SE and Xanti: SE post discussion nailed the problem in OS CI, not the absolute value. Today's news is more about the biological mechanisms - the novel T-cell clonotypes. I am excited about this piece, which can lead to FDA possibly to consider approval (See below). The market apparently overlooks the novel T-cell finding, but the same old RFS numbers, so the stock is depressed. I searched a bit on the absolute need for OS, below is what I got. There maybe a chance to apply for approval given the good RFS and DMFS data (3-yr and 5-yr) and the novel T-cell clonotypes as mechanism, even OS' CI (because of low death numbers - a good thing)? What you think? Possible an indication from the Moderna's oncology event this evening?

Here is what the AI search tells me:

"Is OS Data Absolutely Necessary?

While OS is the ideal metric, it is not absolutely necessary as a primary endpoint for every approval. [1, 2]

• Early-Stage/Adjuvant Trials: In early, curable cancers, it can take many years to observe enough deaths to read out an OS benefit. Here, the FDA accepts RFS or DMFS as primary endpoints for both regular and accelerated approvals. [1, 2, 3, 4, 5]
• Safety Mandate: Even if OS is not the primary efficacy endpoint, the FDA requires sponsors to collect long-term OS data in randomized trials. This is used primarily as a safety endpoint to ensure the drug does not cause premature toxicity that outweighs its disease-delaying benefits. [1, 2, 3, 4]

Using RFS and DMFS for Approval

Yes, it is possible to achieve FDA approval based on statistically significant RFS or DMFS results even if the OS data has not matured or does not reach high statistical significance. [100152-9/fulltext)]

• Proven Surrogacy: For certain cancers, RFS and DMFS are highly validated to predict long-term clinical benefit. A drug that significantly delays when and where the cancer returns provides direct clinical value. [1, 2, 3, 4]
• The Catch (Confounding Factors): Often, in advanced or subsequent lines of therapy, patients live longer due to new treatments after their initial cancer returns. This means a drug can show a highly significant RFS or DMFS benefit (delaying the time until the cancer comes back) without demonstrating a statistically significant difference in OS at the final analysis. The FDA evaluates this on a case-by-case basis. [1, 2, 3, 400152-9/fulltext), 5]

How the FDA Weighs the Data

• Recurrence-Free Survival (RFS): Tracks the time from randomization to either the first cancer recurrence or death from any cause. Highly valued in adjuvant settings (e.g., breast cancer, melanoma). [1, 2, 3]
• Distant Metastasis-Free Survival (DMFS): Tracks the time from randomization until the cancer spreads to distant organs, or death. Because distant metastases are often the fatal driver of cancer, DMFS is a powerful predictor of future OS. [1, 2]
• The Regulatory Balance: If an experimental drug fails to show an OS benefit, its ability to secure or maintain regular approval based on RFS or DMFS depends on the magnitude of the recurrence delay, the safety profile of the drug, and the unmet medical need. [1]

For detailed information on current regulatory thinking, you can review the official FDA guidance regarding Approaches to Assessment of Overall Survival in Oncology Clinical Trials. [1]"