Welcome to PracticeUpdate! We hope you are enjoying access to a selection of our top-read and most recent articles. Please register today for a free account and gain full access to all of our expert-selected content.
Already Have An Account? Log in Now
Ipatasertib Plus Paclitaxel for PIK3CA/AKT1/PTEN-Altered Locally Advanced Unresectable or Metastatic TNBC
TAKE-HOME MESSAGE
- In Cohort A of the IPATunity130 trial, 255 patients with metastatic triple-negative breast cancer (mTNBC) with PIK3CA/AKT1/PTEN alterations previously untreated in the advanced setting were randomized 2:1 to paclitaxel with either the AKT inhibitor ipatasertib or placebo. There was no significant difference in median progression-free survival (7.4 vs 6.1 months) or overall survival (24.4 vs 24.9 months) duration between arms.
- This study showed no benefit from adding ipatasertib to first-line chemotherapy for biomarker-selected mTNBC, in contrast to positive results from previous phase II trials of ipatasertib and capivasertib in mTNBC. The authors conclude that the excellent 25-month overall survival in the paclitaxel and placebo arms suggests that a more indolent form of TNBC may have been enriched owing to the underlying mutations, which were required for participant enrollment.
abstract
This abstract is available on the publisher's site.
Access this abstract nowBACKGROUND
In the randomized phase II LOTUS trial, combining ipatasertib with first-line paclitaxel for triple-negative breast cancer (TNBC) improved progression-free survival (PFS), particularly in patients with PIK3CA/AKT1/PTEN-altered tumors. We aimed to validate these findings in a biomarker-selected TNBC population.
PATIENTS AND METHODS
In Cohort A of the randomized double-blind placebo-controlled phase III IPATunity130 trial, taxane-eligible patients with PIK3CA/AKT1/PTEN-altered measurable advanced TNBC and no prior chemotherapy for advanced disease were randomized 2:1 to ipatasertib (400 mg, days 1-21) or placebo, both plus paclitaxel (80 mg/m2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed PFS.
RESULTS
Between February 2018 and April 2020, 255 patients were randomized (168 to ipatasertib, 87 to placebo). At the primary analysis there was no significant difference between treatment arms in PFS (hazard ratio 1.02, 95% CI, 0.71-1.45; median 7.4 months with ipatasertib vs. 6.1 months with placebo). The final analysis showed no difference in overall survival between treatment arms (hazard ratio 1.08, 95% CI, 0.73-1.58; median 24.4 vs. 24.9 months, respectively). Ipatasertib was associated with more grade ≥3 diarrhea (9% vs. 2%) and adverse events leading to dose reduction (39% vs. 14%) but similar incidences of grade ≥3 adverse events (51% vs. 46%). Exploratory subgroup analyses by PAM50 and Burstein gene expression showed inconsistent results.
CONCLUSIONS
Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered advanced TNBC. Biomarkers for benefit from PI3K/AKT pathway inhibition in TNBC remain poorly understood.
Additional Info
Disclosure statements are available on the authors' profiles:
Ipatasertib plus Paclitaxel for patients with PIK3CA/AKT1/PTEN-Altered Locally Advanced Unresectable or Metastatic Triple-Negative Breast Cancer in the IPATunity130 Phase III Trial
Clin. Cancer Res 2024 Jul 26;[EPub Ahead of Print], RA Dent, SB Kim, M Oliveira, C Barrios, J O'Shaughnessy, SJ Isakoff, S Saji, R Freitas-Junior, M Philco, I Bondarenko, Q Lian, D Bradley, H Hinton, MJ Wongchenko, SJ Reilly, N TurnerFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
The IPATunity130 phase III trial tested the addition of the AKT inhibitor ipatasertib to paclitaxel versus paclitaxel alone in a biomarker-selected group of patients with newly diagnosed triple-negative breast cancer (TNBC). The trial was negative, with no improvement in either progression-free survival or overall survival outcomes in patients who had alterations in PIK3CA, AKT1, or PTEN, which are three key genes in the pathway. These results differed dramatically from the positive results observed in the predecessor LOTUS trial, which included non–biomarker-selected patients with untreated TNBC. The LOTUS trial showed a strong progression-free survival benefit and a numerical overall survival improvement in the biomarker-selected subgroup of patients with TNBC, serving as the impetus for the IPATunity130 study.
The authors discussed many possible reasons for the discrepant results. They focus on sub-subgroup analysis using the intrinsic subtype class of TNBC. Clearly, since we define TNBC by what it is not rather than what it is, it is certainly possible that differing biologic subtypes within a gene pathway–altered group could have responded differently and might have been weighed differently in a random assignment. Further research and a larger number of patients can certainly help to confirm or refute this hypothesis.
The discussion also touches on an important aspect of the study that has nothing to do with subtypes, namely the fact that patients enrolled in IPATunity130 waited a median of 2 months from the diagnosis of metastatic disease to randomization compared with a median of 1 month in the LOTUS trial. It is very likely that more clinically aggressive cancers were excluded, as patients and their physicians could not afford to wait that long to initiate treatment for symptomatic disease. Every effort should be made in the clinical trial design to shorten the time to enrollment for patients with a clinically aggressive type and a short expected survival time. This issue becomes more acute in precision oncology trials, where, by definition, a biomarker must be assessed before enrollment.
One possible reason for the negative results, which was not discussed but should be emphasized, is that many phase III trials fail after positive phase II results. Only approximately 60% of phase III trials are positive, and oncology has a higher failure rate than most other disciplines.1 Most failures in the modern era are owing to a lack of efficacy, as demonstrated in the IPATunity130 trial. All of us involved in the clinical research enterprise should work to narrow the gap in success rates between phase II and phase III studies by improving clinical trial design and furthering translational research, which identifies effective targeted agents.
Reference