An Open-label Study of GSK1120212 Compared With Docetaxel in Stage IV KRAS-mutant Non-small Cell Lung Cancer

PFS is defined as the time from RAN until the earliest date of documented radiological PD or DT due to any cause. PD was assessed by the INV according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. PD is defined as at least a 20% increase in the sum of the diameters (SD) of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation. For participants (PAR) who did not have a documented date of PD or DT, PFS was censored at the date of the last adequate assessment. For PAR who received subsequent anti-cancer therapy prior to the date of documented PD or DT, PFS was censored at the date of the last adequate assessment prior to the initiation of therapy.

Clinical chemistry parameters were summarized according to National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events (CTCAE) grade, version 4.0. Grade (G) 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any G, G3, or G4 occurred. Clinical chemistry parameters included: albumin, alkaline phosphatase (ALKP), alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, calcium (hypercalcemia), calcium (hypocalcemia), creatine kinase, creatinine, glucose (hyperglycemia), glucose (hypoglycemia), potassium (hyperkalemia), potassium (hypokalemia), sodium (hypernatremia), and sodium (hyponatremia). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments.

Clinical chemistry parameters were summarized according to NCI CTCAE grade, version 4.0. Grade (G) 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any grade, Grade 3, or Grade 4 occurred. Clinical chemistry parameters included: albumin, alkaline phosphatase (ALKP), alanine amino transferase (ALT), aspartate amino transferase (AST), total bilirubin, calcium (hypercalcemia), calcium (hypocalcemia), creatine kinase, creatinine, glucose (hyperglycemia), glucose (hypoglycemia), potassium (hyperkalemia), potassium (hypokalemia), sodium (hypernatremia), and sodium (hyponatremia). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments.

Hematology parameters were summarized according to NCI CTCAE grade, version 4.0. Grade (G) 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any G (IAG), G3, or G4 occurred. Hematology parameters included: haemoglobin (increased [inc]), haemoglobin (anemia), lymphocyte count (ct) (inc), lymphocyte ct (decreased [dec]), total absolute neutrophil count (ANC), platelet ct, and white blood cell count (WBC). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments.

Hematology parameters were summarized according to NCI CTCAE grade, version 4.0. Grade (G) 1, Mild; Grade 2, Moderate; Grade 3 (G3), Severe; Grade 4 (G4), Life-threatening or disabling; Grade 5, Death. Data are presented for only those parameters for which an increase to any G (IAG), G3, or G4 occurred. Hematology parameters included: haemoglobin (increased [inc]), haemoglobin (anemia), lymphocyte count (ct) (inc), lymphocyte ct (decreased [dec]), total absolute neutrophil count (ANC), platelet ct, and white blood cell count (WBC). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments.

Data are presented for only those clinical chemistry parameters for which the following worst-case on-therapy changes from Baseline with respect to the normal range were observed: decrease to low, change to normal (CTN) or no change, or increase to high. Clinical chemistry parameters included: lactate dehydrogenase, total protein, and urea/blood urea nitrogen (BUN). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments. Normal ranges for each parameter may vary depending on the laboratory (central versus local) and the participant (age, gender, etc.).

Data are presented for only those clinical chemistry parameters for which the following worst-case on-therapy changes from Baseline with respect to the normal range were observed: decrease to low, change to normal (CTN) or no change, or increase to high. Clinical chemistry parameters included: lactate dehydrogenase, total protein, and urea/blood urea nitrogen (BUN). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments. Normal ranges for each parameter may vary depending on the laboratory (central versus local) and the participant (age, gender, etc.).

Data are presented for only those hematology parameters for which the following worst-case on-therapy changes from Baseline with respect to the normal range were observed: decrease to low, change to normal (CTN) or no change, or increase to high. Hematology parameters included: atypical lymphs, atypical lymphs (percentage [%]), basophils, eosinophils, metamyelocytes, monocytes, myelocytes, neutrophil bands (%). Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments. Normal ranges for each parameter may vary depending on the laboratory (central versus local) and the participant (age, gender, etc.).

Data are presented for only those hematology parameters for which the following worst-case on-therapy changes from Baseline with respect to the normal range were observed: decrease to low, change to normal (CTN) or no change, or increase to high. Hematology parameters included: atypical lymphs, atypical lymphs (percentage [%]), basophils, eosinophils, metamyelocytes, monocytes, and myelocytes. Worst-case on-therapy changes from Baseline were summarized. Worst-case on-therapy was defined using the on-therapy window and changes were indentified using both scheduled and unscheduled assessments. Normal ranges for each parameter may vary depending on the laboratory (central versus local) and the participant (age, gender, etc.).

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Medical or scientific judgment should have been exercised in deciding whether reporting was appropriate in other situations. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury. Medical or scientific judgment should have been exercised in deciding whether reporting was appropriate in other situations. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

Systolic and diastolic blood pressure were measured at the following scheduled time points: Baseline; Days 1, 8, and 15 of Cycle 1 (Study Week 1); and Day 1 of every cycle thereafter until treatment discontinuation. The worst-case on-therapy was determined using both scheduled and unscheduled assessments during the on-therapy period. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.

Systolic and diastolic blood pressure were measured at the following scheduled time points: Baseline; Days 1, 8, and 15 of Cycle 1 (Study Week 1); and Day 1 of every cycle therafter until treatment discontinuation. The worst-case on-therapy was determined using both scheduled and unscheduled assessments during the on-therapy period. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.

Heart rate was measured at the following scheduled time points: Baseline; Days 1, 8, and 15 of Cycle 1 (Study Week 1); and Day 1 of every cycle therafter until treatment discontinuation.The worst-case on-therapy was determined using both scheduled and unscheduled assessments during the on-therapy period. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.

Heart rate was measured at the following scheduled time points: Baseline; Days 1, 8, and 15 of Cycle 1 (Study Week 1); and Day 1 of every cycle therafter until treatment discontinuation.The worst-case on-therapy was determined using both scheduled and unscheduled assessments during the on-therapy period. Change from Baseline was calculated as the value at post-Baseline time point minus the value at Baseline.

Response was assessed by the investigator according to RECIST, version 1.1, using confirmed and unconfirmed responses. Responders were defined as participants achieving either a CR (disappearance of all target and non-target lesions; any pathological lymph nodes must be <10 millimeters [mm] in the short axis; without the appearance of new lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing response were treated as non-responders.

Response was assessed by the investigator according to RECIST, version 1.1, using confirmed and unconfirmed responses. Responders were defined as participants achieving either a CR (disappearance of all target and non-target lesions; any pathological lymph nodes must be <10 millimeters [mm] in the short axis; without the appearance of new lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Participants with unknown or missing response were treated as non-responders.

DOR was assessed by the investigator for participants with CR (disappearance of all target and non-target lesions; any pathological lymph nodes must be <10 mm in the short axis; without the appearance of new lesions) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). DOR is defined as the time from the first documented evidence of CR or PR until the earliest date of documented radiological progression or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters (SD) of target lesions with an absolute increase of at least 5 millimeters (mm) or the appearance of at least 1 new lesion, or the worsening of non-target lesions significant enough to require study treatment discontinuation.

OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For participants who did not die, OS was censored at the date of last contact.

Blood samples for PK analysis of GSK1120212 were collected at the following time points: Cycle 1 (Study Day 15), Cycle 2 (Study Day 22), Cycle 3 (Study Day 43), and Cycle 4 (Study Day 64). Post-dose PK samples collected on Day 15 of Cycle 1 occurred at least 1 hour apart. Participants were instructed to withhold the dose of GSK1120212 until after blood for PK samples had been drawn. Pre-dose samples were taken 15 minutes or less prior to taking the next dose (i.e., trough).