Non-Small Cell Lung Cancer
Conditions
Brief summary
This is a multicenter randomized phase II to determine if the administration of standard platinum-based chemotherapy before MK-3475 in with Chemotherapy naive stage IV Non-small Cell Lung Cancer (NSCLC) will improve the overall response rate (ORR) compared to MK-3475 administered before chemotherapy. Patients will be given Pembrolizumab as maintenance up to 2 years: Carboplatin and paclitaxel or pemetrexed every 3 weeks x 4 cycles followed by pembrolizumab every 3 weeks for up to 2 years. Pembrolizumab every 3 weeks x 4 cycles followed by carboplatin and paclitaxel or pemetrexed every 3 weeks x 4 cycles followed by pembrolizumab every 3 weeks for up to 2 years.
Detailed description
While a genotype-directed strategy has been established as effective in treatment selection for patients with advanced NSCLC, only a minority of patients at this time will have a readily identifiable actionable molecular target. Furthermore, genotype-directed therapy has not been validated for patients with squamous cell carcinoma of the lung. Therefore, the majority of patients with advanced NSCLC will continue to rely on standard platinum-based doublet chemotherapy. Given the plateau in effectiveness of this approach, novel treatment strategies are clearly warranted.
Interventions
DRUGMK-3475
Dose frequency of Q3W, Day 1 of each cycle
DRUGCarboplatin
Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)
DRUGPaclitaxel
Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)
DRUGPemetrexed
Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)
Sponsors
Merck Sharp & Dohme LLC
Alliance Foundation Trials, LLC.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Be ≥ 18 years of age on day of signing informed consent. 2. Have a life expectancy of at least 3 months. 3. Have a histologically or cytologically confirmed diagnosis of stage IV NSCLC. 4. Have a performance status of 0 or 1 on the ECOG. 5. Have a measurable disease based on RECIST 1.1. 6. Have provided tissue from an archival tissue sample or newly obtained core or excisional biopsy of tumor lesion. 7. In patients with non-squamous non-small cell lung cancer, investigators must be able to produce source documentation of the EGFR mutation status or ALK translocation status. 8. Demonstrate adequate organ function. 9. Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours. 10. Female parents of childbearing potential must be willing to use 2 methods of birth control or be surgically sterile. 11. Male patients must agree to use an adequate method of contraception. 12. Patients with sensitizing EGFR mutation or ALK rearrangement must have progressed on an appropriate tyrosine kinase inhibitor (TKI)
Exclusion criteria
1. Has received prior treatment with chemotherapy or biologic therapy for stage IV NSCLC. 2. Is currently participating in or has participated in a study of an investigational agent or using an investigational device. 3. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy. 4. Has had a prior mAb within 4 weeks prior to study Day 1 or who has not recovered from adverse events due to agents administered more than 4 weeks earlier. 5. Has had prior chemotherapy or radiation. 6. Has a known additional malignancy that is progressing or requires active treatment. 7. Has known active CNS metastases and/or carcinomatous meningitis. 8. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. 9. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 10. Has an active infection requiring systemic therapy. 11. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial. 12. Has known psychiatric or substance abuse disorders. 13. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial. 14. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody. 15. Has a known history of HIV. 16. Has known active Hepatitis B or Hepatitis C. 17. Has received a live vaccine within 30 days prior to the planned first dose of study therapy. 18. Has a known history of active TB. 19. Hypersensitivity to pembrolizumab or any of it's excipients.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) Per RECIST 1.1 | 18 Months | The primary objective of this randomized phase II trial to determine the overall response rate (ORR per RECIST 1.1) in Chemotherapy naive patients with stage IV NSCLC after the administration of standard platinum-based chemotherapy before MK-3475 (arm A) and administration of MK-3475 administered before standard platinum-based chemotherapy (arm B). Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Compare Progression-Free Survival (PFS) Per RECIST 1.1 | 24 Months | To compare the progression-free survival (PFS) per RECIST 1.1 in previously untreated patients with advanced NSCLC treated with first line carboplatin-based chemotherapy followed by MK-3475 to patients treated with MK-3475 prior to first-line carboplatin-based chemotherapy. |
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 24 Months | To characterize the adverse events related to MK-3475 by frequency, type and grade in patients with Chemotherapy naive advanced NSCLC based on the sequence of administration with first-line chemotherapy. A count of participants experiencing an adverse event is summarized here, the detailed summary is in the adverse events section of this report. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the ORR Per irRC | 24 Months | To evaluate the ORR per irRC of MK-3475 administered prior to or after treatment with first-line carboplatin-based chemotherapy in patients with previously untreated NSCLC. |
| Evaluate the Overall Survival (OS) | 24 Months | To evaluate the overall survival (OS) of patients with previously untreated advanced NSCLC who received MK-3475 administered prior to or after treatment with first line carboplatin-based chemotherapy. |
| Evaluate PFS Per irRC | 24 Months | To evaluate the PFS per irRC of previously untreated patients with advanced NSCLC who are treated with MK-3475 administered prior to or after first-line carboplatin-based chemotherapy. |
| Evaluate Response Duration of MK-3475 | 24 Months | To evaluate the response duration of MK-3475 based on schedule of administration with standard platinum-based chemotherapy in patients with previously untreated advanced NSCLC. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A Squamous Carcinoma For Squamous Carcinoma\>
\> Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles\>
\> Paclitaxel 200 mg/m2 IV day 1 every 21-days for up to 4 cycles\>
\> Carboplatin: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)\>
\> Paclitaxel: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)\>
\> Pemetrexed: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy) | 9 |
| Arm A Non-squamous Carcinoma For Non-squamous Carcinoma\> \> Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles\>
\> Pemetrexed 500 mg/m2 IV day 1 every 21-days for up to 4 cycles\>
\> Carboplatin: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)\>
\>
\>\> Paclitaxel: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)\>
\>\>
\>
\>\> Pemetrexed: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy) | 34 |
| Arm B Squamous Carcinoma For Squamous Carcinoma:\>
\> Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles\>
\> Paclitaxel 200 mg/m2 IV day 1 every 21-days for up to 4 cycles\>
\> Carboplatin: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)\>
\> Paclitaxel: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)\>
\> Pemetrexed: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy) | 11 |
| Arm B Non-squamous Carcinoma For Non-squamous Carcinoma\> \> Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles\>
\> Pemetrexed 500 mg/m2 IV day 1 every 21-days for up to 4 cycles\>
\> MK-3475: Dose frequency of Q3W, Day 1 of each cycle\>
\> Carboplatin: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)\>
\> Paclitaxel: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)\>
\> Pemetrexed: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy) | 37 |
| Total | 91 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Arm B Pembro Lead in Phase | Withdrawal by Subject | 0 | 0 | 1 | 0 |
| Maintenance MK-3475 | Adverse Event | 0 | 3 | 1 | 2 |
| Maintenance MK-3475 | Death | 0 | 1 | 1 | 0 |
| Maintenance MK-3475 | In active treatment | 2 | 0 | 0 | 1 |
| Maintenance MK-3475 | Lack of Efficacy | 0 | 9 | 0 | 8 |
| Maintenance MK-3475 | Physician discretion | 0 | 0 | 1 | 0 |
| Maintenance MK-3475 | Withdrew to hospice | 0 | 1 | 0 | 0 |
| MK-3475 Arm A, Platinum Doublet Arm B | Adverse Event | 0 | 2 | 0 | 1 |
| MK-3475 Arm A, Platinum Doublet Arm B | Alternative Therapy | 0 | 0 | 1 | 0 |
| MK-3475 Arm A, Platinum Doublet Arm B | Death | 0 | 0 | 1 | 1 |
| MK-3475 Arm A, Platinum Doublet Arm B | Lack of Efficacy | 2 | 6 | 0 | 0 |
| Platinum Doublet Arm A, MK-3475 Arm B | Adverse Event | 1 | 2 | 0 | 2 |
| Platinum Doublet Arm A, MK-3475 Arm B | Death | 1 | 2 | 0 | 2 |
| Platinum Doublet Arm A, MK-3475 Arm B | Deemed ineligible | 0 | 1 | 0 | 0 |
| Platinum Doublet Arm A, MK-3475 Arm B | Lack of Efficacy | 1 | 3 | 4 | 12 |
| Platinum Doublet Arm A, MK-3475 Arm B | Non compliance | 1 | 0 | 0 | 0 |
| Platinum Doublet Arm A, MK-3475 Arm B | Withdrawal by Subject | 0 | 1 | 0 | 0 |
| Platinum Doublet Arm A, MK-3475 Arm B | Withdrew to hospice | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm A Squamous Carcinoma | Arm A Non-squamous Carcinoma | Arm B Squamous Carcinoma | Arm B Non-squamous Carcinoma | Total |
|---|---|---|---|---|---|
| Age, Continuous | 65 years | 69 years | 67 years | 68 years | 68 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 34 Participants | 11 Participants | 37 Participants | 91 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 1 Participants | 1 Participants | 3 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 5 Participants | 33 Participants | 9 Participants | 32 Participants | 79 Participants |
| Sex: Female, Male Female | 2 Participants | 17 Participants | 4 Participants | 20 Participants | 43 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 7 Participants | 17 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 35 / 67 | 10 / 47 | 5 / 13 |
| other Total, other adverse events | 66 / 67 | 46 / 47 | 12 / 13 |
| serious Total, serious adverse events | 17 / 67 | 6 / 47 | 4 / 13 |
Outcome results
Primary
Overall Response Rate (ORR) Per RECIST 1.1
The primary objective of this randomized phase II trial to determine the overall response rate (ORR per RECIST 1.1) in Chemotherapy naive patients with stage IV NSCLC after the administration of standard platinum-based chemotherapy before MK-3475 (arm A) and administration of MK-3475 administered before standard platinum-based chemotherapy (arm B). Overall Response (OR) = CR + PR.
Time frame: 18 Months
Population: All patients that started treatment are included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Both Squamous and Non-Squamous) | Overall Response Rate (ORR) Per RECIST 1.1 | 0.395 proportion of participants |
| Arm B (Both Squamous and Non-Squamous) | Overall Response Rate (ORR) Per RECIST 1.1 | 0.404 proportion of participants |
p-value: 0.2176Fisher Exact
Secondary
Compare Progression-Free Survival (PFS) Per RECIST 1.1
To compare the progression-free survival (PFS) per RECIST 1.1 in previously untreated patients with advanced NSCLC treated with first line carboplatin-based chemotherapy followed by MK-3475 to patients treated with MK-3475 prior to first-line carboplatin-based chemotherapy.
Time frame: 24 Months
Population: All patients that were treated were included in analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A (Both Squamous and Non-Squamous) | Compare Progression-Free Survival (PFS) Per RECIST 1.1 | 5.8 Months |
| Arm B (Both Squamous and Non-Squamous) | Compare Progression-Free Survival (PFS) Per RECIST 1.1 | 4.0 Months |
p-value: 0.8495% CI: [0.67, 1.64]Log Rank
Secondary
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
To characterize the adverse events related to MK-3475 by frequency, type and grade in patients with Chemotherapy naive advanced NSCLC based on the sequence of administration with first-line chemotherapy. A count of participants experiencing an adverse event is summarized here, the detailed summary is in the adverse events section of this report.
Time frame: 24 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A (Both Squamous and Non-Squamous) | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 9 participants |
| Arm B (Both Squamous and Non-Squamous) | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 34 participants |
| Arm B Squamous Carcinoma | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 10 participants |
| Arm B Non-squamous Carcinoma | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 37 participants |
Other Pre-specified
Evaluate PFS Per irRC
To evaluate the PFS per irRC of previously untreated patients with advanced NSCLC who are treated with MK-3475 administered prior to or after first-line carboplatin-based chemotherapy.
Time frame: 24 Months
Other Pre-specified
Evaluate Response Duration of MK-3475
To evaluate the response duration of MK-3475 based on schedule of administration with standard platinum-based chemotherapy in patients with previously untreated advanced NSCLC.
Time frame: 24 Months
Other Pre-specified
Evaluate the ORR Per irRC
To evaluate the ORR per irRC of MK-3475 administered prior to or after treatment with first-line carboplatin-based chemotherapy in patients with previously untreated NSCLC.
Time frame: 24 Months
Other Pre-specified
Evaluate the Overall Survival (OS)
To evaluate the overall survival (OS) of patients with previously untreated advanced NSCLC who received MK-3475 administered prior to or after treatment with first line carboplatin-based chemotherapy.
Time frame: 24 Months