This phase II, open-label, randomized study will evaluate the efficacy and safety of MEHD7945A versus cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck who have progressed during or following platinum-based chemotherapy. Patients will be randomized to receive either MEHD7945A 1100 mg intravenously (iv) every 2 weeks or cetuximab 400 mg/m2 iv loading dose followed by 250 mg/m2 iv weekly. Patients treated with cetuximab (Arm B) may cross-over to MEHD7945A (Arm A) upon central confirmation of progressive disease and upon meeting eligibility criteria. Anticipated time on study treatment is until disease progression or intolerable toxicity occurs.

Inclusion Criteria:

• Adult patients, >/= 18 years of age
• Histologically confirmed Stage III or IV recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN)
• Progressive disease on or after first-line platinum-based chemotherapy regimen for R/M SCCHN (maximum of 6 cycles)
• No more than one platinum-based chemotherapy regimen for R/M SCCHN is allowed
• Prior platinum-based treatment as definitive chemo/radiotherapy for locally advanced disease is allowed if completed/terminated >/= 6 months before the platinum-based regimen for R/M SCCHN
• Consent to provide archival tumor tissue for biomarker testing
• Measurable disease per RECIST v1.1
• ECOG performance status of 0, 1 or 2
• Adequate hematologic, renal and liver function

Exclusion Criteria:

• Nasopharyngeal cancer
• Prior treatment with an investigational or approved agent for the purpose of inhibiting HER family members
• This includes but is not limited to cetuximab, panitumumab, erlotinib, geftinib, and lapatinib
• Prior treatment with an EGFR inhibitor is allowed if it was administered as part of definitive therapy for locally advanced disease and completed >/=1 year before study enrollment
• Leptomeningeal disease as the only manifestation of the current malignancy
• Active infection requiring iv antibiotics
• Active autoimmune disease that is not controlled by non-steroidal anti-inflammatory drugs
• Current severe, uncontrolled systemic disease (e.g. clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; bone fractures)
• History of heart failure or serious cardiac arrhythmia
• History of myocardial infarction within 6 months of Cycle 1, Day 1
• Clinically significant liver disease, including active viral, alcoholic or other hepatitis, cirrhosis, or current alcohol abuse
• HIV infection
• Primary central nervous system (CNS) malignancy or untreated/active CNS metastases (progressing or requiring anticonvulsants or corticosteroids for symptomatic control)
• Pregnant or lactating women
• Malignancies other than SCCHN within 5 years prior to randomization, with the exception of adequately treated basal or squamous cell skin cancer and carcinoma in situ of the cervix