Necitumumab and Trastuzumab in Combination With Osimertinib for the Treatment of Refractory Epidermal Growth Factor Receptor (EGFR)-Mutated Stage IV Non-small Cell Lung Cancer

Concurrent enrollment in another clinical study, unless enrolled only in the follow-up period or an observational study

Any chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment in the prior 3 weeks, other than osimertinib. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable. Stereotactic, palliative radiation for symptomatic bone metastases is acceptable without a washout. Stereotactic brain radiation for asymptomatic brain metastases is acceptable with a 7 day washout

Use of any investigational anticancer therapy received within 28 days prior to the first dose of study drugs

Prior treatment with the combination of two or more of the following therapies which target EGFR/HER: osimertinib (Tagrisso), erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilotrif), lapatinib (Tykerb), neratinib (Nerlynx), vandetanib (Caprelsa), cetuximab (Erbitux), trastuzumab (Herceptin), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla), panitumumab (Vectibix), necitumumab (Portrazza), dacomitinib (Vizimpro), poziotinib, or other combination deemed as "combined HER-inhibition therapy" by the investigator

Has not recovered (recovery is defined as National Cancer Institute \[NC\] Common Terminology Criteria for Adverse Events \[CTCAE v5.0\] grade =\< 1) from the acute toxicities of previous therapy, except treatment-related alopecia, sensory neuropathy, or laboratory abnormalities otherwise meeting the inclusion requirements stated in the inclusion criterion. Other grade 2 or less toxicities not constituting a safety risk based on the investigator's judgment are acceptable

Known small cell lung cancer or small cell transformation

The patient has a known allergy / history of hypersensitivity reaction to any of the treatment components or any other contraindication to one of the administered treatments

History or evidence of current clinically relevant coronary artery disease \>= grade III by the Canadian Cardiovascular Society Angina Grading Scale or uncontrolled congestive heart failure of current \>= class III as defined by the New York Heart Association, or unstable cardiac arrhythmia requiring medication (atrial fibrillation is permitted if clinically stable)

The patient has experienced myocardial infarction within 6 months prior to study enrollment

The patient has any ongoing or active infection, including active tuberculosis or known infection with the human immunodeficiency virus, or active, clinically significant infection requiring the use of parenteral anti-microbial agents, or grade \> 2 by NCI CTCAE (v5.0) within 14 days prior to enrollment

The patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 180 days after the last dose of trial treatment

Progressive or symptomatic brain metastases. Brain metastases that have been radiated, are asymptomatic, and on a stable or decreasing dose of steroids are allowed. Leptomeningeal disease is excluded

Serious accompanying disorder or impaired organ function, including major surgery within 3 weeks before randomization

Requirement for IV alimentation (at the time of enrollment)

History of another cancer within 2 years of study initiation, with the exception of fully treated cancers unlikely to affect the assessment of the study treatment safety or efficacy including early stage breast, prostate, non-melanomatous skin, thyroid, cervical, or endometrial cancer

Gastrointestinal disorder affecting absorption

Participants must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent

Patient unwilling or unable to comply with the protocol

Any condition that, in the opinion of the investigator or sponsor, would interfere with evaluation of the investigational product or interpretation of subject safety or study results

History of arterial or venous thromboembolism within 3 months prior to study enrollment. Patients with a history of venous thromboembolism beyond 3 months prior to study enrollment can be enrolled if they are appropriately anticoagulated

Recent (within 30 days before enrollment) or concurrent yellow fever vaccination

What this study is about