Another Drug Targeting NOTCH Shows Promise for Desmoid Tumors

Another Drug Targeting NOTCH Shows Promise for Desmoid Tumors

PARIS — There are no approved systemic therapies for the treatment of desmoid tumors, but there may be soon — another drug with the novel mechanism of targeting the Notch signaling pathway has shown promising clinical efficacy.

Desmoid tumors are rare, with a peak incidence around 30 years of age and a variable and unpredictable clinical course. Patients are predominantly female and often experience pain, discomfort, and reduced quality of life, commented Robin L. Jones, MD, PhD, team leader in sarcoma clinical trials at The Institute of Cancer Research, London, United Kingdom.

He was presenting new data for AL102, a potent, orally available, gamma secretase inhibitor (GSI) targeting the Notch signaling pathway. In a small clinical trial, the drug was “generally well tolerated,” had a “manageable safety profile,” and showed efficacy across all arms of the study, with consistent results that strengthened over time, he said.

These results from the RINGSIDE study come hot on the heels of those for another drug, nirogacestat, with a similar mechanism of action that is much futher along in development. Results from the larger phase 3 DeFi trial with nirogacestat showed that it significantly improved progression-free survival, as well as showing a reduction in symptoms and better quality of life when compared with placebo.

The results for both new drugs were presented here at the European Society for Medical Oncology 2022 Congress.

Session co-chair Sebastian Bauer, MD, Translational Sarcoma Research Group. University Duisburg-Essen, Essen, Germany, said that it was “only a couple of years back” that the level of evidence for treatments in desmoid tumors was akin to trying to read coffee grinds.

However, results from a “landmark” Alliance Clinical Trials in Oncology study showed that the oral tyrosine kinase inhibitor sorafenib (Nexavar) was able to reduce the risk for death or disease progression is desmoid patients by 87% relative to placebo.

“It’s kind of perceived as a targeted treatment,” Bauer said, “but…it’s a pretty broad treatment [and] really has disadvantages despite its efficacy.”

He continued that the DeFi trial, on the other hand, was a “huge achievement for the sarcoma community,” and now RINGSIDE shows that there is second drug being developed, “which is really good news.”

The current results, which are a “proof of concept,” show that AL102 “causes tumor shrinkage, and appears to be safe,” given the numbers treated so far.

However, there remain some questions, such as why some patients did not respond to AL102, and some progressed immediately.

Bauer said that “it’s a funny science story” to think that GSIs were initially developed to treat Alzheimer’s disease, but that one of these drugs, nirogacestat, could soon be approved as a first-in-class product specifically for the treatment of desmoid tumors.

However, if that happens, will there still be a role for sorafenib, even though it has not been approved for use in desmoid tumors, Bauer wondered.

Details of AL102 Results

The data on AL102 come from the RINGSIDE trial, which is a two-part phase 2/3 trial in adult patients who were treatment-naive or had relapse or refractory disease after prior treatment. They were also required to have progressive disease, defined as ≥10% unidimensional growth within the previous 18 months, or tumor-related pain requiring non-opioid medication.

Part A of the trial was a dose exploration study in which patients were randomly assigned to one of three AL102 regimens of varying intensity, with MRI performed at week 16 and then every 12 weeks to examine tumor response.

A total of 42 patients were enrolled into Part A of the trial. A majority (74%) were female and the median age was 38.5 years. The most common tumor location at diagnosis was extra-abdominal (74%), and 69% of patients had undergone prior treatments. This included surgery in 48% of patients, chemotherapy in 55%, 19% had hormonal therapy, and 17% targeted small molecule therapy.

“Seven discontinuations were noted across the three dosing groups,” Jones said, “and these were for a variety of reasons, including pregnancy.”

Safety was the primary endpoint, and he reported that “the majority of side effects were to be as expected from this class of drugs”, and were largely grade 1-2.

Grade 3 events were uncommon and included two cases of diarrhea, one of stomatitis, and one occurrence of rash, which were “again” as expected. There were no grade 4 or 5 events.

Jones continued: “There appears to be a numerical higher trend for grade 1 and 2 adverse events such as diarrhea in the daily dosing and the higher weekly dosing [regimens], but these were easily managed with dose reductions and temporary interruptions.”

Turning to the efficacy results, he showed that all dose arms showed responses, with reductions in tumor volume observed at 16 weeks and confirmed at 28 weeks.

This was underlined by reductions in tumor cellularity on MRI, which “is generally

believed to be an indicator of anti-tumor efficacy,” Jones explained.

At the data cutoff, 12 patients had undergone at least two MRI scans, revealing that the responses to AL102 were not only consistent across study arms but also “deepen” with time. So far, four partial responses have been confirmed on central review.

Jones said that the results therefore “support the initiation of Part B” of the trial. Part B is a follow-on double-blind, placebo-controlled trial, which has now been initiated.

The study was funded by Ayala Pharmaceuticals. Jones reports relationships with Adaptimmune Therapeutics, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daiichi Sankyo, Deciphera, Immunedesign, Lilly, Springworks, Tracon, UptoDate, PharmaMar, Athenex, MSD. Other authors also report numerous relationships with industry. The full list can be found here.

European Society for Medical Oncology Congress 2022: Abstract 1488MO. Presented September 12, 2022.

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