Verkerk K, Zeverijn L J, van de Haar J, Roepman P, Geurts B S, Spiekman A C, van der Noort V, van Berge Henegouwen J M, Hoes L R, van der Wijngaart H, Jansen A M L, de Leng W W J, Gelderblom A J, Verheul H M W, Voest E E
Division of Molecular Oncology & Immunology, Netherlands Cancer Institute, Amsterdam, The Netherlands; Oncode Institute, Utrecht, The Netherlands.
Hartwig Medical Foundation, Amsterdam, The Netherlands.
ESMO Open. 2025 Jan;10(1):104112. doi: 10.1016/j.esmoop.2024.104112. Epub 2025 Jan 7.
Many patients with cancer exhibit primary or rapid secondary resistance to targeted therapy (TT). We hypothesized that a higher number of altered oncogenic signaling pathways [pathway alteration load (PAL)] would reduce the benefit of TT which only intervenes in one pathway. This hypothesis was tested in the Drug Rediscovery Protocol (DRUP).
DRUP is a prospective, pan-cancer, non-randomized clinical trial (NCT02925234) that treats patients with therapy-refractory metastatic cancer and an actionable molecular profile using matched off-label targeted and immunotherapies. All patients treated with TT with available clinical outcomes and whole genome sequencing were included. PAL was determined based on driver gene alterations and correlated with clinical benefit rate (CBR), progression-free survival (PFS) and overall survival (OS). Outcomes were validated in the independent Hartwig Medical database of metastatic cancers.
In 154 patients treated with TT, the median PAL was 3. Patients with a PAL below median (n = 60) demonstrated a higher CBR (41.7% versus 25.5%, odds ratio 0.48, P = 0.051), longer PFS [median 4.7 versus 2.9 months, adjusted hazard ratio (aHR) 1.70, P = 0.020] and OS (median 13.7 versus 5.6 months, aHR 3.80, P < 0.001) compared with those with PAL ≥3. Two hundred and fifty-eight patients in the Hartwig database showed similar results for CBR (54.2% versus 36.7%, odds ratio 2.04, P = 0.009) and PFS (7.0 versus 4.2 months, aHR 1.55, P = 0.009).
In our population, PAL emerged as a pan-cancer determinant of outcome to TT. Our findings support refined patient selection for TT and highlight the rationale for combinatorial treatment strategies in patients with multiple affected pathways.
许多癌症患者对靶向治疗（TT）表现出原发性或快速继发性耐药。我们假设，更多改变的致癌信号通路[通路改变负荷（PAL）]会降低仅干预一条通路的TT的疗效。该假设在药物重新发现方案（DRUP）中进行了检验。
DRUP是一项前瞻性、泛癌、非随机临床试验（NCT02925234），使用匹配的非标签靶向和免疫疗法治疗难治性转移性癌症且具有可操作分子特征的患者。纳入所有接受TT治疗且有可用临床结果和全基因组测序的患者。PAL根据驱动基因改变确定，并与临床获益率（CBR）、无进展生存期（PFS）和总生存期（OS）相关。结果在转移性癌症的独立哈特维希医学数据库中得到验证。
在154例接受TT治疗的患者中，PAL中位数为3。PAL低于中位数的患者（n = 60）与PAL≥3的患者相比，表现出更高的CBR（41.7%对25.5%，优势比0.48，P = 0.051）、更长的PFS[中位数4.7个月对2.9个月，校正风险比（aHR）1.70，P = 0.020]和OS（中位数13.7个月对5.6个月，aHR 3.80，P < 0.001）。哈特维希数据库中的258例患者在CBR（54.2%对36.7%，优势比2.04，P = 0.009）和PFS（7.0个月对4.2个月，aHR 1.55，P = 0.009）方面显示出类似结果。
在我们的研究人群中，PAL成为TT疗效的泛癌决定因素。我们的研究结果支持对TT进行更精准的患者选择，并突出了对多条受影响通路患者采用联合治疗策略的基本原理。
