The past decade has witnessed the advent of modern immunotherapy. Monoclonal antibodies that target PD-1, PD-L1 and other immune checkpoints are now approved for treating a wide range of tumour types, including non-small cell lung cancer (NSCLC).

Alongside, advances in planning and delivery of high-dose radiotherapy have led to the acceptance of stereotactic ablative radiotherapy – also known as stereotactic body radiotherapy (SBRT) – as an effective primary treatment for early-stage NSCLC patients who are unsuitable for surgery.

There’s also a growing body of preclinical data describing the synergy between ablative radiotherapy and immunotherapy. This has led to a growing interest in discovering clinically effective combinations of the two treatments. However, the clinical promise of potentiating immunotherapy with ablative radiation or vice versa has so far remained largely unrealized.

Now, two newly published JAMA Oncology papers have demonstrated the potential of combining ablative radiotherapy with PD-1 checkpoint blockade in patients with NSCLC.

Alternative approaches

Researchers from the Abramson Cancer Center at the University of Pennsylvania have assessed the effect of treating metastatic NSCLC patients with the immunotherapy drug pembrolizumab following locally ablative therapy. They found that this combination almost tripled the median progression-free survival (PFS) compared with the historical average (JAMA Oncol. 10.1001/jamaoncol.2019.1449).

For this study, 45 NSCLC patients with four or fewer metastatic sites underwent locally ablative therapy (such as surgery or stereotactic radiotherapy) and then received pembrolizumab 4–12 weeks after therapy completion. The median PFS from the start of ablative therapy was 19.1 months, significantly greater than the historical median of 6.6 months. The median PFS from the start of pembrolizumab therapy was 18.7 months. Importantly, the treatment did not lead to any new safety issues or decreases in patient quality-of-life.

“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 a difference,” says lead author Joshua Bauml.

The researchers note that the approach needs further study and that they are still evaluating the impact of this combination on overall survival. However, they point out that the accrual of 45 patients represents a significant number for a single site and shows that a larger, multicentre, randomized controlled trial to test this approach is feasible.

In the second study, a team headed up at the Netherlands Cancer Institute examined whether SBRT can enhance the effect of immune checkpoint inhibition, by increasing response in non-irradiated lung cancer lesions (JAMA Oncol. 10.1001/jamaoncol.2019.1478).

For this multicentre, phase 2 trial, the researchers randomized 76 patients with recurrent metastatic NSCLC to receive either pembrolizumab alone (control arm) or pembrolizumab given within a week of completion of SBRT, which entailed three 8 Gy doses to a single tumour site (experimental arm).

The overall response rate at 12 weeks was 18% in the control arm (40 patients) versus 36% in the experimental arm (36 patients). Median progression-free survival was 1.9 months versus 6.6 months and median overall survival was 7.6 months versus 15.9 months, for control and experimental groups, respectively. The researchers observed no increase in treatment-related toxic effects in the experimental arm.

“The results of this study are encouraging,” the authors concluded. “Further evaluation in a larger phase 2/3 trial is recommended to confirm the findings and elucidate the processes by which SBRT may activate non-inflamed NSCLC tumours toward an inflamed tumour microenvironment, rendering them receptive to immune checkpoint inhibition.”

Future promise

In an accompanying invited commentary, Joshua Walker from Oregon Health & Science University and Billy W Loo Jr from Stanford University School of Medicine highlight the significance of the two papers. “Although not conclusive, these studies appear to provide support for the complementary hypotheses tested in these trials of novel treatment of metastatic NSCLC,” they write.

Loo and Walker note that the combination treatment appears very well tolerated in both studies, a critical finding given concerns regarding possible increased immune-related adverse events when combining SABR with immunomodulation. They also describe the many unanswered questions that must be addressed in future studies, including the significance of metastatic disease burden, timing, the use of biomarkers and many others (JAMA Oncol. 10.1001/jamaoncol.2019.1448).

“At 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,” they state.