Nab-Paclitaxel Plus Gemcitabine and Cisplatin Fails to Meet OS End Point in BTC
Rachna T. Shroff, MD, MS, FASCO discussed the findings from SWOG 1815 and next steps for improving upon treatment with gemcitabine and cisplatin in biliary tract cancer.
Rachna T. Shroff, MD, MS, FASCO
Experts are always looking to improve upon the combination of gemcitabine and nab-paclitaxel for the treatment of patients with biliary tract cancers.
Recently, positive data from the phase 3 TOPAZ trial (NCT03875235) of patients with biliary tract cancer showed that frontline treatment with durvalumab (Imfinzi), gemcitabine, and cisplatin led to an improvement in median overall survival (OS) compared with gemcitabine and cisplatin alone.1 The median OS was 12.8 vs 11.5 months, respectively (HR, 0.80; 95% CI, 0.66-0.97; P = .021). This changed the standard of care for this patient population to now add on durvalumab.
Then in the phase 3 SWOG 1815 trial (NCT03768414), investigators evaluated the addition of nab-paclitaxel (Abraxane) to gemcitabine and cisplatin. However, findings presented at the 2023 American Society of Clinical Oncology Gastrointestinal Cancers Symposium revealed that this combination did not lead to a statistically significant improvement in OS over gemcitabine/cisplatin alone in patients with newly diagnosed, advanced biliary tract cancers.
The trial failed to meet the primary end point, showing a median OS with the triplet regimen (n = 294) at 14.0 months (90% CI, 12.6-16.3) compared with 12.7 months (90% CI, 9.5-16.6) with the doublet (n = 147; P = .65). Patients given the addition of nab-paclitaxel has a progression-free survival (PFS) of 8.2 months (90% CI, 6.7-9.2) vs 6.4 months (90% CI, 5.5-8.5) with gemcitabine and cisplatin alone (P = .43).
While the numbers were small, a signal was observed in select patient subsets as there was a trend toward improved OS at 17.0 months with the triplet (90% CI, 11.3-20.7) compared with 9.3 months (90% CI, 7.0-22.2) with the doublet. Additionally, PFS rates were 9.6 months with the triplet regimen (n = 46; 90% CI, 6.2-14.6) vs 5.6 months (90% CI, 3.9-8.8) with the doublet (n = 24) when given to patients with gallbladder adenocarcinoma.
Patients with locally advanced disease also elicited a better median OS with the triplet (n = 77) at 19.2 months compared with 13.7 months with the doublet (n = 41). Further, the median PFS was 9.3 months with the addition of nab-paclitaxel vs 7.6 months with gemcitabine and cisplatin alone.
“At the end of the day, this study did not meet its primary end point. There was not a clear signal that gemcitabine, cisplatin, and nab-paclitaxel should be used for all patients with newly-diagnosed biliary tract cancers…One of the key takeaways is that it is our responsibility as investigators to see if there are subsets of patients in whom the triplet chemotherapy is safe and effective,”Rachna T. Shroff, MD, MS, FASCO told Targeted Oncology™ in an interview about the data.
In the interview, Shroff, an associate professor of medicine, chief of the GI Medical Oncology, and leader of the Gastrointestinal Clinical Research Team at the University of Arizona Cancer Center, further discussed the findings from SWOG 1815 and next steps for improving upon treatment with gemcitabine and cisplatin in biliary tract cancer.
Targeted Oncology: Can you discuss the SWOG 1815 trial in biliary tract cancer?
Shroff: I had the privilege of discussing the results from SWOG 1815 [at ASCO GI], which is the first randomized phase 3 trial in advanced biliary tract cancers in the United States. This was a study that looked specifically at comparing a triplet chemotherapy regimen of gemcitabine and cisplatin with nab-paclitaxel against the standard of care at the time of gemcitabine and cisplatin alone.
This was a large study. There were 441 patients enrolled across the entire country and it accrued with rapid fire and fully in 2 years, which is monumental and incredibly exciting for a study that was open through the NCI and NCTM. The study was powered to look primarily at whether the addition of nab-paclitaxel improved median overall survival compared with gemcitabine and cisplatin alone. The secondary end points included progression-free survival, overall response rate, etc.
Can you discuss the recently released findings of the trial?
For the study’s primary end point of median overall survival, there was a numerical improvement from 12.7 months to 14 months with the addition of nab-paclitaxel, but this did not meet statistical significance. Similarly, there was an improvement in progression-free survival that was also not statistically significantly different. The overall response rate within the gemcitabine, cisplatin, and nab-paclitaxel arm was 31% compared with 22% with gemcitabine and cisplatin. There were some notable grades 3-5 hematologic toxicities in the triplet chemotherapy arm, but the treatment discontinuation rate was not different.
What's interesting is there were some prespecified stratification factors that we looked at, like disease site and disease stage. There may be some signals of efficacy that warrant further exploration, specifically in gallbladder cancer where we do see a median overall survival of about 19 months, even though it's a small number of patients, and an overall response rate of 44% compared with 22% for gemcitabine and cisplatin. Similarly, there may be a signal in the locally advanced patient population compared with the metastatic [population] with a slight improvement in overall survival compared with the standard of care arm, with the recognition that these are small numbers.
What is next to come with this research?
We are currently doing a bit of a deep dive into the biomarker analyses. This study included archival tissue and prospective blood collection. I think it will be important for us to bring in some of the molecular understanding that we know is important in biliary tract cancers to see if there are other subsets of patients that could benefit. All of that would be hypothesis generating to think through where the next steps are. For instance, in the gemcitabine, cisplatin, and nab-paclitaxel arm, we have to wonder if there could be a trial looking specifically in the perioperative space for locally advanced patients or in gallbladder cancer. We need to think through what that would look like and how we would design it, especially in the setting of now using immunotherapy in the frontline space.
What challenges remain in the biliary tract cancer space?
I think we've made tremendous progress in biliary tract cancers, especially as we start to understand the genomic landscape. We have been able to see a couple of drugs FDA approved, specifically for certain biomarkers. The other big, exciting space is immunotherapy and with gemcitabine, cisplatin, and durvalumab as our new standard of care based on TOPAZ, and the press release from KEYNOTE-966 suggesting that pembrolizumab can also be beneficial when given in combination with gemcitabine and cisplatin. Clearly there's a role for immunotherapy in biliary tract cancers. I think teasing out which patients benefit from immunotherapy, which patients we should be thinking through targeted therapy, which patients perhaps [should have] a triplet is going to be important so that we can identify how to personalize our approach to these patients.
Then, I think the other big space is resistance. As patients get targeted therapies, they develop resistance. So how can we circumvent that resistance? What does the next generation of targeted therapies look like? What does immune resistance look like and how do we help build on checkpoint inhibitors and see what else we can do to make what has historically been a colder tumor hot?
How do you currently decide how to treat patients? What factors influence those decisions?
In newly-diagnosed patients with advanced biliary tract cancer, the level 1 evidence supports gemcitabine and cisplatin with durvalumab for all patients, unless there's a contraindication to receiving immunotherapy. In those patients, gemcitabine and cisplatin alone is still a reasonable option. I do still use gemcitabine, cisplatin, and nab-paclitaxel, especially when I need to see responses and cytoreduction, perhaps again in a perioperative space to try to get somebody to the operating room for potentially curative resection. But far in a way, that is how newly-diagnosed patients should be treated, it is with gemcitabine and cisplatin plus durvalumab, at least for now until we see the pembrolizumab data. At the same time as I start them on therapy, I order comprehensive genomic profiling with biomarker testing so that I can understand what potential actionable alterations each individual patient has. That helps to think through second-line, third-line, and beyond approaches for treating these patients once they've progressed on gemcitabine-based approaches.
Overall, what are the key takeaways from the SWOG 1815 trial?
At the end of the day, this study did not meet its primary end point. There was not a clear signal that gemcitabine, cisplatin, and nab-paclitaxel should be used for all patients with newly-diagnosed biliary tract cancers. Again, I do think 1 of the key takeaways is that it is our responsibility as the investigators to see if there are subsets of patients in whom the triplet chemotherapy is safe and effective. But the other takeaways are that this study being the first randomized phase 3 trial and biliary tract cancers in this country demonstrates that we can do large phase 3 studies in biliary tract cancers, which has historically been thought of as a rare tumor. It also demonstrates the potential for doing these trials through the National Cancer Institute and the National Comprehensive Cancer Network mechanisms, because it was a true cooperative group study. While it was a SWOG Cancer Research Network (SWOG) study, we had accruals from SWOG, Easter Cooperative Oncology Group, and NRG Oncology alliance, and everybody contributed to this in a meaningful way. We accrued rapidly, which I think suggests that when we all come together for a unified cause and collaborate, we can answer an important question in an expeditious manner and get a meaningful answer. To me, the takeaways from SWOG 1815 are just proving that we can and should be doing these types of studies.
