A single-arm, multicentre trial to investigate sotorasib in KRASG12C-mutated non-small cell lung cancer stage III/IV not amenable for curative treatment including patients with comorbidities, and to provide translational knowledge regarding mechanism of relapse and differences in responses, including differences among patients with different co-occurring mutations.

A single-arm multi-institutional phase II study to investigate sotorasib in KRASG12C-mutated non-small cell lung cancer stage III/IV not amenable for curative treatment including patients with comorbidities, and to provide translational knowledge regarding mechanism of relapse and differences in responses, including differences among patients with different co-occurring mutations.

The aim is to investigate whether treatment with sotorasib will provide significant objective response rates in predefined KRASG12C-mutated non-small cell lung cancer patients that are not typically included in phase III-studies. Furthermore, the trial will explore whether patients in performance status ECOG 2 may benefit from sotorasib. In this study, a relevant number of sotorasib-naïve patients (n=100) will be treated with sotorasib and followed for efficacy and side effects. MRI-scans both at base-line and regularly during therapy will give data on intracranial efficacy. Eligible patients will be previously treated with at least 1 line standard (chemo)immunotherapy, or deemed in-eligible for standard (chemo)immunotherapy.

In part II of the study, comprehensive analyses of biological samples taken pretreatment, and post-progression will provide novel information about resistance mechanisms on sotorasib. Furthermore, analyses of biopsies taken at partial response (estimated to be performed in 25-30% of cases) may potentially also characterize non-eradicated residual cells after achieved response. The post-progression biopsies may indicate the optimal next-line therapy.

Inclusion Criteria:

• 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.

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

• 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:

  • 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.

• 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:

  • 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

Exclusion Criteria:

• 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:

  • 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 etc). 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.

• 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.