Ipatasertib-paclitaxel displays potential as first-line treatment for inoperable advanced TNBC

Treatment with ipatasertib plus paclitaxel in the first-line setting demonstrated a trend toward improved overall survival (OS) compared with paclitaxel alone in women with inoperable locally advanced/metastatic triple-negative breast cancer (TNBC), according to final results of the phase II LOTUS trial.

Participants were 124 patients with locally advanced/metastatic TNBC not amenable to curative resection who had not received prior systemic therapy for metastatic disease and had a chemotherapy-free interval of ≥6 months. They were randomized 1:1 to receive paclitaxel (80 mg/m² on days 1, 8, and 15) plus either ipatasertib (400 mg QD on days 1–21; median age 54 years) or placebo (median age 53 years) on 28-day cycles.

Primary analysis findings demonstrated improved progression-free survival (PFS) with ipatasertib-paclitaxel vs paclitaxel-placebo (median 6.2 vs 4.9 months; hazard ratio [HR]_stratified, 0.60, 95 percent confidence interval [CI], 0.37–0.98; p=0.037), particularly in the 42 patients with PIK3CA/AKT1/PTEN alterations (median 9.0 vs 4.9 months; HR, 0.44). [Lancet Oncol 2017;18:1360-1372]

In the present analysis, conducted after a median follow-up of 19 and 16 months (41 and 46 deaths) in the ipatasertib and placebo arms, respectively, OS was numerically improved among ipatasertib vs placebo recipients (median 25.8 vs 16.9 months; HR_stratified, 0.80, 95 percent CI, 0.50–1.28; 1-year OS: 83 percent vs 68 percent). [ESMO Breast Cancer 2020, abstract 139O]

The OS results were consistent across immunohistochemistry PTEN status (median 28.5 vs 17.1 months; HR_unstratified, 0.70, 95 percent CI, 0.36–1.36 [normal PTEN]; median 23.1 vs 15.8 percent; HR_unstratified, 0.83, 95 percent CI, 0.42–1.64 [low* PTEN]), and in those without vs with PIK3CA/AKT1/PTEN alterations (median 23.1 vs 16.2 months; HR_unstratified, 0.72, 95 percent CI, 0.39–1.33 [without alterations]; median OS 25.8 vs 22.1 months; HR_unstratified, 1.13, 95 percent CI, 0.52–2.47 [with alterations]).

Median OS favoured the ipatasertib-paclitaxel combination in all biomarker-defined subgroups, though small sample sizes and TNBC heterogeneity limit interpretation of these results, noted study author Professor Rebecca Dent from the National Cancer Centre Singapore, who presented the results at the ESMO Breast Cancer Virtual Meeting 2020.

The OS improvement with ipatasertib vs placebo was also more pronounced among patients aged <50 years (median 35.2 vs 15.1 months; HR, 0.41, 95 percent CI, 0.20–0.85) compared with patients aged ≥50 years (median 21.8 vs 20.9 months; HR, 1.21, 95 percent CI, 0.71–2.07).

There were no new safety signals compared with previous reports. Grade ≥3 adverse events (AEs) occurred in 56 and 45 percent of ipatasertib and placebo recipients, respectively. Grade ≥3 AEs noted in the ipatasertib arm included diarrhoea, neutropenia, and peripheral sensory neuropathy. Ipatasertib and placebo specifically (excluding paclitaxel) led to treatment discontinuation in four and one patients, respectively, treatment interruption in 22 and 14 patients, and dose reduction in 13 and four patients. Seventy-seven and 90 percent of ipatasertib and placebo recipients, respectively, received subsequent systemic anticancer therapy.

“[The ipatasertib-paclitaxel combination] is extremely well tolerated especially when we compare it to other agents targeting this pathway,” highlighted Dent.

“Median OS of >2 years represents a meaningful outcome in metastatic TNBC,” she continued, noting that the findings warrant confirmation in phase III trials.  

The efficacy of first-line ipatasertib plus paclitaxel plus atezolizumab in locally advanced/metastatic TNBC is currently being assessed in the IPATunity170 trial, while the IPATunity130 trial is examining the effect of ipatasertib plus paclitaxel on patients with PIK3CA/AKT1/PTEN-altered, locally advanced/metastatic TNBC, she said.