Data Continue to Reshape Treatment Considerations Across Advanced GI Malignancies

Recent advancements in systemic therapy have expanded treatment options for patients with various advanced gastrointestinal malignancies, including colorectal cancer (CRC), pancreatic cancer, and neuroendocrine tumors (NETs), according to Mohammed Najeeb Al Hallak, MD, MS.

In an interview with OncLive®, Al Hallak discussed the evolving treatment landscape across these malignancies, highlighting key updates and treatment considerations in the first and subsequent lines of therapy.

Al Hallak, who serves as a hematologist/oncologist at the Karmanos Cancer Institute at Wayne State University in Detroit, Michigan, provided additional insights on frontline treatment selection in unresectable hepatocellular carcinoma in a previous article.

OncLive: What treatments need to be considered in the frontline setting for metastatic pancreatic cancer?

Al Hallak: In 2025, we have several treatment options for [patients with advanced] pancreatic cancer. Most importantly, we have 2 good [frontline chemotherapy] combination options for those with stage IV pancreatic cancer. [One is] the NALIRIFOX regimen, which is the combination of oxaliplatin, 5-fluorouracil, and leucovorin, along with the albumin-bound liposomal irinotecan [Onivyde]. This is an irinotecan that's uniquely packaged inside a liposome that helps protect it from breaking down into the active metabolite SN-38, helping keep the drug intact during circulation without that active metabolite, which we think drives the adverse effects from irinotecan. At least in animal models, we have seen better penetration of [liposomal irinotecan] into the pancreatic tissue and pancreatic cancer.

[NALIRIFOX] gained FDA approval after the phase 3 NAPOLI 3 trial [NCT04083235] that examined this combination against gemcitabine plus nab-paclitaxel [Abraxane] in the first-line setting for [patients with] stage IV pancreatic cancer. NAPOLI 3 showed positive survival data in favor of NALIRIFOX, which [supported] the FDA approval for this regimen.1

The second [most] important regimen that we have is gemcitabine plus nab-paclitaxel. We have the non–FDA approved regimen of FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin] available for us to use; however, the 2 [current] FDA-approved regimens for the first-line setting are NALIRIFOX and [the combination of] gemcitabine and nab-paclitaxel.

How have recent data affected the treatment paradigm for NETs?

[We have] multiple options for the first line, second line, and beyond [for patients with NETs] including somatostatin analog injections, TKIs, everolimus, and peptide receptor radionuclide therapy [PRRT].

New data have shown that PRRT is active in well-differentiated grade 2/3 NETs as a first-line treatment. [Findings from] the [phase 3] NETTER-2 trial [NCT03972488] showed benefit with a progression-free survival [PFS] improvement [for those treated with lutetium Lu 177 dotatate (Lutathera) vs those given high-dose octreotide].2

The TKI cabozantinib was tested [vs placebo] in the phase 3 CABINET trial [NCT03375320], and data showed a PFS benefit in patients with [previously treated] advanced pancreatic and extrapancreatic NETs. [The study included] a minimal number of patients with well-differentiated grade 3 NETs; however, I would say there [was a clear] PFS benefit for patients with grade 1 or 2 NETs.

What are the key clinical updates in metastatic CRC?

Patients with stage IV colon cancer have 2 solid lines of treatment: FOLFOX [fluorouracil, leucovorin, and oxaliplatin] and FOLFIRI [leucovorin, fluorouracil, and irinotecan]. You can use them in combination with either bevacizumab [Avastin] or with an EGFR monoclonal antibody like panitumumab [Vectibix] or cetuximab [Erbitux]. [FOLFOX and FOLFIRI are considered to be] the first 2 lines treatment. Sometimes we combine [the 2 chemotherapy regimens] into 1 line—that's called FOLFOXIRI—[in combination] with bevacizumab.

When patients have progressed on chemotherapy regimens [containing] 5-FU, irinotecan, and oxaliplatin—with or without bevacizumab, panitumumab, or cetuximab—then we arrive at third-line treatment. In the third line, we have several options. We have the new FDA-approved oral TKI fruquintinib [Fruzaqla]. We also have trifluridine/tipiracil [TAS-102; Lonsurf] with or without bevacizumab. We have another option to use regorafenib [Stivarga]. Those are three FDA-approved regimens for the third line and beyond.

[There is also the idea of] rechallenging patients with chemotherapy that they received in the first or second line of treatment, if there is a good [amount of] time that has passed after the exposure to treatment and [disease] progression.

Liver embolization for liver metastases from colon cancer can help control the bulk of disease in the liver. That can also help delay the progression and to extend the response to their treatment.

Fruquintinib is a new option in colon cancer [after being] FDA approved [in November 2023].3 We were part of the [phase 3] FRESCO-2 trial [NCT04322539] in the United States that led to the FDA approval [of fruquintinib]. We had real exposure to fruquintinib even before the FDA approval, and we had seen the efficacy, but that had to be confirmed with the results of FRESCO-2.

Fruquintinib is an oral TKI that targets the intracellular domain of EGFR, and with that, it blocks the signal to activate the cancer cells and prevents the vascularization of the tumors, leading to cell death. There were PFS and overall survival benefits with fruquintinib for patients with colon cancer in the third line and beyond.

References

1. FDA approves irinotecan liposome for first-line treatment of metastatic pancreatic adenocarcinoma. FDA. February 13, 2024. Accessed February 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-irinotecan-liposome-first-line-treatment-metastatic-pancreatic-adenocarcinoma
2. Singh S, Halperin D, Myrehaug S, et al. [177Lu]Lu-DOTA-TATE plus long-acting octreotide versus high‑dose long-acting octreotide for the treatment of newly diagnosed, advanced grade 2-3, well-differentiated, gastroenteropancreatic neuroendocrine tumours (NETTER-2): an open-label, randomised, phase 3 study. Lancet. 2024;403(10446):2807-2817. doi:10.1016/S0140-6736(24)00701-3
3. FDA approves fruquintinib in refractory metastatic colorectal cancer. FDA. November 8, 2023. Accessed February 25, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fruquintinib-refractory-metastatic-colorectal-cancer