Study of PI3K Inhibitor Added to Fulvestrant in Advanced Breast Cancer Affirms Proof-of-Principle

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IN PATIENTS with advanced breast cancer harboring a PIK3CA mutation, the addition of the PI3 kinase (PI3K) inhibitor taselisib to endocrine therapy with fulvestrant (Faslodex) significantly improved progression-free survival compared with fulvestrant alone, in the international phase III SANDPIPER trial, whose results were presented at the 2018 ASCO Annual Meeting.1 However, the lead investigator, José Baselga, MD, PhD, acknowledged that taselisib will not be the drug that shows potential for targeting PI3K in breast cancer. 

José Baselga, MD, PhD

José Baselga, MD, PhD

The drug offered a 2-month improvement in progression-free survival, over fulvestrant alone, in the SANDPIPER trial. But its “modest benefit” is also accompanied by “challenging tolerability,” said Dr. Baselga, Physician-in-Chief at Memorial Sloan Kettering Cancer Center, New York. 

Taselisib is the first agent that blocks preferentially PI3K alpha mutations, the type of PI3K protein that is mutated in estrogen receptor–positive breast cancer. However, it also targets PI3K delta and gamma isotypes, which explains some of the limiting toxicities observed. Taselisib has shown promising clinical benefit in an early trial of patients with head and neck and some gynecologic cancers. 

The take-away message from the study, Dr. Baselga said, is that it showed proof of principle for targeting PI3K. “In the case of breast cancer,” he said, “what we need to do is to work on more specific inhibitors that will be safer…more potent, more selective compounds.” 

Two other PI3K inhibitors—idelalisib (Zydelig) and copanlisib (Aliqopa)—are approved for the treatment of hematologic malignancies, but SANDPIPER is the first controlled study to test this drug class in breast cancer, he said. 

SANDPIPER Details and Results 

SANDPIPER IS the first and largest phase III clinical trial of taselisib. The study enrolled 516 postmenopausal women with locally advanced or metastatic estrogen receptor–positive HER2-negative disease that progressed during or after treatment with aromatase inhibitors. All patients had a PIK3CA mutation, as determined by central testing. Patients were randomly assigned to receive fulvestrant (500 mg) plus placebo or fulvestrant plus taselisib (4 mg/d, orally). 

For the primary endpoint (investigator-assessed progression-free survival), the taselisib arm yielded a significant improvement in median progression-free survival, from 5.4 months with fulvestrant alone to 7.4 months with the combination (hazard ratio [HR] = 0.70; P = .0037). The result was confirmed by blinded independent central review (HR = 0.66). 

“The challenging tolerability of this combination led to frequent treatment discontinuations and may have limited the clinical benefit in this disease setting.”
— José Baselga, MD, PhD

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The response rate was also more than doubled with taselisib on board, from 11.9% to 28.0% (P = .0002), and the clinical benefit rate increased from 37.3% to 51.5%. The median duration of response was 7.2 months with placebo and 8.7 months with taselisib. Overall survival data are immature, he said. 

The addition of taselisib to fulvestrant led to an increase in toxicity, with serious side effects reported in 32.0% of the combination arm vs 8.9% of the single-agent arm. These toxicities were ≥ grade 3 in 49.5% versus 16.4%, respectively. Gastrointestinal toxicities, especially diarrhea, and hyperglycemia were the most common side effects seen with the combination therapy, reported by 60% and 40%, respectively. 

“Overall, the efficacy observed in SANDPIPER was considered modest,” Dr. Baselga concluded. “The challenging tolerability of this combination led to frequent treatment discontinuations and may have limited the clinical benefit in this disease setting.” ■

DISCLOSURE: Dr. Baselga reported financial relationships with GRAIL and other relationships with Bristol-Myers Squibb, Varian Medical Systems, and PMV Pharma. 


1. Baselga J, Dent SF, Cortes J, et al: Phase III study of taselisib (GDC-0032) plus fulvestrant versus fulvestrant in patients with estrogen receptor-positive, PIK3CA-mutant, locally advanced or metastatic breast cancer: Primary analysis from SANDPIPER. 2018 ASCO Annual Meeting. Abstract LBA1006. Presented June 3, 2018.

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