Cln-619 (anti-MICA/B antibody) alone and in combination with pembrolizumab (P) for advanced solid tumors: Updated results of a Ph1 study.
Authors: Melero Bermejo Ignacio , Wang Judy S. , Gutierrez Martin , Hamilton Erika P. , Spira Alexander I. , Rasco Drew W. , Powderly John D. , Millward Michael , Frentzas Sophia , Stec Rafal , Sharma Manish , Shackleton Mark J. , Arance Ana Maria , Joaquin Julia Giner , Lugowska Iwona A. , Liu Tracy , Shearer Todd , Gupta Divya , Jones Jeffrey Alan , Moreno Victor 
Published: June 2024

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Background: CLN-619 is a human IgG1 antibody that prevents proteolytic cleavage of NKG2D ligands MICA/B from tumor cells, increasing tumor cell lysis by innate and adaptive immune cells. CLN-619 monotherapy demonstrated favorable safety and objective responses in multiple tumor types in a Ph1 study (ASCO 2023). Results from dose escalation in combination with P and updated results of monotherapy are reported. Methods: This first-in-human study (NCT05117476) enrolled pts ≥18y, ECOG 0/1 with advanced solid tumors to receive IV CLN-619 either as monotherapy or in combination with P (200 mg IV Q3W). CLN-619 was dosed at 1-10 mg/kg IV Q3W in the combo arm. Corticosteroid pre-medication is mandated before the first dose of CLN-619. Response (RECIST 1.1) is assessed every 9 wks. Results: As of 24 Nov 2023 data-cutoff (DCO), enrollment in both arms of the dose escalation was complete. The combination cohort enrolled 22 (18 evaluable) pts (median 66y, range 38-82; 50% female); pts had received median 3 prior therapies (range 1-7), 41% prior checkpoint inhibitor (CPI). No protocol defined DLTs were observed. Treatment-emergent adverse events (TEAEs) in ≥20% of pts were fatigue (36%), constipation (27%), and nausea (23%). Four patients (18%) experienced Grade (Gr) 1/2 infusion-related reactions. Two patients with NSCLC (1 EGFRm, 1 ALKrearr) had achieved confirmed partial response (PR). After DCO, 1 pt with gastric cancer improved from stable disease (SD) to PR at cycle 7 (pending confirmation). The monotherapy cohort enrolled 42 pts (median 61y, range 26-83; 60% female; median 3 prior (range 1-7); 52% prior CPI). No DLTs were observed. TEAEs in ≥20% of pts were infusion related reactions (26%), fatigue (24%), and abdominal pain (22%). One immune-related AE of maculopapular rash was reported but resolved with steroid taper and did not result in treatment discontinuation. Three previously reported confirmed responses in mucoepidermoid parotid (CR), serous endometrial (PR), and endometroid endometrial (PR) were durable through 13, 7, and 8 (ongoing) months, respectively. Nine pts achieved stable disease (SD) extending through ≥18 wks: 1 HR+ breast, 1 platinum-resistant ovarian, 2 cervical, 1 STK11+ adenocarcinoma lung, 1 uterine carcinosarcoma, 1 pancreatic, 1 salivary adenoid cystic carcinoma, 1 mediastinal intimal sarcoma. Clinical benefit rate at doses ≥1mg/kg (CR+PR+SD≥18 weeks) was 41% (12/29 evaluable pts). Conclusions: CLN-619 + P was well tolerated at doses ranging from 1 to 10 mg/kg. Objective responses were observed, including in tumor types typically unresponsive to P. Longer term follow-up for CLN-619 monotherapy confirms favorable safety and durable clinical benefit with extended treatment, including objective responses in multiple tumor types and pts progressing after CPI. Based on these findings, expansion cohorts will be opened in endometrial cancer and NSCLC. Clinical trial information: NCT05117476 .