GI Armamentarium Undergoes Changes With New Treatment Mechanisms and Applications

Chih-Yi (Andy) Liao, MD

The investigation of new drugs with novel mechanisms of action such as surufatinib and PEN-221 in neuroendocrine tumors (NETs), the use of DNA-damaging agents like olaparib (Lynparza) in pancreatic cancer, and the applications of surgery and systemic therapy in settings that challenge historical dogmas are some of the exciting takeaways from an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, explained Chih-Yi (Andy) Liao, MD.

“For pancreatic cancer, there are a lot of new, exciting targets and treatment options that are being developed. I highly encourage patients to consider clinical trials that are looking at these new treatment strategies. For NETs as well, we’re looking at other new systemic therapies that might be beneficial,” Liao, chair of the event and an assistant professor of medicine at the University of Chicago, said in an interview with OncLive^®.

“The other take-home message is the importance of working in a multidisciplinary team, both for hepatobiliary cancers and for NETs, as it takes a team of different specialists to help us determine how to use the right treatment at the right time to help our patients live a long and healthy life with their cancer,” Liao added.

In the interview, Liao, also a medical oncologist at the University of Chicago Medicine Comprehensive Cancer Center, discussed the focus of each presentation at the webinar, which centered on optimizing therapy in advanced pancreatic cancer, the contemporary use of surgery and systemic therapy in NETs, multidisciplinary approaches to hepatocellular carcinoma (HCC), and the evolving role of liver transplant and systemic therapy.

OncLive^®: In your presentation, you discussed the contemporary management of NETs with systemic therapy. What does treatment sequencing typically look like for these patients?

Liao: For patients with well-differentiated gastrointestinal NETs, typically our first-line systemic therapy is somatostatin analogs, so lanreotide [Somatuline depot] or octreotide [Sandostatin]. For second-line treatment, we have a variety of options, which include targeted therapy drugs like everolimus [Afinitor], sunitinib [Sutent], and new options, such as peptide receptor radionuclide therapy. Sometimes we do use traditional cytotoxic chemotherapy as well, especially in the case of pancreatic NETs.

What key trials have solidified the role of lanreotide in NETs?

We talked about 2 key trials that looked at new roles for lanreotide. These are the first prospective studies in their respective spaces. One is the CLARINET FORTE study [NCT02651987], which looked at patients who had progressed on a standard dose of lanreotide, which is 120 mg every 28 days. Those patients were put on a higher dose of lanreotide, which was 120 mg every 14 days. It turns out that there may be some additional advantage to switching to the higher dose, at least in the study patient population, which generally was a healthier population with more indolent disease and lower liver tumor burden [than what see in the clinic].

We also looked at the SPINET study [NCT02683941], which is the first and largest prospective phase 3 study to look at the role of lanreotide in lung NETs. We’re happy that the study validates that there is clinical benefit [with lanreotide] for this population as well.

What are some future directions with systemic therapy in NETs?

We saw some new exciting developments in targeted therapy. The data from the SANET-p [NCT02589821] and SANET-ep [NCT02588170] studies with surufatinib look very promising. Those studies were done in China, but there is a phase 1 dose-escalation/dose-expansion study of the same drug in the United States that has been conducted that verified the same safety and clinical benefit. The drug has been submitted to the FDA for review for approval, so that might be one option that might be coming soon. Other targeted therapies may be beneficial as well, such as lenvatinib [Lenvima].

In terms of other novel classes of systemic therapy, people are [investigating] using novel targets, such as SSTR2. PEN-221 is an antibody-drug conjugate that targets SSTR2. There are other examples of drugs that link the SSTR2 to CD3 like a bispecific engager. Those are new classes of drugs with new mechanisms of action, and we have seen some very preliminary data [with those agents]. We’re excited to see what the clinical trials show in terms of what benefits they will provide for our patients.

Xavier Keutgen, MD, of the University of Chicago Medicine Comprehensive Cancer Center, discussed the surgical management of patients with NETs. In what situations would a patient stand to benefit from surgery vs systemic therapy?

The main message from Dr Keutgen’s presentation is that there could be a role for surgery in the management of our patients with advanced NETs, which goes against the dogma in the paradigm of advanced and metastatic disease. However, many of our patients with NETs have very indolent disease. If you look at what causes the most morbidity or mortality, it’s often the liver tumor burden. Therefore, if the surgeon can go in and debulk the liver tumors then perhaps that can help reset the clock and perhaps prolong survival for those patients. [Surgery] is one of the many tools in our toolbox in addition to systemic therapy and liver-directed therapy that we have to help our patients with NETs live a long and healthy life.

Ardaman Shergill, MD, of the University of Chicago Medicine Comprehensive Cancer Center, discussed optimizing therapy for patients with advanced pancreatic cancer. How has therapy become more personalized in pancreatic cancer?

She showed us that there are a lot of new and exciting targets. One of the first targeted therapies that was approved [in pancreatic cancer] was olaparib. [The approval was] based on findings from the POLO study [NCT02184195], which was done by my colleague, Dr Hedy Lee Kindler. The results showed that [olaparib] can be beneficial as a maintenance therapy after first-line platinum-based chemotherapy for patients with a germline BRCA mutation. Similarly, drugs like that that target tumors that have alterations in the DNA damage response pathway are currently being investigated.

Dr Shergill also mentioned that one of the other targets that has gained recent attention is KRAS for which there are now specific inhibitors. [Those agents are] being investigated. Of course, we’re also looking at ways to make immunotherapy work better in this population. There are a lot of new and exciting developments and a lot of hope for patients with pancreatic cancer.

Anjana Pillai, MD, of the University of Chicago Medicine Comprehensive Cancer Center, discussed the role of multidisciplinary care for patients with HCC. What is unique about HCC that requires a multidisciplinary care approach?

HCC is special because HCC usually develops in a setting of chronic liver disease, such as cirrhosis. In addition to the cancer itself, the underlying health of the liver is also a major determinant in the patient’s prognosis and morbidity. They go hand in hand, which is why it’s important to work together as a multidisciplinary team not just to treat the cancer, but also to manage the underlying liver dysfunction.

We are lucky to have a true multidisciplinary team here at the University Chicago. Our team includes hepatology, surgery, transplant surgery, interventional radiology, and medical oncology, and we all work together and physically see patients together, and we have a dedicated tumor board for this. It’s important because now we have many new treatment options.

There’s essentially now a continuum, so we’re moving beyond the traditional Barcelona Clinic Liver Cancer schema of how to treat HCC. Now things are more fluid, and it’s more like a continuum. We’re seeing a trend of using systemic therapy earlier on in the patient’s treatment course. That’s why it’s important to work together with our colleagues in other specialties to see what each of us has to offer and what makes sense at each point in the patient’s treatment journey.