435P The AGITG Modulate study: Randomised phase II study testing manipulation of the tumour micro environment (TME) to enable synergy with PD1 inhibitors in microsatellite stable (MSS) metastatic colorectal cancer (mCRC)

Abstract

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/m 2 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%, a 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.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.

Myeloid-Derived Suppressor Cells: Therapeutic Target for Gastrointestinal Cancers

“…JAK2/STAT3 pathway inhibition affects MDSCs by inducing MDSC apoptosis and by promoting MDSC differentiation to mature myeloid cells ( Figure 1 ) [ 79 ]. The MODULATE trial sought to modify the TME to enhance the anti-PD1 response in patients with MSS mCRC by randomizing 90 patients evenly into two arms [ 80 ]. The first arm received nivolumab in combination with BNC105, a vascular-disrupting agent, while the second arm received nivolumab with napabucasin, a STAT3 inhibitor [ 80 ].…”

“…The MODULATE trial sought to modify the TME to enhance the anti-PD1 response in patients with MSS mCRC by randomizing 90 patients evenly into two arms [ 80 ]. The first arm received nivolumab in combination with BNC105, a vascular-disrupting agent, while the second arm received nivolumab with napabucasin, a STAT3 inhibitor [ 80 ]. Alterations in the TME were monitored through repeated baseline tumor biopsies at 6 and 12 weeks.…”

“…Alterations in the TME were monitored through repeated baseline tumor biopsies at 6 and 12 weeks. The study showed an ORR 5% in both treatment groups [ 80 ]. The results proved the rejection of the null hypothesis set at 2%; however, the desired ORR of 15% was not achieved (NCT03647839) [ 80 ].…”

“…The study showed an ORR 5% in both treatment groups [ 80 ]. The results proved the rejection of the null hypothesis set at 2%; however, the desired ORR of 15% was not achieved (NCT03647839) [ 80 ]. In a Phase Ib/II study, 92% of patients (n = 50) with metastatic pancreatic ductal adenocarcinoma achieved disease control when treated with napabucasin, nab-paclitaxel, and gemcitabine ( Table 1 ) [ 78 ].…”