COAST: An Open-Label, Phase II, Multidrug original reports Platform Study of Durvalumab Alone or in Combination With Oleclumab or Monalizumab in Patients With Unresectable, Stage III Non–Small-Cell Lung Cancer Roy S. Herbst, MD, PhD1; Margarita Majem, MD, PhD2; Fabrice Barlesi, MD, PhD3; Enric Carcereny, MD4; Quincy Chu, MD5; Isabelle Monnet, MD, PhD6; Alfredo Sanchez-Hernandez, MD7; Shaker Dakhil, MD8; D. Ross Camidge, MD, PhD9; Leanne Winzer, MSc10; Yee Soo-Hoo, MPH11; Zachary A. Cooper, PhD11; Rakesh Kumar, MD, PhD11; John Bothos, PhD11; Charu Aggarwal, MD, MPH12; and Alex Martinez-Marti, MD13 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. ASSOCIATED CONCLUSION Both combinations increased ORR and prolonged PFS versus durvalumab alone. Safety was CONTENT similar across arms with no new or significant safety signals identified with either combination. These data See accompanying support their further evaluation in a phase III trial. articles on pages 3353 and 3453 J Clin Oncol 40:3383-3393. © 2022 by American Society of Clinical Oncology Appendix Creative Commons Attribution Non-Commercial No Derivatives 4.0 License Protocol Author affiliations INTRODUCTION after concurrent chemoradiotherapy (cCRT). 2-4 and support Durvalumab is a selective, high-affinity, human Thus, the PACIFIC regimen (durvalumab after information (if immunoglobulin G1 monoclonal antibody (mAb) CRT) is now the standard of care in this setting. 4-6 applicable) appear Furthermore, recent 5-year data from PACIFIC at the end of this that blocks programmed cell death ligand-1 (PD- L1) binding to programmed cell death-1 (PD-1) demonstrated robust and sustained OS benefit plus article. and CD80, allowing T cells to recognize and kill durable PFS with durvalumab, with 5-year OS and Accepted on March 18, 2022 and tumor cells.1 In the placebo-controlled phase III PFS rates of 42.9% and 33.1%, respectively. 7 published at PACIFIC trial, durvalumab significantly improved Despite progress, additional work remains to further ascopubs.org/journal/ jco on April 22, 2022: progression-free survival (PFS) and overall survival improve outcomes for this patient population. There- DOI https://doi.org/10. (OS) in patients with unresectable, stage III non– fore, immunotherapy combination strategies that build 1200/JCO.22.00227 small-cell lung cancer (NSCLC) and no progression upon the durvalumab standard of care are being Volume 40, Issue 29 3383 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Herbst et al CONTEXT Key Objective Consolidation treatment with the programmed cell death ligand-1 inhibitor durvalumab after chemoradiotherapy is the standard of care for patients with unresectable, stage III non–small-cell lung cancer. Additional immunomodulation through combination therapy, however, may extend benefit to more patients. The signal-finding phase II COAST study is assessing durvalumab alone or combined with the anti-CD73 monoclonal antibody oleclumab or anti-NKG2A mono- clonal antibody monalizumab as consolidation therapy in this setting. Knowledge Generated Confirmed objective response rate was numerically higher with durvalumab plus oleclumab (30.0%) and durvalumab plus monalizumab (35.5%) versus durvalumab (17.9%), and progression-free survival was prolonged with both combinations (hazard ratios, 0.44 and 0.42, respectively). In addition, safety was similar across the arms with no new or significant safety signals identified. Relevance To our knowledge, COAST is the first randomized phase II study to show improved clinical outcomes with novel immu- notherapy combinations in this setting, supporting their further evaluation in a planned phase III study (PACIFIC-9; ClinicalTrials.gov identifier: NCT05221840). explored to expand the number of patients who respond Radiotherapy is known to increase tumoral expression of and remain progression-free. CD73, HLA-E (NKG2A ligand), and PD-L1; therefore, com- bining blockade of these immune checkpoints with CRT is a Oleclumab (MEDI9447) is a human IgG1l mAb that in- promising means of improving responses.18-21 In preclinical hibits the function of cluster of differentiation 73 (CD73).8 models, radiotherapy combined with anti-CD73 or anti- CD73 is an enzyme found on the surfaces of cancer and NKG2a (with/without anti–PD-[L]1) have increased antitu- immune cells and is involved in conversion of adenosine mor activity versus either alone.18,20,21 Therefore, we hy- monophosphate to extracellular adenosine, which has an pothesized that combining anti-CD73 or anti-NKG2A mAbs immunosuppressive effect on the tumor environment.9 with anti–PD-L1 could improve outcomes in patients with CD73 upregulation by tumors has been shown to in- unresectable, stage III NSCLC who have undergone CRT. crease extracellular adenosine production and result in subsequent local immunosuppression in multiple Here, we report the results from an interim analysis of cancers.10-12 Preclinical models have demonstrated COAST, a global, open-label, randomized, phase II, additive antitumor immunity when oleclumab is com- multidrug platform study of durvalumab alone or in com- bined with other immunotherapies, including PD-1/PD- bination with oleclumab or monalizumab, as consolidation L1 inhibitors.9 In addition, a phase I study of oleclumab therapy in patients with unresectable, stage III NSCLC who combined with durvalumab produced durable re- had not progressed following cCRT. The goal of this signal- sponses with manageable safety in patients with ad- finding study was early identification of novel durvalumab vanced epidermal growth factor receptor (EGFR)– combinations that are more active than durvalumab alone mutated NSCLC.13 for validation in a phase III study. Monalizumab (IPH2201) is a first-in-class, humanized, METHODS IgG4 mAb that specifically binds to and blocks the inhib- itory receptor NKG2A from binding to the major histo- Patients compatibility complex E (HLA-E), thereby reducing Eligible patients were age $ 18 years, with histologically/ inhibition of natural killer and CD81 T cells.14 HLA-E is cytologically documented unresectable, stage III NSCLC, overexpressed in multiple tumor types and, once bound to without progression following definitive platinum-based NKG2A, triggers inhibitory signals that suppress cytokine cCRT (total radiotherapy dose: $ 60 Gy at 1.8 Gy/frac- secretion and direct cytotoxicity of T lymphocytes and tion or bioequivalent dose), completed within 42 days natural killer cells.15 Monalizumab binds specifically and before random assignment. Patients had $ 1 previously with high affinity to NKG2A, thereby suppressing inhibitory irradiated tumor lesion measurable per RECIST v1.1, signals and enhancing antitumor immunity.14,16 In a phase Eastern Cooperative Oncology Group performance status I/II trial of patients with recurrent/metastatic head-and-neck (ECOG PS) of 0/1, adequate organ and marrow function, squamous cell carcinoma, monalizumab combined with and life expectancy $ 12 weeks. Exclusion criteria and the anti-EGFR mAb cetuximab showed promising activity additional patient details are described in Appendix 1 with manageable safety.17 (online only). 3384 © 2022 by American Society of Clinical Oncology Volume 40, Issue 29 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Durvalumab Plus Novel Agents for Unresectable, Stage III NSCLC Study Design and Treatments Safety end points were summarized for the as-treated Patients were randomly assigned (1:1:1), stratified population (patients who received $ 1 dose of study by histology (adenocarcinoma and nonadenocarcinoma), treatment). Adverse events (AEs) were graded by National 1-42 days post cCRT, to one of three arms (Appendix Fig Cancer Institute Common Terminology Criteria for Adverse A1, online only). Patients in the control arm received Events v5.0, and safety data were analyzed using de- 1,500 mg durvalumab once every 4 weeks (Q4W) on day 1 scriptive statistics. of each treatment cycle. Patients in arm A received Twelve-month PFS rates and 95% CIs were estimated by 1,500 mg durvalumab Q4W on day 1 of each cycle and using Kaplan-Meier method. PFS according to tumoral 3,000 mg oleclumab every 2 weeks (Q2W) on days 1 and PD-L1 expression ($ 1% or , 1%) was analyzed by 15 for cycles 1 and 2, then Q4W starting on day 1 of cycle 3. using Kaplan-Meier method. PFS on the basis of tumoral Patients in arm B received 1,500 mg durvalumab Q4W on expression of CD73 (tumor cell [TC] $ 10% or TC , 10%), day 1 of each cycle and 750 mg monalizumab Q2W on days NKG2A ($ median or , median) or HLA-E ($ median or 1 and 15 of each cycle. Dosing regimens for oleclumab and , median) was analyzed using a stratified Cox regression monalizumab were based on prior phase I, combination model to estimate HRs and 95% CIs. studies.13,22 All study drugs were administered intrave- Data analyses used SAS System, version 9.3 or above. nously up to 12 months or until progression or unac- ceptable toxicity. RESULTS End Points and Assessments Patients The primary end point was confirmed objective response Between January 2019 and July 2020, 189 patients were rate (ORR) by investigator assessment per RECIST v1.1 randomly assigned; 186 received $ 1 dose of study drug. (with imaging scheduled as described in Appendix 1). Key Sixty-six patients received durvalumab alone (control arm), secondary end points included safety, duration of re- whereas 59 and 61 patients received durvalumab plus sponse, disease control rate, PFS by investigator assess- oleclumab (arm A) and durvalumab plus monalizumab ment (RECIST v1.1), 12-month PFS rate, and OS. (arm B), respectively (Fig 1). As of May 17, 2021 (data Preplanned exploratory analyses included PFS analyses on cutoff for this interim analysis), overall median follow-up in the basis of tumoral expression of clinically relevant bio- all patients was 11.5 months (range, 0.4-23.4 months). markers including CD73, NKG2A, HLA-E and PD-L1. Ar- Baseline characteristics were generally well balanced be- chival (pre-cCRT) tumor specimens (not mandatory) were tween arms (Table 1). Most patients were White (84.1%), obtained for immunohistochemistry biomarker analysis as male (68.3%), and current/former smokers (93.1%); me- described in Appendix 1. Unplanned exploratory subgroup dian age was 65 years (range, 37-87 years); almost half had analyses of PFS were also performed. squamous cell histology (42.9%); 45.5% had unresect- Statistical Analyses able, stage IIIA disease and 54.5% had stage IIIB/C dis- This phase II study was not designed to test a specific ease; approximately a third had prior cisplatin (34.9%); and hypothesis around the primary end point. A sample size of most were randomly assigned $ 14 days after RT (89.9%). 60 patients per arm was chosen to provide an acceptable Tumoral PD-L1 expression was available for 68.7%, level of precision as described in Appendix 1 for this ad hoc 50.0%, and 51.6% of patients in the durvalumab, durva- interim analysis. lumab plus oleclumab, and durvalumab plus monalizumab arms, respectively. Efficacy end points were assessed in the intent-to-treat population (all patients randomly assigned). For analyses Efficacy involving comparison between an experimental arm and a The primary end point of confirmed ORR by investigator control arm, only control arm patients concurrently enrolled assessment was numerically higher with both combinations with the experimental arm were included. ORR rates versus durvalumab alone (Table 2). Among all randomly (RECIST v1.1) were summarized with 95% CIs on the basis assigned patients, confirmed ORR was 30.0% (n 5 18 of Clopper-Pearson exact method. Time-to-event end responders; 95% CI, 18.8 to 43.2) with durvalumab plus points were analyzed using Kaplan-Meier estimates, with oleclumab and 35.5% (n 5 22 responders; 95% CI, 23.7 to each experimental arm compared with the control arm 48.7) with durvalumab plus monalizumab versus 17.9% (PFS censored as described in Appendix 1). Comparison of (n 5 12 responders; 95% CI, 9.6 to 29.2) with durvalumab PFS between each experimental arm and control arm used only (differences of 12.1% [95% CI, –2.7 to 26.9] and a Cox-regression model, stratified by histology (adenocar- 16.7% [95% CI, 1.5 to 32.0], respectively). The secondary cinoma and nonadenocarcinoma), to estimate hazard ra- end point of disease control rate at 16 weeks was 81.7% tios (HRs) and 95% CIs. There were no formal statistical (95% CI, 69.6 to 90.5) with durvalumab plus oleclumab, comparisons between experimental arms. For exploratory 77.4% (95% CI, 65.0 to 87.1) with durvalumab plus PFS subgroup analyses, HRs and 95% CIs were estimated monalizumab, and 58.2% (95% CI, 45.5 to 70.2) with by using a Cox regression model, stratified by histology. durvalumab only (Table 2). Journal of Clinical Oncology 3385 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Herbst et al Assessed for eligibilitya (N = 258) Excluded (n = 69) Did not meet inclusion criteria (n = 62) Withdrew consent (n = 3) Other reasons (n = 4) Patients randomly assigned (1:1:1 ratio; n = 189) Assigned to durvalumab monotherapy (n = 67) Assigned to durvalumab + oleclumab (n = 60) Assigned to durvalumab + monalizumab (n = 62) Received allocated intervention (n = 66) Received allocated intervention (n = 59) Received allocated intervention (n = 61) Did not receive allocated intervention (n = 1) Did not receive allocated intervention (n = 1) Did not receive allocated intervention (n = 1) Lost to follow-up (n = 0) Lost to follow-up (n = 0) Lost to follow-up (n = 0) Completed all study treatment (n = 17) Completed all study treatment (n = 33) Completed all study treatment (n = 30) Discontinued all study treatment (n = 46) Discontinued all study treatment (n = 26) Discontinued all study treatment (n = 25) Adverse event (n = 9) Adverse event (n = 9) Adverse event (n = 7) Treatment-related toxicity delay > 56 days (n = 0) Treatment-related toxicity delay > 56 days (n = 2) Treatment-related toxicity delay > 56 days (n = 2) from last dose to next planned dose from last dose to next planned dose from last dose to next planned dose Confirmed disease progession (n = 26) Confirmed disease progession (n = 10) Confirmed disease progession (n = 11) Unconfirmed disease progressionb (n = 2) Unconfirmed disease progressionb (n = 1) Unconfirmed disease progressionb (n = 1) Death (n = 1) Death (n = 2) Death (n = 0) Patient decision (n = 4) Patient decision (n = 1) Patient decision (n = 3) Investigator decision (n = 2) Investigator decision (n = 0) Investigator decision (n = 1) Other (n = 2) Other (n = 1) Other (n = 0) All study treatment ongoing (n = 3) All study treatment ongoing (n = 0) All study treatment ongoing (n = 6) Analyzed Analyzed Analyzed Efficacy (n = 67) Efficacy (n = 60) Efficacy (n = 62) Safety (n = 66) Safety (n = 59) Safety (n = 61) FIG 1. CONSORT diagram. aInformed consent received. bUnconfirmed disease progression and investigator determination that the patient was not eligible for a confirmation scan. PFS was prolonged with both combinations versus dur- was consistently demonstrated with both combinations valumab alone (stratified HR of 0.44 [95% CI, 0.26 to 0.75] versus durvalumab alone, irrespective of tumor CD73, for durvalumab plus oleclumab and stratified HR of 0.42 NKG2A, or HLA-E expression (Appendix Fig A3, online [95% CI, 0.24 to 0.72] for durvalumab plus monalizumab only). versus durvalumab alone; Fig 2). The 12-month PFS rate Safety was higher with both combinations (62.6% [95% CI, 48.1 to 74.2] with durvalumab plus oleclumab and 72.7% [95% The safety profiles of both combination regimens were similar CI, 58.8 to 82.6] with durvalumab plus monalizumab to that of durvalumab alone, with similar rates of any-cause versus 33.9% [95% CI, 21.2 to 47.1] with durvalumab treatment-emergent AEs and grade $ 3 treatment-emergent alone; Fig 2). Median PFS was not reached with durva- AEs (Table 3). Among the most common any-grade (grade 3/ lumab plus oleclumab, 15.1 months (95% CI, 13.6 to not 4) treatment-emergent AEs across the combination arms were estimable) with durvalumab plus monalizumab, and cough, dyspnea, pneumonitis, asthenia, and pruritus, which 6.3 months (95% CI, 3.7 to 11.2) with durvalumab alone occurred in 30.5% (1.7%), 25.4% (1.7%), 18.6% (0%), (Fig 2). 16.9% (0%), and 16.9% (0%), respectively, of patients in the durvalumab plus oleclumab arm and 44.3% (0%), 23.0% In exploratory subgroup analyses (Fig 3), PFS benefit was (1.6%), 16.4% (1.6%), 23.0% (0%), and 24.6% (0%), re- observed with both combinations across a range of clini- spectively, of patients in the durvalumab plus monalizumab cally important subgroups, including those on the basis of arm, whereas dyspnea, cough, pneumonitis, and arthralgia histology, type of prior platinum-based chemotherapy, and were the most common any-grade (grade 3/4) treatment- ECOG PS, although patient numbers in these subgroups emergent AEs in the durvalumab only arm, occurring in were small (Fig 3). Evidence of benefit from the combi- 25.8% (3.0%), 18.2% (0%), 16.7% (0%), and 16.7% (0%), nations appeared persistent among patients with unknown respectively (Table 4). The any-grade (grade 3/4) rate of ra- PD-L1 status and PD-L1 TC $ 1% (Kaplan-Meier curves of diation pneumonitis was 11.9% (0%), 4.9% (0%) and 4.5% PFS by tumoral PD-L1 expression provided in Appendix Fig (1.5%) in durvalumab plus oleclumab, durvalumab plus A2, online only). However, analysis of patients with PD-L1 monalizumab, and durvalumab only arms, respectively. The TC , 1% was limited by the numbers of patients available. most common any-grade (grade 3/4) durvalumab-related AEs On the basis of exploratory biomarker analyses, PFS benefit in the combination arms were hypothyroidism, pneumonitis, 3386 © 2022 by American Society of Clinical Oncology Volume 40, Issue 29 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Durvalumab Plus Novel Agents for Unresectable, Stage III NSCLC TABLE 1. Baseline Characteristics and Prior CRT Durvalumab Durvalumab 1 Oleclumab Durvalumab 1 Monalizumab Characteristica (n 5 67) (n 5 60) (n 5 62) Median age, years (range) 66.0 (46-81) 65.0 (37-83) 65.0 (44-87) Male, % 67.2 70.0 67.7 b Race, No. (%) American Indian or Alaska Native 0 1 (1.7) 0 Asian 5 (7.7) 4 (6.8) 5 (8.1) Black or African American 1 (1.5) 5 (8.5) 2 (3.2) Native Hawaiian or Other Pacific Islander 1 (1.5) 0 0 White 57 (87.7) 47 (79.7) 55 (88.7) Other 1 (1.5) 2 (3.4) 0 b ECOG PS, No. (%) 0 30 (45.5) 33 (55.9) 27 (44.3) 1 36 (54.5) 26 (44.1) 34 (55.7) Ever smoked, No. (%) 63 (94.0) 54 (90.0) 59 (95.2) Histology, No. (%) Squamous 30 (44.8) 24 (40.0) 27 (43.5) Nonsquamous 37 (55.2) 36 (60.0) 35 (56.5) Disease stage at study entry, No. (%) IIIA 27 (40.3) 27 (45.0) 32 (51.6) IIIB 34 (50.7) 29 (48.3) 27 (43.5) IIIC 6 (9.0) 4 (6.7) 3 (4.8) PD-L1 status, No. (%)c TC $ 1% 30 (44.8) 23 (38.3) 20 (32.3) TC , 1% 16 (23.9) 7 (11.7) 12 (19.4) Unknown 21 (31.3) 30 (50.0) 30 (48.4) Prior RT dose, Gy, No. (%) 54-66 62 (92.5) 54 (90.0) 57 (91.9) . 66 5 (7.5) 6 (10.0) 5 (8.1) Time from last RT to random assignment, days, No. (%) , 14 9 (13.4) 4 (6.7) 6 (9.7) 14-28 27 (40.3) 27 (45.0) 30 (48.4) 29-42 31 (46.3) 29 (48.3) 26 (41.9) Prior platinum-based CT, No. (%)d Cisplatin 23 (34.3) 28 (46.7) 15 (24.2) Carboplatin 43 (64.2) 28 (46.7) 44 (71.0) NOTE. Data cutoff: May 17, 2021. Abbreviations: CRT, chemoradiotherapy; CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; PD-L1, programmed cell death ligand-1; RT, radiotherapy; TC, tumor cell. a One randomly assigned patient in each arm did not receive treatment. b Race was missing for two patients in the durvalumab arm and one patient in the durvalumab 1 oleclumab arm, and ECOG PS was missing for one patient in each arm (reported percentages are based on patients with available data). c 28, 30, and 32 patients in the durvalumab, durvalumab 1 oleclumab, and durvalumab 1 monalizumab arms, respectively, were not evaluable for PD-L1 TC expression. d In addition, 1, 4, and 3 patients in the durvalumab, durvalumab 1 oleclumab, and durvalumab 1 monalizumab arms, respectively, received cisplatin and carboplatin combined. Journal of Clinical Oncology 3387 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Herbst et al TABLE 2. Antitumor Activity by Investigator Assessment (ITT population) Durvalumab Durvalumab 1 Oleclumab Durvalumab 1 Monalizumab Antitumor Activity (n 5 67) (n 5 60) (n 5 62) Confirmed ORR, % (95% CI)a 17.9 (9.6 to 29.2) 30.0 (18.8 to 43.2) 35.5 (23.7 to 48.7) (No.) (12) (18) (22) Difference in confirmed ORR, % (95% CI)b — 12.1 (‒2.7 to 26.9) 16.7 (1.5 to 32.0) c,d Best overall response by RECIST, No. (%) CR 2 (3.0) 1 (1.7) 3 (4.8) PR 10 (14.9) 17 (28.3) 19 (30.6) SD 37 (55.2) 32 (53.3) 31 (50.0) PD 11 (16.4) 6 (10.0) 4 (6.5) NE 7 (10.4) 4 (6.7) 4 (6.5) c,e DCR at 16 weeks, % (95% CI) 55.2 (42.6 to 67.4) 80.0 (67.7 to 89.2) 77.4 (65.0 to 87.1) (No.) (37) (48) (48) Median DoR, months (95% CI)c NR (7.4 to NA) NR (12.9 to NA) NR (9.0 to NA) Range 1.91 to 17.51 1.81 to 16.91 1.91 to 18.41 NOTE. Data cutoff: May 17, 2021. Abbreviations: CR, complete response; DCR, disease control rate; DoR, duration of response; ITT, intent-to-treat; NA, not applicable; NE, not evaluable; NR, not reached; ORR, objective response rate; PD, progressive disease; PR, partial response; SD, stable disease. a 95% CI by Clopper-Pearson exact method. b Compared with the 67 and 64 patients in the durvalumab arm enrolled concurrently with patients in the durvalumab 1 oleclumab and durvalumab 1 monalizumab arms, respectively. c Confirmed responses. d One patient did not have a postbaseline disease assessment and is, therefore, missing a best overall response. e DCR at 16 weeks 5 CR 1 PR 1 SD for $ 16 weeks. and pruritus, which occurred in 13.6% (0%), 16.9% (0%), online only). Overall, AESIs were reported in 61.0%, 67.2%, and 16.9% (0%), respectively, of patients in the durvalumab and 56.1% of patients in the durvalumab plus oleclumab, plus oleclumab arm, and 18.0% (0%), 9.8% (1.6%), and durvalumab plus monalizumab, and durvalumab only arms, 16.4% (0%), respectively, of patients in the durvalumab plus respectively, including pneumonitis in 20.3%, 18.0%, and monalizumab arm, whereas hypothyroidism was the most 18.2% of patients in each arm, respectively. The incidence of common any-grade (grade 3/4) durvalumab-related AE in the rash was slightly higher in the combination arms (20.3% with durvalumab only arm, occurring in 15.2% (0%; Appendix durvalumab plus oleclumab and 23.0% with durvalumab plus Table A1, online only). monalizumab v 9.1% with durvalumab only). The proportions of patients with treatment-emergent AEs leading to treatment discontinuation were similar DISCUSSION between arms (15.3%, 14.8%, and 16.7% of patients in The COAST trial is, to our knowledge, the first randomized the durvalumab plus oleclumab, durvalumab plus mon- phase II study to show evidence of improved clinical out- alizumab, and durvalumab only arms, respectively). The comes with novel immunotherapy combinations in the most common treatment-emergent AE leading to dis- unresectable, stage III NSCLC setting, specifically com- continuation was pneumonitis (among 5.1%, 4.9%, and bining anti-CD73 or anti-NKG2A treatment with standard- 6.1% of patients in the durvalumab plus oleclumab, of-care anti–PD-L1 therapy in this setting, supporting their durvalumab plus monalizumab, and durvalumab only further evaluation in a planned phase III study (PACIFIC-9; arms, respectively). Overall, 6.8%, 4.9%, and 10.6% of ClinicalTrials.gov identifier: NCT05221840).18-21,23 Interim patients, respectively, died within 90 days of last dose of data indicate that combining oleclumab or monalizumab study drug (regardless of the relationship to study drug; with durvalumab can provide additional clinical benefit, Table 3). In total, 4 deaths were related to study drug, 2 versus durvalumab alone. Both combination regimens (pneumonitis and radiation pneumonitis) in the durvalu- increased ORR and prolonged PFS versus durvalumab mab arm, 1 (pneumonitis) in the durvalumab plus ole- alone. Importantly, the PFS curves showed an early sep- clumab arm, and 1 (myocardial infarction) in the aration at approximately 2-4 months that was sustained durvalumab plus monalizumab arm. over time. In addition, PFS benefit was observed with The incidence of AEs of special interest (AESIs) related to both combinations across a range of clinically important durvalumab was similar between arms (Appendix Table A2, subgroups, including histology, ECOG PS, and prior 3388 © 2022 by American Society of Clinical Oncology Volume 40, Issue 29 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Durvalumab Plus Novel Agents for Unresectable, Stage III NSCLC No. of Events/ Median PFS, Total No. of Months 12-Month PFS Treatment Arm Patients (%) (95% CI)a Rate, % (95% CI) HR, % (95% CI)b,c Durvalumab + monalizumab 21/62 (33.9) 15.1 (13.6 to NE) 72.7 (58.8 to 82.6) 0.42 (0.24 to 0.72) Durvalumab + oleclumab 22/60 (36.7) NR (10.4 to NE) 62.6 (48.1 to 74.2) 0.44 (0.26 to 0.75) Durvalumab 38/67 (56.7) 6.3 (3.7 to 11.2) 33.9 (21.2 to 47.1) – 1.0 0.9 0.8 PFS (probability) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 2 4 6 8 10 12 14 16 18 20 Time Since Random Assignment (months) No. at risk: Durvalumab + monalizumab 62 55 46 44 41 35 25 11 6 1 1 Durvalumab + oleclumab 60 49 46 40 37 30 22 13 9 5 0 Durvalumab 67 50 32 27 20 16 13 9 7 3 0 FIG 2. Progression-free survival (ITT population). Data cutoff: May 17, 2021 (median follow-up of 11.5 months; range, 0.4-23.4 months). aInterim analysis was performed when all patients had a 10-month minimum potential follow-up; Kaplan-Meier estimates for PFS, PFS rate, and 95% CIs. bPFS HR and 95% CI estimated by Cox regression model, stratified by histology (adenocarcinoma and nonadenocarcinoma). cCompared with the 67 and 64 patients in the durvalumab arm enrolled concurrently with patients in the durvalumab 1 oleclumab and durvalumab 1 monalizumab arms, respectively. HR, hazard ratio; ITT, intention-to-treat; NE, not estimable; NR, not reached; PFS, progression-free survival. platinum-based chemotherapy, although the patient pruritus, were slightly more frequent in the combination arms numbers in these subgroups were small. compared with the control arm; however, all events were The tumoral PD-L1 status was available for a subset of grade 1 or 2. A larger study will be required to better un- patients (50.0%-68.7% across all arms). With the caveat of derstand any differences in the incidences of specific AESIs limited sample sizes in the different PD-L1 subgroups, and immune-related AEs across the different combinations evidence of benefit from the combinations appeared per- versus durvalumab alone. sistent among patients with unknown PD-L1 status and PD- Several studies are investigating alternative combination L1 TC $ 1% (Fig 3). However, the number of patients regimens in unresectable, stage III NSCLC, including anti–PD- with PD-L1 TC , 1% was limited and, thus, no definitive [L]1 therapies combined with anti-T cell immunoreceptor with conclusions can be drawn for this subgroup on the immunoglobulin and ITIM domains immunotherapy and basis of this study. Similarly, further analysis of patients with PARP or CTLA-4 inhibitors,24-27 anti–PD-[L]1 therapies given PD-L1 TC $ 1% will require a larger study. The phase III concurrently with cCRT (eg, durvalumab in the phase III PACIFIC-9 study requires provision of tumor tissue samples PACIFIC-2 study28), or bifunctional fusion proteins that target and documented tumor PD-L1 status as part of the eligi- both the transforming growth factor-b and PD-L1 pathways bility criteria.23 (eg, bintrafusp alfa), also given concurrently with cCRT.29 The The safety profiles were consistent across all three arms and COAST study is the first randomized study to demonstrate consistent with the safety profile of durvalumab in PACIFIC, improved clinical outcomes by additional immunomodulation with similar rates of discontinuation because of AEs.2 Both through combination therapy, suggesting that the clinical combination arms displayed manageable safety profiles, with benefit of the standard-of-care PACIFIC regimen can be no new or significant safety signals identified in either; the further improved by addressing mechanisms of treatment incidences of any AESIs, including pneumonitis, were similar resistance and relapse, such as the CD73 and NKG2A across all three arms and also consistent with the durvalumab pathways. The results of the COAST study also provide further arm in PACIFIC.2 Immune-related AEs, specifically, rash and support for targeting these pathways with oleclumab and Journal of Clinical Oncology 3389 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Herbst et al A B D+O D Stratified HR D+M D Stratified HR No. of Events/Patients (95% CI)a No. of Events/Patients (95% CI)a Overall 22/60 38/67 0.44 (0.26 to 0.75) 21/62 36/64 0.42 (0.24 to 0.72) PD-L1 status TC t 1% 8/23 18/30 0.40 (0.17 to 0.94) 5/20 17/28 0.19 (0.07 to 0.54) TC < 1% 1/7 9/16 — 6/12 9/16 0.87 (0.31 to 2.48) Unknown 13/30 11/21 0.67 (0.30 to 1.50) 10/30 10/20 0.63 (0.25 to 1.60) Histology Squamous 7/24 16/30 0.38 (0.15 to 0.92) 10/27 15/28 0.54 (0.24 to 1.20) Nonsquamous 15/36 22/37 0.50 (0.26 to 0.97) 11/35 21/36 0.35 (0.17 to 0.73) Disease stage at entry IIIA 11/27 13/27 0.68 (0.31 to 1.53) 11/32 12/25 0.66 (0.29 to 1.52) IIIB 9/29 21/34 0.32 (0.14 to 0.70) 8/27 20/33 0.24 (0.10 to 0.57) IIIC 2/4 4/6 — 2/3 4/6 — Prior platinum-based CT Carboplatin 13/28 21/43 0.67 (0.33 to 1.36) 15/44 20/41 0.51 (0.26 to 1.01) Cisplatin 8/28 16/23 0.29 (0.12 to 0.69) 6/15 15/22 0.37 (0.14 to 0.98) ECOG PS 0 13/33 16/30 0.56 (0.27 to 1.18) 10/27 15/28 0.56 (0.25 to 1.27) 1 9/26 21/36 0.35 (0.16 to 0.77) 11/34 20/35 0.33 (0.16 to 0.71) -1 0 1 2 -1 0 1 2 D + O Better D Better D + M Better D Better FIG 3. Exploratory PFS subgroup analyses by investigator assessment (ITT population): (A) durvalumab 1 oleclumab versus durvalumab alone and (B) durvalumab 1 monalizumab versus durvalumab alone. Data cutoff: May 17, 2021 (median follow-up of 11.5 months; range, 0.4-23.4 months). aPFS HR and 95% CI estimated by Cox regression model, stratified by histology (adenocarcinoma and nonadenocarcinoma), for these unplanned exploratory analyses. CT, chemotherapy; D, durvalumab; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; M, monalizumab; O, oleclumab; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; TC, tumor cell. monalizumab in other tumor types. Additionally, this model in this trial versus PACIFIC2; in addition, this trial enrolled could represent a new way to test novel combinations in an a higher number of patients who were older or had stage immunotherapy-naı̈ve setting. IIIB/C disease, all of which are factors that might be as- Despite the inherent challenges associated with naı̈ve cross- sociated with either a poorer prognosis or reduced clinical trial comparisons, when compared with the PACIFIC study,2-4 benefit with durvalumab in this trial, relative to PACIFIC.2,3,7 the ORR and PFS observed with the durvalumab (control) arm Furthermore, although the three arms in COAST were fairly of this study appeared to be lower. To better understand these well balanced, there were a few imbalances in the baseline disparities, we reviewed the baseline characteristics of pa- characteristics between them. For example, within the tients in this trial against those in PACIFIC for any clinically durvalumab plus oleclumab arm, higher proportions of meaningful differences. Specifically, there was a lower pro- patients had ECOG PS 0 and prior cisplatin-based portion of patients who were Asian, received prior cisplatin, chemotherapy and a lower proportion were randomly and were randomly assigned , 14 days after radiotherapy assigned , 14 days after radiotherapy, relative to the other TABLE 3. Safety Summary (as-treated population) Incidence Durvalumab Durvalumab 1 Oleclumab Durvalumab 1 Monalizumab Any TEAEs, No. (%) 65 (98.5) 57 (96.6) 61 (100) Grade $ 3 TEAEs, No. (%) 26 (39.4) 24 (40.7) 17 (27.9) Study drug-related AEs, No. (%) 49 (74.2) 46 (78.0) 50 (82.0) Study drug-related SAEs, No. (%) 6 (9.1) 7 (11.9) 5 (8.2) TEAEs leading to treatment discontinuation, No. (%) 11 (16.7) 9 (15.3) 9 (14.8) Deathsa,b, No. (%) 7 (10.6) 4 (6.8) 3 (4.9) NOTE. Data cutoff: May 17, 2021. Abbreviations: AEs, adverse events; SAEs, serious adverse events; TEAEs, treatment-emergent adverse events. a All reported deaths within 90 days after last dose, regardless of relationship to study drug. b In total, four deaths were related to study drug, two (pneumonitis and radiation pneumonitis) in the durvalumab arm, one (pneumonitis) in the durvalumab 1 oleclumab arm, and one (myocardial infarction) in the durvalumab 1 monalizumab arm. 3390 © 2022 by American Society of Clinical Oncology Volume 40, Issue 29 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Durvalumab Plus Novel Agents for Unresectable, Stage III NSCLC TABLE 4. TEAEs Occurring in $ 10% of Patients in Any Arm (all causality; as-treated population) Durvalumab Durvalumab 1 Oleclumab Durvalumab 1 Monalizumab (n 5 66) (n 5 59) (n 5 61) Preferred Term Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4 Patients with at least 1 TEAE, 65 (98.5) 23 (34.8) 57 (96.6) 21 (35.6) 61 (100) 16 (26.2) No. (%) Cough 12 (18.2) 0 18 (30.5) 1 (1.7) 27 (44.3) 0 Dyspnea 17 (25.8) 2 (3.0) 15 (25.4) 1 (1.7) 14 (23.0) 1 (1.6) Asthenia 10 (15.2) 0 10 (16.9) 0 14 (23.0) 0 Pneumonitis 11 (16.7) 0 11 (18.6) 0 10 (16.4) 1 (1.6) Pruritus 7 (10.6) 0 10 (16.9) 0 15 (24.6) 0 Hypothyroidism 10 (15.2) 0 9 (15.3) 0 12 (19.7) 0 Arthralgia 11 (16.7) 0 9 (15.3) 0 10 (16.4) 0 Diarrhea 7 (10.6) 1 (1.5) 7 (11.9) 0 12 (19.7) 0 Fatigue 7 (10.6) 0 8 (13.6) 0 9 (14.8) 0 Pyrexia 6 (9.1) 0 8 (13.6) 0 10 (16.4) 0 Rash 6 (9.1) 0 9 (15.3) 0 8 (13.1) 0 Back pain 7 (10.6) 2 (3.0) 5 (8.5) 0 9 (14.8) 0 Hyperthyroidism 8 (12.1) 0 6 (10.2) 0 6 (9.8) 0 Pneumonia 9 (13.6) 6 (9.1) 5 (8.5) 4 (6.8) 4 (6.6) 1 (1.6) Productive cough 7 (10.6) 0 6 (10.2) 0 5 (8.2) 0 Decreased appetite 6 (9.1) 0 6 (10.2) 0 5 (8.2) 0 Constipation 10 (15.2) 0 4 (6.8) 0 2 (3.3) 0 Amylase increased 7 (10.6) 1 (1.5) 4 (6.8) 0 4 (6.6) 1 (1.6) Insomnia 7 (10.6) 0 3 (5.1) 0 4 (6.6) 0 Nausea 8 (12.1) 0 1 (1.7) 0 5 (8.2) 0 Lymphocyte count decreased 4 (6.1) 2 (3.0) 8 (13.6) 4 (6.8) 1 (1.6) 0 Radiation pneumonitis 3 (4.5) 1 (1.5) 7 (11.9) 0 3 (4.9) 0 Hyperglycemia 2 (3.0) 0 6 (10.2) 0 3 (4.9) 0 Anxiety 0 0 1 (1.7) 0 7 (11.5) 0 NOTE. Data cutoff: May 17, 2021. Abbreviation: TEAE, treatment-emergent adverse event. arms. However, the implications of such imbalances re- strategies. The planned phase III PACIFIC-9 study should main uncertain, and the promising results reported here provide further insights into the patient selection approach.23 support further evaluation. Additional limitations of this study include that it was an Exploratory analyses across a range of tumor biomarkers open-label study with response data on the basis of in- demonstrated PFS benefit with both combination regimens vestigator assessment (rather than central review) and the versus durvalumab alone, irrespective of biomarker expres- sample sizes were not powered to assess superiority of the sion; however, given the small sample sizes for these analyses, combination arms. the results should be interpreted with caution, requiring confirmation in larger studies. Moreover, tumor biopsies were In conclusion, interim data indicate that the addition of either collected before CRT, which may upregulate tumor tissue novel agent oleclumab or monalizumab to durvalumab pro- expression of biomarkers, such as CD73 and HLA-E,18-21 vided additional clinical benefit over durvalumab alone in potentially rendering these pre-CRT–based biomarkers in- patients with unresectable, stage III NSCLC without disease accurate predictors of clinical benefit. Obtaining evaluable progression following cCRT. The safety profiles were similar biopsies after cCRT is challenging in large studies. None- across arms with no new or significant safety signals identified theless, additional translational analyses (eg, circulating tumor with either combination. These findings support further DNA) are warranted and ongoing to better understand which evaluation of these combinations in the larger, registration- patients may derive benefit from these unique combination intent PACIFIC-9 study.23 Journal of Clinical Oncology 3391 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Herbst et al AFFILIATIONS AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF 1 Yale Cancer Center, New Haven, CT INTEREST 2 Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Disclosures provided by the authors are available with this article at DOI 3 Gustave Roussy, Villejuif, France https://doi.org/10.1200/JCO.22.00227. 4 Institut Català d’Oncologia, Badalona-Hospital Germans Trias i Pujol, Barcelona, Spain 5 Cross Cancer Institute, Edmonton, AB, Canada DATA SHARING STATEMENT 6 Centre Hospitalier Intercommunal de Créteil, Créteil, France Data underlying the findings described in this manuscript may be 7 Consorcio Hospitalario Provincial de Castellón, Castellón, Spain obtained in accordance with AstraZeneca’s data sharing policy described 8 Cancer Center of Kansas, Wichita, KS at: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/ 9 University of Colorado Anschutz Medical Campus, Aurora, CO Disclosure 10 AstraZeneca, Cambridge, United Kingdom 11 AstraZeneca, Gaithersburg, MD AUTHOR CONTRIBUTIONS 12 Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA Conception and design: Roy S. Herbst, Yee Soo-Hoo, Zachary A. Cooper, 13 Vall d’Hebron Institute of Oncology (VHIO), Hospital Universitari Vall Rakesh Kumar, John Bothos, Charu Aggarwal d’Hebron, Barcelona, Spain Administrative support: Yee Soo-Hoo Provision of study materials or patients: Roy S. Herbst, Margarita Majem, CORRESPONDING AUTHOR Quincy Chu, Alfredo Sanchez-Hernandez, D. Ross Camidge, Yee Soo- Roy S. Herbst, MD, PhD, Yale New Haven Health, Smilow Cancer Hoo, Charu Aggarwal, Alex Martinez-Marti Hospital, 333 Cedar St, Box 208028, New Haven, CT 06510-8028; Collection and assembly of data: Roy S. Herbst, Enric Carcereny, Quincy e-mail: roy.herbst@yale.edu. Chu, Isabelle Monnet, Alfredo Sanchez-Hernandez, Shaker Dakhil, D. Ross Camidge, Yee Soo-Hoo, Zachary A. Cooper, Rakesh Kumar, John Bothos, Charu Aggarwal, Alex Martinez-Marti EQUAL CONTRIBUTION Data analysis and interpretation: Roy S. Herbst, Margarita Majem, Fabrice R.S.H. and C.A. contributed equally to this work. Barlesi, Quincy Chu, D. Ross Camidge, Leanne Winzer, Yee Soo-Hoo, Zachary A. Cooper, Rakesh Kumar, John Bothos, Charu Aggarwal, Alex PRIOR PRESENTATION Martinez-Marti Presented in part at the European Society of Medical Oncology Virtual Manuscript writing: All authors Annual Meeting, September 16-21, 2021. Final approval of manuscript: All authors Accountable for all aspects of the work: All authors SUPPORT Supported by AstraZeneca. ACKNOWLEDGMENT The authors would like to thank the patients who participated in the study, their families and caregivers, as well as investigators and personnel CLINICAL TRIAL INFORMATION across 82 sites in nine countries. Medical writing support, under the NCT03822351 direction of the authors, was provided by Andrew Gannon and Connor Keating of Ashfield MedComms (New York, NY), an Ashfield Health company, and was funded by AstraZeneca. REFERENCES 1. Stewart R, Morrow M, Hammond SA, et al. 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Vokes E, Adjei A, Ahn M, et al: P2.18-01 A multicenter, double-blind, randomized, controlled study of bintrafusp alfa (M7824) in unresectable stage III NSCLC. J Thorac Oncol 14:S902, 2019 (suppl 10) n n n Journal of Clinical Oncology 3393 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Herbst et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST 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 The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Roy S. Herbst Alfredo Sanchez-Hernandez Leadership: Junshi Pharmaceuticals, Immunocore Honoraria: Bristol-Myers Squibb/Medarex, MSD Oncology, AstraZeneca, Roche/ Consulting or Advisory Role: AstraZeneca, Genentech/Roche, Merck, Pfizer, Genentech, Janssen Oncology, Sanofi, Novartis AbbVie, Biodesix, Bristol-Myers Squibb, Lilly, EMD Serono, Heat Biologics, Consulting or Advisory Role: Bristol-Myers Squibb/Medarex, Roche/Genentech, Junshi Pharmaceuticals, Loxo, Nektar, NextCure, Novartis, Sanofi, Seattle Janssen Oncology, Sanofi, AstraZeneca Genetics, Shire, Spectrum Pharmaceuticals, Symphogen, TESARO, Neon Speakers’ Bureau: Bristol-Myers Squibb/Medarex, Janssen Oncology, Therapeutics, Infinity Pharmaceuticals, ARMO Biosciences, Genmab, AstraZeneca, Novartis, MSD Oncology, Roche/Genentech Halozyme, Tocagen, Bolt Biotherapeutics, I-Mab, Mirati Therapeutics, Takeda, Travel, Accommodations, Expenses: Janssen Oncology, Roche, AstraZeneca, Cybrexa Therapeutics, eFFECTOR Therapeutics, Candel Therapeutics, Bristol-Myers Squibb/Medarex, pfizer, Sanofi Oncternal Therapeutics, STCube Pharmaceuticals Inc, WindMIL, Xencor, Bayer, D. Ross Camidge Checkpoint Therapeutics, DynamiCure Biotechnology, Foundation Medicine, Honoraria: Roche, takeda, AstraZeneca, Daiichi Sankyo, bio-thera, Ribon Gilead/Forty Seven, HiberCell, Immune-Onc Therapeutics, Inc, Johnson and Therapeutics, Bristol-Myers Squibb, AbbVie, Apollomics, Elevation Oncology, Johnson, Ocean Biomedical, Inc, Oncocyte Corp, Refactor Health, Inc, Ribbon EMD Serono, Helsinn Therapeutics, Lilly, Nuvalent, Inc, Seattle Genetics, Kestrel Therapeutics, Ventana Medical Systems Labs, Amgen Astellas BioPharma, Eisai, GlaxoSmithKline, Janssen, OnKure, Research Funding: AstraZeneca, Merck, Lilly, Genentech/Roche Mersana, Pfizer, QiLu Pharmaceutical, Sanofi, Anheart Therapeutics, BeiGene, Margarita Majem Blueprint Medicines, Hengrui Pharmaceutical, Puma Biotechnology, Turning Consulting or Advisory Role: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Point Therapeutics Sharp & Dohme, Pfizer, Boehringer Ingelheim, Novartis, Tesaro, Helsinn Research Funding: Inivata (Inst) Therapeutics, Takeda, Sanofi, Janssen Oncology, Pierre Fabre Leanne Winzer Research Funding: BMS (Inst) Employment: AstraZeneca, IQvia Travel, Accommodations, Expenses: AstraZeneca, Roche, Lilly Stock and Other Ownership Interests: AstraZeneca Fabrice Barlesi Yee Soo-Hoo Honoraria: Genentech/Roche, Pfizer, Pierre Fabre, AstraZeneca, Bristol-Myers Employment: AstraZeneca/MedImmune Squibb, Boehringer Ingelheim, Lilly, Novartis, Pierre Fabre, Merck Serono, MSD Stock and Other Ownership Interests: AstraZeneca/MedImmune Oncology, Takeda, Bayer, Seattle Genetics, Mirati Therapeutics Travel, Accommodations, Expenses: AstraZeneca/MedImmune Consulting or Advisory Role: Roche/Genentech, Pfizer, Novartis, Pierre Fabre, Bristol-Myers Squibb, AstraZeneca/MedImmune, Boehringer Ingelheim, Lilly, Zachary A. Cooper Merck Serono, MSD Oncology, Takeda, Bayer, Mirati Therapeutics Employment: AstraZeneca Research Funding: Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Stock and Other Ownership Interests: AstraZeneca/MedImmune Bristol-Myers Squibb (Inst), Pierre Fabre (Inst), AbbVie (Inst), Amgen (Inst), Rakesh Kumar Bayer (Inst), Boehringer Ingelheim (Inst), Eisai (Inst), Lilly (Inst), Ipsen (Inst), Employment: AstraZeneca/MedImmune Innate Pharma (Inst), Novartis (Inst), Merck Serono (Inst), MSD Oncology (Inst), Stock and Other Ownership Interests: AstraZeneca Pfizer (Inst), Sanofi/Aventis (Inst), Takeda (Inst) Travel, Accommodations, Expenses: Roche/Genentech, Bristol-Myers Squibb, John Bothos AstraZeneca/MedImmune, MSD Oncology Employment: AstraZeneca/MedImmune Stock and Other Ownership Interests: AstraZeneca/MedImmune Enric Carcereny Travel, Accommodations, Expenses: AstraZeneca/MedImmune Consulting or Advisory Role: Roche/Genentech, Bristol-Myers Squibb, Takeda, Pfizer, MSD Oncology, Boehringer Ingelheim, AstraZeneca Spain Charu Aggarwal Speakers’ Bureau: MSD Oncology, BMSi, Takeda, AstraZeneca Spain, Roche Consulting or Advisory Role: Genentech, Lilly, Celgene, Merck, AstraZeneca, Travel, Accommodations, Expenses: Bristol-Myers, Roche, Takeda Blueprint Genetics, Shionogi, Daiichi Sankyo/AstraZeneca, Regeneron/Sanofi, Eisai, BeiGene, Turning Point Therapeutics, Pfizer, Janssen, Boehringer Quincy Chu Ingelheim Honoraria: Novartis, Bristol-Myers Squibb, Merck, Boehringer Ingelheim, Lilly, Speakers’ Bureau: AstraZeneca, Roche/Genentech AstraZeneca, Pfizer, Eisai, AbbVie, Takeda, Roche, Amgen, Anheart Research Funding: Genentech/Roche (Inst), Incyte (Inst), Macrogenics (Inst), Therapeutics, Esperas Pharma, Ocellaris Pharma, Johnson & Johnson/Janssen, Merck Sharp & Dohme (Inst), AstraZeneca/MedImmune (Inst) Sanofi Consulting or Advisory Role: Novartis, Bristol-Myers Squibb, Roche, Merck, Alex Martinez-Marti Lilly, Boehringer Ingelheim, Pfizer, AstraZeneca, Eisai, AbbVie, Takeda, Roche, Consulting or Advisory Role: Bristol-Myers Squibb, Roche, Merck Sharp & Amgen, Bayer, Anheart Therapeutics, Esperas Pharma, Ocellaris Pharma, Dohme, Pfizer, Boehringer Ingelheim, MSD Oncology, AstraZeneca/ Astellas Pharma, Johnson & Johnson/Janssen MedImmune Research Funding: AstraZeneca Speakers’ Bureau: Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Boehringer Ingelheim, AstraZeneca/MedImmune Isabelle Monnet Travel, Accommodations, Expenses: Roche, Bristol-Myers Squibb, Pfizer, Travel, Accommodations, Expenses: Takeda, Pfizer, Oxyvie Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca/MedImmune No other potential conflicts of interest were reported. © 2022 by American Society of Clinical Oncology Volume 40, Issue 29 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Durvalumab Plus Novel Agents for Unresectable, Stage III NSCLC APPENDIX 1. SUPPLEMENTARY METHODS Diagnostics, Ventana Medical Systems; Tucson, AZ); CD73, Cell Signaling Technology antibody clone D7F9A IHC assay (specific an- Exclusion Criteria tibody concentration of 0.5 mg/ml; Cell Signaling Technology; Danvers, MA); histocompatibility complex E (HLA-E), Abcam antibody clone Patients with mixed small-cell and non–small-cell histology, current or MEM-E/02 IHC assay (specific antibody concentration of 0.75 mg/mL; prior use of immunosuppressants within 14 days of first dose of study Abcam, Cambridge, United Kingdom); and NKG2A, Abcam antibody drug, prior exposure to any anti–programmed cell death-1, anti– clone EPR23737-127 (specific antibody concentration of 0.2 mg/mL; programmed cell death ligand-1 (PD-L1), or anticytotoxic Abcam). All of the IHC-stained slides were converted into high- T-lymphocyte–associated antigen-4 therapy for non–small-cell lung resolution digital images of the whole section (e-slide) using Aperio AT cancer, any unresolved grade . 2 toxicity (per National Cancer In- Turbo or Aperio XT scanners (Leica Biosystems; Buffalo Grove, IL) with stitute Common Terminology Criteria for Adverse Events version 5.0 a 203 objective magnification. Digital images were manually anno- [NCI CTCAE v5.0]) from prior chemoradiotherapy (CRT), or history of tated by a pathologist to designate the tumor areas. Marker quanti- venous thrombosis within 3 months before random assignment were fication was performed by Definiens AG (Munich, Germany) via image excluded. Further exclusion criteria included history of active primary analysis using Definiens Developer software program, employing immunodeficiency, history of grade $ 2 pneumonitis following CRT, customized algorithms for NKG2A and HLA-E, which were reported as active or prior documented autoimmune disorders, and major surgery marker-positive cells/mm2 of tumor area and the percentage of HLA- within 28 days before the first dose of study drug. E1 cells in tumor epithelium, respectively. PD-L1 and CD73 were All patients provided written informed consent. The study was carried reported as the percentage of positive tumor cells as scored by a out in accordance with protocols and principles set out in the Dec- pathologist. The number of patients with evaluable samples for each laration of Helsinki and International Conference on Harmonisation marker was PD-L1 (n 5 108), CD73 (n 5 107), NKG2A (n 5 105), and Good Clinical Practice Guidelines, as well as any applicable local laws HLA-E (n 5 103). and requirements. Statistical Analyses Tumor Assessment Imaging This phase II study was not designed to test a specific hypothesis Imaging scans were taken during screening; within 28 days of cycle around the primary end point. A sample size of 60 patients per arm was 1 day 1; from cycle 1 day 1, every 8 weeks (6 7 days) for the first chosen to provide an acceptable level of precision for the estimated 12 months (treatment period); then every 12 weeks (6 7 days) until 24 difference in objective response rate between the control and ex- months; and, thereafter, every 6 months (6 4 weeks) until 60 months. perimental arms, being approximately 6 18% based upon an exact 2-sided 95% CI. This ad hoc interim analysis reported here was Immunohistochemistry conducted after all patients had a minimum follow-up of 10 months to support further development of the experimental arms. Archival (preconcurrent CRT) tumor specimens (which were not mandatory for enrollment) were obtained and a pathologist examined a For progression-free survival, patients with no progressive disease or hematoxylin and eosin–stained slide from each tissue block for the death at the time of analysis, or those lost to follow-up, were censored presence of tumor. Sections of 4-mm thickness were cut from a at the date of their last evaluable progression-free disease assessment. representative tumor block, selected from each patient for immuno- Patients with a death or progressive disease, immediately after two or histochemistry (IHC) analysis. The IHC tests used for each biomarker more consecutively missed or nonevaluable disease assessments, were as follows (using previously optimized conditions): PD-L1 ex- were censored at the date of last progression-free disease assessment pression was tested using the Ventana antibody clone SP263 IHC (before the missed or nonevaluable assessments) or random as- assay (specific antibody concentration of 1.61 mg/mL; Roche signment, whichever occurred last. Journal of Clinical Oncology Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Herbst et al Study treatment up to 12 months Control Durvalumab 1,500 mg IV Locally advanced, monotherapy Q4W unresectable, stage III NSCLC 1-42 days post-cCRT No progression Randomly Arm A after prior cCRT assigned Durvalumab 1,500 mg IV Q4W 1:1:1 + oleclumab 3,000 mg IV ECOG PS 0 or 1 Stratification by Oleclumab Q2W for cycles 1 and 2, histology then Q4W starting cycle 3 Randomly assigned (adenocarcinoma and (n = 189) nonadenocarcinoma) Arm B Durvalumab 1,500 mg IV Q4W + monalizumab 750 mg IV Q2W FIG A1. COAST study design. cCRT, concurrent chemoradiotherapy; ECOG PS, Eastern Coop- erative Oncology Group performance status; IV, intravenously; NSCLC, non–small-cell lung cancer; Q2W, once every 2 weeks; Q4W, once every 4 weeks. © 2022 by American Society of Clinical Oncology Volume 40, Issue 29 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Durvalumab Plus Novel Agents for Unresectable, Stage III NSCLC A PD-L1 TC t 1% No. of Events/ Total No. of Median PFS, Months 12-Month PFS Treatment Arm Patients (%) (95% CI)a Rate, % (95% CI) HR, % (95% CI)b Durvalumab + monalizumab 5/20 (25.0) NR (13.6 to NE) 90.0 (65.6 to 97.4) 0.19 (0.07 to 0.54) Durvalumab + oleclumab 8/23 (34.8) NR (5.5 to NE) 63.0 (39.3 to 79.6) 0.40 (0.17 to 0.94) Durvalumab 18/30 (60.0) 4.4 (3.5 to 12.8) 32.9 (14.4 to 52.9) — 1.0 0.9 0.8 PFS (probability) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 2 4 6 8 10 12 14 16 18 20 Time Since Random Assignment (months) No. at risk: Durvalumab + monalizumab 20 20 19 19 19 14 10 6 3 1 1 Durvalumab + oleclumab 23 18 17 15 14 11 8 5 4 3 0 Durvalumab 30 23 13 10 7 5 5 2 2 1 0 B PD-L1 TC  1% No. of Events/ Total No. of Median PFS, Months 12-Month PFS Treatment Arm Patients (%) (95% CI)a Rate, % (95% CI) HR, % (95% CI)b Durvalumab + monalizumab 6/12 (50.0) 12.3 (3.5 to NE) 53.0 (20.9 to 77.3) 0.87 (0.31 to 2.48) Durvalumab + oleclumab 1/7 (14.3) NR (13.0 to NE) 100.0 (100.0 to 100.0) NE Durvalumab 9/16 (56.3) 7.3 (3.0 to NE) 36.1 (13.2 to 59.9) — 1.0 0.9 0.8 PFS (probability) 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 2 4 6 8 10 12 14 16 18 20 Time Since Random Assignment (months) No. at risk: Durvalumab + monalizumab 12 10 8 7 5 5 4 1 0 0 0 Durvalumab + oleclumab 7 7 7 6 6 6 5 2 2 1 0 Durvalumab 16 12 10 8 5 4 4 4 2 1 0 FIG A2. Exploratory PFS in patients with tumoral PD-L1 expression (A) $1% and (B) ,1%. Data cutoff: May 17, 2021 (median follow-up of 11.5 months; range, 0.4-23.4 months). aKaplan-Meier estimates for PFS, PFS rate, and 95% CIs. bPFS HR and 95% CI estimated by Cox regression model, stratified by histology (adenocarcinoma and nonadenocarcinoma). HR, hazard ratio; ITT, intention to treat; NE, not estimable; NR, not reached; PD-L1, programmed cell death ligand-1; PFS, progression-free survival. Journal of Clinical Oncology Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Herbst et al A B D+O D Stratified HR D+M D Stratified HR No. of Events/Patients (95% CI)a No. of Events/Patients (95% CI)a Overall 22/60 38/67 0.44 (0.26 to 0.75) 21/62 36/64 0.42 (0.24 to 0.72) CD73 status TC t 10% 5/11 12/19 0.48 (0.17 to 1.39) 4/9 12/19 0.46 (0.15 to 1.46) TC < 10% 4/19 15/27 0.27 (0.09 to 0.82) 7/22 15/27 0.33 (0.13 to 0.81) Unknown 13/30 11/21 0.67 (0.30 to 1.50) 10/31 11/21 0.55 (0.22 to 1.36) NKG2A status t median 2/11 17/27 0.21 (0.05 to 0.91) 3/15 17/27 0.18 (0.05 to 0.64) < median 6/16 11/21 0.58 (0.21 to 1.61) 8/15 11/21 0.86 (0.34 to 2.15) Unknown 14/33 10/19 0.59 (0.26 to 1.36) 10/32 10/19 0.42 (0.17 to 1.04) HLA-E status t median 4/17 11/17 0.20 (0.05 to 0.72) 5/18 11/17 0.20 (0.06 to 0.64) < median 2/12 16/28 0.20 (0.04 to 0.89) 6/11 16/28 0.67 (0.26 to 1.73) Unknown 16/31 11/22 0.80 (0.37 to 1.75) 10/33 11/22 0.51 (0.21 to 1.26) 0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0 D + O Better D Better D + M Better D Better FIG A3. Exploratory PFS analysis by tumor CD73, NKG2A, and HLA-E expression per investigator assessment (ITT population): (A) durvalumab 1 oleclumab versus durvalumab alone and (B) durvalumab 1 monalizumab versus durvalumab alone. Data cutoff: May 17, 2021 (median follow-up of 11.5 months; range, 0.4-23.4 months). aHR calculations were performed using Cox regression models in patients with evaluable biomarker expression. CD73, cluster of differentiation 73; D, durvalumab; HLA-E, histocompatibility complex E; HR, hazard ratio; ITT, intention-to-treat; M, monalizumab; NE, not evaluable; O, oleclumab; PFS, progression-free survival; TC, tumor cell. TABLE A1. Durvalumab-Related TEAEs Occurring in $10% of Patients in Any Arm (as-treated population) Durvalumab Durvalumab 1 Oleclumab Durvalumab 1 Monalizumab (n 5 66) (n 5 59) (n 5 61) Preferred Term Any Grade Grade 3/4 Any Grade Grade 3/4 Any Grade Grade 3/4 Patients with at least one 49 (74.2) 5 (7.6) 45 (76.3) 2 (3.4) 47 (77.0) 7 (11.5) durvalumab-related TEAE, No. (%) Asthenia 6 (9.1) 0 7 (11.9) 0 7 (11.5) 0 a Pneumonitis 7 (10.6) 0 10 (16.9) 0 6 (9.8) 1 (1.6) Pruritus 6 (9.1) 0 10 (16.9) 0 10 (16.4) 0 Hypothyroidism 10 (15.2) 0 8 (13.6) 0 11 (18.0) 0 Diarrhea 2 (3.0) 1 (1.5) 3 (5.1) 0 8 (13.1) 0 Rash 4 (6.1) 0 7 (11.9) 0 6 (9.8) 0 NOTE. Data cutoff: May 17, 2021. Abbreviation: TEAE, treatment-emergent adverse event. a In addition, radiation pneumonitis of any grade (grade 3/4) occurred in two (1) patients in the durvalumab arm. © 2022 by American Society of Clinical Oncology Volume 40, Issue 29 Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved. Durvalumab Plus Novel Agents for Unresectable, Stage III NSCLC TABLE A2. AESIs Related to Durvalumab (as-treated population). Durvalumab Durvalumab 1 Oleclumab Durvalumab 1 Monalizumab (n 5 66) (n 5 59) (n 5 61) Grouped Term Any Grade Any Grade Any Grade Any AESIa, No. (%) 37 (56.1) 36 (61.0) 41 (67.2) b Pneumonitis 12 (18.2) 12 (20.3) 11 (18.0) Rash 6 (9.1) 12 (20.3) 14 (23.0) Hypothyroid events 10 (15.2) 9 (15.3) 12 (19.7) Diarrhea 7 (10.6) 7 (11.9) 12 (19.7) Hyperthyroid events 8 (12.1) 6 (10.2) 6 (9.8) Dermatitis 4 (6.1) 4 (6.8) 2 (3.3) Hepatic events 3 (4.5) 1 (1.7) 0 Other rare/miscellaneousc 0 0 2 (3.3) Renal events 0 1 (1.7) 0 Infusion-related reaction 0 1 (1.7) 0 Type 1 diabetes mellitus 0 0 1 (1.6) Colitis 1 (1.5) 0 0 Hypersensitivity/anaphylactic 1 (1.5) 0 0 reactions Myositis 1 (1.5) 0 0 NOTE. Data cutoff: May 17, 2021. Abbreviation: AESI, adverse event of special interest. a Patients with multiple events in the same category were counted once in that category; patients with events in more than one category were counted once in each of those categories. b Includes immune-mediated lung disease, interstitial lung disease, and pneumonitis. c Includes iridocyclitis and pericarditis. Journal of Clinical Oncology Downloaded from ascopubs.org by 92.177.142.130 on October 2, 2023 from 092.177.142.130 Copyright © 2023 American Society of Clinical Oncology. All rights reserved.