Adding nab-paclitaxel (Abraxane, Celgene) to the combination of gemcitabine-cisplatin may prolong survival for patients with advanced biliary tract cancers (BTCs) compared to use of gemcitabine-cisplatin alone, results from a phase 2 trial suggest.
The study, led by Rachna Shroff, MD, University of Arizona Cancer Center, Tucson, was published online April 18 in JAMA Oncology.
However, in an accompanying commentary, Marc Roth, MD, and Laura Goff, MD, Vanderbilt University, Nashville, Tennessee, urge caution in interpreting the admittedly "promising" results until those results are confirmed in a phase 3 trial that is now underway.
Because overall survival (OS) for patients treated with the current gold standard, gemcitabine-cisplatin alone, is less than 1 year, the editorialists note that patients are desperate for better options.
Nevertheless, Roth told Medscape Medical News that physicians and patients should realize that the trial was small and that long-term benefit relative to current therapy is not clear.
"There's a big difference between phase 2 and phase 3 clinical trials in making sure you're powered to find the appropriate outcome," Roth noted.
The smaller phase 2 trial is more concerned with dosing and toxicity than efficacy, he pointed out.
BTCs are rare — about 6000 cases are diagnosed in the United States each year — and outcomes are typically poor because the aggressive cancers are often discovered only in late stages.
The phase 3 trial, which began accruing patients in February, is the first randomized phase 3 study in the United States for biliary cancer.
Increased PFS and OS
In the trial of 60 patients who started treatment, the researchers found that adding nab-paclitaxel to gemcitabine-cisplatin resulted in median progression-free survival (PFS) of 11.8 months (95% confidence interval [CI], 6.0 – 15.6) and median OS of 19.2 months (95% CI, 13.2 months to not estimable) in an intention-to-treat analysis.
Historically, for patients with advanced BTCs who had undergone standard treatment, the median PFS was 8 months and the median OS was 11.7 months.
"It's been about 9 years that we've been using gemcitabine and cisplatin as the backbone for newly diagnosed biliary tract malignancies," Arizona's Shroff told Medscape Medical News. She added that although other phase 2 studies have tested other combinations, "there is no phase 3 randomized study that has demonstrated superiority to gemcitabine and cisplatin thus far."
Of the 60 patients, 38 (63%) had intrahepatic cholangiocarcinoma; nine (15%) had extrahepatic cholangiocarcinoma; and 13 (22%) had gallbladder cancer. Most (47 patients [78%]) had metastatic disease, and 13 (22%) had locally advanced disease. The average age was 58.4 years.
The open-label, single-arm trial was conducted at the University of Texas MD Anderson Cancer Center, Houston, and the Mayo Clinic, Phoenix, Arizona.
"Unexpected, Fantastic" Finding
Initially, patients received gemcitabine 1000 mg/m2, cisplatin 25 mg/m2, and nab-paclitaxel 125 mg/m2 on days 1 and 8 of 21-day cycles. However, because the first 32 patients who were enrolled experienced hematologic adverse events, doses were reduced to 800, 25, and 100 mg/m2, respectively, in 28 patients.
The partial response rate was 45%, and the disease control rate was 84%.
Adverse events (AEs) of grade 3 or higher occurred in 58% of patients, and nine patients (16%) withdrew from the study because of them. Neutropenia was the most common severe AE, experienced by 19 patients (33%).
Shroff said most severe AEs were seen among those who received the original higher doses. The lower doses will be used for the phase 3 trial.
She added that for 12 of the 60 patients with unresectable biliary cancer, the cancers improved so as to become resectable. Those patients left the study not because of toxicity or disease progression but to undergo curative resections.
That "was a completely unexpected but fantastic finding — 20% of patients underwent curative treatment as a result of a fantastic response to the triplet regimen," she said. "Because of that, they're investigating the triplet regimen in the neoadjuvant preoperative setting for intrahepatic cholangiocarcinoma based on these data."
The added months of survival that the early results suggest are invaluable to patients, Shroff said.
"We had patients on these studies who were looking for milestones, trying to make it to their daughter's wedding or the birth of a grandchild. That impact of 8 months of additional time is profound," she said.
Shroff said they decided to test nab-paclitaxel because it was very active in pancreatic cancer, which, like BTCs, is characterized by a dense stroma of cells that protects the tumor from chemotherapy.
"Nab-paclitaxel seems to diminish that stroma," she said.
Trial Limitations
The study authors caution that in addition to lack of randomization and controls and a small number of patients, the trial was not powered to detect improvement in PFS in BTC subtypes compared with historical controls. Also, median follow-up and duration of treatment exposure differed for the two dose groups, and the percentage of patients with intrahepatic cholangiocarcinomas was large, at 63%.
Still, editorialist Roth praised the authors for coordinating the phase 2 and now a phase 3 randomized controlled trial. In the past, gathering enough patients for such trials has been difficult because these cancers are so rare.
He noted that for other malignancies, immunotherapies and small-molecule inhibitors are increasingly being used, whereas for BTCs, treatments are still based on systemic chemotherapy, and improvements there are critical.
The phase 3 randomized clinical trial will compare gemcitabine-cisplatin plus nab-paclitaxel with gemcitabine-cisplatin, which will serve as a control arm.
The National Cancer Institute is collaborating with the Southwest Oncology Group on the phase 3 trial. Patients nationally will likely have access to nearby trial sites in a wide variety of settings, Shroff said.
The study was supported by Celgene. Shroff reports financial ties to Celgene, Halozyme Therapeutics, Agios Pharmaceuticals, Eli Lilly, Seattle Genetics, Exelixis, Merck, and Codiak Biosciences. Coauthors also report ties to pharmaceutical companies, including Celgene. Goff has financial ties to multiple pharmaceutical companies.
JAMA Oncol. Published online April 18, 2019. Abstract, Commentary
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