A recently published phase 2 study in Lancet Oncology showed that the combination of neoadjuvant durvalumab with stereotactic body radiotherapy (SBRT) is safe and grants a nearly 55% major pathologic response rates among patients with early-stage non-small cell lung cancer (NSCLC) [1]. The response rate rose further up to 70% when patients with EGFR mutations were excluded from the analysis. Physician’s Weekly spoke with corresponding author Nassar Altorki, a Professor of Cardiothoracic Surgery and the Director of the Division of Thoracic Surgery at New York Presbyterian-Weill Cornell Medical Center in New York.

The results of a single center open-label phase 2 study (NCT02904954) published in The Lancet Oncology showed that a combination of neoadjuvant immunotherapy agent durvalumab and stereotactic body radiotherapy can improve major pathological response to 53.3% (n=16; 95% CI 34.3-71.7)  compared with 6.7%  in the durvalumab monotherapy cohort (n=30; 95% CI 0.8-22.1) in patients with early-stage NSCLC (P<0.0001) [1]. The experimental arm met the primary end point of the trial. Furthermore, of those receiving dual therapy with major pathological response, 50% of those (n=8) manifested a pathologic complete response (CR).

Between January 2017 and September 2020, 60 patients at New York-Presbyterian and Weill Cornell Medical Center were randomly assigned to receive durvalumab plus radiotherapy (n=30) or durvalumab alone (n=30); 2 cycles of durvalumab every 3 weeks (1.12g IV over 60 minutes). Radiotherapy was 8 Gy for 3 consecutive days immediately before the first cycle of durvalumab. All patients without systemic disease progression underwent surgical resection;  in each group that was 26 (87%) of 30 patients. The primary endpoint of major pathologic response in the primary tumor in the intention-to-treat population was met. The authors suggest that stereotactic body radiotherapy might be a potent immunomodulator in NSCLC.

Of the 16 patients in the durvalumab plus radiotherapy group with major pathological response, 8 (50%) had a complete pathologic response. No complete pathologic responses were observed in the durvalumab group. In the dual therapy group, responses were observed in 8 (44%) of 18 patients with adenocarcinoma and 8 (66%) of 12 with squamous cell carcinoma. Both responses in the durvalumab group occurred in patients with squamous cell carcinoma.

Immune-related adverse events  in 3 patients (10%) in the durvalumab plus radiotherapy group did not receive the second cycle of durvalumab (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopenia). Grade 3 and 4 adverse events occurred in 6 patients (20%) in the durvalumab plus radiotherapy group and 5 (17%) in the durvalumab group, with the most common being increased lipase (10%) in the durvalumab plus radiotherapy group and hyponatremia (10%) in the durvalumab group.

A total of 10 serious adverse events occurred in two patients (7%) in each group; 6 events were considered related to treatment, consisting of fatigue in two patients and adrenal insufficiency, pancreatitis, hyponatremia, and decreased platelet count in one patient each. There were no treatment-related deaths or deaths in the first 30 days after surgery.

The investigators concluded, “Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial.”

Physician’s Weekly spoke with Dr. Altorki about his team’s findings:

How do your data compare to previous strategies?

“First of all, I want to thank everybody who participated in this. Imagine, this is a collaboration between thoracic surgery, imaging, radiology, radiation oncology, medical oncology, and our Institute of Bioinformatics. A lot of people who came together around a good idea. And obviously I cannot thank the patients enough for –  60 patients walk in and their doctors say, listen, you have lung cancer, but I can give you something new and I do not really know if it is going to work or not. That is not an easy choice, and I admire each and every patient who chooses to join the trial.

In contrast to prevailing strategies, combining immunotherapy with stereotactic body radiotherapy might be associated with a more favorable safety profile and higher patient compliance than is currently reported using combinations with full-dose chemotherapy or chemoradiation. The interest here, of course, stems from the inroads that immune checkpoint inhibition made in advanced stage lung cancer, stage 3 and stage 4. Now that that has become the standard of care, sometimes with chemotherapy, sometimes alone, and the idea was, can we actually use it in early-stage disease?

The idea for setting up this particular study was that presumably there will be less immune suppressive mechanism operational at the earlier stage of disease. We thought that if you suppress whatever is there at that point, maybe you will get a better long-term survival. Furthermore, we hoped that if you activate the immune system that there may be a long lived effect on any micro-metastases as well.

That was the distinct rationale behind this study, as compared with prior data. The general concept is supported by some preclinical work in the lab in animal models of non-small cell lung cancer and there is work from Dr. Formenti was part of the group in breast cancer, all suggesting that you can enhance the response to single agent immune checkpoint inhibition in breast cancer, and now our data suggests that that trend holds true in lung cancer, as well.

We designed this trial in patients with early stage disease, randomized the patient to get single agent anti PD-L1 [durvalumab, in this case], compared to a combination of checkpoint inhibition with anti-PD-L1 therapy and what I like to call low-dose radiation, which here was 3 consecutive doses of 8Gy radiation. We measured pathological response, as a short-term metric, as an outcome measure for efficacy. Some people may argue that that is not a good enough metric, you will not be able to look at survival. I agree with that. But for a short term outcome, major pathological response would be an acceptable metric. We found that major pathological response occurred in roughly over 50% of the patients in the dual therapy arm compared with 7% of the patients in the single immune checkpoint inhibition [durvalumab] arm. Moreover, in the wild-type EGFR patient cohort, it probably approaches 70%. Even when you adjust for PD-L1 expression, which was a bit skewed between the two arms despite the randomization, the effect is large. I think that is something that is potentially very interesting to pursue in larger trials.

That is where we are focused now; on trying to expand this into a much larger trial using the same design, and hopefully in a multicenter setting.”

The safety profile was remarkable, can you comment?.

“It was indeed interesting, because people would have expected that you would get much worse side effects if you combine the two. But, in fact, we have had no peri-operative mortality and no difference in the complication rate between the two arms. Currently, we are trying to compile all the surgical adverse events and publish them because I think that is an important point to make and it does not increase the very operative model. If anything, our data seem to even favor the dual therapy, but more data is needed.”

What are the next steps?

“Well, you know, could we have run a bigger trial? Could we have had other centers participate? Yes. That was a challenge. Could we have stratified the patients for PD-L1 expression? Yes, we could have, but we tried to adjust for that, and I think the difference in response rate is still pretty big.

We feel that it is improbable that the measured response is all PD-L1-related. One supplementary approach was that the trial was a great opportunity for us to collect biomaterials from these patients. We also collected blood throughout the course of the treatment; we are looking at circulating tumor DNA, at changes in gene expression pathways, changes in the whole exome. We are really excited about trying to dissect the molecular and circulating biomarkers associated with this trial.

My other concern is trying to convince people that we need to actually compare this approach against what seems to be emerging as a new standard of care, which is a combination of chemotherapy and immunotherapy, and that has shown some spectacular results that were presented at ASCO recently [the 2021 American Society of Clinical Oncology Annual Meeting].

But I think if we compare the two, it may be good for patients if we can actually show that there may be similarities in response rates at least, and possibly even in survival.

 

Who would have thought that patients with stage 4 lung cancer would now be treated with single agent immune checkpoint inhibition if they have a PD-L1 over 50%? It is amazing. It really is. It turns everything on its head and in terms of the utility of local therapy as well.  The reduction of the antigen load in a patient with advanced disease may be an important part of how these people respond; that is  a hypothesis that needs to be tested. I think overall, it has been very good for patients.”

 

  1. ALtorki NK et al. Neoadjuvant durvalumab with or without stereotactic body radiotherapy in patients with early-stage non-small-cell lung cancer: a single-centre, randomised phase 2 trial. Lancet Oncol. 2021 Jun;22(6):824-835.

 

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