What Can Be Learned From Negative Findings of Two Trials in Biliary Tract Cancer

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Biliary tract cancer is particularly difficult to treat, with a median overall survival of about 1 year with standard-of-care gemcitabine-based regimens. Advanced biliary tract cancer is an area of significant unmet need because of its aggressive nature, limited treatment options, and poor prognosis. Unfortunately, two important studies presented at the 2023 ASCO GI Cancers Symposium did little to move the field forward toward better outcomes.

The open-label, phase III SWOG-1815 trial failed to meet its primary endpoint of overall survival for the addition of nab-paclitaxel to gemcitabine and cisplatin in newly diagnosed patients with locally advanced or metastatic biliary tract cancer.1 In addition, in IMbrave151 the addition of bevacizumab to atezolizumab, cisplatin, and gemcitabine failed to improve progression-free survival, the primary endpoint, in a clinically meaningful manner.2

Median overall survival with the addition of nab-paclitaxel was 14.0 months compared with 12.7 months with standard gemcitabine plus cisplatin (hazard ratio [HR] = 0.93). In IMbrave151, after a median follow-up of 10.8 months, median progression-free survival was 8.3 months with bevacizumab plus atezolizumab/cisplatin/gemcitabine and 7.9 months with the regimen without bevacizumab (HR = 0.76; 95% confidence interval [CI] = 0.51–1.14).

“SWOG 1815 did not meet its primary endpoint, but I still think it had a positive impact in the space of biliary tract cancers,” said Rachna T. Shroff, MD, of the University of Arizona Cancer Center, who offered several positive thoughts as she concluded her presentation of the data. “SWOG 1815 is the first randomized phase III trial in biliary tract cancer and proved we can do a randomized phase III trial in a rare tumor. It also proved that an NCI-sponsored study opening through a National Clinical Trials Network mechanism can open quickly and can answer an important and meaningful question in an expeditious way.”

Rachna T. Shroff, MD

Rachna T. Shroff, MD

Anthony El-Khoueiry, MD

Anthony El-Khoueiry, MD

Anthony El-Khoueiry, MD, of the University of Southern California, Norris Comprehensive Cancer Center, also drew some positive signs from IMbrave151, the first randomized trial to investigate concurrent blockade of PD-L1 and vascular endothelial growth factor (VEGF) combined with a chemotherapy backbone in patients with biliary tract cancer. VEGF blockade coupled with chemotherapy may augment responses to PD-L1 inhibition by promoting an immune-permissive tumor microenvironment. IMbrave151, therefore, evaluated the addition of atezolizumab to gemcitabine plus cisplatin and further the addition of bevacizu­mab to this triplet.

“IMbrave151 did not identify a clear winner between the two experimental arms based on median progression-free survival, and longer follow-up is needed for overall survival. The 6-month landmark progression-free survival and overall survival favored the bevacizumab arm; this in combination with a longer median duration of response in the bevacizumab arm suggest a clinical benefit in a subset of patients,” Dr. El-Khoueiry said.

SWOG 1815 Details

From February 2019 to February 2021, SWOG 1815 enrolled 441 patients newly diagnosed with locally advanced or, primarily, metastatic cholangiocarcinoma or gallbladder cancer. Patients were randomly assigned 2:1 to receive either gemcitabine at 800 mg/m2, cisplatin at 25 mg/m2, and nab-paclitaxel at 100 mg/m2 or standard dosing of gemcitabine at 1,000 mg/m2 and cisplatin at 25 mg/m2. Both regimens were administered on days 1 and 8 of a 21-day cycle. Overall survival was the primary endpoint.

The combination had appeared encouraging in a previous study, in which treatment resulted in a median overall survival of 19.2 months.3 “It was this signal that led to the design for the pivotal and first randomized phase III trial in biliary tract cancers in the United States, SWOG 1815,” Dr. Shroff said.

Endpoints Not Met

In terms of overall survival, there was a numerical improvement with nab-paclitaxel but no statistically significant improvement. Similarly, no significant benefit was seen in progression-free survival, where the medians were 8.2 months with the addition of nab-paclitaxel vs 6.4 months with standard therapy (P = .43). The overall response rate (confirmed and unconfirmed) was 31% with the addition of nab-paclitaxel vs 22%, and the disease control rate was 77% vs 69% (neither was statistically significant).

Exploratory analyses of subgroups did reveal some numerical differences favoring the addition of nab-paclitaxel. In patients with gallbladder cancer, median overall survival was 17.0 vs 9.3 months, respectively, and median progression-free survival was 9.6 vs 5.6 months. Response rate in this subtype was 44% vs 22%, she reported.

“There were no significant differences between nab-paclitaxel plus gemcitabine/cisplatin and gemcitabine/cisplatin by disease site. There was an interesting trend toward better survival with nab-paclitaxel, gemcitabine/cisplatin in gallbladder cancer, but the numbers are small,” Dr. Shroff stated.

“When you look at overall survival by disease stage, you do start to see a slight separation in the locally advanced patient population,” she said. For patients with locally advanced disease, median overall survival was 19.2 months in the nab-paclitaxel arm vs 13.7 months (P = .01), and median progression-free survival was 9.3 vs 7.6 months, respectively (P = .04). Response rate for patients with locally advanced disease was 28% vs 21%, and for those with metastatic disease, it was 32% vs 23%.

“The exploratory analyses, showing higher response rates and overall survival in patients with locally advanced disease or gallbladder cancer, suggest potential clinical utility in these settings, which may warrant further evaluations,” Dr. Shroff said. “Ongoing biomarker analyses may identify subsets who could benefit from nab-paclitaxel plus gemcitabine/cisplatin.”

Participants in the nab-paclitaxel arm had more hematologic adverse events grade ≥ 3, mostly neutropenia (37% vs 28%) and anemia (33% vs 22%). The treatment discontinuation rate did not significantly differ between the arms.

IMbrave151 Details

The phase II randomized double-blind IMbrave151 trial evaluated the addition of bevacizumab to the regimen of atezolizumab/cisplatin/gemcitabine as a first-line treatment in advanced biliary tract cancer. As a signal-seeking trial of two experimental arms, no formal hypothesis testing was conducted.

The study randomly assigned 162 participants to receive atezolizumab at 1,200 mg plus bevacizumab every 3 weeks plus cisplatin at 25 mg/m2 and gemcitabine at 1,000 mg/m2 on days 1 and 8 on 21-day cycles or the same without bevacizumab. Patients received eight cycles followed by maintenance atezolizumab with or without bevacizumab. The primary endpoint was progression-free survival.

The 6-month progression-free survival rate was higher in the bevacizumab arm (78.2% vs 63.1%), and that arm also was favored in most subgroups “but within the context of small numbers,” commented Dr. El-Khoueiry. “The benefits seemed notable in females (HR = 0.56), in patients treated outside Asia (HR = 0.60), in patients with locally advanced disease (HR = 0.51), and in those who have not had prior biliary tract cancer surgery (HR = 0.66),” he added. “Of course, these observations are only hypothesis-generating.”

Approximately 25% of patients in each arm responded, and 63% achieved stable disease. The duration of response, however, was not reached in the bevacizumab arm and was 5.8 months in the control arm (HR = 0.22; 95% CI = 0.07–0.73). At 6 months, 88.5% vs 47.4% of responders, respectively, were still in response.

Median overall survival (still immature) was not reached in the bevacizumab arm and was 11.4 months in the control arm (HR = 0.74), and at 6 months, 92.0% and 80.5%, respectively, were alive. Dr. El-Khoueiry considers the data reliable, as the control arm’s survival is consistent with previous studies, he said. 

In an exploratory post hoc analysis of responders, median progression-free survival was not reached in the bevacizumab arm and was 8.3 months in the control arm (HR = 0.51). In contrast, patients with stable disease as best response had a median progression-free survival of about 8 months in either arm. “This tends to suggest that the benefit may be limited to patients who have an objective response,” he added.

The addition of bevacizumab contributed little to the toxicity profile of the regimen. Correlative biomarker studies are ongoing. 

DISCLOSURE: Dr. Shroff has served as a consultant or advisor to AstraZeneca, Basilea, Boehringer Ingelheim, Exelixis, Genentech, Incyte, Merck, QED Therapeutics, Servier, and Taiho Pharmaceutical. Dr. El-Khoueiry reported financial relationships with ABL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol Myers Squibb, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck, QED Therapeutics, Qurient, Roche/Genentech, Senti Biosciences, Servier, Pieris Pharmaceuticals, and Tallac Therapeutics.


1. Shroff RT, Guthrie KA, Scott AJ, et al: SWOG 1815: A phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers. 2023 ASCO GI Cancers Symposium. Abstract LBA490. Presented January 20, 2023.

2. El-Khoueiry AB, Ren Z, Chon H, et al: IMbrave151: A phase 2 randomized, double-blind, placebo-controlled study of atezolizumab with or without bevacizumab in combination with cisplatin plus gemcitabine in patients with untreated, advanced biliary tract cancer. 2023 ASCO GI Cancers Symposium. Abstract 491. Presented January 20, 2023. 

3. Shroff RT, Javle MM, Xiao L, et al: Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: A phase 2 clinical trial. JAMA Oncol 5:824-830, 2019.


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