From the Journals

Combo RT/pembro may show synergy in NSCLC

View on the News

Early studies promising

Over the last 20 years, significant advances have been made in the development of ablative radiotherapy and immunotherapy, particularly in the oncology setting. More recently, combination radiation therapy (RT) and immuno-oncology (IO) approaches have emerged, and the body of evidence for this novel treatment strategy continues to grow.

Recent studies have suggested that combined RT/IO therapy may confer survival benefit for patients with non–small cell lung cancer (NSCLC). Limitations of these studies include design, which have been largely case reports and single-center studies. The recent findings reported by Bauml et al. and Theelen et al. provide insight into the combined use of immune checkpoint blockade and radiotherapy in patients with NSCLC.

While the study by Dr. Theelen and colleagues did not reach its prespecified endpoint, the findings showed promise in some patient subpopulations. Dr. Bauml and colleagues reported favorable survival outcomes in their study, notably progression-free survival, following radical local therapy, when compared with historical outcomes. Intriguingly, the combination approach in both studies was well tolerated, with little to no grade 3-5 toxicities reported.

Taken together, these data constitute early evidence indicative of possible synergy between both therapies. In response, well-designed phase 3 studies are warranted to further explore these effects.

Joshua Walker, MD, PhD, is affiliated with Oregon Health & Science University in Portland. Billy W. Loo Jr., MD, PhD, is with Stanford (Calif.) University. Dr. Walker reported no conflicts of interest. Dr. Loo reported receiving research support from Varian Medical Systems and is a board member of TibaRay. These comments are adapted from their editorial (JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1448 ).



Combination radiotherapy and pembrolizumab may improve clinical outcomes by means of synergy in the treatment of patients with non–small cell lung cancer (NSCLC), according to results from two recent studies.

“The best way to combine immunotherapy with ablative therapies in the curative setting is an area of active investigation,” wrote Joshua M. Bauml, MD, of the University of Pennsylvania, Philadelphia, and colleagues.

Dr. Bauml and colleagues recently reported the results of a phase 2 study exploring the addition of pembrolizumab following the completion of locally ablative therapy in patients with oligometastatic NSCLC in JAMA Oncology.

The single-arm trial included 51 patients who received intravenous pembrolizumab (200 mg every 21 days) for a total of 8 cycles within 4-12 weeks of local ablative therapy completion. Study participants were administered locally ablative therapy to all recognized sites of malignancy.

The researchers measured two primary efficacy outcomes: progression-free survival (PFS) from the initiation of ablative therapy and the PFS from initiation of pembrolizumab. Secondary endpoints were safety, quality of life, and overall survival (OS).

Among patients who received pembrolizumab after ablative therapy, the median PFS was 19.1 months (95% CI, 9.4-28.7 months), which was significantly longer than the historical outcome (median PFS, 6.6 months; P = .005). In addition, the 24-month OS was 77.5%. With respect to safety, no decrease in quality of life or new safety signals were reported in the study.

One key limitation of the study was the single-arm design. As a result, distinguishing the effects of pembrolizumab over ablative therapy alone is not possible with the present data.

“This study is the first to show improved outcomes for immunotherapy after locally ablative therapy in patients with oligometastatic NSCLC,” Dr. Bauml and his colleagues wrote.

In another phase 2 trial (PEMBRO-RT study) reported in the same issue, Willemijn S.M.E. Theelen, MD, of the Netherlands Cancer Institute in Amsterdam and colleagues examined the use of pembrolizumab after stereotactic body radiotherapy or pembrolizumab alone in patients with recurrent metastatic NSCLC.

“This study evaluates whether stereotactic body radiotherapy enhances the effect of immune checkpoint blockade,” wrote Dr. Theelen and colleagues.

The PEMBRO-RT study included 76 patients with recurrent metastatic NSCLC who were randomized to pembrolizumab following radiotherapy or pembrolizumab alone. Intravenous pembrolizumab was administered at 200 mg/kg every 3 weeks, with the first dose given within 7 days after completion of radiotherapy.

The primary outcome was the overall response rate (ORR) at 12 weeks. Secondary outcomes included OS, PFS, and safety.

Among patients who received pembrolizumab after radiotherapy versus pembrolizumab alone, the ORR at 12 weeks was 36% and 18%, respectively (P = .07). In addition, the median PFS and OS were not statistically significant (P = .19 and P = .16, respectively).

“Positive results were largely influenced by the PD-L1–negative subgroup, which had significantly improved progression-free survival and overall survival,” the researchers wrote.

With respect to safety, no differences in grade 3-5 adverse effects were observed between the treatment groups. In addition, no significant differences were seen in pulmonary toxicities.

One key limitation of the study was the lack of information regarding optimal radiotherapy dosing and schedule.

“The results of this study are encouraging, and further evaluation in a larger phase 2/3 trial is recommended,” Dr. Theelen and colleagues wrote.

Further studies are needed to fully understand the links between combination radiotherapy and pembrolizumab in patients with NSCLC.

The study by Dr. Bauml and colleagues was funded by the Abramson Cancer Center and Merck & Co. The authors reported financial affiliations with Amgen, AstraZeneca, Bristol-Myers Squibb, Celgene, Janssen, Takeda, and several others.

The study by Dr. Theelen and colleagues was funded by Merck Sharp & Dohme. The authors reported financial affiliations with AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Sharp & Dohme, Roche, Takeda, and several others.

SOURCE: Bauml JM et al. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1449. Theelen WSME et al. JAMA Oncol. 2019 Jul 11. doi: 10.1001/jamaoncol.2019.1478.

Next Article: