Neoadjuvant Durvalumab Plus Radiotherapy Elicits Major Pathological Response in Early-Stage NSCLC

Out of 30 patients, 16 demonstrated significant pathological responses and 8 achieved a complete pathological response.

The addition of neoadjuvant durvalumab (Imfinzi) to stereotactic body radiotherapy evoked major pathological responses compared with durvalumab alone in patients with early-stage non-small-cell lung cancer (NSCLC), according to results from a phase 2 trial.

In the single-center, open-label, randomized, controlled, phase 2 trial (NCT02904954), 16 out of 30 patients treated with neoadjuvant durvalumab following stereotactic body radiotherapy demonstrated significant pathological responses, including 8 patients who achieved a complete pathological response. In contrast, only 2 out of 30 patients in the durvalumab monotherapy group reported major pathological responses.

There were no dose reductions or interruptions reported within a cycle. Three patients (10%) in the neoadjuvant therapy group reported immune-related adverse events (AE). The second cycle of durvalumab for these patients was withheld as a response. These patients reported grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia.

Furthermore, 5 (17%) patients in the monotherapy group and 6 (20%) in the neoadjuvant therapy group reported grade 3 to 4 AEss, the most common being hyponatraemia and hyperlipasaeima.

No deaths, treatment-related or otherwise, were reported within the 30 days following surgery.

“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,” explained lead study author Nasser K Altorki, MD, Department of Cardiothoracic Surgery, and colleagues. “Additionally, in our current trial, the median time to surgical resection was only 5.3 weeks, calculated from the day therapy was initiated, which is considerably shorter than the 12 to 16 weeks commonly required for preoperative therapy using chemotherapy or chemoradiotherapy, without higher toxicity or any apparent reduction in activity, as measured by major pathological response.”

The trial screened 96 patients from NewYork Presbyterian and Weill Cornell Medical Center, both in New York City, and enrolled 60 participants between January 5,2017, and September 15, 2020. Selected patients qualified through a biopsy-proven diagnosis within clinical stage I to IIIA disease deemed surgically resectable with curative intent. To be eligible for the trial, patients were required to have an ECOG performance score of either 0 or 1, be 18 years or older, and to have sufficient cardiopulmonary, hematological, or other end organ function.

The participants were randomized 1:1 to receive either neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions) or durvalumab monotherapy. All patients were slated to receive 2 cycles of durvalumab 3 weeks apart at a dose of 1.12 g by intravenous infusion over 60 minutes.

In both groups, 26 (87%) patients had already had their tumors surgically resected.

The presence of 10% of fewer viable tumor cells in the primary tumor was considered a major pathological response. A tumor without any viable tumor cells in the resected lung cancer specimen and all sampled regional lymph nodes was considered a complete pathological response.

Secondary end points, which include 2-year disease-free survival for the whole cohort, defined as the time from randomization to tumor recurrence or death, will be reported on at a later date. Data has not yet sufficiently matured.

Altorki noted the study was limited by its small sample size. However, the results have established the value for a larger trial sample, and an ongoing, slightly larger trial (n = 90) by the Swiss Group for Clinical Cancer Research (NCT 04245514) will study the effect of neoadjuvant durvalumab that various doses and fractionations of radiotherapy have on major pathological responses.

Furthermore, he added, it is important to note that neither major pathological response nor complete response directly equate to survival. As a result, Altor recommends that ongoing large, randomized trials should seek to validate the relationship between pathological response and survival by assessing neoadjuvant chemotherapy plus immune checkpoint blockade with major pathological response as the primary end point.

Finally, since there was no monotherapy group treated solely through the stereotactic body radiotherapy, researchers were left to wonder what the effect would have been from 8 Gy radiotherapy alone. Current published literature on radiotherapy is limited and there is very little about the effect in major pathological response, they wrote.

“In summary, our results show that a neoadjuvant regimen of durvalumab combined with stereotactic body radiotherapy given as 3 fractions of 8 Gy to the primary tumor is well tolerated, safe, and associated with a significant improvement in major pathological response,” wrote Altorki and colleagues. “Enhancement of the anti-tumor immune response mediated by this regimen could potentially be driven by enhanced recruitment and activation of antigen-presenting cells and increased expression of MHC molecules. Efforts are ongoing to initiate a similar trial with a larger sample size.”


Altorki NK, McGraw TE, Borczuk AC, 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; 22: 824–35.