Strides in GI Cancer Subsets Influence Advances

Tanios S. Bekaii-Saab, MD

A few decades ago, in gastrointestinal (GI) cancers, the standard of care for various malignancies was fluorouracil. Now molecular classifications are guiding treatment decisions as advances in subgroups of patients drive the momentum of the rapid changes across tumor types.

For example, the trajectory of treatments for patients with chemotherapy-refractory, HER2-positive metastatic colorectal cancer (CRC) has evolved from limited treatment options to having several targeted modalities. Patients have derived a clinical benefit with tucatinib (Tukysa) plus trastuzumab (Herceptin) according to data from the phase 2 MOUNTAINEER trial (NCT03043313) and in January 2023, gained a second option with tucatinib tacking on another FDA approval for patients with RAS wild-type HER2-positive disease.^1-3 Further, fam-trastuzumab deruxtecan-nxki (Enhertu) has bolstered efficacy according to data from the DESTINYCRC01 trial (NCT03384940).⁴

Expert perspectives on integrating the latest research and standards in testing into clinical practice will mingle with findings from original abstracts during the upcoming 20th Annual Meeting of the International Society of Gastrointestinal Oncology (ISGIO), hosted by Physicians’ Education Resource, LLC (PER). The multidisciplinary conference is set to take place as an interactive hybrid meeting October 13 and 14, 2023, virtually and live in Tempe, Arizona. This year’s meeting will feature presentations from investigators who have led key trials, according to Tanios S. Bekaii-Saab, MD, who serves as program cochair. Bekaii-Saab is a professor of medicine at Mayo Clinic College of Medicine and Science and a consultant in the Division of Hematology/Oncology at Mayo Clinic in Scottsdale, Arizona.

Bekaii-Saab will colead the meeting with Weijing Sun, MD, FACP, who is the Sprint Professor of Medical Oncology and director of the Medical Oncology Division at the University of Kansas School of Medicine and associate director of the University of Kansas Cancer Center (KU Cancer Center) both headquartered in Kansas City.

In an interview with OncologyLive, Bekaii-Saab highlighted the unmet needs in GI malignancies and discussed how interdisciplinary meetings, such as ISGIO, provide the framework for disseminating information and driving innovative advances.

What is the largest unmet need in the GI space?

We’re starting to see a lot of benefit with more targeted therapies with immune therapies, but unfortunately, these remain extremely limited to a small subset of patients across GI malignancies. One of the biggest challenges is how to expand those benefits to many patients. Is it by breaking down the various GI cancers into smaller and smaller subgroups? With immunotherapy can we identify better biomarkers for patients with nonmicrosatellite instability [MSI]–high tumors?

[We have tried the] strategy where you take all patients and try to turn their tumor from cold to hot, and that has failed. But it is obvious that there’s a small subgroup of patients who may benefit, but they are yet to be determined. How do we best move forward with those patients and, at the same time, create new ways to bring immunotherapy closer to many of these cancers?

Same with targeted therapies. Take for example, HER2 in colorectal cancer. The benefit is immense for 40% of the patients, yet 60% don’t see that benefit. What’s going on for that 60%? There are a lot of questions that still need to be answered, including how we can improve that 40% to 100% and identify early signs or early mechanisms of resistance for the 40% who may progress at some point.

What applies to HER2 applies to FGFR, immune therapy, and so many [other] things. Although we have improved outcomes significantly in lots of these cancers by identifying targets of relevance, that benefit remains limited to few patients.

Expanding that beyond the few is the biggest unmet need. I think we’re on track, but we’re not where we need to be.

What have some of the trends been in the difficult-to-treat cancers, such as pancreatic cancer and neuroendocrine tumors (NETs)?

Pancreas cancer is one of the most challenging cases, and one example of some of the changes that have been happening is breaking down this cancer into multiple subgroups. One of those is a rare alteration in KRAS [called] G12C, which was not [actionable] before. Thinking about G12C and the advances we’ve had, one of the topics is how we move beyond G12C, which is a less common target, to G12D, to G12V, to others, since we’re starting to see that 1 KRAS that we never imagined was druggable is now druggable, but unfortunately, the only druggable piece of it is a rare piece.

Relating to neuroendocrine tumors, one of the challenges that has been ongoing is where we place peptide receptor radionuclide therapy [PRRT]. How does it fit in the overall schema of [managing] NETs? We want to know if they have a role beyond what was studied and what the experience has been like with them. What are the challenges and next steps?

We’ve seen incredible outcomes with PRRT for a lot of these patients, with some responses that we’ve never seen before. But it’s not [an option] for all. NETs are very diverse in their origins and their behavior, so we want to know how we can expand.

With NETs and pancreas cancer, what we’re trying to do is discuss the advancements that are happening in real time and challenge the practical solutions for a more diverse clinical practice. [We want to] continue to build on those favorable experiences.

A recent paper, which you coauthored, highlighted the role of immunotherapies in biliary tract cancers.⁵ What emerging trends do you anticipate seeing for this patient population and what studies are driving the progress?

There are 2 studies: TOPAZ-1 [NCT03875235] with durvalumab [Imfinzi] and chemotherapy and then KEYNOTE-966 [NCT04003636] with pembrolizumab [Keytruda] and chemotherapy, and both were in unselected patient populations. [Outcomes] showed a slight improvement, which seems to be most meaningful for approximately 10% to 20% of the patients. But that didn’t seem to add much value for the other 80% of patients. The problem is we don’t have the tools today to select the 20% [suitable for treatment] and spare the other 80% treatment with the immunotherapy. Then how do we study that subgroup of patients that doesn’t appear to benefit and see if we can enhance outcomes with an anti–PD-1, VEGF inhibitor, anti–CTLA4, or LAG3 inhibitors?

Immunotherapy seems to be now established as part of our standard for first-line therapy with gemcitabine and cisplatin, but many questions remain, mostly related to selection. Where do we go next? We are trying to understand if there are any biomarkers that help us better select patients who may respond or exclude those who do not and develop strategies to enhance response, whether that’s adding other agents. Those are all unmet needs that remain, although it’s obvious that immunotherapy is here to stay in for most patients with potential costs.

In CRC, with targeted therapeutics on the rise, what variants should patients be tested for and what unmet needs exist for community clinicians?

For CRC there are multiple targets of interest, but the 4 most relevant at the point of entry when the patient sees the clinician is to have HER2 expression, BRAF, and RAS mutations assessed, and microsatellite status. Because MSI would lead you to first-line therapy and HER2 amplifications would lead you to exclude patients from receiving EGFR inhibitors. Eventually it will also help you assess which patients would need HER2-targeted therapies. BRAF mutations will also help you exclude EGFR inhibitors and assess patients who may be qualified for RAF-directed strategies in second line and beyond. RAS mutations may help identify patients who may need to be considered for an EGFR inhibitor plus a RAS inhibitor, such as those with G12C [point mutations] who are eligible for an agent such as adagrasib [Krazati], which has efficacy in that subgroup of patients.

There are also other targets of interest, such as NTRK fusions, which are not as relevant in the early stage of the disease, at least for now. Those would be something that you want to look for as well as RET fusions and other alterations that continue to emerge. These are rare fusions, but they may have some point of relevance. But from the get-go, you have 4 elements that are key— MSI status, HER2 amplification, BRAF V600E mutations, and RAS mutations. You need those 4 to make any decision before you move to firstline therapy and beyond.

It’s standard to do MSI-high, ROS1, and I still see BRAF. HER2 amplification is an emerging target and has an FDA approval now and second line, but I think for the community, what they need to understand is that it is an important element to help them essentially decide on who should not be receiving EGFR inhibitors.

What are the testing barriers to treatment administration community oncologists face?

The logistical challenges are how you get the tissue and then how you get the tissue to the right place. Beyond that it’s how we, in a timely fashion, get the results from that tissue, so that we can come up with a treatment plan for the patient. That certainly is a big challenge.

What I do is for patients who I see first, I [order] liquid biopsy as I’m requesting and sending out the tissue. The reason for this is liquid biopsy will give me results in a week. Now, if [the mutations] are not on liquid [results], that doesn’t mean it’s not in the tissue. But if it’s in liquid, it is in tissue. And so, in that sense, a positive is good, because it saves time on waiting on the tissue. We’ve started using more of this dual approach of liquid and tissue at the same time to resolve some of the logistical problems that we face with just tissue testing. It doesn’t help with all the patients, but at least with a large majority of them, where we have a quick assessment as we’re waiting for tissue confirmation, but we can move forward with liquid results.

How has the role of the multidisciplinary team evolved in GI cancers?

At every aspect of our care, a multidisciplinary team is important but more so in the earlier stages of the disease. In hepatocellular carcinoma [HCC], for example, the multidisciplinary team remains committed to the patient all the way through until the disease becomes more advanced because you need to have pathology, you need an interventional radiologist, you need early assessment. We’re bringing some patients from nontransplant eligible to transplantable, from unresectable to resectable. You want that team to be present at all times.

Further, our modalities in HCC, for example, we’re examining the role of combining locoregional with systemic approaches. In data from IMbrave050 [NCT04102098] adjuvant therapy with atezolizumab [Tecentriq]/bevacizumab [Avastin] is likely to become a standard option for our patients.⁶ Now more than ever, multidisciplinary involvement is needed. The same is true in pancreas cancer, at least in the early stages of the disease, and in colon cancer. Oligometastatic disease is a multidisciplinary problem and needs to be addressed as such with locoregional and systemic therapy.

For some aspects of our care, you need full involvement of the multidisciplinary team to optimize outcomes and survival.

As a chair of the 2023 ISGIO conference, how would you say it has changed in the past few years?

Things have evolved quite a bit over the past 3 to 4 years at ISGIO. The meeting has been revitalized, reenergized, and expanded geographically as it has started moving locations. The quality of the sessions and the involvement of multidisciplinary speakers has certainly brought ISGIO to the next level.

The goal of ISGIO is to not only bring the most up-to-date, cutting edge information [to the audience], but also ensure that it’s discussed in a way that’s relevant to the day-to-day practice. So, the way that ISGIO is built is that you take the latest, the best, the most complex issue or modality [and deliver it in a] practice-informing, practice-changing format. ISGIO ends up being at the heel of a lot of the meetings that happened during the year from the ASCO [Gastrointestinal Cancers Symposium] to the ASCO Annual Meeting to the American Association of Cancer Research Annual Meeting, so there’s a lot of information that has percolated through the year that gets summarized and formatted in a way that is friendly to the practitioner.

What do you want the attendees of ISGIO to come away with after the conference?

The key piece here is we want to deliver an understanding of how the treatment paradigm continues to shift and learn how to take that shift and adapt it to the current clinical practice. We also want to stimulate and excite [attendees] about what’s coming next. And we hope that the “what’s next” is not just a checkbox that we’re going to wait on, but [will incite] wider participation in clinical trials and [increase] referrals for trials that continue to advance the case. We want to [focus on] how things are affected in the current practice and how we can participate in or create solutions for practice in 2024, 2025, 2026, etc.

References

1. Strickler J, Cercek A, Siena S, et al. Primary analysis of MOUNTAINEER: a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol. 2022;33(suppl 4):S375-S376. doi:10.1016/j.annonc.2022.04.440
2. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. April 20, 2020. Accessed May 31, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tucatinib-patients-her2-positive-metastatic-breast-cancer
3. FDA grants accelerated approval to tucatinib with trastuzumab for colorectal cancer. FDA. January 19, 2023. Accessed May 31, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-tucatinib-trastuzumab-colorectal-cancer
4. Strickler J, Cercek A, Siena S, et al. Primary analysis of MOUNTAINEER: a phase 2 study of tucatinib and trastuzumab for HER2-positive mCRC. Ann Oncol. 2022;33(suppl 4):S375-S376. doi:10.1016/j.annonc.2022.04.440
5. Serrano Uson Junior PL, Bekaii-Saab TS. Moving beyond single-agent checkpoint inhibition in biliary tract cancers: what is the next frontier? Immunotherapy. 2023;15(7):531-540. doi:10.2217/ imt-2022-0201
6. Chow P, Chen M, Chen AL, et al. IMbrave050: phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation. Cancer Res. 2023;83(suppl 8):CT003. doi:10.1158/1538-7445.AM2023-CT003