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

on behalf of the LOTUS investigators

doi:10.1007/s10549-021-06143-5

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

on behalf of the LOTUS investigators

Breast Medical Oncology

Research output: Contribution to journal › Article › peer-review

38 Scopus citations

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.

Original language	English (US)
Pages (from-to)	377-386
Number of pages	10
Journal	Breast Cancer Research and Treatment
Volume	189
Issue number	2
DOIs	https://doi.org/10.1007/s10549-021-06143-5
State	Published - Sep 2021

Keywords

First-line therapy
Ipatasertib
Oral
PI3K/AKT
Triple-negative breast cancer

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1007/s10549-021-06143-5

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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. / on behalf of the LOTUS investigators.
In: Breast Cancer Research and Treatment, Vol. 189, No. 2, 09.2021, p. 377-386.

Research output: Contribution to journal › Article › peer-review

@article{0218edcf8a404d6796cf5e23346ca2c4,

title = "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",

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.",

keywords = "First-line therapy, Ipatasertib, Oral, PI3K/AKT, Triple-negative breast cancer",

author = "{on behalf of the LOTUS investigators} and Rebecca Dent and Mafalda Oliveira and Isakoff, {Steven J.} and Im, {Seock Ah} and Marc Espi{\'e} and Sibel Blau and Tan, {Antoinette R.} and Cristina Saura and Wongchenko, {Matthew J.} and Na Xu and Denise Bradley and Reilly, {Sarah Jayne} and Aruna Mani and Kim, {Sung Bae} and Lee, {K. S.} and Sohn, {J. H.} and Kim, {J. H.} and Seo, {J. H.} and Kim, {J. S.} and S. Park and M. Velez and S. Dakhil and S. Hurvitz and V. Valero and G. Vidal and R. Figlin and Allison, {M. A.K.} and D. Chan and M. Cobleigh and V. Hansen and N. Iannotti and W. Lawler and M. Salkini and L. Seigel and G. Romieu and M. Debled and C. Levy and A. Hardy-Bessard and S. Guiu and Estevez, {L. Garcia} and R. Villanueva and Martin, {A. Gonzalez} and Rovira, {P. Sanchez} and A. Monta{\~n}o and Plaza, {M. I.Calvo} and Saenz, {J. A.Garc{\'i}a} and I. Garau and B. Bermejo and Alonso, {E. Vega} and Wang, {H. C.}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.",

year = "2021",

month = sep,

doi = "10.1007/s10549-021-06143-5",

language = "English (US)",

volume = "189",

pages = "377--386",

journal = "Breast Cancer Research and Treatment",

issn = "0167-6806",

publisher = "Springer New York",

number = "2",

}

TY - JOUR

T1 - 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

AU - on behalf of the LOTUS investigators

AU - Dent, Rebecca

AU - Oliveira, Mafalda

AU - Isakoff, Steven J.

AU - Im, Seock Ah

AU - Espié, Marc

AU - Blau, Sibel

AU - Tan, Antoinette R.

AU - Saura, Cristina

AU - Wongchenko, Matthew J.

AU - Xu, Na

AU - Bradley, Denise

AU - Reilly, Sarah Jayne

AU - Mani, Aruna

AU - Kim, Sung Bae

AU - Lee, K. S.

AU - Sohn, J. H.

AU - Kim, J. H.

AU - Seo, J. H.

AU - Kim, J. S.

AU - Park, S.

AU - Velez, M.

AU - Dakhil, S.

AU - Hurvitz, S.

AU - Valero, V.

AU - Vidal, G.

AU - Figlin, R.

AU - Allison, M. A.K.

AU - Chan, D.

AU - Cobleigh, M.

AU - Hansen, V.

AU - Iannotti, N.

AU - Lawler, W.

AU - Salkini, M.

AU - Seigel, L.

AU - Romieu, G.

AU - Debled, M.

AU - Levy, C.

AU - Hardy-Bessard, A.

AU - Guiu, S.

AU - Estevez, L. Garcia

AU - Villanueva, R.

AU - Martin, A. Gonzalez

AU - Rovira, P. Sanchez

AU - Montaño, A.

AU - Plaza, M. I.Calvo

AU - Saenz, J. A.García

AU - Garau, I.

AU - Bermejo, B.

AU - Alonso, E. Vega

AU - Wang, H. C.

PY - 2021/9

Y1 - 2021/9

N2 - 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.

AB - 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.

KW - First-line therapy

KW - Ipatasertib

KW - Oral

KW - PI3K/AKT

KW - Triple-negative breast cancer

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UR - http://www.scopus.com/inward/citedby.url?scp=85110118987&partnerID=8YFLogxK

U2 - 10.1007/s10549-021-06143-5

DO - 10.1007/s10549-021-06143-5

M3 - Article

C2 - 34264439

AN - SCOPUS:85110118987

SN - 0167-6806

VL - 189

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EP - 386

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 2

ER -

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

Abstract

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ASJC Scopus subject areas

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