Rachna T. Shroff, MD, on Biliary Tract Cancers: Recent Findings on Use of Gemcitabine, Cisplatin, and Nab-paclitaxel
2023 ASCO Gastrointestinal Cancers Symposium
Rachna T. Shroff, MD, of the University of Arizona Cancer Center, discusses phase III results from the SWOG 1815 study, which compared gemcitabine, cisplatin, and nab-paclitaxel vs gemcitabine and cisplatin in patients with newly diagnosed, advanced biliary tract cancers. Although adding nab-paclitaxel to gemcitabine and cisplatin did not improve median overall survival in this population, exploratory analyses in patients with locally advanced disease or gallbladder cancer suggest potential clinical utility in these settings, which may warrant further evaluation (Abstract LBA490).
Disclaimer: This video transcript has not been proofread or edited and may contain errors.
SWOG 1815 was the first randomized phase three trial in newly diagnosed advanced biliary tract cancers in the United States. It is a study that was designed based on a phase two trial that was initially completed, and with the knowledge that there is a significant need for better therapeutics for newly diagnosed advanced biliary tract cancers. We are seeing more and more of these cancers including extra-hepatic, intra-hepatic cholangiocarcinomas and gallbladder cancer, but currently, Gemcitabine and Cisplatin, even with the addition of immunotherapy, still has a median overall survival of just around 12 months in advanced disease. So we had completed a single-arm phase two study of 60 patients that looked at Gemcitabine, Cisplatin with the addition of NAB-paclitaxel in advanced biliary tract cancer patients, and there we saw some really early promising signs of efficacy with the median overall survival of 19.2 months. So that is what led to the pivotal SWOG 1815 trial, which is a randomized phase three looking at Gemcitabine, Cisplatin and Nab-paclitaxel compared to the standard of care at the time, Gemcitabine and Cisplatin.
This was a study opened through SWOG but opened across the entire NCTN, and so it was truly a herculean effort with accruals across all of the cooperative groups to a total end of 441 patients. Patients were randomized in a 2:1 fashion to the triplet regimen versus the standard of care, and the primary endpoint was overall survival. The study was powered to look for a hazard ratio of 0.7 with an improvement in median overall survival that led to that end of 441 patients. There were some pre-specified stratification factors including disease site, disease stage, and performance status. The study basically showed that the median overall survival with Gemcitabine, Cisplatin, and Nab-paclitaxel was numerically improved at 14 months compared to 12.7 months with Gemcitabine and Cisplatin, but this did not reach statistical significance. Similarly, the median progression-free survival was numerically improved, but also was not statistically significantly different.
The overall response rate was also slightly better with the triplet regimen at 31% versus 22%. And when you look at that broken down by disease site and disease stage, there are some interesting signals that emerge, including a median OS in gallbladder cancer that trends towards better survival and a overall response rate in gallbladder cancer that is double from 22% to 44% with Gem, Cis, Nab-paclitaxel. Similarly, locally advanced patients seem to have a better median OS than the metastatic patients, but again, the numbers were small so it was hard to really detect statistically significant differences there. When we look at the Grade 3-4 toxicities, the triplet regimen, not surprisingly, had more hematologic toxicities, primarily anemia, neutropenia, and thrombocytopenia. And while these were more so in the triplet regimen, the treatment discontinuation rate between the two arms did not vary significantly.
In summary, it really shows that Gemcitabine and Cisplatin with Nab-paclitaxel did not improve overall survival, but there may be some worthwhile exploratory analysis in further investigation that should be done to look at potential subsets including locally advanced patients and/or gallbladder cancer. We also have ongoing biomarker analyses going right now to really see if there are other subsets within molecular profiles of patients that could benefit from the triplet regimen.
Laura A. Dawson, MD, of Canada’s Princess Margaret Cancer Centre, discusses phase III findings from the NRG/RTOG1112 study, which showed that stereotactic body radiation therapy (SBRT) administered prior to sorafenib vs sorafenib alone, improved outcomes in patients with advanced hepatocellular carcinoma. SBRT may become a new standard treatment option for patients with locally advanced disease, especially in the presence of macrovascular invasion (Abstract 489).
Nick Pavlakis, PhD, MBBS, of Australia’s Royal North Shore Hospital, discusses phase III findings from the INTEGRATE IIa study of regorafenib vs placebo in refractory advanced gastroesophageal cancer. The trial provides a platform for the investigation of combination therapy with an immune checkpoint inhibitor, now underway in the INTEGRATE IIb study, which is evaluating regorafenib plus nivolumab compared with standard chemotherapy in patients with this type of cancer who have received two lines of prior therapy (Abstract LBA294).
Filippo Pietrantonio, MD, of Italy’s Istituto Nazionale dei Tumori, discusses phase II results from the INFINITY trial of tremelimumab and durvalumab as neoadjuvant treatment of patients with microsatellite instability–high (MSI) resectable gastric or gastroesophageal junction adenocarcinoma (GAC/GEJAC). These results open the way to investigate nonoperative management in patients with clinical, pathologic, and molecular complete response after T300/D (300 mg of tremelimumab and 1,500 mg every 4 weeks of durvalumab) (Abstract 358).
Richard S. Finn, MD, of the David Geffen School of Medicine at the University of California, Los Angeles, discusses findings from the RATIONALE-301 study, which showed that patients with unresectable hepatocellular carcinoma (HCC) treated with first-line tislelizumab had better health-related quality-of-life outcomes compared with those treated with sorafenib, particularly in terms of fatigue and physical functioning. These results, along with the effects on overall survival, response rate, and a favorable safety profile, support the benefit of tislelizumab as a potential first-line treatment option in this patient population (Abstract 495).
Julien Taïeb, MD, PhD, of Hôpital Européen Georges Pompidou, Université Paris-Cité, discusses the clinical implications of new phase III findings from the SUNLIGHT study, which showed that trifluridine and tipiracil (FTD/TPI) plus bevacizumab resulted in improved outcomes compared with FTD/TPI alone in patients with refractory metastatic colorectal cancer. This three-drug regimen may represent a new standard of care for patients whose cancer has progressed despite two lines of therapy (Abstract 4).