Discussion
NSCLC, tumor, toxicities, PDAC, tumors, TRAEs
TUMOR, DISEASE, SOLID TUMORS, NSCLC, TUMORS
This phase I, first-in-human study of the anti-CD73 monoclonal antibody oleclumab in patients with advanced solid tumors showed a manageable safety profile when administered alone or in combination with durvalumab, with no DLTs and the maximum investigated dose of oleclumab, 40 mg/kg, being feasible for use in combination with standard-dose durvalumab. Oleclumab exposure profile was consistent with those of other monoclonal antibodies and supportive of the Q2W administration schedule, while pharmacodynamic studies showed activity consistent with the mechanism of action of oleclumab, namely inhibition of the enzymatic activity of CD73 and reduction in cell surface CD73 levels. There were isolated cases of durable ORs, predominantly in EGFRm NSCLC, with the combination of oleclumab and durvalumab, consistent with preclinical findings [Prolonged exposure to oleclumab in combination with durvalumab was tolerable, with 5 patients receiving treatment for > 1 year. Although just over half the patients had ≥ 1 TRAE, the incidence of Grade 3–4 TRAEs was < 20% in all expansion cohorts treated at the maximum dose of oleclumab, and there was a low overall rate (5%) of treatment discontinuation due to TEAEs. Three (2%) patients died due to TEAEs. Common TEAEs and TRAEs did not include any unexpected toxicities, and the safety profile of combination therapy reflected the anticipated AEs associated with durvalumab [Oleclumab exposure was dose-dependent across the 4 dose levels evaluated and was not impacted by concomitant use of durvalumab. Oleclumab PK appeared linear at doses ≥ 10 mg/kg Q2W and were similar to those of other human IgG1 monoclonal antibodies, with an estimated half-life of 13 days [Target engagement in the periphery was demonstrated by a sustained decrease in free soluble CD73 with oleclumab, suggesting saturation of binding to soluble CD73. Flow cytometry analysis of peripheral blood mononuclear cells showed decreased CD73 levels on both CD4+ and CD8+ T lymphocytes, consistent with the internalization of the bound CD73 protein [Aggregated safety, PK, pharmacodynamic, and anti-tumor activity data informed the selection of the oleclumab 40 mg/kg dose level for the combination expansion phase. Antitumor activity with the combination of oleclumab and durvalumab was promising in patients with EGFRm NSCLC, and ORs seen in patients in the expansion cohorts were associated with durable disease control of up to ~ 3 years, including in tumors typically resistant to immunotherapy. In the phase II ATLANTIC study of single-agent durvalumab as third-line or later treatment for advanced NSCLC, OR rate and DC rate at 6 months in 102 patients with EGFRm, Exploratory analysis of CD73 expression on tumor cells in baseline samples with best overall response suggests that high expression may be associated with clinical benefit in patients with MSS-CRC and PDAC. In the EGFRm NSCLC expansion cohort there was no association between response and CD73 expression in the archival tissue assessed. However, the baseline archival sample time-point was not pre-specified or controlled, which may have led to additional variability arising due to the potential effect of prior treatment (such as an EGFR inhibitor) on CD73 expression [