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

Phase 2

Terminated

Conditions: 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 IVB Lung Cancer AJCC v8
Locally Advanced Lung Non-Squamous Non-Small Cell Carcinoma
Stage IIIC Lung Cancer AJCC v8
Stage IVA Lung Cancer AJCC v8
Unresectable Lung Non-Squamous Non-Small Cell Carcinoma
Stage IV Lung Cancer AJCC v8

Interventions: Drug: Bintrafusp Alfa
Drug: Pemetrexed
Drug: Carboplatin
Drug: Cisplatin

Registration Number: NCT04971187

Lead Sponsor: M.D. Anderson Cancer Center

Brief 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.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 3

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (bintrafusp alfa, pemetrexed, carboplatin/cisplatin)	Pemetrexed	Patients receive bintrafusp alfa IV over 1 hour on day 1 and pemetrexed IV over 10 minutes on day 1. Patients also receive carboplatin IV over 15 minutes or cisplatin IV over 6-8 hours at the physician's discretion on day 1 of cycles 1-4. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Treatment (bintrafusp alfa, pemetrexed, carboplatin/cisplatin)	Cisplatin	Patients receive bintrafusp alfa IV over 1 hour on day 1 and pemetrexed IV over 10 minutes on day 1. Patients also receive carboplatin IV over 15 minutes or cisplatin IV over 6-8 hours at the physician's discretion on day 1 of cycles 1-4. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Treatment (bintrafusp alfa, pemetrexed, carboplatin/cisplatin)	Carboplatin	Patients receive bintrafusp alfa IV over 1 hour on day 1 and pemetrexed IV over 10 minutes on day 1. Patients also receive carboplatin IV over 15 minutes or cisplatin IV over 6-8 hours at the physician's discretion on day 1 of cycles 1-4. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Treatment (bintrafusp alfa, pemetrexed, carboplatin/cisplatin)	Bintrafusp Alfa	Patients receive bintrafusp alfa IV over 1 hour on day 1 and pemetrexed IV over 10 minutes on day 1. Patients also receive carboplatin IV over 15 minutes or cisplatin IV over 6-8 hours at the physician's discretion on day 1 of cycles 1-4. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Best Objective Response Rate (ORR) Within 6 Months	Within 6 months since initiation of treatment	Objective response was assessed by RECIST 1.1. The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Progression Free Survival (PFS) at 18 Weeks	18 weeks	PFS is defined as the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier as per Response evaluation criteria in solid tumors (RECIST) version 1.1 at 18 weeks.

Secondary Outcome Measures

Name	Time	Method
Progression Free Survival (PFS)	Up to 1 year	PFS is defined as the date of randomization to the date of disease progression or death due to any cause, whichever occurs earlier as per Response evaluation criteria in solid tumors (RECIST) version 1.1.
Duration of Response (DoR)	Up to 1 year	The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation)
Safety and Tolerability	Up to 30 days post-treatment	Safety and tolerability as measured by all adverse events (AEs). Safety and tolerability will be described using frequency of AEs and AEs of Common Terminology Criteria for Adverse Events (CTCAE 5.0). Safety analyses will include all patients who have received at least one dose of study drug and will be evaluated descriptively.
Disease Control Rate (DCR)	Up to 1 year	DCR was defined as the proportion of patients who had an overall response of complete response (CR), partial response (PR), or stable disease (SD). According to Response Evaluation Criteria In Solid Tumours (RECIST) Version 1.1
Overall Survival (OS)	Up to 1 year	Overall Survival (OS) is defined as the time from treatment to death due to any cause, or censored at date last known alive.