PD-1/L1 inhibitors in patients with advanced NSCLC has led to increased interest in using these drugs early in the disease. However, they also pointed out that recent trials evaluating the use of these drugs as neoadjuvant therapy in patients with early-stage lung cancer reported major pathologic response rates in only 14% to 20%.

"These major pathological response rates are similar to those reported after neoadjuvant chemotherapy alone and highlight the need to explore additional approaches to enhance the efficacy of immune checkpoint blockade," the authors wrote, adding that evidence has suggested that SBRT may be a potent immunomodulator in NSCLC.

In this single-center randomized trial conducted from January 2017 to September 2020, Altorki and colleagues evaluated the use of SBRT to enhance the antitumor response associated with durvalumab in patients age 18 and older with early NSCLC and an Eastern Cooperative Oncology Group performance status of 0 or 1.

The study included 60 patients (mean age 70-71) who were assigned 1:1 to either durvalumab monotherapy or durvalumab plus SBRT; 26 patients in each group had their tumors resected. Demographic, clinical, and pathologic factors were well balanced between the groups.

The primary endpoint of the trial was the difference in major pathologic response, defined as the presence of 10% or fewer viable tumor cells in the primary tumor, between the two groups. Major pathologic response included complete pathologic response, which was defined as tumors without any viable tumor cells in the resected specimen and all sampled regional lymph nodes.

Altorki and colleagues observed a major pathologic response in 16 patients (53.3%) in the combination group compared with just two patients (6.7%) in the durvalumab-alone group. In addition, eight patients in the combination group had a complete pathologic response.

Three patients in the durvalumab/SBRT group had a second cycle of durvalumab withheld due to immune-related adverse events, including grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopenia.

Grade 3/4 adverse events occurred in 17% of patients in the monotherapy group and 20% of patients in the combination group, with the most frequent being hyponatremia (10% of patients in the monotherapy group) and hyperlipasemia (10% of patients in the combination group). Two patients in each group had serious adverse events (stroke and pulmonary embolism in the monotherapy group, and pancreatitis and fatigue in the combination group).

The preoperative combination of durvalumab and SBRT "resulted in a significant and clinically meaningful increase in the proportion of patients with a major or complete pathological response," the authors wrote. "In contrast with prevailing strategies, combining immunotherapy with stereotactic body radiotherapy might be associated with a more favorable safety profile and higher patient compliance than is currently reported using combinations with full-dose chemotherapy or chemoradiation."

Larger randomized trials are needed to validate this neoadjuvant strategy, they added.

In an commentary, Boris Sepesi, MD, and Tina Cascone, MD, PhD, both of the University of Texas MD Anderson Cancer Center in Houston, noted that studies have shown that neoadjuvant immune checkpoint strategies for patients with operative NSCLC, such as a combination of immune checkpoint inhibitors, or a checkpoint inhibitor combined with chemotherapy or SBRT, produce a much greater proportion of complete pathologic responses compared with chemotherapy alone.

"It is feasible that all of these combinations might become neoadjuvant therapeutic options in the future in appropriately selected patients," they wrote. Long-term results from randomized trials will determine how well systemic chemotherapy or SBRT combined with an immune checkpoint inhibitor will do in improving "gold-standard measures such as overall survival and event-free survival."

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