according to final results of the phase 2 LOTUS trial.
The median OS was 25.8 months in patients who received ipatasertib plus paclitaxel and 16.9 months in patients who received paclitaxel plus placebo. Although this difference was not statistically significant, it was “clinically meaningful,” according to, of the National Cancer Center Singapore. Dr. Dent from the LOTUS trial at the European Society of Medical Oncology: Breast Cancer virtual meeting.
Previously reported data showed a progression-free survival benefit in the ipatasertib arm, compared with the placebo arm – 6.2 months and 4.9 months, respectively (
Patients, treatment, and safety
LOTUS participants had measurable locally advanced/metastatic TNBC that was previously untreated with systemic therapy, and they were stratified by prior adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status.
Patients were randomized 1:1 to receive paclitaxel at a dose of 80 mg/m2 on days 1, 8, and 15 of each 28-day cycle plus either placebo (n = 62) or ipatasertib at a dose of 400 mg on days 1-21 (n = 62).
The safety results didn’t differ between the primary and updated results, Dr. Dent noted.
“What we can say is that the combination is extremely well tolerated, especially when we compare it to other targeted agents targeting this pathway,” she said. “What we do see is noticeable diarrhea ... [and] an increase in sensory neuropathy, which is not entirely unexpected.”
Subsequent systemic anticancer therapy was required in 77% of patients in the ipatasertib arm and 90% of patients in the placebo arm.
The final OS data show a numerical advantage for patients in the ipatasertib arm compared with the placebo arm. The 1-year OS was 83% in the ipatasertib arm and 68% in the placebo arm. The median OS was 25.8 months and 16.9 months, respectively (stratified hazard ratio, 0.80).
“This is a clinically meaningful improvement of 9 months in overall survival, which is indeed not too dissimilar to what we have seen in patients with PD-L1-positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” Dr. Dent said.
However, the 95% confidence interval for the stratified OS hazard ratio crossed 1 (0.50-1.28). Therefore, the findings require confirmatory phase 3 trial results, Dr. Dent said.
The OS improvements with ipatasertib were seen “in all biomarker-defined subgroups – PTEN normal or low, PIK3CA/AKT1/PTEN altered or non-altered,” she said. OS benefits were more pronounced in patients with altered PIK3C/AKT1/PTEN status, but the numbers are too small to make definitive conclusions, according to Dr. Dent.
‘Promising’ results, confirmation needed
Invited discussant, head of the breast cancer department at Gustave Roussy, Paris, said the OS findings from LOTUS are “quite promising,” and the safety data are “reassuring.”
The findings are comparable to those of the recently published( ), she said, noting that “AKT inhibition in combination with paclitaxel deserves phase 3 development, and this is ongoing in major phase 3 trials.”
Dr. Delaloge also noted that the efficacy may not be limited to PIK3CA/AKT–altered tumors, and given the heterogeneity of TNBC – which may explain the differences seen among various studies – “it is very important that such phase 3 trials ideally involve extensive genomical definitions of tumors so that we understand what it is we are talking about and what is the real effect of the drug.”
“The adequate positioning of AKT inhibition in competition/complementation with other ongoing strategies remains to be defined,” she said. “I think these drugs are ready for translation to early phases.”
Dr. Dent said the results of LOTUS warrant confirmation in the ongoing, randomized phase 3evaluating first-line ipatasertib plus paclitaxel for metastatic TNBC. She noted that the small sample sizes and heterogeneity of TNBC among LOTUS participants limited the interpretation of the findings.
In another trial,, researchers are evaluating the first-line role of ipatasertib plus paclitaxel and atezolizumab in locally advanced or metastatic TNBC.
“This is an exciting triplet combination that’s been evaluated already in the phase 1 setting, and now we have a phase 3 study evaluating the triplet,” Dr. Dent said.
The LOTUS trial was funded by Roche/Genentech. Dr. Dent reported receiving honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, and AstraZeneca. Dr. Delaloge reported personal financial interests in AstraZeneca until 2018 and travel and accommodation support from AstraZeneca, Pfizer, Roche, and Pierre Fabre.
SOURCE: Dent R et al. ESMO Breast Cancer 2020,