Pembrolizumab more effective after radiotherapy for NSCLC

Pembrolizumab improved survival in patients with non–small cell lung cancer who previously underwent radiation therapy, according to a secondary analysis of a phase 1 trial.

“Non–small cell lung cancer (NSCLC) is the leading cause of death from cancer both worldwide and in the [United States],” Narek Shaverdian, MD, of the department of radiation oncology at University of California Los Angeles, and colleagues wrote. “Despite clinical trials of anti–PD-1 and anti–PD-ligand therapies producing unprecedented positive clinical outcomes, responses are achieved in about 17% to 19% of unselected patients, highlighting the need to identify strategies to convert nonresponding patients to responders.”

The researchers assessed 98 patients assigned to the pembrolizumab group of the phase 1 KEYNOTE-001 trial, conducted at UCLA between May 22, 2012, and July 11, 2014. The trial’s primary outcome evaluated safety, side effects and efficacy of pembrolizumab.

The secondary analysis by Shaverdian and colleagues evaluated subgroups of patients according to those who had radiotherapy and those who had not. One patient was lost to follow-up, leaving 97 patients in the analysis. Median follow-up was 32.5 months.

Overall, 43% (n = 422) of patients underwent radiotherapy — 38 (39%) received extracranial radiotherapy and 24 (25%) received thoracic radiotherapy — before receiving pembrolizumab.

Those who had any radiotherapy showed a significantly longer median PFS than those with no history of radiotherapy (HR = 0.56 [95% CI, 0.34-0.91]; 4.4 months [95% CI, 2.1-8.6] vs. 2.1 months; [95% CI, 1.6-2.3]).

The same held true for patients who received previous extracranial radiotherapy compared with those who had not (HR = 0.5 [95% CI, 0.30-0.84]; PFS, 6.3 months [95% CI, 2.1-10.4] vs. 2 months [95% CI, 1.8-2.1]).

Patients who previously had any radiotherapy also had a longer OS than those without previous radiotherapy (HR = 0.58 [95% CI, 0.36-0.94]; median OS, 10.7 months [95% CI, 6.5-18.9] vs. 5.3 months [95% CI, 2.7-7.7]), as did those who had extracranial radiotherapy compared with those who did not (HR = 0.59 [95% CI, 0.36-0.96], median OS, 11.6 months [95% CI, 6.5-20.5] vs. 5.3 months [95% CI, 3-8.5]).

Sixty-three percent (n = 15) of those who had previous thoracic radiotherapy demonstrated pulmonary toxicity, compared with 40% (n = 29) without previous thoracic radiotherapy. Thirteen percent (n = 3) who had previous thoracic radiotherapy experienced treatment-related pulmonary toxicity compared with 1% (n = 1) who did not. One patient in each group experienced treatment-related pulmonary toxicity of grade 3 or worse.

“Because Shaverdian and colleagues’ study is a subgroup analysis of patients treated in a phase 1 trial at a single institution, no definitive conclusions can be drawn,” Dirk De Ruysscher, MD, PhD, of the department of radiation oncology at University Hospitals Leuven, Belgium, wrote in an accompanying editorial. “However, the results are completely in line with a wealth of consistent high-level preclinical data that suggests combining radiotherapy with a whole spectrum of immune interventions, including checkpoint inhibitors, leads to superior outcomes. If confirmed in randomized studies, radiotherapy might become an integral part of immunotherapy, similar to multiple drug combinations.” – by Andy Polhamus

Disclosure: Shaverdian reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. De Ruysscher reports no relevant financial disclosures.