How Chemoimmunotherapy, PRRT, and First-Line Immunotherapy Are Reshaping GI Cancer Management

Chemoimmunotherapy advancements in esophageal cancer, the expanding role of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NETs), and evolving first-line immunotherapy strategies in hepatocellular carcinoma (HCC) are reshaping treatment paradigms across gastrointestinal malignancies, according to Tanios S. Bekaii-Saab, MD.

In an interview with OncLive®, Bekaii-Saab discussed findings from the phase 3 RATIONALE-305 (NCT03777657) and RATIONALE-306 (NCT03783442) trials, which reinforced the benefit of chemoimmunotherapy in patients with PD-L1–positive esophageal cancer, particularly those with a combined positive score (CPS) of at least 5. He noted that although tislelizumab-jsgr (Tevimbra) joins nivolumab (Opdivo) and pembrolizumab (Keytruda) as an FDA-approved checkpoint inhibitor in this setting, he said no clear clinical differentiator between these agents has emerged.

He also highlighted the clinical implications of the phase 3 CABINET trial (NCT03375320), which supported the FDA approval of cabozantinib (Cabometyx) for previously treated NETs, along with the continued movement of PRRT into earlier lines of therapy for this patient population. In the HCC setting, Bekaii-Saab reviewed the comparative profiles of the 3 approved first-line immunotherapy-based regimens—atezolizumab (Tecentriq) plus bevacizumab (Avastin); tremelimumab (Imjudo) plus durvalumab (Imfinzi); and ipilimumab (Yervoy) plus nivolumab, outlining considerations for selecting between them. He further discussed future directions, including the integration of bispecific antibodies and the potential for immunotherapy in earlier disease stages.

Bekaii-Saab is the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research and chair of the Division of Hematology and Medical Oncology at Mayo Clinic in Phoenix, Arizona.

Revisit the first 2 portions of OncLive’s interview with Bekaii-Saab, where he discussed considerations in the treatment of patients with advanced biliary tract cancer, as well as sequencing considerations in pancreatic and colorectal cancer.

OncLive: What were your key takeaways from the RATIONALE-305 and RATIONALE-306 trials?

Bekaii-Saab: Overall, the landscape of chemoimmunotherapy in patients with PD-L1–positive [esophageal cancer] is now well established. Those patients do well with chemoimmunotherapy; [patients with] a CPS of 5 or above, or 10 or above, do exquisitely well. The RATIONALE studies helped confirm the value of chemoimmunotherapy.

The only challenge with tislelizumab is whether it is a better choice vs nivolumab or pembrolizumab. The answer is: We don’t know. They all seem to do relatively well in the same space. When you have a new agent approved by the FDA that is similar to others already-approved agents [in a given setting], what patient population should be considered for the new agent vs the established agents? Unfortunately, at this time, we do not have a differentiator.

What were your key takeaways from the CABINET trial and other trends in the management of NETs?

There have been 2 key developments in NETs that are transforming the landscape. One, peptide receptor radionuclide therapy continues to expand its indications across all NETs and move toward the first-line setting. That’s important, and in our practice, it’s being used more consistently in that space.

The CABINET trial led to the approval of cabozantinib in the more refractory setting, giving us another option. Previously, we had sunitinib (Sutent) and everolimus. Sunitinib has modest activity but is highly toxic. Everolimus is also modest in activity, with its own toxicity profile. Cabozantinib now comes in as an additional option for our patients.

The question is whether cabozantinib is preferred over sunitinib or everolimus. The answer is, we frankly don’t know. However, we have a lot more experience with cabozantinib from HCC and other tumor types. Cabozantinib has become a mainstay in our practice, and I put it ahead of sunitinib at this point in time. Anecdotally, it’s a little more active and easier on patients than sunitinib. We start at 40 mg instead of 60 mg, which seems to maintain relative activity with fewer toxicities.

How do you approach immunotherapy-based treatment options for patients with first-line HCC?

In HCC, we now have 3 first-line options: atezolizumab plus bevacizumab; tremelimumab plus durvalumab; and ipilimumab plus nivolumab. They have never been compared head-to-head, but indirect comparisons suggest they all offer similar benefits.

With atezolizumab/bevacizumab, you probably get a strong response rate, a progression-free survival (PFS) benefit, and an overall survival (OS) advantage. With the other two regimens, you don’t see the same PFS benefit, but you do see a long-term OS advantage. Ipilimumab/nivolumab tends to be more toxic because of the high-dose ipilimumab. Bleeding risk is a concern with atezolizumab/bevacizumab, so patients at high risk for bleeding may be better suited for the other regimens.

The preferred options remain atezolizumab/bevacizumab and durvalumab/tremelimumab. I’m not sure who the ideal patient for ipilimumab/nivolumab is, but in scenarios where a patient is at high risk for bleeding and we need a strong response, I might use ipilimumab/nivolumab, provided the patient is younger and more likely to tolerate the regimen. It is a tough regimen with the higher ipilimumab dose.

Where we’re moving next is toward enhancing the role of immunotherapy in HCC. We’re thinking about how to integrate bispecific antibodies into the landscape and how to move immunotherapy into earlier stages. We know that atezolizumab/bevacizumab did not work as well in the adjuvant setting, and we’re waiting on other data. There is also interest in the locally advanced setting for patients who would otherwise receive transarterial chemoembolization or transarterial radioembolization.