Bintrafusp Alfa With Chemotherapy for Tyrosine Kinase Inhibitor-Resistant EGFR-Mutant Non-small Cell Lung Cancer

Inclusion Criteria:

• Age equal or greater than 18 years old and willing to give their signed consent
• Histologically or cytologically confirmed non-squamous, non-small cell lung cancer
• Locally advanced or metastatic disease, not amenable to curative surgery orradiotherapy
• Patients must have one of the following:
• NSCLC which harbors EGFR Exon 19 deletion.
• NSCLC which harbors EGFR L858R mutation.
• NSCLC which harbors EGFR G719X, S768X, L861X mutation, and other activatinguncommon mutations in exon 18-21
• NSCLC which harbors EGFR exon20 insertion
• NSCLC which harbors EGFR T790M mutation EGFR deletion/mutation must be documentedby a Clinical Laboratory Improvement Amendments (CLIA) certified test
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• At least one target lesion, not previously irradiated and not chosen for biopsy duringthe study screening period, that can be accurately measured at baseline at equal orgreater than 10 mm in the longest dimension by Response Evaluation Criteria in SolidTumors (RECIST) 1.1
• Patients must have received at least one line of EGFR tyrosine kinase inhibitor (TKI)treatment, if an Food and Drug Administration (FDA)-approved treatment exist for theEGFR mutation. Patients whose tumor harboring EGFR T790M mutation must have receivedprior osimertinib (or another EGFR TKI with demonstrated activity against T790Mmutation). Patients who received more than one EGFR TKIs are eligible. Up to two linesof TKIs are allowed
• Absolute neutrophil count (ANC) >= 1,500/mm^3 (obtained less than 4 weeks from studyentry)
• Platelet count >= 100,000/mm^3 (obtained less than 4 weeks from study entry)
• Hemoglobin (HgB) >= 9 g/dL (obtained less than 4 weeks from study entry)
• Creatinine =< 1.5 x upper limit of normal (ULN) (obtained less than 4 weeks from studyentry)
• International normalized ratio (INR) =< 1.5 and partial thromboplastin time (PTT) (PTT/activated partial thromboplastin time [aPTT]) < 1.5 x upper limits of normal (ULN) (obtained less than 4 weeks from study entry). Patients receiving warfarin mustbe switched to low molecular weight heparin and have achieved stable coagulationprofile prior to first dose of protocol therapy
• Total serum bilirubin =< 1.5 x ULN (patients with known Gilbert Syndrome, a totalbilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x ULN) (obtained less than 4weeks from study entry)
• Serum glutamic-oxaloacetic transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT) =< 3 X ULN if no liver metastasis present (obtained less than 4 weeks fromstudy entry)
• SGOT, SGPT =< 5 X ULN if liver metastasis present (obtained less than 4 weeks fromstudy entry)
• Human immunodeficiency virus (HIV): stable on antiretroviral therapy (ART) for atleast 4 weeks, no documented evidence of multi-drug resistance, viral load of < 400copies/ml and CD4+ T-cells =< 350 cells/uL (obtained less than 4 weeks from studyentry)
• Hepatitis B virus (HBV)/hepatitis C virus (HCV): participant on a stable dose ofantiviral therapy, HBV viral load below the limit of quantification. HCV viral loadbelow the limit of quantification (obtained less than 4 weeks from study entry)
• Females of childbearing potential must not be breast feeding and must have a negativeserum or urine pregnancy test within 7 days of starting of treatment. The patient mustagree to use adequate contraception for a minimum of two weeks prior to receivingstudy medication until 65 days after discontinuation of the study medication.Acceptable methods of contraception include total and true sexual abstinence, hormonalcontraceptives that are not prone to drug-drug interactions (IUS levonorgestrel intrauterine system [Mirena], medroxyprogesterone injections [Depo-Provera]), copper-bandedintra-uterine devices, and vasectomized partner. All hormonal methods of contraceptionshould be used in combination with the use of a condom by their sexual male partner.Females of childbearing potential are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) orpostmenopausal (defined as 12 months with no menses without an alternative medicalcause). Women will be considered post-menopausal if they have been amenorrheic for thepast 12 months without an alternative medical cause. The following age-specificrequirements must also apply: women < 50 years old: they would be consideredpost-menopausal if they have been amenorrheic for the past 12 months or more followingcessation of exogenous hormonal treatments. The levels of luteinizing hormone (LH) andfollicle-stimulating hormone (FSH) must also be in the post-menopausal range (as perthe institution). Women >= 50 years old: they would be consider post-menopausal ifthey have been amenorrheic for the past 12 months or more following cessation of allexogenous hormonal treatments, or have had radiation-induced oophorectomy with thelast menses > 1 year ago, or have had chemotherapy-induced menopause with > 1 yearinterval since last menses, or have had surgical sterilization by either bilateraloophorectomy or hysterectomy
• Non-sterilized males who are sexually active with a female partner of childbearingpotential must use adequate contraception for the duration of the study and 125 daysafter the last dose of study medication. Adequate contraception methods include: birthcontrol pills (e.g. combined oral contraceptive pill), barrier protection, andabstinence. Patients should not father a child for 125 days after completion of thestudy medication. Patients should refrain from donating sperm from the start of dosinguntil 125 days after discontinuing the study medication. If male patients wish tofather children they should be advised to arrange for freezing of sperm samples priorto the start of the study medication

Exclusion Criteria:

• Previous treatments with cytotoxic chemotherapy or checkpoint immunotherapy orcombination of chemo-immunotherapy for metastatic disease. If the patient had priorchemotherapy as neoadjuvant or adjuvant therapy, the completion of treatment must begreater than 6 months until the beginning of the treatment on trial
• Previous treatment with any anti-TGF-beta medications
• Spinal cord compression or brain metastases unless asymptomatic or stable for at least 2 weeks prior to start of study treatment
• Persisting grade > 1 Common Terminology Criteria for Adverse Events (CTCAE) 5.0toxicity (except alopecia and vitiligo) related to prior therapy; however, sensoryneuropathy grade =< 2 is acceptable
• Current use of immunosuppressive medication, EXCEPT for the following:
• Intranasal, inhaled, topical steroids, or local steroid injection (e.g.,intra-articular injection);
• Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone orequivalent;
• Steroids as premedication for hypersensitivity reactions (e.g., computedtomography [CT] scan premedication).
• Active autoimmune disease that might deteriorate when receiving an immuno-stimulatoryagent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroiddiseases not requiring immunosuppressive treatment are eligible
• Any evidence of current interstitial lung disease (ILD) or pneumonitis or a priorhistory of ILD or non-infectious pneumonitis requiring high-dose glucocorticoids
• No previous malignant disease within the last 3 years except for a.superficial/non-invasive bladder cancer, or basal or squamous cell carcinoma in situtreated with curative intent; b. endoscopically resected gastrointestinal (GI) cancerslimited to the mucosal layer without recurrence in > 1 year
• No prior organ transplantation including allogenic stem-cell transplantation, excepttransplants that do not require immunosuppression
• Active infection requiring systemic therapy
• Live vaccination that has received or will receive within 30 days prior to the firstadministration of study intervention. Seasonal flu vaccines that do not contain a livevirus are permitted. COVID-19 vaccines are permitted
• Known severe hypersensitivity (grade >= 3 National Cancer Institute [NCI] CTCAE 5.0)to investigational product or any component in its formulations, any history ofanaphylaxis, or recent, within 5 months, history of uncontrollable asthma
• Clinically significant (i.e., active) cardiovascular disease: cerebral vascularaccident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 monthsprior to enrollment), unstable angina, congestive heart failure (>= New York HeartAssociation Classification class II), or serious cardiac arrhythmia requiringmedication
• History of bleeding diathesis or recent major bleeding events (i.e. grade >= 2bleeding events in the month prior treatment)
• Males and females of reproductive potential who are not using and effective method ofbirth control and females who are pregnant or breastfeeding or have a positive (urineor serum) pregnancy test prior to study entry. Females who are pregnant orbreast-feeding
• Judgment by the investigator that the patient should not participate in the study ifthe patient is unlikely to comply with study procedures, restrictions and requirement