#ESMO20 Discussion of the phase III CROWN trial results (planned interim analysis): lorlatinib vs crizotinib in treatment naive #ALK#NSCLC by @bensolomon1 - potentially practice changing data in an important subset of lung cancer. #LCSM@OncoAlert
#ESMO20#ALK fusion positive NSCLC is an important subset where we have very potent and active agents with PFS measured in years - but always room for improvement. #LCSM@OncoAlert
#ESMO20 Study design for CROWN shown here. Standard 1:1 randomization to lorlatinib 100mg qday vs crizotinib 250mg bid, stratified by Asian vs not and presence or absence of brain metastases. Primary endpoint was PFS by BICR. #LCSM@OncoAlert
#ESMO20 Baseline characteristics show that 26% of patients had brain metastases (only 6% with prior radiation) and by central MRI review. #LCSM@OncoAlert
Wow.
PFS by BICR HR 0.28 substantially better (across trials) than we saw with alectinib or brigatinib (0.47-0.49). 12 month PFS rate 78% with lorlatinib vs 39% with crizotinib. #LCSM#ESMO20@OncoAlert
#ESMO20 Here we see investigator assessed PFS HR was 0.21 favoring lorlatinib over crizotinib as 1L therapy for #ALK NSCLC. #LCSM@OncoAlert
#ESMO20 Benefit seen across all subgroups with a better HR in patients with brain metastases (HR 0.20) but still impressive in those without (0.32) but overall, benefit seen across the board. #LCSM@OncoAlert
#ESMO20 ORR 76% with lorlatinib vs 58% with crizotinib. Both work quickly (median time to response 1.8m) but duration of response not reached for lorlatinib (11m for crizotinib). #LCSM@OncoAlert
#ESMO20 Lorlatinib has greater CNS penetrance than other ALK TKIs and we see impressive CNS results in CROWN. Intracranial response rate in those with measurable disease was 82% with lorlatinib - 71% were complete responses! #LCSM@OncoAlert
#ESMO20 The intracranial time to progression (BICR, MRI) not reached but the HR was 0.07 (!!!) and that lorlatinib line is about as flat as can be. #LCSM@OncoAlert
#LCSM Very early look at OS - this will be critical to follow. As resistance mechanisms vary by agent used, we don't know much about resistance to first line lorlatinib and over time, analysis of PFS2/PFS3 may be interesting. #LCSM@OncoAlert
#ESMO20 A big consideration is safety with lorlatinib. Note that 72% had grade 3/4 AEs and 5% with fatal AE. Dose interruption seen in about half of patients. AE leading to permanent discontinuation in only 7%. #LCSM@OncoAlert
#ESMO20 The tornado plot shows some unique toxicities with lorlatinib including hyperlipidemia. Of utmost concern to me are the neurocognitive effects - noted in ~20% of patients. I feel these can be underreported, however, if recognized, they respond to dose reduction. #LCSM
#ESMO20 Importantly, lorlatinib associated with better QoL scores - glad these are being captured.
#ESMO20 We all expected lorlatinib to beat crizotinib but a HR of 0.28 certainly surpassed my expectations (like an ALK-DAURA). Seems like a new SOC but some hesitation given impact on sequencing and, most importantly, toxicity - esp neurocognitive impact. #LCSM@OncoAlert
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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
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
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
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.
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.
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).
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
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
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
Dr. @ZPiotrowskaMD presents initial results from the ELIOS trial at #ESMO22 - molecular profiling of #EGFR mutant NSCLC after progression on 1L osimertinib.
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
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
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
Dr. @marinagarassino presents 5-year efficacy and safety update of KEYNOTE-189 (1L carboplatin plus pemetrexed +- pembrolizumab in non-squamous NSCLC) #ESMO22
KEYNOTE 189 is our SOC and has shown a consistent benefit including improving OS even with a crossover rate of 57%. #ESMO22
KEYNOTE 189 shows sustained OS benefit with longer follow up and a 5y OS rate of 18.4% with an OS HR of 0.60. Better PFS and OS also observed. Benefit across PDL1 strata. No new safety signals . #ESMO22