By: Alexander M. Castellino, PhD
A new investigational PI3KCA targeted agent, taselisib (Genentech/Roche), has shown benefit in postmenopausal women with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2–) early-stage breast cancer. Adding the new agent to letrozole significantly improved response rates compared with letrozole alone in all patients, but the improvement was more robust for patients with breast cancer harboring PI3KCA mutations.
In all randomly assigned patients, overall response rate (ORR) was significantly improved with the taselisib-letrozole combination: 50% vs 39.3% for letrozole alone (P = .049). In patients with PIK3CA mutations, taselisib increased overall response rates (ORRs) from 38% with letrozole alone to 56.2% with the combination (P = .033).
The new findings come from the LORELEI study (LBA10) presented here at the European Society for Medical Oncology (ESMO) 2017 Congress.
“The study is hypothesis generating, not practice changing,” commented a discussant for the study, Nadia Harbeck, MD, from the Breast Center, University of Munich, Germany. “LORELEI is the first clinical proof of efficacy of a specific PI3K [phosphatidylinositol-4,5-bisphosphate 3-kinase] inhibitor in early breast cancer. Results of confirmatory phase 3 trials in metastatic breast cancer are eagerly awaited,” she said.
“The full potential of endocrine-based therapy in the early breast cancer setting has not been reached,” Dr Harbeck noted. “Visionary trials are needed to optimally position these new therapy concepts in patient management,” she concluded.
The PI3K signaling pathway is involved with cell proliferation and is the most deregulated pathway in HR+ breast cancer, with about 40% of patients showing activating mutations, explained lead author, Cristina Saura, MD, from Vall d’Hebron University Hospital in Barcelona, Spain. Unlike other PI3K inhibitors, taselisib degrades mutant PI3KCA — the catalytic subunit of PI3K — by a unique mechanism that differentiates it from other PI3K inhibitors, she pointed out.
LORELEI is the first randomized study to demonstrate a significant increase in ORR upon treatment with a PI3K selective inhibitor in these patients with ER+ and HER2– early-stage breast cancer, Dr Saura noted.
“The α-specific story is important because other PI3K inhibitors have had only a small effect, and the benefit-risk ratio was less favorable,” noted Sibylle Loibl, MD, chair of the German Breast Group, who was not involved in the study but provided the comment for ESMO. “In general it is believed that α-specific inhibitors will be more efficacious and less toxic than others,” she said.
“These are the first data indicating that the addition of an α-specific PI3K inhibitor might work in addition to an endocrine therapy in HR+/HER2– breast cancer. More data from LORELEI as well as data from the phase 3 studies in metastatic breast cancer need to be awaited for evaluating the role of PIK3 kinase inhibitors in breast cancer,” she said.
The LORELEI study enrolled 334 women with postmenopausal women across 85 centers and 22 countries. Women were required to have ER+/HER2– operable breast cancer (stage I-III), with tumors 2 cm or greater determined from breast MRI.
All patients had tissue analyzed for PIK3CA mutant cancer cells. Patients were stratified according to tumor size and nodal status.
Women were randomly assigned to receive letrozole plus taselisib (n = 166) or letrozole with matching placebo (n = 168). In the subset of patients with PI3KCA mutations, 73 received taselisib and letrozole and 79 received letrozole and placebo.
Taselisib was given at a daily dose of 4 mg, with a schedule of 5 days on and 2 days off for 16 weeks. Surgery was performed 16 weeks after receipt of therapy.
ORRs were centrally assessed by breast MRI. The ORRs in patients with PI3CA mutational tumors were co-primary endpoints of the study. Pathologic complete response rate in breast and axilla (ypT0/Tis ypN0; total pCR) from local evaluation were also study endpoints.
“Breast MRI is more accurate than clinical palpation, ultrasound, or mammogram for predicting residual disease after neoadjuvant chemotherapy, but there are scarce data on response evaluation by MRI after endocrine therapy,” Dr Saura said.
Patients enrolled had a median age of 64 years. More than 60% has T2 stage tumors and about 65% had N0 disease. In addition, approximately 60% had histologic grade 2 tumors and more than 50% had invasive ductal carcinomas.
With a median cumulative dose of 316 mg, most patients received the planned dose of taselisib. Dose reductions for taselisib were reported in 11.4% of patients and discontinued in 10.8%.
With significant ORRs seen in patients receiving combination taselisib and letrozole, the odds ratio in favor of taselisib was 1.55 (P = .049). Complete responses (CRs) and partial responses (PRs) were reported for 4.8% and 45.2% of patients receiving the taselisib combination, respectively. Corresponding rates for patients receiving letrozole alone were 1.8% and 35.5%, respectively.
For patient with PI3KCA mutations, the odds ratio was 2.03 (P = .033). CR and PR were reported for 6.8% and 49.3% of patients, respectively. Corresponding rates for patients receiving letrozole alone were 2.5% and 35.4%, respectively.
The pCR rates were not significant for the entire cohort and for patients with PI3KCA mutations. For example, in the entire cohort of patients, pCR rates were 1.8% and 0.6% for patients receiving the taselisib combination and letrozole alone, respectively.
“The pCR rate was low with or without the addition of taselisib, but this is not unexpected with only 4 months of endocrine-based therapy,” Dr Saura said.
“We were able to detect a reduction in tumor size after only 16 weeks of treatment, compared to patients who received letrozole plus placebo. Any decrease in tumor measurements is something positive for patients because this means the drug has had activity against their tumor in a short period of time,” Dr Saura said in a statement.
Gastrointestinal disorders (eg, diarrhea, nausea, stomatitis) were seen more frequently with taselisib: 55.1%, vs 32.9% for letrozole alone. Taselisib was also associated with a higher frequency (vs letrozole) of rash (9.6% vs 3.0%) and hyperglycemia (15.6% vs 7.2%).
The most common serious (grade 3/4) adverse events associated with taselisib (vs letrozole) included gastrointestinal disorders (7.8% vs 1.2%), infections (4.8% vs 1.2%), skin/subcutaneous tissue disorders (4.8% vs 0%), vascular disorders (3.6% vs 2.4%), and metabolism and nutrition disorders (3.6% vs 0%), including hyperglycemia (1.2% vs 0%). One sudden death in a taselisib-treated patient was not related to the study drug.
The study was funded by Genentech Inc. Dr Saura has disclosed no relevant financial relationships. Two coauthors received honoraria from Genentech-Roche, and three coauthors are employees of Genentech.
European Society for Medical Oncology (ESMO) 2017 Congress. Presented September 8, 2017. Abstract LBA10.