Almonertinib Combined With Cerebral Radiation Treat Brain Metastases From EGFR Positive NSCLC

An Exploratory Clinical Study of Almonertinib in Combination With Craniocerebral Radiotherapy in First-line Treatment of EGFR Positive Non-Small Cell Lung Cancer(NSCLC) With Brain Metastases

According to literature reports, about 16.3%-19% of newly diagnosed NSCLC patients are associated with brain metastasis, and 30%-50% of NSCLC patients will develop brain metastasis during the whole course of the disease.

Patients with EGFR positive-type had a 10-15% higher risk of brain metastasis than patients with EGFR wild-type. mOS in patients with EGFR positive were twice as high as those with EGFR wild-type, despite the presence of brain metastasis.

Improving the control rate of intracranial lesions in patients with EGFR positive can not only improve the quality of life, but also may translate into survival benefits and improve OS. Previous studies have shown that in lung cancer patients with EGFR-sensitive mutations, craniocerebral radiotherapy prior to delayed craniocerebral radiotherapy significantly prolonged OS.

The first-line treatment of the third generation of EGFR-TKI targeting drug Almonertinib for EGFR-positive NSCLC can eliminate the possible EGFR T790M mutant clones at an early stage and better control the disease progression. Moreover, Almonertinib is easy to pass through the blood-brain barrier, which can not only better control intracranial lesions, but also control, prevent or delay the occurrence of brain metastasis.

This study was intended to conduct a randomized controlled study on the safety and efficacy of early craniocerebral radiotherapy combined with Almonertinib in patients with EGFR positive non-small cell lung cancer with brain metastasis.

Through the above studies we hope to confirm that early craniocerebral radiotherapy combined with Almonertinib is safe and feasible for patients with EGFR positive newly diagnosed with brain metastasis, and can prolong the intracranial progression-free survival (IPFS), and even extend the progression-free survival (PFS) and overall survival (OS).

All eligible patients will receive craniocerebral radiotherapy in combination with Almonertinib.

Here are two types of craniocerebral radiotherapy:

1. SRS or SRT is recommended for patients with ≤4 intracranial metastases and the maximum lesion ≤4cm. 24-15 Gy*1F was recommended if use SRS. 9-12 Gy*3F or 6Gy×5F was recommended if use SRT.
2. For >4 intracranial metastases, or the maximum lesion>4cm, whole-brain radiotherapy (WBRT) of 30Gy/10F was recommended, and then the large residual lesions will be treated with a local dose (≤DT 45Gy/15F). Hippocampal protection is highly recommended.

Inclusion Criteria:

1. Age 18-75 years old (calculated from the time when the subject signed the informed consent), both male and female.

2. Confirmed pathology of EGFR mutation positive（exon 19 deletion, L858R, T790M）NSCLC with brain metastases on enhanced MRI.

3. Subjects had not previously received chemotherapy, EGFR-TKI, biologic or immunotherapy, or other experimental therapy as first-line treatment for advanced NSCLC.

4. According to RECIST 1.1 criteria, subjects must have a measurable target lesion (maximum diameter under MRI/CT ≥10mm, short diameter of lymph node ≥15mm) that has been examined by CT or MRI.Tumor imaging evaluation was performed within 28 days prior to initial treatment.

5. ECOG PS score: 0-1 points.

6. Must be able to swallow tablets，and expected survival ≥3 months.

7. Clinical diagnosis of Alzheimer's patients who can be treated with radiation therapy.

8. All screening laboratory tests are performed according to protocol and need to be performed within 14 days prior to the first dose.The values of laboratory tests performed by screening must meet the following criteria:

   1. Routine blood examination :(no blood transfusion, no G-CSF, no drug correction within 14 days before screening)

      • Hemoglobin (Hb) ≥90 g/L;
      • Absolute neutrophil count (ANC) ≥1.5×109/L;
      • Platelet count (PLT) ≥100×109/L;
      • White blood cell count (WBC) ≥4.0×109/L and ≤15×109/L;

   2. Biochemical test :(no blood transfusion or albumin within 14 days prior to screening)

      • AST and ALT ≤1.5×ULN (such as cancer that has spread to the liver, ≤5×ULN);
      • ALP≤2.5×ULN (such as tumor bone metastases, ≤5×ULN);
      • TBiL≤1.5×ULN.
      • ALB≥30 g/L;
      • Cr≤1.5×ULN, while creatinine clearance (CrCL)≥60 mL/min (Cockcroft - Gault formula);
      • APTT≤1.5×ULN, at the same time of INR or PT≤1.5×ULN (without anticoagulation therapy).

9. Women of childbearing age must have a serum pregnancy test within 3 days prior to the first dose and the results are negative.Women of reproductive age subjects and male subjects whose partners are women of reproductive age must agree to use barrier contraception (i.e., condoms) during the study period and for 180 days after the last administration of the study drug.

10. Volunteered to participate in clinical studies and signed informed consent.

Exclusion Criteria:

1. Exclusion criteria for target diseases:

   1. Subjects who had previously received anti-EGFR-TKI therapy.
   2. Patients with neuromeningeal disease but no intracranial metastases confirmed by MRI and/or CSF malignancy.
   3. Previous radiotherapy for CNS metastases, including measurable or unmeasurable sites of the disease for efficacy assessment.
   4. Patients who had undergone a major surgical procedure (other than placement of vascular access or CNS shunt) or had a major traumatic injury or were expected to require major surgery during the study period within 4 weeks prior to initial dosing.
   5. Subject who can be surgically excised or treated with radical radiotherapy.

2. History and complications:

   1. The patient is using (or cannot be discontinued for at least 1 week prior to the first dosing of the investigational treatment) some drug or herbal supplement known to be a strong depressant or inducer of CYP3A4/5 (Appendix 8).

   2. Excluding uncontrollable nausea and vomiting, chronic gastrointestinal disease, prior gastrectomy or other surgery, may affect the full absorption of the study drug.

   3. exclude the presence of any serious or uncontrolled systemic disease or condition, including:

      • Uncontrolled high blood pressure, diabetes, thyroid disease;
      • Severe heart, lung or kidney disease;
      • Active bleeding constitution;
      • Any bacterial, viral, fungal or other active infection that the Investigator considers to pose a serious risk to the patient;
      • Active hepatitis (HBsAg positive or HBcAb positive, HBV DNA positive), or HCV antibody positive or HIV positive.

   4. Patients with unstable symptomatic metastases: Any unstable and symptomatic CNS or distant metastases that were not controlled by previous surgery, radiotherapy, or corticosteroid treatment within 2 weeks prior to the initial study treatment.Corticosteroids were used before treatment for CNS symptoms, but the symptoms were controllable after treatment, and corticosteroids were used during radiotherapy.

   5. Exclude subjects who are participating in other clinical studies or whose first administration has been less than 3 weeks (or 5 half-lives of the investigational drug) since the end of the previous clinical study (last dosing).

   6. Excluding subjects who expected to require any other form of antitumor therapy (including maintenance therapy with other NSCLC drugs, and/or surgical resection) during the study.

   7. excluded subjects with high suspicion of interstitial pneumonia; Or subjects that may interfere with the detection or management of suspected drug-related pulmonary toxicity;Or other moderate to severe lung diseases that seriously affect lung function.

   8. Subjects with other active malignancies requiring concurrent treatment were excluded.

   9. Subjects with a previous history of malignancy were excluded unless they had achieved a complete response at least 5 years prior to screening and did not require or are not expected to require additional treatment during the study period for basal cell carcinoma of the skin, superficial bladder carcinoma, squamous cell carcinoma of the skin, or cervical carcinoma in situ.Rule out with Ⅱ magnitude myocardial ischemia and myocardial infarction, arrhythmia of the subjects of poor control.

   10. Ruled out according to the NYHA standard Ⅲ ~ Ⅳ level cardiac insufficiency or heart colour to exceed examination: LVEF, left ventricular ejection fraction < 50% of the subjects.

   11. Patients with significant hemoptysis or hemoptysis of half a teaspoon (2.5ml) or more per day within 1 month before randomization.

   12. Patients with bleeding symptoms of significant clinical significance or with definite bleeding tendency, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, or vasculitis, occurred within 1 month prior to randomization.

   13. Artery/venous thrombosis events occurred in the first 3 months at random, such as cerebrovascular accidents (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep venous thrombosis and pulmonary embolism, etc.

   14. Subjects with active tuberculosis (TB) were excluded.In subjects suspected of active TB, chest X-rays and sputum should be examined, and clinical signs and symptoms should be excluded.Subjects with a history of active tuberculosis infection within the previous 1 year were screened, even if they had been treated. Subjects with a history of active TB infection more than 1 year ago should also be excluded unless the course and type of anti-TB treatment previously used is demonstrated to be appropriate.

   15. Excluding subjects who were preparing for or had previously received tissue/organ transplants.

   16. Subjects who received or will receive live vaccine within 30 days prior to the first dose were excluded.

   17. Inclusion of subjects with uncontrolled tumor-related pain is not recommended.Subjects requiring pain medication must have a stable pain control regimen;Symptomatic lesions suitable for palliative radiotherapy (such as bone metastases or nerve invasion metastases) should be completed at least 2 weeks before inclusion; Asymptomatic metastatic foci whose further growth may result in dysfunction or intractable pain (e.g. epidural metastases that do not show spinal cord compression) should be considered for local-regional treatment before randomization, if appropriate.

3. Physical examination and laboratory examination

   1. A known history of positive human immunodeficiency virus (HIV) tests or a known history of acquired immunodeficiency syndrome (AIDS).

   2. Untreated active hepatitis:

      • Hepatitis B: HBV surface antigen (HBV sAg) positive and HBV DNA detection value is higher than the upper limit of normal value;
      • Hepatitis C: Hepatitis C virus antibody (HCV Ab) positive, HCV RNA positive, and abnormal liver function;
      • Complicated with hepatitis B and C co-infection.

   3. Exclude subjects with uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated drainage.

4. Allergic reactions and adverse drug reactions:Study drugs with CYP3A4 inhibition agents, inducers, or drugs with a narrow therapeutic window that are CYP3A4-sensitive substrates were used within 7 days before the first administration.

5. Patients receiving concurrent chemotherapy were excluded.

6. Excludes subjects with mental illness, alcoholism, inability to quit smoking, drug or substance abuse.

7. At the discretion of the Investigator, exclude subjects with history or current evidence of any disease, treatment or laboratory anomaly that may confuse study results, interfere with subjects' participation in the study procedure, or is not in the best interest of subjects' participation in the study.