Abstract A118: PIKHER2: A phase Ib study evaluating oral BKM120 in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer
Authors: Gonçalves Anthony , Guerin Mathilde , Isambert Nicolas , Campone Mario , Resai Keyvan , Autret Aurélie , Pakradouni Jihane , Robert Alexie , Provansal Magali , Charafe-Jauffret Emmanuelle , Sabatier Renaud , Hervieu Alice , Extra Jean-Marc , Viens Patrice , Lokiec François , Boher Jean-Marie 
Published: May 2016

Abstract
Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. Lapatinib is a dual anti-HER2/EGFR tyrosine kinase inhibitor with clinical activity after trastuzumab failure in HER2-positive advanced breast cancer (ABC). BKM120 is a pan-class I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110α. PIKHER2 phase Ib study aimed primarily to determine maximum tolerated dose (MTD) and propose a recommended phase II dose (RP2D) for BKM120 in combination with lapatinib in HER2-positive, trastuzumab-resistant, ABC. Secondary objectives included safety, antitumor activity, pharmacokinetics and biomarker assessments. Methods: PIKHER2 was a multi-center study, enrolling HER2 positive (IHC 3+ or FISH positive) ABC, with disease progressing either while on trastuzumab for metastatic disease or within 12 months of the last infusion for patients who received trastuzumab as adjuvant/neoadjuvant treatment. Oral BKM120 (B; 40, 60 or 80 mg) and lapatinib (L; 750, 1000 or 1250 mg) were administered daily. A modified CRM using an adaptive Bayesian model guided the dose escalation of both agents. PIK3CA mutational status and PTEN/hormone receptor expression IHC was evaluated on available tumor tissue. Results: A total of 24 HER2-positive ABC pts, with a median number of previous lines of cytotoxics = 2 (1-5) and previous lines of anti-HER2 = 2 (1-6) for advanced stage, were treated across 5 dose-levels (B,40 + L,750; B, 60 + L,750; B,80 + L,750; B,80 + L,1000; B,80 + L,1250). Following cycle 1, 5 pts experienced DLTs: G3 ALT elevation, G3 vomiting, G3 stomatitis, G3 hyperglycemia and G3 diarrhea. MTD was reached at B,80 + L,1250 but toxicities and early treatment discontinuation beyond cycle 1 led us to select B,80 + L,1000 as the RP2D. Main drug-related adverse events were: diarrhea (83% of pts, G3 in 21%), nausea/vomiting (83% of pts, G3 in 4%), skin toxicity (75% of pts, G3 in 21%), asthenia (70% of patients, no G3), depression (58% of pts, G3 in 4%), anxiety (42% of pts, no G3), transaminases increase (29% of pts, G3 in 17%). B and L PK parameters values were consistent with those already published for both drugs. A large inter-individual variability was observed for both drugs. There was no significant evidence for drug-drug PK interaction. Disease control rate (DCR) was 79% [57-92%], one patient obtained a complete remission and 6 additional patients experienced stable disease for ≥ 24 weeks (clinical benefit rate, CBR of 29% [12-51%]). PIK3CA mutations and PTEN loss were observed in 4 of 14 and 1 of 21 patients, respectively. DCR and CBR were higher in hormone receptor-negative tumors. Conclusion: Combining BKM120 and lapatinib in HER2-positive trastuzumab-resistant was feasible. Preliminary evidences of antitumor activity were observed in this heavily pre-treated population.
Citation Format: Anthony Gonçalves, Mathilde Guerin, Nicolas Isambert, Mario Campone, Keyvan Resai, Aurélie Autret, Jihane Pakradouni, Alexie Robert, Magali Provansal, Emmanuelle Charafe-Jauffret, Renaud Sabatier, Alice Hervieu, Jean-Marc Extra, Patrice Viens, François Lokiec, Jean-Marie Boher. PIKHER2: A phase Ib study evaluating oral BKM120 in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A118.