Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer

被引：14

作者：

Ambrosini, M. ^{[1
]}

Rousseau, B. ^{[2
]}

Manca, P. ^{[1
,2
]}

Artz, O. ^{[2
]}

Marabelle, A. ^{[3
]}

Andre, T. ^{[4
,5
]}

Maddalena, G. ^{[6
]}

Mazzoli, G. ^{[1
]}

Intini, R. ^{[6
]}

Cohen, R. ^{[4
,5
]}

Cercek, A. ^{[2
]}

Segal, N. H. ^{[2
]}

Saltz, L. ^{[2
]}

Varghese, A. M. ^{[2
]}

Yaeger, R. ^{[2
]}

Nusrat, M. ^{[2
]}

Goldberg, Z. ^{[2
]}

Ku, G. Y. ^{[2
]}

El Dika, I. ^{[2
]}

Margalit, O. ^{[7
,8
]}

Grinshpun, A. ^{[9
,10
]}

Kasi, P. Murtaza ^{[11
]}

Schilsky, R. ^{[12
]}

Lutfi, A. ^{[13
]}

Shacham-Shmueli, E. ^{[7
,8
]}

Afghan, M. Khan ^{[13
]}

Weiss, L. ^{[14
,15
,16
]}

Westphalen, C. B. ^{[14
,15
,16
]}

Conca, V. ^{[17
]}

Decker, B. ^{[18
]}

Randon, G. ^{[1
]}

Elez, E. ^{[19
]}

Fakih, M. ^{[20
]}

Schrock, A. B. ^{[17
]}

Cremolini, C. ^{[17
]}

Jayachandran, P. ^{[21
]}

Overman, M. J. ^{[22
]}

Lonardi, S. ^{[6
]}

Pietrantonio, F. ^{[1
]}

机构：

[1] Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol, Via Giacomo Venezian 1, I-20133 Milan, Italy

[2] Mem Sloan Kettering Canc Ctr, New York, NY USA

[3] Univ Paris Saclay, Dept Therapeut Innovat & Phase Clin Trials 1, Inserm, Villejuif, France

[4] Sorbonne Univ, Paris, France

[5] Hop St Antoine, Dept Med Oncol, Paris, France

[6] Ist Oncol Veneto, IRCCS, Padua, Italy

[7] Sheba Med Ctr, Oncol Dept, Tel Aviv, Israel

[8] Tel Aviv Univ, Med Fac, Tel Aviv, Israel

[9] Hebrew Univ Jerusalem, Sharett Inst Oncol, Hadassah Med Ctr, Jerusalem, Israel

[10] Hebrew Univ Jerusalem, Fac Med, Jerusalem, Israel

[11] Weill Cornell Med, New York, NY USA

[12] Univ Chicago, Chicago, IL USA

[13] Univ Iowa, Carver Coll Med, Dept Internal Med, Iowa City, IL USA

[14] Ludwig Maximilian Univ Munich, Univ Hosp, Dept Internal Med 3, Munich, Germany

[15] Ludwig Maximilian Univ Munich, Klinikum Grosshadern, Univ Hosp, Comprehens Canc Ctr, Munich, Germany

[16] German Canc Consortium DKTK, Partner Site Munich, Munich, Germany

[17] Univ Pisa, Dept Translat Res & New Technol Med & Surg, Pisa, Italy

[18] Fdn Med, Cambridge, MA USA

[19] Vall dHebron Inst Oncol, Barcelona, Spain

[20] City Hope Natl Med Ctr, Dept Med Oncol & Therapeut Res, Duarte, CA USA

[21] Univ Southern Calif, Norris Comprehens Canc Ctr, Keck Sch Med, Div Med Oncol, Los Angeles, CA USA

[22] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX USA

来源：

ANNALS OF ONCOLOGY | 2024年 / 35卷 / 07期

关键词：

metastatic colorectal cancer; POLE mutations; POLD1; mutations; immune checkpoint inhibitors; proof- reading de fi ciency; TUMOR MUTATIONAL BURDEN; DNA-POLYMERASE-EPSILON; MICROSATELLITE INSTABILITY; SOLID TUMORS; DOMAIN MUTATIONS; NIVOLUMAB; BLOCKADE; BENEFIT; COLON;

D O I：

10.1016/j.annonc.2024.03.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Background: POLE and POLD1 proofreading de fi ciency ( POLE/D1pd) de fi ne a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-speci fi c data about the activity and ef fi cacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-de fi cient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. Patients and methods: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading de fi ciency and treated with anti-programmed cell death-ligand 1 alone + / - anti-cytotoxic Tlymphocyte antigen -4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to de fi ne POLE and POLD1pd molecular pro fi les and mutational signatures. Results: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a signi fi cantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a signi fi cantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% con fi dence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with signi fi cantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular pro fi ling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. Conclusions: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

引用

页码：643 / 655

页数：13

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