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

Abstract

PURPOSE Durvalumab significantly improves overall survival for patients with unresectable stage III non–small-cell lung cancer and no progression after concurrent chemoradiotherapy (cCRT). Building upon that standard of care, COAST is a phase II study of durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab or anti-NKG2A monoclonal antibody monalizumab as consolidation therapy in this setting. METHODS Patients with unresectable stage III non–small-cell lung cancer, Eastern Cooperative Oncology Group performance status 0/1, and no progression after cCRT were randomly assigned 1:1:1, ≤ 42 days post-cCRT, to durvalumab alone or combined with oleclumab or monalizumab for up to 12 months, stratified by histology. The primary end point was investigator-assessed confirmed objective response rate (ORR; RECIST v1.1). RESULTS Between January 2019 and July 2020, 189 patients were randomly assigned. At this interim analysis (data cutoff, May 17, 2021), median follow-up was 11.5 months (range, 0.4-23.4 months; all patients). Confirmed ORR was numerically higher with durvalumab plus oleclumab (30.0%; 95% CI, 18.8 to 43.2) and durvalumab plus monalizumab (35.5%; 95% CI, 23.7 to 48.7) versus durvalumab (17.9%; 95% CI, 9.6 to 29.2). Progression-free survival (PFS) was prolonged with both combinations versus durvalumab (plus oleclumab: hazard ratio, 0.44; 95% CI, 0.26 to 0.75; and plus monalizumab: hazard ratio, 0.42; 95% CI, 0.24 to 0.72), with higher 12-month PFS rates (plus oleclumab: 62.6% [95% CI, 48.1 to 74.2] and plus monalizumab: 72.7% [95% CI, 58.8 to 82.6] v durvalumab alone: 33.9% [95% CI, 21.2 to 47.1]). All-cause grade ≥ 3 treatment-emergent adverse events occurred in 40.7%, 27.9%, and 39.4% with durvalumab plus oleclumab, durvalumab plus monalizumab, and durvalumab, respectively. CONCLUSION Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was similar across arms with no new or significant safety signals identified with either combination. These data support their further evaluation in a phase III trial.

Current challenges of unresectable stage III NSCLC: are we ready to break the glass ceiling of the PACIFIC trial?

“…All-grade rates of pneumonitis were similar in the three arms (18.6%, 16.4% and 16.7%, respectively) as well as the treatment discontinuation rates (15.3%, 14.8% and 16.7%, respectively). 35 Although durvalumab arm in COAST trial underperformed compared to the PACIFIC trial, mainly related to different patient characteristics, the results of COAST trial support that combination approaches are feasible, safe and may in the future potentially shift again the prognosis of patients in this setting. Therefore, results of COAST trial support further evaluation of these combinations in the currently recruiting phase III PACIFIC-9 trial (NCT05221840).…”

“…The evaluation of efficacy of consolidation ICI in PD-L1-negative NSCLC can be hindered by the small sample size as PD-L1 status was not required for enrollment in majority of trials, as well as by the post hoc analysis or exploratory analysis regarding the efficacy according to the PD-L1 status. 23 , 35 Although the PACIFIC-R study reported that durvalumab was feasible in PD-L1-negative tumors, the median PFS was shorter than PD-L1 ⩾1% tumors, 31 raising the issue of optimal consolidation approach in PD-L1-negative NSCLC.…”

“…In the second scenario, the combination between anti-PD(L)1 blockers and a tailored immune checkpoint blockade based on the expression patterns of co-inhibitory checkpoints should be ideally used. 35 However, a challenge specific to stage III NSCLC is that tumor biopsies are performed at baseline, before starting the chemoradiation. Therefore, biomarker analysis will not take into account the potential changes induced by the treatment.…”

Radioresistance of Non-Small Cell Lung Cancers and Therapeutic Perspectives

“…COAST is a phase 2 trial that randomized in a 1:1:1 manner patients between durvalumab alone or in association with oleclumab, an anti-CD73 monoclonal antibody, or monalizumab, an anti-NKG2A monoclonal antibody, for up to 12 months of treatment. Median PFS was 6.3 months for durvalumab alone, 15.1 months (HR = 0.65) for the durvalumab + monalizumab arm, and not reached (HR = 0.44) for durvalumab + oleclumab [ 91 ]. These first results have to be analyzed with caution as the durvalumab alone arm compares poorly with the results of the PACIFIC trial.…”

Discovery and pre-clinical evaluation of antibodies to the NKG2A inhibitory receptor

“…As a result, monalizumab is now being studied in multiple clinical trials (NCT04307329, NCT04590963, NCT05221840, and NCT05061550) to increase the proportion of patients responding to ICI. The combination of monalizumab with the anti-EGFR antibody, cetuximab, or with the anti-PD-L1 antibody, durvalumab, has led to encouraging responses in a subset of patients with head and neck cancer squamous cell cancer (HNSCC), colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) 13,[18][19][20][21] . The responses observed to combination mAb therapy are superior to monotherapy with monalizumab (NCT02459301).…”