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?

Amgen’s Imdelltra drives massive survival benefit in ‘watershed moment’ for small cell lung cancer. #ESMO26 fiercepharma.com/pharma/amge…

Kevan Shokat (@kevansf) made KRAS druggable. With daraxonrasib now in the clinic, he is “all in” on the ultimate target: p53 Shokat was named 2026 Stephenson Global Prize winner cancerletter.com/conversatio…

So happy to see my friend Dr. @NarjustFlorezMD honored by Dr. @Tony_Calles and @tactics_md at an #ESMO26 reception full of close friends.

🧿 Shaping the future of #NSCLC at #ESMO26 Delighted to co-chair today’s symposium in Madrid with @MARIANOPROVENCI, Enriqueta Felip & Marcia K. Horn @Exon20Group Translating scientific advances into better outcomes for patients, today and tomorrow.

Beyond excited to recruit @VivekSubbiah to @nyulangone @Perlmutter_CC as the new director of our Early Phase Drug Development Program and the Rare Cancer Program. Congratulate Vivek when you see him at #ESMO26. Welcome to NYC! @JohnPLeonardMD nyulangone.org/news/perlmutt…

🧬 Could genetics predict T-DXd–induced pneumonitis? A fascinating signal from the PROCURE study, published in ESMO Open. 290 patients with advanced HER2+ or HER2-low breast cancer receiving T-DXd. 🔹 ILD incidence: 11.4% (33/290) 🔹 Strongest genetic association: HLA-F region (rs9258213) • OR 6.82 (95% CI 2.60–17.88) • Adjusted OR 5.87 🔹 Additional signals: • HLA-B/HLA-C: immune regulation • SLCO1B1: drug transport • CYP3A4: drug metabolism Why does this matter? T-DXd pneumonitis susceptibility may depend not only on drug exposure but also on the patient’s inherited genetics. ⚠️ Important: Exploratory associations, not validated predictors. Routine genetic screening is NOT recommended yet. Verdict: A promising step toward predicting ADC toxicity before treatment, but independent validation is essential. @ESMO_open @my_esmo @ASCO @oncoalert #BreastCancer #TDXd #PrecisionOncology

ESMO 2026 | TOP 10 LUNG CANCER TRIALS TO WATCH! From DLL3 bispecifics and next-generation KRAS inhibitors to novel ADCs, major lung cancer data are coming at #ESMO26. 🔥 My Top 10 Trials 1.DeLLphi-305 | Tarlatamab + durvalumab | ES-SCLC 2.SAFFRON | Osimertinib + savolitinib | MET-altered EGFR+ NSCLC 3.Krascendo 1 | Divarasib vs approved KRAS G12C inhibitors 4.OptiTROP-Lung06 | Sacituzumab tirumotecan + pembrolizumab | 1L NSCLC 5.OptiTROP-Lung04 | TROP2 ADC after EGFR-TKI progression 6.SigVie-002 | Integrin αvβ6 ADC vs docetaxel 7.SARON | Consolidation RT in oligometastatic NSCLC 8.PERSEE | Pembrolizumab ± chemotherapy | PD-L1 ≥50% 9.DeLLphi-304 | Long-term survival with tarlatamab 10.ASTRIDE | Serplulimab vs atezolizumab + chemotherapy | ES-SCLC Three Presidential presentations deserve special attention: DeLLphi-305, SAFFRON and Krascendo 1. Which trial could have the biggest impact on lung cancer treatment? @myesmo @ESMO_open @ASCO @oncoalert #ESMO26 #LungCancer #Oncology

Dr. @PatelOncology at #AILCC26 discusses AI in medicine. Helping with clinic flow and documentation, patient communication, as well as novel biomarkers. But for decisions, need to avoid deskilling and cognitive surrender.

Dr. @LochrinSarah reminds us that most patients with EGFR NSCLC have poor risk features and combination therapy needs to be considered up front. #AILCC26