An Open-Label Randomized Phase II Study of Combining Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor (TKI)-naïve Epidermal Growth Factor Receptor (EGFR)-Mutant Locally Advanced or Metastatic NSCLC

The primary objective of the study is to evaluate the efficacy of osimertinib plus ramucirumab versus osimertinib alone using progression free survival (PFS). Events associated with PFS include: disease progression per RECIST 1.1 and death due to any cause. A total of 150 patients will be enrolled and randomized in a 2:1 fashion (osimertinib plus ramucirumab vs. osimertinib) to the two treatment arms according to the following stratification factors: types of epidermal growth factor receptor (EGFR) mutations and presence of brain metastasis.

Inclusion Criteria:
• 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 Epidermal Growth Factor Receptor (EGFR) Exon 19 deletion.
• NSCLC which harbors EGFR L858R mutation.
• Measurable disease per RECIST 1.1
• Patients with brain metastases are eligible if they are asymptomatic, are treated, or are neurologically stable for at least two weeks without the use of steroids or on stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent). These criteria must be met on day of consent.
• Ability to take pills by mouth
• Previous treatment with cytotoxic chemotherapy or immunotherapy is allowed
• Patients must have adequate hematologic, coagulation, hepatic, and renal function.

Exclusion Criteria:
• Previous treatment with any EGFR TKIs, including erlotinib, gefitinib, afatinib, avitinib, dacomitinib, rociletinib, or osimertinib.
• Previous treatment with any anti-Vascular Endothelial Growth Factor (VEGF) medications, including vandetinib, nintedanib, bevacizumab, or ramucirumab.
• Spinal cord compression unless asymptomatic or stable for at least 2 weeks prior to start of study treatment.
• Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the exception of alopecia grade 2) at the time of starting study treatment.
• Any evidence of severe or uncontrolled systemic diseases
• Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
• Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
• Patients with uncharacterized eye disorders.
• History of hypersensitivity of osimertinib or ramucirumab (or active or inactive excipients of osimertinib or ramucirumab)
• The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy.
• The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism during the 3 months prior to first dose of protocol therapy.
• The patient has cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis.
• Any hemoptysis within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer.
• The patient has a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.
• The patient has a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.
• The patient is receiving chronic antiplatelet therapy.
Phase II
Rachel Sanborn, M.D.
Eli Lilly and Company
Brenda Fisher
  • Oncology and Hematology Care Westside
  • Providence Cancer Institute Clackamas Clinic
  • Providence Cancer Institute Franz Clinic
  • Providence Cancer Institute Newberg Clinic