Meeting News CoveragePerspective

PD-1 blockade promising in MMR deficient GI cancers

SAN FRANCISCO — Programmed death-1 blockade demonstrated promising activity in mismatch repair deficient gastrointestinal cancers in a phase 2 trial, according to data presented at the Gastrointestinal Cancers Symposium.

“Mutations have been shown to encode proteins that can be recognized and targeted by the immune system, and that the average tumor has dozens of somatic mutations, however mismatch repair deficient tumors harbor thousands of mutations, and this led to the hypothesis that immune augmentation with PD-1 blockade could be highly effective in mismatch repair deficient tumors,” Dung T. Le, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said during her presentation. “The frequency of mismatch repair deficiency varies depending on the reports for different histologies, but in certain histologies there is a higher proportion, including colorectal cancer, endometrial cancer, gastric, ampullary and small bowel cancer.”

Dung T. Le

Le and colleagues enrolled three cohorts of patients; cohort A included patients with mismatch repair (MMR) deficient colon cancer, cohort B included patients with MMR proficient colon cancer and cohort C included patients with any MMR deficient solid tumor. All patients were treated with Keytruda (pembrolizumab, Merck) at 10 mg/kg every 2 weeks, and were tested for MMR status using standard immunohistochemistry for MMR deficiency or a PCR test for microsatellite instability.

Previous data from this trial was presented at ASCO 2015, which “showed a fair number of patients with responses that appear durable,” Le said. “Since that time we’ve expanded the protocol to allow more patients to enroll in cohort C and today I’m presenting the data on the 17 patients with non-CRC GI cancer with [MMR] deficiency.”

The median age of these patients was 60 years (range, 34-92 years), 29% were female, 29% had an ECOG performance of 0, four patients had pancreatic cancer, four had ampullary cancer, three had biliary cancer, three had small bowel cancer and three had gastric cancer. All patients had metastatic disease, 65% had liver metastases, and the median number of prior regimens was two.

Treatment related adverse events were comparable to prior pembrolizumab studies; 76% of patients developed treatment related adverse events, most of which were low grade, while 12% of patients developed grade 3/4 events. Fatigue, thyroid and dermatologic disorders were the most common adverse events.

The objective response rate was 47%; 24% of patients had a complete response while 24% had a partial response, 29% had stable disease, the disease control rate was 76% and median follow-up was 5.3 months. There were responses in patients with gastric, ampullary, small bowel and pancreatic cancer and cholangiocarcinoma, and complete responses occurred in two patients with gastric cancer, one with ampullary cancer and one with cholangiocarcinoma.

“The PFS is non-estimable because it has not been reached, the overall survival … is 21 months with an 18-month survival of approximately 86%,” Le said. “In conclusion [MMR] deficiency is easily determined using existing commercially available tests, [MMR] deficient GI tumors are highly responsive to checkpoint blockade with anti-PD 1. Clinical benefit is noted across tumor sites with [MMR] deficiency including colon, stomach, duodenum, pancreas, ampullary and bile duct cancers, and biochemical response correlates to the radiographic response.” – by Adam Leitenberger

Reference:

Le DT, et al. Abstract 195. Presented at: Gastrointestinal Cancers Symposium; Jan. 21-23, 2016; San Francisco.

Disclosure: Le reports research funding and speaking honorarium from Merck. Please see the full abstract for a list of all other researchers’ relevant financial disclosures.

SAN FRANCISCO — Programmed death-1 blockade demonstrated promising activity in mismatch repair deficient gastrointestinal cancers in a phase 2 trial, according to data presented at the Gastrointestinal Cancers Symposium.

“Mutations have been shown to encode proteins that can be recognized and targeted by the immune system, and that the average tumor has dozens of somatic mutations, however mismatch repair deficient tumors harbor thousands of mutations, and this led to the hypothesis that immune augmentation with PD-1 blockade could be highly effective in mismatch repair deficient tumors,” Dung T. Le, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, said during her presentation. “The frequency of mismatch repair deficiency varies depending on the reports for different histologies, but in certain histologies there is a higher proportion, including colorectal cancer, endometrial cancer, gastric, ampullary and small bowel cancer.”

Dung T. Le

Le and colleagues enrolled three cohorts of patients; cohort A included patients with mismatch repair (MMR) deficient colon cancer, cohort B included patients with MMR proficient colon cancer and cohort C included patients with any MMR deficient solid tumor. All patients were treated with Keytruda (pembrolizumab, Merck) at 10 mg/kg every 2 weeks, and were tested for MMR status using standard immunohistochemistry for MMR deficiency or a PCR test for microsatellite instability.

Previous data from this trial was presented at ASCO 2015, which “showed a fair number of patients with responses that appear durable,” Le said. “Since that time we’ve expanded the protocol to allow more patients to enroll in cohort C and today I’m presenting the data on the 17 patients with non-CRC GI cancer with [MMR] deficiency.”

The median age of these patients was 60 years (range, 34-92 years), 29% were female, 29% had an ECOG performance of 0, four patients had pancreatic cancer, four had ampullary cancer, three had biliary cancer, three had small bowel cancer and three had gastric cancer. All patients had metastatic disease, 65% had liver metastases, and the median number of prior regimens was two.

Treatment related adverse events were comparable to prior pembrolizumab studies; 76% of patients developed treatment related adverse events, most of which were low grade, while 12% of patients developed grade 3/4 events. Fatigue, thyroid and dermatologic disorders were the most common adverse events.

The objective response rate was 47%; 24% of patients had a complete response while 24% had a partial response, 29% had stable disease, the disease control rate was 76% and median follow-up was 5.3 months. There were responses in patients with gastric, ampullary, small bowel and pancreatic cancer and cholangiocarcinoma, and complete responses occurred in two patients with gastric cancer, one with ampullary cancer and one with cholangiocarcinoma.

“The PFS is non-estimable because it has not been reached, the overall survival … is 21 months with an 18-month survival of approximately 86%,” Le said. “In conclusion [MMR] deficiency is easily determined using existing commercially available tests, [MMR] deficient GI tumors are highly responsive to checkpoint blockade with anti-PD 1. Clinical benefit is noted across tumor sites with [MMR] deficiency including colon, stomach, duodenum, pancreas, ampullary and bile duct cancers, and biochemical response correlates to the radiographic response.” – by Adam Leitenberger

Reference:

Le DT, et al. Abstract 195. Presented at: Gastrointestinal Cancers Symposium; Jan. 21-23, 2016; San Francisco.

Disclosure: Le reports research funding and speaking honorarium from Merck. Please see the full abstract for a list of all other researchers’ relevant financial disclosures.

    Perspective

    This oral abstract, looking at the significance of mismatch repair in immunotherapy for gastrointestinal malignancies, was particularly exciting. 

    Immunotherapy is taking center stage in all of oncology, really, and is just now coming to gastrointestinal oncology. One of the key questions is how to predict the patients in which immunotherapy might be effective.

    Dr. Lee and colleagues looked, in a very small group of patients of various types, at the frequency of so-called mismatch repair, which relates to the degree of genetic abnormalities and, ultimately, the degree to which cancers can generate an immune response. 

    What they found was a very striking correlation between this finding of mismatch repair and the ability of immunotherapy to work. 

    This is going to provide an important clue, going forward, in terms of what patients might be amenable to immunotherapy, how immunotherapy might work and what types of immunotherapy might work. I think it will be very foundational information to advancing this field within gastrointestinal oncology. 

    • Vincent J. Picozzi, MD
    • Virginia Mason Medical Center

    Disclosures: Picozzi reports stock and ownership interests in AbbVie, Amgen and Johnson & Johnson; honoraria from Celgene; consulting or advisory roles for Halozyme and Taiho Pharmaceutical; and research funding from Aduro Biotech, Clovis Oncology, FibroGen, Immunomedics, Incyte, OncoMed and Theranostics Health.

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