Expert Highlights Ongoing Research Efforts in HCC, NETs

Daneng Li, MD

The paradigms of hepatocellular carcinoma (HCC) and neuroendocrine tumors (NETs) have both had recent therapeutic additions; however, more research in each area continues to be conducted to further improve survival outcomes.

At the 2019 Gastrointestinal Cancers Symposium, one open-label, single-center, randomized, phase II trial evaluated the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) compared with nivolumab alone in patients with resectable HCC. Preliminary results showed that out of 8 patients, 3 (37.5%) experienced a pathologic complete response (pCR) with the combination treatment; 2 were seen in the nivolumab monotherapy arm and 1 was observed in the combination arm.

This study is a move to an earlier setting for HCC and away from the metastatic HCC setting, explained Daneng Li, MD, where several clinical trials and recently FDA-approved therapies have been explored.

In the NET armamentarium, Li discussed how next steps for research should focus on the optimal sequence of therapies, as well as determining what potential role, if any, checkpoint inhibition has in these patients.

OncLive: What studies in HCC were presented at the 2019 Gastrointestinal Cancers Symposium?

In an interview during the 2019 OncLive^® State of the Science Summit^TM on Gastrointestinal Cancers, Li, an assistant clinical professor, Department of Medical Oncology and Therapeutics Research, and a medical oncologist at City of Hope, shed light on some of the currently available regimens and ongoing research efforts being conducted in HCC and NETs.Li: There were various studies being presented in HCC. One thought-provoking study was a study coming out of The University of Texas MD Anderson Cancer Center, which is looking at preoperative immunotherapy with either nivolumab alone or the combination of nivolumab and ipilimumab. This is very interesting, because the overall landscape of HCC is rapidly changing.

Traditionally, in terms of current FDA-approved treatments, we have oral TKIs and now there are immunotherapies already FDA approved in the second-line setting with single-agent nivolumab as well as pembrolizumab (Keytruda). However, a lot of the focus on HCC has been in the frontline metastatic setting, whether it is combination immunotherapy or immunotherapy with targeted agents. Many are undergoing phase III testing already.

The study that was presented moved the bar even further [from] the first-line metastatic setting, and it looked at the preoperative or adjuvant setting for resectable HCC. This was a preliminary analysis coming out of The University of Texas MD Anderson Cancer Center, where patients were treated with immunotherapy perioperatively; [the investigators] were really looking for pCRs.

As a preliminary interim analysis, out of 8 patients, what they saw was that 3 patients had a pCR, which was fairly remarkable in this population and [patients] were able to undergo successful surgery. This is really moving the bar upfront for patients with early-stage HCC, to see whether or not immunotherapy has a preoperative or adjuvant role.

Cabozantinib (Cabometyx) has been approved in the second-line setting. How is this drug impacting the landscape?

Ultimately, the more thought-provoking question in the long-term is, “Can patients who potentially have borderline resectable disease be downstaged with frontline immuno-oncology treatments to get them to resectability?” [Another challenge is can we] ultimately select for the true patients who will benefit from this in the long-term in terms of decreasing the risk of recurrence.Cabozantinib has an interesting role in the overall landscape for HCC. Currently in the second-line setting for HCC, it is somewhat of a crowded space. You have regorafenib (Stivarga), which is really for patients who can tolerate sorafenib (Nexavar) in the first-line setting, and then you have the recent approvals of cabozantinib, as well as prior approvals of nivolumab and pembrolizumab.

What would you identify as the biggest trend in HCC from the 2019 Gastrointestinal Cancers Symposium?

Setting the immuno-oncology agents aside, because the mechanism of action is somewhat different, cabozantinib is well placed in the overall space. It is for patients who are previously exposed to sorafenib, but it doesn’t include the stringent criteria like regorafenib does. In addition from the CELESTIAL study, there were a few patients who were enrolled that previously had exposure to sorafenib but underwent additional systemic therapies. Therefore, Cabozantinib is potentially well placed in the overall landscape as a TKI for HCC for the second-line setting and beyond.The biggest trend is that, again, we have now several FDA-approved therapies—TKIs and single-agent PD-1 inhibitors in the second-line or above setting. However, it is really a race in the first-line setting for advanced HCC. We are anticipating and still waiting on the long-awaited data of nivolumab versus sorafenib in the first-line setting.

Transitioning to NETs, could you define the standard of care for this patient population?

In addition, there are multiple phase III studies that are going to look at [combination regimens] with FDA-approved TKIs along with immunotherapy agents. For example, some of the major phase III clinical trials in the first-line setting for advanced HCC include bevacizumab (Avastin) plus atezolizumab (Tecentriq) versus sorafenib, as well as lenvatinib (Lenvima) with pembrolizumab versus single-agent lenvatinib. Then, [there is the combination of] cabozantinib with atezolizumab versus sorafenib in the first-line setting. With all of these combination approaches, it will be interesting to see which combination wins out in the frontline setting for advanced HCC.The standard of care currently in the first-line setting for advanced gastroenteropancreatic (GEP)-NETs, still remains the somatostatin analogs, whether it’s octreotide (Sandostatin) or lanreotide (Somatuline Depot). This is based off of the overall well-tolerated safety profile of the medications and minimal side effects. Once a patient progresses on a somatostatin analog, there is a lack of data regarding the sequence of additional treatments and, therefore, it is really an individualized practice for patients.

Are clinical trials being planned to address the lack of data?

Is there a potential for immunotherapy in NETs?

For those with midgut NETs, oftentimes potential second-line therapy would be with Lutathera (lutetium Lu 177 dotatate), but for pancreatic NETs, where there is a wealth of oral targeted agents in addition to Lutathera and chemotherapy, the sequence remains not yet defined and is really individualized on the patient and their situation at the time of progression on somatostatin analogs.We need to do sequencing trials for NETs. If you look at kidney cancer, where there is also a wealth of oral TKIs, they have been able to successfully do sequencing trials that address that question. NETs are a little bit harder because they are a rarer population, but that shouldn’t necessarily stop us. It takes a cooperative effort, but ultimately sequencing data are needed for the field.The use of immunotherapy is very interesting. There have been 2 recent studies looking at the use of single-agent PD-1 immune checkpoint inhibition for NETs; they have been somewhat underwhelming.

At the 2018 ESMO Congress, there was a study looking at the immune checkpoint inhibitor PDR001. They took patients with lung NETs, gastrointestinal (GI) NETs, and pancreas NETs, along with high-grade, poorly differentiated NETs. They really only saw significant responses in the lung NETs cohort, of which 6 of the responses were all atypical carcinoid NETs of the lung. In addition, they had 1 response in the pancreas NETs cohort, and only 1 response in the poorly differentiated high-grade NET cohort.