Pedersen Shares 2023 Year-End GI Malignancy Treatment Updates

Katrina S. Pedersen, MD, MS, an associate professor in the Division of Oncology at the Washington University School of Medicine in St. Louis, Missouri, discussed updates in the treatment of gastrointestinal (GI) cancers, including biliary tract cancer, neuroendocrine tumors (NETs), and peritoneal carcinomatosis in an interview with OncLive^® following an OncLive State of the Science Summit^™, which she chaired. She provided updates on key trials such as the phase 3 KEYNOTE-966 (NCT04003636) and NETTER-2 (NCT03972488) studies in the treatment of biliary tract cancers and NETs, respectively, noting differing interpretations of data on the role of gemcitabine in maintenance therapy for patients with biliary tract cancers.

She also highlighted upcoming and ongoing research taking place at the Washington University School of Medicine. Additionally, Pedersen provided further insights into the changing treatment landscape of GI malignancies in another interview.

How has the recent FDA approval of pembrolizumab plus chemotherapy changed practice for patients with locally advanced, unresectable, or metastatic biliary cancer?

It’s always exciting to see positive randomized, control trials that come out in more rare cancers such as biliary tract cancer [which] has been a bit more forgotten over the years and is seeing a lot more focus and advancement.

Data from the phase 3 KEYNOTE-966 trial [NCT04003636]evaluating gemcitabine and cisplatin with pembrolizumab [Keytruda] vs gemcitabine and cisplatin with placebo [revealed] that the [triplet therapy is] certainly a good and viable option, and it is approved. However, it did come around second to the gemcitabine and cisplatin with durvalumab [Imfinzi] regimen. Most of us have already been using gemcitabine and cisplatin with durvalumab combination, so I haven’t seen much clinical shift to specifically go to pembrolizumab, especially because the outcomes aren’t that different. At most, the addition of the immunotherapy adds a modest benefit. That said, there is benefit.

One thing that I found very interesting was one of the key differences between the 2 studies of chemotherapy and durvalumab vs chemotherapy and pembrolizumab was that the maintenance phase of the treatment in the durvalumab trial—[the phase 3 TOPAZ-1 (NCT03875235) trial]—was durvalumab vs placebo. Many of us over the years would do gemcitabine and cisplatin with gemcitabine maintenance after the induction months of chemotherapy.

The pembrolizumab trial did a gemcitabine with pembrolizumab maintenance vs gemcitabine maintenance [portion of treatment]. It’s interesting to see clinician’s different interpretations of the data. Where I saw similar outcomes which makes me wonder whether I truly do need the chemotherapy maintenance as part of the regimen, I was surprised and thought there would be much more benefit to having the ongoing gemcitabine with the immunotherapy maintenance treatment. Other people have found that this confirms their belief that gemcitabine maintenance in this combination strategy is important. Either way, we can’t go wrong no matter which approach we choose.

What are some of the most exciting research developments regarding NETs that may soon change practice?

The recently presented NETTER-2 trial enrolling patients to receive frontline peptide receptor radionuclide therapy [PRRT] with lutetium Lu 177 dotatate [Lutathera; lutetium (177Lu) oxodotreotide] plus long-acting octreotide vs high-dose somatostatin analogs such as with [long-acting] octreotide at 60 mg for patients with grade 2/3 NETs was interesting. We saw a big difference—patients seemingly did much better getting the upfront [treatment]. However, this is still very early [data] and has not been around long enough to show if [the benefit] is translating to an overall survival [OS] benefit. [A question that remains is if] we are seeing enhanced toxicity with the earlier introduction of radionuclide therapy and the more concerning risks such as developing myelodysplastic syndrome [MDS], which you really wouldn’t get with a much less toxic somatostatin analog.

Additionally, the comparison of a high-dose sandostatin is not how we clinically practice for these high-grade tumors. We tend to start with a chemotherapy-based approach like with capecitabine and temozolomide, or for more high-grade [tumors] platinum with etoposide. This [trial’s data] is not able to change clinical practice as much as it initially appears because the comparison isn’t quite equal, and this should be explored much more. However, especially in a higher-grade population, seeing prospective data and activity with PRRT [when] we’ve mostly used it for treatment of lower-grade [disease] is very exciting.

One other interesting highlight is seeing this advancement towards more targeted therapies. The phase 3 CABINET trial [NCT03375320] that was recently reported was highly positive; investigators stopped the trial early because they met the efficacy end points much earlier than expected. [This brought] another effective target [to light], as we’ve already seen the clinical benefit for our patients.

How has the role of cytoreductive surgery for peritoneal carcinomatosis in GI malignancies changed over the years?

Recently with cytoreductive treatment, we’re starting to see much more standardization or attempts at such with this approach. That will lead to better, more conclusive trials that can start highlighting the benefits of cytoreduction and other intraperitoneal therapy such as HIPEC [hyperthermic intraperitoneal chemotherapy] or EPIC [early post-operative intraperitoneal chemotherapy] where we’re infusing the chemotherapy or other medical treatments into the abdominal cavity itself.

With these more refined approaches, and with this acceleration in research that we’re finally starting to see for patients with peritoneal carcinomatosis, we hope this will translate soon to large data-driven advancements. Considering how long cytoreduction with or without HIPEC has been around, it’s interesting that more people don’t have it, granted access [may be difficult]—the surgeons are highly specialized, the surgeries take a long time, and just a handful of centers can do these sorts of surgeries.

However, what I find very interesting is that when we have seen larger trials from it, like the phase 3 PRODIGE 7 trial [NCT00769405] that came out of France several years ago in colorectal cancer, survival for these patients who undergo cytoreduction is significantly greater than the median OS with systemic therapy alone. There’s a great opportunity to keep leveraging and supporting more research into this area because it seems that patients do benefit from it, but we have to better understand who it would best apply to.

What planned or ongoing research are you and the Washington University faculty involved in?

Collaborations between Kian-Huat Lim, MD, PhD, and his laboratory work, as well as Patrick M. Grierson, MD, PhD, in IRAK4-targeted therapy, have come out of research that’s been specifically developed at Washington University. We have several trials across several GI primary sites including pancreas and esophageal and gastric cancers to combine the IRAK4 inhibitor CA-4948 with standard frontline chemotherapy because, in our preclinical translational research, that seemed to enhance the durability of treatment with very little addition of toxicity. We’re excited to propel that forward and see if that holds true in humans.

Secondarily, Nikolaos Trikalinos, MD, has been doing a number of studies focused on high-grade NETs, which is a rare subset of a rare cancer. There are some exciting targeted therapies that go against the grain in terms of what I thought would be effective for this. We will hopefully be seeing more data readouts to see if they can springboard to other larger studies.

What is your main message for colleagues based on this conversation?

GI malignancies often do not have as good of a survival [rate] for patients compared with other cancers, and we haven’t seen the pace of positive trials improve treatments and keep up with those other tumor types.

However, finally, the momentum has been shifting in more recent years, and I think we’re going to see an acceleration of improved outcomes for patients with metastatic disease. It’s an exciting time to be involved, and certainly being able to see benefit in the patients that we’re treating is very gratifying.