Background: Despite the broad activity of checkpoint inhibitors across tumor types, primary or secondary resistance after initial response represents a major challenge. Tomivosertib (T), a potent and highly selective inhibitor of the immunosuppressive kinases MNK-1 and 2, blocks expression of checkpoint proteins PD-1, PD-L1, and LAG-3 as well as immunosuppressive cytokines IL-6 and IL-8. In preclinical models, T was shown to trigger an anti-tumor immune response and enhance the activity of checkpoint inhibitors in a T-cell dependent manner. In prior clinical studies, T had an acceptable safety profile as a single agent and in combination with anti-PD-L1 agent avelumab. Methods: Patients experiencing insufficient response (progression or stable disease for 12 weeks or more) to any FDA-approved checkpoint inhibitor in any approved indication were eligible. T at 200 mg oral (PO) BID was added to the existing checkpoint inhibitor until disease progression or unacceptable toxicity was noted. Results: 39 pts (23 male, 16 female) were enrolled across seven cancer types. Median age was 68 (range 42-85). Median prior therapies were 2 (range 1-6). The most common cancers were lung (N = 17), urothelial (N = 6), renal (N = 5) and head and neck (N = 5). 36 pts continued on anti PD-1 antibody (Pembrolizumab and Nivolumab, 18 each) and 3 on anti PD-L-1 antibody (Durvalumab 2, Atezolizumab 1) . The most common grade 3/4 treatment related adverse events occurring in more than 1 pt were alanine aminotransferase increase (2), blood creatine phosphokinase increase (2) and maculo-papular rash (2). 7 patients discontinued treatment (18%) due to adverse events attributable to either drug. Three partial responses (PR) per RECIST 1.1 were observed in pts with previous progression on checkpoint inhibitor therapy, one each in NSCLC (1/17), gastric (1/1) and renal cancer (1/5). 7 NSCLC pts (41%) were progression free for ≥ 24 weeks. All NSCLC patients entered the study with progression by RECIST 1.1 on single agent checkpoint inhibitor prior to adding T. Conclusions: The addition of T to existing checkpoint therapy was well tolerated and manifested clinical activity including objective responses in pts with progression on existing checkpoint inhibitor. A Progression Free Survival rate at 24 weeks of 41% was noted in NSCLC patients. Additional studies evaluating the addition of T to checkpoint inhibitor therapy after progression on anti PD-1 or PD-L-1 therapy are planned. Clinical trial information: NCT03616834.