Highlights
- •Evaluation of buparlisib–lapatinib combination in resistant HER2-positive advanced breast cancer.
- •We examined the safety and tolerance and proposed a recommended phase II dose.
- •No significant pharmacokinetic drug–drug interaction was found.
- •Preliminary evidence of clinical activity was observed.
Abstract
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.
Keywords
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Article info
Publication history
Published online: September 23, 2017
Accepted:
August 23,
2017
Received in revised form:
August 22,
2017
Received:
June 26,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
