Second-line chemotherapy regimen improves OS in biliary tract cancer

CHICAGO —Modified FOLFOX chemotherapy plus active symptom control improved OS compared with active symptom control alone among patients with locally advanced or metastatic biliary tract cancer who were previously treated with cisplatin plus gemcitabine, according to results of the ABC-06 trial.

It is the first prospective phase 3 trial to examine the value of chemotherapy after progression on cisplatin plus gemcitabine in this patient population, researchers reported.

“The ABC-02 clinical trial provided level A evidence supporting the use of cisplatin and gemcitabine in the first-line setting for advanced biliary tract cancer,” Angela Lamarca, MD, PhD, MSc, medical oncology consultant for the Christie NHS Foundation Trust and oncologist at the University of Manchester, said during a presentation at the ASCO Annual Meeting. “Unfortunately, the role of second-line chemotherapy remains unclear, with no prospective clinical trials in this setting.”

Biliary tract cancer is rare, accounting for less than 1% of all cancers, according to Lamarca, and the prognosis of patients with biliary tract cancer is poor. Most patients (80%) are diagnosed with advanced disease. The combined 5-year OS rate for all stages is less than 20%.

To address the lack of data on second-line treatment, Lamarca and colleagues compared the safety and efficacy of modified FOLFOX chemotherapy plus active symptom control (ASC) vs. ASC alone in 162 patients from the United Kingdom with advanced or metastatic biliary tract cancer whose disease progressed despite first-line treatment with cisplatin plus gemcitabine.

ASC consisted of early detection and treatment of biliary-related complications during four weekly clinical reviews, according to Lamarca. Patients assigned to modified FOLFOX plus ASC received the chemotherapy regimen every 2 weeks for up to 12 cycles. There were 81 patients in each arm.

All patients were followed until 1 year after enrollment completion or death. The maximum duration between progression on first-line treatment and trial randomization was 6 weeks. All patients were required to have an acceptable hematological, renal and hepatic function.

The primary endpoint was OS. The survival analysis was stratified by platinum sensitivity, serum albumin (less than 35 g/L vs. greater than or equal to 35 g/L) and disease stage (locally advanced vs. metastatic disease). Secondary endpoints included safety, PFS, radiological response, quality of life, health economics and translational research.

During the trial, nine patients assigned to ASC alone received off-study chemotherapy and six patients assigned to ASC plus modified FOLFOX did not receive the chemotherapy regimen. However, because the study was designed as an intention-to-treat analysis, these patients were included in the final results.

Baseline characteristics, including gender, age, serum albumin, disease stage, tumor site, histology and grade of differentiation, were well-balanced between the treatment arms, according to Lamarca. However, there were slightly more patients with platinum-resistant disease or refractory disease in the ASC plus chemotherapy arm (67% vs. 58% in ASC alone arm).

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The primary endpoint of OS was significantly higher among patients who received modified FOLFOX (adjusted HR = 0.69; 95% CI, 0.50-0.97). Lamarca reported a “modest” difference in median OS, which was 6.2 months among patients who received modified FOLFOX plus ASC and 5.3 months among those who received ASC alone. There was a greater “clinically meaningful” difference in OS at 6 months (50.6% in the modified FOLFOX plus ASC arm vs. 35.5% in the ASC alone arm). The improvement in OS was maintained at 12 months, with a 12-month OS rate of 25.9% in the modified FOLFOX plus ASC arm and 11.4% in the ASC alone arm.

The benefit of modified FOLFOX was consistent across various subgroups, including those with a suspected poorer prognosis, such as patients with platinum-resistant or refractory disease (HR = 0.63; 95% CI, 0.41-0.96), patients with low albumin (HR = 0.84; 95% CI, 0.58-1.23) and patients with metastatic disease (HR = 0.70; 95% CI, 0.48-1).

In other results, patients in the modified FOLFOX plus ASC arm had a median radiological PFS of 4 months (95% CI, 3.2-5). One patient (1%) achieved a complete response, three patients (4%) achieved a partial response and 23 patients (28%) achieved stable disease by the end of the follow-up period. The overall disease control rate was 33%.

Forty percent of patients who received ASC alone and 59% who received modified FOLFOX plus ASC experienced grade 3 or 4 adverse events, regardless of causality. In the modified FOLFOX plus ASC arm, there were more reports of fatigue/lethargy (19% vs. 7%), neutropenia (12% vs. 0%), infection (14% vs. 1%) and catheter-related infections (4% vs. 0%). Meanwhile, in the ASC alone arm, there were more reports of anorexia (7% vs. 1%) and thromboembolic events (5% vs. 0%). Other adverse events, including biliary-related events, were similar between the treatment arms.

Three chemotherapy-related deaths were reported. One death was caused by renal failure in a patient who developed diabetic ketoacidosis. A second death was caused by febrile neutropenia, and a third death was caused by an acute kidney injury.

Analyses investigating quality of life, health economics and translational research, which is focusing on DNA damage repair and molecular profiling, are ongoing, Lamarca said. Still, she concluded that modified FOLFOX plus ASC should “become the standard of care in the second-line setting for patients with advanced biliary tract cancer.” – by Stephanie Viguers

Reference:

Lamarca A, et al. Abstract 4003. Presented at: ASCO Annual Meeting; May 31- June 4, 2019; Chicago.

Disclosures: Lamarca reports receiving honoraria from Eisai and Nutricia, research funding from Ipsen, and travel/accommodations/expenses from Abbott Nutrition, Advanced Accelerator Applications, Bayer, Celgene, Delcath Systems, Ipsen, Mylan, Novartis, Pfizer and Sirtex Medical. She also reports serving on the speakers’ bureau for Ipsen, Merck and Pfizer. Please see the abstract for all other authors’ relevant financial disclosures.