Durvalumab with Radiotherapy Leads to Higher Response Rates in Early-Stage NSCLC

The combination of neoadjuvant durvalumab (Imfinzi) and stereotactic body radiotherapy appears to be a well-tolerated regimen that can improve pathological response over durvalumab alone in patients with early-stage non–small cell lung cancer (NSCLC), according to the results of a phase 2 study published in Lancet Oncology (NCT02904954).¹

Results from the trial indicated that 6.7% (n = 2) of patients in the durvalumab monotherapy cohort (n = 30; 95% CI, 0.8-22.1) and 53.3% (n = 16; 95% CI, 34.3-71.7) of those in the durvalumab plus radiotherapy cohort achieved a major pathological response (95% CI, 3.2-79.6; P < .0001). The experimental arm met the primary end point of the trial. Within the dual therapy cohort, 50% of patients (n = 8) experienced a pathologic complete response (CR).

“In this population of patients with operable clinical stages I–IIIA NSCLC, the preoperative combination of immune checkpoint blockade and radiotherapy to the primary tumour resulted in a significant and clinically meaningful increase in the proportion of patients with a major or complete pathological response,” the authors of the study wrote. “In contrast to prevailing strategies, combining immunotherapy with stereotactic body radiotherapy might be associated with a more favourable safety profile and higher patient compliance than is currently reported using combinations with full-dose chemotherapy or chemoradiation.”

PD-1/PD-L1 immune checkpoint inhibitors have made a significant impact on the treatment of patients with advanced NSCLC, which has prompted speculation as to whether the therapy may be effective at earlier stages of the disease, according to corresponding author Nasser K. Altorki, MD, of Weill Cornell Medicine - New York Presbyterian Hospital, and colleagues.^2-4

Although PD-L1 inhibitors such as nivolumab (Opdivo) have yielded major pathological responses as high as 45% in patients with early-stage disease (NCT02259621), the most recent findings have put the range closer to 14-20%, the authors said.^5-7

“These major pathological response rates are similar to those reported after neoadjuvant chemotherapy alone and highlight the need to explore additional approaches to enhance the efficacy of immune checkpoint blockade,” the investigators wrote.

Strategies to improve efficacy in this patient group include dual checkpoint inhibition and combining checkpoint inhibitors with chemotherapy.^8,9 However, there is also evidence to suggest that stereotactic body radiotherapy at doses of 3 fractions of 8 Gy might act as a potent immunomodulator and thereby boost the immune response of immune checkpoint blockade in patients with advanced NSCLC.¹⁰

“Radiotherapy enhances immune response through multiple proposed mechanisms, including induction of immunogenic cell death with release of neoantigens, upregulation of major histocompatibility complex and enhanced antigen presentation, activation of dendritic cells and enhanced antigen cross presentation, modulation of checkpoint expression, and increased T-cell infiltration into the tumour,” the authors wrote.

Investigators set out to determine whether stereotactic body radiotherapy could act as an immunomodulator, enhancing the effects of anti–PD-L1 agent, durvalumab, in patients with early-stage disease.

The phase 2, single-center, open-label trial screened 96 patients between January 2017 and September 2020, of whom 60 were enrolled. All patients received 2 cycles of durvalumab intravenously, at a dose of 1.12 g, 3 weeks apart. Additionally, the experimental arm received 3 consecutive daily fractions of 8 Gy radiotherapy to the primary tumor immediately prior to their first cycle of durvalumab. Those without systemic disease progression (n = 26 in each group, respectively) underwent surgical resection. The primary end point of the study was major pathological response of the primary tumor.

To enroll on the trial, patients needed to have a biopsy-proven diagnosis of stage I to IIIA, surgically resectable NSCLC. Additionally, patients were required to be aged 18 years or older with an ECOG performance status of 0 or 1 with adequate cardiopulmonary, hematologic, and other end organ function. Patients who had a concurrent invasive malignancy, a history of another invasive cancer within the past 3 years, active autoimmune disease, systemic immune suppression, or radiographic evidence of interstitial lung disease were not eligible for the trial.

The experimental arm had an even split of male and female patients who had a median age of 70.0 years (range, 64.2-74.0). The majority of patients had an ECOG performance status of 0 (77%). In total, 33% of patients were current smokers, 53% were former smokers, and 13% were never smokers. The majority of patients had stage IIIA disease (40%) and 43% had underwent invasive mediastinal staging. Moreover, 60% of patients had adenocarcinoma and 40% had squamous histology.

Additional data indicated that no patients achieved a radiographic CR, however, radiographic partial response (PR) was reported in 1 patient in the durvalumab monotherapy arm (3.3%; 95% CI, 0.1-17.2) and in 11 in the dual therapy arm (46.7%; 95% CI, 28.3-65.7%; P = .001). Additionally, 69% of patients who experienced a major or pathologic CR in the durvalumab plus radiotherapy cohort had a PR and 31% had radiographic stable disease. Moreover, the median time from the initiation of therapy to surgical resection was 5.3 weeks, which is less than half the time usually needed following preoperative chemotherapy or chemoradiotherapy.

In terms of safety, 3 patients in the experimental cohort did not undergo the second cycle of durvalumab due to immune-related adverse effects (AEs), including grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopenia. A total of 5 patients in the durvalumab monotherapy group and 6 patients in the dual therapy group experienced grade 3/4 AEs, the most common of which were hyponatremia and hyperlipasemia.

The investigators noted that the concept of radiotherapy alone cannot be dismissed, as it is responsible for the improved outcomes. However, deconvolution and gene expression data suggest that the combination of radiotherapy and checkpoint inhibitor made for a potent therapy.

“These findings argue in favor of a possible synergy between radiation and immune checkpoint blockade in potentiating the anti-tumor immune response,” they wrote.

The investigators stated the next step will be to conduct a similar study with a larger sample size, the process of which is already ongoing.

References

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7. Cascone T, William WN, Weissferdt A, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial. Nat Met. 2021;27(504-514). doi:10.1038/s41591-020-01224-2

8. Reuss J, Anagnostou V, Cottrell TR, et al. Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer. J Immunother Cancer. 2020;8(2):e001282. doi:10.1136/jitc-2020-001282

9. Provencio M, Nadal E, Insa A, et al. Neoadjuvant chemotherapy and nivolumab in resectable non-small-cell lung cancer (NADIM): an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2020;21(11):P1413-1422. doi:10.1016/S1470-2045(20)30453-8

10. Demaria S, Golden EB, Formenti SC. Role of local radiation therapy in cancer immunotherapy. JAMA Oncol. 2015;1(9):1325-1332. doi:10.1001/jamaoncol.2015.2756