Sequencing radiation and immunotherapy drugs in the treatment of non-small cell lung cancer

Keytruda (pembrolizumab), Tecentriq (atezolizumab) and Imfinzi (durvalumab) have ushered in a new era of treatment for non-small cell lung cancer (NSCLC). But there remain many unanswered questions about how and when they should be used with other treatments, including tradition chemotherapy and radiation. Researchers in China set out to fill one of major knowledge gaps with a retrospective study comparing patients who were treated simultaneously treated with radiation and one of the immunotherapy drugs to those who were treated sequentially, first with radiation and then, within 42 days, with one of the immunotherapy drugs.

Corresponding author Feng-Ming (Spring) Kong, M.D., Ph.D., of The University of Hong Kong reported results in JAMA Oncology last week that showed in patients with newly diagnosed, advanced NSCLC, the overall survival was longer in those who that had been treated sequentially than those were treated simultaneously (20.3 months vs. 16.3 months). Advanced NSCLC was defined as cancer that had metastasized or had advanced locally to the point that it was unresectable.

In patients with refractory NSCLC, their results showed an overall survival advantage to treatment with immunotherapy after radiation but the difference did not meet the standards of statistical significance.

But as Kong and her colleagues show in a careful analysis, there are many qualifications and caveats to those overall findings. For example, in patients who did not receive chemotherapy, sequential treatment wasn’t associated with a survival advantage over simultaneously.Other subgroup analyses also added nuance. Sequential treatment was advantageous with respect to overall survival in patients who received high “definitive” radiation treatment, but not among those who received lower doses delivered for palliative purposes. Simultaneous treatment with radiation and an immunotherapy agent was associated with worse outcomes in patients with locally advanced cancer who had been treated with definitive radiation treatment. Sequential therapy was associated with survival benefit in those with locally advanced NSCLC but not among those whose NSCLC had metastasized.

Although chemotherapy was associated with notable differences in outcomes among the newly diagnosed patients, Kong and her colleagues didn’t find that it had any effect, positive or negative, from chemotherapy in the group with refractory NSCLC.

Kong and her colleagues conducted their study, dubbed OCEANUS, by combing through patient records in the Hong Kong Hospital Authority Clinical Data Analysis and Reporting System, a database that encompasses patients treated at 43 public hospitals. Using disease codes, they identified approximately 3,500 patients with NSCLC who had been treated with the immunotherapy drug between Jan 1, 2010, and Dec. 31, 2021. Approximately 10% (335) of those patients had been treated with radiation, 155 with newly diagnosed NSCLC and 180 with refractory disease. The majority (73.7%) of the patients in the study were male, and the median age was 64.

A retrospective study such as this has numerous limitations, which Kong and her colleagues acknowledge. There was a lack of molecular profiling data. The retrospective design adds doubt about inferences that can be drawn. Reasons for sequential treatment being preferable is outside the bounds of this study, but Kong and her colleagues offer a possible explanation: radiation therapy depletes lymphocytes, so delaying immunotherapy until after radiation is finished may allow some time for lymphocyte levels to recover.

Fong and her colleague avoid making any sweeping statements about how treatment regimens for NSCLC should change because of their findings. Instead, they wrote in the conclusion of the JAMA Oncology paper that the findings support a tailored approach to treatment with radiation and immunotherapy agents. They also mention a need for evidence from prospective trials “to refine optimal sequencing and combination approaches in advanced NSCLC.