Study of AZD9291 in NSCLC Patients Harboring T790M Mutation Who Failed EGFR TKI and With Brain and/or LMS

AZD9291 is an oral potent irreversible EGFR TKI selective for sensitizing EGFR mutation and T790M resistance mutation but sparing wild-type EGFR. Preclinical studies indicate that AZD9291 has significant exposure in the brain and activity against EGFR mutant brain metastasis. In addition, anti-tumor activities of AZD9291 in patients with advanced stage EGFR mutant NSCLC including patients with brain metastasis have been reported in an ongoing Phase I study. More recently, AZD9291 at a dose of 160mg also showed promising efficacy in heavily pre-treated patients with leptomeningeal disease from EGFR mutant NSCLC. Among 11 evaluable for response, 6 patients had LM imaging improvement and 3 out of 7 patients with abnormal neurological exam at baseline had symptomatic improvement. Compared to AZD9291, other 3rd generation EGFR TKIs, rociletinib or HM61713 has not been reported to be effective in most of CNS disease of NSCLC. Further, previous studies with AZD9291 showed anecdotal case series or undetermined for T790M mutation status, indicating more systematic study is warranted. Based on these data, the investigators are going to conduct phase II study of AZD9291 in NSCLC patients harboring T790M mutation who failed EGFR TKIs and brain and/or leptomeningeal metastasis.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

* EGFR activating mutant NSCLC patients who failed EGFR TKIs (gefitinib, erlotinib, or afatinib) and develop CNS disease (BM and/or LM) with T790M mutation either tissue or plasma. For patients with intracranial progression, prior radiation therapy is not mandatory. Extracranial progression is allowed.
* Patients who failed to 3rd generation EGFR TKIs (AZD9291 (80mg), Rociletinib, HM61713) and develop CNS progression but stable extracranial disease
* Age ≥18 years
* ECOG performance status of 0 to 2
* For BM, at least one measurable intracranial lesion as ≥ 10mm in the longest diameter by magnetic resonance imaging (MRI)
* For LM, at least one site of CNS leptomeningeal disease that can be assessed by MRI
* Adequate organ function as evidenced by the following;

  * Absolute neutrophil count \> 1.5 x 109/L;
  * platelets \> 100 x 109/L;
  * total bilirubin ≤1.5 UNL;
  * AST and/or ALT \< 5 UNL;
  * CCr ≥ 50mL/min.
* Female subjects must either be of non-reproductive potential
* Subject is willing and able to comply with the protocol
* Signed written informed consent

Exclusion Criteria:

* Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 1 week
* Any unresolved toxicities from prior therapy, greater than CTCAE grade 1
* Mean QT interval corrected for heart rate (QTc) ≥ 470 ms
* Uncontrolled systemic illness including uncontrolled hypertension, active bleeding, or active infection.
* Past medical history of interstitial lung disease, drug induced interstitial lung disease, radiation pneumonitis which required steroid treatment
* History of hypersensitivity to AZD9291
* Known intracranial haemorrahge which is unrelated to tumor Refractory nausea and vomiting

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