Ongoing Research Pushes Precision Oncology Mindset in Gastrointestinal Cancers

With highly anticipated data across gastrointestinal (GI) cancers expected to read out in the near future—including the phase 3 NAPOLI-3 (NCT04083235) and HIMALAYA (NCT03298451) trials in pancreatic cancer and hepatocellular carcinoma (HCC), respectively— researchers are already gearing up for future research efforts that will continue to put precision oncology at the forefront of treatment, according to E. Gabriela Chiorean, MD.

“Molecular profiling [are crucial aspects] of care for every patient with any solid tumor that has advanced-stage, metastatic disease,” said Chiorean in an interview during an Institutional Perspectives in Cancer webinar on gastrointestinal cancers. “The more [we know] about the cancer, the more treatment options there are. There is exciting research moving forward with immune checkpoint inhibitors, especially in liver cancers and neuroendocrine cancers, but also many new targeted therapies, and new chemotherapies in pancreatic cancer and other tumors.”

The virtual meeting, chaired by Chiorean, focused on these precision medicine updates in metastatic pancreatic cancer, hepatocellular carcinoma, and neuroendocrine tumors (NETs), as well as approaches with hyperthermic intraperitoneal chemotherapy.

In an interview with OncLive^® during the webinar, Chiorean, a physician and clinical director of Gastrointestinal Medical Oncology at Seattle Cancer Care Alliance, professor of medicine, of University of Washington School of Medicine, and professor in the Clinical Research Division at Fred Hutchinson Cancer Research Center, discussed some of the recent developments in pancreatic cancer, HCC, and NETs, as well as multidisciplinary approaches for treating these patients.

OncLive^®: How do you optimally use molecular testing in practice and how the results help to inform treatment decisions for your patients with gastrointestinal cancers?

Chiorean: Molecular testing is one of the most significant updates in the management of patients with pancreatic cancer. The National Comprehensive Cancer Network® guidelines have iterated that germline testing for hereditary gene predisposition syndromes is the standard of care for patients with pancreatic cancer, no matter what the stage of the disease.

[Additionally], for all patients with advanced disease that is either locally advanced, unresectable, or metastatic, [NCCN guidelines call for] tumor somatic gene testing, or when not possible, liquid biopsies. The reasons for these recommendations are that about 10% to 20% of patients will be found to harbor genetic alterations that have an impact on their prognosis, as well as on their treatment options. The more treatment options a patient has, the better the potential survival and outcomes.

Pancreatic cancer was a focus at this webinar. One of the highly anticipated trials in pancreatic cancer is the phase 3 NAPOLI-3 trial (NCT04083235). Could you discuss the study design?

NAPOLI-3 is an ongoing study, and [although] we do not have the results yet, they are heavily anticipated. The study will compare gemcitabine plus nab-paclitaxel [Abraxane] vs a new regimen, which substitutes irinotecan with liposomal irinotecan. Instead of having fluorouracil, oxaliplatin, and irinotecan [FOLFIRINOX], we have liposomal irinotecan, oxaliplatin, and 5-fluorouracil [5-FU]/leucovorin, or NALIRINOX. This study encompasses more than 700 patients internationally, and we will hopefully see results by next year.

Another presentation focused on current treatment strategies in neuroendocrine carcinomas. What are some future research directions in this space?

Neuroendocrine tumors are a very complex set of tumors. No 2 patients are alike and, for this reason, neuroendocrine tumors [NETS] require a multidisciplinary approach. At [Fred Hutchinson Cancer Research Center], we have a neuroendocrine tumor board, represented by surgeons, radiation oncologists, interventional radiologists, nuclear radiologists, medical oncologist, and more. The treatments are multifaceted, from systemic therapies, TKIs, to somatostatin receptor analogs, radiolabeled octreotide, and peptide receptor radionuclide therapy [PRRT] with lutetium Lu 177 dotatate [177Lu-Dotatate; Lutathera]. [Additionally], we always try to endeavor clinical trials to study patients with a variety of NETs.

In the community, oftentimes we treat [lung NETs similarly to] small cell lung cancer [SCLC]. Genetically and genomically, these tumors are different.

New research in neuroendocrine carcinoma will examine chemotherapy in combination with immunotherapy to [investigate whether] immunotherapy can increase efficacy in a combined approach. A study [of this nature] will open [later this year] and will include all patients with neuroendocrine carcinomas, no matter where the primary cancer is.

These will be small cell neuroendocrine carcinomas, whether they start in the GI tract, the cervix, or the genitourinary system. The study will [examine] platinum-etoposide chemotherapy with or without atezolizumab [Tecentriq], which is a PD-L1 immune checkpoint inhibitor, used both during chemotherapy, as well as in the maintenance [setting]. [We are trying to determine] whether immunotherapy combined with chemotherapy have a role in neuroendocrine carcinomas that are extrapulmonary, and that have originated in other organs.

This is a highly anticipated study; however, we are hoping for other studies that will look more at repeating PRRT for patients that have already been pretreated with Lutathera. We need to study these concepts, as well as look at novel agents, such as lurbinectedin [Zepzelca], which was recently FDA approved for SCLC. Combination immunotherapy agents have also been studied and seem to have some activity, although not as much as in lung NETs. [Additionally, these doublet regimens are given] in the second- or third-line setting, not as an initial therapy approach. Again, we are seeing much more research being done on these complex NETs.

Treatment updates in HCC were also highlighted at this meeting. What are some factors to consider when selecting among available therapies?

HCC is a disease that has seen novel agents being approved almost every 6 months in the past few years,. It started in the second-line setting, after previous treatment with sorafenib [Nexavar], and we saw a variety of agents like cabozantinib [Cabometyx] and regorafenib [Stivarga] being approved. More recently, we have seen [the approval of] atezolizumab with bevacizumab [Avastin], which is a combination of an antiangiogenic agent plus a checkpoint inhibitor. [This combination has] gained a lot of traction, and is considered the new [standard-of-care treatment] for first-line HCC.

We are eagerly anticipating the results of the phase 3 HIMALAYA study [NCT03298451], which is examining the doublet immunotherapy combination of durvalumab [Imfinzi] and tremelimumab also in the first-line setting. We will have to decide which patients are suitable for either of these combinations by looking at doublet immunotherapy vs immunotherapy combined with an antiangiogenic agent. [Although], it is anticipated that there will be room for patients to be treated with either of these regimens.

The question [that remains is]: what is the optimal second-line treatment? Most of the second-line treatments are approved [based on] initial therapy with sorafenib. Because the field has changed, and sorafenib is rarely being used in the first-line setting, there are a lot of questions about what the optimal second-line therapy is after initial exposure to an immune checkpoint inhibitor. We anticipate a lot of research being done [to answer this question], but for the time being, VEGF TKIs are currently the standard second- and third-line regimens. [Again, new clinical trials will aim to determine whether] VEGF TKIs are still an appropriate second-line treatment, or [if we should] attempt to shift some of these TKIs in combinations with immunotherapy to the first-line [setting].

In HCC, there has been a lot of research, a lot of novel agents being approved. I anticipate the same pattern moving forward, with novel agents being approved in the first-line setting, and novel combinations being examined in the first-line setting and beyond.