Non Small Cell Lung Cancer
Conditions
Brief summary
This is a multi-center phase II trial of intravenous (IV) Pembrolizumab MK-3475 in subjects older than 70 years with advanced Non-small cell Lung Cancer (NSCLC) expressing Programmed death-ligand 1 (PD-L1). 82 patients will be enrolled in this trial to examine the efficacy, the impact on geriatric assessments, the quality of life and the self-reported outcomes.
Detailed description
Subjects will receive MK-3475 at a fixed dose of 200 mg every 3 weeks (Q3W) (Figure 1). Subjects will be evaluated every 9 weeks (63 ± 7 days) with radiographic imaging to assess response to treatment. QoL and Self-reported Health Questionnaires, as well as geriatric follow-up will be performed at the same intervals. Investigators will make all treatment-based decisions using immune-related Response Criteria (irRC). However, for determination of overall response rate (ORR) and progression-free survival (PFS), the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 will be used. Adverse events will be monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment with MK-3475 will continue until two years of therapy have been administered, documented disease progression, unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdraws consent, noncompliance with trial treatment or procedure requirements, or administrative reasons. After the end of treatment, each subject will be followed for a minimum of 30 days for adverse event monitoring (serious adverse events will be collected for up to 90 days after the end of treatment unless the subject starts a new anticancer therapy between days 31 and 90). Subjects will have post-treatment follow-up for disease status, including initiating a non-study cancer treatment and experiencing disease progression, until death, withdrawing consent, or becoming lost to follow-up. Participation in this trial will be dependent upon supplying tumor tissue from a newly obtained formalin-fixed specimen from locations not radiated prior to biopsy. The specimen will be evaluated at a central laboratory facility for expression status of Programmed death-ligand 1(PD-L1) in a prospective manner. Only subjects whose tumors express Programmed death-ligand 1(PD-L1) as determined by the central laboratory facility will be eligible for inclusion in this study.
Interventions
DRUGPembrolizumab
Pembrolizumab (MK-3475) 200 mg, every 3 weeks
Sponsors
Spanish Lung Cancer Group
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with histological or cytological documented stage III B or IV squamous and non-squamous non-small-cell lung cancer previously untreated. 2. Epidermal Growth Factor receptor (EGFR) and Anaplastic lymphoma kinase (ALK) have to be wild-type. 3. The subject must be willing and able to provide written informed consent/assent for the trial. 4. Patients must be aged more than 70 years, on day of signing informed consent. 5. Measurable disease (at least 1 lesion) based on RECIST criteria v1.1. Patients will not be eligible if this lesion was irradiated before inclusion. 6. Be willing to provide tissue from a newly obtained core or excision biopsy of a tumor lesion. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1. Subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor. 7. PD-L1 expression ≥ 1% 8. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group Performance Scale. 9. Screening laboratory values must meet the following criteria (Table 1, see protocol), all screening laboratory tests should be performed within 8 days of treatment initiation. 10. Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
Exclusion criteria
1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. 2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at a dose over 10 mg of prednisone or equivalent, or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 3. Has a known history of active Tuberculosis Bacillus 4. Hypersensitivity to Pembrolizumab or any of its excipients. 5. Has had any prior anti-cancer therapy for his or her metastatic NSCLC. In the case of patients who have progressed to a metastatic stage after having been treated for early stage NSCLC, chemotherapy or radiation therapy as part of this previous treatment is allowed, provided they have been completed more than three months ago. Patients who received adjuvant or neoadjuvant treatment or both for early stages will be eligible for this trial. All adverse events related to these previous treatments must have recovered (i.e., ≤ Grade 1 or at baseline). 6. Has had any previous malignancy (except non melanoma skin cancer, and cancer in situ of: bladder, gastric, colon, cervical/dysplasia, melanoma, breast), unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period. 7. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate if they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids at a dose over 10 mg of prednisone or equivalent, for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. 8. 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., thyroxin, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 9. Has a history of (non-infectious) pneumonitis that required steroids or current 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, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 12. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 13. Has any geriatric
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | From the date of inclusion of the first patient to until end of follow up, up to 36 months. | Defined as the length of time from either the date of diagnosis or the start of the treatment that patients diagnosed with the disease are still alive. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Impact on Functional Assessments Measured With Barthel Scale | Beginning of cycle 1 (week 1), beginning of cycle 4 (week 12), beginning of cycle 7 (week 21), beginning of cycle 10 (week 30), beginning of cycle 13 (week 39), beginning of cycle 16 (week 48) and beginning of cycle 18 (week 54) (each cycle is 3 weeks) | To evaluate the impact on functional geriatric assessments of patients older than 70 years with advanced non-small cell lung cancer. The Barthel Index assesses activities in two major categories: Personal care and mobility. The personal care items include tasks such as drinking from a cup, dressing, grooming, bathing, and bowel and bladder continence. The scoring is as follows: scores of 0-20 indicate total dependency. scores of 21-60 indicate severe dependency. scores of 61-90 indicate moderate dependency. scores of 91-99 indicate slight dependency, score of 100 indicate independent. |
| Progression-free Survival (PFS) | From the inclusion date in the study until first progression or end of follow up, up to 36 months | To describe Progression-free Survival (PFS), according to RECIST criteria v. 1.1 of the first-line treatment with pembrolizumab (MK-3475) in elderly patients with advanced NSCLC. PFS defined as the length of time from the date of randomization to the date of the first documented progression of disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Changes in Health-related Quality of Life With Lung Cancer Symptom Scale | Beginning of cycle 1 (week 1) and beginning of cycle 18 (week 54) (each cycle is 3 weeks) | To evaluate changes in health-related quality of life in responder and non-responder patients older than 70 years with advanced non-small cell lung cancer. QLQ-C30 Quality of Life Questionnaire. The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of multi-item scales and single items. All EORTC QLQ-C30 scale scores range from 0 to 100. A high score for a functional scale represents a high level of functioning, whereas a high score for a symptom scale/single item represents a high level of symptom- atology |
| OS for Patients With a PD-L1 Under 50% | From the initiation of treatment until end of follow up, up to 36 months | Defined as the length of time from the date of the start of the treatment that patients diagnosed with the disease and PD¨-L1 under 50% are still alive. |
| OS for Patients With a PD-L1 Greater Than or Equal to 50% | From the initiation of treatment until end of follow up, up to 36 months | Defined as the length of time from the start of the treatment that patients diagnosed with the disease and PD-L1 greater than or equal to 50% are still alive. |
| Overall Survival Rate at 2 Years. | From the date of inclusion of the first patient until two years follow up visit, up to 24 months | To evaluate the overall survival percentage of the patients included at two years |
Countries
Spain
Participant flow
Pre-assignment details
A total of 83 patients were recruited between January 2017 and November 2019 and 82 patients received treatment. Of these, 74 patients were finally analysed since eight were inclusion errors.
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Arm 1 group, Pembrolizumab (MK-3475) 200 mg, every 3 weeks
Pembrolizumab: Pembrolizumab (MK-3475) 200 mg, every 3 weeks | 74 |
| Total | 74 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Did not meet inclusion criteria | 8 |
Baseline characteristics
| Characteristic | Pembrolizumab Arm |
|---|---|
| Age, Continuous | 78.1 years STANDARD_DEVIATION 5.5 |
| Current cancer stage IIIB | 6 Participants |
| Current cancer stage IV | 68 Participants |
| ECOG performance Status at diagnosis ECOG 0 | 18 Participants |
| ECOG performance Status at diagnosis ECOG 1 | 56 Participants |
| Histology Adenocarcinoma | 32 Participants |
| Histology Aden squamous | 1 Participants |
| Histology Large cell carcinoma | 2 Participants |
| Histology Not otherwise specified / Undifferentiated | 6 Participants |
| Histology Squamous | 33 Participants |
| PD-L1 1-19% | 16 Participants |
| PD-L1 20-49% | 23 Participants |
| PD-L1 ≥50% | 35 Participants |
| Previous antineoplastic treatments Adjuvant chemotherapy | 6 participants |
| Previous antineoplastic treatments Concurrent chemoradiotherapy | 5 participants |
| Previous antineoplastic treatments Neo-adjuvant chemotherapy | 2 participants |
| Previous antineoplastic treatments No therapy | 28 participants |
| Previous antineoplastic treatments Radiotherapy | 24 participants |
| Previous antineoplastic treatments Surgery | 9 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 74 Participants |
| Region of Enrollment Spain | 74 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 64 Participants |
| Smoking history Current smoker | 12 Participants |
| Smoking history Former smoker (≥1 year) | 51 Participants |
| Smoking history Never (≤100 cigarettes/lifetime) | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 46 / 74 |
| other Total, other adverse events | 59 / 74 |
| serious Total, serious adverse events | 46 / 74 |
Outcome results
Primary
Overall Survival
Defined as the length of time from either the date of diagnosis or the start of the treatment that patients diagnosed with the disease are still alive.
Time frame: From the date of inclusion of the first patient to until end of follow up, up to 36 months.
Population: We performed the analyses on the intention-to-treat (ITT) population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Arm | Overall Survival | 19.2 Months |
Secondary
Changes in Health-related Quality of Life With Lung Cancer Symptom Scale
To evaluate changes in health-related quality of life in responder and non-responder patients older than 70 years with advanced non-small cell lung cancer. QLQ-C30 Quality of Life Questionnaire. The EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) is designed to measure cancer patients' physical, psychological and social functions. The questionnaire is composed of multi-item scales and single items. All EORTC QLQ-C30 scale scores range from 0 to 100. A high score for a functional scale represents a high level of functioning, whereas a high score for a symptom scale/single item represents a high level of symptom- atology
Time frame: Beginning of cycle 1 (week 1) and beginning of cycle 18 (week 54) (each cycle is 3 weeks)
Population: Intention to treat population
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pembrolizumab Arm | Changes in Health-related Quality of Life With Lung Cancer Symptom Scale | At the beginning of the first cycle | 66.7 units on a scale |
| Pembrolizumab Arm | Changes in Health-related Quality of Life With Lung Cancer Symptom Scale | At the beginning of the eighteenth cycle | 92.3 units on a scale |
Secondary
Impact on Functional Assessments Measured With Barthel Scale
To evaluate the impact on functional geriatric assessments of patients older than 70 years with advanced non-small cell lung cancer. The Barthel Index assesses activities in two major categories: Personal care and mobility. The personal care items include tasks such as drinking from a cup, dressing, grooming, bathing, and bowel and bladder continence. The scoring is as follows: scores of 0-20 indicate total dependency. scores of 21-60 indicate severe dependency. scores of 61-90 indicate moderate dependency. scores of 91-99 indicate slight dependency, score of 100 indicate independent.
Time frame: Beginning of cycle 1 (week 1), beginning of cycle 4 (week 12), beginning of cycle 7 (week 21), beginning of cycle 10 (week 30), beginning of cycle 13 (week 39), beginning of cycle 16 (week 48) and beginning of cycle 18 (week 54) (each cycle is 3 weeks)
Population: Intention to treat population
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pembrolizumab Arm | Impact on Functional Assessments Measured With Barthel Scale | At the beginning of Cycle 1 | 100 units on a scale |
| Pembrolizumab Arm | Impact on Functional Assessments Measured With Barthel Scale | At the beginning of Cycle 4 | 100 units on a scale |
| Pembrolizumab Arm | Impact on Functional Assessments Measured With Barthel Scale | At the beginning of Cycle 7 | 100 units on a scale |
| Pembrolizumab Arm | Impact on Functional Assessments Measured With Barthel Scale | At the beginning of Cycle 10 | 100 units on a scale |
| Pembrolizumab Arm | Impact on Functional Assessments Measured With Barthel Scale | At the beginning of Cycle 13 | 100 units on a scale |
| Pembrolizumab Arm | Impact on Functional Assessments Measured With Barthel Scale | At the beginning of Cycle 16 | 100 units on a scale |
| Pembrolizumab Arm | Impact on Functional Assessments Measured With Barthel Scale | At the beginning of Cycle 18 | 97 units on a scale |
Secondary
OS for Patients With a PD-L1 Greater Than or Equal to 50%
Defined as the length of time from the start of the treatment that patients diagnosed with the disease and PD-L1 greater than or equal to 50% are still alive.
Time frame: From the initiation of treatment until end of follow up, up to 36 months
Population: It is performed the analyses on the intention-to-treat (ITT) population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Arm | OS for Patients With a PD-L1 Greater Than or Equal to 50% | 23.3 Months |
Secondary
OS for Patients With a PD-L1 Under 50%
Defined as the length of time from the date of the start of the treatment that patients diagnosed with the disease and PD¨-L1 under 50% are still alive.
Time frame: From the initiation of treatment until end of follow up, up to 36 months
Population: It is performed the analyses on the intention-to-treat (ITT) population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pembrolizumab Arm | OS for Patients With a PD-L1 Under 50% | 16.5 Months |
Secondary
Overall Survival Rate at 2 Years.
To evaluate the overall survival percentage of the patients included at two years
Time frame: From the date of inclusion of the first patient until two years follow up visit, up to 24 months
Population: Intention to treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Arm | Overall Survival Rate at 2 Years. | 40.2 percentage of participants |
Secondary
Progression-free Survival (PFS)
To describe Progression-free Survival (PFS), according to RECIST criteria v. 1.1 of the first-line treatment with pembrolizumab (MK-3475) in elderly patients with advanced NSCLC. PFS defined as the length of time from the date of randomization to the date of the first documented progression of disease. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: From the inclusion date in the study until first progression or end of follow up, up to 36 months
Population: It is performed the analyses on the intention-to-treat (ITT) population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Arm | Progression-free Survival (PFS) | 6.1 Months |