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The basket trial that showed pembrolizumab alone rarely works in bile duct and gallbladder cancer: only 6 of 104 patients responded, though those who did stayed in response for years. It is also the trial behind the tumour-agnostic approvals of pembrolizumab for mismatch-repair-deficient and high mutation-burden cancers, which do apply to gallbladder cancer.
KEYNOTE-158 (NCT02628067) is Merck's multi-cohort phase 2 of pembrolizumab 200 mg every three weeks in advanced solid tumours. Its biliary adenocarcinoma cohort enrolled 104 patients with incurable gallbladder or bile duct cancer (ampulla of Vater excluded) that had progressed after standard treatment, regardless of PD-L1 status. Objective response by independent central review was 5.8 percent (6 of 104; 95 percent confidence interval 2.1 to 12.1), median duration of response was not reached (range 6.2 to more than 26.6 months), and median overall and progression-free survival were 7.4 and 2.0 months; response was 6.6 percent in PD-L1 expressers and 2.9 percent in non-expressers. Grade 3 to 5 treatment-related adverse events occurred in 13.5 percent with one grade 5 renal failure. The companion KEYNOTE-028 cohort (24 PD-L1-positive patients) responded in 13 percent. The same trial's mismatch-repair-deficient and tumour mutational burden cohorts underpinned the tumour-agnostic FDA approvals of pembrolizumab (2017 and 2020), which are the route to single-agent immunotherapy for the small minority of gallbladder cancers with those features; for the rest, checkpoint blockade works only in combination with gemcitabine and cisplatin (TOPAZ-1, KEYNOTE-966).
Numbers are from the trial as recorded here; see the source links in the table below. This is orientation, not medical advice: ask your team how closely the trial population matches you.
1,609 enrolled.
95% CI 2.1 to 12.1
Source4 of 22; 95% CI 5 to 40; duration of response 8.1 to 24.3 or more months
Source| Endpoint | Arm | n | Value | HR (95% CI) | p | Source |
|---|---|---|---|---|---|---|
| Objective response rate, biliary adenocarcinoma cohort (independent central review)primary | Pembrolizumab | 104 | 5.8% | - | - | link |
| Overall survival, biliary cohort | Pembrolizumab | 104 | 7.4 months | - | - | link |
| Progression-free survival, biliary cohort | Pembrolizumab | 104 | 2 months | - | - | link |
| Objective response, MSI-H or dMMR pancreatic cancer cohort (label) | Pembrolizumab 200 mg every 3 weeks | 22 | 18% | - | - | link |
A second publication from the KEYNOTE-158 trial, later than the first and described in its title as an update or longer-term analysis. Read it with the primary publication linked from the trial page; the record was linked automatically and its figures have not been checked by hand.
It tells the pathologist which pancreatic cancers to test for the one immunotherapy-responsive subgroup and how.
Every pancreatic cancer should be tested for mismatch repair deficiency because the 1 percent who have it can receive pembrolizumab, but responses in pancreatic cancer are less frequent and less durable than in other MSI-high cancers.
This is the paper Europe PMC returns for registry id NCT02628067 with the most citations, so it is the natural first reading for anyone following the KEYNOTE-158 trial. Read the abstract above alongside the trial page and the registry entry; the record was linked automatically and its figures have not been checked by hand.
Guidelines recommending universal mismatch repair testing in pancreatic cancer, by immunohistochemistry or sequencing rather than PCR alone, rest on this and similar series.
Shares KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer, Tumour mutational burden (TMB), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), PD-1.
Shares Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer, Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations, Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma.
Shares Comprehensive characterisation of pancreatic ductal adenocarcinoma with microsatellite instability: histology, molecular pathology and clinical implications, KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer, Hu 2018: evaluating mismatch repair deficiency in pancreatic adenocarcinoma, challenges and recommendations, Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma.
Shares Gallbladder cancer in biliary tract cancer trials (eligibility and subgroups), Biliary tract cancer (all types), PD-1, Biliary tract cancer (cholangiocarcinoma).
Shares KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer, Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma, Tumour-agnostic (tissue-agnostic) approval, Tumour mutational burden (TMB).
Shares KEYNOTE-158: pembrolizumab in non-colorectal high microsatellite instability or mismatch repair-deficient cancer, Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma, PD-1, Pembrolizumab.
Shares Gallbladder cancer in biliary tract cancer trials (eligibility and subgroups), Biliary tract cancer (all types), PD-1, Biliary tract cancer (cholangiocarcinoma).
Shares Gallbladder cancer in biliary tract cancer trials (eligibility and subgroups), Biliary tract cancer (all types), Biliary tract cancer (cholangiocarcinoma), Gallbladder cancer.