Non-small Cell Lung Cancer (NSCLC)
Conditions
Brief summary
NEOMUN is designed as an open-label, single arm, prospective, monocenter, phase II study of pembrolizumab in a neoadjuvant setting in patients with non-small cell lung cancer of Stage II/IIIA suitable for curative intent surgery.
Detailed description
The study is designed as an open-label, single arm, prospective, monocenter, phase II study of pembrolizumab in a neoadjuvant setting in patients with resectable NSCLC stage II/IIIA suitable for curative intent surgery, taking place in Germany. Planned sample size is N=30. Investigational drug is Pembrolizumab at fixed dose, given 200 mg q3w i.v. for 2 cycles. After completion of immunotherapy lobectomy/ bilobectomy with curative intent is scheduled. Primary objectives are to assess feasibility and safety of a neoadjuvant application of pembrolizumab and to assess antitumor activity of pembrolizumab with regard to clinical and pathologic tumor response. Secondary objective is to assess the impact of neoadjuvant pembrolizumab on patient disease free and overall survival. Exploratory objective is o explore potential predictive biomarkers for pembrolizumab efficacy (immune cell imaging).
Interventions
DRUGPembrolizumab
Pembrolizumab at fixed dose: 200 mg q3w i.v. for 2 cycles
Sponsors
Merck Sharp & Dohme LLC
AIO-Studien-gGmbH
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
1. Cooperation and willingness to complete all aspects of the study 2. Signed and dated written informed consent must be given prior to study inclusion 3. Histological or cytological confirmed NSCLC 4. Clinical stage II-IIIA according to the TNM classification, 7th edition: stage IIIa: T1/T2 N2 (IIIa1-3 Robinson classification) 5. Adequate disease staging by PET/CT and brain MRI 6. At least 1 measurable lesion according to RECIST 1.1 7. Age ≥ 18 years 8. ECOG performance status 0 - 1 9. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. 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. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject 11. Adequate bone marrow function, liver and renal function: 1. Absolute neutrophil count ≥ 1.5 x 109/L 2. Thrombocytes ≥ 100 x 109/L 3. Hemoglobin ≥ 9 g/dL without transfusion or EPO dependency (within 7 days of assessment) 4. INR \< 1.4 ULN and PTT \< 40 seconds during the last 7 days before therapy 5. Bilirubin \< 1.5 x upper limit of normal 6. AST (GOT) and ALT (GPT) \< 2.5 x ULN 7. Albumin \>2.5 mg/dL 8. Serum creatinine OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels \> 1.5 X institutional ULN 12. Adequate lung and cardiac function for intended lung resection according to German S3 guideline
Exclusion criteria
1. Anticancer treatment during the last 30 days prior to start of treatment, including systemic therapy, radiotherapy or major surgery 2. Participation in a clinical trial within the last 30 days prior to study treatment 3. History of allogeneic tissue/solid organ transplant 4. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 5. Evidence of interstitial lung disease. 6. cT4 tumor 7. Symptomatic acute cardiovascular or cerebrovascular disease 8. Known active HBV, HCV or HIV infection 9. Has any other active infection requiring systemic therapy. 10. Patients with active tuberculosis 11. Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor \[TNFR\] family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) 12. A diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 13. Patient has had a prior monoclonal antibody within 4 weeks prior to study Day 1 14. Patient has had prior chemotherapy, targeted small molecule therapy, or radiation therapy in history. 15. 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. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. 16. Has received a live vaccine within 30 days prior to the first dose of trial treatment. \[Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines are live attenuated vaccines, and are not allowed.\] 17. Has known hypersensitivity to pembrolizumab or any of the constituents of the product. 18. Other active malignancy requiring treatment Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 19. Lactating or pregnant women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (allowed methods of contraception, meaning methods with a rate of failure of less than 1% per year are implants, injectable contraceptives, combined oral contraceptives, intrauterine pessars (only hormonal devices), sexual abstinence or vasectomy of the partner). Women of childbearing potential must have a negative pregnancy test (serum β-hCG) at Screening. 20. Any psychiatric illness that would affect the patient's ability to understand the demands of the clinical trial 21. Patient has already been recruited in this trial 22. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. 23. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts \[§ 40 Abs. 1 S. 3 Nr. 3a AMG\].
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response - Δ PET Activity | From screening until pre-surgery radiologic assessment, ca. 6-8 weeks | Δ PET activity (standardized uptake value \[SUV\]). This method uses radiolabeled tracer 82-deoxy-2-\[18F\]fluoro-D-glucose, FDG) during PET imaging of the tumor and accumulation of radiolabeled FDG measured by the PET scanner. Accumulation of FDG relative to normal tissue is related to the proliferative activity of malignant tissue and to the number of viable tumor cells. The endpoint is based on per-patient changes in tumor maximal standardized uptake value during PET examinations of the tumor before the start of treatment and after 2 cycles of neoadjuvant immunotherapy, i.e. between screening and shortly before surgery. Reduction of proliferative activity or of the number of viable tumor cells results in negative values. |
| Number of Patients Treated in Compliance With Protocol | From screening until surgery, ca. 6-8 weeks | The definition for this endpoint was neoadjuvant pembrolizumab treatment followed by successful curative intent tumor resection. |
| Tumor Response According to RECIST 1.1 Criteria | From screening until pre-surgery radiologic assessment, ca. 6-8 weeks | Radiologic tumor assessments were performed at screening and pre-surgery. |
| Tumor Response Evaluation - Pathologic Response | From screening until surgery, ca. 6-8 weeks | Pathologic regression grading according to Junker criteria. The following grades are defined: Grade I No tumor regression or only spontaneous tumor regression in the sections of the primary tumor and mediastinal lymph nodes. Grade IIa Morphological signs of therapy-induced tumor regression in the sections of the primary tumor and/or mediastinal lymph nodes: More than 10% vital tumor tissue Grade IIb Morphological signs of therapy-induced tumor regression: Less than 10% vital tumor tissue Grade III Complete tumor regression, no evidence of vital tumor in the sections of the primary tumor and/or mediastinal lymph nodes. Regression grades IIb and III suggest a good response to neoadjuvant therapy. Reference: Junker K, Langner K, Klinke F, Bosse U, Thomas M. Grading of tumor regression in non-small cell lung cancer : morphology and prognosis. Chest 2001; 120:1584-91. |
| Tumor Response Evaluation - Δ Tumor Size | From screening until pre-surgery radiologic assessment, ca. 6-8 weeks | Δ tumor size was defined as the difference \[mm\] between longest diameter at baseline and pre-surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease-free Survival at 6 Months | 6 months after surgery, i.e. circa 8 months after treatment start | Probability of disease-free survival (DFS) was calculated using Kaplan-Meier statistics from date of surgery to the date until tumor recurrence or death. Follow-up was until 24 months after last-patient-out. |
| Disease-free Survival at 12 Months | 12 months after surgery, i.e. circa 14 months after treatment start | Probability of disease-free survival (DFS) was calculated from date of surgery until tumor recurrence or death using Kaplan-Meier statistics. Follow-up was until 24 months after last-patient-out. |
| Overall Survival at 12 Months | 12 months after surgery, i.e. circa 14 months after treatment start | Probability of overall survival (OS) was calculated from date of surgery until date of death using Kaplan-Meier statistics. Follow-up was until 24 months after last-patient-out. |
| Overall Survival at 18 Months | 18 months after surgery, i.e. circa 20 months after treatment start | Probability of overall survival (OS) was calculated from date of surgery until date of death using Kaplan-Meier statistics. Follow-up was until 24 months after last-patient-out. |
| Overall Survival at 24 Months | 24 months after surgery, i.e. circa 26 months after treatment start | Probability of overall survival (OS) was calculated from date of surgery until date of death using Kaplan-Meier statistics. Follow-up was until 24 months after last-patient-out. |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Pembrolizumab at fixed dose: 200 mg q3w i.v. for 2 cycles
Pembrolizumab: Pembrolizumab at fixed dose: 200 mg q3w i.v. for 2 cycles | 29 |
| Total | 29 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Pembrolizumab |
|---|---|
| Age, Continuous | 60 years |
| ECOG status ECOG 0 | 14 Participants |
| ECOG status ECOG 1 | 15 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 28 Participants |
| Region of Enrollment Germany | 29 participants |
| Sex: Female, Male Female | 16 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 29 |
| other Total, other adverse events | 21 / 29 |
| serious Total, serious adverse events | 8 / 29 |
Outcome results
Primary
Number of Patients Treated in Compliance With Protocol
The definition for this endpoint was neoadjuvant pembrolizumab treatment followed by successful curative intent tumor resection.
Time frame: From screening until surgery, ca. 6-8 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab | Number of Patients Treated in Compliance With Protocol | 29 Participants |
Primary
Tumor Response According to RECIST 1.1 Criteria
Radiologic tumor assessments were performed at screening and pre-surgery.
Time frame: From screening until pre-surgery radiologic assessment, ca. 6-8 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab | Tumor Response According to RECIST 1.1 Criteria | Complete response | 0 Participants |
| Pembrolizumab | Tumor Response According to RECIST 1.1 Criteria | Partial response | 6 Participants |
| Pembrolizumab | Tumor Response According to RECIST 1.1 Criteria | Stable disease | 19 Participants |
| Pembrolizumab | Tumor Response According to RECIST 1.1 Criteria | Progressive disease | 3 Participants |
Primary
Tumor Response Evaluation - Pathologic Response
Pathologic regression grading according to Junker criteria. The following grades are defined: Grade I No tumor regression or only spontaneous tumor regression in the sections of the primary tumor and mediastinal lymph nodes. Grade IIa Morphological signs of therapy-induced tumor regression in the sections of the primary tumor and/or mediastinal lymph nodes: More than 10% vital tumor tissue Grade IIb Morphological signs of therapy-induced tumor regression: Less than 10% vital tumor tissue Grade III Complete tumor regression, no evidence of vital tumor in the sections of the primary tumor and/or mediastinal lymph nodes. Regression grades IIb and III suggest a good response to neoadjuvant therapy. Reference: Junker K, Langner K, Klinke F, Bosse U, Thomas M. Grading of tumor regression in non-small cell lung cancer : morphology and prognosis. Chest 2001; 120:1584-91.
Time frame: From screening until surgery, ca. 6-8 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Pembrolizumab | Tumor Response Evaluation - Pathologic Response | Grade I | 4 Participants |
| Pembrolizumab | Tumor Response Evaluation - Pathologic Response | Grade IIa | 18 Participants |
| Pembrolizumab | Tumor Response Evaluation - Pathologic Response | Grade IIb | 3 Participants |
| Pembrolizumab | Tumor Response Evaluation - Pathologic Response | Grade III | 4 Participants |
Primary
Tumor Response Evaluation - Δ Tumor Size
Δ tumor size was defined as the difference \[mm\] between longest diameter at baseline and pre-surgery.
Time frame: From screening until pre-surgery radiologic assessment, ca. 6-8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Tumor Response Evaluation - Δ Tumor Size | -4.0 mm |
Primary
Tumor Response - Δ PET Activity
Δ PET activity (standardized uptake value \[SUV\]). This method uses radiolabeled tracer 82-deoxy-2-\[18F\]fluoro-D-glucose, FDG) during PET imaging of the tumor and accumulation of radiolabeled FDG measured by the PET scanner. Accumulation of FDG relative to normal tissue is related to the proliferative activity of malignant tissue and to the number of viable tumor cells. The endpoint is based on per-patient changes in tumor maximal standardized uptake value during PET examinations of the tumor before the start of treatment and after 2 cycles of neoadjuvant immunotherapy, i.e. between screening and shortly before surgery. Reduction of proliferative activity or of the number of viable tumor cells results in negative values.
Time frame: From screening until pre-surgery radiologic assessment, ca. 6-8 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab | Tumor Response - Δ PET Activity | -1 standardized uptake value [SUV] |
Secondary
Disease-free Survival at 12 Months
Probability of disease-free survival (DFS) was calculated from date of surgery until tumor recurrence or death using Kaplan-Meier statistics. Follow-up was until 24 months after last-patient-out.
Time frame: 12 months after surgery, i.e. circa 14 months after treatment start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Disease-free Survival at 12 Months | 86.2 Probablity of DFS in % |
Secondary
Disease-free Survival at 6 Months
Probability of disease-free survival (DFS) was calculated using Kaplan-Meier statistics from date of surgery to the date until tumor recurrence or death. Follow-up was until 24 months after last-patient-out.
Time frame: 6 months after surgery, i.e. circa 8 months after treatment start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Disease-free Survival at 6 Months | 86.2 Probablity of DFS in % |
Secondary
Overall Survival at 12 Months
Probability of overall survival (OS) was calculated from date of surgery until date of death using Kaplan-Meier statistics. Follow-up was until 24 months after last-patient-out.
Time frame: 12 months after surgery, i.e. circa 14 months after treatment start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Overall Survival at 12 Months | 93.1 Probability of OS in % |
Secondary
Overall Survival at 18 Months
Probability of overall survival (OS) was calculated from date of surgery until date of death using Kaplan-Meier statistics. Follow-up was until 24 months after last-patient-out.
Time frame: 18 months after surgery, i.e. circa 20 months after treatment start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Overall Survival at 18 Months | 89.7 Probability of OS in % |
Secondary
Overall Survival at 24 Months
Probability of overall survival (OS) was calculated from date of surgery until date of death using Kaplan-Meier statistics. Follow-up was until 24 months after last-patient-out.
Time frame: 24 months after surgery, i.e. circa 26 months after treatment start
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab | Overall Survival at 24 Months | 86.2 Probability of OS in % |