Miguel Gonzalez Velez, MD

MARIPOSA ami-laz is changing the biology of EGFR NSCLC. Hidetoshi Hayashi, @BenjaminBesseMD at @JTOonline Take: MET amplification: 3.4% vs 13.1% ( p=0.002) 2ry EGFR mutations (C797S/L718X/G724X): 1.4% vs 7.6% (p=0.01) No significant increase in other known pathways Similar story as when osimertinib essentially eliminated T790M, MET and C797S took its place. Ami-laz now suppresses those two mechanisms. It is likely that other mutations like HER2 and cell-cycle alterations will increase (Figure 2). @lungoncdoc @EGFRResisters #LCSM #lungcancer #thoraciconcology

SAFFRON (Phase 3) with osimertinib + savolitinib vs. platinum-doublet chemo in EGFR-mutant, MET-overexpressed/amplified NSCLC after osimertinib. Built on the SACHI Phase 3 data from China @TheLancet from Shun Lun Weigo Suo @TonyMok9. Take: MET amp is the most common resistance mechanism after 1L osimertinib (~10-24%). We know that dual EGFR blockade is key (MARIPOSA, ORCHARD and others). Likely they will displace chemo regimens soon. Question remains which combination will be the best? #lungcancer #LCSM #thoraciconcology

ARROS-1 update zidesamtinib in ROS1 TKI-naive NSCLC by @alexdrilon at #WCLC26 Take: ORR 94% is possible!!! in TKI-naive patients, with 86% still in response and 90% still progression-free at 12 months. DOR and PFS both not reached. The CNS data answers the open question from July: IC-ORR 100%, IC-CR rate 70%, median IC-DOR not reached, and no CNS progression events among patients without baseline brain mets. Safety consistent with prior reports, low discontinuation/dose-reduction rates. This is a materially stronger picture than the pretreated cohort behind the original approval (44% ORR). Discussion by @Mal_Itchins puts taletrectinib (TRUSTI/II) as the PFS benchmark to beat of 46 m. @ros1cancer #LCSM #lungcancer

Zidesamtinib approved for pretreated ROS1 @ros1cancer NSCLC based on ARROS-1 by @alexdrilon @BenjaminBesseMD and colleagues. Take: ORR of ~44% between taletrectinib (55%), repotrectinib (38%) and lorlatinib (35%) but seems to have better toxicity profile (Cross-trial comparison) https://t.co/nNNfeo24F4

DESTINY-Lung04. T-DXd vs pembrolizumab + chemo as 1L therapy in HER2-mutant (exon 19/20) NSCLC by @JuliaRotow #WCLC26 Take: Primary endpoint met PFS 14.3mo (T-DXd) vs 8.3mo. ORR 70% vs 44.5%; DOR 13.4 vs 9.7mo; median treatment duration 12mo vs 7mo. OS at 46.9% maturity numerically favors the control arm: 29.3mo (T-DXd) vs 33.1mo (pembro+chemo), HR 1.15 (0.88–1.52). no OS benefit, with many confounding postreatment. Great to see the comparator here is genuine current SOC not a weaker historical control, which makes the PFS win more meaningful but also makes the OS numbers harder to wave away. Again going back to the ORR/PFS/OS dilemma. #NSCLC #LCSM

DESTINY-Lung04 (Phase III) showed PFS with T-DXD vs SOC in HER2 NSCLC. Take: Press release only. No OS/PFS numbers disclosed yet. Pneumonitis is a big risk with chest RT, COPD and other risk factors. T-DXD is the king for HER2 with zongertinib slowly behind supporting and with a very good toxicity profile. #LCSM #Lungcancer

Divarasib (KRASCENDO-1) presented at @myESMO by @FSkoulidis and @BenjaminBesseMD Take: phase 3, previously treated KRAS G12C NSCLC, divarasib vs the current SOC (sotorasib or adagrasib). Median PFS 9.8 vs 5.7 months (HR 0.58, p<0.0001); median OS 17.7 vs 12 months. First head-to-head win of a next-generation KRAS G12C inhibitor vs approved first-generation drugs. Pending: KRASCENDO-2 (phase 3 first-line divarasib plus pembrolizumab vs pembrolizumab plus chemo) and KRASCENDO-170 (phase 1b/2 divarasib plus pembrolizumab first-line, ORR 73%. Many open questions on KRAS/chemo/IO combos, and (ON)/pan-KRAS/degraders will take years to sort out. #LCSM #NSCLC #KRAS #clinicaltrials

Tarlatamab-durvalumab maintenance by Perol and @sands_jacob @NEJM for ES-SCLC discussed by @StephenVLiu at @myESMO Take: DeLLphi-305, phase 3, n=563, maintenance after 1L chemoimmunotherapy without progression. Median OS 21.1 vs 12.7 months (HR 0.42, P<0.001). Median PFS 7.4 vs 1.9 months (HR 0.34). 12-month OS 79.4% vs 53.3%. Grade ≥3 events 46.8% vs 40.6%; CRS, mainly grade 1-2, in nearly half the tarlatamab arm. As expected D-305 moves tarla into first-line maintenance and nearly doubles median survival in a disease where 12-13 months has been the ceiling for years. If we are honest, unless we make big change due to CRS and tocilizumab it will be hard to make tarlatamab mainstream to most patients even in the US and LMICs. #LCSM #SCLC #clinicaltrials

Three Phase III 1L trials now compete in the hunger games of EGFR exon 20 insertion NSCLC. PAPILLON (ami-chemo) @chulkimMD WU-KONG28 (sunvozertinib) Caicun Zhou REZILIENT3 (zipalertinib-chemo) @danieltanmd Cross-trial comparison presented by @LudaBazhenovaMD at #WCLC26 Take: All three beat platinum doublet on PFS PAPILLON HR 0.40 (mPFS 11.4mo) WU-KONG28 HR 0.65 (mPFS 10.3mo) REZILIENT3 HR 0.50 (mPFS 14.5mo). A problem of plenty with three active DIFFERENT regimens and none showing a clean, mature OS win many considerations CNS activity, oral vs. IV, and toxicity burden to choose. #LCSM #lungcancer

Three Phase III 1L trials now compete in the hunger games of EGFR exon 20 insertion NSCLC. PAPILLON (ami-chemo) @chulkimMD WU-KONG28 (sunvozertinib) Caicun Zhou REZILIENT3 (zipalertinib-chemo) @danieltanmd Cross-trial comparison presented by @LudaBazhenovaMD at #WCLC26 Take: All three beat platinum doublet on PFS PAPILLON HR 0.40 (mPFS 11.4mo) WU-KONG28 HR 0.65 (mPFS 10.3mo) REZILIENT3 HR 0.50 (mPFS 14.5mo). A problem of plenty with three active DIFFERENT regimens and none showing a clean, mature OS win many considerations CNS activity, oral vs. IV, and toxicity burden to choose. #LCSM #lungcancer

ADAURA 8-year OS @DrRoyHerbst at #WCLC26 in EGFR-mutated early-stage NSCLC. Take: 8-yr OS 74% vs 58% (HR 0.53, 95% CI 0.38–0.75) in stage II–IIIA. The gap keeps opening after the 5yr report. Interesting to think the cure % now the TARGET study will start answering the duration. I wonder if it will be 3 vs 5 year vs forever? #LCSM #lungcancer