Modest delay in disease progression with the PIK3CA inhibitor taselisib in women with advanced breast cancer

In the phase III SANDPIPER trial, the PIK3CA inhibitor taselisib in combination with fulvestrant halted the growth of advanced breast cancer by 2 months longer than hormone therapy alone. As such, the addition of taselisib to fulvestrant resulted in a significant 30% reduction in the risk of death or disease progression. Whether this 2-month improvement in progression-free survival (PFS) is clinically relevant is subject to debate. Moreover, the addition of taselisib resulted in a substantial increase in toxicity. Nevertheless this study indicates that PIK3CA is a bonafide target in advanced breast cancer and provides proof-of-principle for further studies.

PI3K signalling is involved in tumour growth, proliferation, and survival, and mutations in PIK3CA are frequently observed in hormone receptor-positive, HER2-negative breast cancer. Taselisib is a potent, selective PI3K inhibitor that showed enhanced activity in PIK3CA-mutant breast cancer cell lines. Moreover, early clinical studies demonstrated partial responses in PIK3CA-mutant breast cancer patients both with taselisib as a single-agent and in combination with fulvestrant. SANDPIPER is the first placebo-controlled randomised study evaluating the efficacy and safety of this mutant-selective PI3K inhibitor added to the endocrine agent fulvestrant in a biomarker-defined population (i.e. patients with hormone receptor positive metastatic breast cancer with PIK3CA-mutant tumours).

In SANDPIPER, 516 postmenopausal women with disease recurrence or progression during or after an aromatase inhibitor were randomized (2:1) to receive taselisib (4 mg oral, qd) or placebo in combination with fulvestrant (500 mg). Patients with PIK3CA-mutant tumours, assessed by a central cobas PIK3CA mutation test, were randomized separately from non-mutant tumours. The primary endpoint of the trial was investigator-assessed PFS in patients with PIK3CA-mutant tumours, while secondary objectives included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR) and safety.

SANDPIPER met its primary endpoint by demonstrating a median PFS of 7.4 months in the taselisib-fulvestrant arm, which is significantly longer than the 5.4 months seen in the placebo-fulvestrant arm. This corresponds to a 30% reduction in the risk of disease progression or death in favour of the taselisib regimen (HR[95%CI]: 0.70[0.56-9.89]; p=0.0037). In addition, the ORR was more than doubled when taselisib was added to fulvestrant (28% versus 11.9%; p=0.0002). The clinical benefit rate was reported to be 37.3% in patients treated with fulvestrant alone and 51.5% with taselisib plus fulvestrant. Responses were also more durable with taselisib, reflected by a median DoR of 7.2 months with fulvestrant alone and 8.7 months with taselisib plus fulvestrant. At the time of the analysis, OS data were not yet mature. When they looking at the outcomes by geographic area, the researchers noted that taselisib provided more benefit to study participants who received treatment in North America and Europe, where cancer worsening was delayed by a median of 3.5 months (median PFS 7.9 versus 4.5 months). In other countries including Eastern Europe and Latin America, taselisib appeared to provide very little or no added benefit. More research is needed understand the reasons for this discrepancy.

The efficacy benefit did come at the cost of increased toxicity (grade ≥3 toxicity: 49.5% versus 16.4%; serious side effects: 32.0% versus 8.9%). The most common grade ≥3 adverse events seen in patients who received taselisib were diarrhoea (12%), hyperglycaemia (10%), colitis (3%) and stomatitis (2%). Due to side effects, 17% of women who received taselisib stopped treatment early, compared to only 2% of those who did not receive the targeted therapy.

In summary, taselisib added to fulvestrant leads to a modest, but statistically significant increase in PFS. Also in the other secondary efficacy endpoints a benefit was seen when taselisib was added. However, this increased efficacy did come at the cost of a considerable increase in toxicity. Therefore it is doubtful whether this combination will enter clinical practice. Nevertheless, the trial can be seen as an important proof-of-principle study and identifies PIK3CA as a feasible target in PIK3CA-mutant hormone-receptor positive, HER2-negative advanced breast cancer.

Reference

J. Baselga, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA-mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER. Presented at ASCO 2018; Abstract LBA1006.