The administration of pembrolizumab following locally ablative therapy (LAT) for oligometastatic non-small cell lung cancer (NSCLC) appears to lengthen progression-free survival (PFS) without impairing quality of life, according to the results of a recent study published in JAMA Oncology. LAT is comprised of surgery or stereotactic radiotherapy of all known tumor sites.
“Our understanding of which metastatic patients may benefit from curative therapies as opposed to palliative therapies is still evolving, but our data show promise that the addition of immunotherapy can bring make [sic] a difference,” said lead author, Joshua M. Bauml, MD, assistant professor, Department of Medicine, Division of Hematology-Oncology, Abramson Cancer Center, Perelman Center for Advanced Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
“Multiple trials have shown that if we use these definitive treatment techniques on all visible tumor sites, patients can end up with better outcomes than what they would get with chemotherapy alone, so our trial went one step further and added immunotherapy,” he added.
In this single-arm phase 2 trial of pembrolizumab therapy, 51 eligible patients (24 men; median age: 64 years) with oligometastatic NSCLC ( ≤ 4 metastatic sites) completed LAT to all known disease sites. Within 4-12 weeks of completing LAT, patients received intravenous pembrolizumab therapy: 200 mg every 21 days, for 8 cycles, with the capability to extend to 16 cycles in the absence of progressive disease or unintended toxic effects.
The primary endpoints in this study were PFS from the start of LAT (PFS-L), which began before enrollment in the trial, and PFS from the initiation of pembrolizumab therapy (PFS-P). The study was powered for comparison with historical data reflecting the first efficacy endpoint.
Of 51 patients enrolled, 45 received pembrolizumab. At the time of analysis, 24 patients had progressive disease or had died. Median PFS-L was 19.1 months (95% CI: 9.4–28.7 months) vs a historical median of 6.6 months (P = 0.005). Median PFS-P was 18.7 months (95% CI: 10.1–27.1 months).
In other results, overall mean (SE) survival rate at 12 months was 90.9% (4.3%), and 77.5% (6.7%) at 24 months. Programmed death ligand 1 (PD-L1) expression and CD8 T-cell tumor infiltration were not correlated with PFS-L. Lastly, pembrolizumab following LAT resulted in neither new safety signals nor decrease in quality of life.
Two randomized clinical trials have demonstrated that LAT for oligometastatic NSCLC may improve clinical outcomes. Unlike in the current study, however, other interventions utilized palliative chemotherapy before LAT. Moreover, designation of disease as oligometastatic occurred after chemotherapy, thus creating an “oligoremnant” population.
According to Dr. Bauml and coauthors, the design of these randomized clinical trials may have selected for patients either with more indolent disease trajectories or for tumors more sensitive to systemic therapy, given that any patient whose cancer progressed during systemic therapy would have been excluded from these trials.
The authors acknowledged the challenges inherent in treating this type of cancer. “Appropriate patient selection for LAT in patients with oligometastatic NSCLC is an evolving art. Counting the number of metastases present, for example, is likely a very crude surrogate marker of the underlying biology of the oligometastatic process. Some patients with [three] metastases have a truly oligometastatic phenotype, while others have a clinically undetectable polymetastatic state,” they wrote.
Although PD-L1 expression and CD8 T-cell tumor infiltration were not correlated with clinical outcomes in the current study, the authors acknowledged that their biopsy-based assays may have been underpowered. On the basis of results involving PD-L1 staining in the treatment of patients with stage IV NSCLC, the authors are intrigued by improved outcomes seen in PD-L1-positive cancer, and indicated that PD-L1 positivity should be considered as a stratification factor in future trials.
“The [overall survival] outcomes in our trial are preliminary and require further follow-up but appear favorable. This treatment approach warrants further testing in a randomized clinical trial,” concluded Dr. Bauml and colleagues.