Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer

Abstract

Purpose: Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy.

Patients and methods: Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis.

Results: Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy.

Conclusion: The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.

Fig 1.

Treatment duration (months) for patients exposed to continuous or intermittent buparlisib plus letrozole, with corresponding radiologic response and tumor PI3K pathway mutation status. Gold shading indicates presence of a PIK3CA mutation, and blue shading indicates no alteration. Best response by RECIST is depicted in gold (complete response [CR]), pink (partial response [PR]), gray (stable disease [SD]), and red (progression of disease [PD]) shading. Black shading indicates discontinuation of treatment because of toxicity or withdrawal; orange shading indicates the four patients who are still on active treatment, and light brown shading corresponds to all patients who discontinued treatment because of disease progression. Dark blue shading indicates patients who had primary endocrine therapy, and light green shading indicates patients who had secondary endocrine therapy resistance.

Fig 2.

[¹⁸F]fluorodeoxyglucose–positron emission tomography/computed tomography ([¹⁸F]FDG-PET/CT) metabolic response assessments in patients exposed to continuous buparlisib (BKM120) plus letrozole, with corresponding response by RECIST and tumor PIK3CA status. (A) Seventeen patients in the continuous buparlisib plus letrozole arm were evaluable for [¹⁸F]FDG-PET/CT assessments. More than 25% decrease in tumor [¹⁸F]FDG uptake 15 days after treatment initiation corresponded to a metabolic partial response (PR; blue shading), which was seen in nine patients. More than 25% increase in tumor [¹⁸F]FDG uptake 15 days after treatment initiation corresponded to a metabolic progression of disease (PD; gray shading), which was seen in one patient. All remaining seven patients had metabolic stable disease (SD; gold shading). Two of the patients who exhibited a metabolic partial response 15 days after treatment initiation, one of them exemplified in (B), also had radiographic responses by CT (yellow and pink shading), at their 2-month tumor assessment. All patients with a PIK3CA mutation (orange shading) had metabolic partial responses. (C) Patients who had ≥ 25% reduction in tumor [¹⁸F]FDG uptake (metabolic partial response) on day 15 of treatment relative to pretreatment baseline (blue dots), as well as 8 weeks after treatment initiation (gold triangles), had a longer time on treatment than patients with < 25% decrease in tumor [¹⁸F]FDG uptake (metabolic SD or metabolic PD), both on day 15 and 8 weeks after treatment initiation. SUVmax, maximum standardized uptake value.