Immune chemo-sensitisation looks promising in microsatellite-stable mCRC

Both MAYA and AtezoTRIBE, phase 2 trials reporting on new immunotherapy-containing approaches to treatment for patients with proficient mismatch repair (pMMR)/microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), met their primary endpoint of progression-free survival (PFS).

Almost all MSS colorectal cancers are refractory to immunotherapy and combination strategies to turn these so-called ‘cold’ tumours into ‘hot’ – i.e. immune-responsive – tumours have failed so far.

Inactivation of the MGMT gene by hypermethylation enhances sensitivity for alkylation agents such as temozolomide (TMZ) [1]. Secondary resistance to TMZ may induce a hypermutated status coupled with acquired mutations in MMR genes in diverse tumour types, including CRC [2]. Therefore, the induction of hypermutation by a TMZ priming phase provides the rationale for immune-sensitisation of MSS mCRC.

The single-arm MAYA trial (NCT03832621) enrolled patients with pretreated MSS mCRC and MGMT silencing. Patients were treated with 2 priming cycles of TMZ (150 mg/m² at day 1–5 every 4 weeks). Patients who showed no progression of disease after the priming phase were treated in addition with ipilimumab (1 mg/kg every 8 weeks) plus nivolumab (480 mg every 4 weeks). Primary endpoint of the trial was 8-month PFS in patients entering the second phase of the trial. Dr Filippo Pietrantonio (Istituto Nazionale dei Tumori di Milano, Italy) presented the results [3].

Of 703 pre-screened patients, 204 (29%) were molecularly eligible; 135 patients entered phase 1 of MAYA, 33 (24%) reached the second treatment phase (immunotherapy). The overall response rate (ORR) in this cohort was 42% (14/33). Median PFS was 7.1 months; 12 of 33 patients who started phase 2 had a PFS >8 months. Therefore, MAYA met its primary endpoint. The safety profile was manageable and consistent with previous data. “Although only 5% of patients with mCRC were eligible for the MAYA study, this strategy is worth of being investigated by RCTs,” concluded Dr Pietrantonio. “In addition, biomarkers are needed at the very outset, so that patients unlikely to respond to priming are spared exposure to the primer and its associated toxicities.” This study provided proof of concept that TMZ can induce immune-sensitisation in MSS mCRC.

The AtezoTRIBE trial (NCT03721653) prospectively explored the potency of first-line bevacizumab in combination with upfront triplet chemotherapy to turn MSS mCRC into immune-responsive tumours. The scientific rationale is that the addition of a VEGF inhibitor to immune-checkpoint inhibition not only has an additive effect on inhibiting tumour growth, but also induces reprogramming of the immunosuppressive microenvironment.

In the trial, 218 initially unresectable mCRC patients, irrespective of MMR status, were randomised 1:2 to receive up to 8 cycles of FOLFOXIRI/bevacizumab (arm A) or FOLFOXIRI/bevacizumab/atezolizumab (arm B), followed by maintenance with 5-FU/bevacizumab or 5-FU/­bevacizumab/­atezolizumab until disease progression. The primary endpoint was PFS. Dr Chiara Cremolini (Azienda Ospedaliero-Universitaria Pisana, Italy) presented the first results of AtezoTRIBE [4].

Addition of atezolizumab to FOLFOXIRI plus bevacizumab led to a 1.6-month increase in median PFS compared with FOLFOXIRI plus bevacizumab (13.1 months vs 11.5 months; HR 0.69; P=0.012). Response rates were comparable between arms (59% vs 64%; HR 0,78; P=0.412). A significant interaction effect between MMR status and treatment arm was found (P=0.010). In the proficient MMR subgroup (n=199; arm A/B: 67/132), significantly longer median PFS was reported in arm B (12.9 vs 11.4 months; HR 0.78; P=0.071). In the deficient MMR subgroup, median PFS was 6.6 months in arm A versus Not Reached in arm B (HR 0.11; P=0.002). Overall survival data are not yet mature.

“In the deficient MMR subgroup, impressive results are reported with FOLFOXIRI plus bevacizumab plus atezolizumab, while in the proficient MMR subgroup the addition of atezolizumab still provides a statistically significant benefit, according to the study design,” concluded Dr Cremolini. While not yet practice-changing, this is an important result for a population with an unmet clinical need.

1. Pietrantonio F, et al. Clin Cancer Res. 2020;26:1017-1024.
2. Germano G, et al. Nature 2017;552:116-120.
3. Pietrantonio F, et al. MAYA trial: temozolomide (TMZ) priming followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite stable (MSS), MGMT silenced metastatic colorectal cancer (mCRC). Abstract 383O, ESMO Congress 2021, 16–21 September.
4. Cremolini C, et al. FOLFOXIRI plus bevacizumab (bev) plus atezolizumab (atezo) versus FOLFOXIRI plus bev as first-line treatmentof unresectable metastatic colorectal cancer (mCRC) patients: Results of the phase II randomized AtezoTRIBEstudy by GONO. Abstract LBA20, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November, 2021