Patient case: 32-year-old female with inflammatory myofibroblastic tumor; genetic feature: RANBP2-ALK fusion

Clinical trial: Atezolizumab in Combination With Carboplatin Plus Pemetrexed in Chemotherapy-naïve Patients With Asymptomatic Brain Metastasis

Summary: This is a multicenter, national, nonrandomized, phase II trial in subjects with nonsquamous NSCLC patients that have untreated asymptomatic BM. A pre-screening period using brain MRI for patients diagnosed with advanced non-squamous NSCLC EGFR/ALK wild type and ECOG PS 0-1 will be crucial to identify patients with asyntomatic BM. Forty patients will be recruited.

Detailed description: Atezolizumab will be administered intravenously (iv) at a dose of 1200 mg/ kg over 60 minutes on day 1 of each cycle. The subsequent cycles of atezolizumab can be administered over 30 minutes, if there were no infusion-related toxicities. Pemetrexed will be administered at a dose of 500 mg/m2 iv over 15 minutes on day 1 of each cycle. In addition, folic acid, vitamin B12, and dexamethasone 4mg bid will be administered one day before and after pemetrexed treatment. Carboplatin will be administered at a dose with an area under the curve of 5 over 30 minutes on day 1 of each cycle approximately 30 minutes after the end of the pemetrexed infusion. After completing 4 to 6 cycles of carboplatin plus pemetrexed and atezolizumab, patients will continue with pemetrexed in combination with atezolizumab until unacceptable toxicity, disease progression, patient/physician decision or completion of 2 years of therapy.
  Tumor measurements by CT scan (systemic response) and brain MRI (intracranial response) will be performed every 6 weeks until the 12th week and thereafter every 9 weeks until disease progression. In case of brain progression, rescue with brain radiotherapy should be considered. In case of exclusive brain progression, patients are allowed to receive brain radiotherapy (WBRT or SRS) and then continue with study therapy if the patients maintain clinical benefit and appropriate performance status (ECOG PS≤2).Immunotherapy should be started no later than 4 weeks after completing radiation therapy (brain radiotherapy 2 weeks + 4 weeks of recovery from potential acute toxicity). In case of systemic progression without brain progression, a novel line of systemic treatment should be considered. Patients experiencing systemic progression and/or brain progression will be followed and two post-progression visits will be performed at 30 and 90 days.
  Response will be assessed independently in the brain and systemically: systemic response will be evaluated according to RECIST v1.1 and brain response according to the RANO response assessment criteria for BM (RANO-BM). Adverse events will be assessed throughout and assessed using the CTCAE version 4.03. EORTC quality of life questionnaire EORTC C30 and the submodules QLQ-LC13 and BN20 will be assessed in the ITT population at baseline, cycle 5 (week 12),cycle 9 (week 24), at end of study treatment (30 and 90 days) and/or at disease progression. Periodic evaluations of the trial data will be conducted by an independent DMC to ensure subject safety and to evaluate the efficacy at the interim analyses. Neurocognitive assessment including the standardized neuropsychological tests: Hopkins Verbal Learning Test (HVLT), Trail Making Test (TMT), Rey-Osterrieth complex figure test (ROCF) and Controlled Oral Word Association Test (COWA) will be assessed at baseline cycle 5 (week 12),cycle 9 (week 24), at end of study treatment (30 and 90 days) and/or at disease progression.

Eligibility: Inclusion Criteria:
  -  Patients aged 18 years or older.
  -  Signed written informed consent.
  -  ECOG Performance Status (PS) of 0 to 1.
  -  Subjects with histologically or cytologically confirmed stage IV non-squamous NSCLC who did not received any prior chemotherapy or brain radiotherapy. Patients with EGFR mutation or ALK fusion will be excluded.
  -  Patients who received prior neo-adjuvant, adjuvant chemotherapy or chemoradiotherapy with curative intent for non-metastatic disease must have experienced a treatment-free interval of at least 6 months since the last dose of chemotherapy and/or radiotherapy.
  -  Asymptomatic untreated brain metastases. Steroids treatment (dexamethasone) is allowed and patients that remained asymptomatic for 2 weeks on steroids will be eligible when they were receiving ≤ 4mg dexamethasone once a day.
  -  Systemic measurable disease by computed tomography (CT) per response evaluation criteria in solid tumors version (RECIST) 1.1 criteria AND brain measurable disease by magnetic resonance imaging (MRI) per RANO-BM criteria (at least two measurable lesions ≥10mm, see appendix).
  -  Availability of a formalin-fixed paraffin-embedded block containing tumor tissue or 5 unstained slides
  -  Adequate hematopoietic, hepatic and renal function (including calculated creatinine clearance of 45 ml/min based on the standard Cockcroft and Gault formula).
  -  Patients willing to use highly effective (<1% failure rate) forms of contraception.
  Exclusion Criteria:
  -  History of other malignancy within 3 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, or Stage I uterine cancer
  -  Known activating EGFR mutation or ALK fusion
  -  Leptomeningeal carcinomatosis or metastases in the brain stem, mid-brain, pons, medulla or lesions causing obstructive hydrocephalus
  -  Patients with neurological symptoms, including those receiving > 4mg of dexamethasone will not be eligible for this study
  -  Single exclusive brain metastasis amenable to surgical treatment or radiosurgery in patients not having metastasis in other organ
  -  Spinal hemorrhagic metastases will be excluded
  -  Prior surgical resection of brain or spinal lesions in the prior 28 days
  -  Previous systemic treatment or neo-adjuvant or adjuvant chemotherapy less than 6 months before enrollment
  -  Clinical significant comorbidities that impaired administration of platinum-based chemotherapy
  -  History of autoimmune disease
  -  Active severe infection
  -  History of idiopathic pulmonary fibrosis, drug-induced pneumonitis or radiation pneumonitis out of the radiation field
  -  Positive test for HIV, hepatitis B or hepatitis C
  -  Previous treatment with immune checkpoint inhibitors or agonists (e.g. CD137 and OX-40)
  -  Pregnancy or breast-feeding

Relevance to patient case: not relevant