PACIFIC-9 Starts Dosing Durvalumab With Monalizumab or Oleclumab in Patients With Unresectable NSCLC

The first patient with unresectable, stage III non–small cell lung cancer (NSCLC) who did not progress following definitive platinum-based concurrent chemoradiation therapy (CRT) has been dosed in the phase 3 PACIFIC-9 clinical trial (NCT05221840), according to an announcement by Innate Pharma.¹

PACIFIC-9 is a double-blind, placebo-controlled, randomize, multicenter, international study evaluating the anti-PD-L1 agent durvalumab (Imfinzi) in combination with either the humanized anti-NKG2A monoclonal antibody monalizumab, or the anti-CD73 monoclonal antibody, oleclumab. The target enrollment of the study is 999 patients.²

In the study, patients will be assessed for the primary end point of progression-free survival (PFS), and secondary end points including overall survival (OS), objective response rate (ORR), duration of response, PFS at the 6, 12, 18, 24-month timepoints, PFS2, and other efficacy outcomes.

To enroll in PACIFIC-9, patients must be 18 years of age or older with histologically or cytologically documented NSCLC and have been previously treated with concurrent CRT to locally advanced unresectable disease. Patients must also have a tumor sample available, documented tumor PD-L1 status by central lab, documented EGFR and ALK wild-type status, a WHO performance status of 0 or 1, and adequate organ and marrow function. All patients must have also received at least 2 cycles of platinum-containing chemotherapy concurrent with radiotherapy and 60 Gy ±10% (54 Gy to 66 Gy) of radiation as part of CRT.

“We are very pleased that our key late-stage asset, monalizumab, has progressed into a second Phase 3 trial with our partner, AstraZeneca,” stated Mondher Mahjoubi, chief executive officer of Innate Pharma, in a press release. “Based on the recent COAST clinical trial results, we are excited about the potential of extending the clinical benefit of durvalumab with the addition of monalizumab in patients with unresectable, stage III NSCLC.”

PACIFIC-9 is the follow-up study to COAST (NCT03822351), a phase 2 open-label, multicenter, randomized, multidrug platform study of durvalumab in combination with either monalizumab or oleclumab in patients with unresectable stage III NSCLC. Results showed that both durvalumab plus monalizumab and durvalumab plus oleclumab improved objective responses compared with durvalumab alone. Safety with either combination was not significantly different from the durvalumab-alone arm.^1,3

COAST included 189 patients who were randomized 1:1:1 to either combination arm or to the durvalumab monotherapy arm. The median follow-up in the study was 11.5 months (range, 0.4-23.4). With durvalumab plus oleclumab, the confirmed ORR was 30.0% (95% CI, 18.8%-43.2%) and with durvalumab plus monalizumab, the confirmed ORR was 35.55 (95% CI, 23.7%-48.7%) vs only 17.9% (95% CI, 9.6%-29.2%) with durvalumab alone.³

PFS, a secondary end point in COAST, was also improved with the addition of either monalizumab (stratified hazard ratio [HR], 0.44; 95% CI, 0.26 to 0.75) or oleclumab (stratified d stratified HR, 0.42; 95% CI, 0.24 to 0.72) vs durvalumab alone. The PFS rate at 12 months was high with both combinations compared with durvalumab alone at 62.6% (95% CI, 48.1%-74.2%) with durvalumab plus oleclumab and 72.7% (95% CI, 58.8%-82.6%) with durvalumab plus monalizumab vs 33.9% (95% CI, 21.2%-47.1%) with durvalumab monotherapy.

With both combinations, the safety was similar to that of durvalumab alone, the most common grade 3 treatment-emergent adverse events (TEAEs) in the durvalumab plus oleclumab were cough (30.5%), dyspnea (25.4%), pneumonitis (18.6%), asthenia (16.9%), and pruritus (16.9%). In the durvalumab plus monalizumab arm, the most common TEAEs were also cough (44.3), dyspnea (23.0%), pneumonitis (16.4%), asthenia (23.0%), and pruritus (24.6%).

Data from COAST warranted a further evaluation of the durvalumab-based combination in a phase 3 clinical trial. The PACIFIC-9 study will be conducted at 156 locations across North America, South America, Europe, and Asia. In the United States, there are 19 PACIFIC-9 study sites nationwide.

“Durvalumab has transformed the treatment of patients with unresectable, stage III NSCLC, and we’re excited by the promise of extending its benefit through novel combinations with two potential first-in-class monoclonal antibodies demonstrating strong clinical activity. Based on the stand-out results from COAST, we are pleased that the phase 3 trial is underway, which we hope will bring new treatment options to patients and further increase the potential for long-term survival benefit in this setting," said Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, in a statement.

_REFERENCES:

_{1. First patient dosed in monalizumab phase 3 lung cancer clinical trial triggers $50m payment from Astrazeneca. News release. Innate Pharma. April 29, 2022. Accessed May 3, 2022. https://bit.ly/3OReiRc}

_{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 3, 2022.}

_{3. 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. Published online April 22, 2022. doi: 10.1200/JCO.22.00227}