Gene-Guided Immunotherapy Misses Mark in Recurrent/Metastatic Head and Neck Cancer

Gene-guided treatment selection for recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) failed to improve disease control versus random treatment selection in a small preliminary clinical trial.

Personalized treatment guided by immune gene expression achieved disease control in two of six patients as compared with three of 12 patients who received randomized therapy. The numerical difference between the two groups did not achieve statistical significance, although disease control lasted more than twice as long in patients who received treatment by gene expression guidance.

The trial reflected ongoing efforts to improve treatment options for patients with advanced head and neck cancer that has progressed on prior immuno-oncology (IO) regimens, reported Dan Zandberg, MD, of the UPMC Hillman Cancer Center in Pittsburgh, at the Multidisciplinary Head and Neck Cancers Symposium in Phoenix.

“Efficacy overall was low … in immuno-oncology failure patients,” said Zandberg. “Prospective selection was feasible, and selected patients had a numerically higher DCR [disease control rate], with a longer duration of stable disease. Further correlative analysis of this cohort is ongoing.”

“This represents a small first step toward a more personalized approach to treatment with immunotherapy,” he added.

The investigators employed a unique methodology that relied on rapid-turnaround gene expression profiling of LAG3 and CTLA4 with the OmniSeq Immune Report Card (IRC) to guide drug selection, wrote Christopher Wilke, MD, PhD, and Yvonne Mowery, MD, PhD, also of the Hillman Cancer Center, in a written summary of the presentation. The IRC captures expression of 397 genes, reported as a relative rank score (RRS) for each gene compared to a reference population.

“This abstract is significant for its pioneering effort to introduce a personalized treatment selection strategy based on immune gene expression in R/M [recurrent/metastatic] HNSCC,” noted Wilke and Mowery, who were not investigators in the trial. “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.”

Immunotherapy has improved outcomes for patients with HNSCC and currently represents the standard of care for recurrent/metastatic HNSCC. Patients whose disease progresses on anti-PD-1 therapy have limited treatment options. Use of tumor gene expression to guide treatment decisions has attracted considerable interest among oncology researchers. Zandberg reported findings from a phase II trial of tumor gene expression to select treatment in the post-immunotherapy setting of recurrent/metastatic HNSCC.

Eligible patients had disease that progressed on a prior IO regimen and had received no more than three lines of systemic therapy for HNSCC. Investigators analyzed biopsy specimens with the IRC, which reports findings as an RRS of expression of each gene compared to a reference population, normalized to a value of 1-100.

In this trial, an RRS ≥15.2 for CTLA4 versus LAG3 “selected” a patient to receive nivolumab (Opdivo) plus ipilimumab (Yervoy). If the result was reversed (LAG3 > CTLA4), a patient received nivolumab plus relatlimab (Opdualag). If the RRS difference was <15.2, patients were randomized to the two regimens. The primary endpoint was objective response rate (ORR).

The 18 evaluable patients had a median age of 64, and men accounted for all but one patient. The most primary sites of cancer were the oropharynx (61%, 91% HPV positive) and larynx (22%). Best response to prior anti-PD-1 therapy (with or without chemotherapy) was partial response in six patients and stable disease in six others.

Gene expression results selected six patients to receive nivolumab and relatlimab (none for nivolumab/ipilimumab), and the remaining 12 were randomized to the two regimens. Subsequently, a total of 11 patients received nivolumab/relatlimab and seven received nivolumab/ipilimumab, which produced a DCR of 27%. Median duration of disease control in all 18 patients was 53 days.

Nivolumab-relatlimab led to a DCR of 33% in the six patients selected for the regimen by gene expression and 25% in the 12 patients randomized to the two regimens. Median duration of disease control was 133.5 days with nivolumab/relatlimab versus 55 days for the 12 randomized patients.

A gene expression analysis showed that KRT5 and TRIM29 were the only genes highly expressed in >90% of patients. Seven genes were highly expressed in >50% of patients, and five exhibited low expression in >90% of patients. Potentially clinically relevant genes or that are already targeted were TRIM29; EGFR, GITR, and TGFB1 (highly expressed in >50%); and KIR2DL1 (low expression in >90%).

Gene expression differed between patients previously treated with anti-PD-1 therapy versus chemotherapy. A higher proportion of patients treated with anti-PD-1 expressed TGFB1 (P=0.04). A higher proportion of patients treated with chemotherapy had high expression of GNLY, OAS1, IFIT3, IDO2, and IL12B (P<0.05).

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