Stephen V Liu, MD Profile picture
Sep 20, 2020 13 tweets 12 min read Read on X
#ESMO20 Much anticipated results from CodeBreaK100: AMG 510 (sotorasib) in #KRAS G12C #NSCLC by @DavidHongMD building on exciting data seen over the past two years for this huge unmet need. #LCSM @OncoAlert @myESMO Image
#ESMO20 KRAS G12C occurs in 13% of NSCLC, 3-5% CRC, and other tumors as well. Up until recently, considered "undruggable". Sotorasib is a highly selective KRAS G12C inhibitor that traps KRAS in its inactive GDP bound state. #LCSM @OncoAlert Image
#ESMO20 CodeBreak100 is a phase I escalation/expansion trial of sotorasib monotherapy in KRAS G12C tumors. Primary endpoint was safety. Escalation established preferred dose of 960mg qday. #LCSM @OncoAlert Image
#ESMO20 Analysis here is on 59 patients with KRAS G12C NSCLC (34 were at the 960mg dose). Median f/u 11.7m. Mostly prior smokers, 90% with prior PD(L)1 therapy, fairly heavily pretreated (75% 3rd line or beyond) #LCSM @OncoAlert Image
#ESMO20 KRAS G12C doesn't occur on normal tissue so the toxicity profile of sotorasib is very good. No DLTs. No fatal AEs. Only 1 patient stopped due to treatment related AE. #LCSM @OncoAlert Image
#ESMO20 Few G3+ adverse events. One case of grade 4 ALT elevation that improved with dose reduction/steroids. This is even more impressive when we recall that 90% had prior immunotherapy. Not seeing the toxicity of IO-TKI sequence we see in EGFR/ALK. Different TME in KRAS? #LCSM Image
#ESMO20 Efficacy of sotorasib in KRAS G12C NSCLC. ORR 32.2% with some reduction noted in 71.2% of patients at 6 weeks and an overall DCR of 88.1% (91.2% at 960mg). ORR lower than earlier reports, as expected, but still high in this setting. High SD rate but how durable? #LCSM Image
#ESMO20 Waterfall plot showing efficacy of sotorasib. Responses seen across dose levels, reassuring if dose reduction needed. ORR of 32.5% in a heavily pretreated population is impressive (docetaxel/ramucirumab ~ 23% for reference) with high SD rates (but how durable?). #LCSM Image
#ESMO20 Median PFS with sotorasib in KRAS G12C NSCLC was 6.3m. Respectable in this setting but duration of response more impressive at 10.9m and long duration noted across doses. Median duration of SD was 4m which is not that long - casts the 90% DCR in a different light. #LCSM Image
#ESMO20 Illustrative case provided in patient with STK11 co-mutation, 5 prior therapies since 2013 including chemo and nivolumab. Had CR in target lesions (low burden of disease shown) and had CNS response (though all CNS lesions had been radiated). Progressed at 1.5y, no DLTs. Image
#ESMO20 Efficacy of sotorasib seen across KRAS G12C MAFs and TMB levels (by ctDNA). PDL1 predictive. Responses seen across co-mutations as well, though need larger numbers and need to correlate with duration/resistance, not just response. #LCSM @OncoAlert ImageImage
#ESMO20 Overall, sotorasib showing clear efficacy (RR 32.2%, DOR 10.9m, PFS 6.3m) and excellent safety profile. Would have a clear role today in salvage setting. Good safety profile makes it an appealing candidate for combinations in the 1L setting. #LCSM @OncoAlert Image
#ESMO20 I think we had high expectations for the drug given early reports - but a RR of 35% with sotorasib is a clear win here. The reference is not alectinib/osimertinib, the reference is docetaxel. And given the high incidence of KRAS, the potential impact is huge.

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More from @StephenVLiu

Sep 8
Dr. @marinagarassino at #WCLC24 Presidential Plenary presents Normalized Membrane Ratio of TROP2 as a biomarker for datopotamab deruxtecan in TROPION-Lung01 (Dato-DXd vs docetaxel in previously treated NSCLC which previously showed PFS benefit with Dato-DXd.


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#WCLC24 TROP2 IHC has been a poor predictive marker. Normalized Membrane Ratio (NMR) factors in receptor internalization. Ratio is membrane expression over membrane plus cytoplasmic expression (using optical density from digitized slide) and lower would be more favorable.

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#WCLC24 TROP2 QCS-NMR seems to be a much better predictor of benefit with datopotamab deruxtecan in BEP and in non-sq non-AGA subset: in NMR+, PFS HR 0.57 and KM shows clear separation.
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Read 4 tweets
Apr 23, 2023
Dr. Shun Lu presents interim results from the perioperative NEOTORCH study at the #ASCOPlenarySeries. Randomized pts with resectable stage II/III NSCLC to perioperative chemotherapy with toripalimab (anti-PD1) vs placebo. Another entry in the perioperative space? #LCSM Image
Includes resectable stage II/III (AJCC v8), EGFR/ALK wild type NSCLC. Pts receive 3 cycles of neoadjuvant chemotherapy + toripalimab vs placebo then surgery then 1 more cycle of adjuvant chemo (+tori/pbo) then 13 doses of maintenance toripalimab vs placebo. #ASCOPlenarySeries Image
First interim EFS analysis only for stage III. Includes 404 pts - but 926 screened. Would be interesting to see specific eligibility criteria not met in screening process. Reminder of how selected trial populations are and value of future real-world analyses. #ASCOPlenarySeries ImageImage
Read 11 tweets
Apr 16, 2023
Impressive data from #AEGEAN at #AACR23 from Dr. John Heymach and colleagues. This is the first of several phase III peri-operative IO studies in resectable NSCLC combining neoadjuvant chemo-immunotherapy followed by adjuvant immunotherapy. Image
Included stage IIA-IIIB (AJCC v8) with no EGFR/ALK & excluded pts who would require pneumonectomy. Large study with n=801 (CM816 was n=358). Pts received 4 cycles (not 3) of platinum-based chemo with durvalumab (anti-PDL1) or placebo, then surgery, then durvalumab / placebo x 1y. Image
Almost 75% received carboplatin over cisplatin. Global study; fairly even PDL1 distribution. 80% of pts went to surgery, 78% completed resection (90-95% of those were R0). Overall, 66% of pts began adjuvant phase (but 90% of those who had an R0 resection had adjuvant therapy). ImageImageImage
Read 9 tweets
Dec 8, 2022
There is a lot to consider in this first-line study of the #KRAS G12C inhibitor adagrasib plus pembrolizumab from #ESMOImmuno22. Some pleasant surprises in terms of safety. Definitely encouraging but need to see a bit more to be sold on this strategy. 🤔 #LCSM Image
We're looking for synergy with the two agents - more than an additive effect. Reason to believe there will be based on preclinical data showing the effect on T-cell infiltration from #KRAS inhibition. Similar to what has been shown with MEK inhibition. #ESMOImmuno22 Image
The first-line dataset includes the phase Ib KRYSTAL-1 and the phase II KRYSTAL-7. In KRYSTAL-1 (n=7), 4/7 had a response and all were durable (>9m). G3 TRAEs in 4 pts (lipase elevation, LFTs, muscular pain, pneumothorax). #ESMOImmuno22 ImageImage
Read 10 tweets
Sep 19, 2022
Dr. @ZPiotrowskaMD presents initial results from the ELIOS trial at #ESMO22 - molecular profiling of #EGFR mutant NSCLC after progression on 1L osimertinib. ImageImage
In this study of highly motivated pts at esteemed sites, evaluable paired biopsy at PD only available in 46/115 pts (40%). Interestingly, 75 pts (65%) had paired biopsy but 27 failed NGS (23%). Speaks somewhat to the real world feasibility of a repeat biopsy approach. #ESMO22 Image
Common co-mutations at baseline included TP53, EGFR amp, and CDKN2A loss. Acquired alterations included MET amp, EGFR C797S, ALK fusion, NKX2-1 amp. Mostly mutually exclusive. #ESMO22 ImageImageImage
Read 5 tweets
Sep 11, 2022
Dr. Silvia Novello presents 5y update on KEYNOTE 407 (platinum plus tax and +/- pembrolizumab for 1L squamous NSCLC #ESMO22
With longer follow up, OS favors pembrolizumab arm with mOS 17.2 vs 11.6m (OS HR 0.71) in squamous NSCLC. 5y OS rate 18.4% vs 9.7%. PFS benefit (HR 0.62) and higher RR across PDL1 strata. #ESMO22
For patients who complete 2y of pembrolizumab, 3y OS rate (after completing 2y pembro) was 70% - though not all of those patients are cured (44% were alive without PD or subsequent therapy). #ESMO22
Read 4 tweets

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