Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host immune response. ALX148 (A) is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive immunoglobulin Fc region. ALX148 enhances innate and adaptive immune responses against cancer and has previously been shown to be well tolerated in combination with the checkpoint inhibitor (CPI), pembrolizumab (P), and trastuzumab (T) in a range of solid tumors (ASCO 2019 #2514). ALX148 safety and activity in combination with T or P and standard chemotherapy regimens are reported in patients (pts) including head and neck squamous cell cancer (HNSCC) and HER2 positive gastric/gastroesophageal cancer (GC). Methods: Pts with advanced malignancy were administered AP or AT. Patients with ≥2L HNSCC progressed on platinum therapy received AP, while those with untreated advanced disease received AP+5FU (FU)+platinum. Pts with ≥2L GC progressed on T+FU+platinum received AT +/- ramucirumab (ram)+paclitaxel (pac). Safety, response, pharmacokinetic and pharmacodynamic (PD) markers were assessed. Data are reported as of 21, Jan. 2020. Results: Patients received AP (n=52); AP+FU+platinum (n=1); AT (n=30); or AT+ram+pac (n=3) as of data cutoff. Eighty-two pts experienced any adverse event (AE). Fifty-seven pts administered AP or AT regimens reported mostly low grade ALX148 treatment related (TR) AEs, the most common being fatigue (18%), AST increase (11%), platelets decreased (10%), ALT increase (8.5%), anemia (8.5%), and pruritus (8.5%). Pts receiving AP+FU+platinum or AT+ram+pac reported no TRAEs as of data cutoff. Anticancer activity was observed in response-evaluable pts. AP: HNSCC CPI-naïve (n=10) 40% ORR, mPFS 4.6 [95% CI:0.5;7.5], mOS not reached with 14.4m median follow-up; AP: HNSCC CPI-experienced (n=10) 0% ORR, mPFS 2.0 [95% CI:0.9;3.6], mOS 7.4 [95% CI:3.1;NC]; and AT: GC (n=20) 20% ORR, mPFS 2.2 [95% CI:1.9;5.4], mOS 8.1 [95% CI:3.4;12.8]. Full peripheral CD47 target occupancy and increased infiltrating immune cells in tumor biopsies were seen. Exploratory analysis of biomarkers associated with response is ongoing. Conclusions: Initial data suggests ALX148 demonstrates excellent tolerability in combination with anti cancer antibodies and standard chemotherapy. Clinical activity in pts with advanced CPI naïve HNSCC (including PD-L1 negative) and GC compares favorably with historic controls. Final data from AP and AT cohorts and initial data from chemotherapy combination cohorts will be presented. Clinical trial information: NCT03013218.