I'm Still Struggling With Celcuity's Upcoming Phase 3 Readout - But It Has A Real Chance

Phase 3 data in PIK3CA wild-type HR+/HER2- advanced breast cancer who has received prior treatment with a CDK4/6 inhibitor coming "in late Q1 2025 or Q2 2025."

Word count: 2,303, Reading Time: 11 minutes

Introduction

Celcuity CELC 0.00%↑ will report Phase 3 data in “PIK3CA wild-type HR+/HER2- advanced breast cancer who have received prior treatment with a CDK4/6 inhibitor” in late Q1 2025 or Q2 2025.

Celcuity’s drug, gedatolisib, is an IV administered PI3K/mTOR inhibitor. Previous efforts to develop drugs in this class were stopped due to high toxicity and narrow therapeutic window. The PI3K/AKT/mTOR “PAM” pathway is a significant oncogenic pathway in breast cancer but gedatolisib appears to be the only late-stage drug in development targeting the entire pathway. There are multiple drugs approved and in development that target node-specific parts of the pathway like specific isoforms of PI3K such as PIK3CA+ cancers.

Breast cancer is an incredibly large and fragmented indication but the current standard of care in 2L+ HR+/HER2- metastatic breast cancer is ripe for improvement. Let’s start with what the trial would need to show for approval and to be clinically meaningful.

Bar For Success

First, what to expect from the control arm in the upcoming readout.

The above table from the company slide deck lists the standard of care for various mutation statuses in 2L+ HR+/HER- advanced breast cancer, which I will abbreviate “ABC” from this point forward.

The line to focus on is the bottom line of “all” where fulvestrant’s label shows a mPFS of 1.9 months. (This is in line with other investigational studies that have used it as a control arm.) The PIK3CA+ lines above will become relevant to Celcuity in a future data readout in PIK3CA+ mutated 2L HR+/HER- ABC. The upcoming readout is in PIK3CA+ wild-type ABC excludes PIK3CA+ mutant patients and stratifies for other mutations and previous duration of therapy. Let’s move to the trial design.

Trial Design

Focus on the light blue boxes below. That is the upcoming wild-type readout. The purple boxes are for the mutated trial which reads out in 2H ‘25.

The three arm study will have the control arm (fulvestrant), the gedatolisib plus fulvestrant arm also known as “the doublet” arm, and also a “triplet” arm to test whether the addition of gedatolisib can re-sensitive the patient to CDK4/6 inhibition (palbociclib) when added to fulvestrant. Normally a patient re-treated with a CDK4/6 inhibitor after progression would be expected to have no added benefit from the re-treatment. In addition, this triplet arm will also be a good measure of the tolerability of gedatolisib being added on top of two drugs that already have their own established adverse event profile.

The company maintains the study is extremely overpowered for at least one of the two investigational arms to show greater than 3 month mPFS improvement over fulvestrant alone, which would be considered clinically meaningful and commercially viable.

Efficacy

So, can they do it? Let’s look at the totality of the past data, which is relatively sparse only about 100 patients in total, all in open label single arm trials.

Since the Phase 3 will be focusing on 2L/3L patients who were CDKi-pretreated the only relevant columns below are Arm C and Arm D which looks at 55 patients total. Not extremely strong evidence for which to be confident about a large Phase 3 trial…but I can understand why a small biotech would want to move directly into a Phase 3 if they could for cost savings. Still, we are looking at a small amount of evidence here.

Above you can see the mPFS for Arm C and Arm D which both include a mix of mutated patients. This complicates things as mutated patients would be expected to live longer based on established data as they have a proven mutation along the PIK3CA+ pathway which this drug should be inhibiting.

Luckily, they do breakdown in each arm the objective response rate and PFS% at 12 months for the WT and MT patients, which is helpful to determine drug benefit. (I should also note the “P+F+G” above indicates that these are patients taking the triplet therapy with CDK4/6 inhibition. There is no published data that I have seen for the doublet.)

In Arm C, wild type patients had a 25% ORR and 22% were progression-free at 12 months. In Arm D, wild type patients had a 60% ORR and 49% were progression-free at 12 months.

Celcuity is surely hoping the Phase 3 results look a lot more like Arm D which would be highly likely to beat fulvestrant.

So, what to believe Arm C or Arm D? And why the disparity?

There are reasons for the differences: