A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors

Abstract

Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety, pharmacokinetics, and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments. Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100 mg once weekly (QW) combined with durvalumab 750 mg once every two weeks (Q2W) IV or LY3022855 50 or 100 mg QW IV with tremelimumab 75/225/750 mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750 mg Q2W. Results Seventy-two patients were enrolled (median age 61 years): Part A = 33, Part B = 39. In Part A, maximum tolerated dose was not reached, and LY3022855 100 mg QW and durvalumab 750 mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100 mg QW with durvalumab 750 mg Q2W. ClinicalTrials.gov ID: NCT02718911 (Registration Date: May 3, 2011).

Anti-CSF-1R emactuzumab in combination with anti-PD-L1 atezolizumab in advanced solid tumor patients naïve or experienced for immune checkpoint blockade

“…Similar toxicities were seen for other anti-CSF-1R/PD-1 combination treatments. [29][30][31][32][33][34] ICBs are now standard treatment options with response rates to single agent PD-1/PD-L1 mAbs ranging from 10% to 30% across a number of solid malignancies including NSCLC, UBC and MEL [35][36][37][38][39][40][41] but can be increased to 60% when combined with CTLA4 blockade in MEL. However, this increased therapeutic benefit comes at the price of significantly increased toxicity.…”

Emerging strategies in targeting tumor-resident myeloid cells for cancer immunotherapy

“…Two phase I trials involving LY3022855 monotherapy (NCT02265536, NCT01346358) and one phase I trial involving AMG 820 (NCT01444404) in the management of advanced solid tumors reported zero objective responses (0/86 and 0/25, respectively), though decreases in TAMs were noted in addition to elevations in circulation CSF-1 levels, indicating that proper target engagement occurred [179][180][181]. When LY302285 is used in combination with ICIs including tremelimumab (anti-CTLA-4) or durvalumab (anti-PD-L1), ORR approaches 4.2% (3/72) [182]. Similarly, for AMG820, when combined with pembrolizumab (anti-PD-1) for advanced solid tumors, ORR has been documented at 2.6% (3/116), well below expected response rates seen with pembrolizumab monotherapy [183].…”

Targeting Cellular Components of the Tumor Microenvironment in Solid Malignancies

“…Among patients with diffuse type TGCT, instead, emactuzumab therapy resulted in improved and durable clinical responses, as well as in quality-of-life assessment [ 38 ]. LY3022855, a human immunoglobulin G subclass 1 (IgG1) anti-CSF1R mAb, has been tested alone (NCT01346358) or in combination with tremelimumab (NCT02718911) in patients with advanced solid tumors, demonstrating limited clinical activity despite a good safety profile [ 39 , 40 ].…”