Oleclumab/Monalizumab With Durvalumab Improves Response and PFS Over Monotherapy in NSCLC

Oleclumab (MEDI 9447) and monalizumab (IPH2201) each separately combined with durvalumab (Imfinzi) revealed favorable objective response rates (ORR) and progression-free survival (PFS) compared with durvalumab alone in patients with unresectable stage III non–small cell lung cancer (NSCLC).¹

Patients were randomized 1:1:1 to receive durvalumab plus oleclumab (n = 59; arm A), durvalumab plus monalizumab (n = 61; arm B), or durvalumab alone (n = 66). The durvalumab alone arm was labeled as the control group. The confirmed ORR in the oleclumab arm was 30.0% (n = 18 responders; 95% CI, 18.8%-43.2%) vs 35.5% (n = 22 responders; 95% CI, 23.7%-48.7%) monalizumab arm vs 17.9% (n = 12 responders; 95% CI, 9.6%-29.2%) in the control arm.

COAST is a phase II study (NCT03822351) which enrolled 189 patients with 186 receiving at least 1 dose of durvalumab. Patients in the control arm received 1500 mg durvalumab once every 4 weeks on day 1 of each treatment cycle. Patients in arm A received 1500 mg durvalumab once every 4 weeks on day 1 of each cycle and 3000 mg oleclumab every 2 weeks on days 1 and 15 for cycles 1 and 2, then once every 4 weeks starting on day 1 of cycle 3. Patients in arm B received 1500 mg durvalumab once every 4 weeks on day 1 of each cycle and 750 mg monalizumab every 2 weeks on days 1 and 15 of each cycle. Patients received treatment intravenously for up to 12 months or until progression or unacceptable toxicity. The primary end point is confirmed ORR, and secondary end points included safety, duration of response (DOR), disease control rate (DCR), PFS by investigator assessment (RECIST v1.1), 12-month PFS rate, and overall survival.

The median DOR was not reached (NR) for any of the treatments given. The DCR rate at 16 weeks was 81.7% (95% CI, 69.6%-90.5%) with durvalumab plus oleclumab, 77.4% (95% CI, 65.0%-87.1%) with durvalumab plus monalizumab, and 58.2% (95% CI, 45.5%-70.2%) with durvalumab only.

PFS favored the oleclumab and monalizumab combinations over durvalumab alone. The median PFS was NR (95% CI, 10.4-not evaluable [NE)] for the oleclumab combination, 15.1 months (95% CI, 13.6-NE) for the monalizumab combination, and 6.3 months (95% CI, 3.7-11.2) for durvalumab alone. The 12-month PFS rate was 62.6% (95% CI, 48.1%-74.2%) for the oleclumab group, 72.7% (95% CI, 58.8%-82.6%) for the monalizumab group, and 33.9% (95% CI, 21.2%-47.1%) for durvalumab alone.

Investigators did not find much difference between the patients in the different therapy regimens in complete responses (PR), partial responses (PR), stable disease (SD) or progressive disease (PD). One patient (1.8%) in Arm A, 3 patients (4.8%) in arm B, and 2 patients (3%) in the control arm had a CR. PRs appeared in 17 patients (28.3%) in arm A, 19 patients (30.6%) in Arm B, and 10 patients (14.9%) in the control arm. Investigators found SD in 32 patients (53.3%) in arm A, 31 patients (50%) in arm B, and 37 patients (55.2%) in the control arm. PD was found in 6 patients (10%) in arm A, 4 patients (6.5%) in arm B, and 11 patients (16.4%) in the control arm.

The study defined eligible patients as adults with histologically or cytologically documented unresectable stage III NSCLC, without progression, following definitive platinum-based concurrent chemoradiotherapy completed within 42 days before random assignment. Patients must have had at least 1 previously irradiated tumor lesion measurable per RECIST v1.1, an ECOG performance status of 0 or 1, adequate organ and marrow function, and at least a 12-week life expectancy.

The median age of patients was 65 years (range, 37-87 years). The majority of patients were male (68.3%) and White (84.1%).Nearly half of patients had a squamous cell histology (42.9%). There was not much difference between patients with stage IIIA and other diseases with 45.5% of patients having unresectable, stage IIIA disease and 54.5% having stage IIIB/C disease. Approximately a third had prior cisplatin (34.9%), and most patients were randomly assigned 14 days or longer after radiotherapy (89.9%). Tumoral PD-L1 expression was available for 50.0% of the oleclumab combination arm, 51.6% of the monalizumab combination arm, and 68.7% of the durvalumab alone arm.

The safety profiles were similar across all treatments. The most common any grade adverse events (AEs) across arm A, arm B, and the control arm were pneumonitis (20.3%, 18%, and 18.2%, respectively), rash (20.3%, 23%, and 9.1%, respectively), and hypothyroid events (15.3%, 19.7%, and 15.2%, respectively). Grade 3/4 events occurred in 21 patients (35.6%) in the oleclumab group, 16 patients (26.2%) in the monalizumab group, and in 23 patients (34.8%) in the durvalumab alone group. The most common grade 3/4 events were cough (1.7%, 0%, and 0%, respectively), dyspnea (1.7%, 1.6%, and 3%, respectively), and pneumonia (6.8%, 1.6%, and 9.1%, respectively). Treatment-emergent AEs led to discontinuation in 9 patients (15.3%) in arm A, 9 patients (14.8%) in arm B, and 11 patients (16.7%) in the control arm. Four deaths were related to study drug: 1 in the durvalumab plus oleclumab arm, 1 in the durvalumab plus monalizumab arm, and 2 (pneumonitis and radiation pneumonitis) in the durvalumab arm.

These findings, showing clinical benefit of oleclumab or monalizumab added to durvalumab vs durvalumab alone, support further evaluation of these combinations in the larger, registration-intent PACIFIC-9 study (NCT05221840).²

_REFERENCES:

_{1. 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. Published online April 22, 2022. J Clin Oncol. 2022;JCO2200227. doi:10.1200/JCO.22.00227}

_{2. A global study to assess the effects of durvalumab with oleclumab or durvalumab with monalizumab following concurrent chemoradiation in patients with stage III unresectable non-small cell lung cancer (PACIFIC-9). ClinicalTrials.gov. Updated April 26, 2022. Accessed May 10, 2022. https://clinicaltrials.gov/ct2/show/NCT05221840}