Nab-Paclitaxel Plus SOC Chemo Fails to Improve OS in Newly Diagnosed Advanced Biliary Tract Cancer

The addition of nab-paclitaxel (Abraxane) to gemcitabine and cisplatin did not produce a statistically significant difference in overall survival (OS) and progression-free survival (PFS) outcomes vs gemcitabine plus cisplatin alone in patients with newly diagnosed advanced biliary tract cancer, according to findings from the phase 3 SWOG S1815 phase 3 trial (NCT03768414).

Findings published in the Journal of Clinical Oncology showed that the median OS was 14.0 months (95% CI, 12.4-16.1) for patients receiving nab-paclitaxel plus gemcitabine and cisplatin (n = 294) compared with 13.6 months (95% CI, 9.7-16.6) for those treated with gemcitabine plus cisplatin (n = 147; HR, 0.91; 95% CI, 0.72-1.14; P = .41). The OS rates at 12 months were 56% for nab-paclitaxel, gemcitabine, and cisplatin vs 53% for gemcitabine and cisplatin; at 24 months, these rates were 25% and 28%, respectively.

The median PFS was 7.5 months (95% CI, 6.4-8.5) for nab-paclitaxel, gemcitabine, and cisplatin vs 6.3 months (95% CI, 4.4-8.2) for gemcitabine and cisplatin (HR, 0.89; 95% CI, 0.71-1.12; P = .32).

“Triplet cytotoxic therapy with gemcitabine, nab-paclitaxel, and cisplatin did not improve OS compared with gemcitabine and cisplatin in newly diagnosed patients with advanced biliary tract cancer,” lead study author Rachna T Shroff, MD, MS, FASCO, and colleagues, wrote in a publication of the data. “Acknowledging the heterogeneous biology of biliary malignancies, there is a need for rational genomic, transcriptomic, and artificial intelligence tools to not only select patients for targeted molecular and immune therapies, but also to guide targeted cytotoxic chemotherapies in future clinical trials.”

Shroff is a professor in the College of Medicine, interim clinical affairs director, associate director of clinical investigations, and chief of the Division of Hematology/Oncology at the University of Arizona Cancer Center in Tuscon.

Trial Background and Design

SWOG S1815 was a randomized, open-label trial conducted within the SWOG Cancer Research Network with participation from 151 sites. Patients were eligible for enrollment if they had histologically or cytologically confirmed locally advanced or metastatic intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer. Prior systemic therapy in the locally advanced or metastatic setting was not permitted; prior adjuvant therapy was allowed if completed at least 6 months prior to enrollment. Other key inclusion criteria consisted of a Zubrod performance status of 0 or 1; and adequate hematologic, hepatic, and renal function. A history of grade 2 or higher peripheral neuropathy and active infections requiring systemic therapy excluded patients from enrollment.

Patients were randomly assigned in a 2:1 ratio to receive nab-paclitaxel plus gemcitabine and cisplatin or gemcitabine plus cisplatin alone. Stratification factors included disease site (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer), disease stage (locally advanced vs metastatic), and Zubrod performance status (0 vs 1).

Patients in the experimental arm received nab-paclitaxel at 100 mg/m², gemcitabine at 800 mg/m², and cisplatin at 25 mg/m² on days 1 and 8 of a 21-day cycle. Those in the control arm received gemcitabine at 1000 mg/m² and cisplatin at 25 mg/m² on the same schedule. Treatment continued until disease progression, unacceptable toxicity, or patient withdrawal. Granulocyte colony–stimulating factor use was permitted per ASCO and NCCN guidelines to mitigate hematologic toxicities.

The primary end point was OS. Secondary end points included PFS, overall response rate (ORR), disease control rate (DCR), and safety.

Baseline Characteristics

Patients enrolled in the trial had a median age of 63.2 years (range, 23.2-88.8) in the nab-paclitaxel, gemcitabine, and cisplatin arm vs 63.9 years (range, 23.2-83.6) in the gemcitabine and cisplatin arm. Forty-five percent of patients in both arms were male, and the majority (experimental, 83%; control, 81%) were White. Ten percent of patients in both arms were of Hispanic ethnicity.

Most patients had metastatic disease at baseline (experimental, 74%; control, 72%) and had a Zubrod performance status of 0 (50%; 51%).

Intrahepatic cholangiocarcinoma was the most common histology at 67% of patients in both arms. Gallbladder cancer and extrahepatic cholangiocarcinoma (ECC) affected16% and 17% of patients in the nab-paclitaxel, gemcitabine, and cisplatin arm, respectively; these rates were both 16% in the gemcitabine and cisplatin arm.

All enrolled patients received at least 1 dose of their assigned treatment regimen and were included in the efficacy and safety analyses.

Response and Additional Efficacy Data

Subgroup analyses showed that patients with gallbladder cancer experienced a median PFS of 9.3 months (95% CI, 6.0-12.5) with nab-paclitaxel, gemcitabine, and cisplatin compared with 4.1 months (95% CI, 2.8-6.2) with gemcitabine and cisplatin (P = .01); however, this benefit did not translate to an OS benefit in this subgroup (P = .28).

Among patients with locally advanced disease, numerical but not statistically significant improvements were observed with the experimental regimen for OS (P = .14) and PFS (P = .17).

Among the 290 evaluable patients with measurable disease treated with nab-paclitaxel, gemcitabine, and cisplatin, 6 achieved a complete responses (CR), and 85 had a partial responses (PR). The gemcitabine and cisplatin arm included 146 evaluable patients with measurable disease; 1 achieved a CR and 30 had a PR.

The ORR was 31% in the experimental arm compared with 21% in the control cohort (P = .03). The DCR was 78% vs 67%, respectively (P = .03).

Baseline and post-cycle 3 CA19-9 levels were available for 339 of 441 patients with measurable disease. One participant lacked baseline CA19-9 data, and 96 had missing post-treatment CA19-9 levels.

In an analysis of changes in post-treatment CA19-9 levels, data showed the median change in CA19-9 levels was –12 U/mL (interquartile range [IQR], ±292.31) in the nab-paclitaxel, gemcitabine, and cisplatin arm compared with –3 U/mL (IQR, ±138.38) in the gemcitabine and cisplatin arm (P = .63).

An increase in CA19-9 levels was not significantly associated with ORR in either arm. However, the relationship varied across treatment groups. However, an increase in CA19-9 levels was associated with lower chance of a response in the experimental arm, whereas no significant association was observed in the gemcitabine and cisplatin arm (P = .09).

Safety Considerations

The safety profile of the nab-paclitaxel, gemcitabine, and cisplatin demonstrated a higher incidence of grade 3/4 treatment-related adverse effects compared with gemcitabine and cisplatin. Grade 3 or higher hematologic treatment-related adverse effects were observed in 60% of patients in the gemcitabine, cisplatin, and nab-paclitaxel arm versus 45% in the gemcitabine and cisplatin arm (P = .003).

The most frequently reported hematologic treatment-related adverse effects included anemia, neutropenia, and thrombocytopenia.

Non-hematologic grade 3 or higher treatment-related adverse effects occurred more frequently in the gemcitabine, cisplatin, and nab-paclitaxel arm. Commonly observed effects included elevated ALT, anorexia, constipation, diarrhea, fatigue, hypomagnesemia, nausea, sepsis, sensory peripheral neuropathy, and vomiting.

Seven treatment-related deaths were reported in the gemcitabine, cisplatin, and nab-paclitaxel arm. Causes of death included cardiac arrest, sepsis (n = 3), superior vena cava syndrome, thromboembolic event, and upper gastrointestinal hemorrhage. In contrast, only one grade 5 event occurred in the gemcitabine and cisplatin arm, attributed to progressive disease with potential contribution from cisplatin.

Dose modifications were more frequent in the gemcitabine, cisplatin, and nab-paclitaxel arm, with 88% of participants requiring adjustments compared with 78% in the gemcitabine and cisplatin arm (P = .008). Rates of treatment discontinuation due to toxicity were comparable between the two regimens, occurring in 24% of gemcitabine, cisplatin, and nab-paclitaxel–treated patients and 19% of gemcitabine and cisplatin–treated patients (P = .20).

The study authors emphasized that although gemcitabine, cisplatin, and nab-paclitaxel regimen demonstrates an increased toxicity profile relative to gemcitabine and cisplatin, the findings aligned with the intensified therapeutic approach. They highlighted the need for careful monitoring and patient selection to mitigate the risks associated with this treatment strategy.

“Further studies are warranted to refine the use of gemcitabine, cisplatin, and nab-paclitaxel and identify biomarkers to predict patients most likely to benefit from this intensified treatment regimen,” the authors concluded.

Reference

Shroff RT, King G, Colby S, et al. SWOG S1815: a phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers. J Clin Oncol. Published online December 13, 2024. doi:10.1200/JCO-24-01383