A Step Toward More Personalized Therapy for Patients with Recurrent/Metastatic HNSCC with a Novel Immunotherapy Selection Strategy Based upon Immune Gene Expression

Presenting author:
Dan Zandberg, MD

By Christopher Wilke, MD, PhD, and Yvonne Mowery, MD, PhD, UPMC Hillman Cancer Center

Dan Zandberg, MD, and colleagues from UPMC Hillman Cancer Center presented the results of their prospective phase II study of personalized immunotherapy that seeks to enhance treatment outcomes for patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC), whose disease has progressed on anti-PD-1 or anti-PD-L1 monoclonal antibody (mAb) therapy. Given the poor outcomes and limited treatment options for this patient population, there is an urgent need to develop more effective and personalized therapeutic approaches.

This study's unique methodology is particularly noteworthy, utilizing rapid turnaround gene expression profiling of LAG3 and CTLA4 with the OmniSeq Immune Report Card (IRC) to guide drug selection. OmniSeq IRC reports expression of 397 genes as a relative rank score (RRS) for each gene compared to a reference population (normalized to 1-100). Patients with R/M HNSCC not amenable to curative-intent therapy were eligible if they met the following criteria: progressive disease on anti-PD-1 or anti-PD-L1 therapy (IO) with at least one measurable area of disease by RECIST 1.1, <3 lines of prior systemic therapy for R/M disease, good performance status (ECOG 0-1), and adequate tissue for immune gene expression obtained after progression on immunotherapy. Patients exceeding a threshold RRS difference of 15.2 in relative rank score of CTLA4 and LAG3 expression were “selected” for treatment with nivolumab (anti-PD-1) and relatlimab (anti-LAG3) (N+R) if LAG3 > CTLA4 versus nivolumab and ipilimumab (anti-CTLA-4) (N+I) if CTLA4 > LAG3. Patients without the minimum required difference between CTLA4 and LAG3 expression were randomized 1:1 to these two combination immunotherapy regimens.

Feasibility for this personalized therapeutic selection required real-time clinical-grade evaluation of immune gene expression to avoid delays in treatment initiation. The IRC report was available within one to two weeks of sending the tissue block to OmniSeq (CLIA and CAP accredited). Among 26 patients who were screened and underwent RNA sequencing, 20 were enrolled with 18 evaluable for response. Stable disease was the best response (n = 5) for evaluable patients, and response rates were similar for both regimens (27% for N+R and 28% for N+I). Six patients were “selected” to receive N+R, and none were “selected” for N+I. Disease control rate (DCR) for these patients was 33% (95% CI: 9.7 – 70%) with a 133.5-day median duration of stable disease. Twelve patients were randomized to N+I versus N+R, with a DCR of 25% (95% CI: 8.9 – 53.2%) and 55-day median duration of stable disease. Interestingly, exploratory analysis showed that PRDM1, which represses beta-interferon gene expression, was expressed highly (RRS >75) in 62% of patients with disease progression versus 0% of patients with stable disease (p = 0.04). Additionally, differences in immune gene expression were noted based on most recent prior therapy (Anti-PD-1 alone versus with chemotherapy).

This study highlights the feasibility of the proposed treatment selection strategy, showcasing its practical application in a cohort of patients who had progressed on prior IO. While efficacy was limited with both the N+I and N+R regimens, the abstract highlights the numerical improvement in the DCR and extended duration of stable disease among “selected” compared to randomized patients. These data suggest a potential benefit from an immune gene expression-based personalized treatment approach, laying the groundwork for future investigations and refinement of this strategy.

Dr. Zandberg, principal investigator for the trial, placed these results in context with the following statement: “Anti-PD-1 mAb therapy has revolutionized the field and led to the development of many new immunotherapeutic agents being tested in trials, searching for the next big innovation. The hope is that someday we can benefit all patients with immunotherapy, and it will likely take a personalized approach to treatment, with immunotherapy combinations chosen for each patient based on analysis of their individual tumor immune microenvironment, to get there. Our trial takes a first small step toward this goal.”

In summary, this abstract is significant for its pioneering effort to introduce a personalized treatment selection strategy based on immune gene expression in R/M HNSCC. The study's findings contribute to the evolving landscape of precision medicine, which holds promise for improving outcomes in this challenging clinical scenario. Furthermore, this platform may be extended to other disease sites and to include other targeted immune-based therapeutics.

Abstract 4 - A phase II trial of personalized immunotherapy in patients (pts) with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) that have progressed on prior immunotherapy - was presented during the K. Kian Ang, MD, PhD, FASTRO, Commemorative Plenary Session at the 2024 Multidisciplinary Head and Neck Cancers Symposium on February 29, 2024.




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