Tissue TMB Superior to Blood TMB in Predicting Immunotherapy Response, Cleveland Clinic Study Finds

Tissue TMB Superior to Blood TMB in Predicting Immunotherapy Response, Cleveland Clinic Study Finds

A recent Cleveland Clinic study confirms that tissue-derived tumor mutation burden (tTMB) is a more reliable predictor of immunotherapy response compared to blood-based TMB (bTMB). This finding serves as a cautionary note for physicians considering liquid biopsy results alone for treatment decisions. For pharma BD teams and investors, the data reinforce tissue-based diagnostics as the anchor for companion diagnostic strategy and checkpoint inhibitor positioning.

Key Takeaways

• Tissue-derived tumor mutation burden (tTMB) is a more reliable predictor of immunotherapy response than blood-based TMB (bTMB).
• Physicians should prioritize tTMB for guiding immunotherapy decisions, especially for tumor-agnostic indications with the FDA-approved 10 mut/Mb threshold for pembrolizumab.
• Blood-based TMB (bTMB) shows discordance with tTMB and should not be used as a sole predictive marker.
• The study analyzed 221 patients with solid tumors, comparing tTMB and bTMB results, with 80 patients receiving immune checkpoint inhibitors.
• ASCO guidelines recommend against using bTMB alone due to inconsistent concordance with tissue-based testing.

Why does tissue TMB outperform blood-based TMB in immunotherapy prediction?

Tumor mutational burden immunotherapy predictions have long relied on tissue-based next-generation sequencing as the reference standard. The Cleveland Clinic study, presented at the 2026 ASCO annual meeting, revisited this hierarchy with a retrospective analysis of 221 patients with solid tumors from the institutional genomics repository. Each patient had at least one tTMB and one bTMB result drawn from clinical sequencing performed between July 2019 and July 2025. Among the cohort, 80 patients received immune checkpoint inhibitors (ICIs) and were included in the outcomes analysis.

TMB quantifies the total number of somatic mutations in tumor DNA. High TMB tumors present more neoantigens, making them more visible to the immune system and, in theory, more responsive to ICIs like pembrolizumab. The FDA approved a tTMB threshold of 10 or more mutations per megabase (mut/Mb) as a tumor-agnostic biomarker for pembrolizumab in 2020. Blood-based TMB, derived from circulating tumor DNA through liquid biopsy, has been positioned as a less invasive alternative for patients who cannot safely undergo repeat tissue biopsies. Yet current ASCO guidelines recommend against using bTMB alone, partly because the two measurements frequently disagree.

Suneel Kamath, MD, staff oncologist in the Department of Hematology and Medical Oncology at Cleveland Clinic Cancer Institute and senior author of the abstract, framed the findings bluntly: "This is really a cautionary tale. The bottom line is that if you have a tumor-agnostic indication for high TMB, you should rely on tissue TMB to guide immunotherapy decisions — even if you're tempted to use blood TMB as a last resort."

How did the study measure concordance between tTMB and bTMB?

The researchers compared tTMB and bTMB values across the full 221-patient cohort and then correlated each measurement with clinical outcomes in the 80-patient ICI-treated subset. The study found meaningful discordance between tissue and blood results, with bTMB failing to reliably identify patients who actually benefited from checkpoint blockade. Discordance rates between tissue and blood TMB have been reported in prior published analyses, including a 2024 Communications Medicine study examining bTMB in breast and prostate cancers that also flagged inconsistent clinical utility of blood-based measurements across tumor types.

The Cleveland Clinic data add to a growing body of evidence that ctDNA shedding varies by tumor type, disease burden, and anatomic site — all factors that introduce noise into blood-based TMB quantification. Tumors with low ctDNA fraction, which can occur in early-stage disease or in certain metastatic patterns, are particularly prone to underestimation of true mutational burden when tested from plasma alone.

What does this mean for pharmaceutical business development and investment?

The findings carry immediate weight for pharmaceutical companies developing and marketing immunotherapies, as well as diagnostic companies offering TMB testing. The data reinforce tTMB as the gold-standard biomarker, shaping clinical trial design and patient selection strategies. For BD teams, the calculus shifts toward prioritizing partnerships anchored on validated tTMB data rather than liquid biopsy convenience.

Investors should note the continued dominance of tissue-based diagnostics in companion diagnostics development. Companies with entrenched tTMB platforms — including those with FDA-cleared NGS assays — hold a competitive advantage in the pembrolizumab TMB-high space. Those relying heavily on bTMB face pressure to invest in further validation or pivot toward alternative predictive biomarkers.

That said, the study also highlights a clear market opportunity. Should assay developers crack the concordance problem and improve bTMB accuracy, the less invasive nature of liquid biopsies presents a significant commercial upside. The published literature on blood-based tumor mutational burden already documents promising signals when ctDNA fraction is adequate, and several diagnostic companies are actively refining plasma-based TMB algorithms. Until a validated, highly concordant bTMB assay reaches the market, expect licensing and partnership activity to concentrate around tissue-based NGS capabilities.

For context, the FDA's 2020 tumor-agnostic approval of pembrolizumab for TMB-high solid tumors (≥10 mut/Mb) was based on the KEYNOTE-158 trial, which used tissue-based testing. The FDA approval letter explicitly references tissue-derived TMB, further cementing tTMB's regulatory standing. The FDA review memorandum for pembrolizumab TMB-high approval details the tissue-based assay validation that underpinned the decision.

What to watch next in TMB testing and immunotherapy selection

Persistent mutation burden drives sustained anti-tumor immune responses, but capturing that signal reliably from blood remains an unresolved challenge. Several catalysts will determine whether bTMB can close the gap with tissue-based testing. First, watch for validation studies that standardize bTMB assay parameters — including minimum ctDNA fraction thresholds, panel size, and bioinformatic filtering — to improve concordance with tissue results. Second, monitor development of hybrid diagnostic approaches that combine circulating tumor DNA with tissue sequencing to refine patient selection. Third, evolving ASCO clinical practice guidelines and NCCN guidelines on TMB testing for immunotherapy selection could either restrict or expand bTMB's permissible use in clinical practice.

For dealmakers, the diagnostic sector is ripe for consolidation. Companies that can deliver a validated, highly concordant bTMB assay would disrupt the current tissue-dependent paradigm and capture meaningful market share. Until such a platform emerges, expect M&A activity and partnership deals to concentrate around tissue-based next-generation sequencing capabilities and integrated diagnostic-therapeutic development programs.

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