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

- Provision of signed and dated, written informed consent.

- Age > 18 years.

- 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.

- Documented KRASG12C mutation, based on tissue analysis on either archived tissue or new biopsy before inclusion, and verified locally by a validated method.

- 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.

- 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.

- 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.

- 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:

- 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 the following laboratory values:

- 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).

- Symptomatic brain metastases or leptomeningeal disease. Subjects that have received whole brain radiation therapy ending at least 4 weeks (or stereotactic radiosurgery ending at least 2 weeks) prior to study day 1 are eligible if they meet all the following criteria: a) residual neurological symptoms grade ≤ 2; b) on stable doses of dexamethasone or equivalent for at least 2 weeks, if applicable; and c) follow-up MRI performed within 30 days prior to enrolment shows no progression or new lesions appearing.

- Major surgery within 4 weeks of inclusion

- 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).

- 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.

- Previous treatment with sotorasib or other KRASG12C inhibitor

- Use of warfarin. Other anticoagulation is allowed.

- Patients with significant comorbidities other than those mentioned below:

- 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.

- History of hypersensitivity of active or inactive excipients of sotorasib or drugs with a similar chemical structure or class to sotorasib.

- Treatment with an investigational drug within five half-lives of the compound or 3 months, 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, unless discussed 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/or staff at the study site).

- 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.