Pembrolizumab After Stereotactic Body Radiotherapy in Advanced NSCLC
In a Dutch phase II study reported in JAMA Oncology, Theelen et al found that although use of stereotactic body radiotherapy prior to pembrolizumab increased the objective response rate vs pembrolizumab alone in metastatic non–small cell lung cancer (NSCLC), the difference did not meet study criteria for clinical benefit, and the greatest benefit was observed in patients with programmed cell death ligand 1 (PD-L1)-negative tumors.
As stated by the investigators, high-dose radiotherapy can result in increased tumor antigen release and T-cell infiltration that may augment the effects of checkpoint inhibitor therapy.
Study Details
The trial was conducted at three sites in the Netherlands and included 76 evaluable patients. They were randomly assigned between July 2015 and March 2018 to receive pembrolizumab 200 mg/kg every 3 weeks alone (n = 40) or after radiotherapy with three doses of 8 Gy to a single tumor site (n = 36) until radiographic progression, unacceptable toxicity, or a maximum of 24 months.
The primary outcome measure was improvement in overall response rate at 12 weeks from 20% in the pembrolizumab group to 50% in the radiotherapy/pembrolizumab group with P < .10.
Response Rates
The overall response rate at 12 weeks was 36% in the radiotherapy/pembrolizumab group vs 18% in the pembrolizumab group (P = .07). Median progression-free survival was 6.6 months vs 1.9 months (hazard ratio [HR] = 0.71, P = .19) and median overall survival was 15.9 months vs 7.6 months (HR = 0.66, P = .16).
Among patients with PD-L1–negative tumors (tumor proportion score = 0), response was observed in 4 (22%) of 18 patients in the radiotherapy/pembrolizumab group vs 1 (4%) of 25 in the pembrolizumab group. Significant progression-free survival (HR = 0.49, P = .03) and overall survival (HR = 0.48, P =.046) benefits of radiotherapy/pembrolizumab were observed only in this subgroup.
Adverse Events
Among adverse events of any grade, fatigue and pneumonia were more common in the radiotherapy/pembrolizumab group—51% vs 27% of patients and 26% vs 8%, respectively. No differences in pembrolizumab-related grade ≥ 3 toxicities were observed between groups.
The investigators concluded, “Stereotactic body radiotherapy prior to pembrolizumab was well tolerated. Although a doubling of [overall response rate] was observed, the results did not meet the study’s prespecified endpoint criteria for meaningful clinical benefit. Positive results were largely influenced by the PD-L1–negative subgroup, which had significantly improved progression-free survival and overall survival. These results suggest that a larger trial is necessary to determine whether radiotherapy may activate noninflamed NSCLC toward a more inflamed tumor microenvironment.”
Willemijn S.M.E. Theelen, MD, of the Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was funded by Merck Sharp & Dohme. For full disclosures of the study authors, visit jamanetwork.com.
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