Abstract 2603: Exploratory analysis of Janus kinase 1 (JAK1) loss-of-function (LoF) mutations in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) treated with nivolumab + ipilimumab in CheckMate-142
Authors: Kopetz Scott , Andre Theirry , Overman Michael J. , Zagonel Vittorina , Lonardi Sara , Aglietta Massimo , Gelsomino Fabio , McDermott Ray , Wong Ka Yeung Mark , Hendlisz Alain , Alfonso Pilar Garcia , Lenz Heinz-Josef , Walsh Alice , Moss Rebecca A. , Greenawalt Danielle , Cao Z. Alexander 
Published: August 2018

Background JAK1 LoF mutations were reported as a mechanism of resistance to anti-PD-1 therapy in patients with metastatic melanoma (n = 2) or mCRC (n = 1).1,2 Here, we report an exploratory analysis of CheckMate-142 (NCT02060188) investigating whether JAK1 LoF mutations were present in patients with dMMR/MSI-H mCRC who achieved clinical benefit with nivolumab + ipilimumab treatment.

Methods Patients received nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W × 4 doses and then nivolumab 3 mg/kg Q2W. Whole-exome sequencing was performed on pretreatment biopsies preserved in RNAlater and germline DNA from peripheral blood mononuclear cells. Single nucleotide variants and insertions/deletions were called by 2 variant callers in paired normal and tumor samples, and the union of mutations was included in the downstream analysis as previously described.3 Best overall response was assessed by investigators (RECIST v1.1).

Results JAK1 LoF mutations were identified in 4 of 40 patients evaluated in this analysis. Of these 4 patients, 1 had an ongoing partial response of 9.7 months at data cutoff, and 3 had stable disease (Table); 2 patients with stable disease were still on treatment (12 and 17 months) at data cutoff, and 1 discontinued treatment after 2.9 months due to an unrelated adverse event and had not progressed after 10 months off treatment.

Conclusions Clinical benefit was achieved with nivolumab + ipilimumab in patients with dMMR/MSI-H mCRC who harbored a JAK1 LoF mutation. Additional analyses are needed to assess the effect of concurrent JAK1 loss of heterozygosity and other genetic alterations in patients with dMMR/MSI-H mCRC. 1. Zaretsky JM et al. N Engl J Med. 2016;375:819-829. 2. Shin D et al. Cancer Discov. 2017;7:188-201. 3. Carbone DP et al. N Engl J Med. 2017;376:2415-2426.

Table. Best overall response in patients with dMMR/MSI-H mCRC identified as having wild-type JAK1 or a JAK1 LoF mutationJAK1 LoF mutant n = 4JAK1 wild type n = 36Best overall response, nComplete response01Partial response1a18Stable disease3b11Progressive disease04Not evaluable02fs, frameshift. a JAK1 mutation: I975*. b JAK1 mutations: D899Gfs*10, K860Nfs*16, and K142Rfs*26.

Citation Format: Scott Kopetz, Theirry Andre, Michael J. Overman, Vittorina Zagonel, Sara Lonardi, Massimo Aglietta, Fabio Gelsomino, Ray McDermott, Ka Yeung Mark Wong, Alain Hendlisz, Pilar Garcia Alfonso, Heinz-Josef Lenz, Alice Walsh, Rebecca A. Moss, Danielle Greenawalt, Z. Alexander Cao. Exploratory analysis of Janus kinase 1 (JAK1) loss-of-function (LoF) mutations in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) treated with nivolumab + ipilimumab in CheckMate-142 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2603.