Recurrent Non-Small Cell Lung Carcinoma, Stage IV Non-Small Cell Lung Cancer
Conditions
Brief summary
This randomized phase II/III trial studies how well giving maintenance chemotherapy with or without local consolidation therapy works in treating patients with stage IV non-small cell lung cancer. Drugs used in maintenance chemotherapy, such as docetaxel, pemetrexed disodium, erlotinib hydrochloride, and gemcitabine work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Local consolidation therapy such as radiation/stereotactic body radiation or surgery may kill cancer cells left after initial treatment. Giving maintenance chemotherapy and local consolidation therapy together may work better than maintenance chemotherapy alone in treating patients with stage IV non-small cell lung cancer.
Detailed description
PRIMARY OBJECTIVES: Phase II To evaluate the impact of adding local consolidative therapy (LCT) to maintenance systemic therapy versus maintenance systemic therapy alone on progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC) with no evidence of progression and limited metastatic sites after first-line systemic therapy. Phase III To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on overall survival for patients with metastatic NSCLC with no evidence of progression and limited metastatic sites after first-line systemic therapy. SECONDARY OBJECTIVES: I. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on in-field local failure. II. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on the time to development of new lesions. III. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on toxicity. IV. To evaluate the impact of adding LCT to maintenance systemic therapy versus maintenance systemic therapy alone on duration of maintenance systemic therapy usage. V. To evaluate the effect of adding LCT to systemic therapy in limited stage IV NSCLC on Quality of Life (QOL). VI. To collect biospecimens and evaluate the correlation between clinical outcomes and circulating tumor DNA (ctDNA). Patients are randomized 2:1 between the SBRT and chemotherapy vs. chemotherapy alone arms. After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, then annually thereafter.
Interventions
RADIATION3-Dimensional Conformal Radiation Therapy (3D-CRT)
Undergo 3DCRT
DRUGDocetaxel
Given IV
DRUGGemcitabine
Given IV
RADIATIONIntensity-Modulated Radiation Therapy (IMRT)
Undergo IMRT
DRUGPemetrexed Disodium
Given IV
RADIATIONStereotactic Body Radiation Therapy (SBRT)
Undergo SBRT
DRUGErlotinib Hydrochloride
Given PO
DRUGPembrolizumab
Given IV
Sponsors
NRG Oncology
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have the psychological ability and general health that permits completion of the study requirements and required follow up * Women of childbearing potential and men who are sexually active should be willing and able to use medically acceptable forms of contraception during the trial and for up to 180 days after completion of all treatment to prevent pregnancy or fathering a child. * Pathologically proven diagnosis of NSCLC, with metastases (stage IV disease) present prior to registration; this includes patients newly diagnosed with metastatic disease or those initially diagnosed and treated for stage I-III NSCLC who ultimately develop limited metastases. Limited metastases is defined as 3 or fewer sites of metastatic disease * Appropriate stage for study entry based on the following diagnostic workup: * History/physical examination by a radiation oncologist (and a surgeon if surgery is planned) within 30 days prior to registration * Imaging proof of limited metastatic disease and response to therapy/stable disease, by at least diagnostic quality CT chest through the adrenals or positron emission tomography (PET)/CT within 30 days prior to registration * Zubrod performance status 0, 1, or 2 within 30 days prior to registration * Adequate organ and hematologic/bone marrow function within 14 days prior to registration, defined as follows: * Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × upper limit of normal (ULN) or ≤ 5 × ULN with metastatic liver disease * Total bilirubin ≤ 1.5 × ULN * Absolute neutrophil count (ANC) ≥ 500 cells/mm3 * Platelets ≥ 50,000 cells/mm3 * Renal: * Creatinine ≤ 1.5 x ULN; or * Creatinine Clearance (CrCl) \> 45 mL/min if creatinine \> 1.5 x ULN (calculated CrCl based on Cockcroft-Gault equation) * HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. * For patients who will undergo resection of disease (if randomized to Arm 2 and dispositioned to receive surgery), adequate pre-surgical work-up for anticipated surgery, as defined by institutional guidelines. * Negative serum pregnancy test within one week prior to registration for females of childbearing potential * Patients must have received first-line/induction systemic therapy comprising of immunotherapy and/or platinum-based chemotherapy (at least 4 cycles or courses but less than 6, i.e. 4-5 cycles/courses), and achieved stable disease or a partial response. Though the intention is for every course/cycle to be identical in an induction regimen, Some but not all of the 4-5 cycles may omit an immunotherapy or platinum compound if the treating physician determines it is in the patient's best interest secondary to toxicity or other institutional parameter. * For patients treated with nivolumab, ipilimumab and 2 cycles of chemotherapy, the 4-5 cycles requirement will be met by 4-5 total doses of nivolumab. * For patients treated with nivolumab and ipilimumab, this requirement will be met by 2 doses of ipilimumab and 4-5 doses of nivolumab. * After induction systemic therapy, patients must have a minimum of one site of disease, primary or metastasis, present for potential consolidation with local therapy. All sites of disease present after induction systemic therapy, primary and metastases (up to 3) are able to be consolidated with local therapy; * Prior systemic therapy as part of concurrent treatment approach for previously diagnosed stage I-III NSCLC, adjuvant or neo-adjuvant therapy for stage I-III NSCLC, as adjuvant therapy for previously resected or irradiated NSCLC, or for other previous cancers is permitted * For de novo stage IV NSCLC patients (patients with metastatic disease at first presentation), primary disease must be treatable with local therapy in the form of SBRT or hypofractionated radiation. If the primary disease is found in the peripheral or central lung parenchyma without nodal disease, for instance, SBRT may be employed at the discretion of the treating institution. If primary disease is more advanced with involvement of the mediastinum (T4 tumor, N1-N3 disease, etc.), these volumes should be technically treatable with hypofractionated radiation; surgery should only be used for metastatic tumors that can be completely resected by lobectomy, segmentectomy, or wide wedge resection. * If primary disease in the thoracic cavity was previously treated with local therapy in the form of surgery or radiation, any new local/regional disease recurrence should be technically treatable with SBRT or hypofractionated radiation after induction systemic therapy. * The patient or a legally authorized representative must provide study-specific informed consent prior to registration. * Radiotherapy for patients with brain metastases prior to registration is acceptable. * Patients with brain metastases are eligible if these lesions have been previously treated or resolved and the patients have no clinical or radiographic evidence of progression prior to registration. * Subjects may receive palliative radiotherapy for symptomatic metastases or primary disease prior to registration provided that there is at least one other non-irradiated lesion amenable to LCT at the time of registration.
Exclusion criteria
* Clinical or radiologic evidence of untreated and/or progressive brain metastases prior to registration after induction systemic therapy * Cutaneous metastasis of NSCLC * Metastatic disease invading the esophagus, stomach, intestines, or mesenteric lymph nodes if not a candidate for surgery for these lesions * Prior invasive malignancy (except non-melanomatous skin cancer, low or intermediate risk prostate cancer, or in situ carcinoma of breast, oral cavity, skin, or cervix) unless disease free for a minimum of one year * Metastases located within 3 cm of previously irradiated (\< 3 Gy per fraction) structures if if not a candidate for surgery for these lesions and if: * Spinal cord previously irradiated to \> 40 Gy * Brachial plexus previously irradiated to \> 50 Gy * Small intestine, large intestine, or stomach previously irradiated to \> 45 Gy * Brainstem previously irradiated to \> 50 Gy * Lung previously irradiated with prior V20 Gy \> 35% * Patients receiving targeted therapy (non-cytotoxic systemic therapy) for NSCLC in the first-line setting * Patients with NSCLC who have driver mutations for which targeted therapies (non-cytotoxic, non-immunotherapy based systemic therapy including but not limited to tyrosine-kinase inhibitors) are available. Such designations would include but not be limited to treatments targeting epidermal growth factor receptor (EGFR) mutant or anaplastic lymphoma kinase (ALK) positive NSCLC. * If a patient has progressed in previous areas of primary disease that received definitive doses of radiation, these patients would require re-irradiation in previous high dose anatomic areas and are not eligible for this study. * Patients with malignant pleural effusions that do not resolve after first-line systemic therapy; patients with pleural effusions that have become too small for thoracentesis at the time of registration would be permitted on study, indicating a significant response to first-line systemic therapy * Patients with more than 3 discrete locations of extra-cranial metastatic disease after first-line systemic therapy requiring more than 3 radiation/surgery plans to cover these distinct metastatic disease entities * Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration * Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during treatment and for 180 days after the completion of all treatment. This exclusion is necessary because the treatment involved in this study may be significantly teratogenic. Women who are breastfeeding (and unwilling to discontinue) are also excluded * Participation in any investigational drug study for the treatment of cancer within 4 weeks prior to registration. * For patients who received immunotherapy during induction, patients on chronic steroids or who have active autoimmune disease for which they received systemic treatment in the previous 2 years with corticosteroids, disease modifying agents, or immunosuppressive drugs are not eligible. Replacement therapy (thyroxine, insulin or physiological corticosteroid replacement for adrenal or pituitary insufficiency) is allowed. Patients with active interstitial lung disease or who have a history of pneumonitis for which they had received glucocorticoids are not eligible * Use of bevacizumab or other antiangiogenic therapy in first-line or planned maintenance therapy (due to potential for increased complications from local therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| [Phase II] Progression-free Survival | From randomization to first date of local or regional disease, distant metastases, second primary tumor, death, or last follow-up, whichever comes first. Maximum follow-up time at time of analysis was 5.4 years. | Progression-free survival (PFS) is estimated by the Kaplan-Meier method. Progression-free survival time is measured from randomization to the first date of local or regional disease, distant metastases, second primary tumor, death due to any cause, or last known follow-up (censored). Analysis was to occur after progression or death was reported for 138 participants. |
| [Phase III] Overall Survival | From randomization to death or last follow-up. | Overall survival is estimated by the Kaplan-Meier method. Survival time is measured from randomization to date of death from any cause or last known follow-up (censored). Analysis was to occur after \*\*\*\* deaths were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| In-Field Local Failure | From randomization to first in-field failure, death or last follow-up, whichever occurs first. Maximum follow-up at time of analysis was 5.4 years. The one- and two-year estimates are reported. | In-field local failure is defined as local or marginal failure. In-field local failure rates are estimated by the cumulative incidence method, in which death without failure is treated as competing risk and participants alive without failure are censored at last known follow-up. Analysis was to occur after progression or death was reported for 138 participants. |
| Development of New Lesions | From randomization to the first occurrence of any new lesions, death, or last follow-up, whichever occurs first. Maximum follow-up time at the time of analysis was 5.4 years. One- and two-year estimates are reported. | New lesion rates are estimated by the cumulative incidence method, in which death without new lesions is treated as competing risk and participants alive without new lesions are censored at last known follow-up. Analysis was to occur after progression or death was reported for 138 participants. |
| Number of Participants by Highest Grade Adverse Event Reported | From randomization to last follow-up. Maximum follow-up at time of analysis was 5.4 years. | National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data. |
| Duration of Maintenance Chemotherapy | From randomization to last chemotherapy, which continues until progression or significant toxicity. Maximum follow-up at time of analysis was 5.4 years. | Duration of Maintenance Chemotherapy |
Countries
Canada, Israel, Saudi Arabia, United States
Contacts
PRINCIPAL_INVESTIGATORPuneeth Iyengar
NRG Oncology
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm 1 (Systemic Maintenance Chemotherapy) Patients may receive docetaxel IV over 60 minutes on day 1, erlotinib hydrochloride by mouth daily, or gemcitabine IV over 30 minutes on days 1 and 8. Patients with non-squamous non-small cell lung cancer may receive pemetrexed disodium IV over 10 minutes on day 1 alone or in combination with pembrolizumab IV over 30 minutes. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | 81 |
| Arm 2 (LCT + Systemic Maintenance Chemotherapy) Patients undergo local consolidative therapy (LCT) over 2-5 weeks, consisting of SBRT/hypofractionated radiation to the primary tumor and metastatic sites or surgery of metastatic sites. Hypofractionated radiation using IMRT or 3DCRT can be given in place of SBRT. Within 2 weeks after completion of LCT (3 weeks if surgery occurred), patients receive chemotherapy as in Arm 1. | 134 |
| Total | 215 |
Baseline characteristics
| Characteristic | Arm 1 (Systemic Maintenance Chemotherapy) | Arm 2 (LCT + Systemic Maintenance Chemotherapy) | Total |
|---|---|---|---|
| Age, Customized ≤ 49 years | 4 Participants | 4 Participants | 8 Participants |
| Age, Customized 50 - 59 years | 15 Participants | 29 Participants | 44 Participants |
| Age, Customized 60 - 69 years | 31 Participants | 56 Participants | 87 Participants |
| Age, Customized ≥ 70 years | 31 Participants | 45 Participants | 76 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 7 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 78 Participants | 118 Participants | 196 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 9 Participants | 10 Participants |
| Histology Non-Squamous cell carcinoma | 64 Participants | 104 Participants | 168 Participants |
| Histology Squamous cell carcinoma | 17 Participants | 30 Participants | 47 Participants |
| Number of lesions targeted during treatment 1 | 50 Participants | 78 Participants | 128 Participants |
| Number of lesions targeted during treatment 2 | 19 Participants | 36 Participants | 55 Participants |
| Number of lesions targeted during treatment 3 | 12 Participants | 18 Participants | 30 Participants |
| Number of lesions targeted during treatment 4 | 0 Participants | 1 Participants | 1 Participants |
| Number of lesions targeted during treatment 5 | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 16 Participants | 19 Participants | 35 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 6 Participants | 8 Participants |
| Race (NIH/OMB) White | 59 Participants | 106 Participants | 165 Participants |
| Sex: Female, Male Female | 41 Participants | 66 Participants | 107 Participants |
| Sex: Female, Male Male | 40 Participants | 68 Participants | 108 Participants |
| Systemic Therapy Type Cytotoxic Chemotherapy | 14 Participants | 16 Participants | 30 Participants |
| Systemic Therapy Type Immunotherapy | 67 Participants | 118 Participants | 185 Participants |
| Zubrod performance status 0 | 35 Participants | 47 Participants | 82 Participants |
| Zubrod performance status 1 | 44 Participants | 79 Participants | 123 Participants |
| Zubrod performance status 2 | 2 Participants | 8 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 37 / 81 | 70 / 134 |
| other Total, other adverse events | 71 / 73 | 129 / 130 |
| serious Total, serious adverse events | 14 / 73 | 40 / 130 |
Outcome results
Primary
[Phase III] Overall Survival
Overall survival is estimated by the Kaplan-Meier method. Survival time is measured from randomization to date of death from any cause or last known follow-up (censored). Analysis was to occur after \*\*\*\* deaths were reported.
Time frame: From randomization to death or last follow-up.
Population: The phase III component did not open, therefore there are no participants for this outcome measure.
Primary
[Phase II] Progression-free Survival
Progression-free survival (PFS) is estimated by the Kaplan-Meier method. Progression-free survival time is measured from randomization to the first date of local or regional disease, distant metastases, second primary tumor, death due to any cause, or last known follow-up (censored). Analysis was to occur after progression or death was reported for 138 participants.
Time frame: From randomization to first date of local or regional disease, distant metastases, second primary tumor, death, or last follow-up, whichever comes first. Maximum follow-up time at time of analysis was 5.4 years.
Population: Modified intent-to-treat population (randomized eligible participants).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (systemic maintenance chemotherapy) | [Phase II] Progression-free Survival | 11.1 months |
| Arm 2 (LCT + systemic maintenance chemotherapy) | [Phase II] Progression-free Survival | 13.7 months |
Comparison: Based on expected 6- and 12-month PFS rates of approximately 60% and 39% for the standard arm, assuming approximately exponential distributions, at least 138 PFS events are needed to detect a hazard ratio of 0.6 (a hazard reduction of 40%) with 95% power and a one-sided significance level of 0.15. The Cox proportional hazards model is stratified by histology and systemic therapy type. The hazard ratio estimate must be ≤ 0.83 for the study to proceed to the phase III component.p-value: 0.6695% CI: [0.68, 1.4]Log Rank
Secondary
Development of New Lesions
New lesion rates are estimated by the cumulative incidence method, in which death without new lesions is treated as competing risk and participants alive without new lesions are censored at last known follow-up. Analysis was to occur after progression or death was reported for 138 participants.
Time frame: From randomization to the first occurrence of any new lesions, death, or last follow-up, whichever occurs first. Maximum follow-up time at the time of analysis was 5.4 years. One- and two-year estimates are reported.
Population: Modified intent-to-treat population (randomized eligible participants).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 (systemic maintenance chemotherapy) | Development of New Lesions | 1 year | 32.5 percentage of participants |
| Arm 1 (systemic maintenance chemotherapy) | Development of New Lesions | 2 years | 41.5 percentage of participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Development of New Lesions | 1 year | 28.1 percentage of participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Development of New Lesions | 2 years | 30.5 percentage of participants |
Secondary
Duration of Maintenance Chemotherapy
Duration of Maintenance Chemotherapy
Time frame: From randomization to last chemotherapy, which continues until progression or significant toxicity. Maximum follow-up at time of analysis was 5.4 years.
Population: Modified intent-to-treat population (randomized eligible participants).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm 1 (systemic maintenance chemotherapy) | Duration of Maintenance Chemotherapy | 5.46 months |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Duration of Maintenance Chemotherapy | 6.20 months |
Secondary
In-Field Local Failure
In-field local failure is defined as local or marginal failure. In-field local failure rates are estimated by the cumulative incidence method, in which death without failure is treated as competing risk and participants alive without failure are censored at last known follow-up. Analysis was to occur after progression or death was reported for 138 participants.
Time frame: From randomization to first in-field failure, death or last follow-up, whichever occurs first. Maximum follow-up at time of analysis was 5.4 years. The one- and two-year estimates are reported.
Population: Modified intent-to-treat population (randomized eligible participants).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm 1 (systemic maintenance chemotherapy) | In-Field Local Failure | 1 year | 15.3 percentage of participants |
| Arm 1 (systemic maintenance chemotherapy) | In-Field Local Failure | 2 years | 19.8 percentage of participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | In-Field Local Failure | 1 year | 8.6 percentage of participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | In-Field Local Failure | 2 years | 13.4 percentage of participants |
Secondary
Number of Participants by Highest Grade Adverse Event Reported
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grades adverse event severity as follows: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, 5 = death related to adverse event. Summary data is provided in this outcome measure; see Adverse Events Module for specific adverse event data.
Time frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 5.4 years.
Population: Modified intent-to-treat population (randomized and eligible) who received any protocol treatment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm 1 (systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | None | 1 Participants |
| Arm 1 (systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 7 Participants |
| Arm 1 (systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 15 Participants |
| Arm 1 (systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 35 Participants |
| Arm 1 (systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 11 Participants |
| Arm 1 (systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 5 | 4 Participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 4 | 20 Participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | None | 1 Participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 3 | 56 Participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 1 | 6 Participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 5 | 10 Participants |
| Arm 2 (LCT + systemic maintenance chemotherapy) | Number of Participants by Highest Grade Adverse Event Reported | Grade 2 | 37 Participants |