Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial

Andreas Hagen Røssevold; Nikolai Kragøe Andresen; Christina Annette Bjerre; Bjørnar Gilje; Erik Hugger Jakobsen; Sunil Xavier Raj; Ragnhild Sørum Falk; Hege Giercksky Russnes; Thea Jahr; Randi Ruud Mathiesen; Jon Lømo; Øystein Garred; Sudhir Kumar Chauhan; Ragnhild Reehorst Lereim; Claire Dunn; Bjørn Naume; Jon Amund Kyte

doi:10.1038/s41591-022-02126-1

Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial

Andreas Hagen Røssevold
, Nikolai Kragøe Andresen
, Christina Annette Bjerre
, Bjørnar Gilje
, Erik Hugger Jakobsen
, Sunil Xavier Raj
, Ragnhild Sørum Falk
, Hege Giercksky Russnes
, Thea Jahr
, Randi Ruud Mathiesen
, Jon Lømo
, Øystein Garred
, Sudhir Kumar Chauhan
, Ragnhild Reehorst Lereim
, Claire Dunn
, Bjørn Naume
, Jon Amund Kyte^*

^*Corresponding author for this work

Oslo University Hospital
Rigshospitalet
Stavanger University hospital
St. Olav University Hospital
University of Oslo

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1^positive disease. The randomized, placebo-controlled ALICE trial (NCT03164993, 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33–0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33–0.95; P = 0.033). A numerical advantage was observed for both the PD-L1^positive (n = 27; HR = 0.65; 95% CI 0.27–1.54) and PD-L1^negative subgroups (n = 31; HR = 0.57, 95% CI 0.27–1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4–30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.

Original language	English
Journal	Nature Medicine
Volume	28
Issue number	12
Pages (from-to)	2573-2583
ISSN	1078-8956
DOIs	https://doi.org/10.1038/s41591-022-02126-1
Publication status	Published - 8. Dec 2022

Bibliographical note

Funding Information:
The sponsor of this trial was Oslo University Hospital (OUH). The authors thank the patients, their families and the user representative. We also thank the personnel at the study hospitals for their contributions and excellent patient care. Special thanks to E. Borgen, E.-J. Sande, T. Guren, I. Abdi, M. Stensland, G. Sæter, M. Nguyen, T. Arntsen, G. Skorstad, N. Moharrami, L. Julsrud and G. Hagen. We are also grateful to T. Ahlquist and the team at Roche, to the OUH Bioinformatics Core Facility, the OUH Genomics Core Facility, the OUH Flow Cytometry Core Facility and to the contributing units at the OUH Department of Pathology, headed by M. Førsund, I. J. Ryen and A. Renolen. Roche supported the study with free drug (atezolizumab), free SP142 assays and a funding contribution. NanoString supported the study with free assays and analyses. The study was also supported by grants from the Norwegian Health Region South-East (grants 2017100 to J.A.K. and 2017122 to B.N.) and grants from the Norwegian Cancer Society/Norwegian Breast Cancer Society (grants 182632 and 214972 to J.A.K).

Funding

The sponsor of this trial was Oslo University Hospital (OUH). The authors thank the patients, their families and the user representative. We also thank the personnel at the study hospitals for their contributions and excellent patient care. Special thanks to E. Borgen, E.-J. Sande, T. Guren, I. Abdi, M. Stensland, G. Sæter, M. Nguyen, T. Arntsen, G. Skorstad, N. Moharrami, L. Julsrud and G. Hagen. We are also grateful to T. Ahlquist and the team at Roche, to the OUH Bioinformatics Core Facility, the OUH Genomics Core Facility, the OUH Flow Cytometry Core Facility and to the contributing units at the OUH Department of Pathology, headed by M. Førsund, I. J. Ryen and A. Renolen. Roche supported the study with free drug (atezolizumab), free SP142 assays and a funding contribution. NanoString supported the study with free assays and analyses. The study was also supported by grants from the Norwegian Health Region South-East (grants 2017100 to J.A.K. and 2017122 to B.N.) and grants from the Norwegian Cancer Society/Norwegian Breast Cancer Society (grants 182632 and 214972 to J.A.K). The sponsor of this trial was Oslo University Hospital (OUH). The authors thank the patients, their families and the user representative. We also thank the personnel at the study hospitals for their contributions and excellent patient care. Special thanks to E. Borgen, E.-J. Sande, T. Guren, I. Abdi, M. Stensland, G. Sæter, M. Nguyen, T. Arntsen, G. Skorstad, N. Moharrami, L. Julsrud and G. Hagen. We are also grateful to T. Ahlquist and the team at Roche, to the OUH Bioinformatics Core Facility, the OUH Genomics Core Facility, the OUH Flow Cytometry Core Facility and to the contributing units at the OUH Department of Pathology, headed by M. Førsund, I. J. Ryen and A. Renolen. Roche supported the study with free drug (atezolizumab), free SP142 assays and a funding contribution. NanoString supported the study with free assays and analyses. The study was also supported by grants from the Norwegian Health Region South-East (grants 2017100 to J.A.K. and 2017122 to B.N.) and grants from the Norwegian Cancer Society/Norwegian Breast Cancer Society (grants 182632 and 214972 to J.A.K).

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Røssevold, A. H., Andresen, N. K., Bjerre, C. A., Gilje, B., Jakobsen, E. H., Raj, S. X., Falk, R. S., Russnes, H. G., Jahr, T., Mathiesen, R. R., Lømo, J., Garred, Ø., Chauhan, S. K., Lereim, R. R., Dunn, C., Naume, B., & Kyte, J. A. (2022). Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial. Nature Medicine, 28(12), 2573-2583. https://doi.org/10.1038/s41591-022-02126-1

@article{187f589bcdd74a4a86294abd08b29e2b,

title = "Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial",

abstract = "Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1positive disease. The randomized, placebo-controlled ALICE trial (NCT03164993, 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18\% of patients in the atezo-chemo arm (7/40) and in 7\% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95\% confidence interval (CI) 0.33{\textendash}0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95\% CI 0.33{\textendash}0.95; P = 0.033). A numerical advantage was observed for both the PD-L1positive (n = 27; HR = 0.65; 95\% CI 0.27{\textendash}1.54) and PD-L1negative subgroups (n = 31; HR = 0.57, 95\% CI 0.27{\textendash}1.21). The progression-free proportion after 15 months was 14.7\% (5/34; 95\% CI 6.4{\textendash}30.1\%) in the atezo-chemo arm versus 0\% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.",

author = "R{\o}ssevold, \{Andreas Hagen\} and Andresen, \{Nikolai Krag{\o}e\} and Bjerre, \{Christina Annette\} and Bj{\o}rnar Gilje and Jakobsen, \{Erik Hugger\} and Raj, \{Sunil Xavier\} and Falk, \{Ragnhild S{\o}rum\} and Russnes, \{Hege Giercksky\} and Thea Jahr and Mathiesen, \{Randi Ruud\} and Jon L{\o}mo and {\O}ystein Garred and Chauhan, \{Sudhir Kumar\} and Lereim, \{Ragnhild Reehorst\} and Claire Dunn and Bj{\o}rn Naume and Kyte, \{Jon Amund\}",

note = "Funding Information: The sponsor of this trial was Oslo University Hospital (OUH). The authors thank the patients, their families and the user representative. We also thank the personnel at the study hospitals for their contributions and excellent patient care. Special thanks to E. Borgen, E.-J. Sande, T. Guren, I. Abdi, M. Stensland, G. S{\ae}ter, M. Nguyen, T. Arntsen, G. Skorstad, N. Moharrami, L. Julsrud and G. Hagen. We are also grateful to T. Ahlquist and the team at Roche, to the OUH Bioinformatics Core Facility, the OUH Genomics Core Facility, the OUH Flow Cytometry Core Facility and to the contributing units at the OUH Department of Pathology, headed by M. F{\o}rsund, I. J. Ryen and A. Renolen. Roche supported the study with free drug (atezolizumab), free SP142 assays and a funding contribution. NanoString supported the study with free assays and analyses. The study was also supported by grants from the Norwegian Health Region South-East (grants 2017100 to J.A.K. and 2017122 to B.N.) and grants from the Norwegian Cancer Society/Norwegian Breast Cancer Society (grants 182632 and 214972 to J.A.K).",

year = "2022",

month = dec,

day = "8",

doi = "10.1038/s41591-022-02126-1",

language = "English",

volume = "28",

pages = "2573--2583",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

number = "12",

}

Røssevold, AH, Andresen, NK, Bjerre, CA, Gilje, B, Jakobsen, EH, Raj, SX, Falk, RS, Russnes, HG, Jahr, T, Mathiesen, RR, Lømo, J, Garred, Ø, Chauhan, SK, Lereim, RR, Dunn, C, Naume, B & Kyte, JA 2022, 'Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial', Nature Medicine, vol. 28, no. 12, pp. 2573-2583. https://doi.org/10.1038/s41591-022-02126-1

Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial. / Røssevold, Andreas Hagen; Andresen, Nikolai Kragøe; Bjerre, Christina Annette et al.
In: Nature Medicine, Vol. 28, No. 12, 08.12.2022, p. 2573-2583.

Research output: Contribution to journal › Journal article › Research › peer-review

TY - JOUR

T1 - Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer

T2 - the randomized, double-blind phase 2b ALICE trial

AU - Røssevold, Andreas Hagen

AU - Andresen, Nikolai Kragøe

AU - Bjerre, Christina Annette

AU - Gilje, Bjørnar

AU - Jakobsen, Erik Hugger

AU - Raj, Sunil Xavier

AU - Falk, Ragnhild Sørum

AU - Russnes, Hege Giercksky

AU - Jahr, Thea

AU - Mathiesen, Randi Ruud

AU - Lømo, Jon

AU - Garred, Øystein

AU - Chauhan, Sudhir Kumar

AU - Lereim, Ragnhild Reehorst

AU - Dunn, Claire

AU - Naume, Bjørn

AU - Kyte, Jon Amund

N1 - Funding Information: The sponsor of this trial was Oslo University Hospital (OUH). The authors thank the patients, their families and the user representative. We also thank the personnel at the study hospitals for their contributions and excellent patient care. Special thanks to E. Borgen, E.-J. Sande, T. Guren, I. Abdi, M. Stensland, G. Sæter, M. Nguyen, T. Arntsen, G. Skorstad, N. Moharrami, L. Julsrud and G. Hagen. We are also grateful to T. Ahlquist and the team at Roche, to the OUH Bioinformatics Core Facility, the OUH Genomics Core Facility, the OUH Flow Cytometry Core Facility and to the contributing units at the OUH Department of Pathology, headed by M. Førsund, I. J. Ryen and A. Renolen. Roche supported the study with free drug (atezolizumab), free SP142 assays and a funding contribution. NanoString supported the study with free assays and analyses. The study was also supported by grants from the Norwegian Health Region South-East (grants 2017100 to J.A.K. and 2017122 to B.N.) and grants from the Norwegian Cancer Society/Norwegian Breast Cancer Society (grants 182632 and 214972 to J.A.K).

PY - 2022/12/8

Y1 - 2022/12/8

N2 - Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1positive disease. The randomized, placebo-controlled ALICE trial (NCT03164993, 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33–0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33–0.95; P = 0.033). A numerical advantage was observed for both the PD-L1positive (n = 27; HR = 0.65; 95% CI 0.27–1.54) and PD-L1negative subgroups (n = 31; HR = 0.57, 95% CI 0.27–1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4–30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.

AB - Immune checkpoint inhibitors have shown efficacy against metastatic triple-negative breast cancer (mTNBC) but only for PD-L1positive disease. The randomized, placebo-controlled ALICE trial (NCT03164993, 24 May 2017) evaluated the addition of atezolizumab (anti-PD-L1) to immune-stimulating chemotherapy in mTNBC. Patients received pegylated liposomal doxorubicin (PLD) and low-dose cyclophosphamide in combination with atezolizumab (atezo-chemo; n = 40) or placebo (placebo-chemo; n = 28). Primary endpoints were descriptive assessment of progression-free survival in the per-protocol population (>3 atezolizumab and >2 PLD doses; n = 59) and safety in the full analysis set (FAS; all patients starting therapy; n = 68). Adverse events leading to drug discontinuation occurred in 18% of patients in the atezo-chemo arm (7/40) and in 7% of patients in the placebo-chemo arm (2/28). Improvement in progression-free survival was indicated in the atezo-chemo arm in the per-protocol population (median 4.3 months versus 3.5 months; hazard ratio (HR) = 0.57; 95% confidence interval (CI) 0.33–0.99; log-rank P = 0.047) and in the FAS (HR = 0.56; 95% CI 0.33–0.95; P = 0.033). A numerical advantage was observed for both the PD-L1positive (n = 27; HR = 0.65; 95% CI 0.27–1.54) and PD-L1negative subgroups (n = 31; HR = 0.57, 95% CI 0.27–1.21). The progression-free proportion after 15 months was 14.7% (5/34; 95% CI 6.4–30.1%) in the atezo-chemo arm versus 0% in the placebo-chemo arm. The addition of atezolizumab to PLD/cyclophosphamide was tolerable with an indication of clinical benefit, and the findings warrant further investigation of PD1/PD-L1 blockers in combination with immunomodulatory chemotherapy.

U2 - 10.1038/s41591-022-02126-1

DO - 10.1038/s41591-022-02126-1

M3 - Journal article

C2 - 36482103

AN - SCOPUS:85143604056

SN - 1078-8956

VL - 28

SP - 2573

EP - 2583

JO - Nature Medicine

JF - Nature Medicine

IS - 12

ER -

Atezolizumab plus anthracycline-based chemotherapy in metastatic triple-negative breast cancer: the randomized, double-blind phase 2b ALICE trial

Abstract

Bibliographical note

Funding

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