Durvalumab Combos Yield Better Reponses Than Monotherapy Treatment in Unresectable Stage III NSCLC

Patients with unresectable stage III non-small cell lung cancer derived the most benefit from durvalumab when combined with either oleclumab or monalizumab vs durvalumab alone.

Durvalumab (Imfinzi) combined with oleclumab (MEDI9447) or monalizumab (formerly IPH2201) produced improvements in objective response rate (ORR) and progression-free survival (PFS) compared with durvalumab monotherapy among patients with unresectable stage III non-small cell lung cancer (NSCLC), according to findings from the phase 2 COAST study (NCT05221840),

Investigators reported a numerically improved confirmed ORR of 30.0% (n = 18/60; 95% CI, 18.8%-43.2%) for patients receiving durvalumab plus oleclumab, 35.5% (n = 22/62; 95% CI, 23.7%-48.7%) for those receiving durvalumab plus monalizumab, and 17.9% (n = 12/67; 95% CI, 9.6%-29.2%) for the durvalumab monotherapy cohort.

Additionally, both the oleclumab (hazard ratio [HR], 0.44; 95% CI, 0.26-0.75) and monalizumab (HR, 0.42; 95% CI, 0.24-0.72) combinations yielded prolonged PFS compared with durvalumab alone. The 12-month PFS rates were 72.7% (95% CI, 58.8%-82.6%) for durvalumab and monalizumab, 62.6% (95% CI, 48.1%-74.2%) for durvalumab plus oleclumab, and 33.9% (21.2%-47.1%) for durvalumab monotherapy.

A total of 189 patients were randomly assigned 1:1:1 to either receive durvalumab monotherapy (n = 66), durvalumab with oleclumab (n = 59), or durvalumab plus monalizumab (n = 61). Patients in the monotherapy arm received 1500 mg of durvalumab every 4 weeks on the first day of each treatment cycle. Patients in the experimental arm were given the same durvalumab backbone along with either 3000 mg of oleclumab every 2 weeks on days 1 and 15 for the first 2 cycles, then every 4 weeks thereafter or 750 mg of monalizumab every 2 weeks on days 1 and 15 of each treatment cycle. All treatment regimens were administered for up to 12 months or until disease progression or unacceptable toxicity.

The primary end point of the study was investigator-assessed ORR based on RECIST v1.1 criteria. Secondary outcome measures included safety, duration of response, disease control rate, PFS as per RECIST v1.1 criteria, 12-month PFS rate, and overall survival.

The study indicated that baseline patient characteristics were comparable across all cohorts. The median age in the overall population was 65 years (range, 37-87), and roughly half of patients had squamous cell histology (42.9%). In total, 45.5% of patients had unresectable, stage IIIA disease and 54.5% had stage IIIB/C disease. Tumoral PD-L1 expression was available in 68.7% of patients in the durvalumab monotherapy arm along with 50.0% of those in the durvalumab plus oleclumab cohort and 51.6% of those receiving durvalumab plus monalizumab.

An exploratory PFS subgroup analysis highlighted the efficacy of both durvalumab combination regimens vs single-agent durvalumab regardless of several factors, including histology, previous treatment with a platinum-based therapy, and ECOG performance status. Investigators also observed benefit in the combination arms in those with unknown PD-L1 statuses or those with an expression of 1% of more.

Grade 3 or more treatment-emergent adverse effects (TEAEs) were seen in 39.4% of patients in the durvalumab monotherapy arm, 40.7% of those receiving durvalumab with oleclumab, and 27.9% of those receiving durvalumab and monalizumab. In the oleclumab arm, common grade 3 or higher TEAEs included pneumonia (6.8%), lymphocyte count decrease (6.8%), cough (1.7%), and dyspnea (1.7%). Common high-grade toxicities in the monalizumab arm included dyspnea (1.6%), pneumonitis (1.6%), pneumonia (1.6%), and amylase increase (1.6%). In the single-agent arm, the most common grade 3 or higher TEAEs were pneumonia (9.1%), dyspnea (3.0%), back pain (3.0%), and lymphocyte count decrease (3.0%). In total, 10.6% of the durvalumab monotherapy arm, 6.8% of those in the oleclumab arm, and 4.9% in the monalizumab cohort died within 90 days of their last dose of study drug.

Reference

Herbst RS, Majem M, Barlesi F, et al. COAST: An open-label, phase II, multidrug platform study of durvalumab alone or in combination with oleclumab or monalizumab in patients with unresectable, stage III non–small-cell lung cancer. J Clin Oncol. 2022;40(29):3383-3393. doi:10.1200/JCO.22.00227