OA02.05 Lazertinib vs Osimertinib in 1L EGFR-Mutant Advanced NSCLC: A Randomized, Double-Blind, Exploratory Analysis from MARIPOSA
Introduction: Lazertinib is an oral, central nervous system-penetrant, 3rd-generation
epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that
significantly improved progression-free survival (PFS) versus gefitinib in
patients with treatment-naïve,EGFR-mutant advanced non-small cell
lung cancer (NSCLC; Cho JCO 2023). In the phase 3 MARIPOSA
study (NCT04487080), lazertinib combined with amivantamab, an EGFR-MET
bispecific antibody with immune cell-directing activity, significantly improved
PFS versus osimertinib in the same patient population (HR, 0.70; 95% CI,
0.58-0.85; P<0.001; Cho Ann Oncol 2023). The
MARIPOSA study included a lazertinib monotherapy arm to assess contribution of
components in the combination. This is the first trial to prospectively
evaluate two 3rd-generation EGFR-TKIs in a randomized, double-blind
fashion. Herein, we report results from an exploratory analysis of lazertinib
versus osimertinib.
Methods: In MARIPOSA, 1074 patients were randomized 2:2:1 to receive
amivantamab plus lazertinib, osimertinib monotherapy, or lazertinib
monotherapy. These exploratory analyses focus on the 216 patients randomized to
receive lazertinib (240-mg daily) and the 429 patients randomized to
osimertinib (80-mg daily) in a double-blinded fashion. Serial brain imaging
with MRI was required for all patients. Efficacy endpoints included PFS (by blinded
independent central review [BICR] per RECIST v1.1), overall response rate
(ORR), duration of response (DoR), overall survival (OS), and safety.
Results: At a median follow-up of 22.0 months, median PFS by BICR was 18.5 months (95% CI,
14.8-20.1) for lazertinibversus 16.6 months (95%
CI, 14.8-18.5) for osimertinib(HR, 0.98; 95% CI, 0.79-1.22). ORR was 83% (95% CI, 77-88 for lazertinib versus 85% (95% CI, 81-88) for osimertinib, with median DoR of 16.6 months (95% CI,
14.8-20.2) versus 16.8 months(95% CI, 14.8-18.5), respectively, among confirmed responders. At interim
survival analysis, median OS was not estimable for both arms (HR, 1.00; 95% CI,
0.73-1.38).
Additionally, we evaluated PFS of lazertinib versus osimertinib in subgroups
of high-risk disease. Median PFS for patients with a history of brain
metastases was 16.4 months (95% CI, 12.9-19.4) for lazertinib versus 13.0
months (95% CI, 12.2-16.4) for osimertinib (HR, 0.90; 95% CI, 0.65-1.25).
Median PFS for patients with detectable circulating tumor DNA at baseline was
18.4 months (95% CI, 14.6-20.1) for lazertinib versus 14.8 months (95% CI,
12.9-16.6) for osimertinib (HR, 0.88; 95% CI 0.66-1.17). Median PFS for
patients with TP53 co-mutations was 14.6 months (95% CI,
11.0-19.4) for lazertinib versus 12.9 months (95% CI, 11.1-14.7) for
osimertinib (HR, 0.85; 95% CI 0.58-1.23).
The safety profiles of lazertinib and osimertinib were similar, with
EGFR-related adverse events (AEs) being the most common. Most individual AEs
were grade 1-2. Higher rates of diarrhea, thrombocytopenia, leukopenia, and QT
interval prolongation were observed with osimertinib versus higher rates of
rash and paresthesia with lazertinib. Treatment-related AEs leading to
discontinuations were similar between arms.
Conclusions: Efficacy and safety were similar for lazertinib and
osimertinib. Patients with EGFR-mutant advanced NSCLC, including
those with high-risk features, may benefit from lazertinib as an important new
treatment option.
Amivantamab+Lazertinib 头对头Osimertinib药效数据：
OA02.03 Amivantamab Plus Lazertinib vs Osimertinib in First-lineEGFR-mutant Advanced NSCLC: Longer Follow-up of the MARIPOSA Study
Introduction: Amivantamab is an EGFR-MET bispecific antibody with immune
cell-directing activity. Lazertinib is a central nervous system-penetrant 3rd-generation
EGFR TKI. In the primary analysis of the phase 3 MARIPOSA study (NCT04487080),
at a median follow-up of 22.0 months, amivantamab plus lazertinib significantly
improved progression-free survival (PFS) by blinded independent central review
vs osimertinib in patients with treatment-naïve,EGFR-mutated
advanced NSCLC (HR, 0.70; 95% CI, 0.58-0.85; P<0.001). Early
interim overall survival (OS) analysis showed a favorable trend for
amivantamab-lazertinib over osimertinib (HR, 0.80; 95% CI, 0.61-1.05; P=0.11).
Here, we present updated results with longer follow-up from MARIPOSA.
Methods: MARIPOSA randomized 1074 patients with treatment-naïve, EGFR-mutated
(Exon 19 deletions or Exon 21 L858R substitutions) locally advanced or
metastatic NSCLC 2:2:1 to open-label amivantamab-lazertinib (n=429), blinded
osimertinib (n=429), or blinded lazertinib (n=216; included to assess
contribution of components). This updated analysis, requested by health
authorities, compares amivantamab-lazertinib with osimertinib.
Results: As of May 13, 2024 (median follow-up, 31.1 months), 44% (185/421) and
34% (145/428) of patients were still receiving treatment in the
amivantamab-lazertinib and osimertinib arms, respectively. In total, 155
patients in the amivantamab-lazertinib arm and 233 in the osimertinib arm had
investigator-assessed progressive disease and discontinued treatment. Among
those, 72% (111/155) and 74% (173/233) initiated subsequent therapy,
respectively, with carboplatin-pemetrexed being the most common first
subsequent therapy across arms (amivantamab-lazertinib, 26% [29/111];
osimertinib, 28% [48/173]). PFS after first subsequent therapy (PFS2) favored
amivantamab-lazertinib (HR, 0.73; 95% CI, 0.59-0.91; nominal P=0.004).
Patients receiving amivantamab-lazertinib demonstrated significantly longer
median time to treatment discontinuation and time to subsequent therapy vs
osimertinib (Table). Intracranial PFS showed a favorable trend for
amivantamab-lazertinib vs osimertinib (Table). While not formally tested for
significance, median OS was not estimable for amivantamab-lazertinib vs 37.3
months for osimertinib (HR, 0.77; 95% CI, 0.61-0.96; nominal P=0.019).
At 24 months, 75% and 70% of patients were alive in the amivantamab-lazertinib
and osimertinib arms, respectively; corresponding values at 36 months were 61%
and 53%.
Conclusions: Amivantamab-lazertinib continues to show a trend towards
improved OS while also improving post-progression outcomes vs osimertinib,
reaffirming amivantamab-lazertinib as a first-line standard-of-care for EGFR-mutated
advanced NSCLC.
Amivantamab+Lazertinib 头对头Osimertinib病人生存质量研究：
MA12.07 Amivantamab Plus Lazertinib vs Osimertinib in First-Line, EGFR-Mutant Advanced NSCLC: Patient-relevant Outcomes from MARIPOSA
Introduction:Amivantamab is an epidermal growth factor receptor
(EGFR)-MET bispecific antibody with immune cell-directing activity. Lazertinib
is a highly selective, CNS-penetrant, EGFR tyrosine kinase inhibitor
(EGFR-TKI). In MARIPOSA (NCT04487080), amivantamab plus lazertinib
(amivantamab-lazertinib) significantly prolonged progression-free survival
(PFS) vs osimertinib (hazard ratio [HR], 0.70;P<0.001) in
patients with treatment-naïve, EGFR-mutant advanced non-small cell
lung cancer (NSCLC; Cho Ann Oncol 2023;34:S1306;LBA14). We
evaluated time to symptomatic progression (TTSP) and patient-reported outcomes
(PROs) from MARIPOSA.
Methods: Analyses included the 429 patients randomized to receive
amivantamab-lazertinib and the 429 to osimertinib. TTSP was defined as time
from randomization to onset of new/worsening lung cancer symptoms requiring
change in anticancer therapy, another clinical intervention, or death,
whichever occurred first. PROs were measured using EORTC-QLQ-C30 and NSCLC-SAQ;
all P-values are nominal. The threshold for a meaningful
improvement was a 10-point increase on EORTC-QLQ-C30 functioning scales.
Results: At a median follow-up of 22.0 months, amivantamab-lazertinib
demonstrated a significant improvement in TTSP versus osimertinib (HR, 0.72;
95% confidence interval, 0.57-0.91; P=0.005).
As median treatment duration was 18.5 months for amivantamab-lazertinib versus
18 months for osimertinib, PROs at 18 months are reported to evaluate the long
term impact of treatment on quality of life. Based on the EORTC-QLQ-C30
functioning scales at 18 months, the percentage of randomized patients on
treatment with improved or stable functioning relative to baseline in the
amivantamab-lazertinib versus osimertinib arms was significantly higher for
emotional functioning (38% versus 31%; P<0.05) and cognitive
functioning (38% versus 31%; P<0.05). For other functioning
scales, no statistically significant differences between amivantamab-lazertinib
and osimertinib were observed. Functioning was maintained over time in both
treatment arms as most changes over time were less than the defined threshold
for clinically meaningful differences.
At 18 months, no statistical differences were observed between the
amivantamab-lazertinib and osimertinib arms for the absence of key symptoms
from the EORTC-QLQ-C30 including dyspnea (34% versus 31%), pain (27% versus
26%), and fatigue (15% versus 16%). There were no significant differences in
symptoms between arms based on the NSCLC-SAQ (Figure).
Conclusions: For patients with treatment-naïve, EGFR-mutant
advanced NSCLC, amivantamab-lazertinib significantly delayed symptomatic
progression versus osimertinib indicating greater control of disease and
related symptoms, while maintaining functioning as observed by PRO scales. PROs
were comparable across treatment arms at the 18-month landmark, and treatment
did not lead to meaningful decrements in patient quality of life.
奥希替尼+铂类化疗 1L前期数据：Osi+铂 PFS 25.5个月 VS Osi 单药16.7个月；本项摘要为进一步亚组分析：
MA12.04 FLAURA2: Impact of Tumor Burden on Outcomes of 1L Osimertinib ± Chemotherapy in Patients with EGFR-mutated Advanced NSCLC
Introduction:Osimertinib is a third-generation, central nervous
system (CNS)-active, EGFR-tyrosine kinase inhibitor with demonstrated efficacy
in EGFR-mutated NSCLC and is the preferred first-line treatment for
EGFR-mutated advanced NSCLC. In the Phase III FLAURA2 study (NCT04035486), osimertinib
plus platinum-pemetrexed chemotherapy significantly improved progression-free
survival (PFS) versus osimertinib monotherapy as first-line
treatment of EGFR-mutated advanced NSCLC (investigator-assessed median PFS
[mPFS] 25.5 vs 16.7 months, respectively; HR 0.62, 95% CI 0.49, 0.79;
p<0.0001) and is now a recommended treatment option in this setting. To
understand the impact of baseline tumor burden (characterized by the number of
metastatic anatomical locations and extent of distant metastases at study
entry) on outcomes, we assessed PFS in these patient subgroups from FLAURA2.
Methods: Patients were randomized 1:1 to receive osimertinib plus
platinum-based chemotherapy, or osimertinib monotherapy until progression or a
discontinuation criterion was met. Primary endpoint was investigator-assessed
PFS per RECIST v1.1. Post-hoc analyses of PFS (by investigator assessment) were
performed in baseline tumor burden subgroups characterized by the number of
metastatic anatomical locations (<3 [defined as low] vs ≥3 [high]; patients
with ≥1 metastatic lesion in an anatomical location were counted once within
the specified metastatic anatomical location) and extent of distant metastases
(intra-thoracic [M1a, low] vs extra-thoracic [M1b/M1c, high]; classified
according to Version 8 of the IASLC Staging Manual in Thoracic Oncology). Data
cut-off: 03 April 2023.
Results: 557 patients were randomized to osimertinib plus chemotherapy
(n=279) or osimertinib monotherapy (n=278). The proportion of patients in the
baseline tumor burden subgroups was similar across treatment arms (osimertinib
plus chemotherapy/osimertinib monotherapy): <3 metastatic anatomical
locations, 46/39%; ≥3 metastatic anatomical locations, 54/61%; M1a, 24/25%; M1b
and M1c, 71/72%. Among patients with <3 metastatic anatomical locations,
mPFS (95% CI) was 27.9 months (24.7, not calculable [NC]) with osimertinib +
chemotherapy versus 30.5 months (16.6, NC) with osimertinib; PFS HR 0.75 (95%
CI 0.51, 1.11). In those patients with ≥3 metastatic anatomical locations,
mPFS (95% CI) was 24.9 months (21.9, 27.6) with osimertinib + chemotherapy
versus 16.4 months (13.6, 19.2) with osimertinib; PFS HR 0.57 (95% CI 0.43,
0.77). For patients with intra-thoracic metastases, mPFS (95% CI) was
26.0 months (21.9, NC) versus NC (16.7, NC; PFS HR 0.97 [95% CI 0.59, 1.60]),
and for those with extra-thoracic metastases, mPFS (95% CI) was 25.1
months (22.2, NC) versus 16.4 months (13.6, 19.4; PFS HR 0.54 [95% CI 0.41,
0.71]) in the osimertinib + chemotherapy versus osimertinib arms, respectively.Additional data on factors associated with a poor prognosis, including
presence of liver and/or CNS metastases, will be presented.
Conclusions: Patients with characteristics associated with high tumor
burden at baseline had a clinically meaningful PFS benefit with osimertinib
plus chemotherapy compared with osimertinib monotherapy, further supporting the
clinical utility of this combination and helping clinical decision making in
patients with EGFR-mutated advanced NSCLC.
和上面摘要的同一项临床：Osi+铂 VS Osi 1L用药以后的突变情况，MET扩增最多，两组都一样；此外就是Osi单药组C797S突变，C797S是四代EGFR-TKI解决的突变类型；
MA12.03 FLAURA2: Resistance, and Impact of Baseline TP53 Alterations in Patients Treated With 1L Osimertinib ± Platinum-Pemetrexed
Introduction: Osimertinib, a third-generation, CNS-active EGFR-TKI, is the
preferred first-line treatment for EGFR-mutated (EGFRm) advanced NSCLC;
however, most patients will develop progressive disease (PD) due to treatment
resistance. The Phase III, open-label, randomized FLAURA2 study (NCT04035486)
demonstrated a significant PFS benefit with first-line osimertinib +
platinum-pemetrexed chemotherapy (osi+CTx) versus osimertinib monotherapy (osi)
in patients with EGFRm advanced NSCLC. Preliminary results from a prespecified,
exploratory analysis of acquired resistance mechanisms to osimertinib ±
chemotherapy were presented previously. We report updated analyses further
investigating resistance mechanisms in FLAURA2.
Methods: Patients ≥18 years with untreated EGFRm (Ex19del/L858R)
advanced NSCLC were randomized 1:1 to receive osi+CTx or osi. Paired plasma
ctDNA samples were collected at baseline and PD and/or treatment
discontinuation up to 06Sep2023; samples were analyzed using NGS (Guardant
Health, GuardantOMNITM). Tumor tissue was collected at screening for
central EGFRm testing and exploratory NGS (Foundation Medicine,
FoundationOne®CDx). Clinical outcomes were investigator-assessed (RECIST v1.1).
Results: Of 557 patients randomized to treatment (osi+CTx, n=279; osi,
n=278), 181 matched baseline and PD plasma samples were evaluable for analysis,
(osi+CTx, n=76; osi, n=105). Of these, 167 had EGFRm ctDNA detected at baseline
(osi+CTx, n=68; osi, n=99). Resistance mechanisms were similar across arms,
with no novel mechanisms detected. The most common acquired resistance
mutations were C797S mutation in the osi arm and MET amplification in both arms
(Table). There was no substantial change in tumor mutational burden between
baseline and PD for either arm. At time of analysis, 141 baseline tissue
samples were available for NGS (osi+CTx, n=72; osi, n=69); 41/72 and 38/69 had
TP53 alterations detected, and 31/72 and 31/69 were TP53 wild-type, in the
osi+CTx and osi arms, respectively. PFS Kaplan-Meier curves showed a separation
in favor of patients with wild-type TP53 versus those with TP53 alterations at
baseline, regardless of treatment: osi+CTx, HR not calculated (NC; as <20
events across arms); osi, HR 0.48 (95% CI 0.23, 1.0). Across treatment arms,
PFS Kaplan-Meier curves showed a separation in favor of osi+CTx versus osi,
irrespective of baseline TP53 status: wild-type TP53, HR NC; TP53 altered, HR
0.57 (95% CI 0.29, 1.12).
Conclusions: Although the plasma analysis set remains enriched for
patients with early progression, these more mature data show acquired
resistance mechanisms remain similar across treatment arms. Preliminary
baseline tissue analyses suggest TP53 alterations to be a prognostic factor;
the benefit of osi+CTx versus osi was similar in patients with or without TP53
alterations.
MET扩增作为Osi用药后最常见突变类型，联用MET-TKI 是不是也就合理了，下面这项为摘要，不过目前仅有标题：
PL04.10 Osimertinib With or Without Savolitinib as 1L in De Novo MET Aberrant, EGFRm Advanced NSCLC (CTONG 2008): A Phase II Trial
Abstract is embargoed at this time.
OA10.03 Tarlatamab Sustained Clinical Benefit and Safety in Previously Treated SCLC: DeLLphi-301 Phase 2 Extended Follow-up
Introduction: Tarlatamab, a bispecific T-cell engager (BiTE®) immunotherapy
that targets delta-like ligand 3 (DLL3) on SCLC cells, showed durable
anticancer activity and a manageable safety profile in patients with previously
treated SCLC in the DeLLphi-301 phase 2 study. At the primary analysis, median
duration of response (DOR) was not reached, and overall survival (OS) data were
immature (Ahn MJ,NEJM 2023). Here, efficacy and safety
outcomes from longer follow-up of the DeLLphi-301 study are reported.
Methods: Tarlatamab 10 mg or 100 mg (Q2W) was evaluated in patients with SCLC
who relapsed after 1 platinum-based regimen (± checkpoint inhibitor) and at
least 1 other line of therapy. The primary efficacy endpoint was objective
response rate (ORR) per RECIST 1.1 by blinded independent central review.
Results: Overall, 220 patients received tarlatamab. Data for the longer
follow-up, median of 13.6 months (range 0.1-20.9) for efficacy outcomes, are
shown in the Table. For the 10
mg group, the dose selected for subsequent trials, ORR was 40.4% and median
DOR was not estimable, with responses ongoing in 19 of 40 (47.5%) responders at
data cutoff. Median
progression-free survival was 4.3 months and median OS was 15.2 months for the 10 mg group, with
Kaplan-Meier estimates of OS at 6 and 12 months of 73.4% and 56.7%, respectively.
The longer follow-up revealed no new safety signals in both dose groups:
cytokine release syndrome, primarily grade 1 or 2, and no grade 4 or 5
occurrences, remained the most frequent adverse event (56.8%). Discontinuations
due to treatment-related adverse events remained infrequent (2.7%). Results
from an even longer follow-up will be presented.
Conclusions: Tarlatamab continued to achieve sustained responses and
favorable long-term survival outcomes in patients with previously treated SCLC.
Tarlatamab showed a favorable benefit-risk profile, supporting tarlatamab use
in patients with previously treated SCLC. The longer follow-up at time of
presentation will provide clearer insight on response durability and long-term
survival.
默沙东从和铂引进的DLL3 MK-6070 (aka HPN328)双抗本次也有爬坡数据更新，病人招募的线数和Tarlatamab一样，有过脑转移史的ORR更好一点略奇怪，不过爬坡数据和Amgen I期公布的爬坡数据看，也还可以，后面看看拓展剂量的数据咋样。
OA10.06 Impact of Brain Metastases on Safety and Efficacy of MK-6070, a DLL3-Targeting T Cell Engager, in Small Cell Lung Cancer
Introduction: MK-6070 (aka HPN328) is a DLL3-targeting T cell engager being
studied in an ongoing phase 1/2 trial in patients (pts) with high grade
neuroendocrine tumors associated with DLL3 expression, including small cell
lung cancer (SCLC). Brain
metastases (BM) are frequent in SCLC and cause significant morbidity. We
analyzed the characteristics and outcomes of pts with SCLC treated to date in
the MK-6070 phase 1/2 study (NCTNCT04471727) according to the presence of BM.
Methods: Pts in the phase 1/2 trial receive MK-6070 IV weekly or Q2W with
a priming dose preceding the target dose. Pts with BM are eligible if BM are
asymptomatic, previously treated, and radiologically stable; radiotherapy for
localized BM progression is allowed on study if pts are otherwise benefitting.
Objective response rate (ORR) is determined using RECIST v1.1; a modified
RECIST v1.1 assessing extracranial response (EC-ORR) is also used to include
pts with systemic response and brain-only progression.
Results: As of 09 February 2024, 49 pts with SCLC were treated at ≥
1.215 mg, the minimum effective dose of MK-6070. Median age was 64 (range,
41-81); 100% had ECOG PS 0-1. Median lines of prior therapy was 2(range, 1-6), with 100% receiving prior platinum therapy, and 47 pts (96%)
receiving prior anti-PD1/PD-L1 therapy. 28 pts (57%) had a history of BM and 21
(43%) had no history of BM. Pts with BM were more likely to have received prior
brain radiation (BM, 96%; No BM, 19%); otherwise, baseline characteristics of
pts with BM were similar to those without. Pts with BM had a numerically higher ORR (ORR 37%[95% CI, 19-58] with 1 CR,
EC-ORR 52% [95% CI, 32-71]) and disease control rate (DCR 78% [95% CI, 58-91]) than those without (ORRand EC-ORR 19% [95%
CI, 5-42] and DCR 48% [95% CI, 26-70]). CNS progression events occurred in 9 of
28 (32%) of pts with BM, with no such events observed in those without BM. 4
pts attained an extracranial partial response (EC-PR) but had CNS progression.
These pts underwent radiotherapy to their progressive BM and remained on study
for a median of 6.2 months (range 5.4-27.8 months, with treatment ongoing in 3
pts). 2 of 14 patients with brain non target lesions (NTLs) had confirmed
responses in brain NTLs. TRAEs were similar between groups (BM, 96%; No BM,
95%), including cytokine release syndrome (CRS) (BM, 64%; no BM, 57%). Immune
effector cell-associated neurotoxicity syndrome (ICANS) only occurred in pts
with BM (BM [n=4] 14%; No BM, 0%). ICANS was G1 in 3 pts, G2 in 1 pt.
Conclusions: MK-6070 shows promising efficacy in pts with SCLC,
including pts with BM, with 1 achieving a CR. Pts with EC-PRs were able to
remain on study after brain-only progression for ongoing clinical benefit. This
trial is ongoing and data continue to mature. Updated safety and efficacy data
including duration of response will be presented.
和EGFRmu NSQ NSCLC，PD1 PD-L1几乎无效不一样的是（康方轰动一时的大跌当时也是因为在此适应症上出的数据），IO对SCLC药效很好，所以自然少不了联用，为了依从性，联用的PD-L1都改成Q4W了，看安全性，副作用也不小。
OA10.04 Tarlatamab with a PD-L1 Inhibitor as First-Line Maintenance after Chemo-immunotherapy for ES-SCLC: DeLLphi-303 Phase 1b Study
Introduction: Current first-line maintenance (1LM) therapies for extensive-stage
small cell lung cancer (ES-SCLC) provide limited benefit, necessitating novel
therapeutic approaches to improve outcomes. Tarlatamab, a bispecific T-cell
engager (BiTE®) immunotherapy that directs cytotoxic T cells to
delta-like ligand 3 (DLL3)-positive cancer cells, demonstrated durable response
and clinically meaningful survival outcomes in patients with previously treated
SCLC. Here, safety and efficacy data from the phase 1b, multicenter, open-label
DeLLphi-303 study (NCT05361395) evaluating tarlatamab plus PD-L1 inhibitor as
1LM following chemo-immunotherapy are presented.
Methods: Patients with ES-SCLC that did not progress after completing
4-6 cycles of 1L platinum-etoposide with PD-L1 inhibitor (unless unavailable)
were eligible. Within 8 weeks of starting the last chemo-immunotherapy cycle,
patients received tarlatamab (10 mg IV Q2W) with atezolizumab (1680 mg IV
Q4W) or durvalumab (1500 mg IV Q4W) until progression. Primary endpoints
included dose-limiting toxicities (DLTs), treatment-emergent and
treatment-related AEs (TEAEs, TRAEs). Secondary endpoints included
progression-free survival (PFS), overall survival (OS), and disease control
rate (DCR).
Results: At data cutoff (31May2024), 88 patients (male: 62.5%, median
age: 64.0 years; number of prior 1L platinum‑etoposide cycles: 4, 86.4%; 5,
5.7%; 6, 8.0%) received tarlatamab with atezolizumab or durvalumab (Table).
Median follow-up was 10.0 months (range: 1.4-20.4). No DLTs occurred. The most
common all grade TEAEs were cytokine release syndrome (CRS; 53.4%), dysgeusia
(47.7%), and fatigue (34.1%). The most common grade ≥ 3 TEAEs were hyponatremia
(10.2%), neutropenia (6.8%), and anemia (6.8%). CRS primarily occurred in cycle
1 and was predominantly grade 1-2; grade 3 CRS occurred in 1 patient. Immune
effector cell-associated neurotoxicity syndrome and associated neurological
events occurred in 11.4%/2.3%/0% (any grade/grade 3/grade 4) of patients.
The median time from initiation of 1L chemo-immunotherapy to start of 1LM was
3.6 months (range 2.9-5.8). Beginning from 1LM, median PFS was 5.6 months(95% CI: 3.6-9.0) and median OS was immature due to insufficient
follow-up time; Kaplan-Meier estimate for OS at 9 months was 88.9%. DCR was
62.5% (95% CI: 51.5-72.6); median duration of disease control was 9.3 months(95% CI: 5.6-not estimable).
Conclusions: Tarlatamab in combination with a PD-L1 inhibitor as 1LM
demonstrated a manageable safety profile with durable disease control and
notable survival outcomes in patients with ES-SCLC. No new or unexpected
toxicities were identified. This study supports further investigation of
tarlatamab in combination with a PD-L1 inhibitor as 1LM in the ongoing phase 3
DeLLphi-305 randomized controlled study (NCT06211036).
关于DLL3/CD3双抗，BI更新了BI 764532 LCNEC（肺大细胞神经内分泌癌）的数据，LCNEC占原发肺癌的2-3%左右，估计是想在适应症上差异化抢个先机。
OA10.05 Phase I Trial of DLL3/CD3 IgG-Like T-Cell Engager BI 764532 in Patients with DLL3-Positive Tumors: Patients with LCNEC
Introduction:Delta-like ligand 3 (DLL3) is expressed on many
cancers, including large
cell neuroendocrine carcinoma of the lung (LCNEC). Prognosis in patients
with locally advanced/metastatic LCNEC is poor (5-year survival is ~5%) and
there is a major unmet need for effective treatments. BI 764532 is a DLL3/CD3
IgG-like T-cell engager that binds simultaneously to DLL3 on tumor cells and
CD3 on T-cells, resulting in the formation of a cytolytic synapse that
initiates a selective, T-cell-mediated immune response directed at
DLL3-expressing tumor cells. NCT04429087 is an ongoing Phase I trial of BI
764532 in patients with locally advanced/metastatic DLL3-positive small-cell
lung cancer, extrapulmonary neuroendocrine carcinoma, or LCNEC. The key aim of
Phase Ia is to determine the maximum tolerated dose (MTD) and/or the
recommended dose for expansion of BI 764532. Other objectives include safety,
tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy
(investigator review; Response Evaluation Criteria in Solid Tumors version
1.1). Here, we focus on patients with LCNEC.
Methods: BI 764532 was given intravenously in 4 regimens: Regimen A
(fixed dose once every 3 weeks; Regimen B1 (fixed dose once weekly); Regimen B2
and Regimen B3 (step-in dose, followed by target dose). Treatment continued
until disease progression, unacceptable toxicity, other reasons for withdrawal,
or maximum treatment duration (36 months).
Results: As of February 21, 2024, 168 patients had ≥1 dose of BI 764532
(Regimen A: n=24; Regimen B1: n=10; Regimen B2: n=79; Regimen B3: n=55); 32
patients (19%) were ongoing. Six dose-limiting toxicities (DLTs) were
reported during the MTD evaluation period: 1 patient on Regimen A (grade 3
confusion) and 5 patients on Regimen B2 (grade 4 cytokine release
syndrome [CRS]; grade 3 CRS; grade 5 immune effector cell-associated
neurotoxicity syndrome; grade 3 nervous system disorder; and grade 2
infusion-related reaction). No DLTs occurred in patients with LCNEC and the
adverse event profile was consistent with the overall population. The MTD was
not reached. Fourteen patients with LCNEC were treated. Ten (71%) patients were
male. Median age was 58 years (range 32-79). ECOG PS (0/1/missing): 14%/79%/7%.
Ten (71%) patients had received prior PD1/PD-L1 treatment and ten (71%) had
received ≥2 prior lines of therapy. The incidence of treatment-related adverse
events (TRAEs; any/grade ≥3) in patients with LCNEC was 86%/7%. The most common
TRAEs (any/grade ≥3) were: CRS (36%/0%); dysgeusia (36%/0%); asthenia (21%/0%);
and nausea (21%/0%). One patient (7%) had grade ≥3 eosinophilia. In 13
evaluable patients with LCNEC (Regimen A: n=2; Regimen B1: n=1; Regimen B2:
n=6; and Regimen B3: n=4), overall response rate (ORR)/disease control rate across all dose levels was 54%/77% (70%/90% in 10 patients who received ≥90 µg/kg).
Median duration of response has not been reached. The estimated 6-month rates
of duration of response and progression-free survival (PFS) were 63% and 28%,
respectively, and median PFS was 3.6 months (2.4-not calculated). At data
cut-off, 5 of 7 responding patients (71%) were still on treatment.
Conclusions: BI 764532 showed promising efficacy and safety in patients
with LCNEC, with an ORR of 70% at active dose levels.
SCLC的治疗看完双抗，看ADC，自从DS7300数据出来后，小细胞肺癌领域也算是往前迈了巨大一步，DS7300本次有中期分析的数据更新；同时更新的还有翰森的B7H3 ADC HS-20093，DAR4的设计，加上恒瑞同款linker-payload之前诸多数据看，10mg/kg，Q3W药效和DS7300大差不差，安全性可能血液毒稍微高点，比着来就行。
OA04.03 Ifinatamab Deruxtecan (I-DXd) in Extensive-Stage Small Cell Lung Cancer (ES-SCLC): Interim Analysis of Ideate-lung01
Abstract is embargoed at this time.
OA04.06 Efficacy and Safety of HS-20093 in Extensive Stage Small Cell Lung Cancer in A Multicenter, Phase 1 Study (ARTEMIS-001)
Introduction: ARTEMIS-001 study is a multicenter, open-label phase 1 study
investigating the safety and efficacy of HS-20093 (GSK5764227), an
antibody-drug conjugate targeting B7-H3, in advanced solid tumors
(NCT05276609). Promising antitumor activity was observed across multiple tumor
types, particularly in extensive stage small cell lung cancer (ES-SCLC) during
the dose-escalation phase of the study (Jie Wang et al., JCO, 2023). Here, we
present the latest efficacy and safety results of HS-20093 in ES-SCLC patients
(pts) from both the dose-escalation and dose-expansion phases.
Methods: The study is currently at the dose-expansion phase and included
4 cohorts of pts with diverse advanced solid tumors. Within ES-SCLC cohort, pts
received HS-20093 at 8.0 mg/kg or 10.0 mg/kg dose every 3 weeks until disease
progression. All pts had previously undergone platinum-based standard therapy.
Efficacy endpoints were objective response rate (ORR), disease control rate
(DCR), duration of response (DoR), progression free survival (PFS) and overall
survival (OS). B7-H3 expression in tumor tissue was analyzed retrospectively.
Results: Fifty-sixpts received ≥1 dose of HS-20093 at 8.0
mg/kg (N = 31) or 10.0 mg/kg (N = 25). All pts received platinum plus
etoposide, 73.2% received immunotherapy (IO), and 23.2% received
topoisomerase 1 inhibitor (TOPO1i). Out of 56 pts, 53 pts were evaluable for
efficacy (8.0 mg/kg: 31 pts; 10.0 mg/kg: 22 pts). The median follow-up duration
was 9.0 and 11.1 months for pts at 8.0 and 10.0 mg/kg dose, respectively (as of
30 Jun 2024). HS-20093 showed encouraging efficacy in ES-SCLC. ORR was61.3% for pts at 8.0 mg/kg dose and 50.0% for pts at 10.0 mg/kg dose.DCR, median DoR, median PFS for pts at 8.0 and 10.0 mg/kg dose were
80.6% and 95.5%, 6.4 and 8.9 months, 5.9 and 7.3 months,respectively. Median OS was 9.8 months for pts at 8.0 mg/kg dose and not
reached for pts at 10.0 mg/kg dose. The ORR in 32 pts who were previously
exposed to IO plus platinum but were TOP1i naive was 75.0% and 66.7% at 8.0 and
10.0 mg/kg dose, respectively. No correlation was observed between B7-H3
expression level and tumor objective response to treatment; however, the pts
with B7-H3 IHC expression (≥1%) demonstrated a trendency toward prolonged
median PFS. Safety profile was consistent with previous reports. Grade ≥3
treatment-related adverse events (with incidence ≥10%) were neutrophil count
decreased (39.3%), white blood cell count decreased (33.9%), lymphocyte count
decreased (25.0%), platelet count decreased (17.9%), and anaemia (16.1%).
Conclusions: HS-20093 demonstrated encouraging antitumor activity and
manageable safety in pts with previously-treated ES-SCLC. A phase 3 study is
currently ongoing in China to compare the efficacy and safety of HS-20093 with
standard-of-care chemotherapy in pts with relapsed SCLC (NCT06498479). The
clinical development program of HS-20093 is planned to be expanded into US, EU,
and rest of the world.
相比之下，两个Trop2 ADC对SCLC的药效还是不如B7H3 ADC，以及从恒瑞对Trop2的IHC染色看，SCLC在这些靶点的表达貌似都不算太高的样子。
OA04.04 Sacituzumab Govitecan as Second-Line Treatment in Patients with Extensive Stage Small Cell Lung Cancer
Introduction: Treatment options are limited for patients with extensive stage
small cell lung cancer (ES-SCLC) that progresses after platinum-based
chemotherapy (chemo) and anti-programmed death ligand 1 (PD-L1) therapy.
Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is being
evaluated in patients with metastatic or locally advanced solid tumors in
TROPiCS-03 (NCT03964727), an open-label, multicohort, phase 2 trial. In a
preliminary analysis of the ES-SCLC cohort (N=30), SG demonstrated promising
antitumor activity and manageable safety (Dowlati et al, ESMO 2023). Here, we
report updated results with additional patients and longer follow-up from the
ES-SCLC cohort.
Methods: Adult patients with ES-SCLC that progressed after no more than
1 prior line of platinum-based chemo and anti-PD-(L)1 therapy received SG 10
mg/kg on days 1 and 8 of a 21-day cycle. The primary endpoint was objective
response rate (ORR) by investigator assessment per RECIST v1.1. Secondary
endpoints included clinical benefit rate (CBR), duration of response (DOR),
progression-free survival (PFS), overall survival (OS), and safety.
Results: As of March 8, 2024, 43 patients were enrolled, and the median
follow-up was 12.3 months (range, 8.1-20.1). Median age was 67 years (range,
48-83) and 81.4% of patients had an ECOG performance status of 1. Of the 43
patients, 20 (46.5%) patients had platinum-resistant disease (chemo-free
interval <90 days). Treatment was ongoing for 7 (16.3%) patients. In the
efficacy analysis (n=43), ORR was 41.9% and CBR was 48.8%(Table). The
median DOR was 4.73 months (95% CI, 3.52-6.70), median PFS was 4.40 months (95%
CI, 3.81-6.11), and median OS was 13.60 months (95% CI, 6.57-14.78). ORRs were
35.0% and 47.8% in platinum-resistant and -sensitive patients, respectively.In the safety analysis (n=43), any-grade treatment-emergent, treatment-related
adverse events (TE TRAEs) occurred in 97.7% (grade ≥3, 60.5%) of patients.
There were no TE TRAEs leading to discontinuation of study treatment. There was
1 TE TRAE that led to death (neutropenic sepsis).
Conclusions: SG as second-line treatment for ES-SCLC demonstrated
promising antitumor activity in the fully enrolled ES-SCLC cohort. This
activity was seen in patients with both platinum-resistant and -sensitive
disease. Safety was manageable and consistent with that observed in other SG
studies.
OA04.05 SHR-A1921, A TROP-2 Targeted Antibody-Drug Conjugate (ADC), In Patients (pts) with Advanced Small-Cell Lung Cancer (SCLC)
Introduction: SHR-A1921 is a novel ADC composed of a humanized anti-TROP-2 IgG1
monoclonal antibody attached to a DNA topoisomerase I inhibitor via a
tetrapeptide-based cleavable linker. Here, we report the clinical activity and
safety of SHR-A1921 in pts with pretreated extensive-stage SCLC, a condition
with a poor prognosis and limited therapeutic options.
Methods: This was a first-in-human, dose-escalation, dose-expansion, and
efficacy-expansion phase 1 study (NCT05154604). In SCLC expansion cohort, pts with
extensive-stage disease who had relapsed to/refractory from platinum-based
chemotherapy, regardless of TROP-2 expression level, were enrolled to receive
SHR-A1921 at selected dose of 3.0 mg/kg every 3 weeks until disease progression
or unacceptable toxicity.
Results: As of Feb 19, 2024, 17 pts were enrolled, among whom, 6
(35.3%) were still on treatment. At the study entry, 52.9% of pts had received
≥2 prior lines of therapy. 64.7% of pts had been treated with anti-PD-1/PD-L1
antibodies and 11.8% had been treated with DNA topoisomerase I inhibitors.
TROP-2 expression was detectable in 16 pts, and all showed a low level with an
H-Score of 0-50. Median follow-up was 5.3 months (range 1.3-9.4). Among the
15 pts evaluable for tumor response, ORR was 33.3% (95% CI 15.2-58.3), DCR was
66.7% (95% CI 41.7-84.8), and median DoR was 4.4 months (95% CI 2.3-not reached
[NR]). Among all pts, median PFS was 3.8 months (95% CI 1.4-NR), and median OS
was not reached. All pts experienced treatment-related adverse events (TRAEs),
and the most common TRAEs included stomatitis (58.8%), nausea (35.3%), vomiting
(23.5%), decreased appetite (23.5%), and anemia (23.5%). 6 pts (35.3%)
experienced grade ≥3 TRAEs, with the most common being stomatitis (11.8%). No
treatment-related interstitial lung disease/pneumonitis occurred. No TRAEs led
to treatment discontinuation or death.
Conclusions: SHR-A1921 showed promising clinical efficacy and a
manageable safety profile in pts with heavily pretreated extensive-stage SCLC,
even with low TROP-2 expression.
接着是几个没啥看头的ADC结果，主要是NSCLC的，这个领域现在太卷了，EGFRmu NSQ的药效但凡靶点凑合，TOPi基本上是一做一个行；EGFR wt NSQ的中规中矩； 而SQ NSCLC ADC单药打多西他赛都能折，本次也没啥太有意思的数据，直接往下划，后面还有点值得看的。
OA08.03 Datopotamab Deruxtecan Vs Docetaxel in Patients with Non-Small Cell Lung Cancer: Final Overall Survival from TROPION-Lung01
Abstract is embargoed at this time.
OA08.05 Tusamitamab Ravtansine vs Docetaxel in Previously Treated Advanced Nonsquamous NSCLC: Results from Phase 3 CARMEN-LC03 Trial
Abstract is embargoed at this time.
OA08.06 Sacituzumab Govitecan vs Docetaxel in Patients with mNSCLC Non-responsive to Last Anti-PD-(L)1-containing Regimen: EVOKE-01
Introduction: The phase 3 EVOKE-01 study included patients with metastatic
non-small cell lung cancer (mNSCLC) progressing after platinum-based
chemotherapy and anti-PD-(L)1 treatment. The primary endpoint of overall
survival (OS) was not statistically significant; however, results showed
numerical improvement favoring sacituzumab govitecan (SG) vs docetaxel (hazard
ratio [HR], 0.84; 95% CI, 0.68-1.04). As response to anti-PD-(L)1 treatment has
prognostic impact on OS, best response to last anti-PD-(L)1-containing regimen
(non-responsive, stable disease [SD]/progressive disease [PD], vs responsive,
complete response [CR]/partial response [PR]) was a stratification factor and
prespecified subgroup for analysis. We report patient characteristics and
results from this subgroup of the EVOKE-01 study (NCT05089734).
Methods: In EVOKE-01, patients were randomized to receive SG (10 mg/kg
IV; days 1, 8) or docetaxel (75 mg/m2IV; day 1) in 21-day
cycles. The primary endpoint was OS. Key secondary endpoints included investigator-assessed
progression-free survival (PFS) and objective response rate (ORR). In these
subgroup analyses, outcomes were evaluated by objective response to last
anti-PD-(L)1-containing regimen. OS of the non-responsive subgroup were further
analyzed by histology (squamous and nonsquamous). Descriptive statistics are
reported.
Results: The intent-to-treat (ITT) population included 63.5% (n=383)
patients with disease non-responsive to last anti-PD-(L)1-containing regimen
(n=192 SG; n=191 docetaxel) and 36.3% (n=219) with responsive. In the
non-responsive subgroup, patient characteristics were balanced between the
treatment arms (Table). In the non-responsive subgroup, median OS was
11.8 months with SG and 8.3 months with docetaxel (HR, 0.75; 95% CI,
0.58-0.97); for the responsive subgroup, HR was 1.09; 95% CI, 0.76-1.56.
Improvement in OS with SG was observed regardless of whether patients had SD
(HR, 0.79; 95% CI, 0.55-1.13) or PD (HR, 0.67; 95% CI, 0.46-0.98) as best
response to last anti-PD-(L)1-containing regimen. The OS benefit of SG over
docetaxel in the non-responsive subgroup was similar in both squamous (HR,
0.62; 95% CI, 0.38-1.02) and nonsquamous (HR, 0.79; 95% CI, 0.59-1.07)
histology. The Table summarizes additional
efficacy results. In the safety population, grade ≥3 treatment-emergent adverse
event (TEAE) incidence was 66.6% (SG) and 75.7% (docetaxel). TEAEs led to death
in 3.4% (SG) and 4.5% (docetaxel). Treatment-related TEAEs led to
discontinuation in 6.8% (SG) and 14.2% (docetaxel).
Conclusions: SG demonstrated clinically meaningful OS improvement vs
docetaxel in a subgroup of patients with mNSCLC non-responsive (SD/PD) to last
anti-PD-(L)1-containing regimen. The benefit was observed regardless of SD or
PD as best response to last anti-PD-(L)1-containing regimen or histology.
OA08.07 Sacituzumab Govitecan + Pembrolizumab + Carboplatin in 1L Metastatic Non-Small Cell Lung Cancer: The EVOKE-02 Study
Introduction: Pembrolizumab + platinum-based chemotherapy is standard of care
first-line (1L) treatment for advanced/metastatic non-small cell lung cancer
(mNSCLC) lacking actionable genomic alterations (AGAs) regardless of PD-L1
expression; however, novel combinations are needed to improve outcomes.
Sacituzumab govitecan (SG) demonstrated durable activity in mNSCLC and was
safely combined with pembrolizumab in the clinical setting. We report initial
results by dose and histology from cohorts C (non-squamous) and D (squamous) of
patients with mNSCLC treated in 1L setting with SG + pembrolizumab +
carboplatin in the ongoing, multicohort, phase 2 study, EVOKE-02 (NCT05186974).
Methods: Adults without prior systemic treatment for mNSCLC, without
AGAs, with an ECOG PS of 0-1, and with any PD-L1 tumor proportion score (TPS)
via 22C3 assay were eligible. Patients received intravenous SG 10 or 7.5mg/kg
(days 1, 8) + pembrolizumab 200mg (day 1; up to 35 cycles) + carboplatin AUC5
(day 1; initial 4 cycles only) in 21-day cycles. A safety run-in was conducted
to assess dose-limiting toxicities (DLTs) and determine the recommended SG
dose. The primary efficacy endpoint was independent review committee
(IRC)-assessed objective response rate per RECIST v1.1. Secondary endpoints
included IRC-assessed progression-free survival, duration of response, and
safety.
Results: During the safety run-in (SG 10mg/kg, n=5), DLT criteria for
dose reduction were not met. At a subsequent planned safety evaluation, SG dose
was reduced to 7.5 mg/kg because of myelosuppression, mainly neutropenia. Among
patients with non-squamous (n=54) and squamous (n=41) histology, median age was
67 and 68 years, 72.2% and 65.9% had an ECOG PS score of 1, and the majority
(85.2% and 80.2%) had PD-L1 TPS <50%. Efficacy results by histology and
safety results by dose are shown in theTable. Grade 3 rates
of neutropenia were reduced at SG 7.5 mg/kg compared with SG 10 mg/kg (24.2% vs
65.5%).
Conclusions: SG + pembrolizumab + carboplatin demonstrated encouraging
activity in patients predominantly with PD-L1 TPS<50% non-squamous and
squamous non-AGA-driven mNSCLC. The safety profile of SG with standard doses of
pembrolizumab and carboplatin is manageable at the 7.5 mg/kg dose with
appropriate supportive measures.
PT01.13.05 Exposure-Response Analyses to Support Ph3 Dose Selection for I-Dxd (Ifinatamab Deruxtecan) in Extensive Stage SCLC Patients
Introduction: I-DXd (DS-7300), showed promising efficacy at ≥6.4 mg/kg in
heavily pretreated extensive stage small cell lung cancer (ES-SCLC) patients in
the ongoing Phase 1/2 study (IDeate-PT01, NCT04145622). Here, we report the
exposure response (ER) analysis of I-DXd for safety and efficacy to support
dose selection for Phase 3 development in ES-SCLC.
Methods: Interim data from ES-SCLC patients receiving I-DXd (8 or 12
mg/kg IV Q3W) in the dose optimization part of Phase 2 study (IDeate-L01,
NCT05280470) and from patients with advanced solid tumors receiving I-DXd (0.8
to 16 mg/kg IV Q3W) in IDeate-PT01 were included in the analysis. Individual
exposures for I-DXd and DXd (released payload) were derived based on a
developed population pharmacokinetic (PK) model based on the same patients PK
data. All patients were included in the exposure-safety (ES) analysis. Only
ES-SCLC subjects were considered for exposure-efficacy (EE) analysis. ER
analyses were conducted with selected efficacy and safety endpoints that have
observed event rates >10% (8 out of 19 prespecified treatment emergent
adverse events; TEAEs). Effects of other variables than exposure on the event
probability were also evaluated. Modelling was performed using logistics
regression analysis for binary endpoints.
Results: As of 25thJuly 2023, 256 patients were
included in the ES analysis. ES analyses identified significant relationships
between increased I-DXd exposure (C1 AUC) and any grade gastrointestinal (GI)
disorders, and between DXd exposure (C1 or steady state AUC) and any grade and
grade ≥3 anemia, any serious adverse event (SAE) and drug interruption.
Positive ES relationships were also identified between DXd maximum
concentration (C1 Cmax) and any adverse event (AE) grade ≥3 and any grade
neutropenia. Geographical region, age, ECOG score, and cancer type were
associated with some safety endpoint probability, but further evaluation is
needed as the data become mature from these studies. Model projected median
event rates at doses of interest, 8 mg/kg and 12 mg/kg were 60.6% and 74.8% for
any grade GI disorders, 36.8% and 46.2% for any AE grade ≥3, 26.1% and 39.5%
for any SAE, respectively. Difference between projected median event rates was
<10% for all other safety endpoints. A total of 110 ES-SCLC patients were
included in the EE analysis. EE analysis demonstrated significant
relationships between all I-DXd exposure metrics and efficacy endpoints:
objective response rate (ORR) and best tumor response. Model projected ORR
median event rates at 8 mg/kg and 12 mg/kg were 30.7% and 51.7% respectively.
Significant increase in tumor shrinkage is observed with increasing I-DXd
exposure. Further EE analyses for progression free survival, duration of
response, and overall survival are planned when data with longer follow-up are
available. Overall, ER analyses predicted higher rates of efficacy with
increasing I-DXd dose. However, frequency of TEAEs only marginally (<14%)
increased, with both 8 mg/kg Q3W and 12 mg/kg Q3W showing manageable safety
profiles.
Conclusions: Based on overall benefit-risk assessment and ER analyses,
12 mg/kg Q3W was selected as the recommended I-DXd dose for Phase 3 study
(IDeate-L02; NCT06203210) and IDeate-L01 extension part for continued
development in ES-SCLC.
OA16.04 Preliminary Results from a FIH Study of GQ1005, A Novel HER2-ADC, in Patients with Advanced HER2-Expressing Solid Tumors and HER2-Mutated NSCLC
Introduction: GQ1005 is an innovative antibody-drug conjugate that specifically
targets HER2-expressing tumor cells using Topoisomerase I inhibitors (DXd)
delivered through a stable and cleavable linker. Preclinical studies have shown
that GQ1005 exhibits similar antitumor efficacy to Enhertu and better stability
than Enhertu, with a notable absence of toxicity, suggesting a superior
therapeutic profile. This report presents initial findings from an ongoing
phase I clinical trial, which seeks to assess the safety, tolerability,
pharmacokinetics, and antitumor efficacy of GQ1005 in
patients with advanced solid tumors expressing HER2 and patients (pts) with
HER2-mutated NSCLC.
Methods: Patients aged 18 years and older with locally advanced or
metastatic solid tumors previously treated with standard therapy and with a
measurable disease according to RECIST v1.1 criteria were included in the
study. The Maximum Tolerated Dose (MTD) was determined using the Bayesian
Optimal Interval (BOIN) design. GQ1005 was given intravenously at a specified
dose (2, 4, 6, 7.2, and 8.4 mg/kg) Q3W until either intolerable
toxicities occurring or disease progressed.
Results: As of March 26th, 2024, 131 patients with HER2-expressing or
HER2-mutated advanced solid tumors predominantly in breast (70), lung (34) and
gastric/gastroesophageal junction (19), were enrolled. Median age was 56 (from
34 to 74), and the patients had median 3 (range, 1-11) prior lines of
anti-tumor therapies, 76% had an ECOG performance status of 1. The median
exposure time of GQ1005 was 15.9 weeks (range 3.0-60.9). No DLT was observed in
all doses, hence MTD was not achieved. Every patient experienced
treatment-related adverse events (TRAEs). Drug-related AEs led to
discontinuation in 6 patients (4.6%) and death in 1 patient (0.8%). The most
common all-grade TRAEs (>15.0%) were elevated aspartate aminotransferase
(41.2%), nausea (40.5%), anemia (35.1%), alanine aminotransferase increased
(31.3%), leukopenia (26.0%), decreased appetite (26.0%), thrombocytopenia
(25.2%), neutropenia (22.9%), vomiting (22.1%), fatigue (19.8%), proteinuria
(17.6%), and dry eye (15.3%). Grade ≥3 TRAEs occurred in 21 patients (16.0%),
including anemia (3.8%), decreased lymphocyte count
(3.8%),γ-glutamyltransferase (GGT) increase (3.8%), leukopenia (2.3%),
thrombocytopenia (1.8%) and nausea (0.8%) . Interstitial lung disease occurred
in 12 patients (9.2%) and most of them were reported in 8.4mg/kg dose. Among
119 evaluable patients, 1 case had complete response, 52 cases achieved partial
response, the unconfirmed ORR was 44.5%, and the unconfirmed DCR was 81.5%. In
34 patients with advanced HER2-mutated NSCLC with median age of 59.5 (range
38-74), 50% had prior ≥2 lines of anti-tumor therapies. No DLTs occurred and
Grade ≥3 TRAEs were recorded in 6 pts (17.6%). AEs were manageable and
tolerable, consistent with previous findings. 32 pts had at least 1 tumor
assessment. Moreover, best tumor response was observed in 12/32 (37.5%) pts,
and DCR was 90.6% (29/32).
Conclusions: Based on the initial data from the first-in-human trial,
GQ1005 shows great potential for excellent tolerability and promising antitumor
activity in patients with heavily pretreated HER2-expressing advanced solid
tumors and HER2-mutated NSCLC. The phase Ib trial in four cohorts with a
dose of 7.2 mg/kg is ongoing. (NCT06154343)
对于NSCLC，DS8201对her2突变的药效是明显好于her2 过表达的，但是her2突变NSCLC人群太少了，要更大的适应症还得拼过表达人群，于是DESTINY-Lung03把her2过表达IHC的标准线重新划了一下，之前看到的her2在乳腺癌上一般都是用≥10%划线，此处用≥25%的细胞染色为划线标准。
OA16.05 Trastuzumab Deruxtecan Monotherapy in Pretreated HER2-overexpressing Nonsquamous Non-Small Cell Lung Cancer: DESTINY-Lung03 Part 1
Methods: Patients with HER2-OE unresectable, locally advanced or metastatic NSCLC with disease progression on or after one or two prior regimens received T-DXd 5.4 mg/kg intravenously every 3 weeks. HER2-OE was defined as ≥25% of tumor cells with immunohistochemistry (IHC) 2+ or 3+ by central testing using the DAKO HER2-low IHC assay. The endpoints of the T-DXd monotherapy arm were investigator-assessed confirmed ORR, duration of response (DOR), and progression-free survival (PFS); overall survival (OS); and safety.
Results: At data cutoff (DCO; October 23, 2023), 36 patients with HER2-OE NSCLC had received T-DXd 5.4 mg/kg; median (range) duration of T-DXd total treatment was 7.2 (0.7-19.8) months and median (range) duration of follow up was 11.7 (1.4-21.2) months. Patients were predominantly female (61.1%) and from Asia (88.9%); median age (range) was 66.5 (47-80) years, and targeted therapy was the most common prior treatment modality (58.3%). Additional patient characteristics and safety data are in the table. The confirmed ORR was 44.4% (95% CI 27.9, 61.9), and median DOR was 12.2 (95% CI 5.5, not estimable) months. Median PFS was 8.2 (95% CI 6.7, 11.1) months and median OS was 14.7 (95% CI 14.6, not estimable) months. At DCO, the adjudication committee determined that there were no cases of drug-related interstitial lung disease/pneumonitis; adjudication committee review is ongoing. Updated efficacy and safety results will be available for the presentation.
Conclusions: T-DXd monotherapy (5.4 mg/kg) demonstrated encouraging antitumor activity in patients with pretreated advanced or metastatic HER2-OE NSCLC, consistent with results from DESTINY-Lung01. The safety profile was acceptable and generally manageable, consistent with the known profile of T-DXd.
PT02.10.03 Cutoff Determination for C-met Protein Overexpression by VENTANA MET (SP44) IHC to Determine Teliso-v Eligibility in NSCLC
Introduction: c-Met (also known as MET protein) overexpression occurs in
approximately 25% of patients with advanced epidermal growth factor receptor
wildtype non-squamous non-small cell lung cancer (EGFRWT NSQ
NSCLC) and is associated with poor prognosis. Telisotuzumab vedotin (Teliso-V)
is a first-in-class, c-Met protein-directed antibody-drug conjugate that has
shown efficacy in patients with c-Met protein-overexpressing advanced EGFR WT
NSQ NSCLC. The VENTANA MET (SP44) immunohistochemical (IHC) assay measures
c-Met protein expression on formalin-fixed paraffin-embedded tumor samples.
This study aimed to determine the optimal cutoff values for c-Met protein
overexpression to identify patients with EGFR WT NSQ NSCLC who
are most likely to benefit from treatment with Teliso-V.
Methods: Tumor samples from patients with EGFR WT
NSQ NSCLC enrolled in an ongoing first-in-human study of Teliso-V
(NCT02099058) were retrospectively analyzed for c-Met protein expression using
the VENTANA MET (SP44) IHC assay. The membrane staining intensity and
the percentage of c-Met staining positivity on tumor cells were assessed and
their association with best objective response to Teliso-V treatment was
evaluated. Receiver operating characteristic (ROC) analysis was used to determine
the membrane staining intensity threshold (ie, 1+, 2+, or 3+) that best
associated with best objective response. Statistical analyses, including
sensitivity, specificity, positive predictive value, negative predictive value,
and Fisher’s exact test p-value were performed for each of the prespecified
candidate cutoffs to determine the percentage of tumor cells indicating c-Met
positivity: 10%, 25%, 50%, 75%, 90%, and 100%. Statistical outcome
evaluation and comparison of Fisher’s exact test p-values and the Youden index
were used to determine the optimal cutoff value of c-Met protein overexpression
to identify eligibility for Teliso-V treatment. Reported p-values are nominal.
Results: Best objective response rates above and below each potential
threshold for each intensity were compared in 30 patients. Among evaluated
staining intensities and candidate cutoffs, 25% c-Met positivity with 3+ staining intensity on tumor
cells was identified as the most optimal cutoff and intensity, with best
objective response rates of 56% and 10% for those above (n=9) and below
(n=21) the cutoff (p=0.0139) and an area under the ROC curve of 0.736 for the
staining intensity. A threshold of 50% cell positivity with 3+ staining
intensity resulted in best objective response rates of 67% and 12% for those
above (n=6) and below (n=24) the cutoff (p=0.0157).
Conclusions: A cutoff value of 25% c-Met-positive tumor cells with 3+
intensity was selected to determine positivity of c-Met protein overexpression
in patients with EGFR WT NSQ NSCLC eligible for Teliso-V
treatment. A cutoff value of 50% was selected to determine high expression of
c-Met protein.
OA16.03 Telisotuzumab Vedotin in Asian Patients with C-Met Protein-Overexpressing Non-Squamous EGFR WT NSCLC: Results from LUMINOSITY
Abstract is embargoed at this time.
不用划了，没了。
