SWOG 1815 Biomarker Analyses May Identify Biliary Tract Cancer Subsets Who Could Benefit From Nab-Paclitaxel Triplet

Although the addition of nab-paclitaxel (Abraxane) to gemcitabine/cisplatin failed to significantly improve overall survival (OS) vs gemcitabine/cisplatin alone in patients with newly diagnosed, advanced biliary tract cancers enrolled to the phase 3 SWOG 1815 trial (NCT03768414), a signal was observed in select subsets that warrants further investigation, according to Rachna T. Shroff, MD, MS.

Data from the trial, presented at the 2023 Gastrointestinal Cancers Symposium, showed that nab-paclitaxel plus gemcitabine and cisplatin (n = 294) resulted in a median OS was 14.0 months (90% CI, 12.6-16.3) vs 12.7 months (90% CI, 9.5-16.6) with the doublet (n = 147; P = .65).

Although the numbers were small, a subset of patients with gallbladder adenocarcinoma who received the triplet (n = 46) did demonstrate a trend toward improved OS vs those who received the doublet (n = 24), at 17.0 months (90% CI, 11.3-20.7) and 9.3 months (90% CI, 7.0-22.2), respectively. A similar signal was seen in those with locally advanced disease who received the triplet (n = 77) vs the doublet (n = 41), at 19.2 months and 13.7 months, respectively.

“[SWOG 1815] shows us that we should and could [conduct] trials in this disease, and that we can do it in a meaningful way [to] hopefully improve patient outcomes,” Shroff, the lead study author of the trial, said in an interview with OncLive^®. “…It was not a positive study, but I do believe that further exploration [is warranted]. As we do biomarker analyses and investigate some of these subsets, perhaps [we will find] a patient population that could benefit from gemcitabine, cisplatin, and nab-paclitaxel. We just need to [understand whether] this is the case and who [these patients are].”

In the interview, Shroff expanded on the rationale for evaluating the addition of nab-paclitaxel to gemcitabine/cisplatin in patients with newly diagnosed biliary tract cancers, data presented from SWOG 1815, and how this study may pave the way for future research efforts in the paradigm.

Shroff is an associate professor of Medicine, interim chief of the Division of Hematology/Oncology, leader of the Gastrointestinal Clinical Research Team, medical director of the Clinical Trials Office and of Arizona Clinical Trials Network, associate director of clinical investigations in the Clinical and Translational Oncology Program, and chief of the Section of GI Medical Oncology, at the University of Arizona Cancer Center, Tucson, AZ.

OncLive^®: What was the rationale for comparing gemcitabine, cisplatin, and nab-paclitaxel with gemcitabine and cisplatin alone in patients with newly diagnosed biliary tract cancers?

Shroff:The concept of SWOG 1815 was born out of a single-arm phase 2 trial [NCT02392637] that involved 60 patients between MD Anderson Cancer Center and Mayo [Clinic] Arizona. [The trial] looked at the triplet regimen [of] gemcitabine, cisplatin, and nab-paclitaxel in [patients with] newly diagnosed biliary tract cancer and [showed] some promising signals of efficacy, with a median OS of 19.2 months. We felt it was important to compare [this triplet] to a control [regimen] of gemcitabine and cisplatin to [understand] the added value of nab-paclitaxel.

Could you expand on the design of the SWOG 1815 trial and the population of patients enrolled?

This study specifically looked at patients with advanced, newly diagnosed biliary tract cancer. These are patients with locally advanced or metastatic disease who had intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer.

[Patients were] randomized 2:1, so 2 patients went onto the triplet arm for every 1 patient who went onto the standard-of-care [arm with] gemcitabine and cisplatin. The regimens were given in a 21-day cycle and patients continued the treatment until disease progression was documented. [The study’s] primary end point [was] OS and [the goal was] to understand the value of adding a third drug [to the gemcitabine/cisplatin backbone]. We wanted to understand [nab-paclitaxel's impact [on] efficacy [in these patients].

What key efficacy data were presented at the meeting?

We [observed] a numerical improvement in median OS from 12.7 months to 14 months [with the addition of nab-paclitaxel vs gemcitabine/cisplatin alone, respectively], but this did not reach statistical significance. Similarly, median progression-free survival was also numerically improved, but not significantly improved. The overall response rate data also show that the triplet regimen had a higher overall response [vs the doublet] at 31% vs 22%, again, not reaching statistical significance.

However, there [were] some interesting signals that we learned based on prespecified stratification factors. For instance, the triplet seems to [show] more efficacy in [those with] gallbladder cancer and [those with] locally advanced [disease]. These were small numbers, but [these findings] could merit further clinical investigation.

What should be taken away from the analysis regarding safety?

[The rate of] grade 3/4 treatment-related adverse effects in the triplet arm were statistically higher [than what was observed in the doublet arm]—especially [with regard to] hematologic toxicity. We saw a lot of anemia, neutropenia, and thrombocytopenia. However, it’s important to point out that the treatment discontinuation rate was not different between the 2 arms. Those of us who have been using the triplet [since] the phase 2 [trial] have figured out the best way to mitigate some of those hematologic toxicities and how to leverage things like growth factor support.

Despite the negative outcome of this study, what did the research bring to the paradigm?

We are absolutely moving the needle in biliary tract cancers, and SWOG 1815 is part of that legacy. One of the most impactful [lessons] from this study is that we can absolutely do a randomized phase 3 trial in a rare disease like biliary tract cancers. We opened [the study] within a National Clinical Trials Network mechanism through the National Cancer Institute and were able to [conduct our research] quickly and meaningfully.

What future avenues for research exist in biliary tract cancer?

[Biliary tract cancer is] the ‘golden child’ of precision oncology. As we better understand different molecular subsets, we’re getting more [drugs] FDA approved [for different] biomarkers. [We have] targeted therapies and even immunotherapies. There’s so much changing in the landscape that it’s hard to keep up with, which is exciting.

Also, there is a lot of work going into understanding newer targets, exploring what else immunotherapy can do and thinking through [how to] improve outcomes [in the] neoadjuvant, adjuvant, or potentially curative [setting with these therapies] to improve outcomes.

What other exciting data were shared at the meeting?

So many great abstracts [were] presented at this year’s meeting. [As] someone who treats pancreatic cancer, I’m particularly excited about data [from the phase 3] NAPOLI 3 [trial (NCT04083235)], as well as the SPOTLIGHT [trial (NCT03504397)]. In general, it’s an exciting meeting, because there are a lot of pivotal data from important trials that have been completed and are reading out.

Editor’s Note: Dr. Shroff has a consulting or advisory role at AstraZeneca, Basilea, Boehringer Ingelheim, Exelexis, Genentech, Incyte, Merck, QED Therapeutics, SERVIER, and Taiho Pharmaceutical; and received research fundings from Bayer, Bristol-Myers Squibb, Exelixis, Faeth Therapeutics, Immunovaccine, Loxo/Lilly, Merck, NGM Biopharmaceuticals, Novocure, Nucana, Pieris Pharmaceuticals, QED Therapeutics, Rafael Pharmaceuticals, Seattle Genetics, and Taiho Pharmaceutical.

Reference

Shroff RT, Guthrie KA, Scott AJ, et al. SWOG 1815: 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. 2023;41(suppl 4):LBA490. doi:10.1200/JCO.2023.41.3_suppl.LBA490