预约演示
更新于：2025-12-25
Divarasib
更新于：2025-12-25
概要
基本信息
药物类型 小分子化药 |
别名 Divarasib Adipate、GDC-6036、RG 6330 + [5] |
作用方式 抑制剂 |
作用机制 KRAS G12C抑制剂(KRAS G12C突变抑制剂) |
非在研适应症- |
原研机构 |
非在研机构- |
最高研发阶段临床3期 |
首次获批日期- |
最高研发阶段(中国)临床3期 |
特殊审评突破性疗法 (美国)、孤儿药 (日本) |
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结构/序列
分子式C29H32ClF4N7O2 |
InChIKeyZRBPIAWWRPFDPY-IRXDYDNUSA-N |
CAS号2417917-17-8 |
关联
21
项与 Divarasib 相关的临床试验NCT06793215
A Phase III, Randomized, Open-Label Study Evaluating the Efficacy and Safety of Divarasib and Pembrolizumab Versus Pembrolizumab and Pemetrexed and Carboplatin or Cisplatin in Patients With Previously Untreated, KRAS G12C-Mutated, Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer
NCT06835465
A Phase 1, Open-Label, Single-Dose, Two-Period, Fixed Sequence, Crossover Study to Determine the Effect of Rifampin on the Pharmacokinetics of Divarasib in Healthy Subjects
NCT06734208
A Phase 1, Open-Label, Single-Dose, Parallel-Cohort Study to Evaluate the Pharmacokinetics of Divarasib in Subjects With Impaired Hepatic Function
100 项与 Divarasib 相关的临床结果
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100 项与 Divarasib 相关的转化医学
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100 项与 Divarasib 相关的专利（医药）
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34
项与 Divarasib 相关的文献（医药）2025-10-20JOURNAL OF CLINICAL ONCOLOGY
Single-Agent Divarasib in Patients With
KRAS G12C
–Positive Non–Small Cell Lung Cancer: Long-Term Follow-Up of a Phase I Study
Article
作者: Karasic, Thomas ; Latten-Jansen, Loes ; Cardoso Guedes, Joao Daniel ; Laurie, Scott ; Cosman, Rasha ; Guedes, João Daniel ; Dallagnol, Tabatha Nakakogue ; Falcon, Alejandro ; Kim, Tae Won ; Yau, Kenneth K. ; Geva, Ravit ; Krebs, Matthew G. ; LoRusso, Patricia ; Lambrechts, Marc ; Patel, Manish ; Suchomel, Julia ; Sacher, Adrian G. ; Fernandez, Eugenio ; Ahn, Myung-Ju ; Aljumaily, Raid ; De Azevedo, Sergio ; Laurie, Scott A. ; Takács, István ; Kumar, Rajiv ; Jones, Robert ; Del Conte, Gianluca ; Ou, Sai-Hong ; Lin, Mark T. ; Amatu, Alessio ; Prenen, Hans ; Lorusso, Patricia ; Barrios, Carlos ; Safin, Rustem ; Siena, Salvatore ; Stec, Rafal ; Britschgi, Christian ; Mandlekar, Sandhya ; Arbor, Kathryn ; Van Dongen, Marloes ; Han, Sae-Won ; Desai, Jayesh ; De Miguel, Maria ; Chang, Julie ; Cheng, Michael ; Gelderblom, Hans ; Schutzman, Jennifer L. ; Luo, Jia ; Ngo, Huy ; Garralda Cabanas, Elena ; Delmonte, Angelo ; Mackiewicz, Jacek ; Krebs, Matthew ; Deva, Sanjeev ; Mayo, Mariah C. ; Rothschild, Sacha ; Royer-Joo, Stephanie ; Jacobina Silva, Carolina Gomes ; Cervantes Ruizperez, Andres ; Freres, Pierre ; Lee, Jong-Seok ; Medina, Laura ; Perets, Ruth ; Qi, Ting ; Munster, Pamela ; Miller, Wilson ; Shacham-Shmueli, Einat ; Bazhenova, Lyudmila ; Paz-Ares Rodriguez, Luis ; Fløtten, Øystein ; Cremolini, Chiara ; De Miguel Luken, Maria ; Santoro, Armando ; Alonso, Guzman ; Gort, Eelke ; De Cassia Costamilan, Rita ; Patel, Manish R. ; Sacher, Adrian ; Jun, Tomi ; Qi, Nina ; Burns, Timothy ; Moreno, Victor ; Saleh, Mansoor ; Láng, István ; Dharia, Neekesh V. ; Massarelli, Erminia ; Shi, Zhen ; Guren, Tormod ; Forster, Martin ; Choi, Yoonha ; Markman, Ben ; Paz-Ares, Luis ; Bowyer, Samantha ; Aimi, Junko ; Häfliger, Simon ; Hou, Xuefeng ; Miller, Wilson H. ; Dziadziuszko, Rafal ; Koli, Kalpesh ; Kim, Se Hyun
Divarasib (GDC-6036), an oral, highly potent and selective next-generation KRAS G12C inhibitor, has demonstrated a manageable safety profile and promising antitumor activity in patients with advanced
KRAS G12C
–positive non–small cell lung cancer (NSCLC). Here, we report long-term (≥1 year) follow-up of single-agent divarasib from the ongoing, open-label, and multicenter phase I study (ClinicalTrials.gov identifier:
NCT04449874
). The primary objective was safety, and the other objectives included preliminary antitumor activity. Overall, 65 patients with advanced
KRAS G12C
–positive NSCLC received single-agent oral divarasib 50-400 mg once daily and 31 patients (48%) were treated beyond 1 year. Divarasib continued to be well tolerated, and the safety profile beyond 1 year was consistent with the overall safety profile. In patients with measurable disease at baseline across all dose levels (n = 63), the confirmed objective response rate was 55.6% (95% CI, 42.5 to 68.1), and the median duration of response was 18.0 months (95% CI, 11.1 to 24.9). The median progression-free survival was 13.8 months (95% CI, 9.8 to 25.4) in the overall population (N = 65) and 15.3 months (95% CI, 12.3 to 26.1) among patients assigned to the 400-mg dose level (n = 44). With extended follow-up, divarasib demonstrated long-term safety and antitumor activity in patients with advanced
KRAS G12C
–positive NSCLC.
2025-07-01CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY
KRAS G12C inhibitors as monotherapy or in combination for metastatic colorectal cancer: A proportion and comparative meta-analysis of efficacy and toxicity from phase I-II-III trials
Review
作者: Öksüz, Nejat Emre ; Akkus, Erman ; Erul, Enes
BACKGROUND:
1-2 % of metastatic colorectal cancers (mCRC) harbor an activating KRAS-G12C mutation. This study aims to pool the results of available clinical trials of KRAS-G12C inhibitors, comparing monotherapy and combinations.
METHODS:
A systematic literature search was conducted in the MEDLINE database and ESMO/ASCO meeting abstracts. Phase I-II-III trials that investigated a KRAS-G12C inhibitor in patients with mCRC were included. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Pooled proportions and comparative subgroup analyses for monotherapy and combinations were presented with the random effects model.
RESULTS:
596 patients with previously treated mCRC in 14 study cohorts treated with one of sotorasib, adagrasib, divarasib, or olomorasib as monotherapy or in combination with cetuximab/panitumumab were included. Combination treatment revealed an ORR of 33.9 % (95 %CI: 20.7-48.4) (I2: 87.1), which is significantly higher than monotherapy [16.7 %, (95 %CI: 8.3-27.3) (I2: 73.2)] (p = 0.045). Median PFS was significantly longer with the combination [5.7 months (95 %CI: 4.4-7.1) (I2: 80.8) vs. 4.2 months (95 %CI: 3.6-4.7) (I2:0.0), p = 0.027]. Grade 3-4 treatment-related adverse events (TRAEs) were significantly more frequent with the combination [32.8 % (95 %CI: 26.4-39.6) (I2:42.5) vs.16.5 % (95 %CI: 4.9-33.1) (I2: 84.2), p = 0.047]. Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.
CONCLUSION:
This analysis suggests that KRAS-G12C inhibitors in combination with anti-EGFR agents may provide a doubled ORR and 1.5-month PFS benefit compared to monotherapy in previously treated mCRC patients, but with a doubled grade 3-4 TRAEs, including skin toxicities, paronychia, and hypomagnesemia. Treatment preferences should be individualized in these highly pretreated patients.
2025-06-01ANNALS OF ONCOLOGY
Genomic landscape of clinically acquired resistance alterations in patients treated with KRASG12C inhibitors
Article
作者: Kim, J E ; Fece de la Cruz, F ; Kushner, E W ; Corcoran, R B ; Gainor, J F ; Parikh, A R ; Morales-Giron, A A ; Ehnstrom, S ; Klempner, S J ; Nakamura, H ; Pappas, L ; Norden, B L ; Lin, J J ; Heist, R S ; Matsubara, H ; Riedl, J M ; Kopetz, S ; Parseghian, C ; Ellis, H ; Vakaris, A ; Caughey, B ; Patel, P S ; Hata, A N ; Barnes, H
BACKGROUND:
Mutant-selective inhibitors of KRASG12C (KRASG12Ci) have demonstrated efficacy in KRASG12C cancers. However, resistance invariably develops, resulting in short-lived responses. We aimed to define the genomic landscape of acquired resistance to KRASG12Ci and to elucidate whether novel classes of KRAS inhibitors can overcome these resistance mechanisms.
METHODS:
To assess clinical frequencies of acquired resistance alterations, we evaluated genomic sequencing data from postprogression cell-free DNA samples in patients treated with KRASG12Ci at two United States cancer centers, alongside data from six previously published studies. Cell viability assays using engineered cell models were employed to functionally validate candidate resistance drivers and to evaluate novel classes of KRAS inhibitors.
RESULTS:
A total of 143 patients were analyzed. Most patients had non-small-cell lung cancer (NSCLC, n = 68) or colorectal cancer (CRC, n = 58) and were treated with single-agent KRASG12Ci (n = 109) or combined with anti-EGFR antibodies (n = 30). RAS/MAPK alterations emerged in 46% of patients (n = 66), with 39% developing one or more new KRAS alterations (n = 56) and 23% (n = 33) showing multiple concurrent alterations. The genomic landscape of acquired alterations included KRAS-activating mutations (25% of patients), KRAS amplifications (22%), RAF/MAPK mutations/fusions (21%), KRAS switch-II pocket mutations (14%), and NRAS/HRAS mutations (8%). Notably, the proportion of patients with one or more acquired RAS/MAPK alteration was significantly higher in CRC compared with NSCLC (69% versus 26%, P < 0.001). Functional studies confirmed most alterations as resistance drivers. Sotorasib, adagrasib, and divarasib demonstrated distinct activity against KRAS switch-II pocket mutations, yet all were responsive to the RAS(ON) G12C-selective tri-complex inhibitor RM-018. The KRAS-selective inhibitor Pan KRAS-IN-1 effectively targeted KRAS-activating mutations, and the RAS(ON) multiselective tri-complex inhibitor RMC-7797 demonstrated high potency across all RAS alterations.
CONCLUSIONS:
Acquired RAS/MAPK alterations are recurrent drivers of resistance to KRASG12Ci detected in CRC and, less frequently, in NSCLC. Preclinical data suggest that novel (K)RAS inhibitors may overcome many of these resistance alterations.
100 项与 Divarasib 相关的药物交易
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研发状态
10 条进展最快的记录, 后查看更多信息
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| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 美国 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 中国 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 澳大利亚 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 比利时 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 巴西 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 加拿大 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 丹麦 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 法国 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 德国 | 2025-10-24 | |
| KRAS G12C突变非鳞状非小细胞肺癌 | 临床3期 | 中国香港 | 2025-10-24 |
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临床结果
临床结果
适应症
分期
评价
查看全部结果
临床1期 | 32 | 齋製繭窪構膚襯膚膚壓(積構艱糧獵遞構築範壓) = >10% 淵鹽獵廠鏇選艱構鏇製 (範鏇窪膚鬱襯觸繭繭廠 ) 更多 | 积极 | 2025-10-17 | |||
临床1期 | KRAS G12C突变非小细胞肺癌 KRAS G12C | 65 | 鏇獵製選繭鹽遞蓋獵淵(繭醖繭膚鑰窪鏇餘襯觸) = Divarasib continued to be well tolerated, and the safety profile beyond 1 year was consistent with the overall safety profile. 願鹽構築壓製鏇構膚鬱 (鏇夢簾窪鏇鑰鏇壓餘醖 ) | 积极 | 2025-07-09 | ||
临床1期 | 74 | 築顧憲憲壓廠糧製餘憲(襯齋遞窪選範廠窪窪製) = 11 (14.9%) patients 獵餘壓獵廠襯繭淵憲積 (蓋顧鏇網製範廠鏇鬱鹹 ) | 积极 | 2025-04-28 | |||
临床1期 | KRAS G12C突变阳性肿瘤 KRAS G12C | 104 | Divarasib 50-400 mg | 糧襯憲齋觸糧鹹夢觸廠(糧遞鏇淵鏇製鹽膚鬱選) = 襯齋餘膚憲簾窪醖膚選 憲憲鑰齋願艱餘鏇遞糧 (齋願壓製廠構鬱觸夢簾 ) 更多 | 积极 | 2024-09-09 | |
糧襯憲齋觸糧鹹夢觸廠(糧遞鏇淵鏇製鹽膚鬱選) = 鹽憲獵醖壓獵鹽憲範糧 憲憲鑰齋願艱餘鏇遞糧 (齋願壓製廠構鬱觸夢簾 ) 更多 | |||||||
临床3期 | 转移性非小细胞肺癌 KRAS G12C+ | - | 壓製廠蓋淵觸積衊廠簾(簾膚鬱顧選鏇選淵餘鏇) = 觸築獵餘積糧鬱鬱艱網 廠壓積襯築鬱壓廠蓋壓 (築鏇齋鑰鑰夢範餘鹹膚, 39.6 ~ 72.2) 更多 | - | 2024-09-09 | ||
临床1期 | 137 | 鬱鬱膚遞選鹽網鬱夢淵(顧齋餘鬱膚鑰餘鹽製願) = 齋簾壓鹽廠遞艱膚壓淵 構衊膚願簾夢網簾選蓋 (糧夢壓觸齋餘築襯膚鏇 ) 更多 | 积极 | 2023-08-24 | |||
(non-small-cell lung cancer) | 鹽糧構憲醖遞積衊廠糧(構憲窪遞製選顧鑰鏇糧) = 鏇壓衊遞遞鑰窪繭糧鹹 壓齋網憲願製鏇鏇鹹壓 (鏇壓範顧積鑰膚鏇築蓋 ) 更多 | ||||||
临床1期 | KRAS G12C突变的实体瘤 KRAS G12C Mutation | 137 | - | 积极 | 2023-08-24 | ||
(NSCLC) | 醖選壓餘簾壓鑰鏇衊夢(觸願鹹鹹獵構網鑰鹹觸) = 襯糧淵鬱觸艱積獵膚廠 積獵艱醖選繭顧艱觸範 (淵蓋構網壓選鑰鹹鹽蓋, 39.9 ~ 66.7) 更多 | ||||||
临床1期 | 137 | 選窪廠壓觸鹽遞範壓選(餘簾淵築廠鏇願壓襯艱) = 繭網遞衊繭製遞蓋鏇襯 構選鑰觸淵艱窪範構餘 (鑰簾遞鏇夢鹽窪窪襯願, 39.9 ~ 66.7) | - | 2023-08-24 | |||
临床1期 | 结直肠癌 KRAS G12C Mutation | 29 | 鏇夢齋獵製遞衊積網窪(顧淵獵獵鹽鹹襯窪艱製) = 願鑰鬱顧鑰範襯鹹糧構 顧遞簾構鹹衊膚範襯鹽 (範蓋獵鬱鏇廠製願窪壓 ) 更多 | 积极 | 2023-04-14 | ||
临床1期 | 14 | 衊範鏇網網壓鬱鏇顧壓(簾餘糧糧糧鏇鬱糧鏇鹹) = 範壓鑰構壓窪繭顧襯蓋 選鏇齋製鏇窪襯獵鏇壓 (鹹壓製鑰選淵夢網繭壓 ) 更多 | - | 2022-09-12 |
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