Sequencing Strategies May Shift With Emerging Options in GI Malignancies

Anthony El-Khoueiry, MD

With the rapid uptake oof novel therapies, shifts in treatment strategies are anticipated in gastrointestinal (GI) malignancies, including hepatobiliary cancers, locally advanced and metastatic pancreatic cancer, gastric/gastroesophageal junction cancers, and metastatic colorectal cancer (mCRC), according to a panel of experts from the University of Southern California Norris Comprehensive Cancer Center (USC Norris) who presented during an OncLive^® Institutional Perspectives in Cancer webinar on gastrointestinal malignancies.

Notably, Anthony El-Khoueiry, MD, cochair of the event, shed light on the evolving frontline paradigms in hepatobiliary cancers that could challenge current standards of care. He is associate professor of clinical medicine in the Division of Medical Oncology, member of the Gastrointestinal Cancers Program, director of the Phase 1 Drug Development Clinical Program, and medical director of the Clinical Investigations Support Office at USC Norris.

El-Khoueiry was joined by fellow faculty from the USC Norris Comprehensive Cancer Center:

• Syma Iqbal, MD, co-chair of the event, assistant professor, Division of Oncology, assistant program director, Oncology Fellowship Program, educational officer, Division of Oncology, co-director, Liver Cancer Program, USC Norris Comprehensive Cancer Center
• Steven Grossman, MD, PhD, deputy director for Cancer Services, inaugural cancer physician in chief, USC Norris Comprehensive Cancer Center
• Diana L. Hanna, MD, program director, Phase 1 Cancer Research, oncologist, Hoag Family Cancer Institute
• Heinz-Josef Lenz, MD, FACP, associate director for clinical research, co-leader, Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, professor of medicine and preventive medicine, section head, GI Oncology, Division of Medical Oncology, co-director, Colorectal Center, Keck School of Medicine of USC

During the meeting, the panelists spoke about optimizing surgical resection in locally advanced pancreatic cancer, the incorporation of novel combination regimens in advanced pancreatic cancer, the roles of immunotherapy and targeted therapy in advanced upper GI cancers, and the evolving landscapes of hepatobiliary cancer and mCRC.

Emerging Therapies Could Shake Up Frontline Treatment in Hepatobiliary Cancers

El-Khoueiry: Although the frontline treatment landscape is continuing to evolve in hepatocellular carcinoma [HCC], atezolizumab [Tecentriq] plus bevacizumab [Avastin] is the current standard of care. Several other combinations, such as cabozantinib [Cabometyx] plus atezolizumab in the COSMIC-312 trial [NCT03755791] and tremelimumab plus durvalumab [Imfinzi] in the HIMALAYA trial [NCT03298451], are emerging.

For patients with contraindications to immunotherapy, single-agent sorafenib [Nexavar] or lenvatinib [Lenvima] are indicated. Findings from the CheckMate 459 trial [NCT02576509] demonstrated that nivolumab [Opdivo] was not superior to sorafenib; however, durvalumab was found to be noninferior to sorafenib in the HIMALAYA trial. Therefore, single-agent checkpoint inhibitors maintain a role for special populations of HCC.

Other forward-looking strategies include checkpoint inhibitors plus liver-directed therapies, as well as adjuvant and neoadjuvant therapies. Ultimately, accrual to clinical trials and data generation remain critical aspects of HCC research.

In biliary cancers, the frontline standard of care for patients is likely to change with the anticipated positive results of the ongoing TOPAZ-1 trial [NCT03875235], which is evaluating durvalumab or placebo in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. Another emerging triplet of gemcitabine, nab-paclitaxel [Abraxane], and cisplatin should also be watched for potential incorporation into clinical practice.

Ultimately, biliary tract cancers represent a heterogenous patient population composed of molecularly distinct subgroups. Therefore, the role of targeted therapy is growing beyond FGFR2- and IDH1-mutated populations to potentially include groups with HER2, BRAF, BRCA, and other [mutations]. This research underscores the importance of early molecular testing to guide therapy in this patient population.

Immunotherapy in Upper GI Cancers

Iqbal: The biggest impacts in GI oncology have been with the addition of immunotherapy. We have had anti-VEGF therapy in some format across tumors in GI cancers, like gastric cancer, CRC, and HCC with the [tyrosine kinase inhibitors]. However, by incorporating immunotherapy, we have made advances across disease types. 

Nothing had happened for so many years, and we saw so many negative trials across tumor types. It’s been a time of big change to the frontline standards. We have had several FDA approvals in the past year, not just in upper GI cancer but hepatobiliary cancer. In the past couple of years, we [also] saw the incorporation of olaparib [Lynparza] in pancreatic cancer. 

The field is moving forward in a significant manner for the f irst time in a very long time. Much of that has to do with the incorporation of immunotherapy, adding to anti-VEGF therapy.

The Growing Role of Resection in Locally Advanced Pancreatic Cancer

Grossman: The theme for the treatment of locally advanced pancreatic cancer is clearly that all these patients— to the extent that they are physiologically able to receive chemotherapy—should be treated with an intent to proceed to resection. Even though most patients won’t make it there based [on some institutions’] experiences that have been published, we are talking about 20% of patients who could undergo resection. Of all patients, about 12% of [those who have] what is now considered T4 unresectable disease can move to an R0 resection. There is hope. We need to give that hope to patients and proceed with as robust an induction sequence of therapies as possible. That way, as many patients as possible can move to resection.

Early Detection and Targeted Therapy Signals Hope in Advanced Pancreatic Cancer

Hanna: Pancreatic cancer is always associated with such a dismal prognosis. We have come such a long way in this disease, but we have such a long way to go. The biggest keys are ensuring that comprehensive genetic testing [is done] in the patient and in the tumor, [testing that is] both blood and tissue based. Enrolling patients on clinical trials [is also important], as is focusing and putting effort into early detection strategies.

These are the ways that we are going to make an imprint and improve how patients do with this disease, because it continues to have such an impact. We are seeing it more LUNG CANCER in younger patients and it’s rising in terms of its impact on cancer-related mortality. We need to keep putting emphasis and effort on enrolling patients on studies to learn as much as we possibly can about the genetics and biology of the disease. We are hopeful that we can continue to help people in the future.

Selecting Between Salvage-line Therapies in CRC

Lenz: In CRC, oral therapies have become standard-of-care management strategies. Although regorafenib [Stivarga] and TAS-102 [trifluridine/tipiracil; Lonsurf] demonstrated similar efficacy, the agents have very different toxicity profiles, which can guide treatment selection. Moreover, the starting dose of regorafenib should not be 160 mg/day. Furthermore, regorafenib should be given to patients with a performance status of more than 1, whereas TAS-102 should be given to patients with a performance status of 2.

As intriguing data have emerged, [we see that] regorafenib may have utility in combination with nivolumab; however, further evaluation is ongoing as the data have not been confirmed [in a phase 3 trial] thus far. Similarly, TAS-102 may have utility in combination with bevacizumab as potentially the optimal way to administer oral fluoropyrimidine to patients with CRC.