TH-138: Phase II Randomized Trial of Carboplatin + Pemetrexed + Bevacizumab, With or Without Atezolizumab in Stage IV Non-squamous NSCLC Patients Who Harbor a Sensitizing EGFR Mutation or Have Never Smoked
While cigarette smoking remains the primary cause of most lung cancer cases, lung carcinoma in never smokers account for nearly 20 percent of cases. Never smokers with lung cancer typically present with different molecular profiles from that of smokers, which results in prognostic and therapeutic implications. Molecular changes in NSCLC that have therapeutic significance include mutations in the epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) gene. These driver mutations typically are present in lung tumors found in never or light smokers. The addition of bevacizumab to carboplatin and paclitaxel in first-line treatment of non-squamous NSCLC showed improved survival compared to carboplatin and paclitaxel alone, 12.3 vs. 10.3 months respectively. Results from the POINTBREAK trial demonstrated that carboplatin + pemetrexed + bevacizumab is an alternative option to carboplatin + paclitaxel + bevacizumab, with comparable survival but less toxicity. In recent years, immunotherapy has emerged as a form of treatment that can lead to robust responses in a subset of patients. The PD-1 inhibitor nivolumab and the PD-L1 inhibitor atezolizumab have shown prolonged survival in comparison to docetaxel in patients who previously progressed with chemotherapy, irrespective of PD-L1 expression. Thus, this study combines immunotherapeutic agent atezolozumab with an ant-angiogenic agent, bevacizumab, and double platinum therapy (carboplatin and pemetrexed).
• Must have histologically or cytologically confirmed stage IV non-squamous non-small cell lung cancer
• Must have either tumors that harbor an EGFR mutation in exon 19 or exon 21, or must be never smoker wild-types. Never smoker wild-types are defined as patients with tumors without an ALK or ROS1 rearrangement, and are not harboring any EGFR mutation (this includes exons 19 or 21, exon 20, and any other rare EGFR mutations). Never smoker wild-type patients must have smoked less than 100 cigarettes in a lifetime. Patients with an EGFR mutation in exon 19 or 21 may be included irrespective of their smoking history. If a patient whose tumor originally had an exon 19 or 21 mutation develops a secondary activating or sensitizing mutation in exon 18-21 as a result of resistance to EGFR TKI therapy, then that patient is eligible. If tissue-based testing for EGFR mutation status is not available, blood-based EGFR testing that confirms presence of a mutation in exon 19 or 21 is acceptable, and these patients may be included in the stud
• Must have measurable disease by CT or MRI, defined as at least one lesion that can be accurately measured in at least one dimension in accordance with RECIST criteria v 1.1
• Tumors that harbor an EGFR exon 19 or exon 21 mutation must have received prior treatments with one or more TKIs. A minimum washout period of 3 days is required to begin treatment in this trial. Patients who are never smoker wild-types must be treatment naïve
• Must be chemotherapy, anti-VEGF therapy alone, and immunotherapy naive, with the exception of prior oral TKIs which are required for EGFR mutated patients. Patients who have received prior anti-VEGF therapy in combination with a TKI for advanced stage EGFR-mutated disease may be included. The number of prior oral TKIs and duration of use is neither specified nor limited.
• History of treated asymptomatic CNS metastases are eligible, provided they meet all of the following criteria:
‣ No ongoing requirement for corticosteroids as therapy for CNS disease
⁃ No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to randomization
⁃ No clinical evidence of interim progression between the completion of CNS-directed therapy and the screening radiographic study
⁃ New asymptomatic CNS metastases detected at the screening scan must be ≤1 cm in size with no prior radiation therapy. These patients may then be eligible without the need for an additional brain scan prior to randomization, if all other criteria are met
• May have received curative intent therapy (adjuvant therapy or therapy for locally advanced NSCLC), if this therapy was completed greater than 1 year from entry into the trial
• Age \> 18 years
• ECOG performance status of 0 or 1
• Must have normal organ and marrow function as defined below. The use of G-CSF should follow standard recommendations and physician discretion. If blood transfusion is performed for achieving hemoglobin levels, the levels should stay at ≥ 9.0 mg/ml for at least a week after transfusion.
∙ Absolute neutrophil count \> 1,500/mcL Hemoglobin ≥ 9.0 mg/ml Platelets \> 100,000/mcL Total bilirubin ≤1.5 X institutional upper limit of normal (ULN) AST/ALT (SGOT/SGPT) \< 3 times institutional normal limits, or up to 5 times institutional normal limits if the patient has liver metastases Creatinine OR Creatinine clearance ≤1.5 X ULN, OR \> 40 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal as per Cockcroft-Gault formula International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Activated Partial Thromboplastin Time (aPTT) \<1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants Thyroid stimulating hormone (TSH) Within normal limits a
∙ a: If TSH is not within normal limits at baseline, the subject will still be eligible if total T3 or free T4 are within normal limits.
• Full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). If receiving warfarin, the patient must have an INR ≤3.0. For heparin and LMWH there should be no clinically significant active bleeding (with no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices).
• Ability to understand and willingness to sign a written informed consent and HIPAA consent document.
• A biopsy, either core, cell block from FNA or cell block from surgical resection, must be available for the study. If the sample is not adequate, the patient must agree to provide a fresh biopsy specimen before the start of treatment. Any available archival tissue will also be collected. While a biopsy sample must be adequate and available for the study, an inadequate tissue sample would not be explicitly exclusionary and further discussion with the sponsor is allowed to assess the eligibility of the patient for the trial if, for clinical or other reasons, a new biopsy sample cannot be obtained.
• Urinary protein must be ≤1+ on dipstick or routine urinalysis (UA; if urine dipstick or routine analysis is ≥2+, a 24 hour urine collection for protein must demonstrate \<1000 mg of protein in 24 hours to allow participation in the protocol).
• Females of child-bearing potential must be willing to use an effective method of contraception, for the course of the study through at least 6 months after the last dose of study medication.
• Males who have Women of Child-bearing Potential (WOCBP) partners must agree to use effective method of contraception for the course of the study through 8 months after the last dose of study medication.
‣ Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.