Research on Novel Targets and Potential Risk Factors Drives Improvements in the Management of GI Cancers

Cathy Eng, MD, FACP, FASCO

Continued advancements in the treatment landscape for gastrointestinal (GI) cancers not only requires the investigation of novel agents but also an emphasis on elucidating the role of genetic and environmental factors in the development of GI cancers, according to faculty from an OncLive^® State of the Science Summit™ on GI Cancer.

The event was chaired by Cathy Eng, MD, FACP, FASCO, a professor of medicine in the Division of Hematology/Oncology, the David H. Johnson Endowed Chair in Surgical and Medical Oncology, co-leader of the Gastrointestinal Cancer Research Program, co-director of GI Oncology, director of the VICC Young Adults Program, and co-chair of the NCI Gastrointestinal Steering Committee at the Vanderbilt-Ingram Cancer Center (VICC) in Nashville, Tennessee.

Presentations highlighted current strategies and novel developments in upper GI tumors, hepatobiliary cancers, CRC, gastric cancer, and pancreatic cancer. Other topics included the role of intestinal dysbiosis and GI carcinogenesis, germline genetic features in appendiceal cancer, and the need for anticipatory, multidisciplinary guidance in clinical practice.

Eng was joined by her colleagues at VICC:

• Michael K. Gibson, MD, PhD, research director, Translational Research in Head and Neck Oncology, associate professor of medicine, Vanderbilt Health
• Mariana Xavier Byndloss, DVM, PhD, assistant professor of pathology, microbiology and immunology, Vanderbilt University Medical Center (VUMC)
• Andreana N. Holowatyj, PhD, MSCI, assistant professor of medicine and cancer biology at VUMC and VICC
• Dana B. Cardin, MD, MSCI, associate professor of medicine, Division of Hematology/Oncology, VICC
• Kristen Ciombor, MD, MSCI, associate professor of medicine, Division of Hematology/Oncology, Department of Medicine, VICC, VUMC
• Sekhar Padmanabhan, MD, assistant professor, Division of Surgical Oncology & Endocrine Surgery, Department of Surgery, VUMC
• Laura Goff, MD, associate professor of Medicine, Hematology/Oncology, executive medical director, VICC Patient Care Center, co-chair, Data and Safety Monitoring Committee, VICC
• Rajiv Agarwal, MD, assistant professor of medicine, Division of Hematology and Oncology, VUMC
• Justin Lo, MD, PhD, fellow, Division of Hematology/Oncology, Department of Medicine, VICC
• Brian C. Grieb, MD, PhD, instructor, clinical medicine, clinical fellow, Division of Hematology/ Oncology, Department of Medicine, VUMC
• Jordan D. Berlin, MD, Ingram Professor of Cancer Research, professor of medicine, VICC associate director, clinical research strategy, director, Phase I Program in Gastrointestinal Malignancies, Clinical Trials, Department of Medicine, VUMC

Below, Gibson, Byndloss, Holowatyj, Cardin, Ciombor, Padmanabhan, Goff, and Agarwal summarize the main messages from their presentations.

Biomarker-Directed Options May Personalize the Treatment Landscape in GI Cancers

Gibson: There are lots of studies [of] immunotherapy, Claudin 18.2 [CLDN18.2-], and FGFR2b[-directed agents] [ongoing]. [One of these is the phase 3] CheckMate-649 trial [(NCT02872116) of] nivolumab [Opdivo]. It's an interesting study that causes some controversy in retrospect. The [study] took all-comers but stratified patients based on their PD-L1 expression. The primary end point was [progression-free survival and overall survival (OS)] in patients [whose tumors] had [a PD-L1 combined positive score (CPS) of 5 or more], but they also looked at the data in everybody. You can see [median OS increases] from 11.6 to 13.8 [months] in all randomized [patients] regardless of the PD-L1 expression.

Another frontline [agent being studied] is zolbetuximab. This is a drug that binds to CLDN18.2 [which is] overexpressed in cancers. It's a transmembrane cell linking molecule [that] becomes expressed on the surface of tumors. The antibody zolbetuximab binds it and either activates [adenoid cystic carcinoma (AdCC)] or downregulates [CLDN 18.2]. This was studied in [the] frontline [setting for patients with] recurrent metastatic adenocarcinoma and CLDN18.2 overexpression; these patients [were randomly assigned] 1:1 [to zolbetuximab plus oxaliplatin and capecitabine ([Xeloda] CAPOX) vs placebo plus CAPOX] in the [phase 3] GLOW trial [NCT03653507]. There's another [phase 3] trial called SPOTLIGHT [NCT03504397] that uses FOLFOX but they're [otherwise] the same. The progression-free survival [PFS] and overall survival [OS] is better when you add zolbetuximab to CAPOX. In the interventional group, the median OS was about 14 months [and OS was about 12 months in the control group]…

Finally, there's one more [trial] targeting FGFR2b called the FIGHT trial [NCT03694522]. This is a smaller, phase 2 study, and the phase 3 FIGHT study [NCT03343301] is accruing. FGFR2b is a molecule that cancer cells overexpress, and it allows them to evade immune attack from the host immune system. This is a similar trial [using placebo as a] control, which is usually either FOLFOX or CAPOX plus or minus the study targeted drug of choice. In this case, it's bemarituzumab [formerly FPA144]. The primary end point is PFS, and secondary end points [include] OS and response rate. [We have seen] the OS [data] [for] a couple of subgroups. The intention-to-treat arm shows a statistically significant increase [in median OS]. At this time, it's 13.5 months [with bemarituzumab] vs about 9 months with chemotherapy alone.

This is an amazing set of trials for a disease that I've been managing for 25 years. Watching all this progress happen so quickly does bring a lot of hope to me and to our patients. Certainly, this is a long time coming and was sorely needed.

Research Continues to Elucidate the Link Between Intestinal Dysbiosis and the Risk of Developing CRC

Byndloss: We became interested in [studying this relationship] because of the finding that specific cancers are becoming more common in young adults, [including] CRC. We don't really know why this is happening.

We do know that the [cancers] increasing [in frequency are] mostly sporadic, suggesting that these individuals don't necessarily have increased genetic risk for the disease. [Therefore], environmental factors could be playing a key role in this increase[d frequency]. It turns out that a key risk factor [is diet]. We're trying to understand why this [change] in our dietary habits is increasing your risk for cancer. We're really focusing on how this diet is affecting what we refer to as pro-oncogenic bacteria associated with CRC. Our focus is on colibactin-producing E. coli, which is a member of the microbiota that produces a genotoxin. We are particularly interested in this microbe because it's been more frequently associated [with] individuals with CRC and in late-stage disease. Colibactin causes DNA breakage and increases mutation rates, increasing carcinogenesis. This is ongoing work.

We're developing a mouse model of obesity-induced cancer, in which we start by inducing carcinogenesis in these mice with a chemical, [which is followed by giving] them this carcinogenic strain of E coli. We [then] follow them over time, giving them a high-fat or a low-fat diet.

Investigation of the Potential Role of Germline Genetic Features in Appendiceal Cancer Susceptibility Provides Several Key Implications

Holowatyj: We think that appendiceal cancer may be a previously underrecognized indication for hereditary cancer genetic testing or even a cancer syndrome. Genetic testing or evaluation of all patients with appendix cancer, irrespective of age or family history should be a consideration in clinical workflows. Equally as important, cascade testing and genetic counseling of family members who are at risk of these syndromes would also direct potentially life-saving cancer prevention and surveillance strategies [to these patients], or even [reduce the] possible risk of secondary malignancies overall. The next question I [often] hear is: Can we find novel appendix cancer susceptibility genes? We think so. With our clinical partners at Vanderbilt University, as well as patients across the United States, we're undertaking this loaded question with the Genetics of Appendix Cancer [GAP] study. Overall, the study seeks to fill this gap in our knowledge and really drive the needle forward in understanding what's clinically relevant and actionable for this patient population.

Chemotherapy Provides More Widespread Benefit in Managing Metastatic Pancreatic Cancer Than Previously Understood

Cardin: In summarizing how we treat metastatic pancreatic cancer, chemotherapy helps more patients than we thought, [based on our] past [knowledge of who] could tolerate a triplet therapy. With appropriate dose modifications and support, [chemotherapy] will lead to better outcomes. Targeted therapies are taking their time to come along in pancreatic cancer, but they're getting there. [In the meantime], it is important for us to continue to make sure we're [performing a] family history screening of patients for germline mutations. [We should] also make sure [to conduct] molecular profiling for patients who are appropriate [for] and interested in systemic therapy.

Of course, clinical trials are essential for us moving the needle [forward] and [improving] survival. We'll continue to work towards those things. [Overall], there are some glimmers of hope on the horizon for this very difficult to treat disease.

Ongoing Efforts to Target Actionable Genomic Biomarkers in CRC Reinforce Importance of Germline Testing

Ciomber: Back when we only had 5-fluorouracil [5-FU] as our best supportive care [in CRC], the median OS was less than 6 months. Now patients are routinely living years with even unresectable metastatic disease. Clearly, we have more to [learn], but we are making progress. Just like with other diseases, we're starting to learn what the driver mutations and alterations are [for CRC], and many of these are now actionable, which is encouraging. [However], we need to know what the molecular profiles are for each patient. Practically speaking, we're still not doing a good job in getting that information.

[There were] some data presented a few years ago now [looking at] guideline-recommended biomarkers [in CRC]. We're not talking about big, platform-based next-generation sequencing, but [specifically] looking at microsatellite instability [MSI], RAS and BRAF [alterations]. Now [we also screen for] HER2, but that wasn't incorporated in this study. Still, [the study found that] less than half of all eligible patients were being tested for these biomarkers. If you don't test, you can't find these [markers] and you can't identify the right treatments for your patients.

…We [now] have very actionable mutations and alterations in CRC in addition to our cytotoxic chemotherapies that we've known about for a long time, which is exciting. I think there's more on the horizon. It leads to a lot of hope in our patients and a lot of exciting trials to look forward to.

The Use of Hepatic Artery Infusion (HAI) Pump vs Systemic Chemotherapy Continues to Spark Debate in Metastatic CRC

Padmanabhan: Typically, if [patients are] fit [they should receive] triplet chemotherapy with bevacizumab [Avastin]. If they're not, doublet chemotherapy with bevacizumab is standard as was shown in the [phase 3] TRIBE study [NCT00719797]. Adding bevacizumab to systemic chemotherapy improves survival, and reintroducing triplet chemotherapy with bevacizumab after first progression, as shown by the [phase 3] TRIBE-2 study [NCT02339116] improves survival. [However], at some point, our patients get dose-limiting toxicities, and they're on maintenance chemotherapy. That's where we are right now.

[It is] time that we start comparing pump chemotherapy vs modern systemic chemotherapy. [It's a topic] that's been hotly debated for the past 30 years…The problem [is that] that the existing randomized control trials are over 10 years old and used outdated chemotherapy regimens. All the data [on the use of HAI was from a] single-center experience at Memorial Sloan Kettering Cancer Center and [has] all the selection bias that comes with that. I've heard [it said] so many times that HAI doesn't work anywhere except the Upper East Side. [Although] that might be true, this has never been compared head-to-head with modern systemic chemotherapy in a phase 3 trial. We need a trial [to determine this].

Thankfully, my colleague Michael Lidsky, MD, of Duke Health, has really spearheaded an effort through the ECOG-ACRIN cooperative group to [conduct the upcoming] randomized phase 3 PUMP study, [which] is going to compare systemic therapy, with or without HAI for patients with technically unresectable CRC liver metastases.

Key Phase 3 Trials Shift Treatment Paradigm in Biliary Tract Cancer

Goff: [The phase 3 SWOG 1815 trial (NCT03768414) was] a negative study. [However], one of the big things [it showed] is that we can conduct a large, randomized phase 3 trial in biliary cancers relatively quickly. This study accrued [patients] over the course of about 2 years. [For] a long time, people would just say [that] we'll never know because biliary cancer is too rare. [Additionally], finding out that [the optimal chemotherapy backbone is] a doublet rather than an aggressive triplet is useful for future combinations. The foundation for backbones for biliary cancer was confirmed to be gemcitabine and cisplatin. Parallel to the data from SWOG 1815, we had the [phase 3] TOPAZ-1 trial [NCT03875235], which [utilized] a combination of gemcitabine and cisplatin with durvalumab [Imfinzi]. …The conclusions from TOPAZ-1 [are that] durvalumab plus gemcitabine/cisplatin significantly improved OS vs placebo and gemcitabine/cisplatin, and the safety profiles were quite similar.

[Similarly, data from the phase 3 KEYNOTE-966 (NCT04003636) trial showed] that adding pembrolizumab [Keytruda] to gemcitabine/cisplatin provided a statistically significant and clinically meaningful improvement in OS. The median duration of response was prolonged in the pembrolizumab group…This is exciting [because] 2 studies now suggest an improvement [in survival] over gemcitabine/cisplatin [alone]... I do believe that there's an independent contribution from immunotherapy in this disease. Unlike some other diseases, which usually have had higher response rates [with] single-agent immunotherapy, [these rates in] biliary cancers have been disappointing apart from rare MSI-high disease, which happens in [a small patient population]. There is a subset of patients who seem to have a long duration of response and prolonged survival [with] this combination…

[There are many] different lines and options for biliary cancer, which is incredibly exciting. Our standards of care now are gemcitabine and cisplatin with durvalumab [or] pembrolizumab [Keytruda], unless patients are ineligible for immunotherapy. We [also] have several options in the second-line setting. It's important to know what patients' molecular alterations may be. Chemotherapy does work in a second-line setting compared with best supportive care. 5-FU, liposomal irinotecan, or FOLFOX have shown benefit in that setting.

Integrating Supportive Care in Clinical Practice is Vital for Improving Patient Outcomes in CRC

Agarwal: When we're talking about support across the disease trajectory for HCC, we're talking about providing anticipatory guidance, navigating uncertainty, and [having] a multidisciplinary approach that really must be fluid to adjust to the function of the liver. In summary, supportive care can be integrated early and as appropriate to help mitigate total suffering and navigate uncertainty. Patients with GI malignancies need support and guidance for their cancer in the context of their unique biological and disease characteristics. It's important to review quality of life outcomes of trials when you're evaluating new treatment regimens, whether that's the first line or the refractory setting for all GI malignancies. [Lastly], changes in cancer care really do affect changes in supportive care integration.

Disclosures:

Dr Holowatyj reports receiving grants from The Dalton Family Foundation, the National Institutes of Health (NIH), Pfizer, the American Cancer Society and the Appendix Cancer Pseudomyxoma Peritonei (ACPMP) Research Foundation. She also chairs the Scientific Advisory Board for the ACPMP Research Foundation.

Dr Cardin reports receiving research support from Elicio Pharmaceuticals; Xbiotech Pharmaceuticals, Novartis; she served in an advisory role for KOL Connection and Clarivate Consulting.

Disclosure information was not found/submitted for Drs. Gibson, Byndloss, Ciombor, Padmanabhan, Goff, and Agarwal.