Ceralasertib/Durvalumab Combo Shows Efficacy in NSCLC Following Anti–PD-L1 Therapy

Benjamin Besse, MD, PhD

The combination of ceralasertib plus durvalumab (Imfinzi)improved overall response rate in patients withnon‒small cell lung cancer (NSCLC) who progressed on an anti-PD-1/PD-L1 therapy, according to preliminary data from the HUDSON trial. Ceralasertib was superior for objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in all treatment groups.

“Preliminary signals of efficacy were observed in the patients who received ceralasertib plus durvalumab— potentially more pronounced in ATM selected patients,” said Benjamin Besse, MD, PhD, head of the Department of Medical Oncology and medical oncologist at Gustave Roussy, Villejuif, France. He presented findings from the ongoing phase 2 trial at the 2020 IASLC World Conference on Lung Cancer.

HUDSON (NCT03334617) is an open-label, multi-drug, biomarker-directed, multicenter umbrella study. All patients received durvalumab along with ceralasertib, olaparib (Lynparza), or oleclumab (MEDI9447). Ceralasertib is an oral inhibitor of ATR, ataxia-telangiectasia receptor (ATR). ORR was the primary endpoint.

Patients were segregated into biomarker matched (n = 85) or nonmatched groups. In the matched group, patients were assigned to treatment based on biomarker. Most patients had a history of smoking. The vast majority had nonsquamous disease.

The nonmatched group was further divided into patients with primary resistance (n = 74), defined as development of resistance within 6 months of immune checkpoint inhibitor treatment, and those with secondary resistance (n = 103) who received at least 6 months of immune checkpoint inhibitor treatment. Patients in this group had a fourth treatment option, durvalumab plus danvatirsen.

Treatments for patients in the biomarker matched group by homologous recombination repair (HRR), STK11, ATM, or 73H. Patients with HRR or STK11 were assigned to olaparib, patients positive for ATM were assigned to ceralasertib, and those positive for 73H were assigned to oleclumab. Those with targetable EGFR, ALK, ROS1, BRAF, MET, or RET alterations were excluded from the trial.

The median overall follow-up in the matched cohort ranged from 1.4 to 5.0 months. ORR was 11.1% in the ceralasertib ATM group compared with 9.5% in the olaparib HRR group, and 4.8% in the olaparib STK11 group. There was no response in the oleclumab 73H group.

The median overall follow-up in the primary resistance cohort ranged from 1.4 to 2.8 months. ORR was 10.5% in the ceralasertib group. There were no other treatment responses in this cohort.

The median overall follow-up in the acquired resistance cohort ranged from 2.6 months to 4.6 months. ORR was 8.3% in the ceralasertib group compared with 4.3% in the olaparib group, and 4.2% in the oleclumab group. There was no response in the danvatirsengroup.

The median PFS in the matched group was highest with ceralasertib at 7.43 months (95% CI, 3.45-9.46) followed by olaparib HRR (2.79 months; 95% CI, 1.48-5.26). The median PFS was less than 2 months for the oleclumab and olaparib STK11 groups.

In the primary resistance cohort, the median PFS was 4.24 months (95% CI, 1.94-6.77) in the ceralasertib group. Olaparib was next at 3.38 months (95% CI, 2.10-4.93). The median PFS was less than 2 months for danvatirsen and oleclumab.

In the acquired resistance cohort, ceralasertib produced a median PFS (4.96 months; 95% CI 3.55-5.98). The median PFS was 4.17 months (2.69-4.37) in the olaparib group, followed by danvatirsen (3.09 months; 95% CI, 2.83-6.14) and oleclumab (2.63 months; 95% CI, 1.64-2.79).

The median OS in the matched group was highest with ceralasertib at 15.80 months (95% CI, 11.01-not calculated) followed by olaparib HRR (9.63 months; 95% CI, 5.26-15.97). The median OS was 9.49 months (95% CI, 7.49-not calculated) in the oleclumab group and 5.75 months (95% CI, 5.29-10.84) in the olaparib STK11 group.

In the primary resistance cohort, the median OS was 11.60 months (95% CI, 10.45-not calculated). Olaparib was next at 7.16 months (95% CI, 4.93-10.28). The median OS was 7.06 months (95% CI, 4.90-7.06) in the oleclumab group and 6.01 months (95% CI, 3.55-6.51) in the danvatirsen group.

In the acquired resistance cohort, ceralasertib produced a median OS (17.38 months; 95% CI, 14.06-not calculated). The median OS was 15.51 months (95% CI, 8.80-19.75) in the olaparib group, followed by oleclumab (12.78 months; 95% CI, 6.14-12.78) and danvatirsen (11.20 months; 95% CI, 9.72-12.55).

Reference

Besse B. HUDSON: An open-label, multi-drug, biomarker-directed, phase 2 platform study in patients with NSCLC who progressed on anti-PD(L)1 therapy. Presented at: International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer; January 28-31, 2021; Virtual. Abstract OA07.08.