Sacituzumab Govitecan and Bevacizumab for NSCLC Brain Metastases

Inclusion Criteria:

• In order to be eligible to participate in this study, a subject must meet all of thefollowing criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Participant is an adult ≥ 18 years of age at the time of informed consent.

3. ECOG performance status ≤1.

4. Estimated life expectancy of 12 weeks or more.

5. Pathology proven metastatic non-squamous NSCLC

6. For those without an actionable oncogenic driver: progression on immunotherapyand/or platinum-doublet chemotherapy (concurrent or sequential, in any order).If contra-indication for immunotherapy: progression on platinum-doubletchemotherapy.

7. For those with an actionable oncogenic driver: progression on targeted therapyand platinum-doublet chemotherapy. For the latter group, previous ICI isallowed but not mandatory.

8. BM not in eloquent area (all patients have at least to be discussed with aneurologist, and preferably they are discussed in the local neuro-oncologyMDT).

9. Maximum BM size 2 cm in longest diameter (for each BM).

10. At least one untreated brain metastasis ≥ 5mm:

11. Patients with largest measurable intracranial lesion ≥5 mm but <10 mm maybe allowed to enroll upon agreement with the principal investigator (forpatients with target lesions of ≥ 5mm but <10 mm, 1.5 mm slice thicknessbrain MRI is required).

12. Prior local treatment is permissible provided unequivocal progression inthe lesion has since occurred (discussed in neuro-oncology MDT) or if newlesions have occurred.

13. For at least 7 days prior to first dose of SG and bevacizumab in thisstudy: Patient must be asymptomatic from CNS metastases and on a stabledose of corticosteroids, with a maximum of 4 mg dexamethasone/day.Anti-epileptic dose should also be stable for 7 days.

14. Participant must have recovered from all toxicities related to prior treatmentsto grade ≤ 1 (CTCAE v 5.0). Exception to this criterion are alopecia andneuropathy of any grades.

15. Adequate organ function including the following laboratory values at thescreening visit:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L (without growth factorsupport),
• Platelets ≥ 100 x 109/L (without growth factor support),
• Hemoglobin (Hb) ≥ 6 mmol/l (= 9 g/dl) (7 days without transfusions orgrowth factor support),
• Aspartate transaminase (AST) ≤ 2.5 x ULN, or ≤ 5 × ULN if known livermetastases
• Alanine transaminase (ALT) ≤ 2.5 x ULN, or ≤ 5 × ULN if known livermetastases
• Serum albumin > 3 g/dL
• Total bilirubin ≤ 1.5 ULN,
• Creatinine clearance ≥ 30 mL/min by calculation using Cockcroft-Gaultformula or based on 24-hour urine sample assessment.

13. Participant is capable of following instructions regarding study treatmentadministration, and must be able to communicate with the Investigator andcomply with the requirements of the study procedures.

14. Negative serum or urine pregnancy test within 7 days prior to study treatmentin women with childbearing potential. Patient must be willing to use effectivemethods of contraception. Female patients must be postmenopausal, surgicallysterile, or they must agree to use a physical barrier method of contraceptionin addition to either an intrauterine device or hormonal contraception until atleast 4 months after termination of study drug.

Exclusion Criteria:

• A potential subject who meets any of the following criteria will be excluded fromparticipation in this study:

1. Leptomeningeal metastasis (based on MRI or CSF cytology, if strong suspiciondespite negative MRI, CSF analysis should be done).

2. Previous treatment with TROP2 inhibitor or angiogenesis inhibitor.

3. Known hypersensitivity to the study drugs, its metabolites, or formulationexcipient.

4. Positive serum pregnancy test or women who are breastfeeding.

5. Contra-indication for MRI.

6. History of allogeneic bone marrow or solid organ transplant.

7. Have had a prior anticancer biologic agent (ADC, ICI) within 4 weeks prior toenrolment or have had prior chemotherapy, targeted small molecule therapy, orradiation therapy within 2 weeks prior to enrolment and have not recovered (ie, ≥ Grade 2 is considered not recovered) from AEs at the time of study entry.a. Note: Patients participating in observational studies are eligible.

8. Have not recovered (ie, ≥ Grade 2 is considered not recovered) from AEs due toa previously administered agent.

9. Note: patients with any grade vitiligo or alopecia are an exception tothis criterion and will qualify for the study.

10. Note: if patients received major surgery, they must have recoveredadequately from the toxicity and/or complications from the interventionprior to starting therapy.

11. Have an active second malignancy. Note: patients with a history of malignancythat has been treated completely, with no evidence of active cancer for 3 yearsprior to enrollment, or patients with surgically cured tumours with low risk ofrecurrence (eg, nonmelanoma skin cancer, histologically confirmed completeexcision of carcinoma in situ, or similar) are allowed to enroll.

12. Met any of the following criteria for cardiac disease:

13. Myocardial infarction or unstable angina pectoris within 6 months ofenrollment.

14. History of serious ventricular arrhythmia (ie, ventricular tachycardia orventricular fibrillation), high-grade atrioventricular block, or othercardiac arrhythmias requiring antiarrhythmic medications (except foratrial fibrillation that is well controlled with antiarrhythmicmedication); history of QT interval prolongation.

15. New York Heart Association (NYHA) class III or greater congestive heartfailure or left ventricular ejection fraction of < 40%.

16. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn'sdisease) or GI perforation within 6 months of enrolment.

17. Have active serious infection requiring antibiotics.

18. Have known history of HIV-1 or 2 (or positive HIV-1/2 antibody, if done atscreening) with detectable viral load OR taking medications that may interferewith SN-38 metabolism.

19. Have known active hepatitis B virus (HBV) or hepatitis C virus (HCV). Inpatients with a history of HBV or HCV, patients with detectable viral loadswill be excluded.

20. Have other concurrent medical or psychiatric conditions that, in theinvestigator's opinion, may be likely to confound study interpretation orprevent completion of study procedures and follow-up examinations.

21. Any medical condition that, in the investigator's or sponsor's opinion, posesan undue risk to the patient's participation in the study

22. Use of other investigational drugs (drugs not marketed for any indication)within 28 days or 5 half-lives (whichever is longer) of first dose of studydrug.

23. Clinically severe pulmonary compromise resulting from intercurrent pulmonaryillnesses including, but not limited to, any underlying pulmonary disorder (ie,pulmonary embolism within 1 months of enrolment, severe asthma, severe chronicobstructive pulmonary disease, restrictive lung disease, uncontrolled pleuraleffusion, etc.); any autoimmune, connective tissue, or inflammatory disorderswith pulmonary involvement (ie, rheumatoid arthritis, Sjogren syndrome,sarcoidosis, etc.); or prior pneumonectomy.

24. Contra-indications specific to bevacizumab

25. Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg). Anti-hypertensivetherapy to achieve these parameters is allowable.

26. Prior history of hypertensive crisis or hypertensive encephalopathy.

27. Significant vascular disease (e.g., aortic aneurysm requiring surgicalrepair or recent peripheral arterial thrombosis) within 6 months prior tostart of treatment.

28. History of hemoptysis (≥ one-half teaspoon of bright red blood perepisode) within 1 month prior to start of treatment.

29. Evidence of bleeding diathesis or coagulopathy (in the absence oftherapeutic anticoagulation).

30. Current or recent (within 10 days of start of treatment) use of aspirin (> 325 mg/day) or treatment with dipyridamole, ticlopidine, clopidogrel, andcilostazol.

31. Current use of full-dose oral or parenteral anticoagulants or thrombolyticagents for therapeutic purposes that has not been stable for > 2 weeksprior to start of treatment. The use of full-dose oral or parenteralanticoagulants is permitted as long as the INR or aPTT is withintherapeutic limits (according to the medical standard of the enrollinginstitution) and the patient has been on a stable dose of anticoagulantsfor at least 2 weeks prior to start of treatment.

32. Prophylactic anticoagulation for the patency of venous access devices isallowed, provided the activity of the agent results in an INR < 1.5 × ULNand aPTT is within normal limits within 14 days prior to start oftreatment.

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

34. Core biopsy or other minor surgical procedure, excluding placement of avascular access device, within 7 days prior to the first dose ofbevacizumab.

35. History of abdominal or tracheoesophageal fistula or gastrointestinalperforation within 6 months prior to start of treatment.

36. Clinical signs of gastrointestinal obstruction or requirement for routineparenteral hydration, parenteral nutrition, or tube feeding.

37. Evidence of abdominal free air not explained by paracentesis or recentsurgical procedure.

38. Serious, non-healing wound, active ulcer, or untreated bone fracture.

39. Proteinuria, as demonstrated by urine dipstick or > 1.0 g of protein in a 24-hour urine collection. All patients with ≥ 2+ protein on dipstickurinalysis at baseline must undergo a 24-hour urine collection and mustdemonstrate ≤ 1 g of protein in 24 hours.

40. Clear tumour infiltration into the thoracic great vessels is seen onimaging.

41. Clear cavitation of pulmonary lesions is seen on imaging.