KEYTRUDA (Page 14 of 23)

14.9 Gastric Cancer

First-line Treatment of Locally Advanced Unresectable or Metastatic HER2-Positive Gastric or Gastroesophageal Junction Adenocarcinoma

The efficacy of KEYTRUDA in combination with trastuzumab plus fluoropyrimidine and platinum chemotherapy was investigated in KEYNOTE-811 (NCT03615326), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 698 patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma who had not previously received systemic therapy for metastatic disease. PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (5-FU plus cisplatin [FP] or capecitabine plus oxaliplatin [CAPOX]), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms:

  • KEYTRUDA 200 mg, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2 /day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX). KEYTRUDA was administered prior to trastuzumab and chemotherapy on Day 1 of each cycle.
  • Placebo, trastuzumab 8 mg/kg on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 for up to 6 cycles and 5-FU 800 mg/m2 /day for 5 days (FP) or oxaliplatin 130 mg/m2 up to 6-8 cycles and capecitabine 1000 mg/m2 bid for 14 days (CAPOX).

All study medications, except oral capecitabine, were administered as an intravenous infusion every 3-week cycle. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. In an interim efficacy analysis, the major outcome measures assessed were ORR and DoR by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

At the time of the interim analysis, ORR and DoR were assessed in the first 264 patients randomized. Among the 264 patients, the population characteristics were: median age of 62 years (range: 19 to 84), 41% age 65 or older; 82% male; 63% White, 31% Asian, and 0.8% Black; 47% ECOG PS of 0 and 53% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (Stage IV) and 3% had locally advanced unresectable disease. Ninety-one percent (n=240) had tumors that were not MSI-H, 1% (n=2) had tumors that were MSI-H, and in 8% (n=22) the status was not known. Eighty-seven percent of patients received CAPOX.

A statistically significant improvement in ORR was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy. Efficacy results are summarized in Table 75.

Table 75: Efficacy Results for KEYNOTE-811
EndpointKEYTRUDA200 mg every 3 weeksTrastuzumabFluoropyrimidine and Platinum Chemotherapyn=133PlaceboTrastuzumabFluoropyrimidine and Platinum Chemotherapyn=131
+ Denotes ongoing response
*
Response: Best objective response as confirmed complete response or partial response
p-Value based on stratified Miettinen and Nurminen method (compared to an alpha boundary of 0.002)
Based on observed duration of response
Objective Response Rate
ORR * (95% CI)74% (66, 82)52% (43, 61)
Complete response rate11%3.1%
Partial response rate63%49%
p-Value <0.0001
Duration of Response n=99n=68
Median in months (range)10.6 (1.1+, 16.5+)9.5 (1.4+, 15.4+)
% with duration ≥6 months 65% 53%

In a pre-specified subgroup analysis of ORR based on PD-L1 status, the ORR in patients with PD-L1-positive disease (CPS ≥1) was 76% (95% CI: 67, 83) in the pembrolizumab arm (n=117) versus 51% (95% CI: 41, 60) in the control arm (n=112). In patients with tumors that were PD-L1 CPS<1, the ORR was 63% (95% CI: 35, 85) in the pembrolizumab arm (n=16) versus 58% (95% CI: 34, 80) in the control arm (n=19).

In a subsequent interim analysis of pre-specified subgroups based on PD-L1 status in the full study population (n=698), the HR for PFS and OS in patients with PD-L1 CPS<1 (N=104) was 1.03 (95% CI: 0.65, 1.64) and 1.41 (95% CI: 0.90, 2.20), respectively.

First-line Treatment of Locally Unresectable or Metastatic HER2-Negative Gastric or Gastroesophageal Junction Adenocarcinoma

The efficacy of KEYTRUDA in combination with fluoropyrimidine- and platinum-containing chemotherapy was investigated in KEYNOTE-859 (NCT03675737), a multicenter, randomized, double-blind, placebo-controlled trial that enrolled 1579 patients with HER2-negative advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Patients with an autoimmune disease that required systemic therapy within 2 years of treatment or a medical condition that required immunosuppression were ineligible. Randomization was stratified by PD-L1 expression (CPS ≥1 or CPS <1), chemotherapy regimen (FP or CAPOX), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). Patients were randomized (1:1) to one of the following treatment arms; treatment was administered prior to chemotherapy on Day 1 of each cycle:

  • KEYTRUDA 200 mg, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and 5-FU 800 mg/m2 /day for 5 days (FP) or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX).
  • Placebo, investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 and 5-FU 800 mg/m2 /day for 5 days (FP) or oxaliplatin 130 mg/m2 and capecitabine 1000 mg/m2 bid for 14 days (CAPOX).

All study medications, except oral capecitabine, were administered as an intravenous infusion every 3-week cycle. Platinum agents could be administered for 6 or more cycles following local guidelines. Treatment with KEYTRUDA continued until RECIST v1.1-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. The major efficacy outcome measure was OS. Additional secondary efficacy outcome measures included PFS, ORR, and DoR as assessed by BICR using RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The population characteristics were: median age of 62 years (range: 21 to 86), 39% age 65 or older; 68% male and 32% female; 55% White, 34% Asian, 4.6% Multiple, 4.2% American Indian or Alaskan Native, 1.3% Black, and 0.2% Native Hawaiian or other Pacific Islander; 76% Not Hispanic or Latino and 21% Hispanic or Latino; 37% ECOG PS of 0 and 63% ECOG PS of 1. Ninety-seven percent of patients had metastatic disease (Stage IV) and 3% had locally advanced unresectable disease. Seventy-eight percent had tumors that expressed PD-L1 with a CPS ≥1 and 5% (n=74) had tumors that were MSI-H. Eighty-six percent of patients received CAPOX.

A statistically significant improvement in OS, PFS, and ORR was demonstrated in patients randomized to KEYTRUDA in combination with chemotherapy compared with placebo in combination with chemotherapy at the time of a pre-specified interim analysis of OS. Efficacy results are summarized in Table 76 and Figures 17 and 18.

Table 76: Efficacy Results * for KEYNOTE-859
EndpointKEYTRUDA200 mg every 3weeksandFP or CAPOXn=790PlaceboandFP or CAPOXn=789KEYTRUDA200 mg every 3weeksandFP or CAPOXn=618PlaceboandFP or CAPOXn=617KEYTRUDA200 mg every 3weeksandFP or CAPOXn=279PlaceboandFP or CAPOXn=272
All PatientsCPS≥1CPS≥10
+ Denotes ongoing response
*
Based on a pre-specified interim analysis
Based on the stratified Cox proportional hazard model
One-sided p-Value based on stratified log-rank test
§
Response: Best objective response as confirmed complete response or partial response
One-sided p-Value based on stratified Miettinen & Nurminen method
#
Based on Kaplan-Meier estimates
OS
Number (%) of patients with event603 (76)666 (84)464 (75)526 (85)188(67)226 (83)
Median in months (95% CI)12.9 (11.9, 14.0)11.5 (10.6, 12.1)13.0 (11.6, 14.2)11.4 (10.5, 12.0)15.7 (13.8, 19.3)11.8 (10.3,12.7)
Hazard ratio (95% CI)0.78 (0.70, 0.87)0.74 (0.65, 0.84)0.65 (0.53, 0.79)
p-Value (stratified log-rank)<0.0001<0.0001<0.0001
PFS
Number (%) of patients with event572 (72)608 (77)443 (72%)483 (78%)190 (68)210(77)
Median in months (95% CI)6.9 (6.3, 7.2)5.6 (5.5, 5.7)6.9 (6.0, 7.2)5.6 (5.4, 5.7)8.1 (6.8, 8.5)5.6 (5.4,6.7)
Hazard ratio (95% CI)0.76 (0.67, 0.85)0.72 (0.63, 0.82)0.62 (0.51, 0.76)
p-Value (stratified log-rank)<0.0001<0.0001<0.0001
Objective Response Rate
ORR § (95% CI)51% (48, 55)42% (38, 45)52% (48, 56)43% (39, 47)61% (55, 66)43% (37, 49)
Complete response rate9%6%10%6%13%5%
Partial response rate42%36%42%37%48%38%
p-Value <0.00010.0004<0.0001
Duration of Response n=405n=331n=322n=263n=169n=117
Median in months # (95% CI)8.0 (7.0, 9.7)5.7 (5.5, 6.9)8.3 (7.0, 10.9)5.6 (5.4, 6.9)10.9 (8.0, 13.8)5.8 (5.3, 7.0)
Range in months1.2+, 41.5+1.3+, 34.7+1.2+, 41.5+1.3+, 34.2+1.2+ -41.5+1.4+ -31.2+
Figure 17: Kaplan-Meier Curve for Overall Survival by Treatment Arm in KEYNOTE-859

Figure 17
(click image for full-size original)

Figure 18: Kaplan-Meier Curve for Overall Survival in KEYNOTE-859 (CPS≥1)

Figure 18
(click image for full-size original)

In an exploratory subgroup analysis in patients with PD-L1 CPS<1 (n=344) at the time of the pre-specified interim analysis of OS, the median OS was 12.7 months (95% CI: 11.4, 15.0) for the KEYTRUDA arm and 12.2 months (95% CI: 9.5, 14.0) for the placebo arm, with a HR of 0.92 (95% CI: 0.73, 1.17).

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