KEYTRUDA (Page 8 of 23)

14.2 Non-Small Cell Lung Cancer

First-line treatment of metastatic nonsquamous NSCLC with pemetrexed and platinum chemotherapy

The efficacy of KEYTRUDA in combination with pemetrexed and platinum chemotherapy was investigated in KEYNOTE-189 (NCT02578680), a randomized, multicenter, double-blind, active-controlled trial conducted in 616 patients with metastatic nonsquamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease and in whom there were no EGFR or ALK genomic tumor aberrations. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by smoking status (never vs. former/current), choice of platinum (cisplatin vs. carboplatin), and tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%). Patients were randomized (2:1) to one of the following treatment arms:

  • KEYTRUDA 200 mg, pemetrexed 500 mg/m2 , and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by KEYTRUDA 200 mg and pemetrexed 500 mg/m2 intravenously every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.
  • Placebo, pemetrexed 500 mg/m2 , and investigator’s choice of cisplatin 75 mg/m2 or carboplatin AUC 5 mg/mL/min intravenously on Day 1 of each 21-day cycle for 4 cycles followed by placebo and pemetrexed 500 mg/m2 intravenously every 3 weeks.

Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by the investigator, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Patients randomized to placebo and chemotherapy were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed at Week 6, Week 12, and then every 9 weeks thereafter. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were ORR and DoR, as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 64 years (range: 34 to 84), 49% age 65 or older; 59% male; 94% White and 3% Asian; 56% ECOG PS of 1; and 18% with history of brain metastases. Thirty-one percent had tumor PD-L1 expression TPS <1% [negative]. Seventy-two percent received carboplatin and 12% were never smokers. A total of 85 patients in the placebo and chemotherapy arm received an anti-PD-1/PD-L1 monoclonal antibody at the time of disease progression.

The trial demonstrated a statistically significant improvement in OS and PFS for patients randomized to KEYTRUDA in combination with pemetrexed and platinum chemotherapy compared with placebo, pemetrexed, and platinum chemotherapy. Table 61 and Figure 5 summarize the efficacy results for KEYNOTE-189.

Table 61: Efficacy Results in KEYNOTE-189
EndpointKEYTRUDA200 mg every 3 weeksPemetrexedPlatinum Chemotherapyn=410PlaceboPemetrexed Platinum Chemotherapyn=206
NR = not reached
*
Based on the stratified Cox proportional hazard model
Based on a stratified log-rank test
Response: Best objective response as confirmed complete response or partial response
§
Based on Miettinen and Nurminen method stratified by PD-L1 status, platinum chemotherapy, and smoking status
OS
Number (%) of patients with event127 (31%)108 (52%)
Median in months (95% CI)NR(NR, NR)11.3(8.7, 15.1)
Hazard ratio * (95% CI)0.49 (0.38, 0.64)
p-Value <0.0001
PFS
Number of patients with event (%)245 (60%)166 (81%)
Median in months (95% CI)8.8 (7.6, 9.2)4.9 (4.7, 5.5)
Hazard ratio * (95% CI)0.52 (0.43, 0.64)
p-Value <0.0001
Objective Response Rate
ORR (95% CI)48% (43, 53)19% (14, 25)
Complete response0.5%0.5%
Partial response47%18%
p-Value §<0.0001
Duration of Response
Median in months (range)11.2 (1.1+, 18.0+)7.8 (2.1+, 16.4+)

At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with pemetrexed and platinum chemotherapy arm was 22.0 months (95% CI: 19.5, 24.5) compared to 10.6 months (95% CI: 8.7, 13.6) in the placebo with pemetrexed and platinum chemotherapy arm, with an HR of 0.56 (95% CI: 0.46, 0.69).

Figure 5: Kaplan-Meier Curve for Overall Survival in KEYNOTE-189*
*
Based on the protocol-specified final OS analysis
Figure 5
(click image for full-size original)

First-line treatment of metastatic squamous NSCLC with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy

The efficacy of KEYTRUDA in combination with carboplatin and investigator’s choice of either paclitaxel or paclitaxel protein-bound was investigated in KEYNOTE-407 (NCT02775435), a randomized, multi-center, double-blind, placebo-controlled trial conducted in 559 patients with metastatic squamous NSCLC, regardless of PD-L1 tumor expression status, who had not previously received systemic therapy for metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 status (TPS <1% [negative] vs. TPS ≥1%), choice of paclitaxel or paclitaxel protein-bound, and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1) to one of the following treatment arms; all study medications were administered via intravenous infusion:

  • KEYTRUDA 200 mg and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles, and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by KEYTRUDA 200 mg every 3 weeks. KEYTRUDA was administered prior to chemotherapy on Day 1.
  • Placebo and carboplatin AUC 6 mg/mL/min on Day 1 of each 21-day cycle for 4 cycles and paclitaxel 200 mg/m2 on Day 1 of each 21-day cycle for 4 cycles or paclitaxel protein-bound 100 mg/m2 on Days 1, 8 and 15 of each 21-day cycle for 4 cycles, followed by placebo every 3 weeks.

Treatment with KEYTRUDA and chemotherapy or placebo and chemotherapy continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease as determined by BICR, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Patients randomized to the placebo and chemotherapy arm were offered KEYTRUDA as a single agent at the time of disease progression. Assessment of tumor status was performed every 6 weeks through Week 18, every 9 weeks through Week 45 and every 12 weeks thereafter. The main efficacy outcome measures were PFS and ORR 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, and OS. An additional efficacy outcome measure was DoR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 65 years (range: 29 to 88), 55% age 65 or older; 81% male; 77% White; 71% ECOG PS of 1; and 8% with a history of brain metastases. Thirty-five percent had tumor PD-L1 expression TPS <1%; 19% were from the East Asian region; and 60% received paclitaxel.

The trial demonstrated a statistically significant improvement in OS, PFS and ORR in patients randomized to KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy compared with patients randomized to placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy. Table 62 and Figure 6 summarize the efficacy results for KEYNOTE-407.

Table 62: Efficacy Results in KEYNOTE-407
EndpointKEYTRUDA 200 mg every 3 weeksCarboplatin Paclitaxel/Paclitaxel protein-boundn=278Placebo Carboplatin Paclitaxel/Paclitaxel protein-boundn=281
NE = not estimable
*
Based on the stratified Cox proportional hazard model
Based on a stratified log-rank test
ORR primary analysis and DoR analysis were conducted with the first 204 patients enrolled.
§
Based on a stratified Miettinen-Nurminen test
OS
Number of events (%)85 (31%)120 (43%)
Median in months (95% CI)15.9 (13.2, NE)11.3 (9.5, 14.8)
Hazard ratio * (95% CI) 0.64 (0.49, 0.85)
p-Value 0.0017
PFS
Number of events (%)152 (55%)197 (70%)
Median in months (95% CI)6.4 (6.2, 8.3)4.8 (4.2, 5.7)
Hazard ratio * (95% CI) 0.56 (0.45, 0.70)
p-Value <0.0001
n=101 n=103
Objective Response Rate
ORR (95% CI)58% (48, 68)35% (26, 45)
Difference (95% CI)23.6% (9.9, 36.4)
p-Value §0.0008
Duration of Response
Median duration of response in months (range)7.2 (2.4, 12.4+)4.9 (2.0, 12.4+)

At the protocol-specified final OS analysis, the median in the KEYTRUDA in combination with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm was 17.1 months (95% CI: 14.4, 19.9) compared to 11.6 months (95% CI: 10.1, 13.7) in the placebo with carboplatin and either paclitaxel or paclitaxel protein-bound chemotherapy arm, with an HR of 0.71 (95% CI: 0.58, 0.88).

Figure 6: Kaplan-Meier Curve for Overall Survival in KEYNOTE-407*
*
Based on the protocol-specified final OS analysis
Figure 6
(click image for full-size original)

First-line treatment of metastatic NSCLC as a single agent

KEYNOTE-042

The efficacy of KEYTRUDA was investigated in KEYNOTE-042 (NCT02220894), a randomized, multicenter, open-label, active-controlled trial conducted in 1274 patients with Stage III NSCLC who were not candidates for surgical resection or definitive chemoradiation, or patients with metastatic NSCLC. Only patients whose tumors expressed PD-L1 (TPS ≥1%) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit and who had not received prior systemic treatment for metastatic NSCLC were eligible. Patients with EGFR or ALK genomic tumor aberrations; autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of radiation in the thoracic region within the prior 26 weeks of initiation of study were ineligible. Randomization was stratified by ECOG PS (0 vs. 1), histology (squamous vs. nonsquamous), geographic region (East Asia vs. non-East Asia), and PD-L1 expression (TPS ≥50% vs. TPS 1 to 49%). Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of either of the following platinum-containing chemotherapy regimens:

  • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;
  • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for a maximum of 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies.

Treatment with KEYTRUDA continued until RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ)-defined progression of disease, unacceptable toxicity, or a maximum of 24 months. Administration of KEYTRUDA was permitted beyond RECIST-defined disease progression if the patient was clinically stable and deriving clinical benefit as determined by the investigator. Treatment with KEYTRUDA could be reinitiated at the time of subsequent disease progression and administered for up to 12 months. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measure was OS in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC. Additional efficacy outcome measures were PFS and ORR in the subgroup of patients with TPS ≥50% NSCLC, the subgroup of patients with TPS ≥20% NSCLC, and the overall population with TPS ≥1% NSCLC as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 63 years (range: 25 to 90), 45% age 65 or older; 71% male; and 64% White, 30% Asian, and 2% Black. Nineteen percent were Hispanic or Latino. Sixty-nine percent had ECOG PS of 1; 39% with squamous and 61% with nonsquamous histology; 87% had M1 disease and 13% had Stage IIIA (2%) or Stage IIIB (11%) and who were not candidates for surgical resection or definitive chemoradiation per investigator assessment; and 5% with treated brain metastases at baseline. Forty-seven percent of patients had TPS ≥50% NSCLC and 53% had TPS 1 to 49% NSCLC.

The trial demonstrated a statistically significant improvement in OS for patients (PD-L1 TPS ≥50%, TPS ≥20%, TPS ≥1%) randomized to KEYTRUDA as compared with chemotherapy. Table 63 and Figure 7 summarize the efficacy results in the subgroup of patients with TPS ≥50% and in all randomized patients with TPS ≥1%.

Table 63: Efficacy Results of All Randomized Patients (TPS ≥1% and TPS ≥50%) in KEYNOTE-042
TPS ≥1%TPS ≥50%
EndpointKEYTRUDA200 mg every 3 weeksChemotherapyKEYTRUDA200 mg every 3 weeksChemotherapy
n=637n=637n=299n=300
*
Based on the stratified Cox proportional hazard model
Based on a stratified log-rank test; compared to a p-Value boundary of 0.0291
Not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints
§
Not significant compared to a p-Value boundary of 0.0291
Based on observed duration of response
OS
Number of events (%)371 (58%)438 (69%)157 (53%)199 (66%)
Median in months (95% CI)16.7 (13.9, 19.7)12.1 (11.3, 13.3)20.0 (15.4, 24.9)12.2 (10.4, 14.2)
Hazard ratio * (95% CI)0.81 (0.71, 0.93)0.69 (0.56, 0.85)
p-Value 0.00360.0006
PFS
Number of events (%)507 (80%)506 (79%)221 (74%)233 (78%)
Median in months (95% CI)5.4 (4.3, 6.2)6.5 (6.3, 7.0)6.9 (5.9, 9.0)6.4 (6.1, 6.9)
Hazard ratio *, (95% CI)1.07(0.94, 1.21)0.82(0.68, 0.99)
p-Value NS §
Objective Response Rate
ORR (95% CI)27% (24, 31)27% (23, 30)39% (33.9, 45.3)32% (26.8, 37.6)
Complete response rate0.5%0.5%0.7%0.3%
Partial response rate27%26%39%32%
Duration of Response
% with duration ≥12 months 47%16%42%17%
% with duration ≥18 months 26%6%25%5%

The results of all efficacy outcome measures in the subgroup of patients with PD-L1 TPS ≥20% NSCLC were intermediate between the results of those with PD-L1 TPS ≥1% and those with PD-L1 TPS ≥50%. In a pre-specified exploratory subgroup analysis for patients with TPS 1-49% NSCLC, the median OS was 13.4 months (95% CI: 10.7, 18.2) for the pembrolizumab group and 12.1 months (95% CI: 11.0, 14.0) in the chemotherapy group, with an HR of 0.92 (95% CI: 0.77, 1.11).

Figure 7: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-042 (TPS ≥1%)

Figure 7
(click image for full-size original)

KEYNOTE-024

The efficacy of KEYTRUDA was also investigated in KEYNOTE-024 (NCT02142738), a randomized, multicenter, open-label, active-controlled trial in 305 previously untreated patients with metastatic NSCLC. The study design was similar to that of KEYNOTE-042, except that only patients whose tumors had high PD-L1 expression (TPS of 50% or greater) by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit were eligible. Patients were randomized (1:1) to receive KEYTRUDA 200 mg intravenously every 3 weeks or investigator’s choice of any of the following platinum-containing chemotherapy regimens:

  • Pemetrexed 500 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;
  • Pemetrexed 500 mg/m2 every 3 weeks and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed 500 mg/m2 every 3 weeks for patients with nonsquamous histologies;
  • Gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 75 mg/m2 every 3 weeks on Day 1 for 4 to 6 cycles;
  • Gemcitabine 1250 mg/m2 on Days 1 and 8 and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles;
  • Paclitaxel 200 mg/m2 every 3 weeks and carboplatin AUC 5 to 6 mg/mL/min every 3 weeks on Day 1 for 4 to 6 cycles followed by optional pemetrexed maintenance (for nonsquamous histologies).

Patients randomized to chemotherapy were offered KEYTRUDA at the time of disease progression.

The main efficacy outcome measure was PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Additional efficacy outcome measures were OS and ORR as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

The study population characteristics were: median age of 65 years (range: 33 to 90), 54% age 65 or older; 61% male; 82% White and 15% Asian; 65% with ECOG PS of 1; 18% with squamous and 82% with nonsquamous histology and 9% with history of brain metastases. A total of 66 patients in the chemotherapy arm received KEYTRUDA at the time of disease progression.

The trial demonstrated a statistically significant improvement in both PFS and OS for patients randomized to KEYTRUDA as compared with chemotherapy. Table 64 and Figure 8 summarize the efficacy results for KEYNOTE-024.

Table 64: Efficacy Results in KEYNOTE-024
EndpointKEYTRUDA200 mg every 3 weeksChemotherapy
n=154n=151
NR = not reached
*
Based on the stratified Cox proportional hazard model for the interim analysis
Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.
p-Value is compared with 0.0118 of the allocated alpha for the interim analysis
PFS
Number (%) of patients with event73 (47%)116 (77%)
Median in months (95% CI)10.3 (6.7, NR)6.0 (4.2, 6.2)
Hazard ratio * (95% CI)0.50 (0.37, 0.68)
p-Value (stratified log-rank)<0.001
OS
Number (%) of patients with event44 (29%)64 (42%)
Median in months (95% CI)30.0(18.3, NR)14.2(9.8, 19.0)
Hazard ratio * (95% CI) 0.60 (0.41, 0.89)
p-Value (stratified log-rank)0.005
Objective Response Rate
ORR (95% CI)45% (37, 53)28% (21, 36)
Complete response rate4%1%
Partial response rate41%27%
p-Value (Miettinen-Nurminen)0.001
Median duration of response in months (range)NR(1.9+, 14.5+)6.3(2.1+, 12.6+)
Figure 8: Kaplan-Meier Curve for Overall Survival in KEYNOTE-024*
*
Based on the protocol-specified final OS analysis conducted at 169 events, which occurred 14 months after the interim analysis.
Figure 8
(click image for full-size original)

Previously treated NSCLC

The efficacy of KEYTRUDA was investigated in KEYNOTE-010 (NCT01905657), a randomized, multicenter, open-label, active-controlled trial conducted in 1033 patients with metastatic NSCLC that had progressed following platinum-containing chemotherapy, and if appropriate, targeted therapy for EGFR or ALK genomic tumor aberrations. Eligible patients had PD-L1 expression TPS of 1% or greater by an immunohistochemistry assay using the PD-L1 IHC 22C3 pharmDx kit. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Randomization was stratified by tumor PD-L1 expression (PD-L1 expression TPS ≥50% vs. PD-L1 expression TPS=1-49%), ECOG PS (0 vs. 1), and geographic region (East Asia vs. non-East Asia). Patients were randomized (1:1:1) to receive KEYTRUDA 2 mg/kg intravenously every 3 weeks, KEYTRUDA 10 mg/kg intravenously every 3 weeks or docetaxel intravenously 75 mg/m2 every 3 weeks until unacceptable toxicity or disease progression. Patients randomized to KEYTRUDA were permitted to continue until disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or confirmation of progression at 4 to 6 weeks with repeat imaging or for up to 24 months without disease progression. Assessment of tumor status was performed every 9 weeks. The main efficacy outcome measures were OS and PFS as assessed by BICR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%. Additional efficacy outcome measures were ORR and DoR in the subgroup of patients with TPS ≥50% and the overall population with TPS ≥1%.

The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 or older; 61% male; 72% White and 21% Asian; 66% ECOG PS of 1; 43% with high PD-L1 tumor expression; 21% with squamous, 70% with nonsquamous, and 8% with mixed, other or unknown histology; 91% metastatic (M1) disease; 15% with history of brain metastases; and 8% and 1% with EGFR and ALK genomic aberrations, respectively. All patients had received prior therapy with a platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease.

Tables 65 and 66 and Figure 9 summarize efficacy results in the subgroup with TPS ≥50% population and in all patients, respectively.

Table 65: Efficacy Results of the Subgroup of Patients with TPS ≥50% in KEYNOTE-010
EndpointKEYTRUDA2 mg/kg every 3 weeksn=139KEYTRUDA10 mg/kg every 3 weeksn=151Docetaxel75 mg/m2 every 3 weeksn=152
NR = not reached
*
Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model
All responses were partial responses
OS
Deaths (%)58 (42%)60 (40%)86 (57%)
Median in months (95% CI)14.9 (10.4, NR)17.3 (11.8, NR)8.2 (6.4, 10.7)
Hazard ratio * (95% CI) 0.54 (0.38, 0.77)0.50 (0.36, 0.70)
p-Value (stratified log-rank)<0.001<0.001
PFS
Events (%)89 (64%)97 (64%)118 (78%)
Median in months (95% CI)5.2 (4.0, 6.5)5.2 (4.1, 8.1)4.1 (3.6, 4.3)
Hazard ratio * (95% CI) 0.58 (0.43, 0.77)0.59 (0.45, 0.78)
p-Value (stratified log-rank)<0.001<0.001
Objective Response Rate
ORR (95% CI)30% (23, 39)29% (22, 37)8% (4, 13)
p-Value (Miettinen-Nurminen)<0.001<0.001
Median duration of response in months (range)NR(0.7+, 16.8+)NR(2.1+, 17.8+)8.1(2.1+, 8.8+)
Table 66: Efficacy Results of All Randomized Patients (TPS ≥1%) in KEYNOTE-010
EndpointKEYTRUDA2 mg/kg every 3 weeksn=344KEYTRUDA10 mg/kg every 3 weeksn=346Docetaxel75 mg/m2 every 3 weeksn=343
NR = not reached
*
Hazard ratio (KEYTRUDA compared to docetaxel) based on the stratified Cox proportional hazard model
All responses were partial responses
OS
Deaths (%)172 (50%)156 (45%)193 (56%)
Median in months (95% CI)10.4 (9.4, 11.9)12.7 (10.0, 17.3)8.5 (7.5, 9.8)
Hazard ratio * (95% CI) 0.71 (0.58, 0.88)0.61 (0.49, 0.75)
p-Value (stratified log-rank)<0.001<0.001
PFS
Events (%)266 (77%)255 (74%)257 (75%)
Median in months (95% CI)3.9 (3.1, 4.1)4.0 (2.6, 4.3)4.0 (3.1, 4.2)
Hazard ratio * (95% CI) 0.88 (0.73, 1.04)0.79 (0.66, 0.94)
p-Value (stratified log-rank)0.0680.005
Objective Response Rate
ORR (95% CI)18% (14, 23)19% (15, 23)9% (7, 13)
p-Value (Miettinen-Nurminen)<0.001<0.001
Median duration of response in months (range)NR(0.7+, 20.1+)NR(2.1+, 17.8+)6.2(1.4+, 8.8+)
Figure 9: Kaplan-Meier Curve for Overall Survival in all Randomized Patients in KEYNOTE-010 (TPS ≥1%)
Figure 9
(click image for full-size original)

Neoadjuvant and adjuvant treatment of resectable NSCLC

The efficacy of KEYTRUDA in combination with neoadjuvant chemotherapy followed by surgery and continued adjuvant treatment with KEYTRUDA as a single agent was investigated in KEYNOTE-671 (NCT03425643), a multicenter, randomized, double-blind, placebo-controlled trial conducted in 797 patients with previously untreated and resectable Stage II, IIIA, or IIIB (N2) NSCLC by AJCC 8th edition. Patients were enrolled regardless of tumor PD-L1 expression. Patients with active autoimmune disease that required systemic therapy within 2 years of treatment, a medical condition that required immunosuppression, or a history of interstitial lung disease or pneumonitis that required steroids were ineligible. Randomization was stratified by stage (II vs. III), tumor PD-L1 expression (TPS ≥50% or <50%), histology (squamous vs. nonsquamous), and geographic region (East Asia vs. non-East Asia).

Patients were randomized (1:1) to one of the following treatment arms:

  • Treatment Arm A: neoadjuvant KEYTRUDA 200 mg on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, KEYTRUDA 200 mg was administered every 3 weeks for up to 13 cycles.
  • Treatment Arm B: neoadjuvant placebo on Day 1 in combination with cisplatin 75 mg/m2 and either pemetrexed 500 mg/m2 on Day 1 or gemcitabine 1000 mg/m2 on Days 1 and 8 of each 21-day cycle for up to 4 cycles. Within 4-12 weeks following surgery, placebo was administered every 3 weeks for up to 13 cycles.

All study medications were administered via intravenous infusion. Treatment with KEYTRUDA or placebo continued until completion of the treatment (17 cycles), disease progression that precluded definitive surgery, disease recurrence in the adjuvant phase, disease progression for those who did not undergo surgery or had incomplete resection and entered the adjuvant phase, or unacceptable toxicity. Assessment of tumor status was performed at baseline, Week 7, and Week 13 in the neoadjuvant phase and within 4 weeks prior to the start of the adjuvant phase. Following the start of the adjuvant phase, assessment of tumor status was performed every 16 weeks through the end of Year 3, and then every 6 months thereafter.

The trial was not designed to isolate the effect of KEYTRUDA in each phase (neoadjuvant or adjuvant) of treatment.

The major efficacy outcome measures were OS and investigator-assessed event-free survival (EFS). Additional efficacy outcome measures were pathological complete response (pCR) rate and major pathological response (mPR) rate as assessed by blinded independent pathology review.

The study population characteristics were: median age of 64 years (range: 26 to 83); 45% age 65 or older and 7% age 75 or older; 71% male; 61% White, 31% Asian, 2% Black, 4% race not reported; 9% Hispanic or Latino; 63% ECOG PS of 0 and 37% ECOG PS of 1. Thirty percent had Stage II and 70% had Stage III disease; 33% had TPS ≥50% and 67% had TPS <50%; 43% had tumors with squamous histology and 57% had tumors with non-squamous histology; 31% were from the East Asian region.

Eighty-one percent of patients in the KEYTRUDA in combination with platinum-containing chemotherapy arm received definitive surgery compared to 76% of patients in the placebo in combination with platinum-containing chemotherapy arm.

The trial demonstrated statistically significant improvements in OS and EFS for patients randomized to KEYTRUDA in combination with platinum-containing chemotherapy followed by KEYTRUDA as a single agent compared with patients randomized to placebo in combination with platinum-containing chemotherapy followed by placebo alone.

Table 67 and Figure 10 summarize the efficacy results for KEYNOTE-671.

Table 67: Efficacy Results in KEYNOTE-671
EndpointKEYTRUDA200 mg every 3 weekswithchemotherapy/KEYTRUDAn=397Placebo withchemotherapy/Placebon=400
NR = not reached
*
Based on Kaplan-Meier estimates
Based on Cox regression model with treatment as a covariate stratified by stage, tumor PD-L1 expression, histology, and geographic region
Based on stratified log-rank test
§
Compared to a two-sided p-Value boundary of 0.0109
Compared to a two-sided p-Value boundary of 0.0092
OS
Number of patients with event (%)110 (28%)144 (36%)
Median in months * (95% CI)NR (NR, NR)52.4 (45.7, NR)
Hazard ratio (95% CI)0.72 (0.56, 0.93)
p-Value , §0.0103
EFS
Number of patients with event (%)139 (35%)205 (51%)
Median in months * (95% CI)NR (34.1, NR)17.0 (14.3, 22.0)
Hazard ratio (95% CI)0.58 (0.46, 0.72)
p-Value , <0.0001
Figure 10: Kaplan-Meier Curve for Overall Survival in KEYNOTE-671
Figure 10
(click image for full-size original)

The trial demonstrated a statistically significant difference in pCR rate (18.1% vs. 4.0%; p<0.0001) and mPR rate (30.2% vs. 11.0%; p<0.0001).

Adjuvant treatment of resected NSCLC

The efficacy of KEYTRUDA was investigated in KEYNOTE-091 (NCT02504372), a multicenter, randomized, triple-blind, placebo-controlled trial conducted in 1177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC by AJCC 7th edition. Patients had not received neoadjuvant radiotherapy or chemotherapy. Adjuvant chemotherapy up to 4 cycles was optional. Patients were ineligible if they had active autoimmune disease, were on chronic immunosuppressive agents, or had a history of interstitial lung disease or pneumonitis. Randomization was stratified by stage (IB vs. II vs. IIIA), receipt of adjuvant chemotherapy (yes vs. no), PD-L1 status (TPS <1% [negative] vs. TPS 1-49% vs. TPS ≥50%), and geographic region (Western Europe vs. Eastern Europe vs. Asia vs. Rest of World). Patients were randomized (1:1) to receive KEYTRUDA 200 mg or placebo intravenously every 3 weeks.

Treatment continued until RECIST v1.1-defined disease recurrence as determined by the investigator, unacceptable toxicity or up to one year. Tumor assessments were conducted every 12 weeks for the first year, then every 6 months for years 2 to 3, and then annually through year 5. After year 5, imaging was performed as per local standard of care. The major efficacy outcome measure was investigator-assessed disease-free survival (DFS). An additional efficacy outcome measure was OS.

Of 1177 patients randomized, 1010 (86%) received adjuvant platinum-based chemotherapy following resection. Among these 1010 patients, the median age was 64 years (range: 35 to 84), 49% age 65 or older; 68% male; 77% White, 18% Asian; 86% current or former smokers; and 39% with ECOG PS of 1. Eleven percent had Stage IB, 57% had Stage II, and 31% had Stage IIIA disease. Thirty-nine percent had PD-L1 TPS <1% [negative], 33% had TPS 1-49%, and 28% had TPS ≥50%. Fifty-two percent were from Western Europe, 20% from Eastern Europe, 17% from Asia, and 11% from Rest of World.

The trial met its primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population for patients randomized to the KEYTRUDA arm compared to patients randomized to the placebo arm. In an exploratory subgroup analysis of the 167 patients (14%) who did not receive adjuvant chemotherapy, the DFS HR was 1.25 (95% CI: 0.76, 2.05). OS results were not mature with only 42% of pre-specified OS events in the overall population.

Table 68 and Figure 11 summarize the efficacy results for KEYNOTE-091 in patients who received adjuvant chemotherapy.

Table 68: Efficacy Results in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy
EndpointKEYTRUDA200 mg every 3 weeksn=506Placebon=504
NR = not reached
*
Based on the unstratified univariate Cox regression model
DFS
Number (%) of patients with event 177 (35%)231 (46%)
Median in months (95% CI)58.7(39.2, NR)34.9(28.6, NR)
Hazard ratio * (95% CI)0.73 (0.60, 0.89)
Figure 11: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-091 for Patients Who Received Adjuvant Chemotherapy
Figure 11
(click image for full-size original)

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