Bintrafusp Alfa With Chemotherapy for Tyrosine Kinase Inhibitor-Resistant EGFR-Mutant Non-small Cell Lung Cancer
Condition: Locally Advanced Lung Non-Squamous Non-Small Cell Carcinoma; Metastatic Lung Non-Squamous Non-Small Cell Carcinoma; Stage III Lung Cancer AJCC v8; Stage IIIA Lung Cancer AJCC v8; Stage IIIB Lung Cancer AJCC v8; Stage IIIC Lung Cancer AJCC v8; Stage IV Lung Cancer AJCC v8; Stage IVA Lung Cancer AJCC v8; Stage IVB Lung Cancer AJCC v8; Unresectable Lung Non-Squamous Non-Small Cell Carcinoma
MeSH terms: Carcinoma; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Bintrafusp Alfa; Pemetrexed; Carboplatin; Cisplatin
Intervention description: Given IV; Given IV; Given IV; Given IV
Intervention MeSH terms: Cisplatin; Carboplatin; Pemetrexed
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This phase II trial studies the effect of bintrafusp alfa with pemetrexed and platinum-based
      chemotherapy (carboplatin or cisplatin) in treating patients with EGFR mutant non-small cell
      lung cancer that have spread to nearby tissue or lymph nodes (locally advanced) or other
      places in the body (metastatic) and cannot be removed by surgery, and remains despite
      treatment with tyrosine kinase inhibitors (Resistant). Immunotherapy with bintrafusp alfa, a
      bifunctional fusion protein composed of the monoclonal antibody anti-PD-L1 and TGF-beta, may
      help the body's immune system attack the cancer, and may interfere with the ability of tumor
      cells to grow and spread. Pemetrexed may stop the growth of tumor cells by blocking some of
      the enzymes needed for cell growth. Chemotherapy drugs, such as carboplatin and cisplatin,
      work in different ways to stop the growth of tumor cells, either by killing the cells, by
      stopping them from dividing, or by stopping them from spreading. Giving bintrafusp alfa with
      pemetrexed and platinum-based chemotherapy may help to control the disease.
    

Eligibility criteria:

        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 or
             radiotherapy

          -  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 activating
                  uncommon mutations in exon 18-21

               -  NSCLC which harbors EGFR exon20 insertion

               -  NSCLC which harbors EGFR T790M mutation EGFR deletion/mutation must be documented
                  by 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 during
             the study screening period, that can be accurately measured at baseline at equal or
             greater than 10 mm in the longest dimension by Response Evaluation Criteria in Solid
             Tumors (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 the
             EGFR mutation. Patients whose tumor harboring EGFR T790M mutation must have received
             prior osimertinib (or another EGFR TKI with demonstrated activity against T790M
             mutation). Patients who received more than one EGFR TKIs are eligible. Up to two lines
             of TKIs are allowed

          -  Absolute neutrophil count (ANC) >= 1,500/mm^3 (obtained less than 4 weeks from study
             entry)

          -  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 study
             entry)

          -  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 must
             be switched to low molecular weight heparin and have achieved stable coagulation
             profile prior to first dose of protocol therapy

          -  Total serum bilirubin =< 1.5 x ULN (patients with known Gilbert Syndrome, a total
             bilirubin =< 3.0 x ULN, with direct bilirubin =< 1.5 x ULN) (obtained less than 4
             weeks 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 from
             study entry)

          -  SGOT, SGPT =< 5 X ULN if liver metastasis present (obtained less than 4 weeks from
             study entry)

          -  Human immunodeficiency virus (HIV): stable on antiretroviral therapy (ART) for at
             least 4 weeks, no documented evidence of multi-drug resistance, viral load of < 400
             copies/ml and CD4+ T-cells =< 350 cells/uL (obtained less than 4 weeks from study
             entry)

          -  Hepatitis B virus (HBV)/hepatitis C virus (HCV): participant on a stable dose of
             antiviral therapy, HBV viral load below the limit of quantification. HCV viral load
             below 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 negative
             serum or urine pregnancy test within 7 days of starting of treatment. The patient must
             agree to use adequate contraception for a minimum of two weeks prior to receiving
             study medication until 65 days after discontinuation of the study medication.
             Acceptable methods of contraception include total and true sexual abstinence, hormonal
             contraceptives that are not prone to drug-drug interactions (IUS levonorgestrel intra
             uterine system [Mirena], medroxyprogesterone injections [Depo-Provera]), copper-banded
             intra-uterine devices, and vasectomized partner. All hormonal methods of contraception
             should 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) or
             postmenopausal (defined as 12 months with no menses without an alternative medical
             cause). Women will be considered post-menopausal if they have been amenorrheic for the
             past 12 months without an alternative medical cause. The following age-specific
             requirements must also apply: women < 50 years old: they would be considered
             post-menopausal if they have been amenorrheic for the past 12 months or more following
             cessation of exogenous hormonal treatments. The levels of luteinizing hormone (LH) and
             follicle-stimulating hormone (FSH) must also be in the post-menopausal range (as per
             the institution). Women >= 50 years old: they would be consider post-menopausal if
             they have been amenorrheic for the past 12 months or more following cessation of all
             exogenous hormonal treatments, or have had radiation-induced oophorectomy with the
             last menses > 1 year ago, or have had chemotherapy-induced menopause with > 1 year
             interval since last menses, or have had surgical sterilization by either bilateral
             oophorectomy or hysterectomy

          -  Non-sterilized males who are sexually active with a female partner of childbearing
             potential must use adequate contraception for the duration of the study and 125 days
             after the last dose of study medication. Adequate contraception methods include: birth
             control pills (e.g. combined oral contraceptive pill), barrier protection, and
             abstinence. Patients should not father a child for 125 days after completion of the
             study medication. Patients should refrain from donating sperm from the start of dosing
             until 125 days after discontinuing the study medication. If male patients wish to
             father children they should be advised to arrange for freezing of sperm samples prior
             to the start of the study medication

        Exclusion Criteria:

          -  Previous treatments with cytotoxic chemotherapy or checkpoint immunotherapy or
             combination of chemo-immunotherapy for metastatic disease. If the patient had prior
             chemotherapy as neoadjuvant or adjuvant therapy, the completion of treatment must be
             greater 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) 5.0
             toxicity (except alopecia and vitiligo) related to prior therapy; however, sensory
             neuropathy 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 or
                  equivalent;

               -  Steroids as premedication for hypersensitivity reactions (e.g., computed
                  tomography [CT] scan premedication).

          -  Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory
             agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid
             diseases not requiring immunosuppressive treatment are eligible

          -  Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior
             history 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 situ
             treated with curative intent; b. endoscopically resected gastrointestinal (GI) cancers
             limited to the mucosal layer without recurrence in > 1 year

          -  No prior organ transplantation including allogenic stem-cell transplantation, except
             transplants that do not require immunosuppression

          -  Active infection requiring systemic therapy

          -  Live vaccination that has received or will receive within 30 days prior to the first
             administration of study intervention. Seasonal flu vaccines that do not contain a live
             virus 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 of
             anaphylaxis, or recent, within 5 months, history of uncontrollable asthma

          -  Clinically significant (i.e., active) cardiovascular disease: cerebral vascular
             accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months
             prior to enrollment), unstable angina, congestive heart failure (>= New York Heart
             Association Classification class II), or serious cardiac arrhythmia requiring
             medication

          -  History of bleeding diathesis or recent major bleeding events (i.e. grade >= 2
             bleeding events in the month prior treatment)

          -  Males and females of reproductive potential who are not using and effective method of
             birth control and females who are pregnant or breastfeeding or have a positive (urine
             or serum) pregnancy test prior to study entry. Females who are pregnant or
             breast-feeding

          -  Judgment by the investigator that the patient should not participate in the study if
             the patient is unlikely to comply with study procedures, restrictions and requirement