Pictilisib Plus Fulvestrant Ends For ER-Positive, Endocrine-Resistant Breast Cancer

Pictilisib fails to improve progression-free survival over placebo in fulvestrant-treated women with oestrogen receptor-positive breast cancer resistant to aromatase inhibitor therapy

medwireNews: Investigation of the phosphatidylinositol 3-kinase (PI3K) inhibitor pictilisib in combination with fulvestrant for oestrogen receptor (ER)-positive, endocrine-resistant breast cancer has halted following FERGI results showing no progression-free survival (PFS) benefit compared with fulvestrant alone.

The first part of the phase II trial was conducted in 168 postmenopausal women with or without PIK3CA mutations, and showed comparable PFS of 6.6 and 5.1 months for the 89 patients randomly assigned to receive oral pictilisib 340 mg/day and the 79 given placebo, respectively.

All patients also received intramuscular fulvestrant 500 mg (day 1 and 15 of cycle 1, day 1 subsequent cycles), the researchers say.

Similarly, in the second part of the trial conducted in women with a known PIK3CA mutation, PFS did not significantly differ between the 61 patients who received pictilisib 260 mg/day plus fulvestrant and the 20 patients given placebo plus fulvestrant, at 5.4 and 10.0 months, respectively.

Pictilisib-treated patients in the first part of the trial had higher rates of grade 3 or more severe adverse events than their placebo-treated counterparts, at 61% versus 28%, whereas the rate was comparable in the second part, at 36% versus 37%.

Treatment-related serious events in part 1 of the study were reported in 16% and 1% of the pictilisib and placebo groups, respectively; 5% of both treatment arms experienced serious events in the second part.

“[D]osing of pictilisib was limited by toxicity, potentially limiting its efficacy”, write Ian Krop, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-authors in The Lancet Oncology.

“For future assessment of PI3K inhibition as an approach to overcome resistance to hormonal therapy, inhibitors with greater selectivity than that of pictilisib might be needed to improve tolerability and potentially increase efficacy”, they suggest.

Thomas Bachelot, from Centre Leon Berard in Lyon, France, and co-authors of an accompanying comment note, however, that PI3K inhibition may be a poor target for endocrine-resistant breast cancer as PIK3CA activating mutations are usually associated with a good prognosis in ER-positive, HER2-negative disease.

They also suggest that patient selection for the trial might have been “inadequate” as patients with metastatic disease were chosen on the basis of their primary tumour sample and there is thought to be poor correlation for the PIK3CA alterations between primary and metastatic specimens.

“PI3K inhibitors might have an important role in subcategories of luminal breast cancers”, the commentators conclude.

“Nevertheless, better understanding of molecular mechanisms of hormone resistance and better selection of patients than at present are mandatory.”

They continue: “Accumulation of clinical data along with development of new and more specific PI3K inhibitors than at present, such as α-subunit-specific inhibitors, will probably lead in the coming years to efficient development of this much anticipated treatment strategy.”


Krop IE, Mayer IA, Ganju V, et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 2016; Advance online publication 4 May. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00106-6

Bachelot T, Campone M, Tredan O. PI3K targeting in breast cancer: the end of the beginning? Lancet Oncol 2016; Advance online publication 4 May. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00148-0

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