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Nab-paclitaxel plus gemcitabine-cisplatin extends survival in patients with biliary tract cancers
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The addition of nanoparticle albumin-bound (nab)-paclitaxel to standard gemcitabine-cisplatin therapy improved median PFS and OS among patients with advanced biliary tract cancers compared with data from historical controls, according to results from a phase 2 trial published in JAMA Oncology.
“Preclinical study data suggest that nab-paclitaxel enhances gemcitabine delivery to pancreatic tumors by depleting the surrounding stroma. This raises the possibility of similar effects in other stroma-rich cancers, including [biliary tract cancers],” Rachna T. Shroff, MS, MD, section chief of gastrointestinal medical oncology, chair of the data and safety monitoring board, and associate professor at University of Arizona College of Medicine-Tucson, and colleagues wrote. “A phase 1/2 trial reported a high response rate with gemcitabine-cisplatin plus nab-paclitaxel administration in advanced pancreatic cancer, and several small studies have shown some activity of taxanes in newly diagnosed and refractory [advanced biliary tract cancers].”
In the open-label, single-arm, phase 2 trial conducted at The University of Texas MD Anderson Cancer Center and the Mayo Clinic in Phoenix, Shroff and colleagues evaluated 60 patients (mean age, 58.4 years; 55% men) with advanced biliary cancers.
Thirty-eight patients (63%) had intrahepatic cholangiocarcinoma, 13 (22%) had gallbladder cancer, nine (15%) had extrahepatic cholangiocarcinoma, 47 (78%) had metastatic disease and 13 (22%) had local progression.
The first 32 patients enrolled received starting doses of 1,000 mg/m2 gemcitabine , 25 mg/m2 cisplatin and 125 mg/m2 nab-paclitaxel on days 1 and 8 of 21-day cycles. However, grade 3 to grade 4 hematologic adverse events among these patients prompted researchers to reduce the starting doses to 800 mg/m2 gemcitabine, 25 mg/m2 cisplatin and 100 mg/m2 nab-paclitaxel, for the other 28 study participants.
Investigator-evaluated PFS in the intention-to-treat population served as the study’s primary endpoint. Complete plus partial response, disease control, rates of adverse events and OS served as secondary endpoints.
Researchers followed patients for a median of 12.2 months (95% CI, 9.4-19.4).
Results showed median PFS of 11.8 months (95% CI, 6-15.6), with a 12-month PFS rate of 45% (95% CI, 30-60). Median OS was 19.2 months (95% CI, 13.2 to not estimable), with a 12-month OS rate of 66% (95% Ci, 51-78).
The partial response rate was 45% and the rate of disease control was 84%.
These outcomes appear favorable compared with those of historical populations treated with first-line gemcitabine-cisplatin, for whom median PFS was 8 months and median OS 11.7 months, according to the researchers.
Patients in the safety analysis (n = 57) underwent a median of six (interquartile range, 3-11) treatment cycles. Twenty-six patients (46%) maintained their starting doses throughout the trial.
Thirty-three patients (58%) experienced grade 3 or higher adverse events, and nine patients (16%) discontinued the study due to adverse events.
The most prevalent grade 3 or higher adverse event was neutropenia, which occurred in 33% of patients in the safety analyses, including 10 patients in the high-dose group and nine in the reduced-dose group.
Researchers observed no significant correlation between treatment efficacy and starting dose, tumor type or disease status. Reduced-dose treatment did not improve tolerability compared with high-dose therapy.
Study limitations included its lack of a randomized, controlled design and relatively low number of patients, as well as the fact that it was not powered to identify PFS improvements in the biliary tract cancer subtypes.
The current study represents a key step toward the development of new treatment options for patients with biliary tract cancers, Laura W. Goff, MS, MD, associate professor of medicine and associate director of the hematology/oncology fellowship program at Vanderbilt University Cancer Center, and Mark T. Roth, MD, resident at the department of internal medicine at Vanderbilt-Ingram Cancer Center, wrote in a related editorial
“Caution should be exercised, however, when attempting to extrapolate results from early-stage clinical trials for use in clinical practice until they are verified in larger, randomized trials,” the authors wrote. “Historically, larger trials in biliary tract cancer ... have been thought too difficult to execute due to their relative rarity. However, several recent trials in biliary cancers through the National Cancer Institute have enrolled very quickly, setting the stage for SWOG 1815, which compares this triplet regimen to standard gemcitabine and cisplatin treatment.” – by Jennifer Byrne
Disclosures: Shroff reports grants, personal fees or nonfinancial support from Agios Pharmaceuticals, Celgene, Codiak Biosciences, Eli Lilly, Exelixis, Halozyme Therapeutics, Merck and Seattle Genetics. Please see the study for all other authors’ relevant financial disclosures. Goff reports grants or personal fees from Agios Pharmaceuticals, ArQule, Asian Pharmaceuticals, Astellas Pharma, Basilea Pharmaceuticals, Bayer/Onyx, BeiGene, Bristol-Myers Squibb, Competitive Drug Development International, Eisai, Eli Lilly, H3Biomedicine, Incyte, Leap Therapeutics, Newlink Genetics and Sun Pharma. Roth reports no relevant disclosures.
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Roth MT and Goff LW. JAMA Oncology. 2019;doi:10.1001/jamaoncol.2019.0269.
Shroff RT, et al. JAMA Oncology.2019;doi:10.1001/jamaoncol.2019.0270.
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