證明新藥是否優(yōu)于現(xiàn)有標(biāo)準(zhǔn)藥物，通常需要開展隨機(jī)對照試驗進(jìn)行比較。由于早期癌癥與晚期癌癥相比，死亡率較低、生存期較長，療效已經(jīng)接近天花板，只能通過大量增加患者人數(shù)、延長隨訪時間，才有可能看出療效差異有無統(tǒng)計學(xué)顯著性。例如，晚期乳腺癌隨機(jī)對照試驗通常只需數(shù)以百計患者、5年之內(nèi)就能決定新藥的生死，早期乳腺癌隨機(jī)對照試驗可能需要數(shù)以千計患者、5至10年才能判斷新藥的優(yōu)劣。如果將治療相似早期癌癥的新藥放在一起比較，只設(shè)立1個標(biāo)準(zhǔn)對照組，并且在入組期間根據(jù)早期療效不斷優(yōu)勝劣汰并且調(diào)整治療方案，無疑可以大大減少對照組患者，大大節(jié)省時間和金錢，這種方法又稱自適應(yīng)隨機(jī)化或者適應(yīng)性隨機(jī)化，俗稱隨機(jī)應(yīng)變。I-SPY就是通過影像和分子分析預(yù)測療效，對新藥進(jìn)行一系列研究的早期乳腺癌復(fù)發(fā)風(fēng)險較高患者術(shù)前個體化治療新藥隨機(jī)應(yīng)變對照試驗平臺，這些新藥通過快速海選，如果優(yōu)于現(xiàn)有標(biāo)準(zhǔn)藥物，又被稱為畢業(yè)。從I-SPY1開始到I-SPY2，最初由美國國立衛(wèi)生研究院基金會領(lǐng)導(dǎo)，成員包括美國食品藥品監(jiān)督管理局、高等醫(yī)學(xué)院校癌癥研究中心、癌癥慈善基金會以及大型制藥公司，現(xiàn)在由量子飛躍醫(yī)療衛(wèi)生協(xié)作組織提供管理支持。I-SPY2始于2010年3月，預(yù)計將于2030年12月結(jié)束，對27種新藥組成的37種治療方案與標(biāo)準(zhǔn)治療方案（紫杉醇±曲妥珠單抗→多柔比星＋環(huán)磷酰胺）進(jìn)行比較，目前已經(jīng)畢業(yè)并且通過三期臨床試驗獲批上市的新藥包括奈拉替尼、帕妥珠單抗、恩美曲妥珠單抗、帕博利珠單抗、度伐利尤單抗、奧拉帕利、他拉唑帕利等等，當(dāng)然也包括已經(jīng)畢業(yè)但是三期臨床試驗失敗未能上市的新藥維利帕利等等。 - I-SPY TRIAL (NCT01042379): Neoadjuvant and Personalized Adaptive Novel Agents to Treat Breast Cancer (I-SPY)
- Official Title: I-SPY Trial (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging And moLecular Analysis 2)
2024年9月14日，英國《自然》旗下《自然醫(yī)學(xué)》在線發(fā)表I-SPY2.2研究報告2篇，分別對HER2陰性早期乳腺癌復(fù)發(fā)風(fēng)險較高患者術(shù)前采用滋養(yǎng)層細(xì)胞表面抗原TROP2抗體綴合藥物德達(dá)托泊單抗±免疫細(xì)胞程序性死亡配體PD-L1抑制劑度伐利尤單抗與紫杉類或多柔比星＋環(huán)磷酰胺標(biāo)準(zhǔn)化療方案進(jìn)行隨機(jī)應(yīng)變對照試驗。 該多中心多組隨機(jī)應(yīng)變對照二期臨床試驗分別于2022年6月至2023年9月、2022年9月至2023年8月入組103例患者給予德達(dá)托泊單抗、106例患者給予德達(dá)托泊單抗＋度伐利尤單抗，根據(jù)磁共振成像以及粗針活檢結(jié)果指導(dǎo)治療方案選擇，包括對預(yù)測病理完全緩解（主要終點(diǎn)）可能性較高患者進(jìn)行早期手術(shù)切除、對預(yù)測病理完全緩解可能性較低患者追加化療。 結(jié)果，德達(dá)托泊單抗與標(biāo)準(zhǔn)化療相比，對其他亞型乳腺癌均未達(dá)到預(yù)設(shè)成功（畢業(yè)）標(biāo)準(zhǔn)，僅對免疫陽性DNA修復(fù)缺陷三陰性乳腺癌達(dá)到畢業(yè)標(biāo)準(zhǔn)，估計病理完全緩解率為41%。未觀察到新的毒性反應(yīng)，口腔炎和眼部事件發(fā)生級別較低。 對于47例HER2陰性免疫陽性乳腺癌患者，德達(dá)托泊單抗＋度伐利尤單抗±化療達(dá)到預(yù)設(shè)成功（畢業(yè)）標(biāo)準(zhǔn)，37例（79%）獲得病理完全緩解率，其中20例患者（54%）用德達(dá)托泊單抗＋度伐利尤單抗治療后直接手術(shù)不再化療全部獲得病理完全緩解、14例（38%）患者追加紫杉醇化療后手術(shù)未用多柔比星＋環(huán)磷酰胺化療獲得病理完全緩解，加起來占37例患者的92%。對于23例激素受體陰性免疫陰性乳腺癌患者，德達(dá)托泊單抗＋度伐利尤單抗±化療與標(biāo)準(zhǔn)化療相比，全部達(dá)到預(yù)設(shè)成功（畢業(yè)）標(biāo)準(zhǔn)。未觀察到新的毒性反應(yīng)，僅用德達(dá)托泊單抗＋度伐利尤單抗治療的最常見副作用是口腔炎、未出現(xiàn)腎上腺功能不全。 因此，該研究結(jié)果表明，德達(dá)托泊單抗對免疫陽性DNA修復(fù)缺陷三陰性乳腺癌尤其有效，德達(dá)托泊單抗＋度伐利尤單抗是大有希望的治療組合，可以避免許多患者（尤其免疫陽性乳腺癌）接受化療，故有必要進(jìn)一步開展大樣本隨機(jī)對照三期臨床試驗進(jìn)行驗證。Nat Med. 2024 Sep 14. IF: 58.7Datopotamab-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.University of Alabama at Birmingham, Birmingham, AL, USA; Emory University, Atlanta, GA, USA; University of California San Francisco, San Francisco, CA, USA; University of Chicago, Chicago, IL, USA; North Carolina State University, Raleigh, NC, USA; University of California San Diego, San Diego, CA, USA; University of California Davis, Davis, CA, USA; Yale University, New Haven, CT, USA; Columbia University, New York, NY, USA; Oregon Health Sciences University, Portland, OR, USA; University of Pennsylvania, Philadelphia, PA, USA; University of Minnesota, Minneapolis, MN, USA; University of Colorado Denver, Denver, CO, USA; The Mayo Clinic, Rochester, MN, USA; HOAG Family Cancer Institute, Newport Beach, CA, USA; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Cooperman Barnabas Medical Center, New Brunswick, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Stritch School of Medicine, Loyola University Chicago, Chicago, IL, USA; Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA; City of Hope Orange County Lennar Foundation Cancer Center, Orange County, CA, USA; University of Southern California, Los Angeles, CA, USA; Sparrow Health System, Lansing, MI, USA; Wake Forest University, Winston-Salem, NC, USA; Sanford Health, Sioux Falls, SD, USA; Quantum Leap Healthcare Collaborative, San Francisco, CA, USA; University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Gemini Group, Ann Arbor, MI, USA.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: NCT01042379DOI: 10.1038/s41591-024-03266-2Nat Med. 2024 Sep 14. IF: 58.7 Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial. Rebecca A. Shatsky, Meghna S. Trivedi, Christina Yau, Rita Nanda, Hope S. Rugo, Marie Davidian, Butch Tsiatis, Anne M. Wallace, A. Jo Chien, Erica Stringer-Reasor, Judy C. Boughey, Coral Omene, Mariya Rozenblit, Kevin Kalinsky, Anthony D. Elias, Christos Vaklavas, Heather Beckwith, Nicole Williams, Mili Arora, Chaitali Nangia, Evanthia T. Roussos Torres, Brittani Thomas, Kathy S. Albain, Amy S. Clark, Carla Falkson, Dawn L. Hershman, Claudine Isaacs, Alexandra Thomas, Jennifer Tseng, Amy Sanford, Kay Yeung, Sarah Boles, Yunni Yi Chen, Laura Huppert, Nusrat Jahan, Catherine Parker, Karthik Giridhar, Frederick M. Howard, M. Michele Blackwood, Tara Sanft, 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, Diane Heditsian, Barbara LeStage, Jane Perlmutter, Paula Pohlmann, Angela DeMichele, Douglas Yee, Laura J. van 't Veer, Nola M. Hylton, Laura J. Esserman. University of California San Diego, San Diego, CA, USA; Columbia University, New York, NY, USA; University of California San Francisco, San Francisco, CA, USA; University of Chicago, Chicago, IL, USA; North Carolina State University, Raleigh, NC, USA; University of Alabama at Birmingham, Birmingham, AL, USA; The Mayo Clinic, Rochester, MN, USA; Cooperman Barnabas Medical Center, New Brunswick, NJ, USA; Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA; Yale University, New Haven, CT, USA; Emory University, Atlanta, GA, USA; University of Colorado, Denver, CO, USA; University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA; University of Minnesota, Minneapolis, MN, USA; The Ohio State University, Columbus, OH, USA; University of California Davis, Davis, CA, USA; HOAG Family Cancer Institute, Newport Beach, CA, USA; University of Southern California, Los Angeles, CA, USA; Sparrow Health System, Lansing, MI, USA; Loyola University Chicago Stritch School of Medicine, Chicago, IL, USA; University of Pennsylvania, Philadelphia, PA, USA; University of Rochester Medical Center, Rochester, NY, USA; Lombardi Comprehensive Cancer Center Georgetown University, Washington, DC, USA; Wake Forest University, Winston-Salem, NC, USA; City of Hope Orange County Lennar Foundation Cancer Center, Irvine, CA, USA; Sanford Health, Sioux Falls, SD, USA; Quantum Leap Healthcare Collaborative, San Francisco, CA, USA; University of Texas MD Anderson Cancer Center, Houston, TX, USA; The Gemini Group, Ann Arbor, MI, USA. Sequential adaptive trial designs can help accomplish the goals of personalized medicine, optimizing outcomes and avoiding unnecessary toxicity. Here we describe the results of incorporating a promising antibody-drug conjugate, datopotamab-deruxtecan (Dato-DXd) in combination with programmed cell death-ligand 1 inhibitor, durvalumab, as the first sequence of therapy in the I-SPY2.2 phase 2 neoadjuvant sequential multiple assignment randomization trial for high-risk stage 2/3 breast cancer. The trial includes three blocks of treatment, with initial randomization to different experimental agent(s) (block A), followed by a taxane-based regimen tailored to tumor subtype (block B), followed by doxorubicin-cyclophosphamide (block C). Subtype-specific algorithms based on magnetic resonance imaging volume change 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 pathologic complete response, which is the primary endpoint assessed when resection occurs. There are two primary efficacy analyses: after block A and across all blocks for six prespecified HER2-negative subtypes (defined by hormone receptor status and/or response-predictive subtypes). In total, 106 patients were treated with Dato-DXd/durvalumab in block A. In the immune-positive subtype, Dato-DXd/durvalumab exceeded the prespecified threshold for success (graduated) after block A; and across all blocks, pathologic complete response rates were equivalent to the rate expected for the standard of care (79%), but 54% achieved that result after Dato-DXd/durvalumab alone (block A) and 92% without doxorubicin-cyclophosphamide (after blocks A + B). The treatment strategy across all blocks graduated in the hormone-negative/immune-negative subtype. No new toxicities were observed. Stomatitis was the most common side effect in block A. No patients receiving block A treatment alone had adrenal insufficiency. Dato-DXd/durvalumab is a promising therapy combination that can eliminate standard chemotherapy in many patients, particularly the immune-positive subtype. ClinicalTrials.gov registration: NCT01042379 DOI: 10.1038/s41591-024-03267-1
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