867MO - Epigenetic therapy modulates the tumor microenvironment to sensitize anti-PD-1 refractory head and neck cancers to immunotherapy

Background

Immune checkpoint blockade (ICB) is an effective treatment in a subset of patients diagnosed with recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC). We assessed whether systemic administration of a low-dose DNA methyltransferase inhibitor (5’azacytidine, 5’aza) can improve tumor antigenicity in ICB-refractory HNSCC patients and improve outcomes upon re-challenge with immunotherapy.

Methods

In this non-randomized, open-label phase Ib clinical trial, participants with R/M HNSCC who progressed on anti-programmed cell death protein PD-1 (anti-PD-1) therapy were administered low-dose 5’aza for either 5- or 10-days subcutaneously (s.c.) in combination with fixed doses of durvalumab and tremelimumab for up to 12 months. The primary objective was to assess the biologically effective dose (BED) of 5’aza as determined by molecular changes in paired baseline and on-treatment tumor biopsy samples; the secondary objective was safety.

Results

Between March 31, 2017, and March 12, 2020, twelve participants were registered and received the combination of s.c. low-dose 5’aza (40 mg/m²) and ICB. 58% (7/12) of participants had prolonged overall survival (OS) of >12 months after the initiation of study treatment. The 2-year OS rate was 24.7% (95% CI: 4.5%, 53.2%). 38% (3/8) of participants with evaluable paired tissue had a > 2-fold increase from baseline in their interferon-gamma (IFN-ɣ) signature and CD274 (PD-L1) expression within the TME and were defined as molecular responders. This was accompanied by increased HLA and APM expression (mean fold change in molecular responders vs. non-responders, HLA: 1.6 vs. 0.8 and APM: 1.7 vs. 0.8, respectively), increased number of expressed cancer-testis antigens (average in molecular responders vs non-responders: 5.3 vs. 1.7), and hypomethylation of >15 tumor suppressor genes (∼12-23% decrease in methylation in a subset of the responders). All three molecular responders were still alive at the end of the study.

Conclusions

Low-dose 5’aza was linked to increased IFN-ɣ signature and PD-L1 expression in R/M HNSCC patients. Increased expression of these established biomarkers of response to ICB correlated with prolonged OS upon re-challenge with ICB.

Clinical trial identification

NCT03019003.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

AstraZeneca and the National Institutes of Health.

Disclosure

S. Pai: Financial Interests, Personal, Advisory Board: Merck/MSD, Sensei, Cue Biopharma, Incendia, Recurrent Respiratory Papillomatosis Foundation, Scopus; Financial Interests, Institutional, Research Funding: Merck, AstraZeneca, Cue Biopharma. J.C. Park: Financial Interests, Institutional, Research Funding: Oncorus, Inhibrix, ISA Therapeutics, ALX Oncology, SQZ Biotech. R. Haddad: Financial Interests, Personal, Ownership Interest: TOSK; Financial Interests, Personal, Advisory Board: Merck, Eisai, BMS, AstraZeneca, GSK, EMD Serono, Bayer, Coheres Biosciences, Boehringer Ingelheim, Genmab, Galera Therapeutics, Merus, ALX Oncology, PDS Biotechnology, Scholar Rock, Aveo; Financial Interests, Institutional, Research Funding: Merck, BMS, AstraZeneca, Genetech, Pfizer, Kura, EMD Serono, Incyte; Financial Interests, Personal, Other: Nanobiotix, ISA Pharmaceuticals, Boehringer Ingelheim, Hookipa Pharma. All other authors have declared no conflicts of interest.