Low-dose radiotherapy in combination with the monoclonal antibody durvalumab and chemotherapy as neoadjuvant therapy was well tolerated in patients with potentially resectable stage III non–small cell lung cancer (NSCLC), according to a small study conducted in China and presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.1
“Although the standard treatment for most stage III NSCLC is chemoradiotherapy followed by durvalumab consolidation, neoadjuvant immunochemotherapy confers clinical benefits for potentially resectable disease.2 It has been shown that adding 45 Gy in 25 fractions of radiotherapy to durvalumab and chemotherapy yields high pathologic responses but with excess toxicity,” said Juan Li, MD, of the Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Affiliated Cancer Hospital of the University of Electronic Science and Technology of China.
Dr. Li acknowledged that neoadjuvant chemoimmunotherapy may be sufficient for patients with resectable disease. However, for “potentially resectable” disease, she believes patients need a safe and reliable means of downgrading tumors and achieving pathologic complete responses. “Our aim is to find the optimal radiotherapy dose,” she said.
Study Details
Dr. Li and her co-investigators designed a phase Ib study to assess the safety and tolerability of low-dose radiotherapy plus durvalumab and chemotherapy as neoadjuvant therapy for potentially resectable stage III NSCLC. The study’s 3 x 3 dose-escalation design used fixed-dose durvalumab and chemotherapy with dose-escalated radiotherapy as follows: 10 Gy in 5 fractions (cohort 1); 20 Gy in 10 fractions (cohort 2); and 30 Gy in 15 fractions (cohort 3), all with concurrent durvalumab at 1,500 mg and chemotherapy (260 mg/m2 of nab-paclitaxel plus carboplatin AUC = 5) on day 1 for two 21-day cycles. When questioned about the use of two and not four cycles of chemotherapy, Dr. Li explained that in China, a regimen of two cycles prior to surgery is the standard.
Surgery was scheduled within 4 to 6 weeks after the last dose of neoadjuvant therapy; this was followed by adjuvant durvalumab at 1,500 mg, every 4 weeks, for up to 1 year. The primary endpoints were safety and tolerability. The study enrolled nine patients; two-thirds had stage IIIB disease, and three-fourths had PD-L1 expression from 1% to 49%.
All Tumors Downsized
“All patients (100%) achieved tumor downstaging after planned neoadjuvant therapy, with a median interval to surgery after neoadjuvant therapy of 44 days,” Dr. Li reported. “No treatment-related surgical delays or deaths were observed, and the majority of adverse events were regarded as grade 1 or 2. None were grade 4.”
By cohort, the objective response rate was 66%, all partial responses. The pathologic complete response rate was 33%, including 33% in cohort 1, 0% in cohort 2, and 67% in cohort 3. Major pathologic responses were achieved in 67% of patients, including 33% in cohort 1, 67% in cohort 2, and 100% in cohort 3. R0 resections were possible for 78% overall, including 33% in cohort 1 and 100% in the other two cohorts, Dr. Li reported.
Tumor mutational burden values were higher in patients who responded or achieved complete or major pathologic responses than in patients with less of a response or stable disease, although these differences were not statistically significant. There were also no significant differences in response according to PD-L1 expression. At the data cutoff, event-free survival data were immature.
No dose-limiting toxicity (grade ≥ 3 radiation- or immune-associated pneumonia) was recorded. Grade 3 or 4 adverse events were reported in 33.3%, mostly leukopenia (22%). The optimal radiotherapy dosage was determined to be 30 Gy in 15 fractions.
“We know this is a very small sample size, and further research is necessary to validate the safety and efficacy of this approach,” Dr. Li added.
DISCLOSURE: Dr. Li reported no conflicts of interest.
REFERENCES
1. Li J, Li Q, Lu S, et al: Phase Ib trial of neoadjuvant low dose radiotherapy, chemotherapy, and durvalumab for potentially resectable stage III NSCLC. 2023 World Conference on Lung Cancer. Abstract MA16.05. Presented September 12, 2023.
2. Forde PM, Spicer J, Lu S, et al: Nivolumab + platinum-doublet chemotherapy (chemo) vs chemo as neoadjuvant treatment for resectable (IB-IIIA) non-small cell lung cancer in the phase 3 CheckMate 816 trial. Cancer Res 81(13 suppl):CT003, 2021.
