The combination of the ATR inhibitor ceralasertib and the immune checkpoint inhibitor durvalumab has demonstrated notable survival rates and clinical benefits among patients who have advanced non–small cell lung cancer (NSCLC) with RAS mutations, according to data presented at the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer.1
Gary Middleton, MD
Patients with RAS mutations, specifically KRAS, achieved a survival advantage, with the Bayesian estimate of the durable clinical benefit rate approaching 40% and an objective response rate estimate of 13.1%. Furthermore, the median progression-free survival estimate for this subgroup was nearly 6 months, and the median overall survival was more than 2 years.
“The data confirm and extend the preliminary efficacy signals seen in HUDSON with this combination in immune checkpoint blockade–pretreated non–small cell lung cancer,” said lead study author Gary Middleton, MD, Director of the Birmingham Experimental Cancer Medicine Centres, Lead for the Birmingham CRUK Clinical Academic Training Program, and Chair of the National Cancer Research Institute Lung Cancer Clinical Studies Group, United Kingdom. “The outcome data in patients with RAS mutation, which have not been reported before, warrant further investigation,” he noted.
As Dr. Middleton explained, ceralasertib works by inhibiting ATR, an essential molecule for DNA repair, and has demonstrated efficacy for managing DNA malfunctions under conditions of replicated stress. Ceralasertib may resensitize immune checkpoint blockade–resistant melanoma to durvalumab therapy, said Dr. Middleton. Data from a phase II study of advanced or metastatic melanoma showed that 44% of patients with primary resistance to prior immune checkpoint blockade responded to the combination of ceralasertib and durvalumab,2 he added.
For this National Lung Matrix Trial (NLMT), Dr. Middleton and colleagues used a Bayesian adaptive design to screen targeted agents for signals of activity in molecularly defined cohorts. Ceralasertib was given in combination with durvalumab in arm J, cohorts J1 (RAS-mutant), and NAJ (RAS wild-type); durvalumab was given intravenously at 1,500 mg on day 1, with ceralasertib given orally at 240 mg twice daily on days 15 to 28 of each 28-day cycle.
Preliminary Efficacy Signals
The results of the trial were divided into two separate cohorts: one with KRAS mutations and the other with no KRAS mutations. For the KRAS-mutant cohort (n = 19), the durable clinical benefit rate was estimated at 39.7%, with an estimated objective response rate of 13.1%. The median progression-free survival for patients with KRAS mutations was 5.9 months, and the median overall survival was 25.0 months. Of note, 10 of the 19 patients with KRAS mutations remained on treatment for more than 9 months, said Dr. Middleton.
In comparison, the no KRAS mutation, or wild-type, cohort (n = 14) saw a durable clinical benefit rate of 30.5% and an objective response rate estimate of 4.5%. Progression-free survival in this group was 3.7 months, and overall survival was less than 1 year (11.6 months).
Determining the immunologic and molecular basis of response or resistance to ceralasertib plus durvalumab after prior immune checkpoint blockade is a translational priority.— Gary Middleton, MD
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According to Dr. Middleton, these findings confirm the results of previous research suggesting that RAS mutations may play a critical role in NSCLC and may potentially improve the results of personalized treatment plans. However, Dr. Middleton also emphasized the need for further research into therapeutic combinations after immune checkpoint blockade failure.
“Determining the immunologic and molecular basis of response or resistance to ceralasertib plus durvalumab after prior immune checkpoint blockade is a translational priority,” he concluded. “These results may help to improve options for patients with advanced non–small cell lung cancer.”
DISCLOSURE: Dr. Middleton reported no conflicts of interest.
1. Middleton G, Fletcher P, Savage J, et al: A phase II trial of ceralasertib and durvalumab in advanced non-small cell lung cancer with and without RAS mutations: Results of NLMT Arm J. 2023 World Conference on Lung Cancer. Abstract MA06.06. Presented September 10, 2023.
2. Kim R, Kwon M, An M, et al: Phase II study of ceralasertib (AZD6738) in combination with durvalumab in patients with advanced/metastatic melanoma who have failed prior anti-PD-1 therapy. Ann Oncol 33:193-203, 2022.