Atezolizumab Immunotherapy in Patients With Advanced NSCLC (AJCC 7th Edition)

Overview

About this study

Phase II trial of induction immunotherapy with atezolizumab for patients with unresectable stage IIIA and IIIB NSCLC  (AJCC 7th Edition) eligible for chemoradiotherapy with curative intent.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

Inclusion Criteria:

  • Age ≥ 18 years.
  • Newly diagnosed stage IIIA/B NSCLC, PS 0-1.
  • No active autoimmune disease or uncontrolled infection, normal bone marrow, renal, hepatic function, FEV1 > 1.2L, no significant underlying heart or lung disease.
  • Pathologically proven diagnosis of NSCLC.
  • Measurable Stage IIIA or IIIB disease.
  • Tissue available for PD-L1 testing and for correlative science testing.
  • Patients must be considered unresectable or inoperable. Patients with nodal recurrence after surgery for early-stage NSCLC are eligible if the following criteria are met:
    • No prior chemotherapy or radiation for this lung cancer;
    • Prior curative-intent surgery at least 3 months prior to the nodal recurrence.
  • Stage III A or B disease with minimum diagnostic evaluation within 6 weeks to include:
    • History/physical examination;
    • Contrast enhanced CT of the chest and upper abdomen;
    • MRI of the brain with contrast (or CT with contrast if MRI is medically contraindicated);
    • PET/CT.
  • If pleural fluid is visible on CT scan thoracentesis to exclude malignancy should be obtained. Patients with effusions that are too small to tap are eligible.
  • Patients must be at least 4 weeks from major surgery and must be fully recovered.
  • Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks or at least 4 unstained slides, with an associated pathology report, for central testing of tumor PD-L1 expression:
    • If an archived tumor block exists, then either the block or at least 4 unstained slides from the block should be submitted. Tumor tissue should be of good quality based on total and viable tumor content, i.e. at least 50 viable tumor cells and intact tissue architecture. Fine needle aspiration, brushing,and lavage samples are not acceptable. If the block is tissue from a core-needle biopsy, then the block should contain tissue from at least three cores to be sufficient for evaluation;
    • Patients who do not have existing (archived) tissue specimens meeting eligibility requirements may undergo a biopsy during the screening period. Acceptable samples include core needle biopsies for deep tumor tissue (minimum of three cores) or excisional, or forceps biopsies for endobronchial or nodal lesions. The tissue should be fixed in formalin and embedded on site and sent as a block.
  • Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment (Cycle 1, Day 1):
    • ANC ≥ 1500 cells/µL;
    • WBC counts > 2500/µL;
    • Lymphocyte count ≥ 300/µL;
    • Platelet count ≥ 100,000/µL;
    • Hemoglobin ≥ 10.0 g/dL;
    • Total bilirubin ≤ 1.5 x upper limit of normal (ULN) with the following exception:
      • Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled.
    • AST and ALT ≤ 3.0 x ULN
    • Alkaline phosphatase ≤ 2.5 x ULN
    • Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation:
      • (140 - age) x (weight in kg) x (0.85 if female)/ 72 x (serum creatinine in mg/dL)
  • Measurable disease per RECIST v1.1.
  • For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use highly effective form(s) of contraception (i.e., one that results in a low failure rate [< 1% per year] when used consistently and correctly) and to continue its use for 150 days after the last dose of Atezolizumab.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

Exclusion Criteria:

  • Active autoimmune disease.
  • Greater than minimal, exudative, or cytologically positive pleural effusions.
  • Involved contralateral hilar nodes.
  • 10% weight loss within the past month.
  • Known EGFR exon 19 or 21 mutation or ALK rearrangement.
  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; non-invasive conditions such as carcinoma in situ of the breast, localized prostate cancer, carcinoma in situ of the oral cavity, or cervix are all permissible.
  • Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable.
  • Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
  • Prior severe infusion reaction to a monoclonal antibody.
  • Severe, active co-morbidity, defined as follows:
    • Significant history of uncontrolled cardiac disease; i.e., uncontrolled hypertension, unstable angina, myocardial infarction within the last 6 months, uncontrolled congestive heart failure, and cardiomyopathy with decreased ejection fraction;
    • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration or within 2 weeks of cycle 1 day 1;
    • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 days before registration.
  • Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
  • Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, HIV testing is required for entry into this protocol due to the immunologic basis for induction treatment.
  • Pregnancy, lactation, or inability or unwillingness to use medically acceptable forms of contraception if pregnancy is a risk.
  • Any history of allergic reaction to paclitaxel or other taxanes, or to carboplatin.
  • Uncontrolled neuropathy grade 2 or greater regardless of cause.
  • Any approved anticancer therapy, including chemotherapy, hormonal therapy, or radiotherapy, within 3 weeks prior to initiation of study treatment; however, the following are allowed:
    • Hormone-replacement therapy or oral contraceptives;
    • Herbal therapy > 1 week prior to Cycle 1, Day 1 (herbal therapy intended as anticancer therapy must be discontinued at least 1 week prior to Cycle 1, Day 1).
  • Known clinically significant liver disease, including active viral, alcoholic, or other hepatitis; cirrhosis; fatty liver; and inherited liver disease.
  • Patients with past or resolved hepatitis B infection (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible.
  • Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  • Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.
  • Inability to comply with study and follow-up procedures.
  • History of active autoimmune disease, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Bell's palsy, Guillain-Barré syndrome, multiple sclerosis, autoimmune thyroid disease, vasculitis, or glomerulonephritis.
  • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
  • Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.
  • Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:
    • Patients with psoriasis must have a baseline ophthalmologic exam to rule out ocular manifestations;
    • Rash must cover less than 10% of body surface area (BSA);
    • Disease is well controlled at baseline and only requiring low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alcometasone dipropionate 0.05%);
    • No acute exacerbations of underlying condition within the last 6 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors; high potency or oral steroids).
  • History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan.
  • Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications.
  • Active tuberculosis.
  • Major surgical procedure within 28 days prior to Cycle 1, Day 1 or anticipation of need for a major surgical procedure during the course of the study.
  • Administration of a live, attenuated vaccine within 4 weeks before Cycle 1, Day 1 or anticipation that such a live, attenuated vaccine will be required during the study.
  • Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (e.g., FluMist®) within 4 weeks prior to Cycle 1, Day 1 or at any time during the study.
  • Malignancies other than the disease under study within 5 years prior to Cycle 1, Day 1, with the exception of those with a negligible risk of metastasis or death and with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent) or undergoing active surveillance per standard-of-care management (e.g., chronic lymphocytic leukemia Rai Stage 0, prostate cancer with Gleason score ≤ 6, and prostate-specific antigen [PSA] ≤ 10 mg/mL, etc.).

Medication-Related Exclusion Criteria:

  • Prior treatment with anti-PD-1, or anti-PD-L1 therapeutic antibody or pathway targeting agents.
  • Treatment with systemic immunostimulatory agents (including but not limited to interferon [IFN].

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Panayiotis Savvides, M.D., Ph.D.

Closed for enrollment

Contact information:

Cancer Center Clinical Trials Referral Office

(855) 776-0015

More information

Publications

  • Immune checkpoint inhibitors have improved clinical outcomes associated with numerous cancers, but high-grade, immune-related adverse events can occur, particularly with combination immunotherapy. We report the cases of two patients with melanoma in whom fatal myocarditis developed after treatment with ipilimumab and nivolumab. In both patients, there was development of myositis with rhabdomyolysis, early progressive and refractory cardiac electrical instability, and myocarditis with a robust presence of T-cell and macrophage infiltrates. Selective clonal T-cell populations infiltrating the myocardium were identical to those present in tumors and skeletal muscle. Pharmacovigilance studies show that myocarditis occurred in 0.27% of patients treated with a combination of ipilimumab and nivolumab, which suggests that our patients were having a rare, potentially fatal, T-cell-driven drug reaction. (Funded by Vanderbilt-Ingram Cancer Center Ambassadors and others.). Read More on PubMed
  • Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population. Read More on PubMed
  • Despite the availability of radiotherapy, cytotoxic agents, and targeted agents, a high unmet medical need remains for novel therapies that improve treatment outcomes in patients with lung cancer who are ineligible for surgical resection. Building upon the early promise shown with general immunostimulatory agents, immuno-oncology is at the forefront of research in this field, with several novel agents currently under investigation. In particular, agents targeting immune checkpoints, such as the cytotoxic T-lymphocyte antigen-4 (CTLA-4) receptor and programmed death-1 (PD-1) receptor, have shown in early clinical trials potential for improving tumor responses and survival in patients with non-small cell lung cancer (NSCLC). Here, we examine the rationale for targeting immune checkpoints in lung cancer and review the clinical data from studies with immune checkpoint inhibitors currently in development. The challenges associated with optimizing treatment with these agents in lung cancer also are discussed. Read More on PubMed
  • Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. Read More on PubMed
  • Immune-related response criteria (irRC) was developed to adequately assess tumor response to immunotherapy. The irRC are based on bidimensional measurements, as opposed to unidimensional measurements defined by Response Evaluation Criteria in Solid Tumors, which has been widely used in solid tumors. We aimed to compare response assessment by bidimensional versus unidimensional irRC in patients with advanced melanoma treated with ipilimumab. Read More on PubMed
  • Assessment of the change in tumour burden is an important feature of the clinical evaluation of cancer therapeutics: both tumour shrinkage (objective response) and disease progression are useful endpoints in clinical trials. Since RECIST was published in 2000, many investigators, cooperative groups, industry and government authorities have adopted these criteria in the assessment of treatment outcomes. However, a number of questions and issues have arisen which have led to the development of a revised RECIST guideline (version 1.1). Evidence for changes, summarised in separate papers in this special issue, has come from assessment of a large data warehouse (>6500 patients), simulation studies and literature reviews. HIGHLIGHTS OF REVISED RECIST 1.1: Major changes include: Number of lesions to be assessed: based on evidence from numerous trial databases merged into a data warehouse for analysis purposes, the number of lesions required to assess tumour burden for response determination has been reduced from a maximum of 10 to a maximum of five total (and from five to two per organ, maximum). Assessment of pathological lymph nodes is now incorporated: nodes with a short axis of 15 mm are considered measurable and assessable as target lesions. The short axis measurement should be included in the sum of lesions in calculation of tumour response. Nodes that shrink to <10mm short axis are considered normal. Confirmation of response is required for trials with response primary endpoint but is no longer required in randomised studies since the control arm serves as appropriate means of interpretation of data. Disease progression is clarified in several aspects: in addition to the previous definition of progression in target disease of 20% increase in sum, a 5mm absolute increase is now required as well to guard against over calling PD when the total sum is very small. Furthermore, there is guidance offered on what constitutes 'unequivocal progression' of non-measurable/non-target disease, a source of confusion in the original RECIST guideline. Finally, a section on detection of new lesions, including the interpretation of FDG-PET scan assessment is included. Imaging guidance: the revised RECIST includes a new imaging appendix with updated recommendations on the optimal anatomical assessment of lesions. Read More on PubMed
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