Abstract 435P
Background
PD-1 checkpoint inhibitors are active in microsatellite unstable (MSI) mCRC, which have an inflamed TME but are inactive in MSS-mCRC. The resistance of MSS mCRC is potentially related to the TME which excludes immune cells. The Modulate study tested 2 strategies designed to alter the TME in MSS mCRC, thereby enabling synergy with PD1 inhibitors.
Methods
Eligibility included MSS mCRC, measurable disease, failure of standard prior therapies including oxaliplatin, fluoropyrimidine, irinotecan, bevacizumab and an EGFR inhibitor (if ras/raf wild type), adequate organ function, PS0-1 and informed consent. Eligible patients were randomised to arm A (nivolumab 240mg q2w plus the vascular disrupting agent BNC105 16mg/m2 d1,8 q3w) or arm B (nivolumab 240mg q2w plus the STAT3 inhibitor napabucasin 240mg bd po). All pts had baseline tumour biopsies repeated at 6w and 12w to assess changes in the TME. The primary endpoint was response rate (RR) (iRECIST). Secondary endpoints included toxicity, progression free survival (PFS) and overall survival (OS). A Simon 2 stage design was used, with each arm evaluated independently, with a null response rate (RR) of 2%, desired RR of 15%, α 5%, ß 95%.
Results
From September 2018 to March 2020, 45 pts were enrolled to each arm. Baseline demographics arm A/B were male; 59%,54%; median age 62y,63y; PS0 48%,46%; liver metastases 73%,85%. Median treatment duration was arm A/B 12.3 w (2.1-105w) and 7.5 w (0.1 to 24w). Treatment was well tolerated with the most frequent grade 3/4 AEs being anaemia 9% (arm A) and diarrhoea 13% and abdominal pain (11%) (arm B). Immune related AEs were infrequent. Table: 435P
Efficacy results
| Arm A | Arm B | |
| RR (%) (95% CI) | 5(1-17) | 5(1-17) |
| Median PFS (m) (95% CI) | 1.4 (1.3-2.5) | 1.5 (1.3-1.9) |
| Median OS (m) (95% CI) | 7.5 (4.6-11.9) | 5.2 (3.5-7.8) |
Conclusions
Although neither treatment achieved the anticipated RR, it was well tolerated and anti-tumour activity was demonstrated in both arms with encouraging OS for arm A. Ongoing translational evaluation will examine the impact of the interventions on the TME.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Australasian GI Trials Group.
Funding
Bristol Myers Squibb.
Disclosure
N.C. Tebbutt: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Roche; AstraZeneca. All other authors have declared no conflicts of interest.