Ceralasertib/Durvalumab Demonstrates Efficacy in RAS-Mutant Advanced NSCLC Post Immune Checkpoint Blockade

Treatment with the combination of ceralasertib (AZD6738) and durvalumab (Imfinzi) elicited preliminary efficacy signals in patients with advanced non–small cell lung cancer (NSCLC) with and without RASmutations who received prior treatment with immune checkpoint blockade, according to data from cohort J1 and cohort NAJ of the phase 2 National Lung Matrix trial (NCT02664935) presented at the 2023 IASLC World Conference on Lung Cancer.¹

Findings showed that evaluable patients in cohort J1 with RAS mutations who received prior immune checkpoint inhibitors (n = 19) experienced a durable clinical benefit (DCB) rate of 39.7% (95% CI, 20.3%-61.6%) and an overall response rate (ORR) of 13.1% (95% CI, 3.2%-31.7%). In evaluable patients without actionable RAS mutations in cohort NAJ (n = 14), the DBC rate and ORR were 30.5% (95% CI, 11.8%-55.1%) and 4.5% (95% CI, 0.2%-21.8%), respectively.

“These data confirm and extend the preliminary efficacy signals seen in the [phase 2] HUDSON trial [NCT03334617] with [the ceralasertib/durvalumab] combination in immune checkpoint blockade–pretreated NSCLC,” lead study author Gary Middleton MB, BS, MD, FRCP, said in a presentation of the data. Middleton is a professor of medical oncology in the Institute of Immunology and Immunotherapy, an honorary consultant oncologist at University Hospitals Birmingham, and director of the Birmingham Experimental Cancer Medicine Centre in the United Kingdom.

Ceralasertib represents a highly selective and potent inhibitor of ATR, which serves as a pivotal sensor for detecting DNA damage and as a crucial activator of the DNA damage checkpoint. In previously reported data from a phase 2 trial (NCT03780608) evaluating ceralasertib plus durvalumab in patients with advanced/metastatic melanoma who progressed after prior anti–PD-1 therapy, the combination elicited an ORR of 31.0% and a disease control rate of 63.3%, indicating that ceralasertib could re-sensitize immune checkpoint blockade–resistant melanoma to durvalumab.²

The National Lung Matrix trial was a multi-drug, genetic marker–directed, non-comparative, multicenter, multi-arm phase 2 study designed to evaluate different experimental targeted drugs in patients with NSCLC stratified by multiple prespecified actionable target biomarkers.³

In all cohorts, patients at least 18 years of age were required to have histologically or cytologically confirmed stage III or stage IV NSCLC with measurable disease per RECIST v1.1 and adequate hematologic, hepatic, and renal function.

The prior treatment requirements were as follows:

• Patients who refused any standard-of-care first-line therapy
• Patients who exhausted all standard-of-care therapy that the treating oncologist thought was appropriate
• Patients who have progressed after surgical resection and adjuvant therapy
• Patients who relapsed within 6 months of completion of definitive chemoradiation

Patients were excluded if they had previous symptomatic brain metastases or spinal cord compression, unless they received adequate treatment, had no evidence of progression or symptoms, and had no requirement for steroid treatment in the 28 days prior to the start of study treatment. Those with asymptomatic brain metastases were allowed if they did not require immediate radiotherapy or surgical intervention, and had no requirement for steroid treatment in the 28 days before enrollment.

In cohort J1, patients needed to have KRAS mutations, a successful test result for STK11/LKB1, and a core gene pass rate of more than 90%.1 Cohort NAJ was comprised of patients who had no actionable genetic changes that would have qualified them for other trial arms and a core gene pass rate of more than 90%.

Patients in cohorts J1 and NAJ received oral ceralasertib at 240 mg twice per day from day 15 to day 28 of each 28-day cycle plus intravenous durvalumab at 1500 mg on day 1 of every cycle.

Among 20 patients enrolled in cohort J1, 19 received prior immune checkpoint blockade. Fourteen of 18 patients in cohort NAJ were previously treated with immune checkpoint blockade.

The primary end points were confirmed ORR per RECIST v1.1 criteria and DCB rate, defined as progression-free survival (PFS) at more than 22 weeks. Secondary end points included best percent change in tumor lesion sum, PFS, and overall survival (OS).

Additional data from cohort J1 showed that patients previously treated with immune checkpoint blockade achieved a median PFS was 5.87 months (95% CI, 3.76-9.87) and a median OS of 25.0 months (95% CI, 12.8-59.3). In cohort NAJ, patients who received prior immune checkpoint blockade experienced a median PFS of 3.58 months (95% CI, 2.18-6.93) and a median OS of 11.6 months (95% CI, 6.6-23.4).

“The outcome data in patients with RAS mutations had not been reported before, and this warrants further investigation. [However], understanding who benefits from these combinations after immune checkpoint blockade failure is critically important, and that goes for this combination as much as any other combination,” Middleton concluded.

Reference

1. Middleton G, Fletcher P, Mehmi M et al A phase II trial of ceralasertib and durvalumab in advanced non-small cell lung cancer (NSCLC) with and without RAS mutations: results of NLMT arm J. Presented at: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract MA06.06.
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. 2022;33(2):193-203. doi:10.1016/j.annonc.2021.10.009
3. National Lung Matrix trial: multi-drug phase II trial in non-small cell lung cancer. ClinicalTrials.gov. Updated May 11, 2023. Accessed October 10, 2023. https://www.clinicaltrials.gov/study/NCT02664935