Non-Small Cell Lung Cancer
Conditions
Keywords
Locally advanced, metastatic, Non-Small Cell Lung Cancer, MEDI4736, Durvalumab, PD-L1
Brief summary
A study to assess the Effects of MEDI4736 (Durvalumab) in Patients With Locally Advanced or Metastatic Non Small Cell Lung Cancer in terms of efficacy, safety and tolerability
Detailed description
This study is designed to investigate the efficacy, safety, tolerability of a new drug, MEDI4736 (Durvalumab), in patients with Locally Advanced or Metastatic Non Small Cell Lung Cancer. MEDI4736 will be investigated in patients who have received at least two prior treatment regimens including one platinum-based chemotherapy
Interventions
DRUGMEDI4736
MEDI4736 (durvalumab) by intravenous infusion every two weeks. Treatment from Day 1 for a maximum of 12 months or study drug withdrawal if this occurs earlier. Patients who achieve CR, PR or SD through the end of the initial 12-month treatment period can restart treatment with MEDI4736 (durvalumab) when they eventually do progress. This retreatment period can continue for as long as the investigator considers to patient to be receiving clinical benefit.
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 130 Years
Healthy volunteers
No
Inclusion criteria
* Aged at least 18 years. * Documented evidence of NSCLC (stage IIIB/IV disease) * Disease progression or recurrence after both a platinum-based chemotherapy and at least 1 additional regimen for treatment of NSCLC * World Health Organisation (WHO) Performance Status of 0 or 1 * Estimated life expectancy of more than 12 weeks * Patient's tumour sample must be PD-L1 positive (≥25%of tumour cells with membrane staining (Cohort 1 and 2) or PD-L1 positive with ≥90% of tumour cells with membrane staining (Cohort 3))
Exclusion criteria
* Prior exposure to any anti-PD-1 or anti-PD-L1 antibody * Brain metastases or spinal cord compression or unless asymptomatic, treated and stable (not requiring steroids). * Active or prior autoimmune disease or history of immunodeficiency * Evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses or active infections including hepatitis B, C and HIV. * Evidence of uncontrolled illness such as symptomatic congestive heart failure, uncontrolled hypertension or unstable angina pectoris. * Any unresolved toxicity CTCAE \>Grade 2 from previous anti-cancer therapy. * Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE \>Grade 1 * Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | Responses recorded during initial 12 month treatment period (up to primary analysis DCO) | Patients commenced treatment with durvalumab on Day 1 and continued on a Q2W schedule for a maximum of 12 months. Tumor assessments using computed tomography / magnetic resonance imaging were performed every 8 weeks. Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) measurements as given by the Independent Central Review (ICR) were used to derive the primary variable of ORR . |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Response (TTR) | Responses recorded during initial 12 month treatment period (up to primary analysis DCO) | TTR (per RECIST 1.1 as assessed by the ICR) is defined as the time from the date of first dose until the date of first documented response (which is subsequently confirmed). TTR was only analyzed for Cohort 2. |
| Duration of Response (DoR) | Time from response to progression, death, or last assessment (up to approximately 2 years 3 months for the primary analysis DCO) | DoR (per RECIST 1.1 as assessed by the ICR) was defined as the time from the date of first documented response (which was subsequently confirmed) until the first date of documented progression or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). DoR was only analyzed for Cohort 2. Cohort 2: Median DoR was 12.3 months in the PD-L1 high (TC\>=25%) group at DCO (Q3 was NR). Of the 7 evaluable patients, the median DoR was not reached in the PD-L1 low/neg group (TC \<25%); therefore the DoR "number of participants analyzed" field has been entered as "0" and the DoR results field has been left blank. |
| Overall Survival (OS) | From date of first treatment until final DCO (up to approximately 3 years 8 months) | OS was defined as the time from the date of first dose until death due to any cause (ie, date of death or censoring - date of first dose + 1). Results are reported as median OS, calculated using the Kaplan-Meier methodology. |
Countries
Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Italy, Japan, Philippines, Poland, Singapore, South Korea, Spain, Taiwan, Thailand, United Kingdom, United States
Contacts
STUDY_DIRECTORPhillip Dennis, MD, PhD
AstraZeneca
Participant flow
Recruitment details
First patient in: 25 Feb 2014; Last patient in: 28 Dec 2015. Primary Analysis data cut-off (DCO): 03 Jun 2016; Final Analysis DCO: 7 Nov 2017. Patients were treated with durvalumab (10 milligrams \[mg\] / kilogram \[kg\] every 2 weeks \[Q2W\] intravenously \[iv\]). 101 sites in 16 countries treated patients in this study.
Pre-assignment details
Patients were enrolled in 3 cohorts. Cohort enrolment was dependent upon epidermal growth factor receptor (EGFR) / anaplastic lymphoma kinase (ALK) status and programmed cell death ligand-1 (PD-L1) expression level (percent of tumor cells \[TC\] with membrane staining).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (EGFR/ALK+) Consisted of patients who were EGFR/ALK positive and retrospectively or prospectively determined to be PD-L1 high (TC \>=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC \<25%) or PD-L1 status unknown. | 111 |
| Cohort 2 Consisted of patients who were EGFR/ALK wild type/unknown and retrospectively or prospectively determined to be PD-L1 high (TC \>=25%). In addition, the cohort included patients enrolled prior to Amendment 1 who were retrospectively determined to be PD-L1 low/neg (TC \<25%) or PD-L1 status unknown. | 265 |
| Cohort 3 (TC >= 90%) Consisted of patients who were EGFR/ALK wild type/unknown and prospectively determined to be PD-L1 high (TC \>=90%). | 68 |
| Total | 444 |
Baseline characteristics
| Characteristic | Cohort 1 (EGFR/ALK+) | Cohort 2 | Cohort 3 (TC >= 90%) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 45 Participants | 110 Participants | 24 Participants | 179 Participants |
| Age, Categorical Between 18 and 65 years | 66 Participants | 155 Participants | 44 Participants | 265 Participants |
| Age, Continuous | 61.0 years STANDARD_DEVIATION 11.45 | 62.0 years STANDARD_DEVIATION 9.35 | 61.0 years STANDARD_DEVIATION 10.58 | 62.0 years STANDARD_DEVIATION 10.13 |
| AJCC staging at initial diagnosis Missing | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| AJCC staging at initial diagnosis Stage IA | 2 Participants | 3 Participants | 0 Participants | 5 Participants |
| AJCC staging at initial diagnosis Stage IB | 0 Participants | 4 Participants | 0 Participants | 4 Participants |
| AJCC staging at initial diagnosis Stage II | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| AJCC staging at initial diagnosis Stage IIA | 1 Participants | 1 Participants | 1 Participants | 3 Participants |
| AJCC staging at initial diagnosis Stage IIB | 0 Participants | 5 Participants | 0 Participants | 5 Participants |
| AJCC staging at initial diagnosis Stage III | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| AJCC staging at initial diagnosis Stage IIIA | 9 Participants | 13 Participants | 5 Participants | 27 Participants |
| AJCC staging at initial diagnosis Stage IIIB | 8 Participants | 28 Participants | 9 Participants | 45 Participants |
| AJCC staging at initial diagnosis Stage IV | 90 Participants | 208 Participants | 53 Participants | 351 Participants |
| Best response to previous therapy complete response | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Best response to previous therapy non-evaluable | 2 Participants | 15 Participants | 2 Participants | 19 Participants |
| Best response to previous therapy not applicable | 6 Participants | 10 Participants | 4 Participants | 20 Participants |
| Best response to previous therapy partial response | 31 Participants | 39 Participants | 18 Participants | 88 Participants |
| Best response to previous therapy progression | 38 Participants | 114 Participants | 26 Participants | 178 Participants |
| Best response to previous therapy stable disease | 34 Participants | 86 Participants | 18 Participants | 138 Participants |
| Histology type Non-squamous | 110 Participants | 210 Participants | 48 Participants | 368 Participants |
| Histology type Squamous | 1 Participants | 55 Participants | 20 Participants | 76 Participants |
| Number of regimens of previous anti-cancer therapy | 3 Number of regimens STANDARD_DEVIATION 2 | 3 Number of regimens STANDARD_DEVIATION 1.38 | 2 Number of regimens STANDARD_DEVIATION 0.8 | 3 Number of regimens STANDARD_DEVIATION 1.54 |
| Overall disease classification Locally advanced | 9 Participants | 20 Participants | 7 Participants | 36 Participants |
| Overall disease classification Metastatic | 102 Participants | 245 Participants | 61 Participants | 408 Participants |
| PD-L1 expression level <90% | 33 Number of patients (per PD-L1 category) | 122 Number of patients (per PD-L1 category) | 0 Number of patients (per PD-L1 category) | 155 Number of patients (per PD-L1 category) |
| PD-L1 expression level Missing | 1 Number of patients (per PD-L1 category) | 0 Number of patients (per PD-L1 category) | 0 Number of patients (per PD-L1 category) | 1 Number of patients (per PD-L1 category) |
| PD-L1 expression level Negative (<25%) | 30 Number of patients (per PD-L1 category) | 95 Number of patients (per PD-L1 category) | 0 Number of patients (per PD-L1 category) | 125 Number of patients (per PD-L1 category) |
| PD-L1 expression level Positive (>=25%) | 77 Number of patients (per PD-L1 category) | 149 Number of patients (per PD-L1 category) | 68 Number of patients (per PD-L1 category) | 294 Number of patients (per PD-L1 category) |
| PD-L1 expression level Positive (>=90%) | 47 Number of patients (per PD-L1 category) | 72 Number of patients (per PD-L1 category) | 67 Number of patients (per PD-L1 category) | 186 Number of patients (per PD-L1 category) |
| PD-L1 expression level Total per cohort | 111 Number of patients (per PD-L1 category) | 265 Number of patients (per PD-L1 category) | 68 Number of patients (per PD-L1 category) | 444 Number of patients (per PD-L1 category) |
| PD-L1 expression level Unknown | 3 Number of patients (per PD-L1 category) | 21 Number of patients (per PD-L1 category) | 0 Number of patients (per PD-L1 category) | 24 Number of patients (per PD-L1 category) |
| Primary tumor location | 111 Participants | 265 Participants | 68 Participants | 444 Participants |
| Race/Ethnicity, Customized Asian | 66 Participants | 51 Participants | 24 Participants | 141 Participants |
| Race/Ethnicity, Customized Black or African American | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 6 Participants | 19 Participants | 2 Participants | 27 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 105 Participants | 246 Participants | 66 Participants | 417 Participants |
| Race/Ethnicity, Customized White | 44 Participants | 212 Participants | 42 Participants | 298 Participants |
| Sex: Female, Male Female | 70 Participants | 103 Participants | 29 Participants | 202 Participants |
| Sex: Female, Male Male | 41 Participants | 162 Participants | 39 Participants | 242 Participants |
| Smoking history Missing | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Smoking history Non-smoker | 65 Participants | 39 Participants | 9 Participants | 113 Participants |
| Smoking history Smoker | 46 Participants | 225 Participants | 59 Participants | 330 Participants |
| Time from informed consent to first dose <=14 days | 21 Participants | 68 Participants | 7 Participants | 96 Participants |
| Time from informed consent to first dose > 42 days | 1 Participants | 13 Participants | 3 Participants | 17 Participants |
| Time from informed consent to first dose Between 14 and 21 days | 24 Participants | 73 Participants | 13 Participants | 110 Participants |
| Time from informed consent to first dose between 21 and 42 days | 65 Participants | 111 Participants | 45 Participants | 221 Participants |
| Weight | 59 kg STANDARD_DEVIATION 14.15 | 68 kg STANDARD_DEVIATION 14.52 | 66 kg STANDARD_DEVIATION 15.79 | 66 kg STANDARD_DEVIATION 14.93 |
| Weight group <70 kg | 81 Participants | 146 Participants | 40 Participants | 267 Participants |
| Weight group >90 kg | 3 Participants | 22 Participants | 7 Participants | 32 Participants |
| Weight group Between 70 and 90 kg | 27 Participants | 97 Participants | 21 Participants | 145 Participants |
| WHO performance status (0) Normal activity | 45 Participants | 86 Participants | 19 Participants | 150 Participants |
| WHO performance status (1) Restricted activity | 65 Participants | 178 Participants | 49 Participants | 292 Participants |
| WHO performance status (2) In bed <=50% of the time | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| WHO performance status (3) In bed >50% of the time | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| WHO performance status (4) 100% bed ridden | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 70 / 111 | 217 / 265 | 41 / 68 |
| other Total, other adverse events | 96 / 111 | 233 / 265 | 60 / 68 |
| serious Total, serious adverse events | 18 / 111 | 77 / 265 | 24 / 68 |
Outcome results
Primary
Objective Response Rate (ORR)
Patients commenced treatment with durvalumab on Day 1 and continued on a Q2W schedule for a maximum of 12 months. Tumor assessments using computed tomography / magnetic resonance imaging were performed every 8 weeks. Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) measurements as given by the Independent Central Review (ICR) were used to derive the primary variable of ORR .
Time frame: Responses recorded during initial 12 month treatment period (up to primary analysis DCO)
Population: The Full analysis set \[FAS\] - evaluable for response per ICR set, included all treated patients who had a baseline tumor assessment and had measurable disease at baseline according to the ICR.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (EGFR/ALK+) PD-L1+ (>=25%) | Objective Response Rate (ORR) | 12.2 % of patients evaluable for response |
| Cohort 1 (EGFR/ALK+) PD-L1+ (<25%) | Objective Response Rate (ORR) | 3.6 % of patients evaluable for response |
| Cohort 2 PD-L1+ (>=25%) | Objective Response Rate (ORR) | 16.4 % of patients evaluable for response |
| Cohort 2 PD-L1+ (<25%) | Objective Response Rate (ORR) | 7.5 % of patients evaluable for response |
| Cohort 3 (TC>=90%) | Objective Response Rate (ORR) | 30.9 % of patients evaluable for response |
Secondary
Duration of Response (DoR)
DoR (per RECIST 1.1 as assessed by the ICR) was defined as the time from the date of first documented response (which was subsequently confirmed) until the first date of documented progression or death in the absence of disease progression (ie, date of PFS event or censoring - date of first response + 1). DoR was only analyzed for Cohort 2. Cohort 2: Median DoR was 12.3 months in the PD-L1 high (TC\>=25%) group at DCO (Q3 was NR). Of the 7 evaluable patients, the median DoR was not reached in the PD-L1 low/neg group (TC \<25%); therefore the DoR number of participants analyzed field has been entered as 0 and the DoR results field has been left blank.
Time frame: Time from response to progression, death, or last assessment (up to approximately 2 years 3 months for the primary analysis DCO)
Population: The FAS - evaluable for response per ICR set for Cohort 2, included all treated patients in Cohort 2 who had a baseline tumor assessment and had measurable disease at baseline according to the ICR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2 PD-L1+ (>=25%) | Duration of Response (DoR) | 12.3 Months |
Secondary
Overall Survival (OS)
OS was defined as the time from the date of first dose until death due to any cause (ie, date of death or censoring - date of first dose + 1). Results are reported as median OS, calculated using the Kaplan-Meier methodology.
Time frame: From date of first treatment until final DCO (up to approximately 3 years 8 months)
Population: The FAS included all treated patients who had a baseline tumor assessment and had measurable disease at baseline according to the Investigator site assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (EGFR/ALK+) PD-L1+ (>=25%) | Overall Survival (OS) | 13.3 Months |
| Cohort 1 (EGFR/ALK+) PD-L1+ (<25%) | Overall Survival (OS) | 9.9 Months |
| Cohort 2 PD-L1+ (>=25%) | Overall Survival (OS) | 10.9 Months |
| Cohort 2 PD-L1+ (<25%) | Overall Survival (OS) | 9.3 Months |
| Cohort 3 (TC>=90%) | Overall Survival (OS) | 13.2 Months |
Secondary
Time to Response (TTR)
TTR (per RECIST 1.1 as assessed by the ICR) is defined as the time from the date of first dose until the date of first documented response (which is subsequently confirmed). TTR was only analyzed for Cohort 2.
Time frame: Responses recorded during initial 12 month treatment period (up to primary analysis DCO)
Population: The FAS - evaluable for response per ICR set for Cohort 2, included all treated patients in Cohort 2 who had a baseline tumor assessment and had measurable disease at baseline according to the ICR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2 PD-L1+ (>=25%) | Time to Response (TTR) | 1.9 Months |
| Cohort 2 PD-L1+ (<25%) | Time to Response (TTR) | 2.1 Months |