An Embarrassment of Riches Treatment Sequencing in Gastrointestinal Cancers

Laura W. Goff, MD, MSCI, MMHC

Professor of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center Executive Medical Director, Cancer Patient Care Center, Vanderbilt- Ingram Cancer Center Nashville, TN

Treatment options have expanded over the past few decades across many cancer types. Although these advances provide new opportunities for patients, they also pose new challenges for treatment sequencing for providers. In this article, Laura Goff, MD, MSCI, MMHC, discusses the current state and future directions of treatment sequencing in lower gastrointestinal (GI) cancers.

Q/ How has the question of treatment sequencing in GI cancers evolved over the past 10 years, and what is at stake when choosing a sequence of therapy for an
individual patient?

Goff /There is more attention being paid to the question of sequencing our treatments.^1,2 Thankfully, we have a lot more treatments, and they are more effective. We are seeing patients live longer, and we oncologists are charged with caring for patients over the course of their entire life. So we are thinking: How will this first-line therapy affect what options may be open to them down the road? How long will they live overall?

In addition, one of the more important factors when thinking about sequencing therapies is how patients will tolerate their therapy now and down the road. For example, we do not want to give a lot of therapy that will cause severe neuropathy early on in the course of a patient’s disease, because they may end up with neuropathy for the rest of their lives.³ Are there ways we could time that better, or space out therapies to minimize long-term toxicity? Are there ways to think about de-escalation to maintenance therapy, again, to prolong the quality of life for a patient while not sacrificing overall survival?

Q/ What are the barriers to addressing the issue of treatment sequencing?

Goff /There are several barriers to addressing treatment sequencing. One may be a relative lack of data. It is hard to collect data over a long period of time, or subsequent lines of therapy, due to the nature of how clinical trials are conducted. Patients move around, and may change centers, so it may be hard to keep track of all of the data longitudinally. Especially now that patients are living longer, it may take many years to ascertain: What impact does the choice of the first-line therapy have on how long a patient lives?

Other barriers, notably in some of the GI cancers, are that the standards of care can change, which is a wonderful thing.¹ But it changes our understanding of what to do next, when the frontline therapy has changed.

Biliary Tract Cancer

Q/ In broad strokes, how are therapies currently sequenced in biliary tract cancer?

Goff /In the advanced setting, the current frontline standard involves gemcitabine and cisplatin chemotherapy combined with immunotherapy, either durvalumab or pembrolizumab.⁴ Following that, we have a few options, and that is where things become more of an art than a science. Tailoring the subsequent therapies to the individual patient becomes critically important. We may need to make some decisions based on whether they have abnormal liver function tests or elevated bilirubin. Obviously, if they have a driver gene alteration, that is going to affect our choices.⁵ We also need to evaluate other potential overlapping toxicities. For example, if patients have preexisting neuropathy, oxaliplatin may not be a particularly good choice.² As additional lines of therapy are being considered, the likelihood of benefit gets smaller, which makes an in-depth discussion on the patient’s goals and wishes critically important.

All patients with biliary tract cancers should have molecular testing done on their tumors, if at all possible.⁶ Right now, molecularly targeted therapy is primarily standard in the second line and beyond. There are ongoing clinical trials looking at moving up molecularly selected treatments to the earlier lines of therapy.² Patients who have a driver gene alteration in 1 of several pathways would typically receive that targeted therapy in the second line. If no molecular alteration is found for a patient, then there are a couple of different chemotherapy options, either FOLFOX chemotherapy, or 5-fluorouracil with nanoliposomal irinotecan.

Q/ What are some of the greatest unmet needs regarding treatment sequencing in biliary tract cancer?

Goff /Always we would like more therapies and more effective therapies in order to treat patients well. Some of the interesting questions that we will be looking at over the next few years will be: Is there a value to continuing immunotherapy beyond the first line with chemotherapy?² Certainly, there is the question of whether targeted therapy is going to supplant first-line chemoimmunotherapy. Is there a value in combining targeted therapy with chemotherapy, with immunotherapy, and in what order? Are we best serving our patients for their overall survival?

Hepatocellular Carcinoma

Q/ What percentage of patients have an actionable mutation in this disease state? Who should have gene testing?

Goff /Actionable alterations in pure hepatocellular carcinoma (HCC) are rare.¹ Patients should continue to undergo next-generation sequencing if they are fit for therapy, because what we are finding is that we may still identify patients who have a mixed phenotype, the combined hepatocellular carcinoma and cholangiocarcinoma. We will intermittently find patients who have a classic cholangiocarcinoma driver alteration—an FGFR fusion, for example.⁷ This is likely due to the fact that they come from a common progenitor cell.

Q/ How has the introduction of immune checkpoint inhibitors as first-line therapy disrupted treatment sequencing algorithms for subsequent therapies that were based on first-line sorafenib?

Goff /The arrival of atezolizumab and bevacizumab, and then subsequently other immune checkpoint inhibitor combinations, has blown up our algorithms for how we care for patients with hepatocellular carcinoma.¹ Again, in the best possible way. We are thrilled to have this problem of questioning which of our effective regimens do we need to use first and are our subsequent therapies still active following our new immunotherapy combination doublets.

Q/ What other factors are shaping the discussion of treatment sequencing in HCC?

Goff /Whenever we are taking care of patients with hepatocellular carcinoma, we have to be mindful that many of them have background comorbidities, particularly cirrhosis.¹ So, we are oftentimes dealing with 2 diseases: hepatocellular carcinoma and cirrhosis. This can affect the options that patients are able to tolerate. In HCC, we have 2 pathways that we are targeting when we treat. We target the immune system with immunotherapy, and we target the VEGF pathway, sometimes with additional targets.

Does it make sense to use those 2 classes of drugs up front? Or is it better to space those out? Are there some patients for whom targeting VEGF is really off the table? Specifically, patients with cirrhosis may not be candidates for VEGF inhibition if they have large varices or background significant cardiovascular disease, which is now a growing risk factor for metabolic-associated hepatotoxicity.⁸

Q/ What are some of the greatest unmet needs regarding treatment sequencing in HCC?

Goff /We have a couple of critical questions to answer in the treatment of hepatocellular carcinoma in the near future. First, is there a best first-line regimen? As of ASCO 2024, we have 3 doublet regimens that have all been standard frontline tyrosine kinase inhibitors (TKIs). We have atezolizumab and bevacizumab, durvalumab and tremelimumab, and now nivolumab and ipilimumab, all of which showed improvement in overall survival compared with frontline TKIs.^9-11 We do not know if 1 of those 3 regimens is better than the others to start.

We do not know if there is a benefit to starting with lower dose immunotherapy, or atezolizumab and bevacizumab, and saving the ability to escalate to nivolumab and ipilimumab. Or is it better to maximize our immunotherapy up front, and get a high response rate? Will that put patients at the highest likelihood of really prolonged overall survival? It is hard to say at the moment what the right first-line regimen is.

Additionally, we would like to know [the answer to] a question similar to those with biliary tract cancer: Is there value in extending immunotherapy beyond the first line, either in combination with an alternative VEGF targeting agent, or in escalating therapy from a single to a doublet, or in the case of the MONTBLANC study (NCT05844046), from a doublet to a triplet in the second line?¹²

Our preliminary suggestions from a couple of small prospective studies are that single-agent TKIs do seem to perform about the same in the second-line regimen following immune checkpoint inhibitor–containing regimens as they did following frontline sorafenib.¹ It is still a modest response, but quite similar. But again, we have a lot of questions. Does it matter what you do first? Does it matter what you do second? I think we still have a lot to figure out.

Colorectal Cancer

Q/ How does the conversation around treatment sequencing differ in colorectal cancer vs other GI cancers?

Goff /Patients with colorectal cancer have historically lived longer than patients with hepatobiliary cancers.¹³ We have known from the care of patients with colorectal cancer that thinking about the course of their life possibly over many years makes it really, really important to incorporate considerations about toxicity and long-term adverse effects of therapy in the decision-making when planning the sequence.

Because colorectal cancer is more common, some of the sequencing questions are a little bit farther along. At ASCO, we saw data about the combination of nivolumab and ipilimumab in patients with microsatellite instability (MSI)–high colorectal cancer.¹⁴ One of the most interesting components was seeing that even PFS-2 was improved for patients who had gotten first-line nivo-ipi.¹⁵ We were able to start to see how even in the second line, the choice of first-line therapy was continuing to have an impact.

The other interesting hint we get from colorectal cancer sequencing is in the area of HER2-positive colorectal cancer. HER2 positivity happens in biliary tract cancers as well, but because colorectal cancer is more common, we have been able to see a little bit about how the sequencing of targeted therapies may be developed.¹⁶ For HER2 colorectal cancer, tucatinib plus trastuzumab is often used as the first HER2 therapy, following frontline chemotherapy.¹⁷ Trastuzumab deruxtecan works in patients who have received other HER2-directed therapy, but it may have some higher rates of adverse effects.¹⁸ Therefore, the treatment algorithm is evolving where tucatinib plus trastuzumab may be sequenced first, then utilizing trastuzumab-deruxtecan upon progression.¹⁷ These data points are things we hope to eventually have for the treatment of other hepatobiliary cancers.

Looking Forward

Q/ Have any exciting data regarding treatment sequencing clinical trials recently been presented, or is there anything you’re looking forward to?

Goff /The study of regorafenib plus pembrolizumab following progression in hepatocellular carcinoma that was presented at ASCO is quite important in our understanding of historical response rates for patients following progression on immune checkpoint inhibitor-containing regimens.¹⁹ Although the response rates are low, this prospective data is foundational to our understanding for future studies. This is coupled with the recent publication of the outcomes of cabozantinib following the frontline treatment with an immune checkpoint inhibitor, also in hepatocellular carcinoma.²⁰ Again, there was a low response rate of about 6.4%, but still on par with the responses we were seeing from cabozantinib following progression on frontline TKI.

We are all eagerly awaiting the results of the IMbrave251 study (NCT04770896), which will really look at the question of continuation of immune checkpoint inhibitor therapy beyond the first line.²¹ For patients who had progressed on atezolizumab plus bevacizumab, this is a randomized trial of continued immune checkpoint inhibitor with TKI vs TKI alone. That should give us more robust data to determine the role of continuation of immune checkpoint inhibitor therapy in the second line.

Key References

1. Cammarota A, Zanuso V, Manfredi GF, Murphy R, Pinato DJ, Rimassa L. Immunotherapy in hepatocellular carcinoma: how will it reshape treatment sequencing? Ther Adv Med Oncol. 2023;15:17588359221148029. doi:10.1177/17588359221148029
2. Wheless M, Agarwal R, Goff L, Lockney N, Padmanabhan C, Heumann T. Current standards, multidisciplinary approaches, and future directions in the management of extrahepatic cholangiocarcinoma. Curr Treat Options Oncol. 2024;25(1):127-160. doi:10.1007/s11864-023-01153-5
3. 19. El-Khoueiry AB, Kim T-Y, Blanc J-F, et al. International, open-label phase 2 study of regorafenib plus pembrolizumab in patients with advanced hepatocellular carcinoma (HCC) previously treated with immune checkpoint inhibitors (ICI). J Clin Oncol. 2024;42(suppl 16):4007. doi:10.1200/JCO.2024.42.16_suppl.4007

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Discuss current state of affairs and future directions of treatment sequencing in GI cancers

• Describe challenges in addressing unmet needs in treatment sequencing in GI cancers

RELEASE DATE: July 1, 2024 EXPIRATION DATE: July 1, 2025

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In accordance with Accreditation Council for Continuing Medical Education (ACCME) guidelines, PER has identified and resolved all conflicts of interest for faculty, staff, and planners prior to the start of this activity by using a multistep process.

Disclosures (Dr Goff): Grant/Research Support: Agios, ASLAN, Basilea, BeiGene, Bristol Myers Squibb, Merck; Consultant: Boehringer Ingelheim, Exelixis, Merck, QED, Relay

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