Non-small Cell Lung Cancer
Conditions
Brief summary
The main purpose of this study is to assess the safety, tolerability and anti-tumor activity of the experimental study drug pembrolizumab (also known as Keytruda or MK-3475) in people with non-small cell lung cancer (NSCLC) that has come back after radiation therapy.
Interventions
DRUGPembrolizumab
Concurrent Pembrolizumab after proton reirradiation
Sponsors
Abramson Cancer Center at Penn Medicine
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic or cytologic diagnosis of NSCLC who have received previous intrathoracic radiation therapy with definitive intent and have a tumor recurrence in or near the prior irradiation fields. Re-biopsy of the recurrence is not required and is left to the discretion of the treating physician, although every effort should be made to confirm recurrence pathologically. * Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 * Age 18 or greater * Patients with prior invasive malignancies are allowed, provided they have been treated with definitive intent and have no evidence of active disease requiring treatment in the past 2 years. * Patients must be capable of giving informed consent and be willing and able to comply with schedule. * Serum total bilirubin ≤ 1.5 X upper limit of normal (ULN) OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN. * Platelets \>100,000 cells/mm3 and ANC \> 1,250 cells/mm3 * Creatinine ≤ 1.5 X ULN OR measured or calculated creatinine clearance ≥50 mL/min for subject with creatinine levels \> 1.5 X institutional ULN. (GFR can also be used in place of creatinine or CrCl). * Clinical target volume (CTV) size must be \<250 cc, no more than 74 Gy of prior radiation in 2 Gy fractions previously administered.
Exclusion criteria
* Allergy to Pembrolizumab or related compounds * History of symptomatic CTCAEv4 grade ≥3 pneumonitis following the initial course of definitive radiation therapy * History of symptomatic idiopathic pulmonary fibrosis or interstitial lung disease * Use of continuous oxygen * Diagnosis of immunodeficiency or exposure to systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. (Nasal or oral inhalers are permissible). * 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. Subjects with vitiligo or resolved childhood asthma/atopy are an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome are not excluded from the study. * History of allogenic tissue or solid organ transplant * Progression while on prior therapy with an anti-programmed cell death (PD)-1, anti-PD-L1, anti-PD-L2, anti-tumor necrosis factor CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) * Patients with known extrathoracic metastases, including brain metastases, or known malignant pleural or pericardial effusion * Prior radiation treatment less than 6 months from the planned start of reirradiation of any part of the intended treatment volume * Pregnant or breast-feeding patients. Men and women of reproductive potential may not participate in this study unless they have agreed to use an effective contraceptive method while in this study. * Known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). * Known active Hepatitis B (e.g., HBsAg positive or HBV DNA detectable) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Progression Free Survival | 2 years | Progression Free Survival is defined as the time from initiation of definitive therapy to the first documented disease progression per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 based on radiologists' review or death due to any cause, whichever occurs first, or last patient follow-up that documented lack of disease progression. Patients who have not had disease progression or who have died, will be censored on the most recent clinical evaluation date that documented that they were progression-free. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Grade 3+ Adverse Event | 2 years | Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. Adverse events were reviewed by the treating physicians and principal investigator to assess potential attribution to reirradiation/chemotherapy or pembrolizumab. |
Countries
United States
Participant flow
Pre-assignment details
Between November 2017 and April 2021, 32 patients were consented and reviewed for eligibility, of which 10 were excluded. Most common reasons for exclusion were internal clinical target volume (iCTV) ≥250 cc on the simulation scan (n = 3), histology other than non-small cell lung cancer (NSCLC) (n = 3), and extrathoracic metastases (n = 2). Twenty-two patients initiated proton beam therapy (PBT) reirradiation (reRT) on-trial and were included in the intention-to-treat analysis.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Single Arm, Open Label
Pembrolizumab: Concurrent Pembrolizumab after proton reirradiation | 22 |
| Total | 22 |
Baseline characteristics
| Characteristic | Single Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 14 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants |
| Age, Continuous | 68 years |
| Anaplastic lymphoma kinase (ALK) translocation | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status Eastern Cooperative Oncology Group (ECOG) performance status: 0 | 7 Participants |
| Eastern Cooperative Oncology Group (ECOG) performance status Eastern Cooperative Oncology Group (ECOG) performance status: 1 | 15 Participants |
| Epidermal growth factor receptor (EGFR) mutation | 1 Participants |
| Histology Adenocarcinoma | 12 Participants |
| Histology Adenosquamous | 1 Participants |
| Histology Non-small cell lung cancer (NSCLC), not otherwise specified | 1 Participants |
| Histology Squamous cell carcinoma | 8 Participants |
| Prior consolidation durvalumab | 8 Participants |
| Prior consolidation durvalumab - Median duration | 12 months |
| Prior overlapping radiation therapy - Definitive chemoradiation Intensity modulated radiation therapy (IMRT) | 11 Participants |
| Prior overlapping radiation therapy - Definitive chemoradiation Passive scatter proton beam therapy (PBT) | 2 Participants |
| Prior overlapping radiation therapy - Definitive chemoradiation Pencil beam scanning proton beam therapy (PBT) | 2 Participants |
| Prior overlapping radiation therapy - Definitive chemoradiation (passive scatter PBT) and SBRT | 1 Participants |
| Prior overlapping radiation therapy - Post-operative chemoradiation (3D-CRT) | 1 Participants |
| Prior overlapping radiation therapy - Pre-operative chemoradiation (IMRT) | 1 Participants |
| Prior overlapping radiation therapy - Pre-operative (IMRT) and post-operative (IMRT) chemoradiation | 1 Participants |
| Prior overlapping radiation therapy - Stereotactic body radiation therapy (SBRT) | 3 Participants |
| Prior surgery for lung cancer Lobectomy | 6 Participants |
| Prior surgery for lung cancer Wedge resection | 2 Participants |
| Programmed death-ligand (PD-L1 ) <1% | 9 Participants |
| Programmed death-ligand (PD-L1 ) 1-50% | 9 Participants |
| Programmed death-ligand (PD-L1 ) >50% | 3 Participants |
| Programmed death-ligand (PD-L1 ) Not Applicable (N/A) | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 18 Participants |
| Recurrence location Nodal | 8 Participants |
| Recurrence location Primary tumor | 4 Participants |
| Recurrence location Primary tumor + nodal | 10 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 14 / 22 |
| other Total, other adverse events | 16 / 22 |
| serious Total, serious adverse events | 10 / 22 |
Outcome results
Primary
Number of Subjects With Progression Free Survival
Progression Free Survival is defined as the time from initiation of definitive therapy to the first documented disease progression per Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 based on radiologists' review or death due to any cause, whichever occurs first, or last patient follow-up that documented lack of disease progression. Patients who have not had disease progression or who have died, will be censored on the most recent clinical evaluation date that documented that they were progression-free.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Number of Subjects With Progression Free Survival | 6 Participants |
Secondary
Number of Participants Who Experienced a Grade 3+ Adverse Event
Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. Adverse events were reviewed by the treating physicians and principal investigator to assess potential attribution to reirradiation/chemotherapy or pembrolizumab.
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Number of Participants Who Experienced a Grade 3+ Adverse Event | 10 Participants |