Immunotherapy and chemoimmunotherapy for patients with squamous cell carcinoma

In the CheckMate 648 trial (NCT03143153), 970 adults with previously untreated, unresectable advanced, recurrent, or metastatic squamous cell carcinoma were enrolled, regardless of tumor cell PD-L1 expression. Patients were randomly assigned to receive either nivolumab (240 mg every 2 weeks) plus chemotherapy with 5-FU and cisplatin (every 4 weeks), nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), or chemotherapy alone. Primary end points for all groups were OS and PFS per blinded independent central review in patients with tumor cell PD-L1 expression of 1% or more (observed in 49% of patients). Further analyses included all patients regardless of PD-L1 status.[43]

In the CheckMate 648 trial (NCT03143153), 970 adults with previously untreated, unresectable advanced, recurrent, or metastatic squamous cell carcinoma were enrolled, regardless of tumor cell PD-L1 expression. Patients were randomly assigned to receive either nivolumab (240 mg every 2 weeks) plus chemotherapy with 5-FU and cisplatin (every 4 weeks), nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), or chemotherapy alone. Primary end points for all groups were OS and PFS per blinded independent central review in patients with tumor cell PD-L1 expression of 1% or more (observed in 49% of patients). Further analyses included all patients regardless of PD-L1 status.[43]

In patients with PD-L1-positive disease, the median OS was 15.4 months for patients who received nivolumab plus chemotherapy (95% CI, 11.9–19.5; n = 158), 13.7 months for patients who received nivolumab plus ipilimumab (95% CI, 11.2–17.0; n = 158), and 9.1 months for patients who received chemotherapy alone (95% CI, 7.7–10.0; n = 157). The corresponding HR (vs. chemotherapy) was 0.54 (99.5% CI, 0.37–0.8; P < .0001) for patients who received nivolumab plus chemotherapy and 0.64 (98.6% CI, 0.46–0.9; P < .001) for patients who received nivolumab plus ipilimumab.[43][Level of evidence A1]

In the CheckMate 648 trial (NCT03143153), 970 adults with previously untreated, unresectable advanced, recurrent, or metastatic squamous cell carcinoma were enrolled, regardless of tumor cell PD-L1 expression. Patients were randomly assigned to receive either nivolumab (240 mg every 2 weeks) plus chemotherapy with 5-FU and cisplatin (every 4 weeks), nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), or chemotherapy alone. Primary end points for all groups were OS and PFS per blinded independent central review in patients with tumor cell PD-L1 expression of 1% or more (observed in 49% of patients). Further analyses included all patients regardless of PD-L1 status.[43]

A statistically significant improvement in median OS, compared with chemotherapy, was also observed in all randomized patients, irrespective of PD-L1 status. Median OS was 13.2 months for patients who received nivolumab plus chemotherapy (95% CI, 11.1–15.7; n = 321), 12.8 months for patients who received nivolumab plus ipilimumab (95% CI, 11.3–15.5; n = 325), and 10.7 months for patients who received chemotherapy alone (95% CI, 9.4–11.9; n = 324). The corresponding HR (vs. chemotherapy) was 0.74 (99.1% CI, 0.58–0.96; P = .0021) for patients who received nivolumab plus chemotherapy and 0.78 (98.2% CI, 0.62–0.98; P = .011) for patients who received nivolumab plus ipilimumab.[43][Level of evidence A1]

In the CheckMate 648 trial (NCT03143153), 970 adults with previously untreated, unresectable advanced, recurrent, or metastatic squamous cell carcinoma were enrolled, regardless of tumor cell PD-L1 expression. Patients were randomly assigned to receive either nivolumab (240 mg every 2 weeks) plus chemotherapy with 5-FU and cisplatin (every 4 weeks), nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), or chemotherapy alone. Primary end points for all groups were OS and PFS per blinded independent central review in patients with tumor cell PD-L1 expression of 1% or more (observed in 49% of patients). Further analyses included all patients regardless of PD-L1 status.[43]

However, among patients whose tumors expressed less than 1% of PD-L1, OS was not significantly changed by the addition of nivolumab to chemotherapy (n = 329; median OS, 12.2 months with chemotherapy and 12 months with nivolumab plus chemotherapy) or by the combination of nivolumab with ipilimumab (n = 330; median OS, 12.2 months with chemotherapy and 12 months with nivolumab plus ipilimumab).

In the CheckMate 648 trial (NCT03143153), 970 adults with previously untreated, unresectable advanced, recurrent, or metastatic squamous cell carcinoma were enrolled, regardless of tumor cell PD-L1 expression. Patients were randomly assigned to receive either nivolumab (240 mg every 2 weeks) plus chemotherapy with 5-FU and cisplatin (every 4 weeks), nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks), or chemotherapy alone. Primary end points for all groups were OS and PFS per blinded independent central review in patients with tumor cell PD-L1 expression of 1% or more (observed in 49% of patients). Further analyses included all patients regardless of PD-L1 status.[43]

Grade 3 or higher adverse events occurred in 147 patients (47%) who received nivolumab plus chemotherapy, 102 patients (32%) who received nivolumab plus ipilimumab, and 108 patients (36%) who received chemotherapy alone. No new safety signals were observed.

The results of ESCORT-1st (NCT03691090), a randomized, double-blind, multicenter, placebo-controlled trial conducted in China, corroborated the positive impact of checkpoint inhibitors combined with first-line chemotherapy on patient survival. In this trial, 596 patients with previously untreated locally advanced or metastatic esophageal squamous cell cancer were randomly assigned (1:1) to receive either the humanized anti-PD-1 monoclonal antibody camrelizumab (200 mg; n = 298) or placebo (n = 298). Patients in both groups also received up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All drugs were given IV every 3 weeks. Co-primary end points were OS and independent review committee (IRC)-assessed PFS.[44]Camrelizumab is only approved for use in China.

The results of ESCORT-1st (NCT03691090), a randomized, double-blind, multicenter, placebo-controlled trial conducted in China, corroborated the positive impact of checkpoint inhibitors combined with first-line chemotherapy on patient survival. In this trial, 596 patients with previously untreated locally advanced or metastatic esophageal squamous cell cancer were randomly assigned (1:1) to receive either the humanized anti-PD-1 monoclonal antibody camrelizumab (200 mg; n = 298) or placebo (n = 298). Patients in both groups also received up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All drugs were given IV every 3 weeks. Co-primary end points were OS and independent review committee (IRC)-assessed PFS.[44]Camrelizumab is only approved for use in China.

With a median follow-up of 10.8 months, patients who received camrelizumab plus chemotherapy had significantly improved OS compared with patients who received placebo plus chemotherapy (median OS, 15.3 months [95% CI, 12.8–17.3] vs. 12.0 months [11.0–13.3]; HR, 0.70; 95% CI, 0.56–0.88; one-sided P = .0010).

The results of ESCORT-1st (NCT03691090), a randomized, double-blind, multicenter, placebo-controlled trial conducted in China, corroborated the positive impact of checkpoint inhibitors combined with first-line chemotherapy on patient survival. In this trial, 596 patients with previously untreated locally advanced or metastatic esophageal squamous cell cancer were randomly assigned (1:1) to receive either the humanized anti-PD-1 monoclonal antibody camrelizumab (200 mg; n = 298) or placebo (n = 298). Patients in both groups also received up to 6 cycles of paclitaxel (175 mg/m2) and cisplatin (75 mg/m2). All drugs were given IV every 3 weeks. Co-primary end points were OS and independent review committee (IRC)-assessed PFS.[44]Camrelizumab is only approved for use in China.

Grade 3 or higher treatment-related adverse events occurred in 189 patients (63.4%) in the camrelizumab group and 201 patients (67.7%) in the placebo group. Treatment-related deaths occurred in 9 patients (3.0%) in the camrelizumab group and 11 patients (3.7%) in the placebo group.

In KEYNOTE-590 (NCT03189719), a double-blind, placebo-controlled, randomized, phase III trial, 1,020 patients with previously untreated, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer (regardless of PD-L1 status) were screened.[45] A total of 749 patients were randomly assigned (1:1) to receive either pembrolizumab (200 mg) or placebo plus chemotherapy (5-FU at 800 mg/m2 on days 1–5 and cisplatin 80 mg/m2 on day 1 [for up to 6 cycles]). Treatment was repeated once every 3 weeks for up to 35 cycles. The primary end points were: (1) OS in patients with esophageal squamous cell carcinoma and a PD-L1 combined positive score (CPS) of 10 or more, and (2) OS and PFS in patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS of 10 or more irrespective of the histology, and all randomized patients. A total of 548 enrolled patients (73%) had squamous cell histology, 286 of whom (52%) had a CPS of 10 or more.Notably, in an exploratory analysis in patients with a PD-L1 CPS of less than 10, median OS was 10.5 months in the pembrolizumab and chemotherapy group versus 10.6 months in the placebo and chemotherapy group (HR, 0.86; 95% CI, 0.68–1.10).

In KEYNOTE-590 (NCT03189719), a double-blind, placebo-controlled, randomized, phase III trial, 1,020 patients with previously untreated, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer (regardless of PD-L1 status) were screened.[45] A total of 749 patients were randomly assigned (1:1) to receive either pembrolizumab (200 mg) or placebo plus chemotherapy (5-FU at 800 mg/m2 on days 1–5 and cisplatin 80 mg/m2 on day 1 [for up to 6 cycles]). Treatment was repeated once every 3 weeks for up to 35 cycles. The primary end points were: (1) OS in patients with esophageal squamous cell carcinoma and a PD-L1 combined positive score (CPS) of 10 or more, and (2) OS and PFS in patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS of 10 or more irrespective of the histology, and all randomized patients. A total of 548 enrolled patients (73%) had squamous cell histology, 286 of whom (52%) had a CPS of 10 or more.Notably, in an exploratory analysis in patients with a PD-L1 CPS of less than 10, median OS was 10.5 months in the pembrolizumab and chemotherapy group versus 10.6 months in the placebo and chemotherapy group (HR, 0.86; 95% CI, 0.68–1.10).

At the first interim analysis (after a median follow-up of 22.6 months), patients who received pembrolizumab plus chemotherapy had superior OS compared with patients who received placebo plus chemotherapy for each of the following subgroups:[45][Level of evidence A1]

In KEYNOTE-590 (NCT03189719), a double-blind, placebo-controlled, randomized, phase III trial, 1,020 patients with previously untreated, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer (regardless of PD-L1 status) were screened.[45] A total of 749 patients were randomly assigned (1:1) to receive either pembrolizumab (200 mg) or placebo plus chemotherapy (5-FU at 800 mg/m2 on days 1–5 and cisplatin 80 mg/m2 on day 1 [for up to 6 cycles]). Treatment was repeated once every 3 weeks for up to 35 cycles. The primary end points were: (1) OS in patients with esophageal squamous cell carcinoma and a PD-L1 combined positive score (CPS) of 10 or more, and (2) OS and PFS in patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS of 10 or more irrespective of the histology, and all randomized patients. A total of 548 enrolled patients (73%) had squamous cell histology, 286 of whom (52%) had a CPS of 10 or more.Notably, in an exploratory analysis in patients with a PD-L1 CPS of less than 10, median OS was 10.5 months in the pembrolizumab and chemotherapy group versus 10.6 months in the placebo and chemotherapy group (HR, 0.86; 95% CI, 0.68–1.10). › At the first interim analysis (after a median follow-up of 22.6 months), patients who received pembrolizumab plus chemotherapy had superior OS compared with patients who received placebo plus chemotherapy for each of the following subgroups:[45][Level of evidence A1]

Patients with esophageal squamous cell carcinoma and a PD-L1 CPS of 10 or more (median OS, 13.9 months vs. 8.8 months; HR, 0.57; 95% CI, 0.43–0.75; P < .0001).

In KEYNOTE-590 (NCT03189719), a double-blind, placebo-controlled, randomized, phase III trial, 1,020 patients with previously untreated, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer (regardless of PD-L1 status) were screened.[45] A total of 749 patients were randomly assigned (1:1) to receive either pembrolizumab (200 mg) or placebo plus chemotherapy (5-FU at 800 mg/m2 on days 1–5 and cisplatin 80 mg/m2 on day 1 [for up to 6 cycles]). Treatment was repeated once every 3 weeks for up to 35 cycles. The primary end points were: (1) OS in patients with esophageal squamous cell carcinoma and a PD-L1 combined positive score (CPS) of 10 or more, and (2) OS and PFS in patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS of 10 or more irrespective of the histology, and all randomized patients. A total of 548 enrolled patients (73%) had squamous cell histology, 286 of whom (52%) had a CPS of 10 or more.Notably, in an exploratory analysis in patients with a PD-L1 CPS of less than 10, median OS was 10.5 months in the pembrolizumab and chemotherapy group versus 10.6 months in the placebo and chemotherapy group (HR, 0.86; 95% CI, 0.68–1.10). › At the first interim analysis (after a median follow-up of 22.6 months), patients who received pembrolizumab plus chemotherapy had superior OS compared with patients who received placebo plus chemotherapy for each of the following subgroups:[45][Level of evidence A1]

Patients with esophageal squamous cell carcinoma (OS, 12.6 months vs. 9.8 months; HR, 0.72; 95% CI, 0.60–0.88; P = .0006).

In KEYNOTE-590 (NCT03189719), a double-blind, placebo-controlled, randomized, phase III trial, 1,020 patients with previously untreated, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer (regardless of PD-L1 status) were screened.[45] A total of 749 patients were randomly assigned (1:1) to receive either pembrolizumab (200 mg) or placebo plus chemotherapy (5-FU at 800 mg/m2 on days 1–5 and cisplatin 80 mg/m2 on day 1 [for up to 6 cycles]). Treatment was repeated once every 3 weeks for up to 35 cycles. The primary end points were: (1) OS in patients with esophageal squamous cell carcinoma and a PD-L1 combined positive score (CPS) of 10 or more, and (2) OS and PFS in patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS of 10 or more irrespective of the histology, and all randomized patients. A total of 548 enrolled patients (73%) had squamous cell histology, 286 of whom (52%) had a CPS of 10 or more.Notably, in an exploratory analysis in patients with a PD-L1 CPS of less than 10, median OS was 10.5 months in the pembrolizumab and chemotherapy group versus 10.6 months in the placebo and chemotherapy group (HR, 0.86; 95% CI, 0.68–1.10). › At the first interim analysis (after a median follow-up of 22.6 months), patients who received pembrolizumab plus chemotherapy had superior OS compared with patients who received placebo plus chemotherapy for each of the following subgroups:[45][Level of evidence A1]

Patients with a PD-L1 CPS of 10 or more (OS, 13.5 months vs. 9.4 months; HR, 0.62; 95% CI, 0.49–0.78; P < .0001).

In KEYNOTE-590 (NCT03189719), a double-blind, placebo-controlled, randomized, phase III trial, 1,020 patients with previously untreated, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer (regardless of PD-L1 status) were screened.[45] A total of 749 patients were randomly assigned (1:1) to receive either pembrolizumab (200 mg) or placebo plus chemotherapy (5-FU at 800 mg/m2 on days 1–5 and cisplatin 80 mg/m2 on day 1 [for up to 6 cycles]). Treatment was repeated once every 3 weeks for up to 35 cycles. The primary end points were: (1) OS in patients with esophageal squamous cell carcinoma and a PD-L1 combined positive score (CPS) of 10 or more, and (2) OS and PFS in patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS of 10 or more irrespective of the histology, and all randomized patients. A total of 548 enrolled patients (73%) had squamous cell histology, 286 of whom (52%) had a CPS of 10 or more.Notably, in an exploratory analysis in patients with a PD-L1 CPS of less than 10, median OS was 10.5 months in the pembrolizumab and chemotherapy group versus 10.6 months in the placebo and chemotherapy group (HR, 0.86; 95% CI, 0.68–1.10). › At the first interim analysis (after a median follow-up of 22.6 months), patients who received pembrolizumab plus chemotherapy had superior OS compared with patients who received placebo plus chemotherapy for each of the following subgroups:[45][Level of evidence A1]

All randomized patients (OS, 12.4 months vs. 9.8 months; HR, 0.73; 95% CI, 0.62–0.86; P < .0001).

In KEYNOTE-590 (NCT03189719), a double-blind, placebo-controlled, randomized, phase III trial, 1,020 patients with previously untreated, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer (regardless of PD-L1 status) were screened.[45] A total of 749 patients were randomly assigned (1:1) to receive either pembrolizumab (200 mg) or placebo plus chemotherapy (5-FU at 800 mg/m2 on days 1–5 and cisplatin 80 mg/m2 on day 1 [for up to 6 cycles]). Treatment was repeated once every 3 weeks for up to 35 cycles. The primary end points were: (1) OS in patients with esophageal squamous cell carcinoma and a PD-L1 combined positive score (CPS) of 10 or more, and (2) OS and PFS in patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS of 10 or more irrespective of the histology, and all randomized patients. A total of 548 enrolled patients (73%) had squamous cell histology, 286 of whom (52%) had a CPS of 10 or more.Notably, in an exploratory analysis in patients with a PD-L1 CPS of less than 10, median OS was 10.5 months in the pembrolizumab and chemotherapy group versus 10.6 months in the placebo and chemotherapy group (HR, 0.86; 95% CI, 0.68–1.10).

The 24-month OS rate in each of the above subgroups was double in the pembrolizumab and chemotherapy group compared with the placebo and chemotherapy group (approximately 30% vs. 15%).

In KEYNOTE-590 (NCT03189719), a double-blind, placebo-controlled, randomized, phase III trial, 1,020 patients with previously untreated, locally advanced, unresectable, or metastatic esophageal cancer or Siewert type 1 gastroesophageal junction cancer (regardless of PD-L1 status) were screened.[45] A total of 749 patients were randomly assigned (1:1) to receive either pembrolizumab (200 mg) or placebo plus chemotherapy (5-FU at 800 mg/m2 on days 1–5 and cisplatin 80 mg/m2 on day 1 [for up to 6 cycles]). Treatment was repeated once every 3 weeks for up to 35 cycles. The primary end points were: (1) OS in patients with esophageal squamous cell carcinoma and a PD-L1 combined positive score (CPS) of 10 or more, and (2) OS and PFS in patients with esophageal squamous cell carcinoma, patients with a PD-L1 CPS of 10 or more irrespective of the histology, and all randomized patients. A total of 548 enrolled patients (73%) had squamous cell histology, 286 of whom (52%) had a CPS of 10 or more.Notably, in an exploratory analysis in patients with a PD-L1 CPS of less than 10, median OS was 10.5 months in the pembrolizumab and chemotherapy group versus 10.6 months in the placebo and chemotherapy group (HR, 0.86; 95% CI, 0.68–1.10).

Grade 3 or higher treatment-related adverse events occurred in 266 patients (72%) in the pembrolizumab group and 250 patients (68%) in the placebo group.