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Ipatasertib Plus Paclitaxel Falters in Advanced Triple-Negative Breast Cancer Phase III Trial


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The combination of ipatasertib plus paclitaxel failed to improve progression-free survival in PIK3CA/AKT1/PTEN-altered locally advanced, unresectable or metastatic triple-negative breast cancer, according to results from cohort A of the phase III IPATunity130 trial, presented at the 2020 San Antonio Breast Cancer Symposium.1 At a median follow-up of 8.3 months, median progression-free survival was 7.4 months with ipatasertib plus paclitaxel vs 6.1 months in the placebo/paclitaxel arm, which was not significantly different statistically.

“Results from this trial differ from findings in both randomized phase II trials of AKT inhibition in advanced triple-negative breast cancer: the LOTUS trial2 of ipatasertib and the PAKT trial3 of capivasertib,” said lead author Rebecca A. Dent, MD, Senior Consultant and Head of Medical Oncology Department, National Cancer Centre, Singapore.


“Results from this trial differ from findings in both randomized phase II trials of AKT inhibition in advanced triple-negative breast cancer: the LOTUS trial of ipatasertib and the PAKT trial of capivasertib.”
— Rebecca A. Dent, MD

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This study is another example of a failed phase III trial on the heels of positive phase II data. However, researchers are not ready to call this a death knell for this novel targeted agent and are awaiting results from other phase III trials.

The PIK3CA/AKT pathway is implicated in cellular metabolism, cell proliferation, and invasion. About 35% of all triple-negative breast cancers harbor PIK3CA/AKT1/PTEN alterations, suggesting that targeting AKT is a therapeutic opportunity.

Ipatasertib, a highly selective AKT inhibitor, was evaluated as first-line therapy for triple-negative breast cancer in the phase II LOTUS trial.2 The combination of ipatasertib plus paclitaxel improved progression-free survival by 40% in an unselected patient population with locally advanced triple-negative breast cancer. An even more robust 56% improvement in progression-free survival was observed in patients in that trial with PIK3CA/AKT1/PTEN-altered triple-negative breast cancer.

IPATunity130 Details

The progression-free survival benefit in PIK3CA/AKT1/PTEN-altered triple-negative breast cancer in the LOTUS trial served as the rationale for the IPATunity130 trial in a biomarker-selected population. IPATunity130 was a double-blind, placebo-controlled phase III trial that enrolled patients with measurable locally advanced inoperable or metastatic triple-negative breast cancer and a PIK3CA/AKT1/PTEN alteration who were naive to chemotherapy for advanced disease. Neoadjuvant or adjuvant chemotherapy completed more than 12 months before enrollment in IPATunity130 was allowed.

A total of 255 patients were randomly assigned 2:1 to receive ipatasertib (400 mg/d on days 1–21) plus paclitaxel (80 mg/m2 on days 1, 8, and 15) vs paclitaxel (same dose and schedule) and placebo in 28-day cycles. Crossover at disease progression or for any reason was not allowed. Treatment was continued until disease progression or unacceptable toxicity. Stratification was according to prior receipt of neoadjuvant/adjuvant chemotherapy, geographic region, and tumor alteration status (PIK3CA/AKT1/PTEN alteration vs PTEN alteration without PIK3CA/AKT1–activating mutation).

At baseline, 48% of patients in the experimental arm had received prior (neo)adjuvant chemotherapy vs 55% of patients in the control arm. Locally advanced unresectable disease was found in 21% of the ipatasertib arm vs 13% of the placebo arm. PD-L1 positivity (according to the SP142 assay) was found in 29% of the ipatasertib arm vs 40% of the placebo arm, but was unknown in approximatley one-third of patients, meaning this may have been an underestimation. Activating PIK3CA/AKT1 mutations were detected in 51% of all patients, and PTEN alteration without a -PIK3CA/AKT1–activating mutation was seen in 49% of all patients.

Key Findings

Median investigator-assessed progression-free survival (the primary endpoint) was 7.4 months for the ipatasertib arm vs 6.1 months for the placebo arm (hazard ratio = 1.02, 95% confidence interval = 0.71–1.45). The investigator-assessed objective response rate was 39% with ipatasertib vs 35% with placebo. The clinical benefit rate was 47% and 45% in the respective treatment arms.

Subgroup analysis for progression-free survival showed no difference between treatment arms, with ipatasertib plus paclitaxel vs placebo plus paclitaxel. In addition, paclitaxel dose intensity, duration of treatment, and treatment discontinuation rates were similar between the two arms.

Safety was also similar. There was no reported difference in the rate of serious adverse events between the treatment groups. Grade 3 or higher adverse events were observed in 46% and 44% of patients, respectively. Deaths occurred in 1% of patients on each treatment arm. No new safety concerns were reported for each agent. Adverse events leading to dose reduction were more commonly seen with ipatasertib plus paclitaxel than with placebo plus paclitaxel: 35% vs 14%. The most common adverse events of all grades were diarrhea (80% vs 31%; grade ≥ 3, 9% vs 2%), alopecia (46% vs 44%), and nausea (36% vs 23%).

The investigators plan to analyze potential biomarkers of response to ipatasertib and explore molecular heterogeneity in the enrolled patient population. Overall survival data will be presented in the future. 

DISCLOSURE: Dr. Dent has received honoraria from AstraZeneca, MSD, Pfizer, and Roche/Genentech; has served as a consultant or advisor to AstraZeneca, Eisai, Merck, Novartis, Pfizer, and Roche; and has been reimbursed for travel, accommodations, or other expenses by Amgen, Merck, Pfizer, and Roche.

REFERENCES

1. Dent R, Kim SB, Oliveira M, et al: Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for -PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: Primary results from IPATunity130 Cohort A. 2020 San Antonio Breast Cancer Symposium. Abstract GS3-04. Presented December 11, 2020.

2. Kim SB, Dent R, Im SA, et al: Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS). Lancet Oncol 18:1360-1372, 2017.

3. Schmid P, Abraham J, Chan S, et al: Capivasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer: The PAKT trial. J Clin Oncol 38:423-433, 2020.


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