Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host’s immune response. ALX148 (A) is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. ALX148 is well tolerated in combination with pembrolizumab (P) or trastuzumab (T) with no maximum tolerated dose (MTD) identified (ASCO 2018 #3068, SITC 2018 #P335). Safety and antitumor activity of ALX148 (10 mg/kg QW) in combination with T or P are reported in patients (pts) including those with anti-HER2 or checkpoint inhibitor (CPI) relapsed/refractory diseases. Methods: Patients with malignancy including non-small cell lung cancer (NSCLC: CPI resistant/refractory or PD-L1 tumor proportion score <50%) and head and neck squamous cell carcinoma (HNSCC: progressed on platinum therapy) received A+P. Patients with HER2 malignancy including gastric/gastroesophageal junction (GEJ) cancer (progressed on T + fluoropyrimidine-based therapy) received A+T. Safety, response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed. Preliminary data from fully enrolled cohorts are reported as of 20 Jan 2019 (safety)/28 Jan 2019 (efficacy). Results: Seventy-nine pts received A+P (All, n=50; NSCLC, n=23; HNSCC, n=20) or A+T (All, n=29; Gastric/GEJ, n=23) as of data cutoff. Forty-seven pts reported mostly low grade treatment related adverse events. The most common were fatigue (11%), AST increase (9%), ALT increase (8%), anemia (8%), and platelets decreased (6%). In select tumor histologies, anticancer activity was observed in initial response-evaluable pts [NSCLC (n=23) 1PR, 8SD; HNSCC (n=17) 3PR, 4SD; and Gastric/GEJ (n=21) 4PR, 6SD]. Preliminary results indicate favorable ALX148 PK and CD47 target occupancy profiles, and positive effects on tumor infiltrating immune cells. Results will be updated at presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics to date. Objective responses were observed in patients with late line NSCLC, HNSCC, and Gastric/GEJ, including disease relapsed/refractory to prior CPI and HER2-targeted therapies. Clinical trial information: NCT03013218