PO.CL01.03 · 临床研究

TP53共突变与RET融合伙伴在RET重排晚期NSCLC中的预后与预测效应

Prognostic and predictive effects of TP53 co-mutations and RET fusion partners in RET -rearranged advanced NSCLC

编号 2434 展板 4 时间 4/20 09:00–12:00 区域 Section 40 主讲 Daniela Miliziano, MD (hc)

分会场 Biomarkers Predictive of Therapeutic Benefit 3

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作者与单位 Authors & Affiliations

Daniela Miliziano¹, Julia K. Rotow², Meghanne Lomibao³, Tolulope Adeyelu⁴, Arianna Marinello¹, Helena Bote-de Cabo⁵, Jamie Feng⁶, Andrea De Giglio⁷, Mariana Brandão⁸, Florian Guisier⁹, Michael Duruisseaux¹⁰, Christina Falcon³, Massimiliano Cani¹¹, Francesca Colamartini¹², Barliz Waissengrin¹³, Isabelle Monnet¹⁴, Anna Eisert¹⁵, Emilio Bria¹⁶, Amin H. Nassar¹⁷, Ayesha Aijaz¹⁸, Patricia Iranzo¹⁹, Colin R. Lindsay²⁰, Elizabeth Fabre²¹, Vladmir Cordeiro de Lima²², Judith Raimbourg²³, Laura Mezquita²⁴, Nicolas Minatta²⁵, Sophie Cousin²⁶, Katarzyna Szymczak²⁷, Vincent Fallet²⁸, Clarisse Audigier-Valette²⁹, Helene Doubre³⁰, Philippe Rochigneux³¹, Annarita Avanzo³², Antonio Calles³³, Marco Tagliamento³⁴, Diego Cortinovis³⁵, Balazs Halmos³⁶, Nicholas Girard³⁷, Andrew Elliott⁴, Jair Bar³⁸, Alessio Cortellini³⁹, Diana N. Ionescu⁴⁰, Frances A. Shepherd⁴¹, Fabrice Barlesi⁴², Karen L. Reckamp¹³, David Planchard¹, Benjamin Besse¹, Alexander Drilon³, Mihaela Aldea¹

¹Department of Medical Oncology, Gustave Roussy, International Center for Thoracic Cancers, Villejuif, France,²Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, MA,³Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY,⁴Caris Life Sciences, Phoenix, AZ,⁵Department of Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain,⁶Department of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada,⁷Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy,⁸Clinic of Thoracic Oncology & Phase 1 Clinical Trials Unit, Institut Jules Bordet-Hôpital Universitaire de Bruxelles, Université Libre de Bruxelles, Brussels, Belgium,⁹Normandie Univ, UNIROUEN, AIMS Lab QuantIF team, CHU Rouen, Department of Pneumology and Inserm CIC-CRB 1404, Rouen, France,¹⁰Respiratory Department and Early Phase (EPSILYON), Louis Pradel Hospital, Hospices Civils de Lyon Cancer Institute, Lyon, France; Cancer Research Center of Lyon (INSERM U1052, CNRS 5286), Lyon, France; Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France,¹¹Department of Oncology, University of Turin, S. Luigi Gonzaga University Hospital, Orbassano, Turin, Italy,¹²Medical Oncology, Santa Maria Della Misericordia Hospital, University of Perugia, Perugia, Italy,¹³Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA,¹⁴Pneumology and Thoracic Oncology Department, Intercommunal Hospital of Créteil (CHI), Créteil, France,¹⁵Department of Medical Oncology, University Hospital of Cologne, Cologne, Germany,¹⁶Università Cattolica del Sacro Cuore, Rome, Italy; Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Ospedale Isola Tiberina – Gemelli Isola, Rome, Italy,¹⁷Division of Oncology, Yale University School of Medicine, New Haven, CT,¹⁸Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK,¹⁹Medical Oncology Department, Vall d'Hebron Hospital Universitari / Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain,²⁰Division of Cancer Sciences, University of Manchester, Manchester, United Kingdom,²¹Department of Thoracic Oncology, European Hospital Georges Pompidou, Paris, France,²²Department of Medical Oncology, A. C. Camargo Cancer Center, São Paulo, Brazil,²³Institut de Cancérologie de l'Ouest, St Herblain, France,²⁴Medical Oncology Department, Hospital Clinic of Barcelona, Barcelona, Spain,²⁵Department of Medical Oncology, Hospital Italiano, Buenos Aires, Argentina,²⁶Department of Medical Oncology, Institut Bergonié, Bordeaux, France,²⁷Department of Oncology and Radiotherapy and Early Phase Clinical Trials Center, University of Gdańsk, Gdańsk, Poland,²⁸Department of Pneumology and Thoracic Oncology, Tenon Hospital, AP-HP – Sorbonne Université, Paris, France,²⁹Department of Thoracic Oncology, Hospital Sainte Musse, Toulon, France,³⁰Department of Pulmonary Medicine, Hôpital Foch, Suresnes, France,³¹Department of Medical Oncology, Paoli-Calmettes Institute, Aix Marseille University, Marseille, France,³²Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Naples, Italy,³³Department of Medical Oncology, Hospital General Universitario Gregorio Marañón, Madrid, Spain,³⁴Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy,³⁵Medical Oncology, Fondazione IRCCS S. Gerardo dei Tintori, Monza; Department of Medicine, Università Milano-Bicocca, Milan, Italy,³⁶Montefiore Medical Center – Albert Einstein College of Medicine, New York, NY,³⁷Department of Medical Oncology, Institut Curie, Paris, France,³⁸Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel,³⁹Department of Medical Oncology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy,⁴⁰Department of Pathology, British Columbia Cancer Agency, Vancouver, BC, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada,⁴¹Division of Medical Oncology, Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, ON, Canada,⁴²Université Paris-Saclay, Gustave Roussy, Inserm, Prédicteurs moléculaires et nouvelles cibles en oncologie (U981), F-94805, Villejuif, France

摘要 Abstract

中文摘要

背景：RET融合发生于约1-2%的晚期NSCLC（aNSCLC）中。选择性RET抑制剂（SRIs）显著改善了结局，但约10%的患者在6个月内、约30%的患者在12个月内出现进展。响应或早期进展的预测因素仍不明确。方法：一项来自47个国际中心的RET+ aNSCLC多中心回顾性分析（RET-MAP）评估了SRI结局的临床/基因组相关因素。多变量Cox模型估计了无进展生存（PFS）和总生存（OS），并检验了与一线（1L）SRI相对于化疗±免疫检查点抑制剂（CH±ICI）的交互作用。同时，在一个外部Caris Life Sciences（CLS）RET+ aNSCLC队列中表征了基因组/转录组特征。结果：在510例RET-MAP患者中（中位年龄63岁；59%女性；36%曾吸烟者；92%腺癌），401例接受了SRI（1L n=151；后线 n=250）。SRI（任何线）的中位PFS为17.1个月（95%CI，14.5-21.1），中位OS为30.4个月（95%CI，27.0-41.1）。TP53共突变见于27%（78/292例检测），与更短的PFS（8.9 vs 19.2个月；p<0.001）和OS（22.7 vs 30.9个月；p=0.002）相关，而1L SRI相对于CH±ICI并无显著的治疗-TP53交互作用（p=0.22）。融合伙伴提供了额外信号：与CCDC6（17%，65/373）相比，KIF5B（73%，274/373）的PFS（13.4 vs 60.2个月；p<0.001）和OS（26.6 vs 73.0个月；p=0.002）更差，且CCDC6相对于KIF5B存在显著的治疗-融合交互作用，倾向于SRI优于CH±ICI（p=0.007）。多变量分析显示，更短的PFS和OS独立地与TP53突变（HR 1.74，p<0.001；HR 1.77，p=0.001）、KIF5B融合（HR 1.98，p=0.002；HR 1.64，p=0.040）、ECOG≥2（HR 2.20，p<0.001；HR 3.06，p<0.001）和脑转移（HR 1.59，p=0.003；HR 1.88，p<0.001）相关；更差的OS与非腺癌组织学（HR 1.74，p=0.049）和吸烟（HR 1.42，p=0.034）相关。值得注意的是，与CCDC6相比，KIF5B融合富集TP53突变（40% vs 19.6%，p=0.011），提示部分重叠的生物学特征。在CLS队列（N=211）中，TP53突变型肿瘤（74/211）富集RB1突变，具有更高的PD-L1表达和肿瘤突变负荷，并表现出M1巨噬细胞/B细胞浸润增加而中性粒细胞减少；就融合伙伴而言，CCDC6显示更高的PD-L1，而整体转录组在其他方面与KIF5B相似。结论：在RET+ aNSCLC中，TP53突变对SRI疗效的更差结局具有预后意义，但不能预测相对于CH±ICI的差异获益。融合伙伴同时具有预后和预测相关性；CCDC6与更惰性的病程和从SRI获得更大的相对获益相关。外部分析支持TP53突变型疾病中存在炎症性微环境，进一步强化了RET驱动的肺癌中在生物学上不同且在临床上有意义的亚群。

查看英文原文 English abstract

Background: RET fusions occur in ~1-2% of advanced NSCLC (aNSCLC). Selective RET inhibitors (SRIs) significantly improve outcomes, yet ~10% of patients progress by 6 months and ~30% by 12 months. Predictors of response or early progression remain poorly defined. Methods: A multicenter retrospective analysis (RET-MAP) of RET+ aNSCLC from 47 international centers evaluated clinical/genomic correlates of SRI outcomes. Multivariable Cox models estimated progression-free (PFS) and overall survival (OS) and tested interactions with first-line (1L) SRI versus chemotherapy ± immune checkpoint inhibitor (CH±ICI). In parallel, genomic/transcriptomic features were characterized in an external Caris Life Sciences (CLS) RET+ aNSCLC cohort. Results: Among 510 RET-MAP patients (median age 63; 59% female; 36% ever-smokers; 92% adenocarcinoma), 401 received an SRI (1L n=151; later lines n=250). Median PFS on SRI (any line) was 17.1 months (95% CI, 14.5-21.1), median OS 30.4 months (95% CI, 27.0-41.1). TP53 co-mutation was present in 27% (78/292 tested) and was associated with shorter PFS (8.9 vs 19.2 months; p<0.001) and OS (22.7 vs 30.9 months; p=0.002), without a significant treatment-by- TP53 interaction for 1L SRI versus CH±ICI (p=0.22). Fusion partner contributed with additional signal: KIF5B (73%, 274/373) had inferior PFS (13.4 vs 60.2 months; p<0.001) and OS (26.6 vs 73.0 months; p=0.002) compared with CCDC6 (17%, 65/373), and a significant treatment-by-fusion interaction favored SRI over CH±ICI in CCDC6 versus KIF5B (p=0.007). On multivariate analysis, shorter PFS and OS were independently associated with TP53 mutation (HR 1.74, p<0.001; HR 1.77, p=0.001), KIF5B fusion (HR 1.98, p=0.002; HR 1.64, p=0.040), ECOG ≥2 (HR 2.20, p<0.001; HR 3.06, p<0.001), and brain metastases (HR 1.59, p=0.003; HR 1.88, p<0.001); worse OS was associated with non-adenocarcinoma histology (HR 1.74, p=0.049) and smoking (HR 1.42, p=0.034). Notably, KIF5B fusions were enriched for TP53 mutations versus CCDC6 (40% vs 19.6%, p=0.011), suggesting partially overlapping biology. In the CLS cohort (N=211), TP53 -mutant tumors (74/211) were enriched for RB1 mutations, had higher PD-L1 expression and tumor mutational burden, and demonstrated increased M1 macrophage/B-cell infiltration with reduced neutrophils; by fusion partner, CCDC6 showed higher PD-L1, while global transcriptomes were otherwise similar to KIF5B . Conclusions: In RET+ aNSCLC, TP53 mutation is prognostic for inferior outcomes on SRIs but not predictive of differential benefit versus CH±ICI. Fusion partner carries both prognostic and predictive relevance; CCDC6 is associated with a more indolent course and greater relative benefit from SRI. External profiling supports an inflammatory microenvironment in TP53 -mutant disease, reinforcing biologically distinct-and clinically meaningful-subsets within RET -driven lung cancer.

利益披露 Disclosure

D. Miliziano, None. J. Rotow, Amgen consulting fees or honoraria. AstraZeneca consulting fees or honoraria. BioAtla consulting fees or honoraria. BMS consulting fees or honoraria. Boehringer Ingelheim consulting fees or honoraria. M. Lomibao, None. T. Adeyelu, Caris Life Sciences Employment, Stock. A. Marinello, None.. H. Bote-de Cabo, None. J. Feng, AstraZeneca Other, Speaker’s honoraria and advisory board. Merck Other, Speaker’s honoraria and advisory board. Pfizer Other, Speaker’s honoraria and advisory board. Amgen Other, Speaker’s honoraria and advisory board. Roche Other, Speaker’s honoraria. CPD Network (Oncology Education) Other, Speaker’s honoraria. DAVA Oncology Travel. Boehringer-Ingelheim Travel. Eli Lilly Other, PI in sponsored trials. Black Diamond Therapeutics Other, PI in sponsored trials. A. De Giglio, None.. M. Brandão, None.. F. Guisier, None. M. Duruisseaux, Takeda Other, Institutional research funding, advisory board. Astra-Zeneca Travel, Other, Institutional research funding, advisory board. Roche Travel, Other, advisory board. MSD Travel, Other, advisory board. Amgen Travel, Other, advisory board. Pfizer Other, advisory board. Boehringer Ingelheim Other, advisory board. BMS Other, advisory board. Abbvie Other, advisory board. Guardant Other, advisory board. Novartis Other, advisory board. Gamamabs Pharma Other, advisory board. GSK Other, advisory board. Sanofi Other, advisory board. Lilly Other, advisory board. Merus Other, advisory board. C. Falcon, None.. M. Cani, None.. F. Colamartini, None.. B. Waissengrin, None. I. Monnet, Regeneron Other, Honoraria. Takeda Other, Financial support. MSD Other, Financial support. Pfizer Other, Financial support. Oxyvie Other, Financial support. A. Eisert, None.. E. Bria, None. A. H. Nassar, Korean Society of Medical Oncology Travel, Other, Honoraria. TEMPUS Other, Honoraria. OncLive Other, Honoraria. Oklahoma University Other, Honoraria. Targeted Oncology Other, Honoraria. American Association for Cancer Research Travel. Guidepoint global Other, Consultation fees. Putnam associates Other, Consultation fees. Capvision Other, Consultation fees. Revolution Medicine Other, Equity. Summit Therapeutics Other, Equity. A. Aijaz, None.. P. Iranzo, None. C. R. Lindsay, Revolution Medicines Other, research funding (Institutional), participation in advisory boards or educational sessions. Boehringer Ingelheim Other, research funding (Institutional). Qiagen Other, research funding (Institutional). Amgen Other, participation in advisory boards or educational sessions. Eli Lilly Other, participation in advisory boards or educational sessions. E. Fabre, None. V. Cordeiro de Lima, BMS Other, institutional research funding. J. Raimbourg, None.. L. Mezquita, None. N. Minatta, BMS Consulting/advisory board. S. Cousin, None.. K. Szymczak, None. V. Fallet, Amgen Travel. C. Audigier-Valette, None. H. Doubre, Pfizer Travel, accommodation, congress registration expenses. P. Rochigneux, GSK Other, Investigator in clinical trials. A. Avanzo, None. A. Calles, AstraZeneca Honoraria. M. Tagliamento, None.. D. Cortinovis, None.. B. Halmos, None.. N. Girard, None.. A. Elliott, None.. J. Bar, None.. A. Cortellini, None.. D. Ionescu, None.. F. Shepherd, None. F. Barlesi, Roche Other, Consulting. Genentech Other, Consulting. Novartis Other, Consulting. Bristol Myers Squibb Other, Consulting. AstraZeneca Consulting. MedImmune Other, Consulting. Boehringer Ingelheim Consulting. Lilly Consulting. Merck Serono Other, Consulting. MSD Oncology Other, Consulting. Takeda Other, Consulting. Bayer Other, Consulting. Amgen Other, Consulting. Eisai Europe Other, Consulting. K. L. Reckamp, None.. D. Planchard, None. B. Besse, Abbvie Other, Honoraria, conseils. Biontech SE Other, Honoraria. BristolMyerSqibb Other, Honoraria. Chugai pharmaceutical Other, Honoraria. CureVac AG Other, Honoraria. Daiichi Sankyo Honoraria. F. Hoffmann-La Roche Ltd Honoraria. Pharmamar Honoraria. Regeneron Honoraria. Sanofi aventis Honoraria. Turning Point Therapeutics Honoraria. Eli Lilly Conseils. Astrazeneca steering committee. Janssen steering committee. MSD Other, steering committee. Ose Immunotherapeutics Other, steering committee. Pharmamar Other, steering committee. Roche-Genentech Other, steering committee. Sanofi Other, steering committee. Takeda Other, steering committee. A. Drilon, 14ner/Elevation Oncology Other, Honoraria. Amgen Other, Honoraria. Abbvie Other, Honoraria. AnHeart Therapeutics Other, Honoraria. ArcherDX Other, Honoraria. AstraZeneca Other, Honoraria. Beigene Other, Honoraria. BergenBio Other, Honoraria. Blueprint Medicines Other, Honoraria. Bristol Myers Squibb Other, Honoraria. Boehringer Ingelheim Other, Honoraria. Chugai Pharmaceutical Other, Honoraria. EcoR1 Other, Honoraria. EMD Serono Other, Honoraria. Entos Other, Honoraria. Exelixis Other, Honoraria. Helsinn Other, Honoraria. Hengrui Therapeutics Other, Honoraria. Ignyta/Genentech/Roche Other, Honoraria. Janssen Other, Honoraria. M. Aldea, Amgen ). AstraZeneca ). Sandoz ). Owkin ). Lifen ). OncLive Honoraria.

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