2024 ASCO丨吳一龍教授:KRAS G12C抑制劑氟澤雷塞+EGFR單抗方案“一線首秀”亮眼,有望開啟NSCLC治療新篇章

2024 ASCO丨吳一龍教授:KRAS G12C抑制劑氟澤雷塞+EGFR單抗方案“一線首秀”亮眼,有望開啟NSCLC治療新篇章

在剛剛落幕的2024年美國臨床學會(ASCO)年會上,多項國產抗腫瘤創新藥研究成功躋身“重磅研究摘要”(Late-Breaking Abstract, LBA)之列,彰顯了重要的臨床價值和開創性意義,其中就包括KRAS G12C抑制劑氟澤雷塞(Fulzerasib)聯合西妥昔單抗一線治療KRAS G12C突變晚期非小細胞肺癌(NSCLC)的KROCUS研究(摘要號LBA8511),這也是KRAS G12C抑制劑聯合EGFR抑制劑用於一線NSCLC治療的臨床資料“全球首發”[1]。

KROCUS是一項由歐洲研究者開展、面向歐洲患者的多中心“出海”研究,不僅證實了氟澤雷塞聯合西妥昔單抗方案一線使用的良好療效和安全性,也對KRAS G12C抑制劑一線聯合方案的未來臨床探索提供了更多可能。值此機會,“醫學界”邀請到廣東省人民醫院吳一龍教授、領銜開展KROCUS研究的西班牙專家Rafael Rosell教授、在ASCO年會現場口頭報告研究成果的義大利專家Vanesa Gregorc教授共同探討研究成果及其意義。

KROCUS研究“強效縮瘤”,滿足KRAS G12C突變晚期NSCLC患者精準治療需求

KRAS突變是晚期NSCLC中常見的癌基因突變之一,而KRAS G12C突變在眾多KRAS突變型別中佔比最高,在歐美國家非鱗NSCLC患者中整體檢出率可達10%-13%。吳一龍教授介紹道,近年來的大樣本測序研究資料顯示,我國NSCLC患者攜帶KRAS G12C突變的比例約為2%-3%[2]。

近年來,NSCLC靶向治療快速發展,KRAS G12C突變晚期NSCLC患者的精準治療需求也亟待滿足。Vanesa Gregorc教授指出,既往KRAS突變被視為“不可成藥”靶點,KRAS G12C突變患者只能被迫接受化療、免疫治療等非靶向療法。目前,KRAS G12C抑制劑在晚期NSCLC二線治療中已經取得顯著進展並有相應藥物在國外獲批,但KRAS G12C抑制劑一線聯合治療方案仍在探索中。KROCUS研究正致力於解決這一問題。

既往臨床前研究顯示,由EGFR等受體酪氨酸激酶(RTKs)介導的RAS通路反饋性啟用是KRAS抑制劑耐藥和療效有限的原因之一;而KRAS抑制劑還可能透過下調MIG6水平導致EGFR表達上調,進一步促進EGFR介導的耐藥[4-6]。因此KROCUS研究在設計思路上,採用了同時抑制EGFR和KRAS G12C的聯合用藥策略,以期達到更好的治療療效並延緩治療耐藥的發生。

截至2024年4月,KROCUS研究共入組40例KRAS G12C突變晚期一線NSCLC患者,在本次ASCO年會上公佈的療效分析資料顯示:33例接受過至少一次治療後腫瘤評估的患者中,氟澤雷塞聯合西妥昔單抗治療的客觀緩解率(ORR)高達81.8%,含1例完全緩解(CR)和2例靶病灶縮小100%的部分緩解(PR),疾病控制率(DCR)高達100%,多數患者的腫瘤縮小幅度超過50%,且88%患者仍在繼續接受治療,中位緩解持續時間(mDoR)尚未達到。

圖1.KROCUS研究最佳治療應答評估結果

領銜開展KROCUS研究的Rafael Rosell教授和Vanesa Gregorc教授分別介紹了臨床試驗中令人印象深刻的兩例患者案例,首例患者基線時已有腦轉移,但在接受氟澤雷塞聯合西妥昔單抗方案治療後,腦轉移灶縮小,腫瘤評估達到客觀緩解、無需再行放療,體現了氟澤雷塞良好的入腦能力和顱內療效;另一例患者則在確診時已有腦、骨、軟組織等全身多處轉移,且轉移灶導致了嚴重併發症,患者在入組研究接受聯合治療後實現了快速且深度的疾病緩解,反映了聯合治療的出色療效。

出色安全性為聯合治療“上分”,或在未來實現“去化療”目標

KROCUS研究在安全性方面同樣表現出色,Rafael Rosell教授介紹,氟澤雷塞聯合西妥昔單抗方案治療期間,患者未報告≥4級的治療相關不良事件(TRAEs),聯合治療的安全性優勢對比KRAS G12C突變患者既往常用的化療更為明顯,有望在未來實現“去化療”式治療,也讓研究者們更有信心將氟澤雷塞聯合西妥昔單抗方案推進至臨床III期研究進一步評估。

吳一龍教授則提及了今年在《新英格蘭醫學雜誌》發表的FLAURA2研究評論文章[3],指出從既往治療我國EGFR突變NSCLC患者的經驗來看,我國患者普遍不傾向於接受化療。Vanesa Gregorc教授也表示:“KRAS G12C突變患者既往接受一線化療是不得已之舉,臨床醫生和患者都更傾向於使用療效更好、副作用更小的靶向藥物替代化療,KROCUS研究在KRAS G12C突變晚期NSCLC一線治療中的探索具有“先驅性”,氟澤雷塞聯合西妥昔單抗有望實現一線治療的目標”。

Vanesa Gregorc教授還專門指出,既往已經報道的KRAS抑制劑治療常見的肝酶升高、腹瀉等不良反應在KROCUS研究中均非常少見,患者報告發生率最高的治療相關不良反應(TRAE)是皮疹(55.6%,但僅有1例3級),這對氟澤雷塞與西妥昔單抗聯合治療的應用非常有利。

圖2.KROCUS研究安全性資料總覽

單藥治療與聯合方案齊頭並進,氟澤雷塞即將惠及中國患者

除了KROCUS聯合研究,氟澤雷塞單藥治療KRAS G12C突變晚期NSCLC也有良好表現。

在2023年歐洲腫瘤內科學會亞洲大會(ESMO Asia)上,吳一龍教授彙報了氟澤雷塞針對我國NSCLC患者的一項臨床II期註冊研究。初步研究結果顯示,氟澤雷塞治療KRAS G12C突變晚期NSCLC的確認ORR(cORR)為46.6%,DCR為90.5%,中位無進展生存期(mPFS)為8.3個月。

吳一龍教授表示,與此前獲美國FDA批准的兩款KRAS G12C抑制劑(Sotorasib, Adagrasib)相比,氟澤雷塞在臨床II期研究中的ORR、mPFS兩項關鍵療效指標均更有優勢,且治療安全性同樣良好。基於該研究結果,氟澤雷塞已獲得國內治療KRAS G12C突變晚期NSCLC的突破性療法認定,並獲國家藥品監督管理局(NMPA)藥品審評中心(CDE)受理,並納入優先審評,期待其能夠儘快獲批惠及患者。

此外,氟澤雷塞還有與其他各類治療藥物聯合使用、為患者帶來更多獲益的廣泛可能性,如吳一龍教授和Vanesa Gregorc教授都認為,針對同時存在KRAS G12C突變和PD-L1高表達的患者,或可探索氟澤雷塞與PD-L1抑制劑的聯合治療,屆時有望對藥物排兵佈陣進行最佳化、重新定位免疫治療用法,而氟澤雷塞良好的療效和安全性是實現上述目標的必要前提。

專家簡介

Prof. Yi-Long Wu

  • Professor of Oncology, PhD supervisor

  • Winner of Outstanding Science Achievement from IASLC

  • Vice President of Chinese Medical Doctors Association (CMDA)

  • President of Guangdong Medical Doctors Association (GDMDA)

  • Chief expert of Guangdong Provincial Peoples Hospital (GDPH)

  • Honorary Director, Guangdong Province Lung Cancer Research Institute (GLCI)

  • Chair of China Thoracic Oncology Group (CTONG)

  • Highly cited scientists in clinical medicine from 2018 to 2023

  • Chairman of Lung Oncology Society, Guangdong Medical Association

  • Past President Chinese Society of Clinical Oncology (CSCO), Chairman of the steering committee

專家簡介

GREGORC VANESA, MD

Department of Oncology

  • Istituto di Candiolo Fondazione del Piemonte per lOncologia IRCCS (IT)

Since 2021 to present

  • Affiliation: Istituto di Candiolo - IRCCS Fondazione del Piemonte per lOncologia (IT)

  • 2021-to present Deputy Scientific Director

  • 2021-to present Director of Medical Area

  • 2021- to present Director of Medical Oncology Department

Since 2003 to 2021

  • Affiliation: IRCCS Ospedale San Raffaele, Milano (IT)

  • 2021-11/2021 Coordinator of Cancer Center Medical Area

  • 2020-11/2021 Director of the Strategic Diagnostic-Therapeutic Oncological Innovation Program

  • 2015-2021 Director of Thoracic Oncology, Melanoma and Head and Neck Unit at Medical Oncology Department

  • 2003-2015 Staff Physician of Thoracic Oncology, Melanoma and Head and Neck Unit at Medical Oncology Department

專家簡介

RAFAEL ROSELL, MD PHD

  • Director, Cancer Biology & Precision Medicine Program

  • Catalan Institute of Oncology (ICO) – Badalona, Barcelona, Spain

  • Chief Medical Officer

  • Dr Rosell Oncology Institute, Quiron Dexeus Univ Hospital – Barcelona, Spain

  • Founder, Chairman & Chief Scientific Officer

  • Pangaea Biotech SL – Barcelona, Spain

  • Founder & President

  • Molecular Oncology Research Foundation (MORe Foundation) – Barcelona, Spain

  • Founder, Director of International Relations & Projects

  • Spanish Lung Cancer Group – Barcelona, Spain

  • Associate Professor/Lecturer, Medical Oncology

  • Autonomous University of Barcelona – Barcelona, Spain

    Member:

  • International Association for the Study of Lung Cancer (IASLC) Chair, 2005 World Conference on Lung Cancer

  • European Society for Medical Oncology (ESMO) Member, Scientific Program Sub-Committee (NSCLC, metastatic)for ESMO Annual Congress

  • European Organization for Research and Treatment of Cancer (EORTC) Member of the EORTC Protocol Review Committee

  • European Thoracic Oncology Platform (ETOP) Foundation Council and Steering Committee Member

  • American Society of Clinical Oncology (ASCO) Member of Scientific Program Committee 2002-2004

  • Spanish Lung Cancer Group, Former President (1991-2014)

  • International Lung Adenocarcinoma Consensus Classification Panel (ILACCP)

  • Catalan Society of Oncology, Former President

  • Spanish Society of Medical Oncology Spanish Society of Cancer Research (ASEICA), Former President

  • American Association for Cancer Research

  • Honorary Member of Argentina Association of Clinical Oncology (AAOC)

  • Italian Association of Thoracic Oncology (AIOT)

  • Bonnie J Addario Lung Cancer Foundation, member Medical Advisory Board

  • International Association for the Study of Lung Cancer (IASLC)

  • European Cancer Concord (ECC) Founding member

參考文獻

[1]Gregorc V, et al. KROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC[J]. Journal of Clinical Oncology, 2024, 42(suppl_17) : LBA8511.

[2]Lim T K H, Skoulidis F, Kerr K M, et al. KRAS G12C in advanced NSCLC: prevalence, co-mutations, and testing[J]. Lung Cancer, 2023, 184: 107293.

[3]Zhou Q, Meng X, Sun L, et al. LBA12 Efficacy and safety of IBI351 (GFH925), a selective KRASG12C inhibitor, monotherapy in patients (pts) with advanced non-small cell lung cancer (NSCLC): Initial results from a registrational phase II study[J]. Annals of Oncology, 2023, 34(Supplement 4): S1662.

[4]Ryan M B, Fece de la Cruz F, Phat S, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRASG12C inhibition[J]. Clinical Cancer Research, 2020, 26(7): 1633-1643.

[5]Amodio V, Yaeger R, Arcella P, et al. EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer[J]. Cancer Discovery, 2020, 10(8): 1129-1139.

[6]Chen N, Tyler L C, Le A T, et al. MIG6 mediates adaptive and acquired resistance to ALK/ROS1 fusion kinase inhibition through EGFR bypass signaling[J]. Molecular Cancer Therapeutics, 2024, 23(1): 92-105.

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