Immunotherapy Continues to Shape Evolving Treatment Armamentarium of GI Cancers

Deirdre J. Cohen, MD, MS

Several inroads have been made in the realm of gastrointestinal cancers, with novel immunotherapy combinations representing a significant advance spanning several tumor types, according to faculty from an OncLive^® Institutional Perspectives in Cancer (IPC)^™ on GI cancer.

Regimens like atezolizumab (Tecentriq) plus bevacizumab (Avastin) are a mainstay in the frontline treatment of hepatocellular carcinoma (HCC), chemoimmunotherapy regimens have become a standard for select patients with esophageal cancer, and future directions in biliary tract cancer are focused on targeting the immune landscape to improve outcomes.

The event, chaired by Deirdre J. Cohen, MD, MS, the director of the Gastrointestinal Oncology Program, an associate professor of Medicine in Hematology and Medical Oncology, and the medical director of the Cancer Clinical Trials office at the Tisch Cancer Institute at Mount Sinai, highlighted updates across GI cancers, including the use of immunotherapy in esophageal cancer, targeted therapy in biliary tract cancer, and circulating tumor DNA (ctDNA) in colorectal cancer (CRC).

Cohen was joined by her colleagues:

• Augusto Villanueva Rodriguez, MD, PhD, associate professor, Medicine and Liver Diseases, Hematology and Medical Oncology, the Tisch Cancer Institute at Mount Sinai
• Celina Ang, MD, associate professor of Medicine, the Division of Medical Hematology and Oncology, the Tisch Cancer Institute at Mount Sinai
• Peter Kozuch, MD, medical oncologist, site director, Division of Hematology and Medical Oncology, Mount Sinai West, co-chair, Mount Sinai Health System, Disease Focus Group Gastrointestinal Oncology Multidisciplinary Program, associate director, Mount Sinai Health System, Hematology and Medical Oncology Fellowship Program

Below, Ang, Villanueva Rodriguez, Cohen, and Kozuch summarize the main messages from their presentations.

Leveraging Immunotherapy in Esophageal Cancer

Ang: In the neoadjuvant and perioperative settings, perioperative chemotherapy is an acceptable noninferior option to neoadjuvant chemoradiation. PET scans and PET metabolic response can be used to guide therapy, and immunotherapy shows promise when added to perioperative chemotherapy.

Adjuvant nivolumab [Opdivo] is now the standard of care for patients with residual pathologic disease following chemoradiation and surgery. For metastatic disease, first-line chemoimmunotherapy is standard of care for those with HER2 positivity. You can add a checkpoint inhibitor to trastuzumab [Herceptin] and chemotherapy. Immunotherapy is approved [for use] in the second line and beyond. For patients with [metastatic] HER2-positive disease, fam-trastuzumab deruxtecan-nxki [Enhertu] is FDA approved [as a second-line treatment for those who received a prior trastuzumab-based therapy].

Combinations Dominate First-Line Treatment for Advanced HCC

Villanueva Rodriguez: The new standard of care in the first line [for advanced HCC] includes combination therapies, which is a big change to what we had before with sorafenib [Nexavar] [monotherapy]. Combination [therapy] is a mainstay for first-line treatment. The combination can include immunotherapy drugs, such as atezolizumab [Tecentriq] and bevacizumab [Avastin], as seen in the [phase 3] IMbrave150 trial [NCT03434379], or the combination of [tremelimumab] and [durvalumab] in the [phase 3] HIMALAYA trial [NCT03298451].

[Immunotherapy] works for patients with HCC in combination with other TKIs, and there are other trials exploring other combinations and types of targets for immunotherapy. However, combination therapy is a mainstay as a first-line treatment, and immuno-oncology drugs are effective in patients with HCC.

[Ongoing clinical trials are exploring] triplets, which will hopefully improve the [benefit] that we have already [achieved] with a combination of 2 agents in the first line.

Targeting Immune Landscape May Move the Needle in Biliary Tract Cancers

Cohen: Over the past 5 years, the treatment landscape for biliary tract cancers has [expanded], and we have multiple agents to treat our patients. The main thrust of this is our better understanding of the richness of the molecular alterations. More than 50% of these cancers harbor targetable alterations.

Another key path forward is going to be in targeting the immune landscape. [The phase 3] TOPAZ-1 [trial (NCT03875235) of durvalumab (Imfinzi) plus chemotherapy] set the stage for an initial path forward, but we’re going to learn a lot more from that study and others in terms of how to best make [cold] tumors hot and responsive to immunotherapies.

Current & Future Use of ctDNA in CRC

Kozuch: There will be many spaces in which quantitative ctDNA will be helpful. [Using ctDNA to make] decisions about post-operative chemotherapy is going to be relatively immediately applicable.

Colleagues should try to participate in the [phase 2/3] CIRCULATE-US trial [NCT05174169]. This is the NRG-GI008 trial, which allows patients with resected stage II colon cancer who have had a Signatera ctDNA analysis that is positive to enter onto the trial. Those patients with ctDNA after resection of stage IIA or IIB colon cancer will be randomized to FOLFOX [5-fluorouracil, leucovorin, and oxaliplatin] or augmented adjuvant chemotherapy with FOLFIRINOX [leucovorin, 5-fluorouracil, irinotecan hydrochloride, and oxaliplatin].