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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.
The field is moving in three directions: more potent or better tolerated G12C inhibitors (divarasib, with a 53 percent response rate in phase 1 and the Krascendo 1 phase 3; olomorasib; glecirasib and garsorasib approved in China), first-line combinations with pembrolizumab (KRYSTAL-7, SUNRAY-01), and pan-RAS inhibitors such as daraxonrasib that bind the active state. Open questions are why lung tumours respond better than colorectal tumours, how to overcome STK11 and KEAP1 co-mutations, and whether a KRAS inhibitor can be combined safely with a checkpoint inhibitor from the start.
Averages across everyone diagnosed, often years ago. A median is the middle of a group: half the people counted lived longer than the figure shown, and some lived far longer. Your stage, subtype, age, fitness and the treatment you receive matter more than the average, and the numbers are improving quickly.
KRAS is mutated in about a quarter of lung adenocarcinomas in Europe and North America, and G12C, the smoking-associated variant, accounts for about 13 percent of adenocarcinomas, making it the single commonest targetable driver in Western patients. It is rarer in East Asia.
Central tumours arise in the large airways, peripheral ones in the alveoli; both drain to hilar then mediastinal nodes, and the pleural lining is a separate cancer site.
Same organ: Mediastinal germ cell tumour, Pleuropulmonary blastoma (types I, Ir, II and III), Type A and type AB thymoma, Type B1 and type B2 thymoma, Type B3 thymoma, Micronodular thymoma with lymphoid stroma, Adenocarcinoma of the lung, Squamous cell carcinoma of the lung, Large cell carcinoma of the lung, Sarcomatoid carcinoma of the lung, Adenosquamous carcinoma of the lung, Invasive mucinous adenocarcinoma of the lung, Adenocarcinoma in situ and minimally invasive adenocarcinoma of the lung, Basaloid squamous cell carcinoma of the lung, Lymphoepithelial carcinoma of the lung, Pulmonary blastoma (adult), Non-small-cell lung cancer, Lung cancer (all types), Small-cell lung cancer, Mesothelioma, Pleural mesothelioma, Thymoma and thymic carcinoma, Childhood lung and airway tumours (pleuropulmonary blastoma, tracheobronchial tumours), Inflammatory myofibroblastic tumour (IMT), EGFR-mutated non-small-cell lung cancer, ALK-positive non-small-cell lung cancer, ROS1-positive non-small-cell lung cancer, MET exon 14 and MET-amplified non-small-cell lung cancer, RET fusion-positive non-small-cell lung cancer, BRAF V600E-mutant non-small-cell lung cancer, HER2-mutant non-small-cell lung cancer, NTRK fusion-positive non-small-cell lung cancer, PD-L1-high non-small-cell lung cancer without a driver mutation, Resectable stage I to III non-small-cell lung cancer, Unresectable stage III non-small-cell lung cancer, Limited-stage small-cell lung cancer, Extensive-stage small-cell lung cancer, Lung neuroendocrine tumours (typical and atypical carcinoid), Large cell neuroendocrine carcinoma of the lung, Thymoma (WHO types A, AB, B1, B2 and B3), Thymic carcinoma
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Also on OnCo: Symptoms and red flags · Early detection roadmap.
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.
Sotorasib (CodeBreaK 200) or adagrasib (KRYSTAL-12), preferred to docetaxel; adagrasib for active brain metastases; docetaxel with or without ramucirumab afterwards.
Divarasib versus sotorasib or adagrasib (Krascendo 1); olomorasib or adagrasib with pembrolizumab first line (SUNRAY-01, KRYSTAL-7); pan-RAS inhibitors.
Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year.
The targets of this cancer's medicines and the ones linked to it directly.
Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes.
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Fainting, near-fainting, or an irregular or racing heartbeat; several kinase inhibitors prolong the QT interval and the labels require ECG and electrolyte monitoring.
Bleeding that does not stop by itself, bleeding from more than one site, or new bruising in several places or one large area.
Sudden severe abdominal pain, a hard or very tender abdomen, or abdominal pain with vomiting and fever. Boxed warning for gastrointestinal perforation on bevacizumab.
Persistent headache with extreme tiredness, nausea, dizziness on standing or low blood pressure. Vomiting, severe weakness or collapse is adrenal crisis.
CYP3A4: Adagrasib (strong inhibitor) raises Docetaxel exposure (sensitive substrate).. Avoid strong inhibitors; if unavoidable, reduce the dose by 50% (ketoconazole raised exposure 2.2-fold).
CYP2C8: Adagrasib (strong inhibitor) raises Paclitaxel exposure.. Avoid strong CYP2C8 inhibitors or reduce the dose per label.
See all on the product pages:AdagrasibCarboplatinDaraxonrasibDivarasibDocetaxelOlomorasibPaclitaxel / nab-paclitaxelPembrolizumabPemetrexedRamucirumabSotorasib·Printable cards in the navigator
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