Browsing by Author "Shitara, Kohei"

Now showing 1 - 8 of 8
  • No Thumbnail Available
    Item
    A plain language summary of the CheckMate 649 study: nivolumab in combination with chemotherapy compared to chemotherapy alone for untreated advanced or metastatic cancer of the stomach or esophagus
    (2023) Janjigian, Yelena Y.; Shitara, Kohei; Moehler, Markus; Garrido, Marcelo; Salman, Pamela; Wyrwicz, Lucjan; Yamaguchi, Kensei; Skoczylas, Tomasz; Bragagnoli, Arinilda Campos; Liu, Tianshu; Schenker, Michael; Yanez, Patricio; Tehfe, Mustapha; Kowalyszyn, Ruben; Karamouzis, Michalis V.; Bruges, Ricardo; Zander, Thomas; Pazo-Cid, Roberto; Hitre, Erika; Feeney, Kynan; Cleary, James M.; Poulart, Valerie; Cullen, Dana; Lei, Ming; Xiao, Hong; Kondo, Kaoru; Li, Mingshun; Ajani, Jaffer A.
    What is this summary about? This is a summary of the 1-year results of a clinical research study known as CheckMate 649 published in The Lancet in June 2021. The 2-year results on the participants' health and overall quality of life from the same study are in a second publication in Nature in March 2022. Until recently, chemotherapy was the only first treatment option for people with advanced or metastatic gastroesophageal adenocarcinoma who had not been treated before. Patients receiving chemotherapy lived on average for less than 1 year. Nivolumab is an immunotherapy that works by activating a person's immune system to fight back against cancer cells. The goal of CheckMate 649 was to find out if the combination of nivolumab and chemotherapy would help patients with advanced or metastatic gastroesophageal adenocarcinoma live longer and without their cancer getting worse.
  • No Thumbnail Available
    Item
    Association of Tumor Mutational Burden with Efficacy of Pembrolizumab plus Chemotherapy as First-Line Therapy for Gastric Cancer in the Phase III KEYNOTE-062 Study
    (2022) Lee, Keun-Wook; Van Cutsem, Eric; Bang, Yung-Jue; Fuchs, Charles S.; Kudaba, Iveta; Garrido, Marcelo; Chung, Hyun Cheol; Lee, Jeeyun; Castro, Hugo R.; Chao, Joseph; Wainberg, Zev A.; Cao, Z. Alexander; Aurora-Garg, Deepti; Kobie, Julie; Cristescu, Razvan; Bhagia, Pooja; Shah, Sukrut; Tabernero, Josep; Shitara, Kohei; Wyrwicz, Lucjan
    Purpose: This prespecified exploratory analysis evaluated the association between tumor mutational burden (TMB) status and outcomes of first-line pembrolizumab+chemotherapy versus chemotherapy in KEYNOTE-062. Patients and Methods: In patients with advanced gastric cancer and evaluable TMB data, we evaluated the association between TMB (continuous variable; square root scale) assessed with FoundationOne CDx and clinical outcomes [objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)] using logistic (ORR) and Cox proportional hazards (PFS, OS) regression models. Clinical utility of TMB was assessed using the prespecified cutoff of 10 mut/Mb. Results: TMB data were available for 306 of 763 patients (40.1%; pembrolizumab, 107; pembrolizumab+chemotherapy, 100; chemotherapy, 99). TMB was significantly associated with clinical outcomes in patients treated with pembrolizumab and pembrolizumab+chemotherapy (ORR, PFS, and OS; all P < 0.05) but not with chemotherapy (all P > 0.05). The overall prevalence of TMB >= 10 mut/Mb was 16% across treatment groups; 44% of patients who had TMB >= 10 mut/Mb had high microsatellite instability (MSI-H) tumors. Improved clinical outcomes (ORR, PFS, and OS) were observed in pembrolizumab-treated patients (pembrolizumab monotherapy and pembrolizumab+ chemotherapy) with TMB >= 10 mut/Mb. When the analysis was limited to the non-MS I-H subgroup, both the positive association between clinical outcomes with pembrolizumab or pembrolizumab+chemotherapy and TMB as a continuous variable and the clinical utility of pembrolizumab (with or without chemotherapy) versus chemotherapy by TMB cutoff were attenuated. Conclusions: This exploratory analysis of KEYNOTE-062 suggests an association between TMB and clinical efficacy with first -line pembrolizumab-based therapy in patients with advanced gas-tric/gastroesophageal junction adenocarcinoma. However, after the exclusion of patients with MSI-H tumors, the clinical utility of TMB was attenuated.
  • No Thumbnail Available
    Item
    Efficacy and Safety of Pembrolizumab or Pembrolizumab Plus Chemotherapy vs Chemotherapy Alone for Patients With First-line, Advanced Gastric Cancer: The KEYNOTE-062 Phase 3 Randomized Clinical Trial
    (2020) Shitara, Kohei; Van Cutsem, Eric; Bang, Yung-Jue; Fuchs, Charles; Wyrwicz, Lucjan; Lee, Keun-Wook; Kudaba, Iveta; Garrido, Marcelo; Chung, Hyun Cheol; Lee, Jeeyun; Castro, Hugo Raul; Mansoor, Wasat; Braghiroli, Maria Ignez; Karaseva, Nina; Caglevic, Christian; Villanueva, Luis; Goekkurt, Eray; Satake, Hironaga; Enzinger, Peter; Alsina, Maria; Benson, Al; Chao, Joseph; Ko, Andrew H.; Wainberg, Zev A.; Kher, Uma; Shah, Sukrut; Kang, S. Peter; Tabernero, Josep
    IMPORTANCE Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need.
  • No Thumbnail Available
    Item
    Efficacy of Pembrolizumab Monotherapy for Advanced Gastric/Gastroesophageal Junction Cancer with Programmed Death Ligand 1 Combined Positive Score ≥ 10
    (2021) Wainberg, Zev A.; Fuchs, Charles S.; Tabernero, Josep; Shitara, Kohei; Muro, Kei; Van Cutsem, Eric; Bang, Yung-Jue; Chung, Hyun Cheol; Yamaguchi, Kensei; Varga, Eniko; Chen, Jen-Shi; Hochhauser, Daniel; Thuss-Patience, Peter; Al-Batran, Salah-Eddin; Garrido, Marcelo; Kher, Uma; Shih, Chie-Schin; Shah, Sukrut; Bhagia, Pooja; Chao, Joseph
    Purpose: Pembrolizumab demonstrated efficacy in PD-L1-positive [combined positive score (CPS) >= 1] advanced gastric/gastro-esophageal junction (G/GEJ) cancer in the first-, second-, and third-line setting in KEYNOTE-062, KEYNOTE-061, and KEYNOTE-059, respectively. To better delineate the specificity of CPS as a predictor of dinical outcomes, we analyzed pembrolizumab efficacy in patients with CPS >= 10 in these trials.
  • No Thumbnail Available
    Item
    First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial
    (2024) Janjigian, Yelena Y.; Ajani, Jaffer A.; Moehler, Markus; Shen, Lin; Garrido, Marcelo; Gallardo, Carlos; Wyrwicz, Lucjan; Yamaguchi, Kensei; Cleary, James M.; Elimova, Elena; Karamouzis, Michalis; Bruges, Ricardo; Skoczylas, Tomasz; Bragagnoli, Arinilda; Liu, Tianshi; Tehfe, Mustapha; Zander, Thomas; Kowalyszyn, Ruben; Pazo-Cid, Roberto; Schenker, Michael; Feeny, Kynan; Wang, Rui; Lei, Ming; Chen, Clara; Nathani, Raheel; Shitara, Kohei
    Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) >= 5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS >= 5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.
  • No Thumbnail Available
    Item
    First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial
    (2021) Janjigian, Yelena Y.; Shitara, Kohei; Moehler, Markus; Garrido, Marcelo; Salman, Pamela; Shen, Lin; Wyrwicz, Lucjan; Yamaguchi, Kensei; Skoczylas, Tomasz; Bragagnoli, Arinilda Campos; Liu, Tianshu; Schenker, Michael; Yanez, Patricio; Tehfe, Mustapha; Kowalyszyn, Ruben; Karamouzis, Michalis V.; Bruges, Ricardo; Zander, Thomas; Pazo-Cid, Roberto; Hitre, Erika; Feeney, Kynan; Cleary, James M.; Poulart, Valerie; Cullen, Dana; Lei, Ming; Xiao, Hong; Kondo, Kaoru; Li, Mingshun; Ajani, Jaffer A.
    Background First-line chemotherapy for advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastro-oesophageal junction adenocarcinoma has a median overall survival (OS) of less than 1 year. We aimed to evaluate first-line programmed cell death (PD)-1 inhibitor-based therapies in gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma. We report the first results for nivolumab plus chemotherapy versus chemotherapy alone.
  • No Thumbnail Available
    Item
    Health-Related Quality of Life With Nivolumab Plus Chemotherapy Versus Chemotherapy in Patients With Advanced Gastric/Gastroesophageal Junction Cancer or Esophageal Adenocarcinoma From CheckMate 649
    (2023) Moehler, Markus; Xiao, Hong; Blum, Steven I.; Elimova, Elena; Cella, David; Shitara, Kohei; Ajani, Jaffer A.; Janjigian, Yelena Y.; Garrido, Marcelo; Shen, Lin; Yamaguchi, Kensei; Liu, Tianshu; Schenker, Michael; Kowalyszyn, Ruben; Bragagnoli, Arinilda Campos; Bruges, Ricardo; Montesarchio, Vincenzo; Pazo-Cid, Roberto; Hunter, Shannon; Davenport, Eric; Wang, Jinyi; Kondo, Kaoru; Li, Mingshun; Wyrwicz, Lucjan
    PURPOSE In CheckMate 649, first-line nivolumab plus chemotherapy prolonged overall survival versus chemotherapy in patients with advanced/metastatic non-human epidermal growth factor receptor 2 (HER2)-positive gastric/gastroesophageal junction cancer (GC/GEJC) or esophageal adenocarcinoma (EAC). We present exploratory patient-reported outcomes (PROs).METHODS In patients (N = 1,581) concurrently randomly assigned 1:1 to nivolumab plus chemotherapy or chemotherapy and in those with tumor PD-L1 expression at a combined positive score (CPS) of >= 5, health-related quality of life (HRQoL) was assessed using the EQ-5D and Functional Assessment of Cancer Therapy-Gastric (FACT-Ga), which included the FACT-General (FACT-G) and Gastric Cancer subscale (GaCS). The FACT-G GP5 item assessed treatment-related symptom burden. Longitudinal changes in HRQoL were assessed using mixed models for repeated measures in the PRO analysis population (randomly assigned patients with baseline and >= 1 postbaseline assessments). Time to symptom or definitive deterioration analyses were also conducted.RESULTS In the PRO analysis population (n = 1,360), PRO questionnaire completion rates were mostly >80% during treatment. Patient-reported symptom burden was not increased with nivolumab plus chemotherapy versus chemotherapy. Mean improved changes from baseline were greater with nivolumab plus chemotherapy versus chemotherapy for FACT-Ga total, GaCS, and EQ-5D visual analog scale in patients with a CPS of >= 5; results were similar for the overall PRO analysis population. In CPS >= 5 and all randomly assigned populations, nivolumab plus chemotherapy reduced the risk of symptom deterioration versus chemotherapy, on the basis of FACT-Ga total score and GaCS; time to definitive deterioration was longer, and the risk of definitive deterioration in HRQoL was reduced with nivolumab plus chemotherapy across EQ-5D and most FACT-Ga measures (hazard ratio [95% CI] <1).CONCLUSION Compared with chemotherapy alone, first-line nivolumab plus chemotherapy showed stable or better on-treatment HRQoL in patients with advanced/metastatic non-HER2-positive GC/GEJC/EAC and also showed decreased risk of definitive HRQoL deterioration.
  • No Thumbnail Available
    Item
    Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer
    (2022) Shitara, Kohei; Ajani, Jaffer A.; Moehler, Markus; Garrido, Marcelo; Gallardo, Carlos; Shen, Lin; Yamaguchi, Kensei; Wyrwicz, Lucjan; Skoczylas, Tomasz; Bragagnoli, Arinilda Campos; Liu, Tianshu; Tehfe, Mustapha; Elimova, Elena; Bruges, Ricardo; Zander, Thomas; de Azevedo, Sergio; Kowalyszyn, Ruben; Pazo-Cid, Roberto; Schenker, Michael; Cleary, James M.; Yanez, Patricio; Feeney, Kynan; Karamouzis, Michalis, V; Poulart, Valerie; Lei, Ming; Xiao, Hong; Kondo, Kaoru; Li, Mingshun; Janjigian, Yelena Y.
    Standard first-line chemotherapy results in disease progression and death within one year in most patients with human epidermal growth factor receptor 2 (HER2)-negative gastro-oesophageal adenocarcinoma(1-4). Nivolumab plus chemotherapy demonstrated superior overall survival versus chemotherapy at 12-month follow-up in gastric, gastro-oesophageal junction or oesophageal adenocarcinoma in the randomized, global CheckMate 649 phase 3 trial(5) (programmed death ligand-1 (PD-L1) combined positive score >= 5 and all randomized patients). On the basis of these results, nivolumab plus chemotherapy is now approved as a first-line treatment for these patients in many countries(6). Nivolumab and the cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor ipilimumab have distinct but complementary mechanisms of action that contribute to the restoration of anti-tumour T-cell function and induction of de novo anti-tumour T-cell responses, respectively(7-)(11). Treatment combining 1 mg kg(-1) nivolumab with 3 mg kg(-1) ipilimumab demonstrated clinically meaningful anti-tumour activity with a manageable safety profile in heavily pre-treated patients with advanced gastro-oesophageal cancer(12). Here we report both long-term follow-up results comparing nivolumab plus chemotherapyversus chemotherapy alone and the first results comparing nivolumab plus ipilimumab versus chemotherapy alone from CheckMate 649. After the 24.0-month minimum follow-up, nivolumab plus chemotherapy continued to demonstrate improvement in overall survival versus chemotherapy alone in patients with PD-L1 combined positive >= 5 score (hazard ratio 0.70; 95% confidence interval 0.61, 0.81) and all randomized patients (hazard ratio 0.79; 95% confidence interval 0.71, 0.88). Overall survival in patients with PD-L1 combined positive score >= 5 for nivolumab plus ipilimumab versus chemotherapy alone did not meet the prespecified boundary for significance. No new safety signals were identified. Our results support the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastro-oesophageal adenocarcinoma.