A Cancer With an Urgent Unmet Need
Head and Neck Cancer (HNC) is the most prevalent malignancy in Southeast Asia and one of the most devastating.
Despite significant advances in treatment, the five-year survival rate for HNC remains below 50%, and the majority of patients receiving frontline therapy eventually experience locoregional or incurable metastatic relapse.
For relapsed patients, Immune Checkpoint Inhibitors (ICIs) represent one of the most promising treatment avenues available. But there is a critical problem; only 20% of patients treated with ICIs show a measurable response. The remaining 80% are exposed to a treatment that will not work for them, while losing precious time and experiencing significant side effects. And today, there are no validated predictive biomarkers to tell oncologists in advance who will respond and who will not.
This study set out to change that using comprehensive ctDNA genomic profiling to identify the genomic markers that predict ICI response and resistance in advanced HNC patients.
Our Approach: Serial ctDNA Profiling with OncoIndx
We serially profiled ctDNA from 69 advanced HNC patients receiving combinational immune-chemotherapy, capturing genomic snapshots at both baseline (BL) and post-treatment (Tx) using our OncoIndx 1080-gene hybrid capture CGP panel. This longitudinal design allowed us to track how the tumour’s genomic landscape evolved in response to treatment and to identify the molecular features that separated responders from non-responders.
Genomic findings were correlated with Progression-Free Survival (PFS) and Overall Survival (OS) using Kaplan-Meier statistics and multivariate analysis:- the gold standard for establishing the clinical significance of biomarkers in oncology.
Striking Findings With Direct Clinical Implications
The results of this study are among the most clinically significant we have generated in head and neck cancer to date:
- 58% of patients (n=40/69) were responders, while 42% were non-responders: reflecting the well-documented heterogeneity in ICI outcomes in HNC
- At baseline, the non-responder population was significantly enriched with oncogenic gene mutations compared to responders: suggesting that baseline ctDNA profiling can stratify patients before treatment begins
- Co-occurring TP53 and BRCA pathway mutations (mTP53 + BRCA) emerged as powerful negative predictors of both PFS and OS:
- Median PFS of just 2.77 months for mTP53 + BRCA patients vs. 9.1 months for wildtype (HR=3.2–11.6, p<0.0001)
- Median OS of just 4.67 months for mTP53 + BRCA patients vs. 12.63 months for wildtype (HR=11.18–55.27, p<0.0001)
- NOTCH1 or NOTCH2 variants were significantly enriched in the responder population, showing a beneficial effect on both PFS and OS and emerging as a potential positive predictive biomarker for ICI response in HNC
- Elevated ctDNA alterations and high tumour fraction (TF) concentrated in non-responders with subclonal drivers of immunotherapy resistance including NF1, STAT5B, and STK11 mutations disproportionately present in this group, and associated with significantly shorter survival
- Multivariate analysis confirmed ctDNA mutations, tumour fraction, and high mutational heterogeneity as independent risk factors for shorter PFS and OS
- In contrast, total indel burden and NOTCH mutations had beneficial effects on survival reinforcing the complexity of the genomic landscape in HNC and the need for comprehensive rather than single-marker profiling
Why This Matters
This study demonstrates, for the first time using our OncoIndx CGP platform, that minimally invasive plasma ctDNA profiling can identify a rich and heterogeneous landscape of actionable mutations in advanced HNC and crucially, that specific genomic signatures at baseline can predict which patients are likely to benefit from immunotherapy and which are not.
For oncologists managing relapsed HNC patients, this has transformative implications.
Rather than applying ICIs broadly and hoping for a response, ctDNA-based genomic profiling can help stratify patients upfront, directing those with favourable genomic profiles toward immunotherapy while identifying alternative strategies for those whose tumours harbour known resistance markers.
This is liquid biopsy working exactly as it should; not just detecting cancer, but guiding the decisions that determine what happens next.
Presented at the ASCO Annual Meeting 2025 | DOI: 10.1200/JCO.2025.43.16_suppl.6036
Presented by Atul Bharde, PhD | OneCell Dx | Poster Session: Head and Neck Cancer