Gedatolisib for Advanced triple-negative breast cancer (TNBC) and BRCA1/2-positive, HER2-negative breast cancer
Kari Wisinski
Reviewed by Blane Jackson, DDS, MBA. Educational analysis only. Read the editorial policy and disclosures.
NCT03911973 on ClinicalTrials.gov →Study type
interventional
Design
Single-group, open-label, phas…
Target enrollment
37
Est. completion
2024-07
Investor scorecard
Probability of success
moderate
Timeline to catalyst
Data readout expected around mid-2024 (completion date July 2024).
Potential stock impact
ModerateThe combination has a strong biological rationale and talazoparib is already approved, but the trial is small and lacks a control arm. Early-phase data for gedatolisib have shown some activity, but PI3K inhibitors have been disappointing in TNBC. The primary endpoint of ORR will need to be high (likely >30%) to be considered promising. Given the challenges of treating TNBC and potential toxicity, the probability of success is moderate.
What is being tested?
This trial is testing a combination of two drugs for patients with advanced breast cancer that is either triple-negative or has BRCA1/2 mutations and is HER2-negative. Triple-negative breast cancer lacks receptors for estrogen, progesterone, and HER2, making it harder to treat. BRCA mutations impair DNA repair, making cancer cells vulnerable to certain drugs. The two drugs are gedatolisib, which blocks a protein called PI3K/mTOR that helps cancer cells grow, and talazoparib, a PARP inhibitor that prevents cancer cells from repairing their DNA. By combining them, the hope is to attack cancer cells in two ways at once, potentially making the treatment more effective than either drug alone.
How does the trial work?
The trial has two parts. In the first part (phase 1), a small group of patients receives increasing doses of talazoparib along with a fixed dose of gedatolisib to find the highest dose that doesn't cause severe side effects. This is called a safety run-in. Once the recommended dose is found, the second part (phase 2) enrolls more patients to receive that dose. All patients receive the combination treatment; there is no placebo or comparison group. Patients are treated until their cancer progresses or they experience unacceptable side effects. The trial is currently active but no longer recruiting, meaning all planned patients have been enrolled. The study is expected to be completed by July 2024.
What does success look like?
Success in the phase 1 part is finding a safe and tolerable dose. In the phase 2 part, the main measure of success is the objective response rate (ORR) - the percentage of patients whose tumors shrink significantly or disappear. For this trial, a meaningful ORR would likely be above 30-40%, based on historical data for similar treatments in this tough-to-treat population. Secondary measures include how long the response lasts, the clinical benefit rate at 16 weeks (which includes stable disease), and overall survival. If the ORR is high and responses are durable, it would suggest the combination is promising and warrant further study.
What it means for investors
For investors, this trial is important because it tests a novel combination that could address a high unmet need in triple-negative breast cancer and BRCA-mutated tumors. If the results are positive, it could boost the prospects for gedatolisib, which is being developed by Pfizer (though this trial is investigator-initiated). A positive outcome could lead to larger trials and eventual approval, potentially expanding the market for gedatolisib. However, the trial is small (37 patients) and lacks a control group, so results must be interpreted cautiously. If the ORR is high and safety is manageable, it could increase the probability of success for gedatolisib in this indication, positively impacting Pfizer's pipeline. Conversely, if the trial fails or shows modest efficacy, it could dampen enthusiasm. Investors should watch for data readouts, expected around mid-2024, and compare results with competing PARP inhibitors and PI3K inhibitors.
Trial endpoints
Primary endpoints
Secondary endpoints
Competitive landscape
Triple-negative breast cancer (TNBC) accounts for about 15% of all breast cancers and has a poor prognosis, especially in advanced stages. BRCA-mutated HER2-negative breast cancers also represent a significant subset. The market for treatments in these indications is substantial, with PARP inhibitors already generating billions in sales. However, there is still a need for more effective therapies, especially for patients who progress on PARP inhibitors or who have TNBC without BRCA mutations. If this combination proves effective, it could capture a share of this market, but it will face competition from established drugs and emerging combinations.
| Drug | Sponsor | Phase | Differentiation |
|---|---|---|---|
| Olaparib | AstraZeneca/Merck | Phase 1 | PARP inhibitor approved for BRCA-mutated HER2-negative breast cancer; not combined with PI3K inhibitor. |
| Talazoparib | Pfizer | Phase 1 | PARP inhibitor approved for BRCA-mutated HER2-negative breast cancer; being tested here in combination with gedatolisib. |
| Alpelisib | Novartis | Phase 1 | PI3K inhibitor approved for HR+/HER2- breast cancer with PIK3CA mutations; not for TNBC. |
| Sacituzumab govitecan | Gilead | Phase 1 | Antibody-drug conjugate for TNBC; different mechanism (targets Trop-2). |
Historical context
Prior trial results
Gedatolisib has been studied in earlier phase trials for solid tumors, showing manageable safety and some antitumor activity. Talazoparib is already approved for BRCA-mutated HER2-negative breast cancer based on the EMBRACA trial, which showed improved progression-free survival compared to chemotherapy. However, the combination of gedatolisib and talazoparib is novel, and no prior results are available for this specific combination.
Regulatory history
Talazoparib received FDA approval in 2018 for BRCA-mutated HER2-negative breast cancer. Gedatolisib is not yet approved for any indication. This trial is investigator-initiated and not part of a formal registration program, so it may not directly lead to approval but could inform future development.
Similar drug precedents
Other PI3K inhibitors like alpelisib have shown benefit in HR+ breast cancer but have limited activity in TNBC. PARP inhibitors have shown activity in BRCA-mutated breast cancer, but resistance develops. Combining a PI3K inhibitor with a PARP inhibitor is a rational strategy to overcome resistance, as preclinical studies suggest synergy. However, similar combinations have faced toxicity challenges, so safety will be a key factor.