Immunotherapy and chemoimmunotherapy for patients with adenocarcinoma

In a randomized, open-label, international, phase III study (CheckMate-649 [NCT02872116]), 1,581 patients (including 955 with a PD-L1 CPS ≥5) with HER2-negative gastric, gastroesophageal junction, or esophageal adenocarcinomas were randomly assigned (1:1:1) (1:1 after enrollment in the nivolumab-plus-ipilimumab group was closed). A total of 789 patients (473 with a PD-L1 CPS ≥5) were assigned to receive nivolumab and chemotherapy (nivolumab 360 mg with capecitabine and oxaliplatin every 3 weeks, or nivolumab 240 mg with FOLFOX every 2 weeks). A total of 792 patients (482 with a PD-L1 CPS ≥5) were assigned to receive chemotherapy alone (capecitabine and oxaliplatin every 3 weeks or FOLFOX every 2 weeks). Disease site of origin was as follows: 1,100 patients (70%) had gastric adenocarcinoma, 260 patients (17%) had gastroesophageal junction carcinoma, and 211 patients (13%) had esophageal adenocarcinoma.[46]

In a randomized, open-label, international, phase III study (CheckMate-649 [NCT02872116]), 1,581 patients (including 955 with a PD-L1 CPS ≥5) with HER2-negative gastric, gastroesophageal junction, or esophageal adenocarcinomas were randomly assigned (1:1:1) (1:1 after enrollment in the nivolumab-plus-ipilimumab group was closed). A total of 789 patients (473 with a PD-L1 CPS ≥5) were assigned to receive nivolumab and chemotherapy (nivolumab 360 mg with capecitabine and oxaliplatin every 3 weeks, or nivolumab 240 mg with FOLFOX every 2 weeks). A total of 792 patients (482 with a PD-L1 CPS ≥5) were assigned to receive chemotherapy alone (capecitabine and oxaliplatin every 3 weeks or FOLFOX every 2 weeks). Disease site of origin was as follows: 1,100 patients (70%) had gastric adenocarcinoma, 260 patients (17%) had gastroesophageal junction carcinoma, and 211 patients (13%) had esophageal adenocarcinoma.[46]

The median follow-up for OS was 13.1 months (interquartile range [IQR], 6.7–19.1) for the nivolumab-plus-chemotherapy group and 11.1 months (IQR, 5.8–16.1) for the chemotherapy-alone group. Nivolumab plus chemotherapy resulted in improvements in OS (14.4 vs. 11.1 months; HR, 0.71; 98.4% CI, 0.59–0.86; P < .0001) and PFS (HR, 0.68; 98% CI, 0.56–0.81; P < .0001) compared with chemotherapy alone in patients with a PD-L1 CPS of 5 or more (minimum follow-up, 12.1 months).[46][Level of evidence A1]

In a randomized, open-label, international, phase III study (CheckMate-649 [NCT02872116]), 1,581 patients (including 955 with a PD-L1 CPS ≥5) with HER2-negative gastric, gastroesophageal junction, or esophageal adenocarcinomas were randomly assigned (1:1:1) (1:1 after enrollment in the nivolumab-plus-ipilimumab group was closed). A total of 789 patients (473 with a PD-L1 CPS ≥5) were assigned to receive nivolumab and chemotherapy (nivolumab 360 mg with capecitabine and oxaliplatin every 3 weeks, or nivolumab 240 mg with FOLFOX every 2 weeks). A total of 792 patients (482 with a PD-L1 CPS ≥5) were assigned to receive chemotherapy alone (capecitabine and oxaliplatin every 3 weeks or FOLFOX every 2 weeks). Disease site of origin was as follows: 1,100 patients (70%) had gastric adenocarcinoma, 260 patients (17%) had gastroesophageal junction carcinoma, and 211 patients (13%) had esophageal adenocarcinoma.[46]

The unstratified HROS for patients with a PD-L1 CPS of less than 1 who received nivolumab plus chemotherapy versus chemotherapy alone was 0.92 (95% CI, 0.70–1.23). For patients with a PD-L1 CPS of less than 5, the HR was 0.94 (0.78–1.13).

In a randomized, open-label, international, phase III study (CheckMate-649 [NCT02872116]), 1,581 patients (including 955 with a PD-L1 CPS ≥5) with HER2-negative gastric, gastroesophageal junction, or esophageal adenocarcinomas were randomly assigned (1:1:1) (1:1 after enrollment in the nivolumab-plus-ipilimumab group was closed). A total of 789 patients (473 with a PD-L1 CPS ≥5) were assigned to receive nivolumab and chemotherapy (nivolumab 360 mg with capecitabine and oxaliplatin every 3 weeks, or nivolumab 240 mg with FOLFOX every 2 weeks). A total of 792 patients (482 with a PD-L1 CPS ≥5) were assigned to receive chemotherapy alone (capecitabine and oxaliplatin every 3 weeks or FOLFOX every 2 weeks). Disease site of origin was as follows: 1,100 patients (70%) had gastric adenocarcinoma, 260 patients (17%) had gastroesophageal junction carcinoma, and 211 patients (13%) had esophageal adenocarcinoma.[46]

Grades 3 and 4 adverse events occurred in 462 patients (59%) in the nivolumab group and in 341 patients (44%) in the chemotherapy-alone group.

In a randomized, open-label, international, phase III study (CheckMate-649 [NCT02872116]), 1,581 patients (including 955 with a PD-L1 CPS ≥5) with HER2-negative gastric, gastroesophageal junction, or esophageal adenocarcinomas were randomly assigned (1:1:1) (1:1 after enrollment in the nivolumab-plus-ipilimumab group was closed). A total of 789 patients (473 with a PD-L1 CPS ≥5) were assigned to receive nivolumab and chemotherapy (nivolumab 360 mg with capecitabine and oxaliplatin every 3 weeks, or nivolumab 240 mg with FOLFOX every 2 weeks). A total of 792 patients (482 with a PD-L1 CPS ≥5) were assigned to receive chemotherapy alone (capecitabine and oxaliplatin every 3 weeks or FOLFOX every 2 weeks). Disease site of origin was as follows: 1,100 patients (70%) had gastric adenocarcinoma, 260 patients (17%) had gastroesophageal junction carcinoma, and 211 patients (13%) had esophageal adenocarcinoma.[46]

The 3-year efficacy and safety results (minimum follow-up, 36.2 months for patients with a PD-L1 CPS ≥5) reported that the median OS and PFS were substantially unchanged. The OS rate was 21% in the nivolumab-plus-chemotherapy group and 10% in the chemotherapy-alone group. The PFS rate was 13% in the nivolumab-plus-chemotherapy group and 8% in the chemotherapy-alone group.[47]

In KEYNOTE-590 (NCT03189719), patients with esophageal cancer or gastroesophageal junction cancer received either pembrolizumab or placebo plus chemotherapy. A total of 221 patients (27%) had adenocarcinoma histology. For study details, see the Immunotherapy and chemoimmunotherapy for patients with squamous cell carcinoma section.[45]

The role of nivolumab in combination with chemotherapy was also assessed in ATTRACTION-4 (NCT02746796), a randomized, multicenter, double-blind, placebo-controlled, phase III trial. The study enrolled patients with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer, regardless of PD-L1 expression. Only 9% of enrolled patients had gastroesophageal junction cancer. Patients were randomly assigned (1:1) to receive chemotherapy every 3 weeks (oxaliplatin 130 mg/m² IV on day 1 plus either oral S-1 40 mg/m² or oral capecitabine 1,000 mg/m², twice daily on days 1–14), in addition to either 360 mg nivolumab IV or placebo. The trial was conducted in Japan, South Korea, and Taiwan, and assigned 724 patients to treatment: 362 patients to the nivolumab-plus-chemotherapy group and 362 to the placebo-plus-chemotherapy group. The primary end points were centrally assessed PFS and OS in the intention-to-treat population.[48]

The role of nivolumab in combination with chemotherapy was also assessed in ATTRACTION-4 (NCT02746796), a randomized, multicenter, double-blind, placebo-controlled, phase III trial. The study enrolled patients with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer, regardless of PD-L1 expression. Only 9% of enrolled patients had gastroesophageal junction cancer. Patients were randomly assigned (1:1) to receive chemotherapy every 3 weeks (oxaliplatin 130 mg/m² IV on day 1 plus either oral S-1 40 mg/m² or oral capecitabine 1,000 mg/m², twice daily on days 1–14), in addition to either 360 mg nivolumab IV or placebo. The trial was conducted in Japan, South Korea, and Taiwan, and assigned 724 patients to treatment: 362 patients to the nivolumab-plus-chemotherapy group and 362 to the placebo-plus-chemotherapy group. The primary end points were centrally assessed PFS and OS in the intention-to-treat population.[48]

At the time of data cutoff, with a median follow-up of 11.6 months, the median PFS was 10.45 months (95% CI, 8.44–14.75) in the nivolumab-plus-chemotherapy group and 8.34 months (6.97–9.40) in the placebo-plus-chemotherapy group (HR, 0.68; 98.51% CI, 0.51–0.90; P = .0007).[48][Level of evidence B1]

The role of nivolumab in combination with chemotherapy was also assessed in ATTRACTION-4 (NCT02746796), a randomized, multicenter, double-blind, placebo-controlled, phase III trial. The study enrolled patients with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer, regardless of PD-L1 expression. Only 9% of enrolled patients had gastroesophageal junction cancer. Patients were randomly assigned (1:1) to receive chemotherapy every 3 weeks (oxaliplatin 130 mg/m² IV on day 1 plus either oral S-1 40 mg/m² or oral capecitabine 1,000 mg/m², twice daily on days 1–14), in addition to either 360 mg nivolumab IV or placebo. The trial was conducted in Japan, South Korea, and Taiwan, and assigned 724 patients to treatment: 362 patients to the nivolumab-plus-chemotherapy group and 362 to the placebo-plus-chemotherapy group. The primary end points were centrally assessed PFS and OS in the intention-to-treat population.[48]

At the time of data cutoff, with a median follow-up of 26.6 months, the median OS at the final analysis was 17.45 months (95% CI, 15.67–20.83) in the nivolumab-plus-chemotherapy group and 17.15 months (15.18–19.65) in the placebo-plus-chemotherapy group (HR, 0.90; 95% CI, 0.75–1.08; P = .26).[48][Level of evidence A1]

The role of nivolumab in combination with chemotherapy was also assessed in ATTRACTION-4 (NCT02746796), a randomized, multicenter, double-blind, placebo-controlled, phase III trial. The study enrolled patients with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer, regardless of PD-L1 expression. Only 9% of enrolled patients had gastroesophageal junction cancer. Patients were randomly assigned (1:1) to receive chemotherapy every 3 weeks (oxaliplatin 130 mg/m² IV on day 1 plus either oral S-1 40 mg/m² or oral capecitabine 1,000 mg/m², twice daily on days 1–14), in addition to either 360 mg nivolumab IV or placebo. The trial was conducted in Japan, South Korea, and Taiwan, and assigned 724 patients to treatment: 362 patients to the nivolumab-plus-chemotherapy group and 362 to the placebo-plus-chemotherapy group. The primary end points were centrally assessed PFS and OS in the intention-to-treat population.[48]

The most common treatment-related grade 3 or 4 adverse events were decreased neutrophil count (observed in 20% of patients in the nivolumab-plus-chemotherapy group vs. 16% of patients in the placebo-plus-chemotherapy group) and decreased platelet count (observed in 9% of patients in both groups).

The role of nivolumab in combination with chemotherapy was also assessed in ATTRACTION-4 (NCT02746796), a randomized, multicenter, double-blind, placebo-controlled, phase III trial. The study enrolled patients with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer, regardless of PD-L1 expression. Only 9% of enrolled patients had gastroesophageal junction cancer. Patients were randomly assigned (1:1) to receive chemotherapy every 3 weeks (oxaliplatin 130 mg/m² IV on day 1 plus either oral S-1 40 mg/m² or oral capecitabine 1,000 mg/m², twice daily on days 1–14), in addition to either 360 mg nivolumab IV or placebo. The trial was conducted in Japan, South Korea, and Taiwan, and assigned 724 patients to treatment: 362 patients to the nivolumab-plus-chemotherapy group and 362 to the placebo-plus-chemotherapy group. The primary end points were centrally assessed PFS and OS in the intention-to-treat population.[48]

Six treatment-related deaths occurred: three in the nivolumab-plus-chemotherapy group (one each of febrile neutropenia, hepatic failure, and sudden death) and three in the placebo-plus-chemotherapy group (one each of sepsis, hemolytic anemia, and interstitial lung disease).

The role of nivolumab in combination with chemotherapy was also assessed in ATTRACTION-4 (NCT02746796), a randomized, multicenter, double-blind, placebo-controlled, phase III trial. The study enrolled patients with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer, regardless of PD-L1 expression. Only 9% of enrolled patients had gastroesophageal junction cancer. Patients were randomly assigned (1:1) to receive chemotherapy every 3 weeks (oxaliplatin 130 mg/m² IV on day 1 plus either oral S-1 40 mg/m² or oral capecitabine 1,000 mg/m², twice daily on days 1–14), in addition to either 360 mg nivolumab IV or placebo. The trial was conducted in Japan, South Korea, and Taiwan, and assigned 724 patients to treatment: 362 patients to the nivolumab-plus-chemotherapy group and 362 to the placebo-plus-chemotherapy group. The primary end points were centrally assessed PFS and OS in the intention-to-treat population.[48]

Tumor PD-L1 expression was at least 1% in 16% of patients randomized to the nivolumab arm and 15% of patients randomized to the placebo arm.

The role of nivolumab in combination with chemotherapy was also assessed in ATTRACTION-4 (NCT02746796), a randomized, multicenter, double-blind, placebo-controlled, phase III trial. The study enrolled patients with previously untreated (except for neoadjuvant or adjuvant chemotherapy completed ≥180 days before recurrence), HER2-negative, unresectable, advanced or recurrent gastric or gastroesophageal junction cancer, regardless of PD-L1 expression. Only 9% of enrolled patients had gastroesophageal junction cancer. Patients were randomly assigned (1:1) to receive chemotherapy every 3 weeks (oxaliplatin 130 mg/m² IV on day 1 plus either oral S-1 40 mg/m² or oral capecitabine 1,000 mg/m², twice daily on days 1–14), in addition to either 360 mg nivolumab IV or placebo. The trial was conducted in Japan, South Korea, and Taiwan, and assigned 724 patients to treatment: 362 patients to the nivolumab-plus-chemotherapy group and 362 to the placebo-plus-chemotherapy group. The primary end points were centrally assessed PFS and OS in the intention-to-treat population.[48]

When the 3-year follow-up data were reported, the median PFS and OS remained substantially unchanged. The PFS rate was 27.4% in the nivolumab-plus-chemotherapy group and 12.3% in the placebo-plus-chemotherapy group. The OS rate was 23.9% in the nivolumab-plus-chemotherapy group and 19.4% in the placebo-plus-chemotherapy group. No new safety signals or major late-onset treatment-related adverse events were observed in patients who received nivolumab plus chemotherapy.[49]

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

Neoadjuvant pembrolizumab (200 mg IV) or placebo plus cisplatin-based doublet chemotherapy (main cohort, N = 804) every 3 weeks for three cycles.

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

Surgery, adjuvant pembrolizumab or placebo, and chemotherapy for three cycles.

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

Adjuvant pembrolizumab or placebo for 11 cycles.

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

Neoadjuvant pembrolizumab or placebo plus FLOT-based chemotherapy (FLOT cohort) every 2 weeks for four cycles.

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

Surgery, adjuvant pembrolizumab or placebo, plus FLOT for four cycles.

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

Adjuvant pembrolizumab or placebo for 11 cycles.

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

In the main cohort of 804 patients, after a median follow-up of 47.7 months, 52 of 402 patients (12.9%; 95% CI, 9.8%–16.6%) who received pembrolizumab had pathological complete responses. In contrast, only 8 of 402 patients (2.0%; 95% CI, 0.9%–3.9%) who received placebo had pathological complete responses (difference 10.9%; 95% CI, 7.5–14.8; P < .00001).[50][Level of evidence B3]

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

The median EFS was longer when patients received pembrolizumab (44.4 months, 95% CI, 33.0–not reached) when compared with placebo (25.3 months, 95% CI, 20.6–33.9) (HR, 0.81; 95% CI, 0.67–0.99; P = .0198). These values did not meet the threshold for statistical significance (P = .0178).

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

The median OS was 60.7 months (95% CI, 51.5–not reached) in the pembrolizumab group and 58.0 months (41.5–not reached) in the placebo group (HR, 0.90; 95% CI, 0.73–1.12; P = .174).

The multicenter, randomized, placebo-controlled, double-blind, phase III KEYNOTE-585 trial (NCT03221426) evaluated the role of combination neoadjuvant and adjuvant chemotherapy and immune checkpoint inhibition in patients with locally advanced, resectable gastric or gastroesophageal adenocarcinoma. Patients were randomly assigned (1:1) to receive treatment in the following order: A small cohort (n = 203) was instead randomly assigned (1:1) to receive treatment in the following order: The primary end points were centrally reviewed pathological complete response, investigator-reviewed event-free survival (EFS), OS in the intention-to-treat population, and safety in all patients who received at least one dose of treatment.[50] In this trial, meeting the primary end point of pathological complete response did not translate to improvement in relevant primary clinical objectives like OS and EFS. Furthermore, no differential activity was demonstrated in the experimental group based on PD-L1 expression, according to CPS (cutoff, 1%). This was the first published trial evaluating the role of checkpoint inhibitors when given perioperatively to patients with operable gastric or gastroesophageal cancer. Therefore, pending EFS and OS results from studies that used durvalumab or toripalimab are imperative for understanding.

Grade 3 or higher adverse events of any cause occurred in 312 of 399 patients (78%) in the pembrolizumab group and 297 of 400 patients (74%) in the placebo group. The most common adverse events in patients who received pembrolizumab versus placebo were nausea (60% vs. 62%), anemia (42% vs. 40%), and decreased appetite (41% vs. 43%).