Can SBRT Improve Immunotherapy Outcomes in Metastatic NSCLC?

Stereotactic body radiotherapy (SBRT) administered prior to pembrolizumab resulted in a doubled response rate in patients with metastatic non–small-cell lung cancer (NSCLC), according to a new phase II study published in JAMA Oncology. However, this did not reach statistical significance, and a larger trial is likely needed to better assess the regimen’s efficacy.

“Targeting the programmed death–ligand 1 (PD-L1)/ programmed death 1 (PD-1) pathway with immune checkpoint inhibitors has produced long-lasting antitumor immune responses in a subset of NSCLC patients,” wrote study authors led by Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam. “Unfortunately, most patients with NSCLC do not benefit from this treatment owing to primary resistance, possibly because certain tumor antigens are not recognized.”

Some early research has suggested that SBRT could work synergistically with immunotherapy by increasing tumor antigen release, improving antigen presentation, and aiding T-cell infiltration in irradiated tumors. The PEMBRO-RT study randomized 76 patients with metastatic NSCLC to receive either pembrolizumab alone (40 patients) or following SBRT (3 doses of 8 Gy; 36 patients).

The median age in the study was 62 years, and 58% of the cohort were men. There were slightly more PD-L1-negative tumors in the control group that did not receive SBRT (66%) than in the SBRT group (50%). The median follow-up period was 23.6 months.

The objective response rate at 12 weeks was 18% without SBRT, and 36% with SBRT (P = 0.07). This difference was largely due to an improved response rate in PD-L1-negative patients: in the control group, PD-L1-negative patients had an overall response rate of 4%, compared with 22% in the SBRT group (P = 0.14). Previous receipt of radiotherapy did not influence the results substantially.

The median progression-free survival (PFS) in the control group was 1.9 months, compared with 6.6 months in the SBRT group, for a hazard ratio of 0.71 (95% CI, 0.42-1.18; P = 0.19). Though it represents a small group of patients, the PFS benefit only in the PD-L1-negative patients did reach statistical significance, with an HR of 0.49 (95% CI, 0.26-0.94; P = 0.03). No benefit was seen in PD-L1-positive patients.

The median overall survival was 7.6 months without SBRT, and 15.9 months with SBRT, for an HR of 0.66 (95% CI, 0.37-1.18; P = 0.16). Again, the benefit in overall survival was seen only in the PD-L1-negative subgroup, with an HR of 0.48 (95% CI, 0.24-0.99; P = 0.046).

Fatigue and pneumonia occurred more frequently in the SBRT group than in the control group. Grade 3–5 pembrolizumab-related adverse events occurred in 17% of the full cohort, with no difference between the groups.

“The PEMBRO-RT study is the first randomized trial, to our knowledge, to show an augmenting effect of SBRT on the response to PD-1 blockade in patients with metastatic NSCLC,” the authors concluded. “The results of this study are encouraging, and further evaluation in a larger phase 2/3 trial is recommended to confirm the findings.”

In an accompanying editorial, Joshua Walker, MD, PhD, of the Oregon Health & Science University in Portland, and Billy W. Loo, Jr. MD, PhD, of Stanford University School of Medicine, wrote that these results, along with other recent research, “provide a compelling rationale to design new trials” and examine whether radiotherapy along with immunotherapy “may even achieve cures.”

They noted that many unanswered questions remain in the field, including the significance of the number and volume of metastases, the timing of radiotherapy, and the use of various biomarkers. “At this stage of early excitement, it is all the more important to approach these questions through systematic clinical and translational research to maximize the promise that radiotherapy will throw its beams further toward cure through synergy with immunotherapy,” they wrote.