Osimertinib, Carboplatin, Cisplatin, and Etoposide in Treating Patients with Metastatic Non-small Cell Lung Cancer with EGFR, RB1, and P53 Mutations

Mutations are changes in DNA, the genetic material that serves as the body’s instruction book. Some of genetic mutations result in uncontrolled cellular replication and subsequently tumor formation. This phase I trial studies the side effects of osimertinib, carboplatin, cisplatin, and etoposide in treating patients with EGFR, RB1, and P53 mutant non-small cell lung cancer that has spread to other places in the body (metastatic). Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, cisplatin, or etoposide, 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 osimertinib, carboplatin, cisplatin, and etoposide may work better at treating non-small cell lung cancer.

Inclusion Criteria

• Written informed consent
• Advanced biopsy-proven metastatic non-small cell lung cancer
• Either have not started an EGFR tyrosine kinase inhibitor (TKI) or may have started osimertinib within the last 9 weeks
• Somatic activating mutation in EGFR in pre-treatment tumor biopsy or cfDNA
• Evidence of a concurrent P53 alteration by immunohistochemistry (IHC) or next generation sequencing (NGS) on pre-treatment tumor biopsy or cfDNA
• Evidence of a concurrent RB1 alteration by IHC or NGS on pre-treatment tumor biopsy or cfDNA
• Must have a site of disease amenable to repeat biopsy and be willing to undergo a biopsy during treatment
• Measurable (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) indicator lesion not previously irradiated
• Karnofsky performance status (KPS) >= 70%
• Ability to swallow oral medication
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN)
• Total bilirubin =< 1.5 x ULN
• Creatinine =< 1.5 x ULN OR calculated creatinine clearance >= 60 ml/min
• Absolute neutrophil count (ANC) >= 1000 cells/mm^3
• Hemoglobin >= 8.0 g/dL
• Platelets >= 100,000/mm^3

Exclusion Criteria

• Pregnant or lactating women
• Started an EGFR TKI other than osimertinib or started osimertinib more than 9 weeks ago
• Any radiotherapy within 1 week of starting treatment on protocol
• Any major surgery within 1 week of starting treatment on protocol
• Any evidence of active clinically significant interstitial lung disease
• Continue to have unresolved > grade 1 toxicity from any previous treatment
• Have pure small cell histology
• Corrected QT interval using Fridericia's formula (QTcF) > 475 msec or any clinically significant (as deemed by the investigator) abnormalities in rhythm or conduction or morphology of the resting electrocardiogram (EKG)
• Patients are to be excluded from cisplatin treatment arm if they meet any of the following criteria: * Creatinine clearance < 60 ml/min * Hearing impairment requiring assistive device * Neuropathy * The treating provider does not feel as though the patient should receive cisplatin

PRIMARY OBJECTIVE:

I. Determine the safety and toxicity profile of combination osimertinib, platinum (cisplatin or carboplatin), etoposide for patients with metastatic EGFR mutant lung cancers with concurrent RB1 and TP53 alterations.

SECONDARY OBJECTIVES:

I. Measure overall response rate (complete response [CR] + partial response [PR]).

II. Measure progression-free survival.

III. Measure overall survival.

CORRELATIVE OBJECTIVES:

I. Perform next-generation sequencing based mutation testing on tumors before treatment, prior to chemotherapy add in and at progression.

II. Perform next-generation sequencing based mutation testing on circulating-free deoxyribonucleic acid (cfDNA) before treatment, prior to chemotherapy add in, after completion of chemotherapy, with every radiologic assessment and at progression.

III. Assess for biomarkers that may predict for certain resistance mechanisms, such as small cell histologic transformation.

OUTLINE: This is a dose-escalation study of cisplatin, carboplatin, and etoposide.

Patients receive osimertinib orally (PO) on days 1-21. Beginning in cycle 4, patients also receive etoposide intravenously (IV) on days 1-3 and cisplatin or carboplatin IV on day 1 for 4 cycles. From cycle 8 onward, osimertinib monotherapy will be continued. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Helena A. Yu

• Primary ID 18-211
• Secondary IDs NCI-2018-01674
• Clinicaltrials.gov ID NCT03567642