'More Is Not Better' in Two First-Line Trials for Biliary Tract Cancer

SAN FRANCISCO -- More therapy, whether cytotoxic or targeted, failed to improve outcomes in two separate randomized trials of front-line treatment for advanced biliary-tract cancer.

The SWOG 1815 trial showed that adding nab-paclitaxel (Abraxane) to gemcitabine and cisplatin did not improve progression-free (PFS) or overall survival (OS) but did increase toxicity. The hypothesis-generating IMbrave151 trial showed that the addition of bevacizumab (Avastin) to atezolizumab (Tecentriq) and chemotherapy led to a small increase in PFS associated with overlapping confidence intervals for the two treatment groups.

A subgroup analysis of SWOG 1815 suggested a potential benefit in patients with locally advanced disease and those with gallbladder cancer, but the observations pertained to small numbers of patients. Neither of the IMbrave151 regimens appeared to be an improvement over the current standard of care, cisplatin-gemcitabine chemotherapy with or without durvalumab (Imfinzi), said Imane El Dika, MD, of Memorial Sloan Kettering Cancer Center in New York City, during a discussion of the studies at the ASCO Gastrointestinal Cancers Symposium.

"From SWOG 1815 cisplatin, gemcitabine, and nab-paclitaxel does not improve survival over gemcitabine-cisplatin in front-line untreated biliary cancers," said El Dika, whose working title for the data was "More Is Not Better."

"From IMbrave151, two experimental arms were tested, and there was no clear signal to move either forward. Gemcitabine, cisplatin with durvalumab combination remains the standard front-line treatment," El Dika stated. "I urge us all to continue to do the molecular testing at diagnosis, early on, for advanced cancer as integration of targeted therapies and immunotherapies is underway in the front-line setting to expand our treatment options for our patients."

Biliary tract cancers are a heterogeneous type of malignancy with an increasing incidence, noted Rachna Shroff, MD, of the University of Arizona Cancer Center in Tucson, in her introduction to SWOG 1815. Prognosis remains poor, as even the recent addition of durvalumab to standard-of-care gemcitabine and cisplatin resulted in a median OS of about 12 months.

SWOG 1815

The phase III SWOG 1815 trial followed encouraging results from a 60-patient phase II study that showed a median OS of 19.2 months in newly diagnosed advanced biliary cancer treated with nab-paclitaxel, gemcitabine, and cisplatin. SWOG 1815 involved 441 patients randomized 2:1 to gemcitabine-cisplatin with or without nab-paclitaxel. The primary endpoint was OS.

The study population had a median age of about 63, and women accounted for 55% of the total number of patients. Two-thirds of the patients had an intrahepatic primary site and 16% each had extrahepatic or gallbladder cancer.

The primary analysis showed a median OS of 12.7 months with gemcitabine and cisplatin, increasingly slightly to 14.0 months with the addition of nab-paclitaxel. Median PFS increased from 6.4 to 8.2 months with nab-paclitaxel, also a nonsignificant difference.

Analysis of OS by disease site showed no significant differences, although patients with gallbladder cancer appeared to derive greater benefit from nab-paclitaxel (median OS 17.0 vs 9.3 months, median PFS 9.6 vs 5.6 months). Additionally patients with locally advanced disease had a median OS of 19.2 months with the three-drug combination versus 13.7 months with the gemcitabine-cisplatin doublet.

Overall response rate (ORR) also favored the nab-paclitaxel arm for patients with gallbladder cancer (44% vs 22%) and locally advanced disease (34% vs 21%).

Grade 3-4 toxicity (particularly hematologic toxicity) occurred more often with the addition of nab-paclitaxel, but discontinuation because of treatment-related adverse events (AEs) was similar between the two groups.

"Exploratory analyses with a higher overall response rate and overall survival in patients with locally advanced and/or gallbladder cancer does suggest some potential clinical utility [for the three-drug combination] in these settings, which may warrant further evaluation," said Shroff.

IMbrave151

IMbrave151 sought to build on the modest but statistically significant survival benefit previously shown with the addition of durvalumab to chemotherapy. The trial paired gemcitabine-cisplatin chemotherapy with the PD-L1 inhibitor atezolizumab plus or minus the VEGF inhibitor bevacizumab. Designed as a hypothesis-generating study of two experimental treatment strategies, the trial did not include formal testing for statistical significance, said Anthony B. El-Khoueiry, MD, of the USC Norris Comprehensive Cancer Center in Los Angeles.

The rationale for adding bevacizumab came from evidence that VEGF blockade can enhance response to PD-1/L1 inhibition by promoting an "immune-permissive" environment. The atezolizumab-bevacizumab combination already is a standard option for unresectable hepatocellular carcinoma and first-line standard for non-small cell lung cancer, El-Khoueiry noted.

IMbrave151 included 162 patients with untreated advanced biliary tract cancer, randomized to gemcitabine, cisplatin, atezolizumab, and either bevacizumab or placebo. The primary endpoint was PFS, and OS and ORR were key secondary endpoints.

The primary analysis showed that patients randomized to bevacizumab had a median PFS of 8.3 months as compared with 7.9 months for the placebo group (HR 0.76, 95% CI 0.51-1.14). The 6-month PFS showed a larger advantage for bevacizumab (78.2% vs 63.1%). ORR was 24%-25% in both treatment groups, and median OS had yet to be reached for either arm. Duration of response favored the bevacizumab arm, as the median had yet to be reached versus 5.8 months for the placebo arm.

Rates of all-grade, grade 3/4, and serious AEs were similar in the two groups. One notable difference was hypertension, which occurred more often with bevacizumab (38.5% vs 18.5%).

"IMbrave151 is the first randomized study to evaluate PD-L1 and VEGF blockade plus chemotherapy as first-line treatment for advanced biliary tract cancer," said El-Khoueiry. "The addition of bevacizumab to atezolizumab and gemcitabine-cisplatin chemotherapy in this signal-seeking trial modestly improved PFS with a hazard ratio of 0.76.

"I would like to remind everyone that the purpose of the study was hypothesis generation and estimation of the impact of atezolizumab-bevacizumab plus gemcitabine-cisplatin versus atezolizumab-placebo plus gemcitabine-cisplatin on PFS."