Encouraging early results from Tango Therapeutics' vopimetostat combinations with daraxonrasib and zoldonrasib in PDAC, particularly the preservation of activity in later-line disease. #ESMO26 Daraxonrasib + vopimetostat: 81.8% confirmed ORR (18/22), including 85.7% (6/7) in 2L and 84.6% (11/13) in 3L, with 100% disease control. Nine-month PFS was estimated at 88.4% overall. Zoldonrasib + vopimetostat: 54.2% confirmed ORR (19/35), including one CR. Impressive early activity, but several questions deserve attention: • Molecular context: Tango directed KRAS G12D patients toward zoldonrasib, while its daraxonrasib PDAC cohort was predominantly G12V/G12R, with no reported G12D. The FDA's exploratory daraxonrasib monotherapy analysis showed ORRs of 50% in G12V, 24% in G12D, and 7% in G12R. How much of the combination activity reflects molecular selection versus complementary PRMT5 inhibition? A response breakdown by mutation would be particularly informative, especially for G12R. • Response maturity and patient accounting: At the August cutoff, daraxonrasib's 18/22 responses included 11 confirmed and seven awaiting confirmation. Tango subsequently confirmed all seven, bringing the confirmed ORR to 81.8%. But what happened to the seven additional treated PDAC patients excluded by the 14-week evaluability rule? Were their outcomes also updated? The confirmed 18/22 corresponds to 62.1% (18/29) using the all-treated denominator. Likewise, zoldonrasib's confirmed 19/35 corresponds to 48.7% (19/39), with four patients outside the efficacy analysis. These are fixed-numerator sensitivity calculations, not formally reported ITT/mITT ORRs. Updating response-confirmation status without providing corresponding follow-up for initially unevaluable patients leaves an important question unanswered. • Phase 3 dose selection: Daraxonrasib's headline 81.8% ORR pools two dose levels, including three efficacy-evaluable patients at the higher vopimetostat dose. Yet the proposed Phase 3 regimen uses the lower dose. What is the confirmed ORR, response durability, and delivered dose intensity specifically at the proposed Phase 3 dose? And how reliably might activity observed predominantly in 2L/3L translate into the planned first-line population? • Baseline fitness: ECOG 0 was 58.6% in the daraxonrasib cohort versus 33.3% with zoldonrasib. How much does this imbalance influence comparisons between the two combinations? • Tolerability,➡️attenuation or redistribution @Aiims1742? PRMT5 inhibition may attenuate certain RAS-inhibitor toxicities through MAPK signaling. But does it genuinely reduce the overall toxicity burden, or merely redistribute it? At the proposed Phase 3 dose, Tango reported no Grade 3 rash, yet 40% Grade 3 treatment-related adverse events overall. Increasing vopimetostat produced three dose-limiting toxicities in two of four patients. Could selective attenuation of RAS-associated rash coexist with additional PRMT5-associated toxicity, without widening the therapeutic window? Matched-exposure comparisons would be particularly informative. The zoldonrasib combination's 38.5% nausea and vomiting rates reinforce the need to assess overall tolerability rather than isolated adverse events. • Pharmacokinetics: Vopimetostat increased zoldonrasib exposure approximately 1.5–2.4-fold. How much of the observed activity reflects complementary biology versus increased inhibitor exposure? • Dose intensity: With substantial interruptions and reductions, what proportion of the planned dose was actually delivered for each component over successive cycles? Were these modifications predominantly front-loaded or cumulative, and did patients maintain adequate exposure over time?