Amivantamab, Lazertinib and Bevacizumab in Patients With EGFR-mutant Advanced Non-small Cell Lung Cancer With Progression on Previous Third-generation EGFR-TKI

Inclusion Criteria:

1. Histologically confirmed non-squamous NSCLC, stage IIIB/C (not amenable to radicaltherapy) or stage IV according to 8th TNM classification.

2. Presence of a sensitising EGFR-mutation (only patients with exon 19 deletion and/orL858R are eligible) and documentation of T790M status, tested locally by anaccredited laboratory.

3. Radiologically confirmed disease progression on previous treatment with osimertinibor lazertinib.Treatment with osimertinib must have been stopped at least 8 daysbefore enrolment.

4. Achieved objective clinical benefit from osimertinib or lazertinib treatment (e.g.,documented PR/ CR or SD for ≥6 months while on osimertinib or lazertinib treatment).

5. Measurable disease as defined according to RECIST v1.1.

6. Age ≥18 years.

7. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

8. Life expectancy ≥12 weeks.

9. Adequate haematological function:

• Haemoglobin ≥100 g/L,

• Absolute neutrophil count (ANC) ≥1.5× 109/L,

• Platelet count ≥75× 109/L.

10. Adequate renal function:

• Serum creatinine <1.5× ULN and calculated (Cockcroft-Gault formula) or measuredcreatinine clearance >45 mL/min.

11. Adequate liver function:

• ALT and AST ≤3× ULN. If the patient has liver metastases, ALT and AST must be ≤5× ULN.

• Total bilirubin ≤1.5× ULN. Patients with Gilbert's syndrome are eligible ifconjugated bilirubin is within normal limits.

12. Women of childbearing potential, including women who had their last menstruation inthe last 2 years, must have a negative pregnancy test (b-human chorionicgonadotropin [b-hCG]) within 5 weeks before enrolment and within 3 days before thefirst dose of protocol treatment. Women of childbearing potential must use highlyeffective contraceptive methods.

13. Written IC for trial participation must be signed and dated by the patient and theinvestigator prior to any trial-related intervention.

Exclusion Criteria:

1. Patients with known small cell lung carcinoma (SCLC) transformation.

2. Patients with symptomatic brain metastases. Patients with asymptomatic or previouslytreated and stable brain metastases may participate in this study. Patients who havereceived definitive radiotherapy or surgery for symptomatic or unstable brainmetastases and have been clinically stable and asymptomatic for at ≥2 weeks beforeenrolment are eligible, provided they have been either off corticosteroid treatmentor are receiving low-dose corticosteroid treatment (≤10 mg/day prednisone orequivalent) for at least 2 weeks prior to enrolment.

3. Patients with an active or past medical history of leptomeningeal disease.

4. Patients with untreated spinal cord compression. Patients who have been definitivelytreated with surgery or radiotherapy and have a stable neurological status for ≥2weeks prior to enrolment are eligible provided they are off corticosteroid treatmentor are receiving low-dose corticosteroid treatment ≤10 mg/day prednisone orequivalent.

5. Patients with unresolved adverse events (other than alopecia) from prior anticancertherapy that have not resolved to grade ≤1 or baseline.

6. Patients with positive hepatitis B (hepatitis B virus [HBV]) surface antigen (HBsAg)test.

7. Patients with positive hepatitis C antibody (anti-HCV) test.

8. Patients with other clinically active infectious liver disease.

9. Patients who are known positive for HIV, with one or more of the following:

• Receiving antiretroviral therapy (ART) that may interfere with study treatment

• CD4 count <350 at screening.

• AIDS-defining opportunistic infection within 6 months before enrolment.

• Not agreeing to start ART and be on ART >4 weeks plus having HIV viral load <400 copies/mL at end of 4-week period (to ensure ART is tolerated and HIV isunder control).

10. Patients with active cardiovascular disease including, but not limited to:

• Medical history of deep vein thrombosis or pulmonary embolism within 1 monthprior to enrolment or any of the following within 6 months prior to enrolment:Myocardial infarction, unstable angina, stroke, transient ischemic attack,coronary/peripheral artery bypass graft, or any acute coronary syndrome.

• Prolonged corrected QTcF >470 msec, clinically-significant cardiac arrhythmia (e.g., atrial fibrillation with uncontrolled rate) or abnormalities inconduction or morphologiy of electrocardiogram (ECG) (e.g., complete leftbundle branch block, third- or second-degree heart block, PR interval >250msec), or electrophysiologic disease (eg, placement of implantable cardioverterdefibrillator).

• Any factors that increase the risk of QTc prolongation or risk of arrhythmicevents such as, hypokalemia, congenital long QT syndrome, family history oflong QT syndrome, or unexplained sudden death under 40 years in first degreerelatives or any concomitant medications known to prolong QT interval or induceTdP.

• Uncontrolled (persistent) hypertension: systolic blood pressure >160 mm Hg;diastolic blood pressure >100 mm Hg.

• Congestive heart failure (CHF), defined as New York Heart Association (NYHA)class III-IV or hospitalisation for CHF (any NYHA class) within 6 months beforeenrolment.

• An active or past medical history of pericarditis, pericardial effusion that isclinically unstable, or myocarditis.

• Pericardial effusion considered due to the disease under study is permitted ifclinically stable at screening.

• Baseline LVEF either <50% or below the lower limit of normal (LLN) perinstitutional guidelines, as assessed by screening echocardiogram (ECHO) ormultigated acquisition (MUGA) scan.

11. Patients with interstitial lung disease (ILD), including drug-induced ILD orradiation pneumonitis.

12. Patients with a history of haemoptysis (≥2.5 mL of bright red blood per episode)within 1 month prior to enrolment.

13. Patients with evidence of bleeding diathesis or coagulopathy (in the absence oftherapeutic anticoagulation).

14. Patients with current or recent (within 10 days before enrolment) use of aspirin (>325 mg/day) or treatment with dipyridamole, ticlopidine, clopidogrel, andclostazol.

15. Patients with current use of full-dose oral or parenteral anticoagulants orthrombolytic agents for therapeutic purposes that has not been stable for >2 weeksprior to enrolment.

• The use of full-dose oral or parenteral anticoagulants is permitted as long asthe INR or aPTT is within therapeutic limits (according to the medical standardof the enrolling institution) and the patient has been on a stable dose ofanticoagulants for at least 2 weeks prior to enrolment.

• Prophylactic anticoagulation for the patency of venous access devices isallowed, provided the activity of the agent results in an INR <1.5× ULN andaPTT is within normal limits within 14 days prior to enrolment.

• Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day)is permitted.

16. Patients with serious, non-healing wound, active ulcer, or untreated bone fracture.

17. Patients who had a core biopsy or other minor surgical procedure, excludingplacement of a vascular access device, within 7 days prior to enrolment.

18. Patients who had major surgery or significant traumatic injury within 28 days priorto enrolment.

19. Patients who had placement of a vascular access device within 2 days prior to priorto enrolment.

20. Patients with a history of abdominal or tracheoesophageal fistula orgastrointestinal perforation within 6 months prior to enrolment.

21. Patients with clinical signs of gastrointestinal obstruction or requirement forroutine parenteral hydration, parenteral nutrition, or tube feeding.

22. Patients with evidence of abdominal free air not explained by paracentesis or recentsurgical procedure.

23. Patients with concurrent or prior malignancy other than the disease under study. Some exceptions require consultation with the ETOP IBCSG Partners

24. Patients with uncontrolled illness, including but not limited to:

• Uncontrolled diabetes.

• Ongoing or active infection, or diagnosed or suspected viral infection.

• Active bleeding diathesis.

• Impaired oxygenation requiring continuous oxygen supplementation.

• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability toswallow the formulated drug, or previous significant bowel resection

• Psychiatric illness, social situation, or any other circumstances that wouldlimit compliance with study requirements.

• Any ophthalmologic condition that is clinically unstable.

25. History of hypersensitivity to either the drug substance or any excipients inamivantamab, lazertinib and/ or bevacizumab.

26. Prior chemotherapy for NSCLC.

27. Prior treatment with bevacizumab or another anti-angiogenic inhibitor.

28. Prior treatment with a MET/EGFR-targeting antibody.

29. Judgement by the investigator that the patient should not participate in the studyif the patient is unlikely to comply with study procedures, restrictions andrequirements.

30. Women who are pregnant or in the period of lactation.

31. Women of childbearing potential or men who are sexually active with a woman ofchildbearing potential, who are not willing to use at least one method of highlyeffective contraception while receiving protocol treatment and for at least 6 monthsafter the last dose of protocol treatment.