856MO - A randomized phase II study of concurrent vs. sequential pembrolizumab with chemoradiation (CRT) in locally advanced head and neck cancer (LA HNSCC): 4-year results and tumor-immune microenvironment analysis

Background

We previously reported numerically better efficacy with CRT with sequential (S) vs. concurrent (C) pembrolizumab (P). We now report updated results at 4-years and tumor-immune correlates.

Methods

Patients (n=80) with HPV (-) LA HNSCC and intermediate risk HPV + oropharyngeal (> 10 pack years or T4 or N3) were randomized 1:1 to C (n=41) with P starting 1 week prior to CRT (cisplatin 40 mg/m² weekly + RT 70 Gy in 35 fractions) vs. S (n=39) with P starting 2 weeks after CRT. P was 200mg q 3 weeks X 8 doses. Biopsies pre and on treatment (tx; during week 2 of CRT) were available in the first 33 (18C and 15S) patients (pts). Immune landscape was investigated using OPAL 7-color multispectral Vectra imaging, with cell segmentation and phenotyping in QuPath (cite). Cell densities (log % of total) for PD-L1⁺, CD8T (CD3⁺CD8⁺), and Treg (CD3⁺CD8^-FOXP3⁺) cells were computed within tumor (PanCK⁺) or stroma (PanCK^-) compartment. Pre/on tx differences by patient were compared using two-sided paired t-test at FDR corrected α = 0.05. Survival endpoints were summarized with the Kaplan-Meier method and compared between the two treatment arms with a Univariate Cox model.

Results

With a median follow up of 43 months, outcomes at 4-years in C vs. S are: Locoregional control (LRC) [64% vs. 96%, HR 0.12 95% CI (0.02, 0.94), p = 0.043], PFS [49% vs. 67%, HR 0.57 95% CI (0.26, 1.28), p=0.173], OS [ 71% vs. 83%, HR 0.51 95% CI (0.19, 1.37), p=0.181]. Analysis of paired pre/on-tx patient samples showed a significant increase in tumor PD-L1⁺ (p = 0.002) and stroma PD-L1⁺ cell densities in C (p = 0.048), with no change in tumor PD-L1⁺ cell density in S, after tx relative to baseline. No change was detected in CD8T infiltrates, Tregs, or CD8T to Treg ratio upon tx in C. Decreased stromal CD8T (p = 0.04) and Treg (p = 0.03) infiltrates were observed in S.

Conclusions

Longer follow-up shows continued better outcomes in S, and a significant improvement in LRC. Our study uniquely compared pre and on tx paired patient samples by arm, with a significant decrease in stromal CD8 T cells and Tregs in S and increase in PD-L1⁺ cells in C, at two weeks into CRT. Further correlative analysis is ongoing.

Clinical trial identification

NCT02777385.

Editorial acknowledgement

Legal entity responsible for the study

UPMC Hillman Cancer Center.

Funding

Merck.

Disclosure

D.P. Zandberg: Financial Interests, Personal, Advisory Board: Merck, Blueprint Medicines, Glaxo Smith Kline, Prelude Therapeutics; Financial Interests, Personal, Speaker, Consultant, Advisor: Macrogenics; Financial Interests, Personal, Steering Committee Member: Seagen; Financial Interests, Institutional, Principal Investigator: BMS, Merck, Novasenta; Financial Interests, Institutional, Local PI: AstraZeneca, Glaxo Smith Kline, Macrogenics, Aduro, BICARA, Checkmate Pharma. R. Ferris: Financial Interests, Personal, Advisory Board: AbbVie, Bristol Myers Squibb, Coherus BioSciences Inc, DermTech, EMD Serono, Eli Lily, Genmab, Hookipa Biotech GmbH, Instil Bio, Inc., Janssen, Lifescience Dynamics, MacroGenics, Inc., Meira GTx LLC, Merck, Merus N.V., Numab Therapeutics AG, OncoCyte Corporation, Pfizer, Rakuten Medical, Inc., SIRPant Immunotherapeutics, Inc., Seagen, Inc., Vir Biotechnology, Inc.; Financial Interests, Personal, Other, Consultant: Adagene Incorporated, Aduro Biotech, Inc, Arcutis, Bicara Therapeutics, Inc, Brooklyn Immunotherapeutics LLC, Catenion, Dermavant, Everest Clinical Research Company, F. Hoffmann-La Roche Ltd., Fedoration Bio, Inc, Genocea Biosciences, Inc., Kowa Research Institute, Inc, Mirati Therapeutics, Inc, Nanobiotix, Novartis Pharmaceutical Company, Novasenta, PPD Development, L.P., Sanofi, Zymeworks, Inc.; Financial Interests, Institutional, Advisory Board: Eisai Europe Limited; Financial Interests, Personal, Other, Data Safety Monitoring Board: Mirror Biologics, Inc.; Financial Interests, Personal, Officer: Novasenta; Financial Interests, Personal, Stocks/Shares: Novasenta; Financial Interests, Institutional, Local PI: AbbVie; Financial Interests, Institutional, Other, PI: Arcutis, Astra-Zeneca/MedImmune, BI, Bristol Myers Squibb, Castle Biosciences, Dermavant, Eli Lily, Galderma, InflaRx, Merck, Novartis, Novasenta, Regeneron, Tesaro, Amgen, DermTech, Janssen. All other authors have declared no conflicts of interest.