World Neuroendocrine Cancer Day: New Targeted Therapies for NETs

Arturo Loaiza-Bonilla, MD, MSEd, FACP

Several trials offer new approaches to identifying and treating patients with neuroendocrine tumors (NETs). These include advances in use of peptide receptor radionuclide therapy (PRRT) to target somatostatin receptors (SSTRs) and combination therapies with immunotherapy that can be tailored to the patients most likely to be receptive to treatment.

NETs are difficult to diagnose, and symptoms vary widely depending on the location where they form. Different biomarkers can indicate what treatments will be most successful, including radionuclide treatments and immunotherapies.¹ The NETTER-1 trial (NCT01578239) led to the approval of lutetium Lu 177 dotatate (Lutathera) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).² The phase 3 NETTER-2 trial (NCT03972488) is ongoing. Additionally, the phase 3 COMPETE trial (NCT03049189) compared PRRT using lutetium Lu 177 edotreotide versus everolimus (Afinitor), a targeted oral therapy, with a goal of improved progression-free survival (PFS) in patients with NETS in the gastrointestinal tract and pancreas.

Due to the impact NETs have on the release of somatostatin, radiotherapy, immunotherapy, and antibody-drug conjugates (ADCs) investigated for these patients target SSTRs. Somatostatin analogues (SSAs) are used to both to slow tumor growth and treat symptoms caused by hormone release.

Biomarkers for NETs are not reliable for screening due to the rarity of NETs, but they indicate success in targeting tumors. They include PD-L1, CTLA-4, and delta-like ligand-3 (DLL-3), which can be targeted to promote immune response to tumors.

Arturo Loaiza-Bonilla, MD, MSEd, FACP, Enterprise Research Program Director, Cancer Treatment Centers of America, discussed recent trials and advances in neuroendocrine cancer research in an interview with Targeted OncologyTM.

TARGETED ONCOLOGY: How has the neuroendocrine cancer landscape evolved over the last year?

BONILLA: There have been numerous developments, particularly on the research side. With COVID-19, we experienced some interruption in the clinical trials accrual and, in turn, some research was backlogged. We have, however, seen optimization of current available treatment options, as well as an uptick in the use, or at least awareness of theranostic modalities using PRRT over the last year or so. Also, increased understanding about biomarkers may lead to better responses for agents used in this space. It’s an interesting time in the NET landscape, especially with increasing studies on ADC therapies and radiopeptide treatment options.

Can you discuss some trials ongoing or published that have been most practice-changing in the setting recently?

‘Practice-changing’ is challenging with any tumor type because the vast majority of clinical trials have some potential signals, but may not necessarily change the way we practice. The most recent example is the data from the NETTER-1 study for the PRRT [approval], for the lutetium Lu 177 dotatate-based treatments.² NETTER-1 is the phase 3 clinical trial that led to approval of PRRT, or somatostatin-directed radiotherapy for NETs. What we have seen recently is that we're trying to refine which patients benefit the most, because currently, it's mostly approved for patients with NETs that are grade 1 or 2, that have also progressed after the use of some of the same analogues.

We are trying to ascertain if there is any opportunity for better determination of which patients benefit the most, and if the Ki-67 [antigen] makes any difference in patient outcomes and overall response; Additionally, we hope to discover through clinical trials if there is opportunity to include broader Ki-67 scores earlier in the treatment paradigm.

There are ongoing randomized clinical trials for PRRT. One of them is called the COMPETE study, which is a phase 3 trial comparing lutetium Lu 177 edotreotide, which is a specific agent, with everolimus. We're trying to combine it now with mTor inhibitors to see if the combinations are more relevant than using single agents, mostly for grade 1 or grade 2 GEP-NETs that have progressed.

There is also the NETTER-2 phase 3 clinical trial of lutetium Lu 177 dotatate plus SSA in the long-acting form versus a high dose SSA. The goal is to discover if the high dose SSA is relevant now as first-line [treatment]. As mentioned earlier, we want to see if using PRRT earlier in the treatment paradigm is more effective or beneficial for patients. The idea is to see patients that have a little bit higher proliferation index, so for grade 2 or grade 3, we'd consider ki-67 scores between 10% to 55% in patients with NETs. This is very relevant and interesting, because in the current scenarios, many patients who have Ki-67 [scores] in the higher range are not often considered for PRRT treatments, so now we're trying to see if we can change that for a number of the patients.

What biomarkers are being investigated currently?

All the clinical trials that I think are relevant are looking at biomarkers specifically on the tumor cells. The first biomarker that we were looking for was PD-L1 due to the ongoing interest in immunotherapy approaches. What we know is there's a lot of heterogeneity in terms of expression. Most patients who have grade 1 or grade 2 [tumors] tend to have low expressions of PD-L1, but patients with grade 3 tend to have a higher PD-L1 proportion as well as tumor mutational burden [TMB] and other immunotherapy-guide biomarkers. The idea here is to see if we can see which patients may benefit the most by combinations of immunotherapies. Typically, CTLA-4 plus anti–PD-1 inhibitors are for patients with specific cutoffs of PD-L1 levels.

In terms of other biomarkers, we are looking at ADCs targeting certain biomarkers, including cell surface receptors. For example, DLL-3 is a notch ligand that is expressed in tumor-initiating cells in more than 80% of small-cell lung cancers [SCLC] and other high-grade neuroendocrine tumors, particularly for lung, ovary, prostate, and bladder [cancers]. There's no expression in normal tissues. So that gives us a very interesting biomarker that we can target for high-grade neuroendocrine tumors. Hopefully, we can improve outcomes for these patients. We're learning more every day.

Are there any newer targets that are showing promise for NETs?

We are also looking at clonal evolution that can take place with treatments. In the paradigms of NETs, we often use alkylating agents, so temozolomide became one of the staples of the data reported in responses for NETs. We use it in low-grade, intermediate-grade, and high-grade tumors in different settings. What's been described is that sometimes the use of temozolomide can lead to a change in the tumor microenvironment, microsatellite instability, or the TMB of the cancer itself. Using things like liquid biopsies, or sequential biopsies, and determining the TMB of the tumors may help us to see if there are changes in the status that we can use to leverage immunotherapy for those patients.

As for other biomarkers, the DLL-3 biomarker mentioned earlier is key for high-grade NETs. There are some data presented in the past for a rovalpituzumab tesirine (Rova-T).³ They have [demonstrated] some results in early phase studies, but randomized trials have not shown benefit compared with standard of care. So, we need to understand further if we can optimize those and follow the paradigm of other disease types where we have modified an ADC to have maybe a higher payload or better affinity to the biomarkers, and therefore a much more robust response than what we've seen so far.

Other biomarkers [include] SSTRs. For those who may not be familiar, we know that SSTRs are very much present in most neuroendocrine tumors. That's the rationale for use of SSAs in those patients and for the use of PRRT, but we can use [SSTRs] as well, not necessarily when using radiation or alpha-emitting treatments through the PRRT treatments. We can potentially use ADCs for patients who cannot tolerate radiation; or for those undergoing significant past treatment, for example, liver-directed treatments where the dosimetry is too much for them to receive an additional dose of radiation.

There is a peptide drug conjugate called PEN-221, which targets the SSTR-2 ligand and is conjugated to the cytotoxic agent DN1, similar to T-DM1 targeting HER2 receptors in breast cancer. We’ve noted there is some signal from the number of studies and a potential phase 1/2a clinical trial that is currently open, using PEN-221 for SSTR-2 expressing cancers, including NETs and other tumors, such as pheochromocytoma and SCLCs [NCT02936323]. Certainly we will explore and learn more about different biomarkers that we can use.

Are there any upcoming FDA approvals or data that will lead to changes in the standard of care?

There is an increased interest in this disease type that historically was mostly orphaned, or even considered non-malignant, which of course is not the case. While we are still in the process of understanding the results of ongoing clinical trials, the encouraging news is the proliferation of clinical trials related to the neuroendocrine space.

What we see now is the use of targeted drugs, for example, tyrosine kinase inhibitors (TKIs) that are specific, such as cabozantinib [Cabometyx] or others like that combining with immunotherapy. There are combinations such as lenvatinib [Lenvima] and pembrolizumab [Keytruda], atezolizumab [Tencentriq] plus bevacizumab [Avastin], and other cabozantinib-base studies. Wealso see nivolumab [Opdivo] and ipilimumab [Yervoy] being tested. These combinations of targeted drugs plus immune checkpoint inhibitors are becoming very relevant in this space, and I wouldn't be surprised if we begin to see the outcomes from these combination basket studies and possibly do a subset analysis that allows us to have that use case in NETs. The future is there, it's just a matter of understanding how we can better refine these therapies for the patients.

What do you think community oncologists should know about this disease or how to treat it?

We all end up seeing 1 or 2 patients with NETs. We tend to put them in buckets and separate them as rare cases, which makes the impression that these are low incidence diseases. Even though NETs are considered not as prominent as other tumor types such as colon, lung, breast or prostate, they're in conjunction, fairly relevant; and they're rising in incidence.

Be aware of the opportunities for patients to receive PRRT treatments when appropriate. Understand patients with NETs may benefit from certain clinical trials and become aware of the latest advancements. For example, the combinations of temozolomide and capecitabine have been relevant in the NET landscape. Now we have at least 3 or 4 agents that we can use in sequence, but there’s likelihood that we haven’t used PRRT as often as we could. At least get a referral to a center that uses it, and then use appropriate imaging. For example, [using] copper Cu 64 dotatate or gallium Ga 68 dotatate for imaging allows us to see the burden of the disease and make appropriate treatment decisions.

_References:

_{1. Neuroendocrine tumor. Genetic and Rare Diseases Information Center. Published April 25, 2019. Accessed October 28, 2021. https://bit.ly/3BoNW10}

_{2. FDA approves lutetium Lu 177 dotatate for treatment of GEP-NETS. FDA. Published January 26, 2018. Accessed October 28, 2021. https://bit.ly/3nxsAto}

_{3. Mansfield AS, Hong DS, Hann CL, et al. A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing advanced solid tumors. NPJ Precis Oncol. 2021;5(1):74. doi:10.1038/s41698-021-00214-y}