1. Fuerst, Mark L.

Article Content

SAN FRANCISCO-Immunotherapy offers overall survival gains over best supportive care (BSC) in patients with advanced refractory colorectal carcinoma (CRC) not selected for defective mismatch repair.

immunotherapy; color... - Click to enlarge in new windowimmunotherapy; colorectal cancer. immunotherapy; colorectal cancer

Colorectal tumors are classified according to their global genomic status, either microsatellite instable (MSI) or microsatellite stable. MSI is the molecular fingerprint of a mismatch repair deficiency (MMR), where immune checkpoint blockade has demonstrable activity.


MSI-H tumors have shown to be responsive to PD-1 inhibitor therapy. The MSI-H/defective MMR phenotype is a known hallmark of hereditary nonpolyposis CRC, or Lynch syndrome, and is also a distinctive feature in sporadic CRCs and to varying degrees in several other tumor types. There is renewed interest in MSI analysis because the MSI-H/defective MMR phenotype has emerged as an actionable predictive biomarker for immune checkpoint blockade therapy in different cancer types.


Single-agent immunotherapy has not been very successful in this population, which has led to investigations of combination therapy. Durvalumab is a human monoclonal antibody that inhibits binding of PD-L1 to its receptor. Tremelimumab is a monoclonal antibody against the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). Targeting both PD-L1 and CTLA-4 may have additive/synergistic activity, said Eric X. Chen, MD, PhD, of the Princess Margaret Cancer Centre of the University Health Network in Toronto, at the 2019 Gastrointestinal Cancers Symposium.


"This is the first study showing that combined PD-L1 and CTLA-4 inhibition prolongs survival in patients with advanced refractory CRC not selected for defective MMR," said Chen.


Chen and colleagues evaluated whether combining PD-L1 and CTLA-4 inhibition would lead to improved patient survival versus BSC alone in 180 refractory CRC patients (Abstract 481). Patients were eligible if they failed all standard regimens containing fluoropyrimidine, irinotecan, and oxaliplatin (and an EGFR inhibitor if they were RAS wild-type). Prior treatment with anti-VEGF agents or TAS-102 was permitted, but not mandatory.


Some 119 patients were treated with durvalumab (1,500 mg) on day 1 every 28 days and tremelimumab (75 mg) on day 1 for the first 4 cycles plus BCS or BCS alone (61 patients). Patient baseline characteristics were balanced, Chen said. More than 85 percent of patients received at least 90 percent of planned doses of the dual immunotherapies. No patients with known defective MMR tumors were enrolled.


At a median follow-up of 15.2 months, the median overall survival (OS), the primary endpoint, was 6.6 months for the durvalumab plus tremelimumab arm and 4.1 months for the BSC arm. Median progression-free survival was 1.8 months and 1.9 months, respectively. Disease control rate was 22.7 percent for dual immunotherapy group and 6.6 percent for the BSC group.


Grade 3/4 abdominal pain, fatigue, lymphocytosis, and eosinophilia were significantly higher in durvalumab plus tremelimumab arm. However, at 16 weeks, there was significantly less deterioration of quality of life for those on immunotherapy, he explained.


In conclusion, Chen noted: "Durvalumab plus tremelimumab significantly prolonged OS in patients with refractory CRC and preserved quality of life. Adverse events were more frequent with durvalumab plus tremelimumab."


Single-Agent Durvalumab in MSI-H

In another presentation at the meeting (Abstract 670), durvalumab monotherapy was safe and clinically activity in patients with advanced MSI-H tumors, including CRC, inducing responses in about one-quarter of patients.


Two ongoing studies evaluated durvalumab in patients with MSI-H tumors, a phase I/II, multicenter, open-label study in patients with advanced solid tumors and a phase II single-center study in patients with advanced CRC.


Patients with MSI-H tumors (determined locally by immunohistochemistry or sequencing) received durvalumab 10 mg/kg intravenously every 2 weeks for 12 months or until confirmed progressive disease, whichever was first.


A total of 62 MSI-H patients (97% with prior anti-cancer therapy) received treatment in the multicenter study, reported Neil H. Segal, MD, PhD, a gastrointestinal cancer specialist and Clinical Director of the Immunotherapeutics Group at Memorial Sloan Kettering Cancer Center in New York. Among the 62 patients in the MSI-H group, 36 patients had colorectal cancer, 17 patients had endometrial cancer, and nine patients had other types of cancer.


At a median follow-up of 29 months, of the 62 patients with various types of MSI-H tumors, 14 patients achieved objective responses, including one complete response (CR). Among 36 patients with advanced MSI-H colorectal cancer, eight patients had partial responses. Objective response rates were 23 percent for the total population and 22 percent for patients with CRC; nine of 14 responders were ongoing at data cutoff, he noted.


In the single-center study, with a median duration of 30 months follow-up, 11 patients with MSI-H CRC were treated. Durvalumab achieved objective responses in three of 11 patients, including one CR. One patient discontinued treatment due to treatment-related aseptic meningitis, which was resolved with steroids.


The benefit was consistent across different types of tumors, including colorectal cancer, noted Segal, adding that evidence suggests MSI-H is a marker of susceptibility to PD-1 targeted therapy. MSI-H tumors account for 3-4 percent of metastatic colorectal cancer, and recent studies have found these tumors are responsive to PD-1-directed therapy, Segal said.


Treatment-related adverse events occurred in 37 patients (60%). The most common were diarrhea (15%), asthenia (11%), fatigue (11%), nausea (10%), and hypothyroidism (10%). Grade 3/4 treatment-related adverse events occurred in two patients (3%). There were no deaths or treatment discontinuations due to treatment-related adverse events.


In conclusion, Segal said: "Durvalumab had a tolerable safety profile and showed promising antitumor activity and overall survival in patients with MSI-H tumors."


Mark L. Fuerst is a contributing writer.