Sotorasib in Advanced KRASG12C-mutated Non-small Cell Lung Cancer Patients With Comorbidities

Inclusion Criteria:

• Provision of signed and dated, written informed consent.
• Age > 18 years.
• Histologically or cytologically documented NSCLC stage III/IV not amenable forcurative treatment. Patients that have received systemic adjuvant therapy fornon-metastatic disease in the past will need a new biopsy before inclusion if nobiopsy acquired after adjuvant therapy is available.
• Documented KRASG12C mutation, based on tissue analysis on either archived tissue ornew biopsy before inclusion, and verified locally by a validated method.
• Subjects will have received and progressed or experienced disease recurrence on orafter receiving at least 1 prior systemic therapy for NSCLC stage III/IV not amenablefor curative treatment. Prior treatment must include checkpoint inhibitor for advancedor metastatic disease, either given alone or in combination with chemotherapy unlessthe subject has a medical contraindication to one of the required therapies.

1. Adjuvant therapy will count as a line of therapy if the subject progressed on orwithin 6 months of adjuvant therapy administration.
2. Disease progression on or within 6 months of end of prior curatively intendedmultimodal therapy will count as a line of therapy.

• ECOG status 0-2 and a minimum life expectancy of 12 weeks. At least 60 patients shouldbe in ECOG 2. When 40 patients in ECOG 0-1 are included, the inclusion criteria willchange to only ECOG 2.
• At least one lesion, not previously irradiated and not chosen for biopsy during thestudy screening period, that can be accurately measured at baseline according toRECIST 1.1. Brain metastases are not regarded measurable.
• Females should be using adequate contraceptive measures, should not be breast feedingand must have a negative pregnancy test prior to start of dosing if of child-bearingpotential or must have evidence of non-child-bearing potential by fulfilling one ofthe 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 beenamenorrhoeic for 12 months or more following cessation of exogenous hormonaltreatments 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, bilateraloophorectomy or bilateral salpingectomy but not tubal ligation.
• Male subjects must be willing to use barrier contraception.
• Mean resting corrected QT interval (QTc) < 470 msec (females) or < 450 msec (males)using the screening clinic ECG machine derived QTc value.
• Adequate bone marrow reserve or organ function (as demonstrated by any of thefollowing 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 nodemonstrable liver metastases or < 5 times ULN in the presence of livermetastases
• Aspartate aminotransferase (AST) < 2.5 times ULN if no demonstrable livermetastases 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 thepresence of documented Gilbert's Syndrome (unconjugated hyperbilirubinaemia) orliver metastases
• Serum creatinine < 1.5 times ULN concurrent with creatinine clearance < 45 mL /min [measured or calculated by Cockcroft and Gault equation]-confirmation ofcreatinine clearance is only required when creatinine is >1.5 times ULN

Exclusion Criteria:

• Previously identified driver mutation (according to local standard of care orguidelines) other than KRASG12C for which an approved therapy is available (includingEGFR, ALK, etc).
• Symptomatic brain metastases or leptomeningeal disease. Subjects that have receivedwhole brain radiation therapy ending at least 4 weeks (or stereotactic radiosurgeryending at least 2 weeks) prior to study day 1 are eligible if they meet all thefollowing criteria: a) residual neurological symptoms grade ≤ 2; b) on stable doses ofdexamethasone or equivalent for at least 2 weeks, if applicable; and c) follow-up MRIperformed within 30 days prior to enrolment shows no progression or new lesionsappearing.
• Major surgery within 4 weeks of inclusion
• Radiotherapy treatment within 2 weeks of inclusion. Subjects must have recovered fromall radiotherapy related toxicity to CTCAE version 5.0 grade 1 or less with theexception of alopecia (any grade of alopecia allowed).
• Anti-tumour therapy (chemotherapy, antibody therapy, molecular targeted therapy,retinoid therapy, hormonal therapy [except for subjects with history of completelyresected breast cancer with no active disease on long term adjuvant endocrinetherapy], or investigational agent) within 4 weeks (chemotherapy within 2 weeks) ofstudy day 1. Targeted small molecule inhibitors, within 14 days of study day 1, orwithin 5 half-lives, whichever is longer. Please note that bisphosphonates or antiRANKL antibody therapy is allowed if needed for management of hypercalcemia or forprevention of skeletal events.
• Previous treatment with sotorasib or other KRASG12C inhibitor
• Use of warfarin. Other anticoagulation is allowed.
• Patients with significant comorbidities other than those mentioned below:
• Comorbidities of special interest (up to grade 2 according to ACE-27 scoringsystem (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 mayhave more than one comorbidity as long as all are within the severity grades asmentioned. Comorbidities of special interest are the following: i. Autoimmune diseases (rheumatoid, colitis, diabetes, skin, multiple sclerosisetc), including immunotherapy-induced morbidity (colitis, pneumonitis,endocrinopathies, non-viral hepatitis, nephritis etc). Immunotherapy-inducedcolitis or pneumonitis must be resolved to maximum CTCAE 2, and a maximum use ofprednisolone 10 mg or equivalent is allowed. ii. Smoking-induced diseases (cardiovascular (coronary artery disease, apoplexia,thromboembolic events), COPD/emphysema etc). Note: Myocardial infarction within 6 monthsprior to enrolment, unstable arrhythmias or unstable angina are not eligible.

▪ The following comorbidities are ineligibility criteria: i. Any evidence of severe oruncontrolled systemic diseases, including uncontrolled hypertension and active bleedingdiatheses, which in the investigator's opinion makes it undesirable for the patient toparticipate in the trial or which would jeopardise compliance with the protocol, or activeinfection 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 situcancers: 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 intravenousalimentation, or inability to take oral medication.

• Use of known cytochrome P450 (CYP) 3A4 sensitive substrates (with a narrow therapeuticwindow), 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 theprincipal investigator. Use of strong inducers of CYP3A4 (including herbal supplementssuch as St. John's wort) within 14 days or 5 half-lives (whichever is longer) prior tostudy day 1 that was not reviewed and approved by the principal investigator.
• History of hypersensitivity of active or inactive excipients of sotorasib or drugswith a similar chemical structure or class to sotorasib.
• Treatment with an investigational drug within five half-lives of the compound or 3months, whichever is greater.
• Previous enrolment in the present study or previous treatment with sotorasib.
• Any unresolved toxicities from prior therapy greater than CTCAE grade 2, unlessdiscussed with Sponsor.
• Women who are pregnant or breast-feeding, or have a positive (urine or serum)pregnancy test prior to study entry
• Involvement in the planning and/or conduct of the study (investigator staff and/orstaff at the study site).
• Judgment by the investigator that the subject should not participate in the study ifthe subject is unlikely to comply with study procedures, restrictions andrequirements.