Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study

Sun, Jong‐Mu; Shen, Lin; Shah, Manish A.; Enzinger, Peter C.; Adenis, Antoine; Doi, Toshihiko; Kojima, Takashi; Metges, Jean-Philippe; Li, Zhigang; Kim, Sung‐Bae; Cho, Byoung Chul; Mansoor, Wasat; Li, Shau-Hsuan; Sunpaweravong, Patrapim; Maqueda, María; Goekkurt, Eray; Hara, Hiroki; Antunes, Luciana da Conceição; Fountzilas, Christos; Tsuji, Akihito; Castro, Victor; Liu, Qi; Shah, Sukrut; Bhagia, Pooja; Kato, Ken; Investigators, Keynote

doi:10.1016/s0140-6736(21)01234-4

Cited by 937 publications

(793 citation statements)

References 28 publications

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“…In recent years, numerous studies have explored potentially applicable biomarkers for selecting suitable patients to receive immunotherapy, especially PD-L1 expression status [ 30 , 31 ]. KEYNOTE-590 have shown that advanced EC patients with low PD-L1 expression experienced an obviously modest survival benefit than that with high PD-L1 expression treated with pembrolizumab plus chemotherapy compared with placebo plus chemotherapy [ 32 ]. However, KEYNOTE-181study, ATTRACTION-3 study, ESCORT study and a meta-analysis [ 33 ] of eight RCTs revealed that PD-L1 expression level was not a determinant of the OS benefit.…”

Section: Discussionmentioning

confidence: 99%

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis

Zhu

Shanzhou

et al. 2021

BMC Cancer

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Background Aim to establish the inhibitors of programmed cell death protein 1 (PD-1) as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC). Methods Published clinical trials in the PubMed, Medline, Embase databases on PD-1 inhibitors for the treatment of ESCC were searched, along with an additional search on abstracts from the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) from inception to September 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were synthesized using STATA. Results A total of 1970 patients (PD-1 inhibitors: 987; chemotherapy: 983) were enrolled in five randomized controlled trials. Compared with conventional chemotherapy, second-line PD-1 inhibitors significantly improved the OS (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.66–0.81; P < 0.001) and ORR (relative risk [RR] = 1.89, 95% CI: 1.16–3.05; P = 0.01) of advanced ESCC patients, especially significantly prolonged the OS in the patients with positive programmed death-ligand 1 (PD-L1) status (HR = 0.64, 95% CI: 0.53–0.77; P < 0.001); but did not better PFS (HR = 0.88, 95% CI: 0.68–1.14; P = 0.330) and DCR (RR = 0.89, 95% CI: 0.59–1.37; P = 0.603). Moreover, PD-1 inhibitors were associated with statistically lower incidences of grade 3–5 TRAEs. Conclusion Second line PD-1 inhibitors significantly improved the OS and ORR of patients with advanced ESCC, especially the OS of those with positive PD-L1 expression, and did not result in significant improvement in PFS and DCR. Compared to chemotherapy, second-line PD-1 inhibitors had superior safety profiles for the treatment of advanced ESCC.

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Section: Discussionmentioning

confidence: 99%

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis

Zhu

Shanzhou

et al. 2021

BMC Cancer

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“…In contrast to CheckMate-577 which included nearly 30% of patients with esophageal SCC, our study was restricted to patients with adenocarcinoma histology. It is relevant to outline this distinction given the fundamental genomic differences between SCC and AC, and the historically greater sensitivity of SCC to ICIs (15,(27)(28)(29). Another intriguing contrast between the two studies is the relapse-or disease-free survival with ICI in patients with GEJ AC.…”

Section: Discussionmentioning

confidence: 99%

“…Clinical trials utilizing ICIs in metastatic gastroesophageal AC have shown positive correlation between therapeutic efficacy of immunotherapy and PD-L1 expression (17,29,32). However, a well-defined cutoff for PD-L1 expression and other biomarkers of response to immunotherapy to guide optimum patient selection are lacking.…”

Section: Discussionmentioning

confidence: 99%

A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study

et al. 2021

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BackgroundMost patients with resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma (AC) receive concurrent chemoradiation (CRT) followed by esophagectomy. The majority of patients do not achieve pathologic complete response (pCR) with neoadjuvant CRT, and the relapse rate is high among these patients.MethodsWe conducted a phase II study (ClinicalTrials.gov Identifier: NCT02639065) evaluating the efficacy and safety of PD-L1 inhibitor durvalumab in patients with locally advanced esophageal and GEJ AC who have undergone neoadjuvant CRT followed by R0 resection with evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every 4 weeks for up to 1 year. The primary endpoint was 1-year relapse free survival (RFS). Secondary endpoint was safety and tolerability of durvalumab following trimodality therapy. Exploratory endpoints included correlation of RFS with PD-L1 expression, HER-2 expression, and tumor immune cell population.ResultsThirty-seven patients were enrolled. The majority (64.9%) had pathologically positive lymph nodes. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events. One-year RFS was 73% (95% CI, 56–84%) with median RFS of 21 months (95% CI, 14–40.4 months). Patients with GEJ AC had a trend toward superior 1-year RFS compared to those with esophageal AC (83% vs. 63%, p = 0.1534). There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10 (100% vs. 66.7%, p = 0.1551) and ≥1 (84.2% vs. 61.1%, p = 0.1510) cutoffs. A higher relative proportion of M2 macrophages and CD4 memory activated T cells was associated with improved RFS (HR = 0.16; 95% CI, 0.05–0.59; p = 0.0053; and HR = 0.37; 95% CI, 0.15–0.93, p = 0.0351, respectively).ConclusionsAdjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ AC led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting. Higher proportion of M2 macrophages and CD4 memory activated T cells was associated with superior RFS.

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“…Furthermore, pembrolizumab in combination with chemotherapy was recently approved by the FDA as a first-line option for patients with advanced and metastatic esophageal cancer independent of histological subtype and PD-L1 status based on the results of the KEYNOTE-590 trial (all patients: pembrolizumab + chemotherapy median OS 12.4 (n = 373) versus placebo + chemotherapy 9.8 (n = 376) months; HR 0.73; 95% CI 0.62-0.86; p < 0.0001) [30,31]. The EMA, however, placed a restriction on the decision, as treatment with pembrolizumab was approved only for patients with a PD-L1 CPS of ≥10 (esophageal squamous cell carcinoma and PD-L1 CPS of ≥10: median OS 13.9 (n = 143) versus 8.8 (n = 143) months; HR 0.57; 95% CI 0.43-0.75; p < 0.0001; esophageal squamous cell carcinoma: 12.6 (n = 274) versus 9.8 (n = 274) months; HR 0.72; 95% CI 0.60-0.88; p = 0.0006; PD-L1 CPS ≥10: 13.5 (n = 186) versus 9.4 (n = 197) months; HR 0.62; 95% CI 0.49-0.78; p < 0.0001) [32,33]. Both authorities defined the chemotherapy backbone as platine and fluoropyrimidine based and did not make any clear statement on the specific choice of backbone treatment combination for the KEYNOTE-590 regimen.…”

Section: Esophageal Adenocarcinomamentioning

confidence: 99%

Immunotherapy for Esophageal Cancers: What Is Practice Changing in 2021?

Puhr

Preusser

2021

Cancers

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The prognosis of advanced esophageal cancer is dismal, and treatment options are limited. Since the first promising data on second-line treatment with checkpoint inhibitors in esophageal cancer patients were published, immunotherapy was surmised to change the face of modern cancer treatment. Recently, several studies have found this to be true, as the checkpoint inhibitors nivolumab and pembrolizumab have achieved revolutionary response rates in advanced as well as resectable settings in esophageal cancer patients. Although the current results of large clinical trials promise high efficacy with tolerable toxicity, desirable survival rates, and sustained quality of life, some concerns remain. This review aims to summarize the novel clinical data on immunotherapeutic agents for esophageal cancer and provide a critical view of potential restrictions for the implementation of these therapies for unselected patient populations.

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Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study

Cited by 937 publications

References 28 publications

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis

PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis

A Phase II Trial of Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma: A Big Ten Cancer Research Consortium Study

Immunotherapy for Esophageal Cancers: What Is Practice Changing in 2021?

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