Abstract
173 Background: DNA mismatch repair (MMR) proficient colorectal cancer (CRC) is resistant to immune checkpoint therapy compared to MMR deficient CRC. DNA hypomethylating agents may promote anti-tumor immune response by re-expression of cancer-testis antigen and reactivating immune genes suppressed by DNA methylation. This trial tested whether epigenetic modulation by concurrent treatment with azacitidine could enhance the anti-tumor activity of pembrolizumab in mCRC. Methods: Phase II trial was conducted to evaluate activity, safety, and tolerability of pembrolizumab in combination with azacitidine in patients with previously treated pMMR metastatic CRC. Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg daily SQ injection on days 1-5 every 3 weeks. The primary endpoint of the study was ORR. Tumors were biopsied pre-treatment and on-treatment for biomarker studies. Results: 30 patients received at least one dose of therapy. One patient experienced a confirmed partial response, one experienced stable disease. ORR was 3% (1/30; 95% CI, 0.1-17%). Median PFS was 1.9 months, median OS was 6.3 months. Treatment was well tolerated with only one patient (3%) experiencing grade 3 adverse event. The patient with a PR had positive pre-treatment TILs, but no evaluable tumor from on-treatment biopsy. 2 of 6 patients who continued therapy despite PD on first restaging experienced temporary stabilization of disease later. 5 of 16 evaluable biopsy pairs demonstrated increased TILs on treatment compared to baseline; however, all of these patients experienced PD. 10 of 15 paired samples demonstrated decreased methylation of hypermethylated loci on-treatment. Clustering analysis demonstrated a correlation between pre-treatment methylation of immune activation genes with overall survival of the patients. Conclusions: Combining azacitidine and pembrolizumab is safe and tolerable for pMMR mCRC with only limited activity. DNA methylation and TIL changes are detectable after 3 cycles of therapy. DNA methylation of immune activation genes correlate with overall survival. RNA sequencing and peripheral immune cell flow cytometry are ongoing. Clinical trial information: NCT02260440.
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