YERVOY (Page 16 of 20)

14.4 Microsatellite Instability-High or Mismatch Repair Deficient Metastatic Colorectal Cancer

The efficacy of YERVOY with nivolumab was evaluated in CHECKMATE-142 (NCT02060188), a multicenter, non-randomized, multiple parallel-cohort, open-label study conducted in patients with locally determined dMMR or MSI-H mCRC who had disease progression during or after prior treatment with fluoropyrimidine-, oxaliplatin-, or irinotecan-based chemotherapy. Key eligibility criteria were at least one prior line of treatment for metastatic disease, ECOG PS 0 or 1, and absence of the following: active brain metastases, active autoimmune disease, or medical conditions requiring systemic immunosuppression. Patients enrolled in the YERVOY and nivolumab MSI-H or dMMR mCRC cohort received YERVOY 1 mg/kg and nivolumab 3 mg/kg intravenously every 3 weeks for 4 doses, followed by nivolumab 3 mg/kg intravenously as a single agent every 2 weeks. Efficacy outcome measures were overall response rate (ORR) as assessed by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) and duration of response (DOR). Tumor assessments were conducted every 6 weeks for the first 24 weeks and every 12 weeks thereafter.

A total of 119 patients were enrolled in the YERVOY and nivolumab cohort. The median age was 58 years (range: 21 to 88), with 32% ≥65 years of age and 9% ≥75 years of age; 59% were male and 92% were white. Baseline ECOG PS was 0 (45%) or 1 (55%), and 29% were reported to have Lynch Syndrome. Across the cohort, 69% received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan; 10%, 40%, 24%, and 15% received 1, 2, 3, or ≥4 prior lines of therapy for metastatic disease, respectively, and 29% had received an anti-EGFR antibody.

Efficacy results are shown in Table 27.

Table 27: Efficacy Results in MSI-H/dMMR Cohort of CHECKMATE-142
a Minimum follow-up 27.5 months for all patients treated with YERVOY and nivolumab (n=119).b Estimated using the Clopper-Pearson method.

YERVOY and Nivolumaba MSI-H/dMMR Cohort

All Patients(n=119)

Prior Treatment (Fluoropyrimidine, Oxaliplatin, and Irinotecan)(n=82)

Overall Response Rate per BICR; n (%)

71 (60%)

46 (56%)

(95% CI)b

(50, 69)

(45, 67)

Complete Response (%)

17 (14%)

11 (13%)

Partial Response (%)

54 (45%)

35 (43%)

Duration of Response

Proportion of responders with ≥6 months response duration

89%

87%

Proportion of responders with ≥12 months response duration

77%

74%

14.5 Hepatocellular Carcinoma

CHECKMATE-040 (NCT01658878) was a multicenter, multiple cohort, open-label trial conducted in patients with HCC who progressed on or were intolerant to sorafenib. Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible.

The efficacy of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in Cohort 4 of CHECKMATE-040. A total of 49 patients received the combination regimen, which was administered every 3 weeks for four doses, followed by single-agent nivolumab at 240 mg every 2 weeks until disease progression or unacceptable toxicity.

The median age was 60 years (range: 18 to 80); 88% were male; 74% were Asian, and 25% were White. Baseline ECOG performance status was 0 (61%) or 1 (39%). Fifty-seven percent (57%) of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non-alcoholic liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had alfa-fetoprotein (AFP) levels ≥400 µg/L. Prior treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received 2 or more prior systemic therapies.

Efficacy results are shown in Table 28.

Table 28: Efficacy Results — Cohort 4 of CHECKMATE-040
a Confirmed by BICR.b Confidence interval is based on the Clopper and Pearson method.

YERVOY and Nivolumab(Cohort 4)(n=49)

Overall Response Rate per BICR,a n (%), RECIST v1.1

16 (33%)

(95% CI)b

(20, 48)

Complete response

4 (8%)

Partial response

12 (24%)

Duration of Response per BICR,a RECIST v1.1

n=16

Range (months)

4.6, 30.5+

Percent with duration ≥6 months

88%

Percent with duration ≥12 months

56%

Percent with duration ≥24 months

31%

Overall Response Rate per BICR,a n (%), mRECIST

17 (35%)

(95% CI)b

(22, 50)

Complete response

6 (12%)

Partial response

11 (22%)

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