Few Responses With New Combo in Biliary Tract Cancer

Neil Osterweil

May 05, 2020

Relapsed or refractory biliary tract cancers are rare, aggressive tumors with few treatment options and poor prognosis.

Immunotherapy has been tried, but in contrast to many other tumor types, immune checkpoint inhibitors have shown little efficacy as monotherapy for biliary tract cancers and are not part of the standard of care.

Now an attempt has been made to improve efficacy by adding a targeted agent that has been suggested to have possible synergy.

In a trial sponsored by the National Cancer Institute, immunotherapy with atezolizumab (Tecentriq, Genentech) was tested in combination with the MEK inhibitor cobimetinib (Cotellic, Genentech).

This combination improved progression-free survival (PFS) compared with the checkpoint inhibitor alone, but only a few patients had clinical responses, the investigators report.

Median PFS, the primary endpoint, was 57 days for patients treated with atezolizumab alone vs 111 days with the combination (P = .0268), reported Mark Yarchoan, MD, from the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland.

The response rate in the interim analysis was low, however. Only one patient in each treatment arm had a partial response, and there were no complete responses, he noted.

The results were presented during the American Association for Cancer Research (AACR) virtual annual meeting.

"Although this is a positive study, the low response rates observed in both treatment arms highlights the challenge of developing immunotherapy for this disease. Additional research is certainly needed to understand the impact of MEK inhibition on the tumor immune microenvironment in cholangiocarcinomas," Yarchoan commented.

Praiseworthy Trial (With Caveats)

"This was an incredible effort," commented Zev A. Wainberg, MD, from the David Geffen School of Medicine at the University of California, Los Angeles.

"However, many questions remain," he continued. "It is hard to stratify for three subsets of a rare disease, so we have to interpret some of these results with caution, particularly if we are to conclude that the intrahepatic cohort had all the benefits," he said,

This finding came from an unplanned, post hoc analysis, which suggested that most of the benefit was in a subgroup of patients with intrahepatic cholagniocarcinoma (43 of 77 patients; 56%). The other participants had extrahepatic cholangiocarcinoma (15 of 77; 19%) or gallbladder cancer (19 of 77; 25%).

Wainberg also highlighted the comparatively high rate of grade 3 treatment-related adverse events (AEs), seen in 44.7% of patients in the combination therapy arm. Events that occurred more frequently in the combination arm included rash, pruritus, dry mouth, diarrhea, nausea, vomiting, thrombocytopenia, and elevated creatine phosphokinase levels.

This makes it difficult to imagine that the combination could be safely administered with a third agent, "so I think we have to take the AEs that have been reported in the study with caution and think about how to minimize them," he said.

Wainberg also cast doubt on the ability of investigators to conduct a phase 3 trial, given the rarity of the cancers and the lack of biomarkers for selecting patients to assess efficacy.

A phase 3 trial of the combination in the second line would have to have either 5-fluorauracil (5-FU) or the FOLFOX regimen (5-FU, leucovorin, oxaliplatin) in the comparator arm, he said.

A Tough Nut

Biliary tract cancers are usually lumped together for treatment purposes, but each subtype has a unique molecular phenotype.

"Patients receiving standard frontline chemotherapy with gemcitabine plus cisplatin have a median survival of less than 1 year. A subset of patients, particularly those with intrahepatic cholangiocarcinoma, may have potentially actionable mutations for which novel targeted therapies may be beneficial. However, the survival benefit for patients receiving standard second-line therapy with FOLFOX is small, highlighting a need for additional treatment options in the second or third line for these patients," Yarchoan said.

The trial was sponsored by the National Cancer Institute. Yarchoan has received grant/research support from Incyte, Bristol-Myers Squibb, Exelixis, Genentech/Roche, and Merck, and has served on advisory boards with Eisai, Exelexis, and Geneos, Wainberg has received research grants from Novarits, Ispen, and Plexxikon, and has consulted for Merck, EMD Serono, Bayer, Lilly, Five Prime, Array, Ipsen, Incyte, and QED.

American Association for Cancer Research (AACR) 2020. Presented April 28, 2020. Abstract CT043

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