SOTORASIB for Non-small cell lung cancer (KRAS G12C-mutated)|Advanced non-small cell lung cancer (stage III/IV)

Inclusion criteria

• {"criterion_text":"- Provision of signed and dated, written informed consent.\n- Mean resting corrected QT interval (QTc) < 470 msec (females) or < 450 msec (males) using the screening clinic ECG machine derived QTc value.\n- Adequate bone marrow reserve or organ function (as demonstrated by any of the following laboratory values:  Absolute neutrophil count > 1.5 x 109/L  Platelet count > 100 x 109/L  Haemoglobin > 9.0 g/dL  Alanine aminotransferase (ALT) < 2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or < 5 times ULN in the presence of liver metastases  Aspartate aminotransferase (AST) < 2.5 times ULN if no demonstrable liver metastases or < 5 times ULN in the presence of liver metastases  Total bilirubin < 1.5 times ULN if no liver metastases or < 3 times ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) or liver metastases  Serum creatinine < 1.5 times ULN concurrent with creatinine clearance > 45 mL /min [measured or calculated by Cockcroft and Gault equation]-confirmation of creatinine clearance is only required when creatinine is >1.5 times ULN\n- Age > 18 years.\n- Histologically or cytologically documented NSCLC stage III/IV not amenable for curative treatment. Patients that have received systemic adjuvant therapy for non-metastatic disease in the past will need a new biopsy before inclusion if no biopsy acquired after adjuvant therapy is available.\n- Documented KRASG12C mutation, based on tissue analysis on either archived tissue or new biopsy before inclusion, and verified locally by a validated method.\n- Subjects will have received and progressed or experienced disease recurrence on or after receiving at least 1 prior systemic therapy for NSCLC stage III/IV not amenable for curative treatment. Prior treatment must include checkpoint inhibitor for advanced or metastatic disease, either given alone or in combination with chemotherapy unless the subject has a medical contraindication to one of the required therapies. a. Adjuvant therapy will count as a line of therapy if the subject progressed on or within 6 months of adjuvant therapy administration. b. Disease progression on or within 6 months of end of prior curatively intended multimodal therapy will count as a line of therapy.\n- ECOG status 0-2 and a minimum life expectancy of 12 weeks. At least 60 patients should be in ECOG 2. When 40 patients in ECOG 0-1 are included, the inclusion criteria will change to only ECOG 2.\n- At least one lesion, not previously irradiated and not chosen for biopsy during the study screening period, that can be accurately measured at baseline according to RECIST 1.1. Brain metastases are not regarded measurable.\n- Females should be using adequate contraceptive measures, should not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:  Post-menopausal defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments  Women under 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) levels in the post-menopausal range for the institution  Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.\n- Male subjects must be willing to use barrier contraception."}

Exclusion criteria

• {"criterion_text":"- Previously identified driver mutation (according to local standard of care or guidelines) other than KRASG12C for which an approved therapy is available (including EGFR, ALK, etc).\n- Radiotherapy treatment within 2 weeks of inclusion. Subjects must have recovered from all radiotherapy related toxicity to CTCAE version 5.0 grade 1 or less with the exception of alopecia (any grade of alopecia allowed).\n- Anti-tumour therapy (chemotherapy, antibody therapy, molecular targeted therapy, retinoid therapy, hormonal therapy [except for subjects with history of completely resected breast cancer with no active disease on long term adjuvant endocrine therapy], or investigational agent) within 4 weeks (chemotherapy within 2 weeks) of study day 1. Targeted small molecule inhibitors, within 14 days of study day 1, or within 5 half-lives, whichever is longer. Please note that bisphosphonates or anti RANKL antibody therapy is allowed if needed for management of hypercalcemia or for prevention of skeletal events.\n- Previous treatment with sotorasib or other KRASG12C inhibitor\n- Use of warfarin. Other anticoagulation is allowed.\n- Patients with significant comorbidities other than those mentioned below:  Comorbidities of special interest (up to grade 2 according to ACE-27 scoring system (see appendix A and (20)), or toxicity CTCAE 2) are eligible (ACE-27 grade 3 or CTCAE grade 3 may be eligible after discussion with Sponsor). Patients may have more than one comorbidity as long as all are within the severity grades as mentioned. Comorbidities of special interest are the following: i. Autoimmune diseases (rheumatoid, colitis, diabetes, skin, multiple sclerosis etc), including immunotherapy-induced morbidity (colitis, pneumonitis, endocrinopathies, non-viral hepatitis, nephritis etc). Immunotherapy-induced colitis or pneumonitis must be resolved to maximum CTCAE 2, and a maximum use of prednisolone 10 mg or equivalent is allowed. ii. Smoking-induced diseases (cardiovascular (coronary artery disease, apoplexia, thromboembolic events), COPD/emphysema). Note: Myocardial infarction within 6 months prior to enrolment, unstable arrhythmias or unstable angina are not eligible.  The following comorbidities are ineligibility criteria: i. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required. ii. Previous malignancy (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, oesophageal, colon, endometrial, cervical, melanoma or breast) unless a complete remission was achieved at least 2 years prior to study entry. iii. Significant gastrointestinal disorder that results in requirement for intravenous alimentation, or inability to take oral medication.\n- Use of known cytochrome P450 (CYP) 3A4 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. 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.\n- History of hypersensitivity of active or inactive excipients of sotorasib or drugs with a similar chemical structure or class to sotorasib.\n- Treatment with an investigational drug within five half-lives of the compound or 3 months, whichever is greater.\n- Any unresolved toxicities from prior therapy greater than CTCAE grade 2, unless discussed with Sponsor.\n- Women who are pregnant or breast-feeding, or have a positive (urine or serum) pregnancy test prior to study entry\n- Involvement in the planning and/or conduct of the study (investigator staff and/or staff at the study site).\n- Judgment by the investigator that the subject should not participate in the study if the subject is unlikely to comply with study procedures, restrictions and requirements.\n- Subjects with symptomatic CNS metastases or leptomeningeal disease who are neurologically unstable or have required increasing doses of steroids to manage CNS symptoms within the 2 weeks prior to study day 1.\n- Major surgery within 4 weeks of inclusion"}

Primary endpoints

• {"endpoint_text":"- Objective Response Rate (ORR) of sotorasib in the all subjects treated population","definition_or_measurement_approach":"Not specified in endpoint text; assessed in the all subjects treated population. Note: measurable lesion requirement at baseline is per RECIST 1.1 (see inclusion criteria)."}

Secondary endpoints

• {"endpoint_text":"- Objective Response Rate (ORR) of sotorasib in the predefined patient groups (including ECOG PS2, specific comorbidities, including immune-related adverse events after (chemo-) immunotherapy)","definition_or_measurement_approach":"Not specified in endpoint text; subgroup analyses in predefined patient groups."}
• {"endpoint_text":"- Progression Free Survival (PFS)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Duration of Response (DoR)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Disease Control Rate (DCR)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Intracranial Disease Free Survival (iDFS)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Intracranial Time To Recurrence (iTTR)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Tumour shrinkage","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Overall Survival (OS)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Time on treatment post progression","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Change from baseline over time to week 12 in disease related symptoms, physical functioning and global health status as measured by QLQ-C30 and QLQ-LC13","definition_or_measurement_approach":"Measured by patient-reported outcome questionnaires: EORTC QLQ-C30 and EORTC QLQ-LC13 up to week 12."}
• {"endpoint_text":"- To estimate the subject incidence of treatment-emergent adverse events, treatment-related adverse events, changes in vital signs, and clinical laboratory tests","definition_or_measurement_approach":"Safety monitoring by recording TEAEs, TRAEs, vital signs, and laboratory tests per protocol (details not provided in endpoint text)."}
• {"endpoint_text":"- Molecular characterization (see below) of blood and tissue before commencement on sotorasib, at response and at progression on sotorasib","definition_or_measurement_approach":"Molecular analyses of blood and tissue at baseline, response and progression; specific assays described in secondary endpoints."}
• {"endpoint_text":"- NGS (deep targeted sequencing of tumour tissue), STK11/LKB1, KEAP1, p53 etc","definition_or_measurement_approach":"Next-generation sequencing of tumour tissue for specified genes."}
• {"endpoint_text":"- Molecular analyses (incl NGS, e.g. Avenio) of blood samples (ctDNA)","definition_or_measurement_approach":"ctDNA analysis by NGS platforms (e.g., Avenio) of blood samples."}
• {"endpoint_text":"- Array-based microRNA, methylation, mRNA expression","definition_or_measurement_approach":"Array-based analyses of microRNA, methylation and mRNA expression (details not specified)."}
• {"endpoint_text":"- Protein analyses based on IHC, including immune-markers as PD-L1, IL-10, STING, TGFbeta etc","definition_or_measurement_approach":"Immunohistochemistry analyses for protein markers including PD-L1, IL-10, STING, TGFbeta."}
• {"endpoint_text":"- Exploratory analyses to be determined","definition_or_measurement_approach":"Exploratory analyses unspecified in protocol excerpt."}
• {"endpoint_text":"- Intracranial Objective Response Rate (iORR)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Intracranial Disease Control Rate (iDCR)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Intracranial Duration of response (iDoR)","definition_or_measurement_approach":"Not specified in endpoint text."}
• {"endpoint_text":"- Intracranial Progression Free Survival (iPFS)","definition_or_measurement_approach":"Not specified in endpoint text."}

Sweden

Latest Decision Or Authorization Date

13-05-2025

Number Of Sites

2

Number Of Participants

15

Denmark

Latest Decision Or Authorization Date

12-05-2025

Number Of Sites

1

Number Of Participants

7

Norway

Latest Decision Or Authorization Date

14-05-2025

Number Of Sites

8

Number Of Participants

74

Primary sponsor

Full Name

Vestre Viken HF

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Norway

Third parties

• {"country":"","full_name":"Amgen AB","duties_or_roles":"","organisation_type":""}
• {"country":"Norway","full_name":"Vestre Viken HF","duties_or_roles":"5","organisation_type":"Hospital/Clinic/Other health care facility"}