Neoadjuvant buparlisib plus trastuzumab and paclitaxel for women with HER2+ primary breast cancer: A randomised, double-blind, placebo-controlled phase II trial (NeoPHOEBE)

Abstract

Aim The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer. Methods NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15. Results Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA. Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup (Pinteraction = 0.03). Conclusions Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors. Trial registration identifier NCT01816594.

Stathmin guides personalized therapy in oral squamous cell carcinoma

“…This result is in line with a phase 2 trial that suggested that BKM‐120 in combination with paclitaxel could be an effective second‐line treatment for head and neck squamous cell carcinoma patients . However, two other trials failed to demonstrate improvement from the addition of BKM‐120 to chemotherapy in the full or in a PI3K pathway‐activated study population . Here we find for the first time that PI3K inhibitors decrease stathmin expression and phosphorylation.…”

Targeting PI3K in cancer: mechanisms and advances in clinical trials

“…A randomized adaptive phase II/III study (BELLE-4) suggested that addition of buparlisib to paclitaxel did not improve PFS of patients with HER2 negative advanced breast cancer [120]. In a placebo-controlled phase II trial (NeoPHOEBE), addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2 positive early breast cancer was revealed to be unfeasible [121].…”

Biomarkers of response and resistance to PI3K inhibitors in estrogen receptor-positive breast cancer patients and combination therapies involving PI3K inhibitors

“…Likewise, in HER2-positive BC patients, presence of a PIK3CA-mut is associated with worse response rates to neoadjuvant treatment [62]. Phase I/II studies demonstrated the overall feasibility of combining anti-HER2 treatments with PI3Ki (Table 2) [46,[50][51][52][53][54][55][56][57][58][59]63]. A phase II study including HER2-positive, trastuzumab-resistant metastatic BC patients treated with buparlisib and trastuzumab showed an overall response rate of 10%, but grade !…”