Miyashita Hirotaka, Hong David S
Dartmouth Cancer Center, Lebanon, NH, United States.
The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
J Cancer Immunol (Wilmington). 2024;6(2):62-69. doi: 10.33696/cancerimmunol.6.086.
KRAS is a commonly mutated gene in advanced colorectal cancer (CRC). Recently, inhibitors of KRAS G12C were developed and have shown promising efficacy for KRAS G12C mutated non-small cell lung cancer. However, KRAS G12C inhibitor monotherapy has not demonstrated excellent efficacy for KRAS G12C mutated advanced CRC due to multiple resistance mechanisms, especially receptor tyrosine kinase (RTK) signaling activation. To overcome this resistance mechanism, various combinations of epithelial growth factor receptor (EGFR) and KRAS G12C inhibitors, including panitumumab plus sotorasib, have been investigated in clinical trials. The combination of EGFR and KRAS G12C inhibitors for KRAS G12C mutated CRC demonstrated overall response rates ranging from 26% to 62.5% in seven clinical trials of phase I to III, whose data are available so far. The median progression-free survival in these trials ranged from 3.9 to 8.1 months. These efficacy data suggest that KRAS G12C inhibitor combination with EGFR inhibitors is more effective for KRAS G12C mutated advanced CRC than KRAS G12C inhibitor monotherapy. They also showed reasonable safety of the combination regimen. Based on these results, phase III clinical trials are being conducted to investigate EGFR and KRAS G12C inhibitor combinations as a first or second-line treatment for KRAS G12C mutated advanced CRC. Furthermore, other KRAS G12C inhibitors, KRAS G12D inhibitors, and pan-RAS inhibitors are being developed, which could make more patients with advanced CRC eligible for KRAS inhibition.
KRAS是晚期结直肠癌（CRC）中常见的突变基因。最近，KRAS G12C抑制剂已被开发出来，并在KRAS G12C突变的非小细胞肺癌中显示出有前景的疗效。然而，由于多种耐药机制，尤其是受体酪氨酸激酶（RTK）信号激活，KRAS G12C抑制剂单药治疗在KRAS G12C突变的晚期CRC中并未显示出优异的疗效。为了克服这种耐药机制，上皮生长因子受体（EGFR）和KRAS G12C抑制剂的各种联合方案，包括帕尼单抗加索托拉西布，已在临床试验中进行了研究。EGFR和KRAS G12C抑制剂联合用于KRAS G12C突变的CRC，在目前可获得数据的7项I至III期临床试验中，总缓解率为26%至62.5%。这些试验中的无进展生存期中位数为3.9至8.1个月。这些疗效数据表明，KRAS G12C抑制剂与EGFR抑制剂联合用于KRAS G12C突变的晚期CRC比KRAS G12C抑制剂单药治疗更有效。它们还显示出联合方案具有合理的安全性。基于这些结果，正在进行III期临床试验，以研究EGFR和KRAS G12C抑制剂联合作为KRAS G12C突变晚期CRC的一线或二线治疗方案。此外，其他KRAS G12C抑制剂、KRAS G12D抑制剂和泛RAS抑制剂正在研发中，这可能使更多晚期CRC患者有资格接受KRAS抑制治疗。
