Abstract Background: In the CANTOS study, canakinumab (selective interleukin 1β inhibitor) treatment was associated with reduced incidence and mortality from non-small cell lung cancer (NSCLC) in stable post-myocardial infarction patients with elevated high-sensitivity C-reactive protein (hsCRP) levels. The CANOPY-A study was designed to investigate the therapeutic role of canakinumab in NSCLC. Methods: The CANOPY-A study (NCT03447769) is evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult patients with completely resected NSCLC. Patients with American Joint Committee on Cancer/Union for International Cancer Control version 8 stage IIA-IIIA and IIIB (T >5 cm, N2), any histology, completely resected (R0) NSCLC and completion of adjuvant cisplatin-based chemotherapy (≥2 cycles) and radiotherapy (if applicable) are eligible. Patients must not have had prior neoadjuvant chemotherapy or radiotherapy. Patients (~1500) are randomized 1:1 to receive canakinumab (200 mg) or placebo subcutaneously every 3 weeks for 18 cycles or until disease recurrence as determined by investigator, unacceptable toxicity, or treatment discontinuation at the discretion of the investigator. The primary objective is disease-free survival (DFS) per local investigator assessment. Secondary objectives are overall survival (OS), lung cancer-specific survival, safety, pharmacokinetics, immunogenicity, and patient-reported outcomes. Adult patients with stage IIA-IIIA and IIIB (T>5 cm, N2 disease only) NSCLC who are candidates for complete resection surgery (and therefore prospective candidates for the main study) will be asked to participate in a biomarker substudy to understand how resection may impact biomarkers involved in the interleukin 1β inflammatory pathway and mutations present in blood. In the substudy, the levels of hs-CRP, other cytokines, and additional biomarkers in blood will be assessed before and after surgery (endpoint: summary statistics of hs-CRP and other pharmacodynamic biomarkers). For patients who will enroll in the main study, possible associations between pre- and postsurgery biomarker levels with canakinumab efficacy will be assessed (endpoint: DFS and OS by hs-CRP and other pharmacodynamic biomarkers). The CANOPY-A study is currently enrolling. As of October 19, 2020, there are 356 study locations. Citation Format: Alexander Spira, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Pedro De Marchi, Yasushi Goto, Dariusz Kowalski, Shun Lu, Luis Paz-Ares, David R. Spigel, Michael Thomas, Sabine Turri, Vanessa Rodrik-Outmezguine, Wen Zhou, Terri Kreisl, James Chih-Hsin Yang, Edward B. Garon. Canakinumab as adjuvant therapy in patients with completely resected non-small cell lung cancer: CANOPY-A trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT255.

Canakinumab

10.1158/1538-7445.am2021-ct255

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509MO Datopotamab deruxtecan (Dato-DXd) vs docetaxel in previously treated advanced/metastatic (adv/met) non-small cell lung cancer (NSCLC): Results of the randomized phase III study TROPION-Lung01

Annals of Oncology (2023)

M-J. Ahn Aaron Lisberg Luís Paz-Ares Robin Cornelissen Nicolas Girard

10.1016/j.annonc.2023.10.588

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Supplementary Table S5 from Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden

Luís Paz-Ares Marina Chiara Garassino Yuanbin Chen Niels Reinmuth Katsuyuki Hotta

Summary of adverse events of any cause by PD-L1 subgroup (PD-L1 safety population).

Durvalumab

Tremelimumab

10.1158/1078-0432.25232285

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Supplementary Figure S5 from Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden

Luís Paz-Ares Marina Chiara Garassino Yuanbin Chen Niels Reinmuth Katsuyuki Hotta

Kaplan-Meier analysis of OS in the ITT population and the tTMB BEP.

Durvalumab

Tremelimumab

10.1158/1078-0432.25232315

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Supplementary Figure S9 from Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden

Luís Paz-Ares Marina Chiara Garassino Yuanbin Chen Niels Reinmuth Katsuyuki Hotta

Distribution of tTMB scores by treatment arm in the tTMB BEP.

Durvalumab

Tremelimumab

10.1158/1078-0432.25232303

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RELAY Subgroup Analyses by EGFR Ex19del and Ex21L858R Mutations for Ramucirumab Plus Erlotinib in Metastatic Non–Small Cell Lung Cancer

Clinical Cancer Research (2021)

Kazuhiko Nakagawa Ernest Nadal Edward B. Garon Makoto Nishio Takashi Seto

Abstract Purpose: In EGFR-mutated metastatic non–small cell lung cancer (NSCLC), outcomes from EGFR tyrosine kinase inhibitors have differed historically by mutation type present, with lower benefit reported in patients with ex21L858R versus ex19del mutations. We investigated if EGFR-activating mutation subtypes impact treatment outcomes in the phase III RELAY study. Associations between EGFR mutation type and preexisting co-occurring and treatment-emergent genetic alterations were also explored. Patients and Methods: Patients with metastatic NSCLC, an EGFR ex19del or ex21L858R mutation, and no central nervous system metastases were randomized (1:1) to erlotinib (150 mg/day) with either ramucirumab (10 mg/kg; RAM+ERL) or placebo (PBO+ERL), every 2 weeks, until RECIST v1.1–defined progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary and exploratory endpoints included overall response rate (ORR), duration of response (DOR), PFS2, time-to-chemotherapy (TTCT), safety, and next-generation sequencing analyses. Results: Patients with ex19del and ex21L858R mutations had similar clinical characteristics and comutational profiles. One-year PFS rates for ex19del patients were 74% for RAM+ERL versus 54% for PBO+ERL; for ex21L858R rates were 70% (RAM+ERL) versus 47% (PBO+ERL). Similar treatment benefits (ORR, DOR, PFS2, and TTCT) were observed in RAM+ERL–treated patients with ex19del and ex21L858R. Baseline TP53 comutation was associated with superior outcomes for RAM+ERL in both ex19del and ex21L858R subgroups. EGFR T790M mutation rate at progression was similar between treatment arms and by mutation type. Conclusions: RAM+ERL provided significant clinical benefit for both EGFR ex19del and ex21L858R NSCLC, supporting this regimen as suitable for patients with either of these EGFR mutation types.

T790M

Ramucirumab

Clinical endpoint

10.1158/1078-0432.ccr-21-0273

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Citations (33)

4IN ESMO RECOMMENDATION 2011: ADVANCED NSCLC

Lung Cancer (2011)

Cesare Gridelli Benjamin Besse Filippo de Marinis D. Gandara Luís Paz-Ares

Expanded access

10.1016/s0169-5002(11)70141-6

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Afatinib versus gefitinib in patients with EGFR mutation-positive advanced non-small-cell lung cancer: overall survival data from the phase IIb LUX-Lung 7 trial

Annals of Oncology (2017)

Luís Paz-Ares E.H. Tan Kenneth J. O’Byrne L. Zhang Vera Hirsh

In LUX-Lung 7, the irreversible ErbB family blocker, afatinib, significantly improved progression-free survival (PFS), time-to-treatment failure (TTF) and objective response rate (ORR) versus gefitinib in patients with epidermal growth factor receptor (EGFR) mutation-positive non-small-cell lung cancer (NSCLC). Here, we present primary analysis of mature overall survival (OS) data.LUX-Lung 7 assessed afatinib 40 mg/day versus gefitinib 250 mg/day in treatment-naïve patients with stage IIIb/IV NSCLC and a common EGFR mutation (exon 19 deletion/L858R). Primary OS analysis was planned after ∼213 OS events and ≥32-month follow-up. OS was analysed by a Cox proportional hazards model, stratified by EGFR mutation type and baseline brain metastases.Two-hundred and twenty-six OS events had occurred at the data cut-off (8 April 2016). After a median follow-up of 42.6 months, median OS (afatinib versus gefitinib) was 27.9 versus 24.5 months [hazard ratio (HR) = 0.86, 95% confidence interval (CI) 0.66‒1.12, P = 0.2580]. Prespecified subgroup analyses showed similar OS trends (afatinib versus gefitinib) in patients with exon 19 deletion (30.7 versus 26.4 months; HR, 0.83, 95% CI 0.58‒1.17, P = 0.2841) and L858R (25.0 versus 21.2 months; HR 0.91, 95% CI 0.62‒1.36, P = 0.6585) mutations. Most patients (afatinib, 72.6%; gefitinib, 76.8%) had at least one subsequent systemic anti-cancer treatment following discontinuation of afatinib/gefitinib; 20 (13.7%) and 23 (15.2%) patients received a third-generation EGFR tyrosine kinase inhibitor. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.In LUX-Lung 7, there was no significant difference in OS with afatinib versus gefitinib. Updated PFS (independent review), TTF and ORR data were significantly improved with afatinib.NCT01466660.

Afatinib

T790M

10.1093/annonc/mdw611

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Citations (490)

Foreword to ‘The current status and future perspectives on the management of stage III NSCLC: a focus on unresectable cancer treatment paradigms’

British Journal of Cancer (2020)

Luís Paz-Ares

10.1038/s41416-020-01068-0

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Abstract CT287: CANOPY-A: A phase III, multicenter, randomized trial evaluating canakinumab versus placebo as adjuvant therapy in patients with completely resected non-small cell lung cancer (NSCLC)

Cancer Research (2020)

Edward B. Garon Andrea Ardizzoni Fabrice Barlési Byoung Chul Cho Pedro De Marchi

Abstract Background: In the CANTOS study, treatment with canakinumab (selective IL-1β inhibitor) was associated with reduced incidence and mortality of NSCLC in patients with stable post-myocardial infarction who had elevated high-sensitivity C-reactive protein (hs-CRP) levels. The results provided a rationale to investigate the therapeutic role of canakinumab in NSCLC. Methods: The phase III, multicenter, randomized, double-blind, placebo-controlled CANOPY-A study (NCT03447769) is evaluating the efficacy and safety of canakinumab as adjuvant therapy in adult patients with completely resected NSCLC. Patients with AJCC/UICC v.8 stages II-IIIA and IIIB (T>5 cm, N2), any histology, completely resected (R0) NSCLC who have completed adjuvant cisplatin-based chemotherapy (≥2 cycles) and radiation therapy (if applicable) are eligible. Patients must not have had prior neoadjuvant chemotherapy or neoadjuvant radiotherapy. Patients (~1500) are randomized 1:1 to receive canakinumab (200 mg Q3W, SC) or placebo (Q3W, SC) for 18 cycles or until NSCLC disease recurrence as determined by investigator, unacceptable toxicity, treatment discontinuation at the discretion of the investigator or patient, start of a new antineoplastic therapy, death, or loss to follow-up. Randomization is stratified by AJCC/UICC v.8 stage (IIA vs IIB vs IIIA vs IIIB with T>5 cm, N2 disease), tumor histology (squamous vs non-squamous), and region (western Europe and North America vs eastern Asia vs rest of the world). Primary objective is disease-free survival (DFS) per local investigator assessment. Secondary objectives are overall survival (OS), lung cancer specific survival, safety, pharmacokinetics, immunogenicity, and patient reported outcomes. Adult patients with stage IIA-IIIA, IIIB (N2 disease only) NSCLC who are candidates for complete resection surgery (and therefore prospective candidates for the main study) will be asked to participate in a biomarker sub-study to understand how resection surgery may impact biomarkers involved in the IL-1β inflammatory pathway as well as mutations present in blood. For all patients participating into the sub-study, the levels of hs-CRP, other cytokines, and additional biomarkers in blood will be assessed at pre- and post-surgery (endpoint: summary statistics of hs-CRP and other pharmacodynamics [PD] biomarkers). For patients who will also enroll into the main study, possible associations between pre- and post-surgery biomarker levels with canakinumab efficacy will be determined (endpoint: DFS and OS by hs-CRP and other PD biomarkers). The CANOPY-A study is currently enrolling. As of Jan 13, 2020, there are 307 study locations. Citation Format: Edward B. Garon, Andrea Ardizzoni, Fabrice Barlesi, Byoung Chul Cho, Pedro De Marchi, Yasushi Goto, Dariusz Kowalski, Shun Lu, Luis Paz-Ares, David R. Spigel, Alexander Spira, Michael Thomas, Mimi Leung, Jason Baum, Zewen Zhu, Bijoyesh Mookerjee, James Chih-Hsin Yang. CANOPY-A: A phase III, multicenter, randomized trial evaluating canakinumab versus placebo as adjuvant therapy in patients with completely resected non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT287.

Canakinumab

10.1158/1538-7445.am2020-ct287

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