Neratinib + Capmatinib combination for Metastatic breast cancer and inflammatory breast cancer
M.D. Anderson Cancer Center
Reviewed by Blane Jackson, DDS, MBA. Educational analysis only. Read the editorial policy and disclosures.
NCT05243641 on ClinicalTrials.gov →Study type
interventional
Design
Non-randomized, single group, …
Target enrollment
10
Est. completion
2024-11-19
Investor scorecard
Probability of success
very low
Timeline to catalyst
No future catalysts are expected from this trial since it is terminated. Any data may be published in a medical journal, but that is uncertain. Investors should not expect any stock-moving events from this trial.
Potential stock impact
LimitedThe trial was terminated early, which strongly suggests that it either failed to show sufficient efficacy, encountered unacceptable toxicity, or had poor accrual. Given that the trial was small (target 10 patients) and non-randomized, even if it had completed, the results would be preliminary. The lack of prior clinical data for this combination in breast cancer and the competitive landscape with many effective therapies further lower the probability of success. The termination likely means the combination did not meet its endpoints or was not feasible.
What is being tested?
This trial is testing a combination of two targeted cancer drugs: neratinib and capmatinib. Neratinib blocks a family of proteins called HER receptors, which can drive cancer growth. Capmatinib blocks a different protein called c-Met, which can also promote cancer. The idea is that by blocking both pathways at once, the drugs may work better than either alone. The trial is specifically for patients with metastatic breast cancer (cancer that has spread) or inflammatory breast cancer, a rare and aggressive type. Importantly, patients are selected based on a test called CELsignia that measures abnormal activity in these pathways, aiming to enroll only those likely to benefit.
How does the trial work?
This is a phase Ib/II trial, meaning it has two parts. In the phase Ib part, doctors find the safest dose of the combination by giving it to small groups of patients, starting with a low dose and increasing if tolerated. Once the recommended dose is found, the phase II part expands to more patients to see how effective it is. All patients take both drugs orally, likely daily, in cycles. They come to the clinic for regular check-ups, blood tests, and imaging scans to monitor side effects and tumor response. The trial is non-randomized, so everyone gets the same treatment. It is open-label, meaning both patients and doctors know what they are taking.
What does success look like?
Success in the phase Ib part is finding a dose that is safe enough to proceed. In phase II, success is measured by how many patients have their tumors shrink (overall response rate). For metastatic breast cancer, an overall response rate of 20-30% might be considered promising, especially in a heavily pretreated population. Other measures like clinical benefit rate (including stable disease) and progression-free survival are also important. For example, if the combination leads to a median progression-free survival of several months longer than historical controls, that would be encouraging. Ultimately, the trial aims to show enough activity to warrant further study in a larger randomized trial.
What it means for investors
This trial is sponsored by M.D. Anderson Cancer Center, not a pharmaceutical company, so the direct stock impact is limited. However, the drugs involved are developed by Puma Biotechnology (neratinib, brand name Nerlynx) and Novartis (capmatinib, brand name Tabrecta). If the trial shows promising results, it could boost Puma's and Novartis's prospects in breast cancer. For Puma, a positive signal could expand Nerlynx's use beyond HER2-positive breast cancer. For Novartis, it could support capmatinib's use in breast cancer, though its main focus is lung cancer. Given the trial is terminated early (as of status), it likely failed to meet its goals or encountered safety issues, which could be negative for these companies. Investors should watch for any press releases or publications explaining the termination.
Trial endpoints
Primary endpoints
Secondary endpoints
Competitive landscape
The market for metastatic breast cancer treatments is substantial, with global sales exceeding $20 billion annually. Targeted therapies are a major segment, especially for patients with specific genetic alterations. The combination of neratinib and capmatinib targets HER family and c-Met pathways, which are implicated in resistance to other therapies. If successful, it could address a niche population with abnormal pathway activity, but the market is crowded with many effective options. The addressable market is likely limited to a subset of patients who have failed existing therapies and have the specific biomarker, making the commercial opportunity modest compared to broad-use drugs.
| Drug | Sponsor | Phase | Differentiation |
|---|---|---|---|
| Trastuzumab deruxtecan (Enhertu) | Daiichi Sankyo / AstraZeneca | Phase 1 | Antibody-drug conjugate targeting HER2, highly effective in HER2-low and HER2-positive metastatic breast cancer. |
| Sacituzumab govitecan (Trodelvy) | Gilead Sciences | Phase 1 | Antibody-drug conjugate targeting Trop-2, approved for triple-negative breast cancer and other solid tumors. |
| Alpelisib (Piqray) | Novartis | Phase 1 | PI3K inhibitor for PIK3CA-mutated HR+/HER2- metastatic breast cancer, used with fulvestrant. |
Historical context
Prior trial results
Neratinib is approved for HER2-positive breast cancer as extended adjuvant therapy. Capmatinib is approved for MET exon 14 skipping non-small cell lung cancer. Preclinical studies suggested synergy between HER and c-Met inhibitors in breast cancer models. However, this specific combination in breast cancer has limited prior clinical data. A phase I study of neratinib plus capmatinib in solid tumors showed some activity, but not specifically in breast cancer. The trial was terminated early, likely due to lack of efficacy or safety concerns, but no results have been published yet.
Regulatory history
Neratinib (Nerlynx) was approved by the FDA in 2017 for extended adjuvant treatment of HER2-positive early breast cancer. Capmatinib (Tabrecta) was approved in 2020 for metastatic NSCLC with MET exon 14 skipping. Neither drug has a breast cancer indication for capmatinib, and neratinib is not approved for metastatic disease. This trial was an investigator-initiated study, so no regulatory designations like fast track were likely.
Similar drug precedents
Combination therapies targeting multiple pathways have had mixed results in breast cancer. For example, lapatinib (HER2 inhibitor) plus capecitabine improved progression-free survival in HER2-positive metastatic breast cancer. However, many combinations fail due to increased toxicity without added benefit. The early termination of this trial suggests it may have encountered such issues.