PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive
Mathilde Guerin1, Keyvan Rezai2, Nicolas Isambert3
1Aix-Marseille University, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France.
Background:
Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Buparlisib is a pan-class-I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110 isoforms.
Patients And Methods:
PIKHER2 phase IB study aimed primarily to determine a maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for buparlisib in combination with lapatinib in HER2-positive, trastuzumab-resistant, advanced breast cancer. Oral buparlisib (40, 60 or 80 mg) and lapatinib (750, 1000 or 1250 mg) were administered daily. A modified continuous reassessment method using an adaptive Bayesian model guided the dose escalation of both agents. Secondary end-points included antitumour activity and pharmacokinetic (PK) assessments.
Results:
A total of 24 patients were treated across five dose levels. Dose-limiting toxicities included transaminases elevation, vomiting, stomatitis, hyperglycemia and diarrhoea. MTD was declared at buparlisib 80 mg/d + lapatinib 1250 mg/d, but toxicities and early treatment discontinuation rate beyond cycle 1 led to select buparlisib 80 mg + lapatinib 1000 mg/d as the RP2D. Main drug-related adverse events included diarrhoea, nausea, skin rash, asthenia, depression, anxiety and transaminases increase. There was no significant evidence for drug-drug PK interaction. Disease control rate was 79% [95% confidence interval [CI] 57-92%], one patient obtained a complete remission, and six additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate of 29% [95% CI 12-51%]).
Conclusion:
Combining buparlisib and lapatinib in HER2-positive trastuzumab-resistant advanced breast cancer was feasible. Preliminary evidence of antitumour activity was observed in this heavily pre-treated population.
Trial Registration Id:
NCT01589861.
Insights
Combining buparlisib and lapatinib showed feasibility and preliminary antitumor activity in HER2-positive, trastuzumab-resistant advanced breast cancer patients. This PI3K inhibitor combination offers a potential new treatment option for this difficult-to-treat population.
Area of Science:
- Oncology
- Pharmacology
Background:
- The Phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin pathway is often activated in HER2-positive breast cancer.
- This pathway activation may contribute to resistance to trastuzumab therapy.
- Buparlisib is a potent pan-class-I PI3K inhibitor effective against various PI3K isoforms.
Purpose of the Study:
- To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of buparlisib in combination with lapatinib.
- To evaluate the antitumour activity and pharmacokinetics of this combination in patients with advanced HER2-positive, trastuzumab-resistant breast cancer.
Main Methods:
- The PIKHER2 phase IB study used a modified continuous reassessment method with an adaptive Bayesian model for dose escalation.
- Buparlisib and lapatinib were administered orally daily across escalating dose levels.
- Twenty-four patients were enrolled, with dose-limiting toxicities monitored to guide dose selection.
Main Results:
- The MTD was determined at buparlisib 80 mg/day + lapatinib 1250 mg/day, but toxicities led to the selection of buparlisib 80 mg + lapatinib 1000 mg/day as the RP2D.
- Common drug-related adverse events included diarrhea, nausea, and transaminase elevation.
- The disease control rate was 79%, with one complete remission and a clinical benefit rate of 29% for patients with stable disease for ≥24 weeks.
Conclusions:
- The combination of buparlisib and lapatinib is feasible in HER2-positive, trastuzumab-resistant advanced breast cancer.
- Preliminary evidence suggests antitumour activity in this heavily pre-treated patient population.
- Further investigation of this combination in advanced HER2-positive breast cancer is warranted.
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