Neoadjuvant Letrozole Plus Taselisib or Placebo in Postmenopausal Women With ER-Positive, HER2-Negative Early Breast Cancer


Key Points

  • The addition of neoadjuvant taselisib to letrozole increased objective response rates among all patients and also among those with PIK3CA-mutant disease.
  • No differences in pathologic complete response rates were observed.  

In the phase II LORELEI trial reported in The Lancet Oncology, Saura et al found that the addition of the phosphatidylinositol-3 kinase (PI3K) inhibitor taselisib to neoadjuvant letrozole improved objective response rates but not pathologic complete response rates in women with estrogen receptor (ER)-positive, HER2-negative early-stage breast cancer.

The double-blind trial included 334 patients with stage I to III, operable disease from 85 sites in 22 countries. Patients were randomly assigned between November 2014 and August 2016 to receive letrozole at 2.5 mg/d continuously with either 4 mg of oral taselisib (n = 166) or placebo (n = 168) on a 5 days-on, 2 days-off schedule for 16 weeks, followed by surgery.

Patients had to have evaluable tumor tissue for PIK3CA genotyping, and a total of 73 patients in the taselisib group and 79 in the placebo group had a PIK3CA mutation. Coprimary endpoints were objective response by centrally assessed breast magnetic resonance imaging and locally assessed pathologic complete response in the breast and axilla (defined as ypT0/Tis, ypN0) at surgery in all randomly assigned patients and in patients with PIK3CA-mutant tumors.

Response Rates

Median follow-up was 4.9 months. Objective response was observed in 50% of the entire taselisib group vs 39% of the entire placebo group (odds ratio [OR] = 1.55; P = .049) and in 56% vs 38% of the PIK3CA-mutant subgroups (OR = 2.03; P = .033). Response rates in the PIK3CA wild-type subgroups were 46% vs 40% (OR= 1.22; P = .50).

No significant differences were observed in pathologic complete response rates among all patients (2% vs 1%, OR = 3.07; P = .37) or in the PIK3CA-mutant subgroup (1% vs 0%; P = .48).

Adverse Events

The most common grade 3 or 4 adverse events in the taselisib group were gastrointestinal events (8%), infections (5%), and skin and subcutaneous tissue disorders (5%). The most common in the placebo group were vascular disorders (2%), gastrointestinal events (1%), and infections (1%). No grade 4 hyperglycemia was observed in the taselisib group, and the two observed grade 3 cases were asymptomatic. Serious adverse events occurred in 12% vs 2% of patients, with the most common in the taselisib group being infection (5%) and gastrointestinal events (4%).  

The investigators concluded, “The increase in the proportion of patients who achieved an objective response from the addition of taselisib to endocrine therapy in a neoadjuvant setting is consistent with the clinical benefit observed in hormone receptor–positive, HER2-negative metastatic breast cancer.”

Cristina Saura, MD, of the Breast Cancer Unit, Vall d’Hebron University Hospital, Barcelona, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Genentech and F. Hoffmann-La Roche. For full disclosures of the study authors, visit

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