Sunday, October 25, 2026

@stockgutter Oct 14 3 clicks

SG on X

I asked @grok to assess how the full results that $MRNA plans to release at ESMO that would strengthen or weaken the impression from top line results announced in August. The results are copied below. Seems reasonable to me at first glance (without having checked any of the data cited) -- anyone have a different view? ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Items that could weaken (or further strengthen) the positive view include: - Magnitude of benefit: Hazard ratios (HRs), confidence intervals, absolute risk reductions, and landmark rates (e.g., 1- or 2-year RFS/DMFS). The earlier Phase 2b KEYNOTE-942 showed an RFS HR of ~0.51 (~49% relative risk reduction) and a DMFS HR of ~0.41 at 5 years. A substantially weaker Phase 3 effect (for example, HR closer to 0.75–0.85 with modest absolute benefit) could make the result look less compelling given the complexity, cost, and personalized manufacturing of the therapy. A comparable or stronger effect would reinforce the topline. - Statistical robustness and maturity: Width of confidence intervals, exact p-values, number of events, and median follow-up duration. Narrow intervals and a solid number of events support reliability; wide intervals, low event counts, or very short follow-up at the interim analysis could raise questions about reproducibility or durability. Subgroup consistency: Results by stage (IIB/IIC vs. III vs. IV), age, BRAF status, PD-L1 expression, geography, or other factors. Benefit concentrated in higher-risk stages or selected subgroups would narrow the practical population and commercial opportunity relative to a broadly consistent effect. Durability (Kaplan–Meier curves): Early separation that later plateaus or converges would suggest limited long-term impact. Sustained separation would support durability. - Overall survival signal: Any immature OS HR, death counts, or curve separation. An adverse or flat trend (while not decisive this early) could temper enthusiasm pending mature data. - Safety, tolerability, and feasibility details: Grade ≥3 adverse events, serious AEs, immune-related AEs, discontinuations, quality-of-life/patient-reported outcomes, and any manufacturing metrics (production success rate, turnaround time, or treatment delays). Higher toxicity, discontinuations, or practical barriers could offset efficacy gains. The topline noted consistency with prior experience and no new signals, but granular rates matter. - Stronger, consistent, durable efficacy with manageable safety and feasible delivery would solidify the positive assessment, support regulatory filings, and underpin commercial expectations. Marginal magnitude, inconsistency across key subgroups, limited durability, or meaningful safety/feasibility issues would lead to a more cautious view of clinical utility and value, even though the trial formally met its endpoints.