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Pembrolizumab in patients with advanced gastric or gastroesophageal junction adenocarcinoma


Data from all three cohorts of the registrational, phase 2 KEYNOTE-059 trial investigating the use of Pembrolizumab ( Keytruda ), an anti-PD-1 therapy, in patients with advanced gastric or gastroesophageal junction ( GEJ ) adenocarcinoma, including new data in treatment-naïve patients, were presented at the European Society for Medical Oncology ( ESMO ) Congress.
Overall, results showed antitumor activity and durability of response with Pembrolizumab across multiple lines of therapy, with higher response rates observed in PD-L1-positive ( CPS greater tahn or equal to 1 ) patients:

a) in heavily pre-treated patients, Pembrolizumab monotherapy ( Cohort 1 ) showed an overall response rate ( ORR ) of 12% ( 95% CI, 8-17 ) in all patients and 16% ( 95% CI, 11-23 ) in patients with PD-L1 positive tumors.

b) in treatment-naïve patients, Pembrolizumab in combination with chemotherapy ( Cohort 2 ) showed an ORR of 60% ( 95% CI, 39-79 ) in all patients and 69% ( 95% CI, 41-89 ) in patients with PD-L1 positive tumors.

c) in treatment-naïve patients with PD-L1 positive tumors, Pembrolizumab monotherapy ( Cohort 3 ) showed an ORR of 26% ( 95% CI, 12-45 ).

KEYNOTE-059 Study Cohorts

Results presented from KEYNOTE-059 were based on an analysis of efficacy, safety and PD-L1 expression from 315 patients across the study’s three cohorts.
Patients were considered PD-L1 positive if they had a PD-L1 combined positive score of one or more ( CPS greater than or equal to 1 ).
Findings showed:

A] Cohort 1: Pembrolizumab as monotherapy in patients whose disease progressed on or after two or more prior lines of therapy ( n=259 )

Forty-eight percent of these patients had received three or more lines of prior therapy.

The efficacy analysis in all patients, with or without PD-L1 expression, showed an ORR of 12% ( 95% CI, 8-17 ), with complete responses ( CR ) in 3% ( 95% CI, 1-6 ) and partial responses ( PR ) in 9% ( 95% CI, 6-13 ) of patients.

In patients whose tumors expressed PD-L1 ( n=148 ), the ORR was 16% (95% CI, 11-23), with CR in 3% ( 95% CI, 1-8 ) and PR in 13% ( 95% CI, 8-19 ) of patients.

In PD-L1 negative patients ( n=109 ), the ORR was 6% ( 95% CI, 3-13 ), with CR in 3% ( 95% CI, 1-8 ) and PR in 4% ( 95% CI, 1-9 ) of patients.

Median duration of follow-up was 5.6 months ( range: 0.5-24.7 ).

In all patients, 42% ( n=95 ) experienced a reduction in target lesion size.

Median duration of response was 14.2 months ( range: 2.4-19.4+ ).

In all patients, median progression-free survival ( PFS ) was two months ( 95% CI, 2.0-2.1 ), with a six-month PFS rate of 14.6% ; the median overall survival ( OS ) was 5.5 months ( 95% CI, 4.2-6.5 ), with a six-month OS rate of 45.7%.

In patients whose tumors expressed PD-L1, the median PFS was 2.1 months ( 95% CI, 2.0-2.1 ), with a six-month PFS rate of 18.2%; the median OS in these patients was 5.8 months ( 95% CI, 4.4-7.8 ), with a 6-month OS rate of 48.4%.

In PD-L1 negative patients, the median PFS was 2 months ( 95% CI, 1.9-2.0 ), with a 6-month PFS rate of 9.9%; the median OS was 4.6 months ( 95% CI, 3.2-6.5 ), with a 6-month OS rate of 42.9.

B) Cohort 2: Pembrolizumab in combination with chemotherapy in treatment-naïve patients ( n=25 )

The efficacy analysis in all patients showed an ORR of 60% ( 95% CI, 39-79 ), with CR in 4% ( 95% CI, 0-20 ) and PR in 56% ( 95% CI, 35-76 ) of patients.

In patients whose tumors expressed PD-L1 ( n=16 ), the ORR was 69% ( 95% CI, 41-89 ), with no complete responses ( 95% CI, 0-22 ) and PR in 69% ( 95% CI, 41-89 ) of patients.

In PD-L1 negative patients ( n=8 ), the ORR was 38% ( 95% CI, 9-76 ), with CR in 13% ( 95% CI, 0-53 ) and PR in 25% ( 95% CI, 3-65 ) of patients.

Median duration of follow-up was 13.8 months ( range: 1.8-24.1 ).

Across all patients, 96% ( n=24 ) experienced a reduction in target lesion size. Median duration of response was 4.6 months ( range: 2.6-20.3+ ).

In all patients, median PFS was 6.6 months ( 95% CI, 5.9-10.6 ), with a six-month PFS rate of 68.0%; the median OS was 13.8 months ( 95% CI, 8.6-not reached ), with a 6-month OS rate of 76.0%.

C) Cohort 3: Pembrolizumab as monotherapy in treatment-naïve patients whose tumors expressed PD-L1 ( n=31 )

The efficacy analysis showed an ORR of 26% ( 95% CI, 12-45 ), with CR in 7% ( 95% CI, 1-21 ) and PR in 19% ( 95% CI, 8-38 ) of patients.

Median duration of follow-up was 17.5 months ( range: 1.7-20.7 ).

Seventy-seven percent of patients ( n=24 ) experienced a reduction in target lesion size.

The median duration of response was 9.6 months ( range: 2.1-17.8+ ).

The median PFS was 3.3 months ( 95% CI, 2.0-6.0 ), with a 6-month PFS rate of 34.9%; the median OS was 20.7 months ( 95% CI, 9.2-20.7 ), with a 6-month OS rate of 72.9%.


The safety profile of Pembrolizumab was consistent with that observed in previously reported studies.
In Cohorts 1, 2 and 3, grade 3-5 treatment-related adverse events ( TRAEs ) occurred in 46 ( 18% ), 19 ( 76% ), and 7 ( 23% ) patients, respectively.
In Cohort 1, grade 3-5 TRAEs were anemia ( 3% ), fatigue ( 2% ), and dehydration ( 1% ); TRAEs led to discontinuation in seven patients ( 3% ) and death in two patients ( 1% ).
In Cohort 2, grade 3-4 TRAEs were neutropenia ( 24% ), stomatitis ( 20% ), anemia ( 8% ), decreased platelet count ( 8% ), decreased appetite ( 8% ), and fatigue ( 8% ). TRAEs in Cohort 2 led to discontinuation in three patients ( 12% ); there were no treatment-related deaths.
In Cohort 3, grade 3-5 TRAEs occurred in seven patients ( 23% ); there was one treatment-related death ( 3% ) and no discontinuations due to TRAEs.

In Cohorts 1, 2 and 3, grade 3 or higher immune-mediated adverse events occurred in 13, 4, and 3 patients, respectively.
In Cohort 1, grade 3 immune-mediated adverse events were colitis ( n=3 ), pneumonitis ( n=2 ), thyroiditis ( n=1 ), and hypothyroidism ( n=1 ); there were no grade 4-5 immune-mediated adverse events.
In Cohort 2, grade 3 immune-mediated adverse events were palmar-plantar erythrodysesthesia ( n=2 ), nephrotic syndrome ( n=1 ), rash ( n=1 ), and maculopapular rash ( n=1 ); there were no grade 4-5 immune-mediated adverse events.
In Cohort 3, grade 3 immune-mediated adverse events were colitis ( n=1 ) and rash ( n=1 ); there was one grade 5 adverse event ( pneumonitis ). ( Xagena )

Source: Merck ( MSD ), 2017

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