Sym004 in Combination With Nivolumab Versus Nivolumab Monotherapy in EGFR-amplified Squamous Non-Small Cell Lung Cancer

This is an open-label, multicenter, 2-part trial beginning with a Phase 1b part designed to
evaluate the safety and tolerability of Sym004 in combination with nivolumab, followed by a
randomized, Phase 2b part designed to evaluate the antitumor effects of Sym004 in
combination with nivolumab as compared to nivolumab monotherapy in patients with
EGFR-amplified, advanced or metastatic squamous non-small cell lung cancer (NSCLC) who have
progressed on or following a platinum-based chemotherapy.

Part 1 Dose-Escalation (Phase 1b): A 3+3 design will be used to determine the MTD and/or,
subsequently the RP2D, of Sym004 in combination with nivolumab. The starting dose will be 12
mg/kg Sym004 with 3 mg/kg nivolumab administered once every two weeks (Q2W). There are two
potential dose levels of Sym004 (12 mg/kg and 18 mg/kg), as well as a lower dose level at 9
mg/kg if needed based on observed tolerability of the higher planned doses. Patients will
return to the clinic weekly for the first 2 cycles (8-weeks; Cycle 1 and 2), and once every
two weeks thereafter. Radiographic disease assessments will be performed every 8 weeks.

Part 2 Dose-Expansion (Phase 2b): Enrolled patients will be randomized 2:1 to
Sym004+nivolumab (N = 54) or nivolumab monotherapy (N = 27). Patients randomized to
combination therapy (Cohort 1) will be treated at the RP2D of Sym004 in combination with the
standard nivolumab dose (i.e. 3 mg/kg) Q2W. Patients randomized to nivolumab monotherapy
(Cohort 2) will receive the standard nivolumab dose only. Patients will return to the clinic
weekly for the first 2 cycles (8-weeks; Cycle 1 and 2) and once every two weeks thereafter.
Radiographic disease assessments will be performed every 8 weeks.

Main Inclusion Criteria:

- Signed and dated written informed consent

- Male or female ≥18 years of age at the time of informed consent

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

- Life expectancy >3 months assessed during Screening

- Histologically or cytologically confirmed, locally advanced or metastatic squamous
NSCLC

- Squamous NSCLC with EGFR amplification detected by fluorescent in situ hybridization
(FISH) at the central laboratory.

- Progression on or after platinum-based chemotherapy. Patients who receive adjuvant
chemotherapy and progress within 6 months are also eligible

- Part 2 dose-expansion: At least one measurable lesion as defined by RECIST v1.1 which
can be followed by computed tomography (CT) or magnetic resonance imaging (MRI)

- Women of childbearing potential must have negative serum or urine pregnancy test
within 72 hours prior to starting trial treatment

- Women must not be breastfeeding

Main Exclusion Criteria:

- Prior treatment with anti-programmed cell death protein 1 (PD-1) or anti-programmed
death ligand 1 (PD-L1) agents

- Prior treatment with anti-EGFR antibodies (including cetuximab, panitumumab, and
necitumumab) or small molecular inhibitors of EGFR

- Any antineoplastic agent (standard or investigational) within 2 weeks prior to
starting trial treatment

- Radiosurgery or radiotherapy for target lesions within 2 weeks prior to starting
trial treatment

- Prophylactic use of hematopoietic growth factors within 1 week prior to starting
trial treatment

- Active Central Nervous System (CNS) metastases or carcinomatous meningitis

- A condition requiring daily or every other day systemic treatment with either
glucocorticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive
medications within 2 weeks prior to starting trial treatment

- Women who are pregnant

- Women who are breastfeeding