AL101 Shows Promising Activity in Recurrent/Metastatic Adenoid Cystic Carcinoma With NOTCH Activating Mutations

November 4, 2020
Hayley Virgil
Hayley Virgil

Partner | Cancer Centers | <b>MSKCC</b>

The investigational small molecule, γ-secretase inhibitor AL101 monotherapy was found to elicit deep responses with a significant disease control rate in patients with recurrent or metastatic adenoid cystic carcinoma harboring NOTCH activating mutations.

The investigational small molecule, γ-secretase inhibitor AL101 monotherapy was found to elicit deep responses with a significant disease control rate (DCR) in patients with recurrent or metastatic adenoid cystic carcinoma (ACC) harboring NOTCH activating mutations, according to interim results from the phase 2 ACCURACY trial (NCT03691207).1

Data presented during the 2020 ESMO Virtual Congress showed that among 39 evaluable patients who received a 4-mg dose of the agent, 6 patients (15%) experienced partial responses and 21 patients (53%) achieved stable disease; this translated to a disease DCR of 68%.2 Additionally, about 40% of patients continued to receive treatment for at least 6 months after entering the study with progressive disease. The pharmacokinetics data proved to be comparable to those observed in the phase 1 trial of the agent.

AL101 was also reported to be well tolerated. The majority of the treatment-related adverse effects were only grade 1 or 2, and the most commonly reported any-grade toxicities comprised diarrhea (60%), fatigue (51%), nausea (49%), and hypophosphatemia (42%).

“In the context of understanding how aggressive this disease is, [this] is a very promising signal,” Alan Ho, MD, PhD, told OncLive. “Minimally, this provides validation that targeting NOTCH is therapeutically important. What we need to do is see what that signal looks like [when the agent is given at a dose of] 6 mg [so we know] how to move forward.”

In March 2020, dosing commenced for the cohort of patients receiving AL101 at 6 mg once weekly. Up to 42 participants are anticipated to enroll to this cohort.

In an interview with OncLive, Ho, a medical oncologist and Geoffrey Beene Junior Faculty Chair with Memorial Sloan Kettering Cancer Center, discussed the results of the ACCURACY trial and next steps for this research.

OncLive: Could you provide an overview of the ACCURACY trial?

Ho: ACC is one of the most common salivary cancers that we treat; it’s a disease for which no standard therapies are available. The objective of this trial is to really evaluate whether we can inhibit NOTCH pathway signaling to induce clinical efficacy in patients with ACC [who have] NOTCH-mutant disease.

What results have been reported from this trial?

The updated results of this ongoing trial were just shared by Renata Ferrarotto, MD, of the University of Texas MD Anderson Cancer Center at ESMO this year. Results showed that using AL101, which is a compound from Ayala Pharmaceuticals that's being tested in this trial, is an inhibitor of γ-secretase.

When we used AL101 in patients with ACC with NOTCH mutations, we saw pretty impressive efficacy, with 15% of those patients achieving some major tumor regression and about 40% were on the drug 6 months or more. This is impressive because this is the first real demonstration of the validity of NOTCH as a therapeutic target in this disease. What we've also known and are continuing to learn is that NOTCH-mutant ACC is a distinct clinical and biologic entity from NOTCH wild-type [disease]. Indeed, the prognosis with activating NOTCH mutations in ACC is quite significantly poorer compared with wild-type [disease]. Having treated patients on this trial, you do visualize firsthand that this is a very different and much more aggressive disease subset.

How common are NOTCH mutations in this patient population?

In a recent paper, my colleagues at Memorial Sloan Kettering looked at almost 1000 cases of ACC. One of the messages from that paper is that if you really look at primary tumors with ACC, the incidence of NOTCH1 mutations is quite low. However, if you look at patients who have ACC that recurred or metastasized, the rates are much higher—north of 25%. About 18% of those will be activating NOTCH1 mutations; that really speaks to a significant enrichment of this oncogene in patients with much more aggressive and incurable disease.

What's the mechanism of action for AL101?

As I mentioned, a significant fraction of patients with ACC have activating NOTCH mutations, [which] is a family that consists of 4 different genes: NOTCH1, NOTCH2, NOTCH3, and NOTCH4. AL101 targets γ-secretase; γ-secretase enzymatic activity is required for NOTCH mutations to transduce their signal downstream to the cancer cells. The idea is that if you can inhibit γ-secretase with AL101, then you can extinguish NOTCH signaling in these mutant tumors and hopefully induce tumor regression.

What are the next steps for this research?

The ongoing trial, based upon those promising results, is still accruing. This is a cohort where we're testing a slightly higher dose of AL101, at 6 mg [given] intravenously weekly, given the safety and efficacy profile we saw with the 4-mg dose, which were the results we reported at ESMO. We're hoping that we'll continue to see some good efficacy and results coming from that trial.

References

  1. Ferrarotto R, Wirth LJ, Muzaffar J, et al. ACCURACY a phase II trial of AL101, a selective gamma secretase inhibitor, in subjects with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) harboring Notch activating mutations (Notchmut). Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Accessed November 4, 2020. Abstract 919MO.
  2. Ayala Pharmaceuticals presents positive interim data from phase 2 ACCURACY trial of AL101 for the treatment of recurrent/metastatic adenoid cystic carcinoma with Notch activating mutations at ESMO 2020. News release. Ayala Pharmaceuticals, Inc. September 18, 2020. Accessed November 4, 2020. https://bit.ly/2HWSDtr.

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