KEYTRUDA (Page 16 of 21)
14.12 Hepatocellular Carcinoma
The efficacy of KEYTRUDA was investigated in KEYNOTE-224 (NCT02702414), a single-arm, multicenter trial in 104 patients with HCC who had disease progression on or after sorafenib or were intolerant to sorafenib; had measurable disease; and Child-Pugh class A liver impairment. Patients with active autoimmune disease, greater than one etiology of hepatitis, a medical condition that required immunosuppression, or clinical evidence of ascites by physical exam were ineligible for the trial. Patients received KEYTRUDA 200 mg intravenously every 3 weeks until unacceptable toxicity, investigator-assessed confirmed disease progression (based on repeat scan at least 4 weeks from the initial scan showing progression), or completion of 24 months of KEYTRUDA. Assessment of tumor status was performed every 9 weeks. The major efficacy outcome measures were ORR and DoR according to RECIST v1.1, modified to follow a maximum of 10 target lesions and a maximum of 5 target lesions per organ, as assessed by BICR.
The study population characteristics were: median age of 68 years, 67% age 65 or older; 83% male; 81% White and 14% Asian; and 61% ECOG PS of 0 and 39% ECOG PS of 1. Child-Pugh class and score were A5 for 72%, A6 for 22%, B7 for 5%, and B8 for 1% of patients. Twenty-one percent of the patients were HBV seropositive and 25% HCV seropositive. There were 9 patients (9%) who were seropositive for both HBV and HCV. For these 9 patients, all of the HBV cases and three of the HCV cases were inactive. Sixty-four percent (64%) of patients had extrahepatic disease, 17% had vascular invasion, and 9% had both. Thirty-eight percent (38%) of patients had alpha-fetoprotein (AFP) levels ≥400 mcg/L. All patients received prior sorafenib; of whom 20% were unable to tolerate sorafenib. No patient received more than one prior systemic therapy (sorafenib).
Efficacy results are summarized in Table 75.
| Endpoint | KEYTRUDA200 mg every 3 weeksn=104 |
|---|---|
| |
| BICR-Assessed Objective Response Rate (RECIST v1.1) | |
| ORR (95% CI)* | 17% (11, 26) |
| Complete response rate | 1% |
| Partial response rate | 16% |
| BICR-Assessed Duration of Response | |
| % with duration ≥6 months | 89% |
| % with duration ≥12 months | 56% |
14.13 Merkel Cell Carcinoma
The efficacy of KEYTRUDA was investigated in KEYNOTE-017 (NCT02267603), a multicenter, non-randomized, open-label trial that enrolled 50 patients with recurrent locally advanced or metastatic MCC who had not received prior systemic therapy for their advanced disease. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible.
Patients received KEYTRUDA 2 mg/kg every 3 weeks until unacceptable toxicity or disease progression that was symptomatic, rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at least 4 weeks later with repeat imaging. Patients without disease progression were treated for up to 24 months. Assessment of tumor status was performed at 13 weeks followed by every 9 weeks for the first year and every 12 weeks thereafter. The major efficacy outcome measures were ORR and DoR as assessed by BICR per RECIST v1.1.
The study population characteristics were: median age of 71 years (range: 46 to 91), 80% age 65 or older; 68% male; 90% White; and 48% ECOG PS of 0 and 52% ECOG PS of 1. Fourteen percent had stage IIIB disease and 86% had stage IV. Eighty-four percent of patients had prior surgery and 70% had prior radiation therapy.
Efficacy results are summarized in Table 76.
| Endpoint | KEYTRUDA2 mg/kg every 3 weeksn=50 |
|---|---|
| + Denotes ongoing response | |
| |
| Objective Response Rate | |
| ORR (95% CI) | 56% (41, 70) |
| Complete response rate (95% CI) | 24% (13, 38) |
| Partial response rate (95% CI) | 32% (20, 47) |
| Duration of Response | |
| Range in months * | 5.9, 34.5+ |
| Patients with duration ≥6 months, n (%) | 27 (96%) |
| Patients with duration ≥12 months, n (%) | 15 (54%) |
14.14 Renal Cell Carcinoma
First-line treatment with axitinib
KEYNOTE-426
The efficacy of KEYTRUDA in combination with axitinib was investigated in KEYNOTE-426 (NCT02853331), a randomized, multicenter, open-label trial conducted in 861 patients who had not received systemic therapy for advanced RCC. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease requiring systemic immunosuppression within the last 2 years were ineligible. Randomization was stratified by International Metastatic RCC Database Consortium (IMDC) risk categories (favorable versus intermediate versus poor) and geographic region (North America versus Western Europe versus “Rest of the World”).
Patients were randomized (1:1) to one of the following treatment arms:
- KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with axitinib 5 mg orally, twice daily. Patients who tolerated axitinib 5 mg twice daily for 2 consecutive cycles (6 weeks) could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity.
- Sunitinib 50 mg orally, once daily for 4 weeks and then off treatment for 2 weeks.
Treatment with KEYTRUDA and axitinib continued until RECIST v1.1-defined progression of disease or unacceptable toxicity. Administration of KEYTRUDA and axitinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered to be deriving clinical benefit by the investigator. Assessment of tumor status was performed at baseline, after randomization at Week 12, then every 6 weeks thereafter until Week 54, and then every 12 weeks thereafter.
The study population characteristics were: median age of 62 years (range: 26 to 90), 38% age 65 or older; 73% male; 79% White and 16% Asian; 20% and 80% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; and patient distribution by IMDC risk categories was 31% favorable, 56% intermediate, and 13% poor.
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 included ORR, as assessed by BICR. A statistically significant improvement in OS was demonstrated at the first pre-specified interim analysis in patients randomized to KEYTRUDA in combination with axitinib compared with sunitinib. The trial also demonstrated statistically significant improvements in PFS and ORR. An updated OS analysis was conducted when 418 deaths were observed based on the planned number of deaths for the pre-specified final analysis. Table 77 and Figure 19 summarize the efficacy results for KEYNOTE-426.
| Endpoint | KEYTRUDA 200 mg every 3 weeks and Axitinib | Sunitinib |
|---|---|---|
| n=432 | n=429 | |
| NR = not reached | ||
| ||
| OS | ||
| Number of patients with event (%) | 59 (14%) | 97 (23%) |
| Median in months (95% CI) | NR (NR, NR) | NR (NR, NR) |
| Hazard ratio * (95% CI) | 0.53 (0.38, 0.74) | |
| p-Value † | <0.0001‡ | |
| Updated OS | ||
| Number of patients with event (%) | 193 (45%) | 225 (52%) |
| Median in months (95% CI) | 45.7 (43.6, NR) | 40.1 (34.3, 44.2) |
| Hazard ratio * (95% CI) | 0.73 (0.60, 0.88) | |
| PFS | ||
| Number of patients with event (%) | 183 (42%) | 213 (50%) |
| Median in months (95% CI) | 15.1 (12.6, 17.7) | 11.0 (8.7, 12.5) |
| Hazard ratio * (95% CI) | 0.69 (0.56, 0.84) | |
| p-Value † | 0.0001§ | |
| Objective Response Rate | ||
| ORR ¶ (95% CI) | 59% (54, 64) | 36% (31, 40) |
| Complete response rate | 6% | 2% |
| Partial response rate | 53% | 34% |
| p-Value # | <0.0001 | |
| Figure 19: Kaplan-Meier Curve for Updated Overall Survival in KEYNOTE-426 |
In an exploratory analysis, the updated analysis of OS in patients with IMDC favorable, intermediate, intermediate/poor, and poor risk demonstrated a HR of 1.17 (95% CI: 0.76, 1.80), 0.67 (95% CI: 0.52, 0.86), 0.64 (95% CI: 0.52, 0.80), and 0.51 (95% CI: 0.32, 0.81), respectively.
First-line treatment with lenvatinib
KEYNOTE-581
The efficacy of KEYTRUDA in combination with lenvatinib was investigated in KEYNOTE-581 (NCT02811861), a multicenter, open-label, randomized trial conducted in 1069 patients with advanced RCC in the first-line setting. Patients were enrolled regardless of PD-L1 tumor expression status. Patients with active autoimmune disease or a medical condition that required immunosuppression were ineligible. Randomization was stratified by geographic region (North America versus Western Europe versus “Rest of the World”) and Memorial Sloan Kettering Cancer Center (MSKCC) prognostic groups (favorable versus intermediate versus poor risk).
Patients were randomized (1:1:1) to one of the following treatment arms:
- KEYTRUDA 200 mg intravenously every 3 weeks up to 24 months in combination with lenvatinib 20 mg orally once daily.
- Lenvatinib 18 mg orally once daily in combination with everolimus 5 mg orally once daily.
- Sunitinib 50 mg orally once daily for 4 weeks then off treatment for 2 weeks.
Treatment continued until unacceptable toxicity or disease progression. Administration of KEYTRUDA with lenvatinib was permitted beyond RECIST-defined disease progression if the patient was clinically stable and considered by the investigator to be deriving clinical benefit. KEYTRUDA was continued for a maximum of 24 months; however, treatment with lenvatinib could be continued beyond 24 months. Assessment of tumor status was performed at baseline and then every 8 weeks.
The study population characteristics were: median age of 62 years (range: 29 to 88 years), 42% age 65 or older; 75% male; 74% White, 21% Asian, 1% Black, and 2% other races; 18% and 82% of patients had a baseline KPS of 70 to 80 and 90 to 100, respectively; patient distribution by MSKCC risk categories was 27% favorable, 64% intermediate, and 9% poor. Common sites of metastases in patients were lung (68%), lymph node (45%), and bone (25%).
The major efficacy outcome measures were PFS, as assessed by independent radiologic review (IRC) according to RECIST v1.1, and OS. Additional efficacy outcome measures included confirmed ORR as assessed by IRC. KEYTRUDA in combination with lenvatinib demonstrated statistically significant improvements in PFS, OS, and ORR compared with sunitinib. Table 78 and Figures 20 and 21 summarize the efficacy results for KEYNOTE-581.
| Endpoint | KEYTRUDA 200 mg every 3 weeksand Lenvatinib | Sunitinib |
|---|---|---|
| n=355 | n=357 | |
| Tumor assessments were based on RECIST 1.1; only confirmed responses are included for ORR.Data cutoff date = 28 Aug 2020CI = confidence interval; NE= Not estimable; NR= Not reached | ||
| Progression-Free Survival (PFS) | ||
| Number of events, n (%) | 160 (45%) | 205 (57%) |
| Progressive disease | 145 (41%) | 196 (55%) |
| Death | 15 (4%) | 9 (3%) |
| Median PFS in months (95% CI) | 23.9 (20.8, 27.7) | 9.2 (6.0, 11.0) |
| Hazard ratio * (95% CI) | 0.39 (0.32, 0.49) | |
| p-Value † | <0.0001 | |
| Overall Survival (OS) | ||
| Number of deaths, n (%) | 80 (23%) | 101 (28%) |
| Median OS in months (95% CI) | NR (33.6, NR) | NR (NR, NR) |
| Hazard ratio * (95% CI) | 0.66 (0.49, 0.88) | |
| p-Value † | 0.0049 | |
| Objective Response Rate (Confirmed) | ||
| ORR, n (%) | 252 (71%) | 129 (36%) |
| (95% CI) | (66, 76) | (31, 41) |
| Complete response rate | 16% | 4% |
| Partial response rate | 55% | 32% |
| p-Value ‡ | <0.0001 | |
| Figure 20: Kaplan-Meier Curve for PFS in KEYNOTE-581 |
| Figure 21: Kaplan-Meier Curve for Overall Survival in KEYNOTE-581 |
Adjuvant Treatment of RCC (KEYNOTE‑564)
The efficacy of KEYTRUDA was investigated as adjuvant therapy for RCC in KEYNOTE-564 (NCT03142334), a multicenter, randomized (1:1), double-blind, placebo-controlled trial in 994 patients with intermediate-high or high risk of recurrence of RCC, or M1 no evidence of disease (NED). The intermediate-high risk category included: pT2 with Grade 4 or sarcomatoid features; pT3, any Grade without nodal involvement (N0) or distant metastases (M0). The high risk category included: pT4, any Grade N0 and M0; any pT, any Grade with nodal involvement and M0. The M1 NED category included patients with metastatic disease who had undergone complete resection of primary and metastatic lesions. Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion(s) in M1 NED participants) with negative surgical margins ≥4 weeks prior to the time of screening. Patients were excluded from the trial if they had received prior systemic therapy for advanced RCC. Patients with active autoimmune disease or a medical condition that required immunosuppression were also ineligible. Patients were randomized to KEYTRUDA 200 mg administered intravenously every 3 weeks or placebo for up to 1 year until disease recurrence or unacceptable toxicity. Randomization was stratified by metastasis status (M0, M1 NED); M0 group was further stratified by ECOG PS (0,1) and geographic region (US, non-US).
The study population characteristics were: median age of 60 years (range: 25 to 84), 33% age 65 or older; 71% male; 75% White, 14% Asian, 9% Unknown, 1% Black or African American, 1% American Indian or Alaska Native, 1% Multiracial; 13% Hispanic or Latino, 78% Not Hispanic or Latino, 8% Unknown; and 85% ECOG PS of 0 and 15% ECOG PS of 1. Ninety-four percent of patients enrolled had N0 disease; 11% had sarcomatoid features; 86% were intermediate-high risk; 8% were high risk; and 6% were M1 NED. Ninety-two percent of patients had a radical nephrectomy, and 8% had a partial nephrectomy.
The major efficacy outcome measure was investigator-assessed disease-free survival (DFS), defined as time to recurrence, metastasis, or death. An additional outcome measure was OS. A statistically significant improvement in DFS was demonstrated at the pre-specified interim analysis in patients randomized to the KEYTRUDA arm compared with placebo. At the time of the DFS analysis, OS data were not mature, with 5% deaths in the overall population. Efficacy results are summarized in Table 79 and Figure 22.
| Endpoint | KEYTRUDA200 mg every 3 weeksn=496 | Placebon=498 |
|---|---|---|
| NR = not reached | ||
| DFS | ||
| Number (%) of patients with event | 109 (22%) | 151 (30%) |
| Median in months (95% CI) | NR | NR |
| Hazard ratio * (95% CI) | 0.68 (0.53, 0.87) | |
| p-Value † | 0.0010‡ | |
| 24-month DFS rate (95% CI) | 77% (73, 81) | 68% (64, 72) |
| Figure 22: Kaplan-Meier Curve for Disease-Free Survival in KEYNOTE-564 |
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