Selective PI3K Inhibitor Boosts Effect of Letrozole in Neoadjuvant Setting

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Cristina Saura, MD

Cristina Saura, MD

FOR THE first time, an inhibitor of the phosphoinositide 3-kinase (PI3K) pathway (taselisib) used in combination with endocrine therapy in the neoadjuvant setting improved response rates over endocrine therapy alone—with good tolerability—in women with early breast cancer, according to the phase II LORELEI results.1 

“LORELEI is the first randomized study to demonstrate a significant increase in objective response rates measured by MRI [magnetic resonance imaging] upon treatment with a PI3K selective inhibitor plus endocrine therapy,” said Cristina Saura, MD, of Vall d’Hebron Institute of Oncology in Barcelona, who presented the findings at the 2017 European Society for Medical Oncology (ESMO) Congress in Madrid. 

Taselisib is an oral, potent, and selective PI3K inhibitor with enhanced activity against PIK3CA-mutant cancer cells. Its efficacy in the neoadjuvant setting was evaluated in LORELEI, a randomized, double-blind study of letrozole alone or with taselisib in postmenopausal patients with estrogen receptor–positive/ HER2-negative early breast cancer. 

The PI3K pathway controls key cell-signaling processes and is the most deregulated pathway in hormone receptor–positive breast cancer. Taselisib, an alpha-specific PI3K inhibitor, demonstrates unique actions within the PI3K pathway, differentiating it from other PI3K inhibitors, according to the researchers. In phase I trials, taselisib elicited partial responses preferentially in patients with PIK3CA-mutated metastatic breast cancer as monotherapy and in combination with endocrine therapy. LORELEI built upon these earlier successes, this time in the neoadjuvant setting. 

Key Study Details 

IN LORELEI, 334 postmenopausal patients with estrogen receptor–positive, HER2-negative, stage I–III operable breast cancer were enrolled from 85 centers in 22 countries. Patients were randomly assigned to receive letrozole at 2.5 mg/d with either taselisib or placebo (4 mg, 5 days on, 2 days off) for 16 weeks, followed by surgery. The study had two co-primary endpoints: objective response rate, assessed by MRI, and pathologic complete response rate in the breast and axilla. These outcomes were assessed in the whole population and separately for patients with PIK3CA mutations detected at baseline. 

“For me, the main message is that even though all patients seem to derive some benefit from taselisib, those who had this mutation [PIK3CA] seemed to derive more benefit.”
— Cristina Saura, MD

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“Breast MRI is more accurate than clinical palpation, ultrasound, or mammogram for predicting residual disease after neoadjuvant chemotherapy,” Dr. Saura explained. “In estrogen receptor–positive/HER2-negative breast cancer, the absolute size of tumors by breast MRI after neoadjuvant chemotherapy and radiologic complete response (but not pathologic complete response) have been associated with good relapse-free survival…. But there have been scarce data on response evaluation by MRI after endocrine therapy.” 

Primary Endpoint Met 

LORELEI MET ITS PRIMARY ENDPOINT, demonstrating a significance increase in objective response rate with taselisib plus letrozole, as measured by centrally assessed MRI. The treatment effect appeared to be more pronounced in the PIK3CA-mutated population, Dr. Saura reported. 


  • In the phase II LORELEI trial, postmenopausal women with estrogen receptor–positive/HER2-negative stage I–III breast cancer were randomized to receive letrozole with or without the alpha-selective PI3K inhibitor taselisib.
  • Objective response rates were significantly higher when letrozole was combined with taselisib, especially in the subset with PIK3CA mutations, but the rates of pathologic complete response were low in both arms.
  • Response rates were 50.0% in the taselisib/letrozole arm vs 39.3% in the control arm, and in the PIK3CA-mutated subset, 56.2% vs 38.0%, respectively.

The objective response rate was 50.0% in the taselisib/letrozole arm vs 39.3% in the control arm (odds ratio [OR] = 1.55; P = .049). Among the subset of 152 patients with PIK3CA mutations, responses were observed in 56.2% vs 38.0%, respectively (OR = 2.03; P = .033). Stable disease was observed in 38.4% and 49.4%, respectively. 

“For me, the main message is that even though all patients seem to derive some benefit from taselisib, those who had this mutation seemed to derive more benefit,” she commented. 

No significant difference was observed, however, in the achievement of pathologic complete response, neither in the whole population nor in the PIK3CA-mutated subset. “The [pathologic complete response] rate was low, with or without the addition of taselisib,” she noted, “but this is not unexpected after only 4 months of endocrine-based therapy in patients with estrogen receptor–positive/HER2-negative early breast cancer.” 

The rate of pathologic complete response was 1.8% in the taselisib arm and 0.6% in the placebo arm, for an odds ratio of 3.07, which was not significant (P = .370). Among patients with mutations, these rates were 1.4% and 0% (P = .480). 

“Toxicity was manageable and consistent with this class of drug,” reported Dr. Saura. Among taselisib recipients, about 11% had doses reduced, and 11% discontinued the agent. The most serious adverse events with taselisib were gastrointestinal disorders, seen in 7.8%. Less than 5% of patients experienced infections, skin or subcutaneous tissue disorders, vascular disorders, and disorders of metabolism or nutrition. ■ 

DISCLOSURE: Dr. Saura reported no conflicts of interest. 


1. Saura C, De Azambuja E, Hlauschek D, et al: Primary results of LORELEI: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal patients with ER+/ HER2-negative early breast cancer. 2017 ESMO Congress. Abstract LBA10_PR. Presented September 8, 2017.

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