Abstract A118: PIKHER2: A phase Ib study evaluating oral BKM120 in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer

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.

Buparlisib, an oral pan-PI3K inhibitor for the treatment of breast cancer

“…Investig. Drugs (2015) 24 (4) safe and tolerable with a recommended dose of 80 mg/day for buparlisib and 400 mg/day for sonidegib. Toxicity profile was similar to that observed in single-agent studies.…”

“…About 60 --70% of BCs express either or both the estrogen (ER) and the progesterone receptors [4] and about 20 --30% overexpress the HER2 oncogene [5]. Drugs that interfere with ER functions such as tamoxifen or that lower peripheral estrogen levels such as aromatase inhibitors (AIs) significantly reduce relapse and death rates when administered postsurgically in women with operable BC and to prolong progression-free and overall survival in women with advanced or metastatic BC [3,6,7].…”

Tie2–FGFR1 Interaction Induces Adaptive PI3K Inhibitor Resistance by Upregulating Aurora A/PLK1/CDK1 Signaling in Glioblastoma

“…The combination of BKM and various kinase inhibitors was also tested recently to delay tumor progression more efficiently. Some studies have shown promising results (39,40). Therefore, the discovery of escape mechanisms provides not only a potential new approach to PI3K inhibition therapy but also a novel angle to illustrate new and often surprising functional interactions between different signaling pathways.…”

A Phase I Trial of the PI3K Inhibitor Buparlisib Combined With Capecitabine in Patients With Metastatic Breast Cancer

“…However, a phase I study of buparlisib and lapatinib that enrolled 24 patients with refractory HER2 + breast cancer reported increased toxicity with 5 patients experiencing DLTs in the first cycle of treatment. 27 No evidence was found of a PK drug–drug interaction. The recommended phase 2 dose of buparlisib was therefore reported as 80 mg daily with 1000 mg of lapatinib.…”