Novel Second-line Treatments Expand Therapeutic Options in Gastrointestinal Cancers

Kelsey Klute, MD

Second-line treatment developments are receiving increased focus in gastrointestinal (GI) cancers, said Kelsey Klute, MD, who also emphasized the importance of investigating the best ways to select and sequence treatment combinations in this new era of immunotherapeutic and chemotherapeutic advances.

“The second-line setting is a tough space, because a lot of these patients are very sick, and they decline very quickly. One of the big challenges in designing second-line trials [in pancreatic cancer] is: How do we select patients who are likely to get the therapy and have a chance to benefit from it but also design a trial in such a way that it’s representative of these patients?” Klute said in an interview with OncLive^® following an Institutional Perspectives in Cancer webinar on GI cancers, which she chaired.

In the interview, Klute, assistant professor of internal medicine in the Division of Oncology and Hematology at the University of Nebraska Medical Center, reviewed key points from each presentation shared at the meeting, including the importance of frontline checkpoint inhibitors in advanced gastric cancer and the need for predictive biomarkers in hepatocellular carcinoma (HCC). Klute also highlighted ongoing and upcoming research at Nebraska Medicine investigating the effects of immunotherapy in HER2-negative gastric and esophagus cancer and esophagus and gastroesophageal junction (GEJ) cancer.

OncLive^®: In your presentation on pancreatic cancer, you highlighted the phase 3 NAPOLI 3 trial (NCT04083235). What are the clinical implications of the data, and what do the findings mean for trial development?

Klute: In terms of clinical implications, the NAPOLI 3 study highlights that there are patients who benefit from second-line therapy. This trial opened the door for asking how to do second-line trials and gave us a standard to compare to.

We have many therapies that we use in the second-line setting that haven’t necessarily been studied in such a rigorous way. In the future, [we will move away from] trying to understand how well gemcitabine plus nab-paclitaxel [Abraxane] works after FOLFIRINOX and instead try to introduce novel agents into that second-line setting.

What would you like to emphasize to your community partners about treatment development in pancreatic cancer?

The first thing to emphasize in this population is that although there may be some benefit to second-line systemic therapy, [it’s just as important, if not more important, to consider] the supportive care. [Adverse effects] like pain, nausea, vomiting, and pancreatic insufficiency are somewhat unique challenges in this population that are tricky to manage, take a lot of time to manage, and can easily be overlooked. If someone with pancreatic insufficiency is having diarrhea every time they eat, you can easily trace that back to the irinotecan they’re getting with their chemotherapy.

It takes a lot of dedicated time to sort out what’s going on with these symptoms. However, managing them can go a long way in terms of patient longevity, and more importantly, their quality of life.

Your colleague, Mridula Krishnan, MBBS, of Nebraska Medicine, spoke about HCC, highlighting studies such as the phase 3 IMbrave150 (NCT03434379), CELESTIAL (NCT01908426), COSMIC-312 (NCT03755791), and HIMALAYA (NCT03298451) trials. What are the implications of those studies?

The biggest implication is that, at this point, we have a huge number of active drugs for advanced HCC, which is exciting. The biggest questions now are: How do we sequence these drugs? How do we best select patients for immunotherapy and dual checkpoint blockade? Having all these options is a good problem to have. Currently, we just do not know how best to use them.

We’ve seen biomarkers be somewhat helpful in guiding treatment selection in certain solid tumors like lung cancer. Has that panned out in HCC?

It has not panned out much at all in HCC. At this point, it’s not clear who benefits most from immunotherapy since we don’t have a good biomarker. PD-L1 doesn’t seem to be a great biomarker in terms of predicting response. We have a lot of work to do to sort that out.

Laura Tenner, MD, MPH, of Nebraska Medicine, spoke about the role of immuno-oncology in GI cancers, discussing studies such as the phase 3 CheckMate649 trial (NCT02872116) and the phase 2 DESTINY-Gastric02 trial (NCT04014075). What is the importance of these data on treatment sequencing?

[These studies showed] the importance and benefit of incorporating checkpoint inhibitors into frontline therapy for advanced gastric cancer. That’s been an exciting point of progress because there hasn’t been much movement in first-line therapy for a while. Platinum plus 5-fluorouracil [5-FU] has been the standard of care, so to see a benefit with the addition of immuno-oncology agents is exciting.

Regarding the DESTINY-Gastric02 trial, it’s nice to see some of that data replicated in the US population. The original study came out of Asia, and there are many differences in how these cancers present and how sick these patients are between the United States and Asia. It’s always a little tricky to understand how a drug that that works well in an Asian population will benefit a US population, so it was great to see the study discussed in western patients.

Advanced gastric cancer is another disease in GI oncology where our number of therapeutic options is expanding. One of the biggest challenges here is that many patients don’t see more than a few lines of therapy. Again, the question is: How do we best select a drug for a patient? PD-L1 seems to be a good biomarker in gastric cancer in terms of predicting degree of benefit from immunotherapy. But in terms of selecting later lines of therapy, such as a HER2-directed therapy or chemotherapy, we don’t have a great means for deciding what to choose next, aside from retesting for HER2 in the second- or third-line setting. We have all these options, and what we need next is a roadmap to tell us how to choose the right therapy for the right patient at the right time.

James Padussis, MD, of Nebraska Medicine, presented on liver resection and liver-directed therapy for colorectal cancer (CRC) with liver metastases. Where do these approaches fit in with systemic therapies?

One of the most important things that I take away from these talks is that in a patient with CRC and liver metastases, various liver-directed therapies should always be discussed or at least be on the table. As a medical oncologist, it’s easy to [default to the next line of chemotherapy. However, I also need to constantly be thinking about whether a patient is] a candidate for resection or hepatic artery infusion.

We should always remember that [patient care should include] multidisciplinary discussions. If a community doesn’t have direct access to a surgeon, we’re here, and we’re happy to see these patients and discuss them with our full multidisciplinary team. We have many ways that we can target liver metastases. It’s a matter of thinking about these options and making sure patients see the right specialists or hear about all the options.

Managing these patients outside the context of a big medical center can be tricky for community oncologists, especially in smaller communities without big hospitals, surgeons who are doing these resections, and access to interventional radiology. Community oncologists should realize that we are more than happy to help entertain those options.

Additionally, hepatic artery infusion was, for a while, a thing of the past but it’s coming back on the scene. There are many interesting studies going on that are sparking renewed interest in using it, which is exciting. At Nebraska Medicine, we’re working on getting our program set up to hopefully make that option available to patients in Omaha [in 2022].

Why do you think hepatic artery infusion fell by the wayside but is now the subject of renewed interest?

Part of the reason its use declined was because of toxicity and complications with the pumps. There was also increasing excitement about more effective systemic therapies. But now we’re seeing our patients live longer and longer. Patients with liver-only metastases have undergone resection and liver-directed therapies with interventional radiology. We are back to looking for more options for these patients, [including hepatic artery infusion]. The management of these patients has just become increasingly multidisciplinary over the course of the past decade. So hepatic artery infusion is becoming another important therapy to have in our back pocket.

Is there any ongoing or planned research at Nebraska Medicine that you’d like to highlight?

One study I’d like to highlight is a first-line study for advanced HER2-negative gastric and esophagus cancer. This study is essentially asking: Can we shorten the duration of chemotherapy in patients getting frontline FOLFOX [leucovorin, 5-FU, and oxaliplatin] with nivolumab [Opdivo]? Historically, we would have patients continue chemotherapy with oxaliplatin until they got neuropathy. Then, they would stay on 5-FU and nivolumab.

However, this study is asking: Can we do a short course of chemotherapy and have patients who have good disease control continue nivolumab as maintenance? This study is also investigating whether adding radiation to immunotherapy stimulates an immune response and prolongs the duration of disease control. It is enrolling essentially any patient who has advanced HER2-negative gastric or esophagus cancer who’s eligible to get FOLFOX and nivolumab. These patients must also have good organ function and a disease site that’s amenable to radiation.

Patients get 3 months of FOLFOX and nivolumab. If they have stable disease at that point, they continue nivolumab alone, and then they are randomized to get radiation or no radiation. Patients are interested in this study because they like the idea of getting less chemotherapy and having immunotherapy potentially work better. We’ve been enrolling patients to this study over the past year.

We also have a trial in the perioperative setting for patients with esophagus and GEJ cancer who will be getting chemotherapy [and] radiation with carboplatin [and paclitaxel]. This study is looking at adding immunotherapy to the preoperative setting, and we’ve been enrolling to it over the past year.

In pancreatic cancer, we have a second-line study open for patients who’ve had disease progression on first-line gemcitabine-based therapy. This study is looking at the NAPOLI regimen nanoliposomal irinotecan [Onivyde] and 5-FU in the second-line setting with an oral agent that’s a novel kinase inhibitor called onvansertib, which seems to be particularly effective in tumors that have mutations in KRAS. We’ve been enrolling to that study for the past few months here, and it’s exciting to have a study in the second-line setting.

In the next few months, we also are planning to open the [phase 2/3] Precision Promise platform trial [NCT04229004], which is a first- and second-line study in advanced pancreas cancer. This trial has various investigational arms and is randomized, so patients may get randomized to standard of care. We’re excited to have access to novel agents in both first- and second-line therapy in pancreas cancer through this study. It’ll be great to have that option for our patients here.