Background

Primary analysis of Lung ART trial has shown (ESMO 2020) a non-statistically significant effect of PORT on disease-free survival (DFS) in N2 NSCLC patients (HR = 0·86 (95% CI 0·68-1·08]; p=0·18). However PORT was associated with a reduction of 51% in the risk of mediastinal relapse (MR). Patterns of relapse as well as prognostic factors of PORT efficacy warranted further investigations to determine which patients could benefit more from PORT.

Methods

Patients were eligible in Lung ART if they had a WHO performance status ≤2, considered to have undergone complete resection with lymph node exploration, proven N2 disease +/- prior neo-adjuvant or adjuvant CT. DFS components (metastatic, mediastinal relapses and deaths) were analysed using competing risks approaches. Prognosis factors for DFS and OS were explored based on prespecified analyses coupled with an exploratory approach.

Results

501 patients were randomised. Among DFS events, there are 161 (54%) metastatic relapses (including 61 (21%) brain metastases), 106 (36%) MR, and 29 (10%) deaths. Three-year metastatic relapse-free survival is 72.31% [66.5;77.1] and 68.47% [61.7;74] in the control and PORT arms, respectively; 3-year MR-free survival is 72.26% [65.9;77.4] and 86.06% [81.2;89.7], respectively. MR occurs mainly within initially involved nodes (66% in control arm, 47% in PORT arm) and significantly less in PORT arm (unadjusted sub-distribution HR= 0.46 (95% CI [0.3;0.7]). The 3 most frequent sites of MR are stations 7 (47%), 4L (42%), 4R (37%) for left-sided tumours; stations 4R (48%), 2R (44%) and 7 (41%) for right-sided tumours. Prognostic factors for DFS include quality of resection, extent of mediastinal involvement and lymph node ratio (involved / explored), with differential effects according to DFS components. With regards to overall survival, extent of nodal involvement is a significant prognostic factor whereas PORT (HR = 0.98 [0.7;1.4]) is not.

Conclusions

Use of PORT in N2 NSCLC patients reduces the risk of MR, but has no significant impact on DFS. Prognostic factors associated with different DFS components were identified which may allow a personalized prescription of PORT.

Clinical trial identification

NCT00410683.

Legal entity responsible for the study

Gustave Roussy.

Funding

French National Cancer Institute (INCa), French Health Ministry (PHRC), Gustave Roussy and Cancer Research UK grant (A13969).

Disclosure

C. Le Pechoux: Non-Financial Interests, Institutional, Advisory Board, Outside the submitted work: AstraZeneca, Nanobiotix, Roche; Non-Financial Interests, Institutional, Invited Speaker, Outside the submitted work: Amgen, Eli Lilly, Medscape; Financial Interests, Personal, Invited Speaker, Outside the submitted work: PriME Oncology. F. Barlesi: Financial Interests, Personal, Other: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Seattle Genetics, Takeda; Financial Interests, Institutional, Other, Outside the submitted work: AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eisai, Eli Lilly Oncology, F. Hoffmann-La Roche Ltd., Genentech, Ipsen, Ignyta, Innate Pharma, Loxo, Novartis, MedImmune, Merck, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis. N. Pourel: Non-Financial Interests, Institutional, Research Grant, Outside the submitted work: Pfizer, Varian. C. Faivre-Finn: Financial Interests, Institutional, Research Grant, Outside the submitted work: AstraZeneca, Elekta. G. Zalcman: Financial Interests, Personal, Advisory Board, All outside the submitted work: BMS, MSD, AstraZeneca, Boehringer Ingelheim; Non-Financial Interests, Institutional, Research Grant, All outside the submitted work: Roche, Takeda AstraZeneca, AbbVie. A. Bardet: Financial Interests, Personal, Other, Consultancy fees: Roche. All other authors have declared no conflicts of interest.

Background

In the randomized phase 3 CheckMate 743 study (NCT02899299), NIVO + IPI significantly prolonged overall survival (OS) vs chemo in pts with unresectable MPM. Here we report updated efficacy and safety with a 3-y minimum follow-up (f/u), as well as novel biomarker analyses.

Methods

Pts with untreated MPM, stratified by histology (epithelioid vs non-epithelioid) and sex, were randomized 1:1 to NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W (≤ 2 y) or to chemo Q3W (6 cycles). The primary endpoint was OS; safety and biomarker assessments were prespecified exploratory endpoints. OS association with a 4-gene inflammatory gene expression signature (CD8A, PD-L1, STAT-1, LAG-3) was estimated by RNA sequencing and categorized as high vs low relative to median score. Lung immune prognostic index (LIPI) score was based on baseline (BL) derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase levels.

Results

With a minimum f/u of 35.5 mo (database lock [DBL] 7 May 2021), NIVO + IPI continued to provide OS benefit vs chemo (HR 0.75, 95% CI 0.63–0.90; Table). In exploratory biomarker analyses, median OS was longer for pts with high vs low inflammatory gene signature score (21.8 vs 16.8 mo) in the NIVO + IPI arm; this signature score was not associated with prolonged OS for chemo. OS showed a trend favoring NIVO + IPI vs chemo across good, intermediate, and poor BL LIPI subgroups; HR (95% CI), 0.78 (0.60–1.01), 0.76 (0.57–1.01), and 0.83 (0.44–1.57), respectively. Grade 3–4 treatment-related adverse events occurred in 30.7% (NIVO + IPI) and 32.0% (chemo) of pts; no increase was reported from the previous DBL. Table: LBA65

Efficacy outcomes with NIVO + IPI vs chemo

Conclusions

With a 3-y minimum f/u, NIVO + IPI continued to provide survival benefit vs chemo in pts with unresectable MPM despite pts being off therapy for 1 y; no new safety signals were observed. Exploratory analyses suggest that a high inflammatory gene signature score may correlate with improved survival benefit with NIVO + IPI.

Clinical trial identification

NCT02899299; 14 September 2016.

Editorial acknowledgement

All authors contributed to and approved the presentation; writing and editorial assistance were provided by Nick Patterson, PhD, of Caudex, London, UK, funded by Bristol Myers Squibb.

Legal entity responsible for the study

Bristol Myers Squibb (Princeton, NJ) and Ono Pharmaceutical Company Ltd. (Osaka, Japan).

Funding

Bristol Myers Squibb.

Disclosure

S. Peters: Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): AbbVie; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Amgen; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Amgen; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): AstraZeneca; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): AstraZeneca; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): AstraZeneca; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Bayer; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Beigene; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Biocartis; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Biodesiex; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Boehringer Ingelheim; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Boehringer Ingelheim; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Boehringer Ingelheim; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Bristol Myers Squibb; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Clovis; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Clovis; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Daiichi Sankyo; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Debiopharm; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): ecancer; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): ecancer; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Eli Lilly; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Eli Lilly; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Foundation Medicine; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): GlaxoSmithKline; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Illumina; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Illumina; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Illumina; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Imedex; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): IQVIA; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Incyte; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Janssen; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Lilly; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Medscape; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Medscape; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Merck Sharp & Dohme; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Merck Sharp & Dohme; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Merck Serono; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Merck Serono; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Merrimack; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Mirati; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Novartis; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Novartis; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Novartis; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): PharmaMar; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Phosplatin Therapeutics; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Phosplatin Therapeutics; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): PER; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): PER; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Pfizer; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Pfizer; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Pfizer; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): PRIME; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): PRIME; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Regeneron; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Roche/Genentech; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Roche/Genentech; Financial Interests, Institutional, Research Grant, Received honoraria (all fees to institution): Roche/Genentech; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): RTP; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): RTP; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Sanofi; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Sanofi; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Seattle Genetics; Financial Interests, Institutional, Advisory Role, Received honoraria (all fees to institution): Takeda; Financial Interests, Institutional, Speaker’s Bureau, Received honoraria (all fees to institution): Takeda. A. Scherpereel: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: AstraZeneca; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Roche; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Speaker’s Bureau: Merck Sharp & Dohme; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Merck Sharp & Dohme. R. Cornelissen: Financial Interests, Personal, Speaker’s Bureau: Roche; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Speaker’s Bureau: Pfizer; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Spectrum. Y. Oulkhouir: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: AstraZeneca. L. Greillier: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Personal, Advisory Board: Novartis. T. Talbot: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Other, Travel/expenses: Bristol Myers Squibb; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb. I. Monnet: Non-Financial Interests, Personal, Invited Speaker, Congress: ESMO 2019: Pfizer; Non-Financial Interests, Personal, Invited Speaker, Congress: ESMO 2018: Roche. S. Hiret: Financial Interests, Personal and Institutional, Advisory Board: Takeda; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca. P. Baas: Financial Interests, Institutional, Advisory Role, Fee to hospital: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Fee to hospital: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role, Fee to hospital: Takeda; Financial Interests, Institutional, Advisory Role, Fee to hospital: BeiGene; Financial Interests, Institutional, Advisory Role, Fee to hospital: AstraZeneca; Financial Interests, Institutional, Advisory Role, Fee to hospital: Merck Sharp & Dohme; Financial Interests, Institutional, Advisory Role, Fee to hospital: Roche; Financial Interests, Institutional, Advisory Role, Fee to hospital: Epizyme; Financial Interests, Institutional, Advisory Role, Fee to hospital: Trizell; Financial Interests, Institutional, Advisory Role, Fee to hospital: Daiichi Sankyo. A.K. Nowak: Financial Interests, Personal, Advisory Role, clinical trials consultant: Bayer; Financial Interests, Personal, Advisory Role, clinical trials consultant: Pharmabcine; Financial Interests, Personal, Advisory Role, clinical trials consultant: Trizell; Financial Interests, Personal, Advisory Board, clinical trial steering committee: Roche; Financial Interests, Personal, Advisory Board, clinical trial steering committee: Boehringer Ingelheim; Financial Interests, Personal, Other, Travel/Accommodation/Expenses: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board, clinical trial steering committee: Merck Sharp & Dohme; Financial Interests, Personal and Institutional, Advisory Role, clinical trials consultant: Douglas Pharmaceuticals; Financial Interests, Personal and Institutional, Research Grant: Douglas Pharmaceuticals; Financial Interests, Personal and Institutional, Advisory Role, clinical trials consultant: Atara Biotherapeutics; Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Other, Travel/Accommodation/Expenses: AstraZeneca. N. Fujimoto: Financial Interests, Personal, Advisory Role: Ono Pharmaceutical; Financial Interests, Institutional, Research Grant: Ono Pharmaceutical; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb. A.S. Tsao: Financial Interests, Institutional, Advisory Board: Genentech; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Ariad; Financial Interests, Institutional, Advisory Board: EMD Serono; Financial Interests, Institutional, Research Grant: EMD Serono; Financial Interests, Institutional, Advisory Board: Merck; Financial Interests, Personal and Institutional, Advisory Board: Seattle Genetics; Financial Interests, Personal and Institutional, Research Grant: Seattle Genetics; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim; Financial Interests, Personal, Advisory Board: Sellas Life Science; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Research Grant: Millennium; Financial Interests, Institutional, Research Grant: Polaris; Financial Interests, Institutional, Research Grant: Epizyme. A.S. Mansfield: Financial Interests, Personal and Institutional, Advisory Role: AbbVie; Financial Interests, Personal and Institutional, Other, Travel/Accommodation/Expenses: AbbVie; Financial Interests, Institutional, Advisory Role: AstraZeneca; Financial Interests, Institutional, Advisory Role: Bristol Myers Squibb; Financial Interests, Institutional, Advisory Role: Genentech; Financial Interests, Institutional, Research Grant: Novartis; Financial Interests, Institutional, Research Grant: Verily; Financial Interests, Institutional, Member of the Board of Directors: Mesothelioma Applied Research Foundation; Financial Interests, Personal and Institutional, Other, Travel/Accommodation/Expenses: Roche; Financial Interests, Institutional, Advisory Role: Janssen; Financial Interests, Institutional, Research Grant: Mark Foundation; Financial Interests, Institutional, Research Grant: NIH. S. Popat: Financial Interests, Personal and Institutional, Advisory Board: Amgen; Financial Interests, Personal and Institutional, Research Grant: Amgen; Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca; Financial Interests, Personal and Institutional, Principal Investigator: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Advisory Board: Beigene; Financial Interests, Personal, Advisory Board: Blueprint; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Principal Investigator: Boehringer Ingelheim; Financial Interests, Personal and Institutional, Advisory Board: Daiichi Sankyo; Financial Interests, Personal and Institutional, Principal Investigator: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Guardant Health; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Merck KGaA; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal and Institutional, Advisory Board: Roche; Financial Interests, Personal and Institutional, Principal Investigator: Roche; Financial Interests, Personal and Institutional, Advisory Board: Takeda; Financial Interests, Personal and Institutional, Principal Investigator: Takeda; Financial Interests, Institutional, Principal Investigator: Ariad; Financial Interests, Institutional, Principal Investigator: Celgene; Financial Interests, Institutional, Principal Investigator: GlaxoSmithKline; Financial Interests, Institutional, Research Grant: Merck Sharp & Dohme; Financial Interests, Institutional, Principal Investigator: Trizel; Financial Interests, Institutional, Principal Investigator: Turing Point Therapeutics. X. Zhang: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. N. Hu: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. D. Balli: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. J. Sanzari: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. G. Zalcman: Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca; Financial Interests, Personal and Institutional, Other, Travel/Accommodation/Expenses: AstraZeneca; Financial Interests, Personal and Institutional, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Other, Travel/Accommodation/Expenses: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Advisory Role: Roche; Financial Interests, Personal and Institutional, Research Grant: Roche; Financial Interests, Personal and Institutional, Other, Travel/Accommodation/Expenses: Roche; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme; Financial Interests, Personal, Advisory Role: Da Volterra; Financial Interests, Personal and Institutional, Advisory Role: Inventiva; Financial Interests, Personal and Institutional, Research Grant: Inventiva; Financial Interests, Institutional, Other, Travel/Accommodation/Expenses: Boehringer Ingelheim; Financial Interests, Institutional, Other, Travel/Accommodation/Expenses: AbbVie; Financial Interests, Institutional, Other, Travel/Accommodation/Expenses: Pfizer. All other authors have declared no conflicts of interest.

Background

Thymic malignancies are rare intrathoracic tumors which still represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of platinum-based chemotherapy.

Methods

NIVOTHYM is the first international multicenter phase II, 2-cohort, single-arm trial evaluating the use of nivolumab (240 mg IV Q2 weeks) +/- ipilimumab (1mg /kg IV Q6 weeks) in patients (pts) with advanced/relapsed type B3 thymoma or thymic carcinoma, after exposure of platinum-based chemotherapy. Primary endpoint is progression-free survival rate at 6 months (PFSR6, binary) based on RECIST 1.1 per independent radiological review. A two-stage design was used (H1 60%, H0 40%, α 10%, power 90%). We report the final results of the nivolumab monotherapy cohort.

Results

From Apr 2018 to Feb 2020, 55 pts were enrolled in 15 centers/5 countries, including 35 (64%) males, 27 (49%) never-smokers and 53 (96%) PS0-1 pts. Median age was 58 years. Histology was thymoma in 10 (18%) pts and thymic carcinoma in 45 (82%) pts; 16 (29%) pts underwent prior surgical resection. After a median follow-up of 13.3 months, nivolumab had been discontinued in 45 pts, related to progression in 30, toxicity in 9, patient or investigator decision in 4, occurrence of other malignancy in 1, and completion in 1 case. In the safety population of 54 pts, adverse events (AEs) of grade 1/2 were observed in 22 (41%) pts and for grade 3/4 AEs in 31 (57%) pts; grade 5 toxicity was reported in 1 patient (respiratory failure). Grade ≥3 immune-related AEs included 2 myocarditis, 4 hepatitis/elevated transaminases, 2 colitis and 1 pneumonitis. Among the 49 eligible pts who started treatment, PFSR6 by central review was 35% (95%CI 22-50) and 39% by local assessment (95%CI 25-54). ORR and DCR were 12% (95%CI 5-25) and 63% (95%CI 48-77), respectively. Using the Kaplan-Meier method, median PFS (local) and OS were 6.0 (95% CI 3.1-10.4) and 21.3 (95% CI 11.6-NE) months, respectively.

Conclusions

Nivolumab monotherapy is demonstrating a manageable safety profile and objective activity, however insufficient to meet the trial primary objective. The second cohort is currently ongoing to assess combination of nivolumab plus ipilimumab.

Clinical trial identification

NCT03134118.

Legal entity responsible for the study

EORTC.

Funding

BMS.

Disclosure

N. Girard: Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Personal, Invited Speaker: MSD; Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Invited Speaker: Boehringer; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Advisory Board: Sivan; Financial Interests, Personal, Advisory Board: Janssen; Financial Interests, Personal, Advisory Board: Boehringer; Financial Interests, Personal, Advisory Board: Novartis; Financial Interests, Personal, Advisory Board: Sanofi; Financial Interests, Personal, Advisory Board: AbbVie; Financial Interests, Personal, Advisory Board: Amgen; Financial Interests, Personal, Advisory Board: Lilly; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Personal, Advisory Board: Grunenthal; Financial Interests, Personal, Advisory Board: Takeda; Financial Interests, Institutional, Research Grant, Local: Roche; Financial Interests, Institutional, Research Grant, Local: Sivan; Financial Interests, Institutional, Research Grant, Local: Janssen; Non-Financial Interests, Invited Speaker, French Thoracic Cancer Intergroup, Treasurer: IFCT; Non-Financial Interests, Officer, International Thymic malignancy interest group, president: ITMIG; Other, My partner is an employee: AstraZeneca. All other authors have declared no conflicts of interest.

Background

PACIFIC established consolidation durvalumab (D) as SoC for unresectable Stage III NSCLC with no progression after cCRT. Combination therapy may improve outcomes. CD73 is involved in RT resistance. RT induces NKG2A ligand and shows additive antitumour effects with PD-1 blockade preclinically. COAST (NCT03822351) is a global phase 2 study of D alone or combined with the anti-CD73 mAb oleclumab (O) or anti-NKG2A mAb monalizumab (M) as consolidation therapy.

Methods

Pts with histologically/cytologically documented unresectable Stage III NSCLC, ECOG PS 0/1 and no progression after cCRT were randomised 1:1:1 ≤42 days post cCRT to receive D 1500 mg IV Q4W alone or combined with O 3000 mg IV Q2W (first 2 cycles, then Q4W) or M 750 mg IV Q2W for up to 12 months, stratified by histology. The primary endpoint was investigator-assessed post cCRT ORR per RECIST v1.1. Key secondary endpoints included PFS and safety.

Results

Between Jan 2019 and Jul 2020, 189 pts were randomised, of whom 186 received D (n=66), D+O (n=59) or D+M (n=61). As of 17 May 2021, median follow-up was 11.5 months (range, 0.4–23.4; all pts). D+O and D+M numerically increased ORR (odds ratio [95% CI] 1.83 [0.80, 4.20] and 1.77 [0.77, 4.11] respectively) and significantly improved PFS versus D alone. Grade ≥3 treatment-emergent AE (TEAE, all-cause) incidence was 39.4%, 40.7% and 27.9% with D, D+O and D+M respectively. Overall, the most common grade 3/4 TEAEs were pneumonia (5.9%) and decreased lymphocyte count (3.2%); both were more common with D and D+O than with D+M. Combined rates of pneumonitis and radiation pneumonitis of any grade were 21.2% with D, 28.8% with D+O and 21.3% with D+M, with grade ≥3 events in 3.0%, 3.4% and 1.6%. Biomarker data will be presented.

Conclusions

Addition of both novel agents improved ORR, PFS and 10-month PFS rate over D alone. Safety was similar across arms with no new safety signals identified. Table: LBA42

Clinical trial identification

NCT03822351 (release date: January 30, 2019).

Editorial acknowledgement

Medical writing support, under the direction of the authors, was provided by Connor Keating, BSc, and Andrew Gannon, MS, MA, of Ashfield MedComms (New York, NY), an Ashfield Health company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

A. Martinez-Marti: Financial Interests, Personal, Other, Honoraria/Advisory Board, Personal Fees and Travel Expenses: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria/Advisory Board, Personal Fees and Travel Expenses: F Hoffmann-La Roche; Financial Interests, Personal, Other, Honoraria/Advisory Board, Personal Fees and Travel Expenses: Merck Sharp and Dohme; Financial Interests, Personal, Other, Honoraria/Advisory Board, Personal Fees and Travel Expenses: Pfizer; Financial Interests, Personal, Other, Honoraria/Advisory Board, Personal Fees and Travel Expenses: AstraZeneca; Financial Interests, Personal, Other, Honoraria/Advisory Board, Personal Fees and Travel Expenses: MSD Oncology; Financial Interests, Personal, Other, Honoraria/Advisory Board, Personal Fees and Travel Expenses: Boehringer Ingelheim. M. Majem: Financial Interests, Personal, Other, Honorarium received from promotional activities: Bristol Myers Squibb; Financial Interests, Personal, Other, Honorarium received from promotional activities: MSD; Financial Interests, Personal, Other, Honorarium received from promotional activities: Boehringer Ingelheim; Financial Interests, Personal, Other, Honorarium received from promotional activities: AstraZeneca; Financial Interests, Personal, Other, Honorarium received from promotional activities: Roche; Financial Interests, Personal, Other, Honorarium received from promotional activities: Kyowa Kirin; Financial Interests, Personal, Other, Honorarium received from promotional activities: Pierre Fabre; Financial Interests, Personal, Other, Honorarium received from promotional activities: Takeda; Financial Interests, Personal, Other, Honorarium received from promotional activities: Bayer; Financial Interests, Personal and Institutional, Research Grant, Contracted support/research grant: Bristol Myers Squibb. F. Barlesi: Financial Interests, Personal, Other, Personal Fees: AstraZeneca; Financial Interests, Personal, Other, Personal Fees: Bayer; Financial Interests, Personal, Other, Personal Fees: Bristol Myers Squibb; Financial Interests, Personal, Other, Personal Fees: Boehringer Ingelheim; Financial Interests, Personal, Other, Personal Fees: Eli Lilly; Financial Interests, Personal, Other, Personal Fees: F Hoffmann-La Roche; Financial Interests, Personal, Other, Personal Fees: Novartis; Financial Interests, Personal, Other, Personal Fees: Merck; Financial Interests, Personal, Other, Personal Fees: MSD; Financial Interests, Personal, Other, Personal Fees: Pierre Fabre; Financial Interests, Personal, Other, Personal Fees: Pfizer; Financial Interests, Personal, Other, Personal Fees: Takeda. Q. Chu: Financial Interests, Personal, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: AbbVie; Financial Interests, Personal, Advisory Role: Astellas; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal and Institutional, Research Grant: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Novartis; Financial Interests, Personal, Advisory Role: Pfizer; Financial Interests, Personal, Advisory Role: Roche; Financial Interests, Personal, Advisory Role: Takeda; Other, Personal, Member, Data Safety and Monitoring Board: Merck KgAa; Financial Interests, Personal, Writing Engagements: Kaleidoscope Strategic Inc.; Non-Financial Interests, Personal, Leadership Role: Lung Cancer Canada; Non-Financial Interests, Personal, Leadership Role: Canadian Mesothelioma Foundation; Financial Interests, Personal, Research Grant: Exactis. I. Monnet: Non-Financial Interests, Personal, Other, ESMO 2019 Congress Invitation: Pfizer; Non-Financial Interests, Personal, Other, ESMO 2018 Congress Invitation: Roche. A. Sanchez: Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: AstraZeneca; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: Janssen; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: Eli Lilly; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: Amgen; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: Roche; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: MSD; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: Novartis; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: Sanofi; Financial Interests, Personal, Other, Honoraria, Personal Fees and Travel Expenses: Pfizer. D.R. Camidge: Financial Interests, Personal, Other, Personal Fees: AstraZeneca. P. He: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Y. Soo-Hoo: Financial Interests, Personal, Full or part-time Employment: AstraZeneca. Z. Cooper: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. R. Kumar: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca; Other, Personal, Other, Patent planned/pending: AstraZeneca. J. Bothos: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. C. Aggarwal: Financial Interests, Personal, Advisory Role: AstraZeneca; Financial Interests, Personal, Advisory Role: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Celgene; Financial Interests, Personal, Advisory Role: Blueprint; Financial Interests, Personal, Advisory Role: Daiichi Sankyo; Financial Interests, Personal, Advisory Role: Eli Lilly; Financial Interests, Personal, Advisory Role: Merck; Financial Interests, Personal, Advisory Role: Roche. R.S. Herbst: Financial Interests, Personal, Other, Personal Fees: AbbVie; Financial Interests, Personal, Other, Personal Fees: ARMO Biosciences; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Other, Personal fees: Biodesix; Financial Interests, Personal, Other, Personal fees: Bolt Biotherapy; Financial Interests, Personal, Other, Personal fees: Bristol Myers Squibb; Financial Interests, Personal and Institutional, Research Grant: Eli Lilly and Company; Financial Interests, Personal, Other, Personal fees: EMD Serono; Financial Interests, Personal and Institutional, Research Grant: Genentech/Roche; Financial Interests, Personal, Other, Personal fees: Genmab; Financial Interests, Personal, Other, Personal fees: Halozyme; Financial Interests, Personal, Other, Personal fees: Heat Biologics; Financial Interests, Personal, Other, Personal fees: IMAB Biopharma; Financial Interests, Personal, Other, Personal fees: Immunocore; Financial Interests, Personal, Other, Personal fees: Infinity Pharmaceuticals; Other, Personal, Member, Board Member (non-executive/ independent): Junshi Pharmaceuticals; Financial Interests, Personal, Other, Personal fees: Loxo Oncology; Financial Interests, Personal and Institutional, Research Grant: Merck and Company; Financial Interests, Personal, Other, Personal fees: Mirati Therapeutics; Financial Interests, Personal, Other, Personal fees: Nektar; Financial Interests, Personal, Other, Personal fees: Neon Therapeutics; Financial Interests, Personal, Other, Personal fees: NextCure; Financial Interests, Personal, Other, Personal fees: Novartis; Financial Interests, Personal, Other, Personal fees: Seattle Genetics; Financial Interests, Personal, Other, Personal fees: Shire PLC; Financial Interests, Personal, Other, Personal fees: Spectrum Pharmaceuticals; Financial Interests, Personal, Other, Personal fees: Symphogen; Financial Interests, Personal, Other, Personal fees: Takeda; Financial Interests, Personal, Other, Personal fees: Tesaro; Financial Interests, Personal, Other, Personal fees: Tocagen; Financial Interests, Personal, Other, Personal fees: Cybrexa; Financial Interests, Personal, Other, Personal fees: Oncternal Therapeutics; Financial Interests, Personal, Other, Personal Fees: Pfizer; Financial Interests, Personal, Other, Personal Fees: Sanofi. All other authors have declared no conflicts of interest.