Phase Ib study of anetumab ravtansive in combination with immunotherapy or immunotherapy plus chemotherapy in mesothelin-enriched advanced pancreatic adenocarcinoma: NCI10208.

4136 Background: Mesothelin (MSLN) is overexpressed in 80-85% of pancreatic adenocarcinomas (PDAC). Anetumab ravtansine (AR) is a fully human anti-MSLN immunoglobulin G1 antibody conjugated to the anti-tubulin maytansinoid DM4. Through NCI-ETCTN, the North American Star Consortium conducted a phase I study to evaluate the safety/tolerability of AR in various combinations in patients (pts) with PDAC. Here, we report preliminary results of the escalation part. Methods: Pts with advanced PDAC after at least one line of treatment were included. AR was combined with nivolumab (ARM1), nivolumab/ipilimumab (ARM 2), or nivolumab plus gemcitabine (Gem) (ARM3), using an integrated biomarker analysis. Two dose levels (DL) of AR were evaluated, DL1=5.5mg/kg and DL2=6.5mg/kg (established RP2D). Key eligibility criterion was MSLN expression in >5% of tumor cells by immunohistochemistry. Pts with prior anti-PD1/anti-CTLA4 treatment were excluded but treatment with prior Gem was allowed. Mandatory blood and paired tumor samples were collected for investigation of the immune microenvironment, genomic/transcriptomic changes and for an in-depth description of AR pharmacokinetics. Results: Data cut-off date was 22/01/2022. A total of n=33 pts were enrolled, n=11 (ARM 1), n=13 (ARM 2) and n=9 (ARM3). Median age of pts was 66 (40-83), 33% of PS=0 and 66% of PS=1. Twenty-six pts (79%) had previously been exposed to Gem. Median number of prior lines of treatment was 3 (1-7). Twenty-eight patients were evaluable for DLT. Grade (G)3/4 TRAEs: 0% in ARM1DL1, 5.3% in ARM1DL2, 0% in ARM2DL1, 16.9% in ARM2DL2, 8.6% in ARM3DL1 and 19.5% in ARM3DL2. There were 2 dose-limiting toxicities in ARM2DL2, one G3 upper gastrointestinal haemorrhage, possibly related to AR, and one G3 thrombocytopenia and G3 anaemia, definitely related to AR. Ocular toxicity events were G1/2 blurred vision in 5/33 (15%) and G1 xerophthalmia in 1/33 (3%), related to both AR and anti-PD1; G2 keratitis in 1/33 (3%), related to AR only. Only G1 peripheral neuropathy was observed in 4/33 (12%) pts. Efficacy data is presented in the table. In ARM3, the range of tumor measurement (ΤΜ) change was ΔTM=–16.8% to +16.2% and 3/8 (36%) pts with SD had previously been exposed to Gem. Conclusions: Based on the observed disease control rate and acceptable toleratbility, ARM3 (both DL1 and DL2) will be tested in the expansion part. A further 20 patients will be recruited for dose confirmation and comprehensive biomarker evaluation. Pharmacokinetic/pharmacodynamic analysis is under way. Clinical trial information: NCT03816358. [Table: see text]