Non-small Cell Lung Cancer, NSCLC
Conditions
Brief summary
The goal of this study is to explore if, for locally advanced non-small cell lung cancer patients whose tumors have high levels of PD-L1 (a marker associated with benefits from immunotherapy), a combination of immunotherapy and a personalized 4-week radiotherapy course could be more effective than standard treatment, which is a combination of chemotherapy and radiotherapy.
Detailed description
This is a Phase II trial evaluating the efficacy and safety of sequential pembrolizumab (200 mg every three weeks) and accelerated, dose-painted radiotherapy for patients with locally advanced NSCLC with PD-L1 expression ≥ 50%. Patients with PD-L1 expression \< 50% will be treated with concurrent chemoradiotherapy as part of standard of care.
Interventions
DRUGPembroRT
Patients whose tumors are found to have high (≥ 50%) PD-L1 expression will automatically be placed in the PembroRT group. These patients will receive three intravenous treatments with pembrolizumab, followed by four weeks of daily radiotherapy, followed by up to 12 more treatments with pembrolizumab. Pembrolizumab is given as an intravenous infusion once every three weeks. This treatment course will last, in total, up to one year. Patients whose tumors are found to have low (\< 50%) PD-L1 will be treated with a standard-o-care regimen and not be a part of this clinical trial.
Sponsors
Montefiore Medical Center
Merck Sharp & Dohme LLC
University of Michigan
New York University
Henry Ford Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Single arm study with 2 cohort (PembrolizumabRT cohort) part of the trial and SOC cohort (not part of the trial)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
Participants are eligible to be included in the study only if all the following criteria apply: 1. Male/female participants who are at least 18 years of age on the day of signing informed consent with histologically confirmed diagnosis of non-small cell lung cancer will be enrolled in this study. 2. Previously untreated, pathologically proven NSCLC with measurable disease (at least 1 unidimensional, radiographically measurable lesion based on RECIST v1.1) and one of the following stages: (prior resection for early stage disease is allowed) 1. AJCC version 8 Stage II disease, medically or technically unresectable 2. AJCC version 8 Stage III disease 3. Whole body PET/CT within 42 days prior to study entry demonstrating hypermetabolic pulmonary lesion(s) and/or thoracic lymph node(s). If PET/CT was obtained more than 42 days prior to study entry and is not repeated, CT within 28 days prior to study entry demonstrating no evidence of metastatic disease is required. 4. MRI of the brain or head CT with contrast within 42 days prior to study entry. 5. PFTs within 42 days of study entry 6. ECOG performance status 0-1 7. Adequate end-organ function, based on routine clinical and laboratory workup: 1. ANC \>1,500 cells/µl, Platelets ≥ 100,000 cells/µl, Hemoglobin ≥ 9.0 g/dl 2. Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance ≥ 50 ml/min 3. Total bilirubin ≤ 1.5 x ULN (or direct bilirubin below the ULN), AST and ALT ≤ 2.5 x ULN 4. International normalized ratio (INR) (or prothrombin time (PT)) and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy, as long as values are within the intended therapeutic range 5. Thyroid stimulating hormone (TSH) within normal limits. If TSH is not within normal limits, the participant may be eligible if T3 and free T4 are within normal limits. 8. A female participant is eligible to participate if she is not pregnant (see
Exclusion criteria
), not breastfeeding, and at least one of the following conditions applies: 1. Not a woman of childbearing potential (WOCBP) as defined in the Appendix 2. A WOCBP who agrees to follow the contraceptive guidance in the Appendix during the treatment period and for at least 120 days after the last dose of study treatment with pembrolizumab (pembroRT cohort) or at least 180 days after the last dose of chemotherapy (chemoRT cohort). 9. A male participant must agree to use contraception during the treatment period and for at least 28 days after the last dose of study treatment and refrain from donating sperm during this period. 10. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | 12 months | To characterize progression-free survival (PFS) rates following treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 50%, the percentage of participants with PFS at 12 months will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Freedom From Distant Metastasis | Up to 18 months following completion of treatment, up to 30 months total | To characterize freedom from distant metastases following treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 50%, cumulative incidence was calculated treating other events as competing risks. Competing risks are those events which prevent the occurrence or modify the risk of the outcome of distant metastasis. For this study, cumulative incidence is defined as the percentage of patients free from distant metastases up to 18 months following completion of treatment / number of people at risk in the study population and is reported as a percentage. |
| Intrathoracic Disease Progression | Up to 18 months following completion of treatment, up to 30 months total | To characterize freedom from intrathoracic disease progression rates following treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 50%, the cumulative incidence rate will be determined using competing risk analysis. For this study, intrathoracic disease progression will be reported as a percentage of patients. |
| Overall Survival (OS) | 1 year and 2 years following completion of treatment, up to 3 years total | Overall survival (OS) of patients alive at 1 year and 2 years following treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 50% was analyzed. OS was defined as the percentage of treated participants who were still alive at 1 year or 2 years following completion of treatment, divided by the total number of treated participants, multiplied by 100. Overall survival was censored at the time of the last clinic visit or contact. |
| Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | 2 months | Radiographic Response will be scored using RECIST V1.1 criteria to quantify objective measures of change in tumor burden. Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden. RECIST will be used to quantify the percentage of patients demonstrating Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), as follows: CR - resolution of all target lesions to background levels PR - at least 30% decrease in sum of diameters of target lesions (noting baseline diameters) SD - neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD (noting smallest sum on study) PD - at least 20% increase in sum of diameters of target lesions (noting smallest sum on study); absolute increase of 5mm must be demonstrated; \>=1 new lesion is considered PD |
| Unplanned Hospitalization Rate | Up to 18 months following completion of treatment, up to 30 months total | The unplanned hospitalization rate will be determined as the percentage of participants hospitalized due to treatment-related toxicities. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORNitin Ohri, MD
Albert Einstein College of Medicine
Participant flow
Recruitment details
Patients were enrolled between August 2018 and November 2021.
Pre-assignment details
Of the 42 patients who were consented into the trial, 5 were excluded prior to randomization. 4 of these patients did not meet inclusion/exclusion criteria and 1 was excluded based on personal reasons. Of these 37 patients, based on assay results, 25 patients were determined to have a PD-L1 tumor expression level of ≥ 50% and 12 patients were observed to have a PD-L1 tumor expression level of \< 50%. The 25 patients with a PD-L1 tumor expression level ≥ 50% were enrolled into the study.
Participants by arm
| Arm | Count |
|---|---|
| PembroRT Cohort Subjects with PD-L1 expression ≥ 50% Combination of pembrolizumab and dose-painted radiotherapy for locally advanced NSCLC patients with high (≥ 50%) PD-L1 expression.
PembroRT: Patients whose tumors are found to have high (≥ 50%) PD-L1 expression will automatically be placed in the PembroRT group. These patients will receive three intravenous treatments with pembrolizumab, followed by four weeks of daily radiotherapy, followed by up to 12 more treatments with pembrolizumab. Pembrolizumab is given as an intravenous infusion once every three weeks. This treatment course will last, in total, up to one year. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | PembroRT Cohort |
|---|---|
| Age, Continuous | 70 years |
| Region of Enrollment United States | 25 participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 6 / 25 |
| other Total, other adverse events | 10 / 25 |
| serious Total, serious adverse events | 0 / 25 |
Outcome results
Primary
Progression-Free Survival (PFS)
To characterize progression-free survival (PFS) rates following treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 50%, the percentage of participants with PFS at 12 months will be reported.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PembroRT Cohort | Progression-Free Survival (PFS) | 19 Participants |
Secondary
Freedom From Distant Metastasis
To characterize freedom from distant metastases following treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 50%, cumulative incidence was calculated treating other events as competing risks. Competing risks are those events which prevent the occurrence or modify the risk of the outcome of distant metastasis. For this study, cumulative incidence is defined as the percentage of patients free from distant metastases up to 18 months following completion of treatment / number of people at risk in the study population and is reported as a percentage.
Time frame: Up to 18 months following completion of treatment, up to 30 months total
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PembroRT Cohort | Freedom From Distant Metastasis | 17 Participants |
Secondary
Intrathoracic Disease Progression
To characterize freedom from intrathoracic disease progression rates following treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 50%, the cumulative incidence rate will be determined using competing risk analysis. For this study, intrathoracic disease progression will be reported as a percentage of patients.
Time frame: Up to 18 months following completion of treatment, up to 30 months total
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PembroRT Cohort | Intrathoracic Disease Progression | 22 Participants |
Secondary
Overall Survival (OS)
Overall survival (OS) of patients alive at 1 year and 2 years following treatment with sequential pembrolizumab and radiotherapy for locally advanced NSCLC with PD-L1 expression ≥ 50% was analyzed. OS was defined as the percentage of treated participants who were still alive at 1 year or 2 years following completion of treatment, divided by the total number of treated participants, multiplied by 100. Overall survival was censored at the time of the last clinic visit or contact.
Time frame: 1 year and 2 years following completion of treatment, up to 3 years total
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PembroRT Cohort | Overall Survival (OS) | 2-year Overall Survival | 19 Participants |
| PembroRT Cohort | Overall Survival (OS) | 1-year Overall Survival | 23 Participants |
Secondary
Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST)
Radiographic Response will be scored using RECIST V1.1 criteria to quantify objective measures of change in tumor burden. Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per organ, the Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden. RECIST will be used to quantify the percentage of patients demonstrating Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive Disease (PD), as follows: CR - resolution of all target lesions to background levels PR - at least 30% decrease in sum of diameters of target lesions (noting baseline diameters) SD - neither sufficient shrinkage to qualify for PR or sufficient increase to qualify for PD (noting smallest sum on study) PD - at least 20% increase in sum of diameters of target lesions (noting smallest sum on study); absolute increase of 5mm must be demonstrated; \>=1 new lesion is considered PD
Time frame: 2 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PembroRT Cohort | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Complete Response (CR) | 1 Participants |
| PembroRT Cohort | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Partial Response (PR) | 11 Participants |
| PembroRT Cohort | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Stable Disease (SD) | 11 Participants |
| PembroRT Cohort | Radiographic Response Rate Based on Response Evaluation Criteria in Solid Tumors (RECIST) | Progressive Disease (PD) | 2 Participants |
Secondary
Unplanned Hospitalization Rate
The unplanned hospitalization rate will be determined as the percentage of participants hospitalized due to treatment-related toxicities.
Time frame: Up to 18 months following completion of treatment, up to 30 months total
Population: Unplanned hospitalization data was not collected.