Non-small Cell Lung Cancer
Conditions
Brief summary
This is a Phase II single center, open-label, single arm study in patients with advanced non-small cell lung cancer (stage IV) with brain metastases. This study will be treated with combination of Pembrolizumab 200mg plus platinum doublet based on histology subtypes.
Detailed description
This is a Phase II single center, open-label, single arm study in patients with advanced non-small cell lung cancer (stage IV) with brain metastases. Patients will be treated with combination of Pembrolizumab 200mg plus platinum doublet based on histology subtypes. After the 4 cycles of combination phase with cytotoxic chemotherapy, maintenance phase will be followed for maximum of 35 cycles. If the disease progression is observed in CNS only which can be controlled with local treatment, systemic treatment can be continued as beyond disease progression. Non-squamous cell carcinoma: 4 cycles of pemetrexed 500mg/m2 + carboplatin AUC 5.0 + pembrolizumab 200mg every 3 weeks Followed by pemetrexed 500mg/m2 + pembrolizumab 200mg every 3 weeks up to 35 cycles Squamous cell carcinoma: 4 cycles of paclitaxel 200mg/m2 + carboplatin AUC 6.0 + pembrolizumab 200mg every 3 weeks Followed by pembrolizumab 200mg every 3 weeks up to 35 cycles
Interventions
DRUGPemetrexed, Carboplatin, Pembrolizumab
* Pemetrexed 500mg/m2 * Carboplatin AUC 5.0 * Pembrolizumab 200mg
DRUGPaclitaxel, Carboplatin, Pembrolizumab
* Paclitaxel 200mg/m2 * Caboplatin AUC 6.0 * Pembrolizumab 200mg
Sponsors
Samsung Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Non-squamous cell carcinoma: 4 cycles of pemetrexed 500mg/m2 + carboplatin AUC 5.0 + pembrolizumab 200mg every 3 weeks Followed by pemetrexed 500mg/m2 + pembrolizumab 200mg every 3 weeks up to 35 cycles Squamous cell carcinoma: 4 cycles of paclitaxel 200mg/m2 + carboplatin AUC 6.0 + pembrolizumab 200mg every 3 weeks Followed by pembrolizumab 200mg every 3 weeks up to 35 cycles
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male/female participants who are at least 19 years of age on the day of signing informed consent with histologically confirmed diagnosis of stage IV non-small cell lung cancer with brain metastases will be enrolled in this study. 2. Must have at least one intracranial target lesion. Intracranial lesion must be equal or greater than the 10mm in longest diameter. 3. Have confirmation that EGFR or ALK-directed therapy is not indicated 4. Have measurable disease based on RECIST 1.1 as determined by the local site investigator/radiology assessment. Target lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. Otherwise, previously treated with radiation is not considered as measurable lesion. 5. Have not received prior systemic treatment for their advanced/metastatic NSCLC. Subjects who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the development of metastatic disease. 6. Have a life expectancy of at least 3 months 7. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Status. 8. Have adequate organ function 9. Male participants: A male participant must agree to use a contraception during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period. 10. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR * b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days after the last dose of study treatment. 11. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
Exclusion criteria
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to IP administration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137). 3. Has received prior systemic anti-cancer therapy including investigational agents prior to IP administration as a metastatic disease treatment, including tyrosine kinase inhibitor. 4. Had major surgery \< 3 weeks prior to first dose 5. No measurable CNS lesion other than CNS lesion treated with stereotactic radiotherapy or surgery 6. Had received whole brain radiotherapy or stereotactic radiotherapy to CNS disease. 7. Has received prior radiotherapy within 1 weeks of start of study intervention. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation to non-CNS disease. 8. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed. 9. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study intervention. 10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug. 11. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, thyroid cancer or early gastric cancer or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded. 12. Has known active carcinomatous meningitis. 13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. 15. Has a history of (non-infectious) pneumonitis that currently required steroids or has current pneumonitis. 16. Has an active infection requiring systemic therapy. 17. Has a known history of Human Immunodeficiency Virus (HIV) infection. 18. Has a active Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive with HBV DNA positive) or known active Hepatitis C virus (defined as HCV RNA is detected) infection. These patients can be participated with appropriate treatment and prophylactic treatment based on the investigator's decision. 19. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator. 20. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 21. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of trial treatment. 22. Has had an allogenic tissue/solid organ transplant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intracranial Objective Response Rate | Up to 24 months | Intracranial objective response is defined as the investigator's best non-confirmed response as CR (complete response) or PR (partial response) as determined using RECIST v1.1. Subjects who do not meet these criteria, including those without a post-baseline tumor assessment, are considered non-responders. Intracranial objective response rate (iORR) is defined as the proportion of subjects who achieved an objective response among all subjects treated with the IP who had measurable disease at baseline. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of t the diameters of target lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) | The time until the date of either disease progression or the all-cause mortality from the date of IP administration. Up to 30 months | PFS is defined as the period between the start date of the investigational drug and the date of the first documented disease progression or death, whichever occurs first. \- PFS (month) = (date of the first documented disease progression or death - date of the start of the investigational drug + 1) / 30.4375 Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum of diameters (nadir) on study (this includes the baseline sum if that is the smallest on study), or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Overall Survival (OS) | The time until defined by date of all-cause mortality from the date of IP Administration. Up to 30 months. | Overall survival defined by date of all-cause mortality from the date of IP Administration will be calculated. |
| Intracranial Duration of Response | Up to 30 months. | The duration for intracranial response will be calculated separately to evaluate the intracranial efficacy of IP drug |
| Objective Response Rate | Up to 30 months. | Objective response rate is defined as the investigator's best non-confirmed response as CR (complete response) or PR (partial response) as determined using RECIST v1.1. Subjects who do not meet these criteria, including those without a post-baseline tumor assessment, are considered non-responders. objective response rate (ORR) is defined as the proportion of subjects who achieved an objective response among all subjects treated with the IP who had measurable disease at baseline. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of t the diameters of target lesion. |
| Adverse Events | from the date of informed consent signature to 30 days after last drug administration | Adverse event will be evaluated using CTCAE v5.0 |
| Intracranial Progression-free Survival | Up to 30 months. | Progression free survival of intracranial disease defined by the date of disease progression of intracranial lesion from the date of IP administration will be calculated. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum of diameters (nadir) on study (this includes the baseline sum if that is the smallest on study), or a measurable increase in a non-target lesion, or the appearance of new lesions |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory Analyses Based on PD-L1 Expression | Up to 30 months. | The exploratory analyses based on the PD-L1 expression (by DAKO PD-L1 22C3 assay) from the baseline samples will be used for the exploratory analyses in subjects who are available for the PD-L1 test |
Countries
South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Non-squamous Cell Carcinoma * 4 cycles of pemetrexed 500mg/m2 + carboplatin AUC 5.0 + pembrolizumab 200mg every 3 weeks
* Followed by pemetrexed 500mg/m2 + pembrolizumab 200mg every 3 weeks up to 35 cycles
Pemetrexed, Carboplatin, Pembrolizumab: - Pemetrexed 500mg/m2
* Carboplatin AUC 5.0
* Pembrolizumab 200mg | 11 |
| Squamous Cell Carcinoma * 4 cycles of paclitaxel 200mg/m2 + carboplatin AUC 6.0 + pembrolizumab 200mg every 3 weeks
* Followed by pembrolizumab 200mg every 3 weeks up to 35 cycles
Paclitaxel, Carboplatin, Pembrolizumab: - Paclitaxel 200mg/m2
* Caboplatin AUC 6.0
* Pembrolizumab 200mg | 2 |
| Total | 13 |
Baseline characteristics
| Characteristic | Non-squamous Cell Carcinoma | Total | Squamous Cell Carcinoma |
|---|---|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 10.75 | 61.69 years STANDARD_DEVIATION 13.28 | 49 years STANDARD_DEVIATION 24.04 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 13 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment South Korea | 11 participants | 13 participants | 2 participants |
| Sex: Female, Male Female | 5 Participants | 6 Participants | 1 Participants |
| Sex: Female, Male Male | 6 Participants | 7 Participants | 1 Participants |
| Smoking history Current | 1 Participants | 1 Participants | 0 Participants |
| Smoking history Former | 4 Participants | 5 Participants | 1 Participants |
| Smoking history Never | 6 Participants | 7 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 2 |
| other Total, other adverse events | 11 / 11 | 2 / 2 |
| serious Total, serious adverse events | 2 / 11 | 0 / 2 |
Outcome results
Primary
Intracranial Objective Response Rate
Intracranial objective response is defined as the investigator's best non-confirmed response as CR (complete response) or PR (partial response) as determined using RECIST v1.1. Subjects who do not meet these criteria, including those without a post-baseline tumor assessment, are considered non-responders. Intracranial objective response rate (iORR) is defined as the proportion of subjects who achieved an objective response among all subjects treated with the IP who had measurable disease at baseline. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of t the diameters of target lesion.
Time frame: Up to 24 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Non-squamous Cell Carcinoma | Intracranial Objective Response Rate | Partial Response | 6 Participants |
| Non-squamous Cell Carcinoma | Intracranial Objective Response Rate | Stable Response | 5 Participants |
| Non-squamous Cell Carcinoma | Intracranial Objective Response Rate | Progressive Disease | 0 Participants |
| Non-squamous Cell Carcinoma | Intracranial Objective Response Rate | Not evaluabe | 0 Participants |
| Squamous Cell Carcinoma | Intracranial Objective Response Rate | Not evaluabe | 1 Participants |
| Squamous Cell Carcinoma | Intracranial Objective Response Rate | Partial Response | 0 Participants |
| Squamous Cell Carcinoma | Intracranial Objective Response Rate | Progressive Disease | 1 Participants |
| Squamous Cell Carcinoma | Intracranial Objective Response Rate | Stable Response | 0 Participants |
Secondary
Adverse Events
Adverse event will be evaluated using CTCAE v5.0
Time frame: from the date of informed consent signature to 30 days after last drug administration
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Non-squamous Cell Carcinoma | Adverse Events | TEAEs | 11 Number |
| Non-squamous Cell Carcinoma | Adverse Events | ADR | 5 Number |
| Non-squamous Cell Carcinoma | Adverse Events | SAE | 2 Number |
| Squamous Cell Carcinoma | Adverse Events | TEAEs | 2 Number |
| Squamous Cell Carcinoma | Adverse Events | ADR | 0 Number |
| Squamous Cell Carcinoma | Adverse Events | SAE | 0 Number |
Secondary
Intracranial Duration of Response
The duration for intracranial response will be calculated separately to evaluate the intracranial efficacy of IP drug
Time frame: Up to 30 months.
Population: For squamous cell carcinoma (SCC), there was no response in a total of 2 patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Non-squamous Cell Carcinoma | Intracranial Duration of Response | 9.3 Months |
Secondary
Intracranial Progression-free Survival
Progression free survival of intracranial disease defined by the date of disease progression of intracranial lesion from the date of IP administration will be calculated. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum of diameters (nadir) on study (this includes the baseline sum if that is the smallest on study), or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: Up to 30 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Non-squamous Cell Carcinoma | Intracranial Progression-free Survival | 9.82 Months |
| Squamous Cell Carcinoma | Intracranial Progression-free Survival | 7.7 Months |
Secondary
Objective Response Rate
Objective response rate is defined as the investigator's best non-confirmed response as CR (complete response) or PR (partial response) as determined using RECIST v1.1. Subjects who do not meet these criteria, including those without a post-baseline tumor assessment, are considered non-responders. objective response rate (ORR) is defined as the proportion of subjects who achieved an objective response among all subjects treated with the IP who had measurable disease at baseline. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of t the diameters of target lesion.
Time frame: Up to 30 months.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Non-squamous Cell Carcinoma | Objective Response Rate | Partial Response | 6 Participants |
| Non-squamous Cell Carcinoma | Objective Response Rate | Stable Disease | 4 Participants |
| Non-squamous Cell Carcinoma | Objective Response Rate | Progressive Disease | 1 Participants |
| Non-squamous Cell Carcinoma | Objective Response Rate | Not evaluable | 0 Participants |
| Squamous Cell Carcinoma | Objective Response Rate | Not evaluable | 1 Participants |
| Squamous Cell Carcinoma | Objective Response Rate | Partial Response | 0 Participants |
| Squamous Cell Carcinoma | Objective Response Rate | Progressive Disease | 1 Participants |
| Squamous Cell Carcinoma | Objective Response Rate | Stable Disease | 0 Participants |
Secondary
Overall Survival (OS)
Overall survival defined by date of all-cause mortality from the date of IP Administration will be calculated.
Time frame: The time until defined by date of all-cause mortality from the date of IP Administration. Up to 30 months.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Non-squamous Cell Carcinoma | Overall Survival (OS) | 10.45 Months |
| Squamous Cell Carcinoma | Overall Survival (OS) | 12.45 Months |
Secondary
Progression Free Survival (PFS)
PFS is defined as the period between the start date of the investigational drug and the date of the first documented disease progression or death, whichever occurs first. \- PFS (month) = (date of the first documented disease progression or death - date of the start of the investigational drug + 1) / 30.4375 Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum of diameters (nadir) on study (this includes the baseline sum if that is the smallest on study), or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: The time until the date of either disease progression or the all-cause mortality from the date of IP administration. Up to 30 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Non-squamous Cell Carcinoma | Progression Free Survival (PFS) | 7.23 Months |
| Squamous Cell Carcinoma | Progression Free Survival (PFS) | 7.7 Months |
Other Pre-specified
Exploratory Analyses Based on PD-L1 Expression
The exploratory analyses based on the PD-L1 expression (by DAKO PD-L1 22C3 assay) from the baseline samples will be used for the exploratory analyses in subjects who are available for the PD-L1 test
Time frame: Up to 30 months.
Population: Although this outcome was pre-specified, the study enrolled only 13 participants and valid PD-L1 expression data were available for very few participants. As such, it was not possible to conduct any meaningful exploratory analyses based on PD-L1 status. Given the limited sample size and incomplete biomarker data, this outcome was not analyzed, and no results are reported.~All samples were collected and handled in accordance with participants' ICF and the protocol approved by the IRB.