The FDA approved Travere's drug for the kidney disease FSGS based on the surrogate endpoint of proteinuria, despite the drug failing on the traditional eGFR endpoint. This decision, following a company-backed effort to validate proteinuria, suggests increased regulatory flexibility and creates a new pathway for kidney disease drug approvals.

A key conceptual shift is viewing ctDNA not as a statistical risk marker, but as direct detection of molecular residual disease (MRD). This framing, similar to how a CT scan identifies metastases, explains its high positive predictive value and justifies its use in making critical treatment decisions.

Menin inhibitors achieve high rates of MRD-negative remissions. However, the median duration is very short (4-6 months), suggesting current MRD assays may not adequately capture residual disease and that "MRD negativity" is not a reliable predictor of long-term benefit for this drug class.

Sensitive MRD tests identify lymphoma patients who appear cancer-free on scans but have molecular disease traces, signaling a high relapse risk. This creates a new, addressable patient population for pre-emptive intervention, allowing companies like Allogene to design trials aimed at preventing relapse rather than treating it after the fact.

The FDA issued guidance supporting minimal residual disease (MRD) as an approval endpoint in multiple myeloma. This directly contradicts the CBER division’s recent rejections of drugs based on single-arm response rates, creating a "schizophrenic" and unpredictable regulatory landscape for developers.

Emerging data from major trials shows that ctDNA clearance during neoadjuvant therapy and negative post-surgical MRD status are strong predictors of improved survival. MRD positivity, in contrast, is associated with worse biology and rapid progression.

Both experts advocate shifting immune cell engager use from late-stage, high-burden cancer to a minimal residual disease (MRD) setting. Treating a low tumor load maximizes the effector-to-target ratio, enhances efficacy, and significantly reduces side effects, potentially moving these therapies to first-line combinations.

The next major advance in adjuvant kidney cancer will be a biomarker to select who needs treatment. The key is developing a Minimal Residual Disease (MRD) test based on the epigenome (e.g., chromatin modifications) rather than just ctDNA mutations. This is because the critical biological signals in RCC are found in epigenetic regulation, not just the genome.

Counterintuitively, blinatumomab benefits patients who are already MRD-negative. This indicates that even the most sensitive tests (down to 10^-6) miss clinically relevant disease. The therapy targets this sub-clinical residual leukemia, preventing future relapse and improving outcomes for patients considered to be in deep remission.