K-SAB Trial - Sotorasib Followed by SBRT to 1-3 Lesions in Advanced NSCLC With KRASG12C Mutation

Main inclusion criteria: 1. Histological or cytological confirmed advanced NSCLC 2. KRASG12C mutation 3. Previous at least one line of treatment with immune- or/and chemotherapy or contraindications for immune- and/or chemotherapy. 4. Adequate organ function to tolerate sotorasib (see section 6.1 and 6.2 for details) 5. 2-5 lesions technically amenable to SBRT with 15 Gy x 3, 10 Gy x 5, or 7-8 Gy x 5. 6. Adequate organ function to tolerate SBRT: o Fulfilment of dose constraints to adequate organs at risk 7. ECOG performance status (PS) 0-1 8. FEV1 ≥1 litre (only applicable for lung targets) 9. Age ≥ 18 years 10. Measurable lesions according to RECIST Main exclusion criteria: 1. Leptomeningeal carcinosis (on MRI or in cerebrospinal fluid) or metastases in the central nervous system 2. Previous RT for any cancer within the last 3 years possibly interfering with the planned RT within this study 3. Life expectancy of less than 6 months 4. Inability to understand given information or undergo study procedures according to protocol 5. Has evidence or a past medical history of interstitial lung disease or active, non-infectious pneumonitis or known pulmonary fibrosis 6. Woman who is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 7 days after the last dose of sotorasib 7. Women of childbearing potential (WOCBP) unwilling to use a highly effective method of contraception during treatment and for an additional 7 days after the last dose of sotorasib. WOCBP using hormonal contraceptives should also use a barrier method 8. WOCBP with a positive pregnancy test assessed at screening or day 1 by a serum pregnancy test and/or urine pregnancy test 9. Centrally located pulmonary target (i.e., within 1 cm of the main bronchi or intermedius bronchus) and targets located within 1 cm of the gut, for SBRT 10. Use of known cytochrome P450 (CYP) 3A4 or P-gp sensitive substrates (with a narrow therapeutic window), within 14 days or 5 half-lives of the drug or its major active metabolite, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator 11. Use of strong inducers of CYP3A4 (including herbal supplements such as St. John´s wort) within 14 days or 5 half-lives, whichever is longer, prior to study day 1 that was not reviewed and approved by the principal investigator 12. Use of proton pump inhibitors (PPIs) within 3 days or H2-receptor antagonists within 1 day prior to study intervention 13. Use of warfarin. Use of Direct-Acting Oral Anticoagulants (DOAC) within 14 days or 5 half-lives, whichever is longer, prior to study day 1. Other anticoagulation may be allowed with principal investigator approval.