ONCAlert | 2018 ASCO Annual Meeting

Ipatasertib/Paclitaxel as First-Line Therapy Improved PFS in Triple-Negative Breast Cancer

Darcy Lewis
Published Online: 9:56 PM, Mon June 5, 2017

Rebecca Dent, MD

Ipatasertib, a highly selective oral ATP-competitive small-molecule Akt inhibitor, in combination with paclitaxel improved progression-free survival (PFS) as a first-line therapy for patients with locally advanced or metastatic triple-negative breast cancer when compared with paclitaxel alone, according to initial findings of the LOTUS trial presented during the 2017 ASCO Annual Meeting.
This effect was more pronounced in predefined biomarker analyses of patients with PIK3CA/AKT1/PTEN-altered tumors, where patients treated with ipatasertib and paclitaxel had a median PFS of 9.0 months compared with 4.9 months in the paclitaxel and placebo arm.
“Adding ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer improved PFS in the biomarker-selected and unselected intent-to-treat [ITT] population,” Rebecca Dent, MD, associate professor, National Cancer Centre, Singapore, and colleagues noted in their poster. “The results of the LOTUS trial support future evaluation of ipatasertib plus paclitaxel in diseases with high prevalence of PI3K/AKT pathway activation and in particular in patients with PIK3CA/AKT1/PTEN-altered tumors.”
LOTUS is a double-blind placebo-controlled randomized phase II trial with the primary endpoints of PFS in the ITT population and PFS in the subgroup of patients with PTEN-low tumors. This subgroup was predefined before analysis as immunohistochemistry (IHC) 0 in ≥50% of tumor cells using the Ventana IHC assay.
Secondary endpoints were objective response rate (ORR) and overall survival (OS) in the ITT population and PTEN-low subgroup. Other secondary endpoints were PFS, ORR, duration of response, and OS in patients with PI3K/AKT pathway-activated tumors, as well as safety and tolerability.
Investigators recruited patients with measurable locally advanced or metastatic triple-negative breast cancer. Patients had not had any prior systemic therapy for advanced/metastatic disease and had an ECOG performance status of 0 or 1. Archival or newly obtained tumor tissue was supplied for central PTEN assessment and all patients had been chemotherapy-free for at least 6 months.
Patients were randomized 1:1 to receive either paclitaxel 80 mg/m2 on days 1, 8, and 15 with 400 mg ipatasertib daily on days 1–21 of a 28-day cycle (n = 62), or paclitaxel 80 mg/m2 on days 1, 8, and 15 plus placebo days 1–21 every 28 days (n = 62). Treatment continued until disease progression or intolerable toxicity. Patients were stratified by adjuvant or neoadjuvant chemotherapy, a chemotherapy-free interval of ≤12 versus >12 months versus no prior chemotherapy, and tumor PTEN status.
Of the 101 patients with samples evaluable for PTEN, 48 (48%) were classified as PTEN low. Of the 103 patients with samples evaluable by NGS, 42 (41%) had PIK3CA/AKT1/PTEN-altered tumors. A substantial proportion of patients with loss of PTEN protein expression did not have a genetic alteration; conversely, most patients with activating mutations in PIK3CA and AKT1 were classified as PTEN non-low by IHC. Baseline characteristics were well balanced in the 2 treatment arms.
As of data cut-off on June 7, 2016, the median follow-up was 10.4 months in the ipatasertib arm and 10.2 months in the paclitaxel monotherapy arm. In the ITT population, PFS with the combination of ipatasertib and paclitaxel was 6.2 months compared with 4.9 months with paclitaxel alone (stratified HR, 0.60; 90% CI, 0.40-0.91; P = .037). The ORR was 40% with the combination regimen versus 32% with paclitaxel and placebo.
In the PTEN-low subgroup, PFS was 6.2 months and 3.7 months with the combination versus paclitaxel alone, respectively (stratified HR, 0.59; 90% CI, 0.30–1.16; P = .18). ORR was 48% compared with 26% with paclitaxel monotherapy, yet the duration of response was greater in the paclitaxel arm with 7.5 months compared with 6.5 months with the combination.
Among the 42 patients with PIK3CA/AKT1/PTEN-altered tumors, ipatasertib/paclitaxel showed a 4.1-month improvement in PFS over paclitaxel alone (HR, 0.44; 90% CI, 0.22-0.87). The effect of ipatasertib on duration of response was more pronounced in patients with PIK3CA/AKT1/PTEN-altered tumors (11.2 vs 6.1 months with paclitaxel). ORR was 50% and 44% with ipatasertib plus paclitaxel and paclitaxel alone, respectively, and OS results were still immature.
The most common adverse events (AEs) were gastrointestinal effects, alopecia, neuropathy, fatigue, and rash, but these events were typically grade 1/2 in severity. The most common grade ≥3 AEs in the ipatasertib arm were diarrhea (23%), neutropenia (18%), peripheral neuropathy (7%), asthenia (5%), and pneumonia (5%). Four patients (7%) discontinued ipatasertib therapy due to AEs, including 2 who discontinued due to diarrhea, and 2% discontinued in the placebo arm. No treatment-related deaths occurred in the ipatasertib arm.
The authors noted that ongoing evaluation of ipatasertib plus paclitaxel in the neoadjuvant setting in the randomized phase II FAIRLANE trial (NCT02301988) may provide further insight into patient selection. A phase III trial with ipatasertib in metastatic breast cancer is also underway.
Dent RA, Kim SB, Im SA, et al. LOTUS (NCT02162719): a double-blind placebo (PBO)-controlled randomized phase II trial of first-line ipatasertib (IPAT) + paclitaxel (P) for metastatic triple-negative breast cancer (TNBC). J Clin Oncol 35, 2017 (suppl; abstr 1009).

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