Anti–PD-1/PD-L1 Antibodies Make Strong Showing in Gastrointestinal Cancers


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Dung T. Le, MD

Although the results may not yet be as impressive as those seen in melanoma, lung, and kidney cancers, monoclonal antibodies targeting the programmed cell death protein 1 (PD-1) are producing responses, with some durability, in gastrointestinal cancers, according to studies presented at the 2016 Gastrointestinal Cancers Symposium. The studies evaluated the anti–PD-1 antibodies pembrolizumab (Keytruda) in advanced esophageal carcinoma and noncolorectal gastrointestinal cancer and nivolumab (Opdivo) in advanced gastric and gastroesophageal junction cancers.

Pembrolizumab: Noncolorectal Gastrointestinal Cancers

High response rates to pembrolizumab were observed among patients with noncolorectal gastrointestinal cancers whose tumors were mismatch repair–deficient, in a study led by Dung T. Le, MD, of the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, Maryland.1

At the 2015 ASCO Annual Meeting, Dr. Le reported high response rates in colorectal cancers of this type.2 In the current phase II study of 17 patients, investigators observed an objective response rate of 47% after treatment with pembrolizumab.

Mismatch repair–deficient tumors harbor thousands of mutations that produce neoantigens, which can be recognized and targeted by T cells. Certain tumor types are more likely than others to have a high frequency of mismatch repair deficiency; it is present in 15% of colorectal tumors and 2% to 20% of gastric, small bowel, and hepatobiliary cancers.

“Mismatch repair deficiency is easily determined using existing commercially available tests,” indicated Dr. Le.

Pembrolizumab and Nivolumab in Gastrointestinal Cancers

  • Pembrolizumab and nivolumab were evaluated in heavily pretreated patients with advanced esophagogastric cancers, including a subset of patients with mismatch repair deficiency.
  • In noncolorectal mismatch repair–deficient gastrointestinal tumors, 47% of patients responded to pembrolizumab.
  • In Checkmate-032, 14% of patients with gastric, esophageal, or gastroesophageal junction cancer responded to nivolumab.
  • In KEYNOTE-028, 40% of patients with esophageal cancer responded to pembrolizumab.
  • With both drugs, better outcomes are observed in patients with PD-L1 positivity.

Patients with proven mismatch repair–deficient advanced noncolorectal gastrointestinal tumors were treated with pembrolizumab at 10 mg/kg every 2 weeks. The population included four patients with ampullary cancer, four with pancreatic cancer, three with biliary cancer, three with small bowel cancer, and three with gastric cancer. The patients had received a median of two prior regimens.

At a median follow-up of 5.3 months, 47% of patients responded, including 24% with complete responses, and a disease control rate of 76% was observed. Clinical benefit was observed in most of the tumor types. Responses ranged from 4 to 20 months, and four patients continue on treatment.

Median progression-free survival has not yet been reached; median overall survival was 21 months; and 18-month survival was approximately 86%, Dr. Le reported.

The rate and type of treatment-related adverse effects were similar to those in prior pembrolizumab studies and were seen (all grades) in 76% of patients; most were low-grade effects.

Pembrolizumab: Esophageal Cancer

In relapsed/refractory metastatic esophageal cancer, the KEYNOTE-028 trial evaluated pembrolizumab at 10 mg/kg every 2 weeks.3 The study restricted enrollment to patients who stained positive for the PD-1 ligand, PD-L1, defined as expression in at least 1% of tumor or inflammatory cells or positive bands in the stroma.


KEYNOTE-028 shows promising activity for pembrolizumab and an excellent safety profile. The gene-expression profile may be a potential biomarker for immune checkpoint inhibition.
— Toshihiko Doi, MD

“PD-L1 is frequently overexpressed in esophageal tumors, and this may be associated with poor prognosis,” said Toshihiko Doi, MD, of the National Cancer Center East, Chiba, Japan. “Pembrolizumab had promising activity in this heavily pretreated patient population.”

Of 83 patients available for PD-L1 screening, 37 were positive (44.6%), and 23 of them were treated with pembrolizumab. The histology was squamous cell carcinoma in 74%, and almost half the study population had received at least three prior lines of therapy.

Seven responses were observed (all partial), for an overall response rate of 30%. By histology, responses were seen in 29% of patients with predominantly squamous cell carcinoma and 40% with adenocarcinoma. Median duration of response was not reached, and some patients were continuing to respond at 1 year.

Dr. Doi also described the study’s application of gene-profile analysis, based on the identification of six genes involved in the adaptive immune response within the tumor microenvironment. This gene signature correlated with response and delay in disease progression.

Patients with high immune gene-signature scores tended to respond to prembrolizumab and to have prolonged progression-free survival, whereas patients with low scores generally did not. Responses were seen in 43% of “inflamed tumors” compared with 11% of “noninflamed” tumors.

“KEYNOTE-028 shows promising activity for pembrolizumab and an excellent safety profile. The gene-expression profile may be a potential biomarker for immune checkpoint inhibition,” Dr. Doi said.

PD-1/PD-L1 Antibodies: Gastroesophageal Cancers

Dr. Le also reported results of nivolumab in 59 patients with advanced or metastatic gastric (n = 31), esophageal (n = 15), or gastroesophageal junction (n = 53) cancers in the CheckMate-032 trial.4 Tumors could be positive or negative for PD-L1 expression. Patients received nivolumab at 3 mg/kg every 2 weeks.

An overall response rate of 14% was observed in this heavily pretreated population (including one complete response); 83% of all patients had received at least two prior lines of treatment. The disease control rate was 32%. Median duration of response was 7.1 months, and median overall survival was 5 months.

“Four of the eight responders had ongoing responses and were continued on treatment,” Dr. Le said. “We saw that 49% of chemotherapy-refractory patients were still alive at 6 months, and 36% were alive at 12 months,” she added.

The study also found some correlation between response and PD-L1 expression, with higher response rates observed in PD-L1–positive patients (27%) than in PD-L1–negative patients (12%) when positivity was defined as ≥ 1% of tumor cells.

Consistent with studies in other tumor types, nivolumab was well tolerated, with only 17% of patients experiencing a grade 3 or 4 adverse event.

Also reported in gastric/gastroesophageal junction cancer were results for avelumab, an anti–PD-L1 antibody that was administered to 75 patients in the JAVELIN study—either as monotherapy or as maintenance therapy following first-line chemotherapy.5

In the second-line setting, a 15% response rate was observed, with median progression-free survival of 2.7 months. Higher response rates were observed in PD-L1–positive patients (20%) vs PD-L1–negative patients (0%), and progression-free survival was longer. ■

Disclosure: Dr. Le has received research funding from Merck, BMS, Aduro Biotech, and honoraria from Merck. For full disclosures for Drs. Le and Doi, visit meetinglibrary.asco.org.

References

1. Le DT, Uram JN, Wang H, et al: PD-1 blockade in mismatch repair deficient non-colorectal gastrointestinal cancers. 2016 Gastrointestinal Cancers Symposium. Abstract 195. Presented January 21, 2016.

2. Le DT, Uram JN, Wang H, et al: PD-1 blockade in tumors with mismatch repair deficiency. 2015 ASCO Annual Meeting. Abstract LBA100. Presented May 29, 2015.

3. Doi T, Piha-Paul SA, Jalal SI, et al: Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475). 2016 Gastrointestinal Cancers Symposium. Abstract 7. Presented January 21, 2016.

4. Le DT, Bendell JC, Calvo E, et al: Safety and activity of nivolumab monotherapy in advanced and metastatic gastric or gastroesophageal junction cancer: Results from the CheckMate-032 study. 2016 Gastrointestinal Cancers Symposium. Abstract 6. Presented January 21, 2016.

5. Chung HC, Arkenau HT, Wyrwicz L, et al: Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal junction cancer. 2016 Gastrointestinal Cancers Symposium. Abstract 167. Presented January 21, 2016.


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