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Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer

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Abstract

Purpose

In LOTUS (NCT02162719), adding the oral AKT inhibitor ipatasertib to first-line paclitaxel for locally advanced/metastatic triple-negative breast cancer (aTNBC) improved progression-free survival (PFS; primary endpoint), with an enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumors (FoundationOne next-generation sequencing [NGS] assay). We report final overall survival (OS) results.

Methods

Eligible patients had measurable previously untreated aTNBC. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor immunohistochemistry PTEN status, and were randomized 1:1 to paclitaxel 80 mg/m2 (days 1, 8, 15) plus ipatasertib 400 mg or placebo (days 1–21) every 28 days until disease progression or unacceptable toxicity. OS (intent-to-treat [ITT], immunohistochemistry PTEN-low, and PI3K/AKT pathway-activated [NGS PIK3CA/AKT1/PTEN-altered] populations) was a secondary endpoint.

Results

Median follow-up was 19.0 versus 16.0 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively. In the ITT population (n = 124), median OS was numerically longer with ipatasertib–paclitaxel than placebo–paclitaxel (hazard ratio 0.80, 95% CI 0.50–1.28; median 25.8 vs 16.9 months, respectively; 1-year OS 83% vs 68%). Likewise, median OS favored ipatasertib–paclitaxel in the PTEN-low (n = 48; 23.1 vs 15.8 months; hazard ratio 0.83) and PIK3CA/AKT1/PTEN-altered (n = 42; 25.8 vs 22.1 months; hazard ratio 1.13) subgroups. The ipatasertib–paclitaxel safety profile was unchanged.

Conclusions

Final OS results show a numerical trend favoring ipatasertib–paclitaxel and median OS exceeding 2 years with ipatasertib–paclitaxel. Overall, results are consistent with the reported PFS benefit; interpretation within biomarker-defined subgroups is complicated by small sample sizes and TNBC heterogeneity.

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Data availability

Qualified researchers may request access to individual patient level data through the clinical study data request platform (https://vivli.org/). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/members/ourmembers/). For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/our_commitment_to_data_sharing.htm).

Abbreviations

AKT :

Protein kinase B

CI :

Confidence interval

IQR :

Interquartile range

ITT :

Intent-to-treat

LAR :

Luminal androgen receptor

OS :

Overall survival

PFS :

Progression-free survival

PI3K :

Phosphoinositide 3-kinase

PIK3CA :

Phosphatidylinositol-4,5-bisphosphate 3‑kinase catalytic subunit alpha

PTEN :

Phosphatase and tensin homolog

TNBC :

Triple-negative breast cancer

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Acknowledgements

We are grateful to the patients who participated in the trial, their families, and the investigators and staff at the 44 participating centers. The LOTUS trial was sponsored by Roche/Genentech. Medical writing assistance for this manuscript was provided by Jennifer Kelly, MA (Medi-Kelsey Ltd, Ashbourne, UK), funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Collaborators: K.S. Lee, J.H. Sohn, J.H. Kim, J.H. Seo, J.S. Kim, S. Park (South Korea); M. Velez, S. Dakhil, S. Hurvitz, V. Valero, G. Vidal, R. Figlin, M.A.K. Allison, D. Chan, M. Cobleigh, V. Hansen, N. Iannotti, W. Lawler, M. Salkini, L. Seigel (USA); G. Romieu, M. Debled, C. Levy, A. Hardy-Bessard, S. Guiu (France); L. Garcia Estevez, R. Villanueva, A. Gonzalez Martin, P. Sanchez Rovira, A. Montaño, M.I. Calvo Plaza, J.A. García Saenz, I. Garau, B. Bermejo, E. Vega Alonso (Spain); H-C. Wang, C-S. Huang, S-C. Chen, Y-H. Chen, L-M. Tseng (Taiwan); A. Wong, C.S.P. Ang (Singapore); M. De Laurentiis, P.F. Conte, F. De Braud, F. Montemurro, L. Gianni (Italy); L. Dirix (Belgium).

Funding

This work was supported by F. Hoffmann-La Roche Ltd, Basel, Switzerland. No grant number is applicable.

Author information

Authors and Affiliations

  1. Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore

    Rebecca Dent

  2. Duke-NUS Medical School, 11 Hospital Crescent, Singapore, Singapore

    Rebecca Dent

  3. Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain

    Mafalda Oliveira & Cristina Saura

  4. Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA, USA

    Steven J. Isakoff

  5. Department of Internal Medicine, Seoul National University Hospital, and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Seock-Ah Im

  6. Department of Medical Oncology, Breast Disease Center, Hospital Saint Louis, Paris, France

    Marc Espié

  7. Oncology Division, Northwest Medical Specialties, Puyallup, WA, USA

    Sibel Blau

  8. Department of Solid Tumor and Investigational Therapeutics, Levine Cancer Institute, Atrium Health, Charlotte, NC, USA

    Antoinette R. Tan

  9. Oncology Biomarker Development, Genentech, Inc., South San Francisco, CA, USA

    Matthew J. Wongchenko

  10. Biostatistics, Genentech, Inc., South San Francisco, CA, USA

    Na Xu

  11. Pharma Development, Roche Products Ltd, Welwyn Garden City, UK

    Denise Bradley & Sarah-Jayne Reilly

  12. Product Development Oncology, Genentech, Inc., South San Francisco, CA, USA

    Aruna Mani

  13. Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

    Sung-Bae Kim

Authors
  1. Rebecca Dent
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  2. Mafalda Oliveira
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  8. Cristina Saura
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Consortia

on behalf of the LOTUS investigators

  • K. S. Lee
  • , J. H. Sohn
  • , J. H. Kim
  • , J. H. Seo
  • , J. S. Kim
  • , S. Park
  • , M. Velez
  • , S. Dakhil
  • , S. Hurvitz
  • , V. Valero
  • , G. Vidal
  • , R. Figlin
  • , M. A. K. Allison
  • , D. Chan
  • , M. Cobleigh
  • , V. Hansen
  • , N. Iannotti
  • , W. Lawler
  • , M. Salkini
  • , L. Seigel
  • , G. Romieu
  • , M. Debled
  • , C. Levy
  • , A. Hardy-Bessard
  • , S. Guiu
  • , L. Garcia Estevez
  • , R. Villanueva
  • , A. Gonzalez Martin
  • , P. Sanchez Rovira
  • , A. Montaño
  • , M. I. Calvo Plaza
  • , J. A. García Saenz
  • , I. Garau
  • , B. Bermejo
  • , E. Vega Alonso
  • , H.-C. Wang
  • , C.-S. Huang
  • , S.-C. Chen
  • , Y.-H. Chen
  • , L.-M. Tseng
  • , A. Wong
  • , C. S. P. Ang
  • , M. De Laurentiis
  • , P. F. Conte
  • , F. De Braud
  • , F. Montemurro
  • , L. Gianni
  •  & L. Dirix

Contributions

RD, MO, SJI, CS, and S-BK were involved in the design of the study. RD, MO, SJI, S-AI, ME, SB, ART, CS, and S-BK obtained the data. MJW, NX, DB, S-JR, and AM analyzed the data. All authors interpreted the data, reviewed, and revised the draft manuscripts, and approved the final version for submission.

Corresponding author

Correspondence to Rebecca Dent.

Ethics declarations

Conflict of interest

R Dent has received honoraria from Roche, Novartis, Lilly, Pfizer, Eisai, Merck, and AstraZeneca. M Oliveira has received honoraria from Roche, has served in a consultancy/advisory role for Roche/Genentech, GlaxoSmithKline, and Puma, and has received travel/accommodation/expenses from Roche, Novartis, Grünenthal Group, Pierre Fabre, and GP Pharm; her institution has received research funding from AstraZeneca, Philips Healthcare, Genentech, Roche, Novartis, Immunomedics, Seattle Genetics, GSK, Boehringer Ingelheim, and Puma Biotechnology. SJ Isakoff has received honoraria from Genentech, Hengrui, Puma, Immunomedics, Myriad and OncoPep, Inc.; his institution has received research funding from Genentech, PharmaMar, AstraZeneca, and Merck. S-A Im has served in a consultancy/advisory role for AstraZeneca, Amgen, Eisai, Lilly, MedPacto, Novartis, Daiichi-Sankyo, Pfizer, and Roche; his institution has received research funding from AstraZeneca, Pfizer, and Roche. M Espié has received research funding from Roche, Novartis, and Pfizer. S Blau reports that her husband is the owner of the company All4Cure. AR Tan has served in a consultancy/advisory role for Immunomedics, Celgene, Pfizer, Genentech/Roche, Novartis, AbbVie, and Eisai; her institution has received research funding from Merck, Pfizer, Tesaro, Genentech/Roche, G1 Therapeutics, and Daiichi-Sankyo. C Saura has received honoraria from AstraZeneca, Celgene, Daiichi-Sankyo, Eisai, Roche, Genomic Health, Novartis, Pfizer, Pierre Fabre, Puma, and Synthon, has served in a consultancy/advisory role for AstraZeneca, Eisai, Roche, Genomic Health, Novartis, Pfizer, Puma, Sanofi, and Synthon, and has received research funding from Genentech and AstraZeneca. MJ Wongchenko, N Xu, and A Mani are employed by Genentech/Roche and hold shares in Roche. D Bradley is employed by Roche Products Ltd, holds shares in Roche, and is named as an inventor on a Roche/Genentech patent application. S-J Reilly is employed by Roche Products Ltd and holds shares in Roche. S-B Kim has served in a consulting/advisory role for Novartis, AstraZeneca, Lilly, Enzychem Lifesciences, Dae Hwa Pharmaceutical Co. Ltd, ISU Abxis, and Daiichi-Sankyo and has received research funding from Novartis, Sanofi Aventis, Kyowa Kirin Inc, and DongKook Pharma Co, Ltd.

Ethical approval

We obtained independent Institutional Review Board approval of the protocol and all study-related documents from each participating institution, and written informed consent from all participants. The trial was performed in accordance with the Helsinki declaration and all amendments.

Informed consent

All patients provided written informed consent before undergoing any study-specific procedures.

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Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Collaborators of the LOTUS investigators are listed in “Acknowledgements”.

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Dent, R., Oliveira, M., Isakoff, S.J. et al. Final results of the double-blind placebo-controlled randomized phase 2 LOTUS trial of first-line ipatasertib plus paclitaxel for inoperable locally advanced/metastatic triple-negative breast cancer. Breast Cancer Res Treat 189, 377–386 (2021). https://doi.org/10.1007/s10549-021-06143-5

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