Non-small Cell Lung Cancer
Conditions
Keywords
T790M, epidermal growth factor receptor (EGFR)
Brief summary
The main purpose of this study is to evaluate the safety of ramucirumab or necitumumab in combination with osimertinib in participants with non-small cell lung cancer (NSCLC).
Interventions
Sponsors
AstraZeneca
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have a diagnosis of NSCLC with at least 1 measurable lesion assessable using standard techniques by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). * Have T790M-positive status using a test validated and performed locally after disease progression on EGFR tyrosine kinase inhibitor (TKI) treatment. * Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at the time of enrollment. * Have serum albumin that is ≥25 grams per liter at the time of enrollment. * Have adequate organ function, with all screening labs performed within 7 days of treatment initiation. * Have a life expectancy of ≥3 months. * Have resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤1 by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Exclusion criteria
* Previous treatment with an EGFR monoclonal antibody (except for past treatment for squamous cell carcinoma of head and neck or metastatic colorectal cancer). * Previous treatment with osimertinib or third generation EGFR TKIs. * Participants with symptomatic or growing brain metastases less than 4 weeks prior to enrollment. * History of drug-induced interstitial lung disease (ILD), ILD, or radiation pneumonitis requiring treatment with steroid prior to study enrollment, or any evidence of clinically active ILD. * Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment. Participants with a history of gross hemoptysis (defined as bright red blood of ≥1/2 teaspoon) within 2 months prior to enrollment are excluded. * Have experienced any arterial thrombotic event or arterial thromboembolic event, including myocardial infarction, unstable angina (history or evidence of current clinically relevant coronary artery disease of current ≥Class III as defined by Canadian Cardiovascular Society Angina Grading Scale or congestive heart failure of current ≥Class III as defined by the New York Heart Association), cerebrovascular accident, or transient ischemic attack, within 6 months prior to enrollment. * Have a history of deep vein thrombosis, pulmonary embolism, or any other significant venous thromboembolism (venous catheter thrombosis or superficial venous thrombosis not considered significant) during the 3 months prior to study enrollment. Participants with venous thromboembolism occurring 3 to 6 months prior to study enrollment are allowed, if being treated with low molecular weight heparin. * Have a history of gastrointestinal perforation and/or fistula within 6 months prior to enrollment. * Have a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea. * Have uncontrolled hypertension, as defined in CTCAE Version 4.0, prior to initiating study treatment, despite antihypertensive intervention. CTCAE Version 4.0 defines uncontrolled hypertension as Grade \>2 hypertension; clinically, the participant continues to experience elevated blood pressure (systolic \>160 millimeters of mercury \[mmHg\] and/or diastolic \>100 mmHg) despite medications. * Are receiving chronic therapy with any of the following medications within 7 days prior to enrollment: * nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin, ibuprofen, naproxen, or similar agents). * other anti-platelet agents (such as clopidogrel, ticlopidine, dipyridamole, or anagrelide). * Have radiologically documented evidence of major blood vessel invasion or encasement by cancer. * Have radiographic evidence of pulmonary intratumor cavitation, regardless of tumor histology. * Are receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, chemoembolization, or targeted therapy or radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks prior to enrollment. * Have abnormal cardiac findings. * Have undergone chest irradiation within 2 weeks prior to study drug administration, have not recovered from all radiation-related toxicities, or requires corticosteroids. A 2-week washout is permitted for focal palliative radiation to non-central nervous system disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs) | Arm A: Cycle 1 through Cycle 2 (14-day cycle); Arm B: Cycle 1 (21-day cycle) | A Dose Limiting Toxicity (DLT) was defined as one of the following Adverse Events (AE) that is likely related to the study drug or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: 1. Any nonhematologic Grade ≥3 toxicity, except for toxicities such as liver or renal function abnormality, skin rash that resolves with appropriate therapy, transient hypersensitivity and injection site reactions, myalgia, fatigue, constipation, electrolyte imbalance, nausea, vomiting, diarrhea 2. Hematologic toxicity was considered a DLT as the following: 1. Grade 4 toxicity lasting ≥7 days, or 2. Grade 3 or 4 thrombocytopenia if associated with bleeding or requires platelet transfusion, or 3. Febrile neutropenia 3. Death if considered related to study treatment 4. Any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose limiting |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab | Predose on Day 1 of Cycle 3, Predose on Day 1 of Cycle 5 | Cmin was the concentration of study drug in the blood immediately before the next dose was administered. |
| Objective Response Rate (ORR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With a Complete Response (CR) or Partial Response (PR) | Baseline to Objective Disease Progression (up to 25 months) | ORR was the best overall response of complete response (CR) or partial response (PR) as classified by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). CR was a disappearance of all target and non-target lesions and normalization of tumor marker level. PR was an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions. |
| Disease Control Rate (DCR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With CR, PR or Stable Disease (SD) | Baseline to Objective Disease Progression (up to 25 months) | DCR was the best overall response of CR, PR, or SD as defined by RECIST v1.1. CR was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or one or more new lesions. |
| Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | Predose on Day (D) 1 of Cycle (C) 2, Predose on Day 1 of Cycle 4, Predose on Day 1 of Cycle 5, Predose on Day 1 of Cycle 7, Predose on Day 1 of Cycle 13 | Cmin was the concentration of study drug in the blood immediately before the next dose was administered. |
| Progression Free Survival (PFS) for Ramucirumab in Combination With Osimertinib | Baseline to Measured Progressive Disease or Death from Any Cause (up to 26 months) | Progression-free survival (PFS) was the time from the date of first study treatment until the date of radiographic documentation of progression (as defined by RECIST v. 1.1) based on investigator assessment or the date of death due to any cause, whichever was earlier. If a participant did not have a complete baseline disease assessment, then the PFS time was censored at the enrollment date, regardless of whether or not objectively determined disease progression or death was observed for the participant; otherwise, if a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last complete objective progression-free disease assessment date. |
| Overall Survival (OS) for Ramucirumab in Combination With Osimertinib | Baseline to Death from Any Cause (up to 29 months) | OS was date of first study treatment until death due to any cause. If the participant was alive at the data inclusion cutoff date for the analysis (or was lost to follow-up), OS was censored on the last date the participant was known to be alive. |
| Duration of Response (DoR) for Ramucirumab in Combination With Osimertinib | Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (up to 25 months) | Duration of Response (DoR) was defined only for participants with a confirmed CR or PR. It was measured from the date of first evidence of a confirmed CR or PR to the date of objective progression or the date of death due to any cause, whichever is earlier. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date, DOR was censored at the date of the last complete objective progression-free disease assessment. |
Countries
France, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
The study consisted of the dose-finding portion (Phase 1a) and the dose-expansion portion (Phase 1b) * Phase 1a, Arm A = combination of ramucirumab and osimertinib; Arm B = combination of necitumumab and osimertinib * Phase 1b included one cohort, the expansion of Arm A with additional participants enrolled i.e., Cohort A, a combination of ramucirumab and osimertinib. Per Protocol, all outcomes for a combination of ramucirumab and osimertinib were analyzed under a single arm i.e., Arm A/Cohort A
Pre-assignment details
Participants who did not complete study were those who discontinued study treatment by the time of study completion.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Ramucirumab + Osimertinib Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason. | 3 |
| Arm B: Necitumumab + Osimertinib Participants received Necitumumab 800 mg given IV on Days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason. | 4 |
| Cohort A: Ramucirumab + Osimertinib Participants received Ramucirumab 10 mg/kg given IV on Day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle. All participants were treated until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason. | 22 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
| Overall Study | Death | 0 | 0 | 1 |
| Overall Study | Physician Decision | 2 | 0 | 1 |
| Overall Study | Progressive Disease | 1 | 3 | 14 |
Baseline characteristics
| Characteristic | Arm A: Ramucirumab + Osimertinib | Arm B: Necitumumab + Osimertinib | Cohort A: Ramucirumab + Osimertinib | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 2 Participants | 10 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 2 Participants | 12 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 22 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 13 Participants | 13 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 4 Participants | 9 Participants | 16 Participants |
| Region of Enrollment France | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment South Korea | 0 Participants | 0 Participants | 6 Participants | 6 Participants |
| Region of Enrollment Spain | 2 Participants | 2 Participants | 8 Participants | 12 Participants |
| Region of Enrollment Taiwan | 0 Participants | 0 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 1 Participants | 1 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 3 Participants | 17 Participants | 21 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 5 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 1 / 4 | 11 / 22 |
| other Total, other adverse events | 3 / 3 | 4 / 4 | 22 / 22 |
| serious Total, serious adverse events | 1 / 3 | 1 / 4 | 8 / 22 |
Outcome results
Primary
Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs)
A Dose Limiting Toxicity (DLT) was defined as one of the following Adverse Events (AE) that is likely related to the study drug or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0: 1. Any nonhematologic Grade ≥3 toxicity, except for toxicities such as liver or renal function abnormality, skin rash that resolves with appropriate therapy, transient hypersensitivity and injection site reactions, myalgia, fatigue, constipation, electrolyte imbalance, nausea, vomiting, diarrhea 2. Hematologic toxicity was considered a DLT as the following: 1. Grade 4 toxicity lasting ≥7 days, or 2. Grade 3 or 4 thrombocytopenia if associated with bleeding or requires platelet transfusion, or 3. Febrile neutropenia 3. Death if considered related to study treatment 4. Any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose limiting
Time frame: Arm A: Cycle 1 through Cycle 2 (14-day cycle); Arm B: Cycle 1 (21-day cycle)
Population: Arm A: participants who either completed the first 2 cycles of treatment or discontinued from study treatment or study participation Arm B: participants who either completed the first cycle of treatment or discontinued from study treatment or study participation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Ramucirumab + Osimertinib | Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Arm B: Necitumumab + Osimertinib | Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
Secondary
Disease Control Rate (DCR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With CR, PR or Stable Disease (SD)
DCR was the best overall response of CR, PR, or SD as defined by RECIST v1.1. CR was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or one or more new lesions.
Time frame: Baseline to Objective Disease Progression (up to 25 months)
Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug. Per Protocol, the outcomes for a combination of ramucirumab and osimertinib were analyzed under a single arm (Arm A/Cohort A), as Cohort A is an extension of Arm A.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Ramucirumab + Osimertinib | Disease Control Rate (DCR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With CR, PR or Stable Disease (SD) | 92 Percentage of Participants |
Secondary
Duration of Response (DoR) for Ramucirumab in Combination With Osimertinib
Duration of Response (DoR) was defined only for participants with a confirmed CR or PR. It was measured from the date of first evidence of a confirmed CR or PR to the date of objective progression or the date of death due to any cause, whichever is earlier. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date, DOR was censored at the date of the last complete objective progression-free disease assessment.
Time frame: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (up to 25 months)
Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug with a confirmed CR or PR (including censored). Number of participants censored = 7.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Ramucirumab + Osimertinib | Duration of Response (DoR) for Ramucirumab in Combination With Osimertinib | 13.37 Months |
Secondary
Objective Response Rate (ORR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With a Complete Response (CR) or Partial Response (PR)
ORR was the best overall response of complete response (CR) or partial response (PR) as classified by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). CR was a disappearance of all target and non-target lesions and normalization of tumor marker level. PR was an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions.
Time frame: Baseline to Objective Disease Progression (up to 25 months)
Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug. Per Protocol, the outcomes for a combination of ramucirumab and osimertinib were analyzed under a single arm (Arm A/Cohort A), as Cohort A is an extension of Arm A.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Ramucirumab + Osimertinib | Objective Response Rate (ORR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With a Complete Response (CR) or Partial Response (PR) | 76 Percentage of Participants |
Secondary
Overall Survival (OS) for Ramucirumab in Combination With Osimertinib
OS was date of first study treatment until death due to any cause. If the participant was alive at the data inclusion cutoff date for the analysis (or was lost to follow-up), OS was censored on the last date the participant was known to be alive.
Time frame: Baseline to Death from Any Cause (up to 29 months)
Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug (including censored). Number of participants censored = 13.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Ramucirumab + Osimertinib | Overall Survival (OS) for Ramucirumab in Combination With Osimertinib | NA Months |
Secondary
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab
Cmin was the concentration of study drug in the blood immediately before the next dose was administered.
Time frame: Predose on Day 1 of Cycle 3, Predose on Day 1 of Cycle 5
Population: All enrolled participants who received at least one dose of necitumumab and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Arm A: Ramucirumab + Osimertinib | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab | D1C3 | NA nanograms per milliliter (ng/mL) |
| Arm A: Ramucirumab + Osimertinib | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab | D1C5 | NA nanograms per milliliter (ng/mL) |
Secondary
Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab
Cmin was the concentration of study drug in the blood immediately before the next dose was administered.
Time frame: Predose on Day (D) 1 of Cycle (C) 2, Predose on Day 1 of Cycle 4, Predose on Day 1 of Cycle 5, Predose on Day 1 of Cycle 7, Predose on Day 1 of Cycle 13
Population: All enrolled participants who received at least one dose of ramucirumab and had evaluable PK data.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Ramucirumab + Osimertinib | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | D1C2 | 41.3 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 56.3 |
| Arm A: Ramucirumab + Osimertinib | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | D1C4 | 66.7 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 34.3 |
| Arm A: Ramucirumab + Osimertinib | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | D1C5 | 76.7 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 27 |
| Arm A: Ramucirumab + Osimertinib | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | D1C7 | 90.7 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 26.6 |
| Arm A: Ramucirumab + Osimertinib | Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab | D1C13 | 103 microgram per milliliter (µg/mL) | Geometric Coefficient of Variation 29.6 |
Secondary
Progression Free Survival (PFS) for Ramucirumab in Combination With Osimertinib
Progression-free survival (PFS) was the time from the date of first study treatment until the date of radiographic documentation of progression (as defined by RECIST v. 1.1) based on investigator assessment or the date of death due to any cause, whichever was earlier. If a participant did not have a complete baseline disease assessment, then the PFS time was censored at the enrollment date, regardless of whether or not objectively determined disease progression or death was observed for the participant; otherwise, if a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last complete objective progression-free disease assessment date.
Time frame: Baseline to Measured Progressive Disease or Death from Any Cause (up to 26 months)
Population: All enrolled participants from the ramucirumab + osimertinib arms who received at least one dose of study drug (including censored). Number of participants censored = 7.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Ramucirumab + Osimertinib | Progression Free Survival (PFS) for Ramucirumab in Combination With Osimertinib | 11.04 Months |