Compelling evidence that prior radiotherapy enhances the antitumor effects of immunotherapy in patients with non-small cell lung cancer (NSCLC) could expand the use of immunotherapy in this patient population.
Patients who had received any prior radiotherapy before being treated with pembrolizumab (Keytruda, Merck & CO) had a 44% significantly reduced risk for disease progression and a 42% significantly reduced risk for death compared to those who did not receive radiotherapy. These effects were even more pronounced for patients who received extracranial radiotherapy compared with those who did not.
These data, from a secondary analysis of the KEYNOTE-001 trial, were published online in Lancet Oncology.
"Our results provide clinical evidence to several preclinical studies that the combination of radiotherapy and immunotherapy is synergistic. In this analysis, the combination of radiation and pembrolizumab works better than pembrolizumab alone by prolonging progression-free survival [PFS] and overall survival [OS]," coauthor Narek Shaverdian, MD, told Medscape Medical News.
Dr Shaverdian is a radiation oncologist at the David Geffen School of Medicine, University of California, Los Angeles, and shares first authorship with his medical oncology colleague, Aaron E. Lisberg, MD, from the same institution.
"This study is significant since it is the largest clinical data set to date supporting the hypothesis that radiation therapy may improve the efficacy of PD-1 blockade in NSCLC," Dr Lisberg told Medscape Medical News.
"[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," writes Dirk De Ruysscher, MD, of the University Hospitals Leuven, Belgium, and the GROW Research Institute, Maastricht, the Netherlands, in an accompanying comment.
"[However, because this] study is a subgroup analysis of patients treated in a phase 1 study at a single institution, no definitive conclusions can be drawn," he adds.
The Single-Institution Study
The results are based on 98 patients with metastatic NSCLC who underwent treatment at the University of California, Los Angeles. The patients were enrolled in KEYNOTE-001. Radiotherapy records were available for these 98 patients. Collection of radiotherapy records was not required for enrolling in KEYNOTE-001, and therefore this is an analysis of patients at a single institution, the researchers explain.
One patient transferred to another institution for care, and the analysis is based on the remaining 97 patients. Patients in the study received pembrolizumab at three different dose levels.
The median age of the patients was 65 years. More than three fourths of the patients were PD-L1 positive. Approximately 40% of patients showed 1-49% expression, and 18% showed ≥50% expression.
Of 97 patients, 42 (43%) received any prior radiotherapy, and 38 (39%) received prior extracranial radiotherapy. Approximately 25% of patients received stereotactic body radiotherapy or stereotactic radiosurgery.
Any prior radiotherapy was provided in the nonmetastatic setting with a curative intent (26%) or in the metastatic setting for palliation of symptoms (64%) or both (10%). Radiotherapy was delivered at a median of 9.5 months before the first cycle of pembrolizumab.
For patients receiving any prior radiotherapy, treatment with pembrolizumab more than doubled PFS (4.4 months vs 2.1 months for those with no prior radiotherapy history) and 6-month PFS (49% vs 23% for no prior radiation).
Similarly, median OS was significantly higher for patients receiving any prior radiotherapy (10.7 months vs 5.3 months), as was 6-month OS (73% vs 43%)
The effects of radiation were more pronounced if patients received prior extracranial radiotherapy: higher median PFS (6.3 months vs 2.0 months) and 6-month PFS (54% vs 21%), and higher median OS (11.6 months vs 5.3 months) and 6-month OS (75% vs 45%).
In a multivariate analysis, only prior radiotherapy and extracranial radiotherapy were reported to significantly prolong PFS and OS.
"Pneumonitis is a side effect of thoracic radiation as well as treatment with pembrolizumab," Dr Shaverdian said. "Therefore, we looked specifically at patients with thoracic radiation." Any pulmonary toxicity was higher in patients who received thoracic radiotherapy (63% [15/24] vs 40% [29/73] for no previous thoracic radiotherapy); but grade 3-5 pulmonary toxicity was not significantly different between these two groups.
Significance of the Study
Dr Shaverdian explained that radiotherapy is known to potentiate several elements of the immune system, such as tumor recognition, antigen presentation, and T-cell activation, and that is why these results should not come as a surprise.
"Radiotherapy might convert a completely or partially non-immunogenic tumour into an immunogenic one," Dr De Ruysscher writes.
"Moreover, as PD-1/PD-L1 is upregulated by radiotherapy and radiotherapy can overcome resistance for PD-(L)1 inhibition, their combination is logical," he adds.
However, the best timing, sequencing, and dosing of these methods are not yet certain. "In preclinical models, the concurrent administration of anti-PD-(L)1 and radiotherapy was superior to sequential," Dr De Ruysscher comments.
In this report, pembrolizumab was provided sequentially — at least 4 months after prior radiotherapy — with a beneficial effect, Dr Shaverdian indicated.
"This study supports the ongoing evaluation of the combination of radiation therapy and PD-1/PD-L1 blockade and also raises the possibility that the beneficial synergy observed between these therapies may not be restricted to concurrent administration," Dr Lisberg told Medscape Medical News.
Dr De Ruysscher also noted that radiotherapy used as an immunologic intervention is different from radiotherapy used to kill all cancer cells without missing any. "The dose and fractionation to evoke an immune response could be dependent on, at present, largely unknown factors, but even at this point, the doses needed are probably substantially below those used radical radiotherapy," he writes. "Reduced radiotherapy doses will reduce toxicity further," he adds.
He concludes that radiotherapy might become an integral part of immunotherapy if these observations are confirmed in randomized studies.
"Checkpoint inhibition has brought so much hope to patients, and hopefully with combinations like radiation and immunotherapy, more patients can benefit and benefit longer," Dr Shaverdian told Medscape Medical News.
"Although these data suggest encouraging activity and warrant further trials, presently, radiotherapy should not be delivered with the sole purpose of improving the efficacy of immunotherapy outside of the context of clinical trials," write the study authors.
What about similar analyses in other tumor types? "These studies are certainly warranted," Dr Lisberg said. He emphasized that, to date, the experience with immune checkpoint blockade has been highly variable across tumor types. "Similar analyses in other tumor types will be important as we aim to identify the optimal immunotherapy treatment strategy for each individual tumor type," he said.
Indeed, several trials are testing just this hypothesis — in breast cancer (NCT02499367), bladder cancer (NCT02662062), glioblastoma (NCT02336165), cervical cancer (NCT02635360), head and neck cancer (NCT02289209), colorectal cancer (NCT02437071), and melanoma (NCT02562625).