SWOG S1815 Shows Need for Subgroup-Specific Triplet Chemotherapy Assessment in Biliary Tract Cancer

Signals of efficacy observed with the addition of nab-paclitaxel (Abraxane) to gemcitabine and cisplatin (GAP) in select subgroups of patients with newly diagnosed advanced biliary tract cancers reinforce the biological heterogeneity of these malignancies and highlight the need for further prospective studies to clarify the triplet’s potential role according to disease site and stage, according to Rachna Shroff, MD, MS, FASCO.

However, overall, the phase 3 SWOG S1815 trial (NCT03768414) showed that the GAP regimen did not significantly improve overall survival (OS) or progression-free survival (PFS) compared with gemcitabine plus cisplatin alone, Shroff explained. Findings, which were published in the Journal of Clinical Oncology, showed that the median OS was 14.0 months (95% CI, 12.4-16.1) with the triplet (n = 294) vs 13.6 months (95% CI, 9.7-16.6) with gemcitabine plus cisplatin alone (n = 147; HR, 0.91; 95% CI, 0.72-1.14; P = .41).1 The median PFS was 7.5 months (95% CI, 6.4-8.5) vs 6.3 months (95% CI, 4.4-8.2) with these respective regimens (HR, 0.89; 95% CI, 0.71-1.12; P = .32).

Subgroup analyses revealed that, among patients with gallbladder cancer, the median OS was 17.0 months (95% CI, 11.3-20.7) vs 9.3 months (95% CI, 7.0-22.2) with the triplet vs gemcitabine plus cisplatin alone, respectively. Similarly, in patients with locally advanced disease, the median OS was 19.2 months (95% CI, 16.3-24.3) vs 13.7 months (95% CI, 8.8-21.8) respectively.

“These were potential signals saying that perhaps patients with gallbladder cancer or locally advanced disease may benefit from the triplet regimen,” said Shroff in an interview with OncLive®. “[However], this needs to be prospectively evaluated with larger numbers to power and answer that question.”

In the interview, Shroff discussed the rationale for adding nab-paclitaxel to gemcitabine plus cisplatin in advanced biliary tract cancers based on prior phase 2 data, highlighted key updated efficacy and safety data from SWOG S1815, and emphasized the need for further research to identify patients who may benefit from this treatment approach.

Shroff is the interim clinical affairs director, the associate director of Clinical Investigations, and co-leader of the Gastrointestinal Clinical Research Team at The University of Arizona Cancer Center in Tucson. She is also a professor in the Department of Medicine, chief of the Division of Hematology/Oncology, medical director for the Oncology Service Line, and associate dean for Clinical and Translational Research at The University of Arizona College of Medicine—Tucson.

OncLive: What are some of the current frontline treatment challenges for patients with advanced biliary tract cancers, particularly with S gemcitabine plus cisplatin?

Shroff: Gemcitabine plus cisplatin has been the standard of care [SOC] for newly diagnosed biliary tract cancers since 2010. [However,] in the pivotal phase 2 ABC-02 study [NCT00262769] evaluating that combination [in patients with locally advanced or metastatic biliary tract cancers], the median OS was [11.7 months],2 which leaves something to be desired in the treatment of newly diagnosed patients. Biliary tract cancers are a heterogeneous group that includes intrahepatic and extrahepatic cholangiocarcinoma and gallbladder cancer.

Each of these different subtypes has its own complicating components, which also makes frontline treatment a bit more complicated for [these patients]. When SWOG S1815 was designed, gemcitabine plus cisplatin was the SOC. Since then, the treatment paradigm has changed. [Based on research such as] the [phase 3] TOPAZ-1 study [NCT03875235], the addition of immunotherapy—e.g. durvalumab [Imfinzi] or pembrolizumab [Keytruda]—to gemcitabine and cisplatin is now the SOC. However, at the time [of the SWOG S1815 trial design], we were trying to see how we could build upon the gemcitabine and cisplatin backbone to improve outcomes for these patients.

What was the rationale for investigating the cytotoxic chemotherapy triplet regimen of nab-paclitaxel plus gemcitabine and cisplatin in advanced biliary cancers?

The rationale for adding nab-paclitaxel [to gemcitabine and cisplatin] was [based on our] theoretical understanding of the way the delivery of the taxane may work. We know a lot of that [mechanism] from our work in pancreatic cancer in terms of its stromal modulation and enhancement of the delivery of additional chemotherapeutic agents. SWOG S1815 was [informed by] a single-arm phase 2 trial [NCT02392637] that was published in JAMA Oncology that treated 60 patients with a triplet regimen [consisting of] gemcitabine and cisplatin plus nab-paclitaxel.3 In that study, the median OS and PFS were improved [with the triplet] compared with historical controls. That provided the signal for [further evaluation] of this [regimen] in a more randomized and prospective fashion.

There were concerns about additive toxicity with a third chemotherapy agent. Thankfully, the phase 2 study helped us identify potential dose adjustments that could be made to the triplet regimen. We identified the ideal dosing that mitigated some of [associated] hematologic toxicities, and that was the dosing that we carried forward into the phase 3 study.

How was the SWOG S1815 trial designed, and why is it significant for the treatment paradigm of advanced biliary tract cancer in the United States?

This was the first randomized phase 3 trial in advanced biliary tract cancer done in the United States [US]. This study rapidly enrolled, even for a National Cancer Institute– and SWOG–sponsored study. This study accrued in less than 2 years, which shows the need for frontline trials for these patients and their desire to be part of moving the needle forward.

The study [enrolled] 441 patients, and they were randomly assigned in a 2:1 fashion to the investigational arm [or control arm.]1 The primary end point was OS. This study included patients with locally advanced and metastatic disease, and that was one of the stratification factors. [Patients were also] specifically stratified by primary tumor [based on] whether they had intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer. Approximately two-thirds of the patients enrolled had intrahepatic cholangiocarcinoma, and there was a relatively even split between [the numbers of patients with] gallbladder cancer and extrahepatic cholangiocarcinoma. This is reflective of what we see in the US in terms of the types of biliary tract cancers we treat.

What key efficacy findings were reported from SWOG S1815?

The median OS was 14.0 months with GAP vs 13.6 months in the gemcitabine/cisplatin arm alone, with a HR of 0.91. This was not a statistically significant improvement in median OS [with GAP], though [the OS] was numerically improved. Importantly, the [OS rate in the] gemcitabine/cisplatin alone arm was better than that seen in the ABC-02 study. The median PFS was also similar between the 2 groups. It was 7.5 months with GAP and 6.3 months for gemcitabine plus cisplatin alone, with an HR of 0.89, which was not statistically significant.

Another key [outcome we evaluated was] overall response rate [ORR]. Response is a meaningful outcome in biliary tract cancers, especially to try to preserve liver function, etc., especially in intrahepatic cholangiocarcinoma. The ORR was higher with GAP, at 31% vs 21% in the gemcitabine/cisplatin alone arm. The P value was .03, so that was statistically significant. In patients who received GAP, the disease control rate was also statistically significantly higher, at 78% vs 67% with gemcitabine plus cisplatin alone.

The stratification factors were interesting. Although there was not a statistically significant improvement in median OS [with GAP vs gemcitabine plus cisplatin alone in the overall population], when we started to break things down and [evaluate the population] by disease site and disease stage, interesting signals emerged. These are exploratory, and [the study was] not powered to detect meaningful differences [in these groups]. The median OS with GAP in patients with gallbladder cancer was 17.0 months vs 9.3 months with gemcitabine plus cisplatin. Similarly, we saw a slight difference in median OS in patients with locally advanced disease who received GAP, at 19.2 months vs 13.7 months in those who received gemcitabine plus cisplatin alone.

What should be known about the safety profile of this cytotoxic chemotherapy regimen?

Not surprisingly, the addition of a third chemotherapy agent does add to toxicity. Most patients were eligible to be evaluated from a safety perspective. There was a higher number of patients who had grade 3 or higher treatment-related hematologic adverse effects [AEs] in the GAP arm, at 60% vs 45% in the gemcitabine/cisplatin alone arm. Nonhematologic AEs were more frequent with GAP vs gemcitabine plus cisplatin alone. However, a lot of these [AEs] were not necessarily surprising, regarding what we see with gemcitabine plus cisplatin alone.

The GAP arm also had significantly higher rates of dose modification compared with the gemcitabine/cisplatin alone arm. [A total of] 88% of patients required dose modification in the GAP arm vs 78% of those in the gemcitabine/cisplatin alone arm. However, in general, the treatment discontinuation rates were not different [between the arms]. Although more patients required dose modifications [with GAP vs gemcitabine plus cisplatin alone], a relatively equal number of patients between the arms discontinued [treatment] because of toxicity.

What subsequent research needs to be conducted to clarify which patient populations could benefit the most from this triplet?

That’s an important question and one that is worthwhile to ask. Grouping all patients with biliary tract cancer together is probably not the best way to move the needle in this disease. Gallbladder cancer is different than cholangiocarcinoma. Patients with locally advanced disease are different [than those with] metastatic [disease]. Evaluating some of these subsets and understanding the role that GAP could play will be important, specifically [for patients with] locally advanced disease.

In the phase 2 trial [investigating this triplet], a significant percentage of patients were downstaged from unresectable to resectable disease. There could be utility for a GAP-type regimen [as part of] a neoadjuvant approach to see if we can downstage or convert patients who have locally advanced disease with a high response rate to a potentially curative surgery, for instance. This study leads to those kinds of provocative questions, which we would need to prospectively ask.

We also have a prospectively collected set of biospecimens from this study. We collected archival tissue, and we collected blood sequentially. This is the largest biospecimen repository of biliary cancers in the US. We’re starting to think through the important questions and see whether we can use that biospecimen repository to identify subsets of patients that may benefit from the GAP regimen over gemcitabine and cisplatin plus immunotherapy.

What is your main message for colleagues regarding the future implications of this research?

The addition of nab-paclitaxel to gemcitabine plus cisplatin did not significantly improve median OS in patients with newly diagnosed, advanced biliary tract cancers; in fact, there may be added toxicities [associated with] using a triplet chemotherapy regimen. However, a lot of questions are left unanswered and would be worthwhile to study in the future. The rapidity with which this study opened and accrued speaks to the need for more large, randomized phase 3 trials in biliary cancers in this country so we can continue to move the needle.

References

1. 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
2. Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362(14):1273-81. doi:10.1056/NEJMoa0908721
3. Shroff RT, Javle MM, Xiao L, et al. Gemcitabine, cisplatin, and nab-paclitaxel for the treatment of advanced biliary tract cancers: a phase 2 clinical trial. JAMA Oncol. 2019;5(6):824-830. doi:10.1001/jamaoncol.2019.0270