A Multinational Study Assessing an Oral EGFR Inhibitor, DZD6008 in Patients Who Have Advanced NSCLC With EGFR Mutations (TIAN-SHAN1)

The study includes two parts: Part A (dose escalation) and Part B (dose expansion). In Part A, locally advanced or metastatic NSCLC patients with EGFR mutations following at least 1 prior EGFR TKI regimen will be enrolled. In Part B, locally advanced or metastatic NSCLC patients with EGFR sensitizing mutations, who are previously treated with 1 line of third-generation of EGFR TKI treatment as well as treatment naïve will be enrolled.

Inclusion criteria

• Patients must be able to provide documented informed consent.
• Aged ≥ 18 years.
• Histologically or cytologically confirmed diagnosis of NSCLC, locally advanced or metastatic, not suitable for curative therapy.
• Documentation of EGFR mutations from a local CLIA-certified laboratory (or equivalent). For Part A monotherapy cohorts and all cohorts of Part B, EGFR sensitizing mutations (Exon19del and/or L858R) are required.
• Provide adequate amount of pretreatment tumor samples collected after disease progression on the last EGFR TKI treatment. (previously treated patients) or before study treatment (treatment naïve patients).
• Part A: Failed (progressed or are intolerant) from at least 1 prior EGFR TKI regimen. Cohort A of Part B: Failed 1 prior third-generation EGFR TKI regimen. Cohorts B of Part B: Patients who are treatment naïve.
• ECOG 0 or 1 with predicted life expectancy ≥ 12 weeks.
• Patients with brain metastases must have a stable BM status.
• Measurable disease per RECIST 1.1.
• Adequate hematopoietic and other organ system functions.
• Male Patients with female partners of childbearing potential should use barrier contraceptives and refrain from donating sperm during their participation in this study and for 3 months following the last dose of the study drug.

Exclusion criteria

• Carry other EGFR alterations than T790M and C797X, including but not limited to uncommon EGFR mutations (G719X, S768I, L861Q, exon 20 insertions mutations, etc.)(Part B).
• NSCLC with mixed small cell lung cancer (SCLC) or NSCLC with histologic SCLC transformation.
• Prior treatment with any of the following: 1)Immunotherapy or other antibody therapy within 4 weeks prior to the first administration; 2)Any cytotoxic chemotherapy, investigational drugs or other anticancer drugs from a previous treatment regimen or clinical study within 14 days prior to the first administration; 3)Radiotherapy with a limited field of radiation for palliation within 7 days of the first dose, radiation to more than 30% of the bone marrow or with a wide field of radiation within 28 days before screening; 4)Currently receiving or unable to stop drug or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP)3A4. A washout period of at least 2 weeks for strong inhibitors and 3 weeks for strong inducers is required prior to the first study drug administration; 5)currently receiving or unable to stop drugs known to be CYP3A4 sensitive substrate with a narrow therapeutic index. A washout period of at least 14 days is required prior to the first study drug administration; 6)currently receiving or unable to stop drugs known to be proton pump inhibitors. A washout period of at least 7 days is required prior to the first study drug administration; 7)major surgery within 4 weeks of the first administration of DZD6008 or anticipated during the study period.
• Any unresolved toxicities from prior anti-cancer therapy greater than CTCAE Grade 1.
• Spinal cord compression or leptomeningeal metastasis.
• Patients with any other malignancy within 2 years of the first administration of study drug.
• Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses as judged by investigator.
• Patients with active infection, including but not limited to HBV, HCV, HIV and active infection of COVID-19.
• Resting QTcF > 470 msec; Any clinically significant abnormalities in rhythm, conduction or morphology of resting ECG;Any factors that increase the risk of QTc prolongation.
• Past medical history of ILD or active ILD.
• Diseases which would preclude adequate absorption of DZD6008.
• Received a live vaccine within 2 weeks before the first administration of DZD6008.
• Women who are pregnant or breastfeeding.
• Hypersensitivity to active or inactive excipients of DZD6008 or sunvozertinib.
• Involvement in the planning and conduct of the study.
• Judgment by the investigator that the patient is unlikely to comply with study procedures