Abstract
On May 5, 2021 and March 19, 2025, the Food and Drug Administration (FDA) granted accelerated and regular approval for pembrolizumab plus trastuzumab and platinum-based chemotherapy for unresectable or metastatic human epidermal growth factor receptor-2 (HER2) gastric or gastroesophageal junction carcinoma. Both approvals were based on KEYNOTE-811, a randomized, multiregional trial, comparing pembrolizumab plus trastuzumab and chemotherapy versus placebo plus trastuzumab and chemotherapy. Accelerated approval was granted based on overall response rate (ORR) in the first 264 patients randomized, showing a statistically significant improvement with pembrolizumab (74.4% vs. 51.9%, p= 0.00006). The final overall survival (OS) analysis demonstrated a clinically meaningful improvement, with a median OS of 20.0 months (95% CI 17.8, 22.1) and 16.8 months (95% CI 14.9, 18.7) in the pembrolizumab and placebo arms respectively (HR 0.80 [95% CI 0.67, 0.94]; p= 0.004). However, in exploratory subgroup analyses treatment benefit appeared to be driven by the PD-L1 CPS ≥1 population (85% of patients, with an OS HR of 0.79 [95% CI 0.66, 0.95]), whereas in the CPS <1 subgroup (15% of patients) treatment with pembrolizumab did not show improvement (HR 1.10, [95% CI 0.72–1.68]). These results are consistent with analysis of pembrolizumab and other immune checkpoint inhibitors across multiple clinical trials in patients with gastric cancer. KEYNOTE-811 utilized a “one-trial” approach allowing accelerated approval based on response rate with subsequent conversion to regular approval based on survival outcomes. KEYNOTE-811 also provided data for earlier access to therapies in a frontline metastatic setting, following FDA’s Project Frontrunner approach.
Introduction
Although gastric cancer is the 5th most common cancer in the world, there are marked regional differences in incidence (1). In the US, new cases of gastric cancer in 2025 are expected in 30,300 people, with estimated 10,780 deaths from the disease (2).
Testing for human epidermal growth factor receptor-2 (HER2) status is standard in all patients considered candidates for systemic therapy, with reports showing amplification or overexpression of HER2 in 7–34% of gastric cancers (3, 4, 5). In the Trastuzumab for Gastric Cancer (ToGA) trial, the results of which served as the basis for the 2010 approval of trastuzumab in gastric cancer, 53% of patients were Asian, and HER2 positivity (22.1%) was similar between European and Asian patients (23.6% and 23.9% respectively) (6). The ToGA trial established the role of trastuzumab treatment in patients with HER2-positive gastric cancer by demonstrating improved survival when trastuzumab was added to standard of care cisplatin combined with a fluoropyrimidine (HR 0.73, 95% confidence interval [CI] 0.60, 0.91). Even with trastuzumab, outcomes are poor for patients with unresectable or metastatic disease (median overall survival [OS] with trastuzumab was 13.7 months in the ToGA trial), and there is an unmet medical need for this patient population.
In this paper, we describe FDA’s review of the approval process of pembrolizumab (KEYTRUDA, Merck, Sharp & Dohme) for the treatment of patients with advanced or metastatic HER2-positive gastric cancer. Accelerated approval for pembrolizumab for this indication was granted on May 5, 2021, based on an interim analysis of response rate of a randomized trial, KEYNOTE-811 (NCT03615326), and traditional approval was granted on March 19, 2025, based on survival outcomes of the same trial. The Investigators’ analyses and interpretation of the trial results were previously published (7, 8).
Trial Design
KEYNOTE-811 is a multiregional, randomized, double-blind trial designed to compare pembrolizumab or placebo in combination with standard of care (SOC) trastuzumab and chemotherapy in patients with previously untreated, unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. Patients who received prior systemic neoadjuvant or adjuvant therapy completed at least 6 months before the diagnosis of unresectable or metastatic disease were eligible. HER2 positivity was defined as immunohistochemistry (IHC) 3+ or 2+ with fluorescence in situ hybridization (FISH) positive as per central laboratory testing using FDA-approved assays. Other key eligibility criteria included disease measurable per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (9) and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.
Patients were randomized 1:1 to receive pembrolizumab 200 mg administered by intravenous (IV) infusion every 3 weeks (Q3W), or placebo. All patients received trastuzumab 8 mg/kg IV on first infusion and 6 mg/kg in subsequent cycles, followed by investigator’s choice of combination chemotherapy of cisplatin 80 mg/m2 IV for up to 6 cycles and 5-FU 800 mg/m2/day IV for 5 days (FP) or oxaliplatin 130 mg/m2 IV up to 6–8 cycles and oral capecitabine 1000 mg/m2 twice daily for 14 days (CAPOX). Treatment was administered in 3-week cycles. Treatment continued until RECIST v1.1-defined progression of disease as determined by Blinded Independent Central Review (BICR), unacceptable toxicity, or a maximum of 24 months. Randomization was stratified by Programmed Death Ligand-1 (PD-L1 expression) (Combined Positive Score [CPS] ≥1 or CPS <1), chemotherapy regimen (FP or CAPOX), and geographic region (Europe/Israel/North America/Australia, Asia, or Rest of the World). PD-L1 status was centrally determined using the PD-L1 IHC 22C3 pharmDx™ kit. Disease recurrence/progression was assessed every 6 weeks.
The primary efficacy outcomes were progression-free survival (PFS) per RECIST 1.1 as determined by the Blinded Independent Central Review (BICR), and overall survival (OS). The key secondary endpoint was overall response rate (ORR) as per RECIST 1.1 by BICR. The overall Type I error was controlled at 1-sided 0.025 using the Maurer and Bretz graphical method with initially 0.002 allocated to ORR, 0.003 to PFS, and 0.02 to OS. Assuming a median PFS of 6.7 months in the placebo arm and 9.6 months in the pembrolizumab arm, a total of 606 PFS events were needed to detect a hazard ratio of 0.70 with 95% power at an initial 1-sided alpha level of 0.003. Assuming a median OS of 13.8 months in the placebo arm and 18.4 months in the pembrolizumab arm, a total of 551 deaths were needed to detect a hazard ratio of 0.75 with 90% power at a 1-sided alpha level of 0.02. Assuming a response rate of 48% in the placebo arm and 73% in the pembrolizumab arm, with a sample size of 260 patients, a difference in ORR of 25% would have had 90% power at an initial 1-sided alpha level of 0.002. A stratified Miettinen-Nurminen method was to be used for the analysis of ORR; the primary analyses for PFS and OS were stratified log-rank tests performed on the intent-to-treat (ITT) population.
Three interim analyses (IA) were planned for this study. IA1 was planned to be based on the first 260 patients with at least 8.5 months of follow up and was planned to be considered the final analysis for ORR. Neither PFS nor OS was planned to be formally tested at the IA1. IA2 was planned to be conducted after 542 (89%) PFS events, which would also correspond to 73% information fraction for OS. IA3 was planned to be the final PFS analysis to be conducted after 606 (100%) PFS events, which would also correspond to 89% information fraction for OS. The final OS analysis was planned to occur at 551 (100%) deaths.
Results
In KEYNOTE-811, a total of 698 patients were randomized to receive pembrolizumab with trastuzumab and chemotherapy (n= 350) or placebo with trastuzumab and chemotherapy (n= 348). Among all patients, 594 (85%, 298 in the pembrolizumab arm and 296 in the placebo arm) had tumors that expressed PD-L1 with a CPS ≥1. There were no marked differences in baseline demographic and disease characteristics for patients between the ITT and CPS ≥1 populations, and characteristics were mostly balanced between arms (Table 1).
Table 1.
Demographic and Baseline Disease Characteristics
| ITT (N= 698) N (%) |
CPS ≥1 (N= 594) N (%) |
|||
|---|---|---|---|---|
| Pembrolizumab + SOC (N= 350) |
Placebo + SOC (N= 248) |
Pembrolizumab + SOC (N= 298) |
Placebo + SOC (N= 296) |
|
| Sex | ||||
| - Male | 284 (81) | 280 (80) | 240 (81) | 237 (80) |
| - Female | 66 (19) | 68 (20) | 58 (19) | 59 (20) |
| Age (years) | ||||
| - Median (range) | 62 (19, 85) | 63 (32, 85) | 63 (19, 85) | 63 (32, 85) |
| - ≥ 65 y.o. | 145 (41) | 156 (45) | 124 (42) | 131 (44) |
| Race | ||||
| - American Indian | 5 (1) | 6 (2) | 5 (2) | 6 (2) |
| - Asian | 119 (34) | 121 (35) | 97 (33) | 97 (33) |
| - Black or African American | 2 (0.6) | 2 (0.6) | 2 (0.7) | 2 (0.7) |
| - Multiple | 6 (2) | 5 (1) | 5 (2) | 4 (1) |
| - White | 218 (62) | 212 (61) | 189 (63) | 186 (63) |
| - Missing | 0 | 2 (0.6) | 0 | 1 (0.3) |
| Ethnicity | ||||
| - Hispanic/Latino | 38 (11) | 45 (13) | 36 (12) | 41 (14) |
| - Not Hispanic/ Latino | 309 (88) | 293 (84) | 259 (87) | 250 (84) |
| - Unknown | 3 (0.9) | 10 (3) | 3 (1) | 5 (2) |
| Geographic region | ||||
| - Asia | 118 (34) | 119 (34) | 96 (32) | 96 (32) |
| - Rest of the World | 119 (34) | 118 (34) | 105 (35) | 104 (35) |
| - WE/Israel/NA/Australia | 113 (32) | 111 (32) | 97 (33) | 96 (32) |
| ECOG PS | ||||
| - 0 | 146 (42) | 146 (42) | 127 (43) | 122 (41) |
| - 1 | 204 (58) | 202 (58) | 171 (57) | 174 (59) |
| Primary tumor location | ||||
| - GEJ | 110 (31) | 122 (35) | 97 (33) | 99 (33) |
| - Gastric | 240 (69) | 226 (65) | 201 (67) | 197 (67) |
| Disease status | ||||
| - Locally advanced | 10 (3) | 7 (2) | 8 (3) | 6 (2) |
| - Metastatic | 340 (97) | 341 (98) | 290 (97) | 290 (98) |
| HER2 status | ||||
| - IHC1+/IHC2+ ISH- | 2 (0.6) | 3 (0.9) | 2 (0.7) | 3 (1) |
| - IHC2+/ISH+ | 62 (18) | 84 (24) | 51 (17) | 68 (23) |
| - IHC3+ | 286 (82) | 261 (75) | 245 (82) | 225 (76) |
| MSI status | ||||
| - MSI-H | 6 (2) | 2 (0.6) | 6 (2) | 2 (1) |
| - Non-MSI-H | 326 (93) | 329 (95) | 282 (95) | 280 (95) |
| - Unknown | 18 (5) | 17 (5) | 10 (3) | 14 (5) |
| Chemotherapy | ||||
| - CAPOX | 297 (85) | 299 (86) | 251 (84) | 253 (85) |
| - FP | 53(15) | 49 (14) | 47 (16) | 43 (15) |
WE: Western Europe; NA: North America.
Source: FDA analysis
At the time of IA1 (data cutoff June 17, 2020), with 434 patients enrolled, ORR and DoR were assessed in the first 264 patients randomized. 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. The ORR was 74.4% (95% CI 66.2, 81.6) and 51.9% (95% CI 43.0, 60.7) in the pembrolizumab and placebo arms (p=0.00006), with median DOR of 10.6 months (range: 1.1+, 16.5+) and 9.5 months (range: 1.4+, 15.4+) respectively. In an exploratory analysis of patients with tumors that were PD-L1 CPS<1, the ORR was 62.5% (95% CI: 35.4, 84.8) in the pembrolizumab arm (n=16) versus 57.9% (95% CI: 33.5, 79.7) in the control arm (n=19).
At the time of IA2 (interim analyses of PFS and OS, data cutoff May 25, 2022), 484 PFS events had occurred. A statistically significant improvement in PFS was demonstrated in patients randomized to KEYTRUDA in combination with trastuzumab and chemotherapy compared with placebo in combination with trastuzumab and chemotherapy (HR 0.72 [95% CI 0.60, 0.87]; p=0.0002). However, the OS prespecified boundary for statistical significance was not crossed (p=0.0842). In an exploratory analysis of patients with tumors that were PD-L1 CPS <1, the PFS HR was 1.17 (95% CI 0.73, 1.89).
Statistical significance for survival was also not reached at IA3 (data cutoff March 29, 2023), with a total of 501 deaths (245 and 256 in the pembrolizumab and placebo arms respectively) and a HR of 0.84 (95% CI 0.70, 1.01); however, in an exploratory analysis of patients with tumors that were PD-L1 CPS<1, the HR for OS was 1.41 (95% CI 0.90, 2.20).
With a data cutoff of March 20, 2024, the final analysis of OS crossed the pre-specified statistical boundary for significance. Median OS was 20.0 months (95% CI 17.8, 22.1) in the pembrolizumab arm and 16.8 months (95% CI 14.9, 18.7) in the placebo arm, with a HR of 0.80 (95% CI 0.67, 0.94; p= 0.004). The HR for the CPS ≥ 1 subgroup was 0.79 (95% CI 0.66, 0.95). In an exploratory analysis of patients with tumors that were PD-L1 CPS <1, the HR for OS was 1.10 (95% CI: 0.72, 1.68). Table 2 summarizes the results of ORR, PFS, and OS in the ITT and PD-L1 CPS ≥1 population at the final analysis data cutoff. The Kaplan-Meier curves of OS in the PD-L1 CPS ≥1 and CPS <1 patient populations are presented in Figure 1.
Table 2.
ORR, PFS, and OS Final Analyses
| ITT (N= 698) | PD-L1 CPS ≥1 (n= 594) | |||
|---|---|---|---|---|
| Pembrolizumab + SOC (n = 350) |
Placebo + SOC (n = 348) |
Pembrolizumab + SOC (n = 298) |
Placebo + SOC (n = 296) |
|
| OS | ||||
| mOS, months (95% CI) | 20.0 (17.8, 22.1) |
16.8 (14.9, 18.7) |
20.1 (17.9, 22.9) |
15.7 (13.5, 18.5) |
| HR (95% CI) | 0.80 (0.67, 0.94) | 0.79 (0.66, 0.95) | ||
| PFS | ||||
| mPFS, months, (95% CI) | 10.0 (8.6, 12.2) |
8.1 (7.0, 8.5) |
10.9 (8.5, 12.5) |
7.3 (6.8, 8.4) |
| HR (95% CI) | 0.73 (0.61, 0.87) | 0.72 (0.60, 0.87) | ||
| ORR | ||||
| ORR % (95% CI) | 72.6 (67.6, 77.2) | 60.1 (54.7, 65.2) | 73.2 (67.7, 78.1) | 58.4 (52.6, 64.1) |
Source: FDA analysis
Figure 1. Kaplan-Meier Curves of Overall Survival Final Analysis in PD-L1 CPS ≥1 and <1 Populations.
Source: FDA analysis
The adverse reaction profile observed in patients receiving pembrolizumab KEYNOTE-811 is generally consistent with the known pembrolizumab safety profile. Pembrolizumab was discontinued due to adverse events (AEs) in 13% of patients. Adverse reactions leading to interruption of any of the multidrug component occurred in 82% and 74% of patients in the pembrolizumab and placebo arms, respectively. Three (0.9%) patients died due to designated immune-related adverse events in the pembrolizumab arm (pneumonitis and hepatitis), while 1 patient (0.3%) died of myocarditis in the control arm. Adverse reactions observed with at least 5% increased incidence between patients treated with pembrolizumab and SOC compared with placebo and SOC were diarrhea (53% vs 47%), rash (35% vs. 28%), hypothyroidism (11% vs. 5%), and pneumonia (11% vs. 5%). There were no clinically meaningful differences in incidence of Grade 3–4 toxicity between arms.
Regulatory considerations
The approval of pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum containing regimens is the first approval of immune checkpoint inhibitors in patients with HER2+ gastric or GEJ cancer. Important considerations included (1) use of ORR as the primary endpoint in the interim analysis of a randomized trial to support accelerated approval and evidence provided by the PFS and OS analyses from the same trial, and (2) use of exploratory subgroup analyses results for regulatory decision-making.
The accelerated approval (AA) pathway aims to provide patients early access to drugs that provide meaningful therapeutic benefit over existing treatments based on results on intermediate end points deemed reasonably likely to predict clinical benefit. FDA generally requires that confirmatory trial(s) be underway prior to granting accelerated approval (10). ORR is an intermediate endpoint frequently used in oncology, as tumors seldom experience spontaneous shrinkage and a response can be attributed to treatment effect. Although ORR can be assessed in single-arm trials, there are limitations to this approach, including (but not limited to) the inadequacy of the approach in combination regimens to isolate the contribution of the add-on therapy; less robust safety assessment (as it can be difficult to assess toxicity in the background of patients who have advanced cancers); and reliance on cross-trial comparisons to historical data, which has the potential for false conclusions when comparing outcomes between the investigational arm and the historical control. In addition, when considering ORR in trials of immune checkpoint inhibitors, modest improvement in response rates, particularly in the setting of single-arm trials, have not always translated in long-term benefit (11). A randomized controlled study provides a robust assessment through direct comparison to a concurrent control arm (particularly in add-on regimens) and contributes to generation of data when the biomarker-selected population of interest outcomes have not been previously characterized. Importantly, longer term follow-up in the same trial could efficiently fulfill postmarketing requirement to verify clinical benefit (i.e., “one-trial” approach).
The accelerated and regular approval of pembrolizumab based on KEYNOTE-811 based on one trial is consistent with FDA’s Project Frontrunner and described in FDA guidance (12). This approach allows for earlier access to therapies in a frontline metastatic setting. The KEYNOTE-811 design included an interim analysis of 264 patients randomized with at least 6 months of follow up (conducted when the trial had enrolled 63% of the planned size) that showed a statistically significant and clinically meaningful difference in ORR (74.4% vs. 51.9% in the pembrolizumab and placebo arms respectively), which was of a magnitude considered reasonably likely to predict an effect on long term outcomes. The accelerated approval provided for access to pembrolizumab 3 years and 10 months before the regular approval, based on a survival benefit. As discussed in FDA’s Guidance, sponsors considering this approach should have in place provisions to preserve the integrity of the trial (e.g., the trial should be fully or near fully enrolled at the time of the interim analysis; firewalls with respect to access to data, overall control of study type I error, etc.).
Generally, drugs approved by the FDA are indicated for use in the patient population studied; however, FDA occasionally restricted indications to a subgroup of patients despite positive study results in the entire study population. In studies with targeted drugs that include subgroups of patients defined by expression levels of specific biomarkers being targeted, outcomes may be variable depending on the expression level of the biomarker. In such cases, analysis of all randomized patients (i.e., the intent-to-treat population) may not adequately characterize the true extent of treatment effects in these subgroups (13). Although in KEYNOTE-811 analysis by PD-L1 cutoffs (CPS <1 vs. ≥1) were prespecified, the efficacy comparisons in each subpopulation were supportive as these comparisons were not formally powered and controlled for overall type I error. At the time of IA1, the ORR in patients treated with pembrolizumab was 76.1% (95% CI 67.3, 83.5) and 62.5% (95% CI: 35.4, 84.8) in the CPS ≥ 1 and <1 subpopulations respectively; this difference was of a relatively small magnitude with overlapping confidence intervals in the context of a small sample size (only 16 patients with CPS <1 in the pembrolizumab arm). At the time of IA2, the PFS HR was 0.70 (95% CI 0.58, 0.85) and 1.17 (95% CI 0.73, 1.89) in the CPS ≥ 1 and <1 subpopulations respectively, raising concerns about the potential lack of benefit in the CPS negative subpopulation and suggesting the treatment effect was primarily driven by the CPS ≥ 1 subpopulation. At the time of IA3, the HR for OS was 0.81 (95% CI 0.67, 0.98) and 1.41 (95% CI 0.90, 2.20) in the CPS ≥ 1and <1 subpopulations respectively. Acknowledging that the subgroup analyses were exploratory and may have been confounded by the small number of patients with CPS <1 (15%), FDA and the Applicant agreed that there was the potential for OS detriment in patients with tumors with CPS <1 when pembrolizumab is added to trastuzumab and chemotherapy for the treatment of HER2+ gastric/GEJC adenocarcinoma. Based on this observation, on November 7, 2023, the indication was restricted to patients whose tumors express PD-L1 CPS ≥1. At the time of the final OS analysis, the PD-L1 CPS <1 population showed a HR of 1.10 (95% CI: 0.72, 1.68), consistent with prior findings in the trial as well as the analysis of multiple clinical trials with immune checkpoint inhibitors in gastric and esophageal cancer (14, 15). As results continue to indicate that the primary benefit appears to be driven by the CPS ≥1 subpopulation, the indication and regular approval remain restricted to these patients.
Conclusions
The approval of the addition of pembrolizumab to trastuzumab and chemotherapy for the 1st line treatment of unresectable or metastatic HER2-positive gastric or GEJ cancer successfully followed a “one trial” approach where a single study provided data on an intermediate endpoint reasonably likely to predict clinical benefit, supporting accelerated approval, and data on the long-term outcomes to support conversion to regular approval. Although the study was designed to assess outcomes in all patients enrolled, the benefit appeared to be driven by the PD-L1 CPS ≥1 subpopulation, while patients with CPS <1 did not appear to be driving benefit, supporting restriction of the indication to patients whose tumors express PD-1. Efficacy and safety results from the KEYNOTE-811 demonstrated a favorable benefit-risk profile and provided substantial evidence of efficacy and acceptable safety necessary to support the approval of pembrolizumab for these patients.
Footnotes
Disclosure of Potential Conflicts of Interest: The authors report no financial interests or relationships with the commercial sponsors of any products discussed in this report.
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