RECIST and iRECIST criteria for the evaluation of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the GERCOR NIPICOL phase II study

Abstract

BackgroundImmune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC). Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria may underestimate response to ICIs due to the pseudoprogression phenomenon. The GERCOR NIPICOL phase II study aimed to evaluate the frequency of pseudoprogressions in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab.MethodsPatients with MSI/dMMR mCRC previously treated with fluoropyrimidines, oxaliplatin, and irinotecan with/without targeted therapies received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles then nivolumab 3 mg/kg every 2 weeks until progression or a maximum of 20 cycles. Computed tomography scan tumor assessments were done every 6 weeks for 24 weeks and then every 12 weeks. The primary endpoint was disease control rate at 12 weeks according to RECIST 1.1 and iRECIST by central review.ResultsOf 57 patients included between December 2017 and November 2018, 48.0% received ≥3 prior lines of chemotherapy, 18.0% had BRAFV600E mutation, and 56.0% had Lynch syndrome-related cancer. Seven patients (12.0%) discontinued treatment due to adverse events; one died due to a treatment-related adverse event. The disease control rate (DCR) at 12 weeks was 86.0% with RECIST 1.1% and 87.7% with iRECIST. Two pseudoprogressions (3.5%) were observed, at week 6 and at week 36, representing 18% of patients with disease progression per RECIST 1.1 criteria. With a median follow-up of 18.4 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The 12-month PFS rate was 72.9% with RECIST 1.1% and 76.5% with iRECIST. The 12-month OS rate was 84%. Overall response rate was 59.7% with both criteria. RAS/BRAF status, sidedness, Lynch syndrome, and other baseline parameters were not associated with PFS.ConclusionPseudoprogression is rare in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab. This combined ICI therapy confirms impressive DCR and survival outcomes in these patients.Trial registration numberNCT03350126.

Perspectives on Immunotherapy of Metastatic Colorectal Cancer

“…In a phase II study of 57 patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab, only 3.5% (2/57) patients experienced PSPD. This result is consistent with the previous study ( 42 ). Parseghian et al.…”

“…In a phase II study of 57 patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab, only 3.5% (2/57) patients experienced PSPD. This result is consistent with the previous study (42). Parseghian et al found that PSPD was not seen in 59 MSS mCRC treated with immunotherapy, which may be related to its poor efficacy (29).There are many other mechanisms of drug resistance in tumors.…”

Bilateral pleural effusion associated with atezolizumab in a patient with Lynch syndrome-related urothelial carcinoma: a case report

“…In this cohort, MMR deficiency was a significant predictor of ORR. In a phase II study that observed the effects of nivolumab plus ipilimumab in patients with MSI-H or MMR-deficient metastatic colorectal cancer, including 56% with LS-related cancers, Cohen et al found that the 12-month progression-free survival (PFS) and overall survival (OS) were 76.5% and 84%, respectively (15). Combined ICI therapy resulted in impressive outcomes in disease control.…”

Immune Checkpoint Inhibition in Metastatic Colorectal Cancer Harboring Microsatellite Instability or Mismatch Repair Deficiency

“…Like in the latter study, the 6-month and 1-year PFS rates were 75% and 71%. A total of 56% of the patients experienced grade 3–4 AEs [ 19 ]. Dostarlimab, another monoclonal antibody targeting PD-1, showed strong and durable antitumor activity in patients with dMMR gastrointestinal tumors in the phase 1/2b GARNET study.…”

“…Importantly, immediate disease progression was observed in 29.4% of patients treated with pembrolizumab versus 12.3% with chemotherapy. Misdiagnosis of MSI/dMMR status and pseudoprogression phenomenon (pseudoprogression represents up to 50% of patients with immediate disease progression [ 27 ]) might partly explain this observation [ 19 , 27 , 28 , 29 ]. Grade 3 or higher treatment-related adverse events were 21.6% versus 65.7%, including death in one patient receiving chemotherapy.…”