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PI3K inhibitor taselisib demonstrates benefit in early breast cancer

Jenny Ng
14 Sep 2017
Adding taselisib to standard neoadjuvant letrozole therapy significantly improves overall response rate (ORR) in postmenopausal patients with oestrogen receptor (ER)-positive, HER2-negative early-stage breast cancer, according to data from the phase II LORELEI trial presented at the European Society for Medical Oncology (ESMO) 2017 Congress held in Madrid, Spain.

Patients who received letrozole plus taselisib achieved a 50 percent ORR vs a 39.3 percent ORR in patients who received letrozole plus placebo (odds ratio [OR], 1.55; p=0.049). [ESMO 2017, abstract LBA10_PR]

“This is the first randomized study to demonstrate a significant increase in ORR upon treatment with a phosphatidylinositol 3-kinase [PI3K]–selective inhibitor plus endocrine therapy in patients with ER-positive, HER2-negative early breast cancer,” noted lead study investigator Dr Cristina Saura of Vall d’Hebron University Hospital in Barcelona, Spain.

The PI3K signalling pathway has been a notable target of cancer therapies due to its important role in regulating key cell signalling processes, including cellular growth, proliferation and survival. It is also one of the most dysregulated, with activating mutations found in around 40 percent of hormone receptor-positive breast cancer patients.

“Taselisib is potent and selective against the PIK3CA protein through a mechanism of action distinct from other PI3K inhibitors,” Saura explained.

The international, randomized, double-blind LORELEI trial included 334 postmenopausal women with stage I–III operable, ER-positive, HER2-negative breast cancer. All patients were tested for the PIK3CA mutation and randomized to receive neoadjuvant letrozole plus taselisib or placebo for 16 weeks.

Among the overall population who received taselisib, eight patients achieved a complete response, 75 experienced a partial response and 67 had stable disease. Among the group of 152 patients who were PIK3CA mutation-positive, the ORR was 56.2 percent in the taselisib arm vs 38 percent in the placebo arm (OR, 2.03; p=0.033). There was no significant difference in pathologic complete response (pCR) between the two treatment arms in either clinical subset.

“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,” said Saura.

Adding taselisib to letrozole led to increased rates of gastrointestinal adverse events, skin and subcutaneous tissue disorders, and metabolic and nutritional disorders. Taselisib was also associated with higher rates of grade 3/4 adverse effects (25.7 percent vs 7.8 percent in the placebo arm), the most common of which included gastrointestinal disorders, infections and infestations, and skin and subcutaneous tissue disorders.

“Though the trial is hypothesis-generating rather than practice changing, the results add to a growing list of promising new approaches to endocrine therapy for early breast cancer,” said Dr Nadia Harbeck of the University of Munich, Munich, Germany, who discussed the results at the ESMO 2017 Congress.

“The full potential of endocrine-based therapy in early breast cancer has not yet been reached. Visionary trials are still needed to optimally position these new therapeutic concepts in patient management,” Harbeck added.

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