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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
KRAS G12C lung cancer carries a mutation that was thought impossible to drug for forty years. Sotorasib and adagrasib now shrink about four in ten tumours after chemotherapy and immunotherapy, though the benefit is measured in months, and newer inhibitors and first-line combinations with immunotherapy are in trials.
KRAS was the first human oncogene identified in a solid tumour, but its smooth surface and picomolar affinity for GTP defeated every attempt at a drug until 2013, when Kevan Shokat's laboratory showed that the mutant cysteine of G12C could be trapped by a covalent inhibitor in a pocket that exists only in the inactive, GDP-bound state. Unlike EGFR or ALK disease, KRAS-mutant lung cancer occurs in smokers, carries a high mutation burden, often expresses PD-L1 and responds to checkpoint inhibitors, so first-line treatment is chemoimmunotherapy or pembrolizumab alone as for driver-negative disease; co-mutations in STK11 and KEAP1, present in a quarter to a third, blunt that response.
Sotorasib produced a 37 percent response rate in previously treated patients in CodeBreaK 100 and received accelerated approval in May 2021, the first KRAS inhibitor; CodeBreaK 200 (2023) then showed it beat docetaxel on progression-free survival (5.6 versus 4.5 months, hazard ratio 0.66) but not overall survival, and the FDA required a new dose-comparison study. Adagrasib produced a 43 percent response rate in KRYSTAL-1 with activity in brain metastases and was approved in December 2022; KRYSTAL-12 (2024) showed progression-free survival of 5.5 versus 3.8 months against docetaxel (hazard ratio 0.58). Resistance emerges within months through secondary KRAS mutations, amplification, bypass through receptor tyrosine kinases and histological transformation, and both drugs have liver toxicity that is worse soon after immunotherapy.
| Setting | Approach | Guideline |
|---|---|---|
| Advanced, first line | As for driver-negative disease: pembrolizumab plus platinum doublet, or pembrolizumab alone if PD-L1 is 50 percent or more; KRAS inhibitors are not yet approved first line. | not mapped |
| Advanced, after chemoimmunotherapy | Sotorasib (CodeBreaK 200) or adagrasib (KRYSTAL-12), preferred to docetaxel; adagrasib for active brain metastases; docetaxel with or without ramucirumab afterwards. | not mapped |
| Advanced, clinical trials | Divarasib versus sotorasib or adagrasib (Krascendo 1); olomorasib or adagrasib with pembrolizumab first line (SUNRAY-01, KRYSTAL-7); pan-RAS inhibitors. | not mapped |