Chabot Clément, Italiano Antoine, Crombé Amandine, Soubeyran Isabelle, Laizet Yech'an, Khalifa Emmanuel, Cousin Sophie
Early Phase Trials Department, Institut Bergonié, Bordeaux, France.
Department of Radiology, Pellegrin University Hospital, Bordeaux, France.
Oncologist. 2024 May 3;29(5):452-455. doi: 10.1093/oncolo/oyae044.
We analyzed the antitumor activity of platinum-based chemotherapies and then immune checkpoint inhibitors (ICI) in all-comers patients with solid tumors having a somatic DNA damage repair gene alteration (DDR-GA) identified through a prospective precision medicine study (NCT02534649). Each DDR-GA was classified as pathogenic (Pa), probably pathogenic (PPa), and unknown pathogenicity (UPa) according to OncoKB and ClinVAR databases. Between January 2018 and May 2020, 662 patients were screened. One hundred ninety-nine tumors with DDR-GA were found in 121 (18.3%) patients. Ninety-six patients received platinum-based chemotherapy in the advanced setting. No difference in objective response rate (ORR) under platinum regimen was observed between the 3 DDR-GA groups. The only predictor of worse progression-free survival (PFS) in Cox regression was the existence of a Pa alteration compared to the UPa group: HR = 2.11 (95% CI = 1.2-3.7), P = .009. Forty-eight patients received ICI alone or in combination. We observed a significant trend in better ORR to ICI according to the DDR-GA status: 1/11 (9%) patients in UPa, 5/17 (29.4%) patients in PPa, and 9/20 (45%) patients in Pa (P = .003, Cochran-Armitage trend test), and an increased 6-month PFS probability of 11%, 44%, and 50% in the UPa, PPa, and Pa groups, respectively (P = .37, log-rank test). Overall, somatic pathogenic DDR-GAs were not associated with ORR or PFS to platinum-based chemotherapy in patients with unselected advanced solid tumors. However, DDR-GA seemed to impact ORR and PFS to ICI, paving the way for a therapeutic combination with ICI and molecules targeting the DDR mechanisms, which are currently evaluated in ongoing clinical trials.
我们通过一项前瞻性精准医学研究（NCT02534649），分析了铂类化疗以及免疫检查点抑制剂（ICI）在所有患有体细胞DNA损伤修复基因改变（DDR-GA）的实体瘤患者中的抗肿瘤活性。根据OncoKB和ClinVAR数据库，每个DDR-GA被分类为致病性（Pa）、可能致病性（PPa）和未知致病性（UPa）。2018年1月至2020年5月期间，共筛选了662例患者。在121例（18.3%）患者中发现了199个具有DDR-GA的肿瘤。96例患者在晚期接受了铂类化疗。在3个DDR-GA组之间，未观察到铂类治疗方案下客观缓解率（ORR）的差异。Cox回归分析中，无进展生存期（PFS）较差的唯一预测因素是与UPa组相比存在Pa改变：风险比（HR）=2.11（95%置信区间[CI]=1.2 - 3.7），P = 0.009。48例患者单独或联合接受了ICI治疗。根据DDR-GA状态，我们观察到ICI的ORR有显著改善趋势：UPa组1/11（9%）的患者、PPa组5/17（29.4%）的患者以及Pa组9/20（45%）的患者（P = 0.003， Cochr an-Armitage趋势检验），并且UPa、PPa和Pa组的6个月PFS概率分别增加了11%、44%和50%（P = 0.37，对数秩检验）。总体而言，在未经选择的晚期实体瘤患者中，体细胞致病性DDR-GA与铂类化疗的ORR或PFS无关。然而，DDR-GA似乎会影响ICI的ORR和PFS，为ICI与靶向DDR机制的分子联合治疗铺平了道路，目前正在进行的临床试验中对此进行评估。
