Phase III Prospective Randomized Trial of Primary Lung Tumor Stereotactic Body Radiation Therapy Followed by Concurrent Mediastinal Chemoradiation for Locally-Advanced Non-Small Cell Lung Cancer
Overview
- Phase
- Phase 3
- Intervention
- Computed Tomography
- Conditions
- Locally Advanced Lung Non-Small Cell Carcinoma
- Sponsor
- NRG Oncology
- Enrollment
- 474
- Locations
- 902
- Primary Endpoint
- Overall survival (OS)
- Status
- Recruiting
- Last Updated
- 28 days ago
Overview
Brief Summary
This phase III trial compares the effect of adding stereotactic body radiation therapy (SBRT) to the usual treatment (conventional image guided radiation therapy [IGRT] and chemotherapy followed by immunotherapy with durvalumab or targeted therapy with osimertinib) versus the usual treatment alone in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be treated by surgery (inoperable). SBRT uses special equipment to position a patient and deliver radiation therapy to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. IGRT is a type of radiation therapy that creates a picture of the tumor to help guide the radiation beam during therapy, making it more accurate and causing less damage to healthy tissue. Usual chemotherapy used in this trial consists of combinations of the following drugs: cisplatin, carboplatin, paclitaxel, nab-paclitaxel, pemetrexed, and etoposide. Cisplatin and carboplatin are in a class of medications known as platinum-containing compounds. Cisplatin works by killing, stopping, or slowing the growth of tumor cells. Carboplatin works in a way similar to the anticancer drug cisplatin but may be better tolerated than cisplatin. Carboplatin works by killing, stopping, or slowing the growth of tumor cells as well. Paclitaxel is in a class of medications called antimicrotubule agents. It works by stopping the growth and spread of tumor cells. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by blocking the action of a certain substance in the body that may help tumor cells multiply. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill tumor cells. Immunotherapy with durvalumab can induce changes in the body's immune system and can interfere with the ability of tumor cells to grow and spread. Osimertinib is in a class of medications called kinase inhibitors. It works by blocking the action of a protein called EGFR that signals cancer cells to multiply. This helps slow or stop the spread of tumor cells. Adding SBRT to the usual treatment of IGRT with chemotherapy and immunotherapy may be more effective at treating patients with locally-advanced non-small cell lung cancer than giving the usual treatment alone.
Detailed Description
PRIMARY OBJECTIVES: I. To compare the overall survival in patients with stage II-IIIC inoperable node-positive non-small cell lung cancer (NSCLC) after image guided, motion-managed conventional radiotherapy to the primary tumor and nodal metastases (Arm 1) or after image guided, motion-managed stereotactic body radiation therapy (SBRT) to the primary tumor followed by conventionally fractionated radiotherapy to nodal metastases (Arm 2) both given with concurrent platinum-based chemotherapy. II. To compare progression-free survival between the experimental arm (Arm 2) and control arm (Arm 1). SECONDARY OBJECTIVES: I. To compare objective response rate (as defined by Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\] 1.1) between the experimental arm and control arm. II. To compare the rate of local control between the experimental arm and control arm. III. To compare patterns of failure (primary, locoregional, or distant) between the experimental arm and control arm. IV. To compare changes in pulmonary function (forced expiratory volume in 1 second \[FEV1\] and diffusion capacity of the lung for carbon monoxide \[DLCO\] assessed at randomization and at 6- and 12- months following completion of radiation therapy) between the experimental arm and control arm. V. To compare changes in quality of life and patient-reported outcomes assessed from pre-treatment to 3 months following radiation therapy of each treatment arm. VI. To determine acute and late toxicity profiles of each treatment arm as measured by the Common Terminology Criteria for Adverse Events (CTCAE) v5. EXPLORATORY OBJECTIVES: I. To characterize and compare longitudinal quality of life and patient-reported outcomes of each treatment arm. II. To collect biospecimens at baseline, after SBRT (for Arm 2 patients), during last 2 weeks of chemoradiation, and after first dose of consolidation therapy, to allow for future analyses. III. To collect 4-dimensional (4D) computed tomography (CT) planning scans and radiation dose to calculate regional lung ventilation and explore pre-treatment 4D-CT based ventilation to predict pulmonary toxicity. IV. To characterize clinical outcomes, toxicities and changes in pulmonary function and quality of life among patients receiving proton and photon radiotherapy. V. To develop and characterize a machine learning/artificial intelligence algorithm for radiotherapy planning and/or quality assurance. OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel intravenously (IV) followed by carboplatin IV weekly (Q7D) during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or positron emission tomography (PET)/CT during follow-up. ARM II: Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Patients are followed up every 3 months for 1 year, every 6 months during years 2 and 3, and then yearly after that for the duration of the study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Pathologically (histologically or cytologically) proven diagnosis of non-operable stage IIB or III, node positive (American Joint Committee on Cancer \[AJCC\] eighth edition) non-small cell lung cancer (NSCLC) with known PD-L1 status prior to registration
- •Patients must have an identified primary tumor and at least one nodal metastasis (peribronchial/hilar/intrapulmonary, mediastinal/subcarinal, supraclavicular/scalene)
- •Up to 4 cycles of systemic therapy received prior to registration for the current study cancer is allowable; any prior chemotherapy for a different cancer is also permissible
- •Patients who refuse surgery, in addition to those who are technically unresectable or medically inoperable, are eligible.
- •Patients with separate tumor nodules in the same lobe of the primary tumor are eligible
- •The patient must be deemed clinically appropriate for curative intent definitive combined modality therapy, based on the following staging assessments:
- •History/physical examination prior to registration;
- •Magnetic resonance imaging (MRI) scan of the brain (preferred) or CT scan of the brain (if available, contrast is preferred for all neuroimaging) prior to registration;
- •CT chest with IV contrast (if contrast is available and unless contraindicated, such as for abnormal kidney function) prior to registration. PET/CT may be used if the CT portion is of identical diagnostic quality as achieved in a stand-alone CT
- •No evidence of distant metastases based on FDG PET/CT scan obtained within 60 days of registration
Exclusion Criteria
- •Prior radiotherapy to the study cancer (local recurrence). Prior radiotherapy for a different cancer/condition to the region of the study cancer that would result in overlap of radiation therapy fields that is determined by the treating physician to impede the treatment of the study malignancy
- •Patients without identifiable primary tumor and at least 1 pathologically enlarged lymph node are not eligible (T3-4N0 or T0N1-3 patients are not eligible). At least 1 radiographically-involved lymph node is required, but pathologic confirmation of involvement is not mandated
- •Centrally located primary tumor \< 2 cm from involved nodal disease that would result in significant overlap of the primary SBRT and nodal radiation fields. This does not include proximity to involved segmental and subsegmental lymph nodes (levels 13 and 14) that would not result in overlap of dose to the proximal bronchial tree or esophagus. Centrally located is defined as within or touching the zone of the proximal bronchial tree, which is a volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi)
- •Participants who are pregnant or unwilling to discontinue nursing
- •Participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) unwilling to use highly effective contraceptives during therapy and for the Food and Drug Administration (FDA)-labeled contraception timeframe required after the final dose of the selected systemic therapy regimen, because the treatment in this study may be significantly teratogenic
Arms & Interventions
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Computed Tomography
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Image Guided Radiation Therapy
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Positron Emission Tomography
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Questionnaire Administration
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Computed Tomography
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Image Guided Radiation Therapy
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Positron Emission Tomography
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Questionnaire Administration
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Stereotactic Body Radiation Therapy
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Pemetrexed
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Carboplatin
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Cisplatin
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Durvalumab
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Paclitaxel
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Etoposide
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Nab-paclitaxel
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Osimertinib
Arm I (image guided RT, chemotherapy, immunotherapy)
Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Pemetrexed
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Carboplatin
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Cisplatin
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Durvalumab
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Paclitaxel
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Osimertinib
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Nab-paclitaxel
Arm II (SBRT, image guided RT, chemotherapy, immunotherapy)
Patients undergo SBRT and conventional IGRT and then receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year or osimertinib PO QD in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Intervention: Etoposide
Outcomes
Primary Outcomes
Overall survival (OS)
Time Frame: Time between date of randomization and date of death due to any cause, assessed up to 8 years
Non-inferiority (NI) between arm 2 and arm 1 (reference level) will be evaluated by comparing the upper bound of the 95% confidence interval for the hazard ratio to the pre-specified NI margin. NI of arm 2 will be concluded if the upper bound of the confidence interval is equal to, or falls below, the pre-specified margin at the final analysis. When evaluating the NI of arm 2 in OS, a Cox proportional hazards (PH) model stratified by stratification factors will be used to compute the hazard ratio and associated 95% confidence interval (CI). OS rates will be estimated using the Kaplan-Meier method. If the NI of arm 2 in OS is demonstrated, the superiority of arm 1 in OS will be tested at 1-sided significance level of 0.025 using a stratified log-rank test by adjusting for stratification factors.
Progression-free survival (PFS)
Time Frame: Time between date of randomization and first date of documented progression or death due to any cause, assessed up to 8 years
The PFS analysis will be conducted using the same methods and stratification factors as the OS analysis. The superiority of arm 2 in PFS will be tested at 1-sided significance level of 0.025 using a stratified log-rank test by adjusting for stratification factors. In the event that the NI of OS is not established, statistical inference of PFS will be considered exploratory in nature only. A Cox PH model stratified by stratification factors will be used to compute the hazard ratio and associated 95% CI.
Secondary Outcomes
- Objective response rate (ORR)(Up to 8 years)
- Time to progression(Up to 8 years)
- Time to primary, locoregional, or distant failure(Up to 8 years)
- Changes in pulmonary function(From randomization to 6 months or 12 months)
- Patient reported outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE)(At 3, 12, and 24 months)
- Functional Assessment of Cancer Therapy Lung (FACT-L) and Trial Outcome Index (TOI)(At 3, 12, and 24 months)
- European Quality of Life Five Dimension (EQ-5D) scale(At 3, 12, and 24 months)
- Incidence of adverse events(Up to 8 years)