Rapidly Expanding Treatment Armamentarium Improves Outcomes and Instills Hope in Patients With GI Cancers

Daneng Li, MD

Across gastrointestinal (GI) cancers, the development and subsequent expansion of immunotherapies and targeted therapies is extending and improving patients’ lives, mitigating the negative effect of treatment-related toxicities, and allowing practitioners to personalize treatment approaches for patients with historically limited treatment options, according to Daneng Li, MD.

“When I first started in GI oncology over 10 years ago, we didn't have much more than FOLFOX [(fluorouracil, leucovorin, and oxaliplatin) in our arsenal]. Now, whether it's colorectal cancer [CRC], gastroesophageal cancer, pancreatic cancer, hepatocellular carcinoma [HCC], or biliary tract cancer, there are all these options that might be available,” Li said following an OncLive® State of the Science Summit™ on gastrointestinal (GI) cancers, which he chaired.

In an interview with OncLive regarding this meeting, Li discussed the evolution of targeted therapy in HCC, the association between immune-related adverse effects (AEs) and patient outcomes in this population, and how early findings from the phase 1/2 Morpheus-Liver study (NCT04524871) support the continued investigation of triplet combinations in HCC.

Li also provided key insights on topics discussed by his colleagues at City of Hope, including the importance of biomarker testing in gastroesophageal and biliary tract cancers, the potential role for targeted therapy in first-line CRC treatment, and when to choose neoadjuvant therapy over upfront surgery and adjuvant therapy in pancreatic cancer.

Li is an associate professor in the Department of Medical Oncology & Therapeutics Research, and co-director of the Neuroendocrine Tumor Program at City of Hope in Duarte, California.

OncLive: How has the evolution from the prior standard of care (SOC) sorafenib (Nexavar) to novel immunotherapies helped improve the treatment landscape in HCC?

Li: The development of immuno-oncology [in] HCC has revolutionized the field for patients with advanced unresectable liver cancer. Going back 4 or 5 years ago, our treatment options were very limited, and many of our patients were not able to live for a prolonged period. With the advent of immunotherapy, particularly novel immunotherapy combinations, our patients are living much longer. Most of our patients are [also] tolerating these therapies much better, so they're not only living longer, but they’re also living better.

How might immune-related adverse effects (irAEs) be used as an early marker of positive response in HCC?

irAEs are complex. I usually tell my patients that if they have some mild irAEs, that might be a good thing, because it might be a sign of the immune system being active and potentially eliciting an action on the tumor itself. We're usually looking for things like new itchiness, a minor rash, [or] some effects on thyroid function. Those are [some] early things that we see. That's reassuring to patients because they're often worried about these AEs. If you can tell them that it could be an early sign of immune activation, that provides reassurance. Certainly, that's what was shown in the subgroup analysis of the phase 3 HIMILAYA trial [NCT03298451]. Patients who had these irAEs did better and had longer overall survival [OS] compared with those who did not.

What has been seen thus far with the use of atezolizumab (Tecentriq) and bevacizumab (Avastin) plus tiragolumab in the Morpheus-Liver study? How might the regimen affect patients' treatment expectations?

[Investigation of] the combination of atezolizumab plus bevacizumab and tiragolumab is aiming to take a step forward. We now have combination treatments that have been able to help our patients significantly in terms of [improving] OS and disease control, as well as [reducing] potential delays and negative quality of life measures [QOL]. [This research] is [asking] how we can build upon that foundation and have even more patients respond to treatment. The addition of tiragolumab [is meant] to really build a foundation for triplet therapy [in HCC].

In the Morpheus-Liver study, we found an encouraging increase in objective response rates [(ORRs) with the experimental regimen]. In addition, there was prolonged progression-free survival [PFS], meaning good, durable tumor control [was experienced by] most of our patients on the early phase study. This warrants additional investigation. There's a [planned] phase 3 study, [IMbrave152/SKYSCRAPER-14 (NCT05904886)],that's about to be launched with a combination of atezolizumab plus bevacizumab plus tiragolumab vs SOC atezolizumab plus bevacizumab. This will define [whether] we are able to provide triplet therapy to our patients as a new SOC at this point.

As discussed by Afsaneh Barzi, MD, PhD, what do data with zolbetuximab (IMAB362) in Claudin18.2 (CLDN18.2)-positive, HER2-negative gastroesophageal junction (GEJ) adenocarcinoma indicate about the importance of testing for CLDN18.2 expression in this population?

In gastroesophageal cancer, there are many different strategies for approaching [the treatment of] our patients. One of the recent developments that is very promising is the potential applicability of targeting CLDN18.2. This provides a novel targeting mechanism that we haven't previously had in this disease. We've seen what [targeting] HER2 amplification has done for this disease, and hopefully CLDN18.2 will be a new target that we can really take advantage of moving forward. Based off the initial phase 3 results [from the SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials], the combination of targeting CLDN18.2 [with zolbetuximab] plus chemotherapy is [promising].

Shifting to the presentation given by Marwan Fakih, MD, how has the current landscape of HER2-targeted therapies for patients with metastatic CRC evolved over time? Could these targeted therapies have a greater effect in the first-line setting?

We've come very far with HER2-targeted therapy. Initially, we only had trastuzumab [Herceptin], and [we went on to] develop more [options such as] pertuzumab [Perjeta]. Now, there are 8 additional combination agents, such as tucatinib [Tukysa] in combination with trastuzumab as well as fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd]. We’re seeing encouraging responses with all these HER2-targeted treatments. Several questions remain, [including] the ideal sequencing of these treatments moving forward.

There may be opportunities in the first-line setting to potentially combine [HER2-targeted therapies] with chemotherapy. [In] patients with somewhat limited disease, we're always trying to [produce] as high of an objective response as possible to potentially downstage patients. If you can get the number of lesions down in [patients with] CRC so there's limited tumor available, it's potentially still curable, even with stage IV disease. [Future research] should look at whether HER2-targeted therapy in combination with chemotherapy can heighten response rates in the first line.

In which scenarios would you utilize total neoadjuvant therapy vs proceeding to immediate surgery followed by adjuvant therapy in pancreatic cancer, as per the data presented by Vincent Chung, MD?

In the United States, we've started to go in the direction [of using neoadjuvant approaches over proceeding directly to surgery]. [However], many of the recent studies that have been presented [have] caused us to [question] whether that is the optimal strategy. At [City of Hope], our practice is that patients who potentially have resectable pancreatic adenocarcinoma are taken straight to surgery. Given the limitations for cross-trial comparisons, patients who end up getting surgery and complete adjuvant treatment tend to have long OS, [whereas] some recent data [have shown] that using a neoadjuvant approach in this setting [may not prolong] OS [as much]. [Therefore], completely resectable patients [should] still go [directly] to surgery and follow the algorithm in terms of adjuvant therapy.

There's still a significant role for neoadjuvant therapy in patients who are potentially borderline resectable because we don't want to go in and have to abort a surgery [for these patients]. This is a [space] for [using] neoadjuvant approaches to test the tumor biology. [It could allow us to] see whether the tumors will ultimately metastasize during that time, or whether we can get additional shrinkage and better control, leading to completion surgery. That's where [this approach is] still necessary.

There's an ongoing Alliance trial looking at triplet combination chemotherapy in the neoadjuvant setting. [This trial will give us] a better idea of whether those results will align with recent studies showing some limitations with neoadjuvant therapy. Until then, we won't know for sure. For us [at City of Hope], it's clear that we would use neoadjuvant [therapy] in the borderline[-resectable] setting, but not necessarily in the [definitively] resectable setting.

As discussed by Richard T. Lee, MD, why is it vital to utilize next-generation sequencing (NGS) when selecting between targeted therapies in the first and second line in biliary tract cancer?

Biliary tract cancer is a heterogeneous group of disorders. Traditionally, we've lumped gallbladder cancer [in with] extrahepatic cholangiocarcinoma, [which we've considered] the same as intrahepatic cholangiocarcinoma [in this disease category]. We've come to find out that these are [at least] 3 different diseases. This is highlighted by the fact that NGS of these patients [reveals] different targetable mutations. We have FDA approved agents that can be used for these patients, depending on what targets are found. [These include] HER2-targeted therapy, BRAF-targeted therapy, [as well as] therapies that target FGFR2 fusions or IDH1 mutations.

It's important that every single patient with biliary tract cancer undergo NGS as early as possible. It might not change initial management [approaches], [as many] patients in the United States [often] want to start treatment right away. [Undergoing NGS] doesn't [mean patients] need to pause their first-line therapy. [However], it can [inform the choice of] subsequent lines of therapy at the time of disease resistance to frontline therapy. There are now many medications in our arsenal, so it's important to test [patients] upfront to help them plan their entire journey.

What main message would you like to impart to colleagues from this event?

The world of GI oncology is changing at a rapid pace. That's due to [increased] focus [on developing] novel therapeutics in this field. That has changed the lives of our patients. [We now have a range of] targeted therapies and novel targets, [as well as] immunotherapies for biliary tract cancers and HCC. These [developments] are encouraging, and [enable] us [to tell] our patients that we have a lot of options for them. A decade ago, we didn't have as many options, [and weren't] even close to being able to tell our patients [this].

Please highlight any key research in GI oncology that is being conducted at City of Hope.

At City of Hope, we are engaged in developing the next generation of novel therapies. One of our institutional priorities is looking at the role of cellular therapy. For all these diseases, we have established ongoing clinical trials looking at novel cell therapy approaches, [such as] T-cell receptor therapy or CAR T-cell therapy. This could be the future not only for GI oncology, but for [all] solid tumors. We're leading the way on that. This brings hope to our patients that [there may be] a completely new type of treatment for them [in the future.]