Datopotamab–deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial

Katia Khoury; Jane L. Meisel; Christina Yau; Hope S. Rugo; Rita Nanda; Marie Davidian; Butch Tsiatis; A. Jo Chien; Anne M. Wallace; Mili Arora; Mariya Rozenblit; Dawn L. Hershman; Alexandra Zimmer; Amy S. Clark; Heather Beckwith; Anthony D. Elias; Erica Stringer-Reasor; Judy C. Boughey; Chaitali Nangia; Christos Vaklavas; Coral Omene; Kathy S. Albain; Kevin M. Kalinsky; Claudine Isaacs; Jennifer Tseng; Evanthia T. Roussos Torres; Brittani Thomas; Alexandra Thomas; Amy Sanford; Ronald Balassanian; Cheryl Ewing; Kay Yeung; Candice Sauder; Tara Sanft; Lajos Pusztai; Meghna S. Trivedi; Ashton Outhaythip; Wen Li; Natsuko Onishi; Adam L. Asare; Philip Beineke; Peter Norwood; Lamorna Brown-Swigart; Gillian L. Hirst; Jeffrey B. Matthews; Brian Moore; W. Fraser Symmans; Elissa Price; Carolyn Beedle; Jane Perlmutter; Paula Pohlmann; Rebecca A. Shatsky; Angela DeMichele; Douglas Yee; Laura J. van ‘t Veer; Nola M. Hylton; Laura J. Esserman

doi:10.1038/s41591-024-03266-2

Datopotamab–deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial

Katia Khoury, Jane L. Meisel, Christina Yau, Hope S. Rugo, Rita Nanda, Marie Davidian, Butch Tsiatis, A. Jo Chien, Anne M. Wallace, Mili Arora, Mariya Rozenblit, Dawn L. Hershman, Alexandra Zimmer, Amy S. Clark, Heather Beckwith, Anthony D. Elias, Erica Stringer-Reasor, Judy C. Boughey, Chaitali Nangia, Christos VaklavasCoral Omene, Kathy S. Albain, Kevin M. Kalinsky, Claudine Isaacs, Jennifer Tseng, Evanthia T. Roussos Torres, Brittani Thomas, Alexandra Thomas, Amy Sanford, Ronald Balassanian, Cheryl Ewing, Kay Yeung, Candice Sauder, Tara Sanft, Lajos Pusztai, Meghna S. Trivedi, Ashton Outhaythip, Wen Li, Natsuko Onishi, Adam L. Asare, Philip Beineke, Peter Norwood, Lamorna Brown-Swigart, Gillian L. Hirst, Jeffrey B. Matthews, Brian Moore, W. Fraser Symmans, Elissa Price, Carolyn Beedle, Jane Perlmutter, Paula Pohlmann, Rebecca A. Shatsky, Angela DeMichele, Douglas Yee, Laura J. van ‘t Veer, Nola M. Hylton, Laura J. Esserman

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

3 Scopus citations

Abstract

Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab–deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin–cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2⁻Immune⁻DNA repair deficiency⁻ subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2⁻Immune⁻DNA repair deficiency⁻ signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379.

Original language	English (US)
Article number	63
Pages (from-to)	3728-3736
Number of pages	9
Journal	Nature medicine
Volume	30
Issue number	12
DOIs	https://doi.org/10.1038/s41591-024-03266-2
State	Published - Dec 2024

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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Khoury, K., Meisel, J. L., Yau, C., Rugo, H. S., Nanda, R., Davidian, M., Tsiatis, B., Chien, A. J., Wallace, A. M., Arora, M., Rozenblit, M., Hershman, D. L., Zimmer, A., Clark, A. S., Beckwith, H., Elias, A. D., Stringer-Reasor, E., Boughey, J. C., Nangia, C., ... Esserman, L. J. (2024). Datopotamab–deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial. Nature medicine, 30(12), 3728-3736. Article 63. https://doi.org/10.1038/s41591-024-03266-2

Khoury, K, Meisel, JL, Yau, C, Rugo, HS, Nanda, R, Davidian, M, Tsiatis, B, Chien, AJ, Wallace, AM, Arora, M, Rozenblit, M, Hershman, DL, Zimmer, A, Clark, AS, Beckwith, H, Elias, AD, Stringer-Reasor, E, Boughey, JC, Nangia, C, Vaklavas, C, Omene, C, Albain, KS, Kalinsky, KM, Isaacs, C, Tseng, J, Roussos Torres, ET, Thomas, B, Thomas, A, Sanford, A, Balassanian, R, Ewing, C, Yeung, K, Sauder, C, Sanft, T, Pusztai, L, Trivedi, MS, Outhaythip, A, Li, W, Onishi, N, Asare, AL, Beineke, P, Norwood, P, Brown-Swigart, L, Hirst, GL, Matthews, JB, Moore, B, Fraser Symmans, W, Price, E, Beedle, C, Perlmutter, J, Pohlmann, P, Shatsky, RA, DeMichele, A, Yee, D, van ‘t Veer, LJ, Hylton, NM & Esserman, LJ 2024, 'Datopotamab–deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial', Nature medicine, vol. 30, no. 12, 63, pp. 3728-3736. https://doi.org/10.1038/s41591-024-03266-2

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title = "Datopotamab–deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial",

abstract = "Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab–deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin–cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2−Immune−DNA repair deficiency− subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2−Immune−DNA repair deficiency− signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379.",

author = "Katia Khoury and Meisel, {Jane L.} and Christina Yau and Rugo, {Hope S.} and Rita Nanda and Marie Davidian and Butch Tsiatis and Chien, {A. Jo} and Wallace, {Anne M.} and Mili Arora and Mariya Rozenblit and Hershman, {Dawn L.} and Alexandra Zimmer and Clark, {Amy S.} and Heather Beckwith and Elias, {Anthony D.} and Erica Stringer-Reasor and Boughey, {Judy C.} and Chaitali Nangia and Christos Vaklavas and Coral Omene and Albain, {Kathy S.} and Kalinsky, {Kevin M.} and Claudine Isaacs and Jennifer Tseng and {Roussos Torres}, {Evanthia T.} and Brittani Thomas and Alexandra Thomas and Amy Sanford and Ronald Balassanian and Cheryl Ewing and Kay Yeung and Candice Sauder and Tara Sanft and Lajos Pusztai and Trivedi, {Meghna S.} and Ashton Outhaythip and Wen Li and Natsuko Onishi and Asare, {Adam L.} and Philip Beineke and Peter Norwood and Lamorna Brown-Swigart and Hirst, {Gillian L.} and Matthews, {Jeffrey B.} and Brian Moore and {Fraser Symmans}, W. and Elissa Price and Carolyn Beedle and Jane Perlmutter and Paula Pohlmann and Shatsky, {Rebecca A.} and Angela DeMichele and Douglas Yee and {van {\textquoteleft}t Veer}, {Laura J.} and Hylton, {Nola M.} and Esserman, {Laura J.}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41591-024-03266-2",

language = "English (US)",

volume = "30",

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journal = "Nature medicine",

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T1 - Datopotamab–deruxtecan in early-stage breast cancer

T2 - the sequential multiple assignment randomized I-SPY2.2 phase 2 trial

AU - Khoury, Katia

AU - Meisel, Jane L.

AU - Yau, Christina

AU - Rugo, Hope S.

AU - Nanda, Rita

AU - Davidian, Marie

AU - Tsiatis, Butch

AU - Chien, A. Jo

AU - Wallace, Anne M.

AU - Arora, Mili

AU - Rozenblit, Mariya

AU - Hershman, Dawn L.

AU - Zimmer, Alexandra

AU - Clark, Amy S.

AU - Beckwith, Heather

AU - Elias, Anthony D.

AU - Stringer-Reasor, Erica

AU - Boughey, Judy C.

AU - Nangia, Chaitali

AU - Vaklavas, Christos

AU - Omene, Coral

AU - Albain, Kathy S.

AU - Kalinsky, Kevin M.

AU - Isaacs, Claudine

AU - Tseng, Jennifer

AU - Roussos Torres, Evanthia T.

AU - Thomas, Brittani

AU - Thomas, Alexandra

AU - Sanford, Amy

AU - Balassanian, Ronald

AU - Ewing, Cheryl

AU - Yeung, Kay

AU - Sauder, Candice

AU - Sanft, Tara

AU - Pusztai, Lajos

AU - Trivedi, Meghna S.

AU - Outhaythip, Ashton

AU - Li, Wen

AU - Onishi, Natsuko

AU - Asare, Adam L.

AU - Beineke, Philip

AU - Norwood, Peter

AU - Brown-Swigart, Lamorna

AU - Hirst, Gillian L.

AU - Matthews, Jeffrey B.

AU - Moore, Brian

AU - Fraser Symmans, W.

AU - Price, Elissa

AU - Beedle, Carolyn

AU - Perlmutter, Jane

AU - Pohlmann, Paula

AU - Shatsky, Rebecca A.

AU - DeMichele, Angela

AU - Yee, Douglas

AU - van ‘t Veer, Laura J.

AU - Hylton, Nola M.

AU - Esserman, Laura J.

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N2 - Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab–deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin–cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2−Immune−DNA repair deficiency− subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2−Immune−DNA repair deficiency− signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379.

AB - Among the goals of patient-centric care are the advancement of effective personalized treatment, while minimizing toxicity. The phase 2 I-SPY2.2 trial uses a neoadjuvant sequential therapy approach in breast cancer to further these goals, testing promising new agents while optimizing individual outcomes. Here we tested datopotamab–deruxtecan (Dato-DXd) in the I-SPY2.2 trial for patients with high-risk stage 2/3 breast cancer. I-SPY2.2 uses a sequential multiple assignment randomization trial design that includes three sequential blocks of biologically targeted neoadjuvant treatment: the experimental agent(s) (block A), a taxane-based regimen tailored to the tumor subtype (block B) and doxorubicin–cyclophosphamide (block C). Patients are randomized into arms consisting of different investigational block A treatments. Algorithms based on magnetic resonance imaging and core biopsy guide treatment redirection after each block, including the option of early surgical resection in patients predicted to have a high likelihood of pathological complete response, the primary endpoint. There are two primary efficacy analyses: after block A and across all blocks for the six prespecified breast cancer subtypes (defined by clinical hormone receptor/human epidermal growth factor receptor 2 (HER2) status and/or the response-predictive subtypes). We report results of 103 patients treated with Dato-DXd. While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype, the treatment strategy across all blocks graduated in the hormone receptor-negative HER2−Immune−DNA repair deficiency− subtype with an estimated pathological complete response rate of 41%. No new toxicities were observed, with stomatitis and ocular events occurring at low grades. Dato-DXd was particularly active in the hormone receptor-negative/HER2−Immune−DNA repair deficiency− signature, warranting further investigation, and was safe in other subtypes in patients who followed the treatment strategy. ClinicalTrials.gov registration: NCT01042379.

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Datopotamab–deruxtecan in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial

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