medwireNews: Data from two phase II studies published in JAMA Oncology lend support to the sequential use of local ablative therapy and PD-1 blockade in patients with metastatic non-small-cell lung cancer (NSCLC).
One trial investigated the use of any modality of local ablation before the administration of pembrolizumab 200 mg every 3 weeks in individuals with oligometastatic disease, while the other compared the outcomes of metastatic NSCLC patients who did versus did not receive stereotactic radiotherapy to a single lesion before treatment with pembrolizumab at the same dose.
Writing in an accompanying commentary, Joshua Walker (Oregon Health & Science University, Portland, USA) and Billy Loo Jr (Stanford University, California, USA) say that the findings are “not conclusive,” but together with results from previous studies, “provide a compelling rationale” to investigate the combination of stereotactic radiotherapy and immune checkpoint inhibition in larger, multicenter, randomized controlled trials.
They caution, however, that “[a]t this stage of early excitement, it is all the more important to approach these questions through systematic clinical and translational research to maximize the promise that radiotherapy will throw its beams further toward cure through synergy with immunotherapy.”
The team led by Joshua Bauml (University of Pennsylvania, Philadelphia, USA) enrolled 45 patients with no more than four metastatic lesions who had received local ablative therapy, most commonly surgery (67%), stereotactic radiotherapy (67%), chemotherapy (53%) and chemoradiotherapy (51%).
Treatment with 8–16 cycles of pembrolizumab – initiated between 4 and 12 weeks after completion of local ablative therapy – led to a median progression-free survival (PFS) from the start of local ablation of 19.1 months, which was significantly longer than the historic median of 6.6 months.
The co-primary endpoint of median PFS assessed from the start of pembrolizumab therapy was 18.7 months.
The overall survival (OS) rates at 12 and 24 months were 90.9% and 77.5%, respectively, and the median duration was 41.6 months, but the study authors point out that “this estimate may be an artifact due to censoring and a single late event,” and highlight the need for additional follow-up for confirmation.
The team did not “identify any clinical variables that were significantly associated with clinical outcomes,” but there was an indication of improved PFS among individuals who tested positive for PD-L1 expression versus those who were negative (24-month PFS rate, 69.3 vs 38.1%).
In the other study, the objective response rate (ORR) was 36% among the 36 participants who were randomly assigned to receive three 8 Gy doses of stereotactic radiotherapy before pembrolizumab, and was 18% for the 40 patients who received the PD-1 inhibitor alone.
Although the ORR doubled with the addition of radiotherapy, “the results did not meet the study’s prespecified end point criteria for meaningful clinical benefit,” say Willemijn Theelen, from the Netherlands Cancer Institute in Amsterdam, and fellow PEMBRO-RT investigators.
The median durations of PFS and OS were likewise numerically, but not significantly, higher in the stereotactic radiotherapy than control group, at 6.6 versus 1.9 months and 15.9 versus 7.6 months, respectively.
Interestingly, survival outcomes were significantly improved with the addition of stereotactic radiotherapy to pembrolizumab in the subgroup of patients with PD-L1-negative tumors, with hazard ratios of 0.49 and 0.48 for PFS and OS, respectively. No such benefit was observed for the PD-L1-positive subgroups.
“These results suggest that a larger trial is necessary to determine whether radiotherapy may activate noninflamed NSCLC toward a more inflamed tumor microenvironment,” concludes the team.
Of note, neither study identified any new safety signals with the combination of local ablative therapy and pembrolizumab.
In the Bauml et al study, there were five cases of pneumonitis, of which two were of grade 3 and one was grade 4. They did not observe any other grade 4 or 5 adverse events that were related to treatment. And patient-reported quality of life remained comparable to that reported at baseline throughout the course of pembrolizumab treatment.
Similarly, there was no significant difference between the study arms of the PEMBRO-RT trial with regard to treatment-related side effects of grade 3–5.
“These data are critical given concerns in the field regarding possible increased immune-related adverse events when combining [stereotactic radiotherapy] and immunomodulation,” emphasize the commentators.
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JAMA Oncol 2019; doi:10.1001/jamaoncol.2019.1449
JAMA Oncol 2019; doi:10.1001/jamaoncol.2019.1478
JAMA Oncol 2019; doi:10.1001/jamaoncol.2019.1448