- Lizza Hendriks (Maastricht, Netherlands)
- Tony S.K. Mok (Shatin, Hong Kong PRC)
1478O - Results of the ASCEND-7 phase II study evaluating ALK inhibitor (ALKi) ceritinib in patients (pts) with ALK+ non-small cell lung cancer (NSCLC) metastatic to the brain (ID 4884)
- Laura Q. Chow (Seattle, WA, United States of America)
Abstract
Background
Ceritinib is approved for the treatment of pts with metastatic ALK+ NSCLC. In previous studies (ASCEND-1 to 5), ceritinib was highly active in ALK+ NSCLC pts with reported intracranial responses in pts with measurable baseline brain lesions. ASCEND-7 (NCT02336451) was designed to specifically study intracranial effects of ceritinib and we report here efficacy and safety in pts with ALK+ NSCLC metastatic to the brain (Arms 1-4).
Methods
Eligible pts had, WHO performance status 0-2, ALK + (FISH) NSCLC, with active brain metastases (BM) either newly diagnosed or progressive, and ≥1 extracranial measurable lesion using RECIST v1.1. Pts may have been pretreated with chemotherapy and/or crizotinib (ALK inhibitor [ALKi]). Pts were assigned to arms 1 to 4 depending on prior treatment (refer to below table). Primary endpoint was investigator assessed whole body overall response rate (CR or PR) and key secondary endpoint was investigator assessed disease control rate (CR or PR or SD). Intracranial responses and extracranial responses were assessed using modified RECIST 1.1 and RECIST 1.1, respectively.
Results
As of 6-Feb-2019, 138 pts were treated in Arms 1-4 (Arm 1: 42; Arm 2: 40; Arm 3: 12; Arm 4: 44), and all the pts discontinued the treatment. Median follow-up for whole body progression free survival was 5.49 months across Arm 1-4. Efficacy endpoints by investigator assessment are reported in the below Table. Most common AEs (>50% all grades in any of the Arms 1-4) regardless of causality were diarrhoea, nausea, ALT increased, vomiting, AST increased, decreased appetite. Majority of these AEs was grade 1/2. 1478O Overall efficacy In patients with measurable brain metastases at baseline. †The usual criteria to select target lesions will be used but a maximum five target lesions located in the brain can be selected at baseline and evaluated at each assessment time point. ‡L is the number of patients included in the duration of response analysis. M, number of patients with measurable brain metastases at baseline DCR, disease control rate; DOR, duration of response; NE, not estimable ORR, overall response rate; OS, overall survival; PFS, progression free survival; RECIST, Response Evaluation Criteria in Solid TumorsArm 1 (prior brain radiotherapy and prior ALKi) N = 42 Arm 2 (no prior brain radiotherapy and prior ALKi) N = 40 Arm 3 (prior brain radiotherapy and no prior ALKi) N = 12 Arm 4 (no prior brain radiotherapy and no prior ALKi) N = 44 Whole body efficacy (RECIST v1.1) ORR, % [95% CI] DCR, % [95% CI] 35.7 [21.6, 52.0] 66.7 [50.5, 80.4] 30.0 [16.6, 46.5] 82.5 [67.2, 92.7] 50.0 [21.1, 78.9] 66.7 [34.9, 90.1] 59.1 [43.2, 73.7] 70.5 [54.8, 83.2] Whole body efficacy (RECIST v1.1) Median DOR, months [95% CI] Estimated 6-month event-free probability, % [95% CI] L‡ = 15 10. 8 [4.1, NE] 64.6 [34.7, 83.5] L‡ = 12 12.8 [3.7, 17.3] 74.1 [39.1, 90.9] L‡ = 6 NE [11.7, NE] 100 [100, 100] L‡ = 26 9.2 [7.3, 23.9] 72.7 [51.1, 86.0] Whole body efficacy (RECIST v1.1) Median PFS, months [95% CI] Estimated 6-month event-free probability, % [95% CI] 7.2 [3.3, 10.9] 58.7 (41.6, 72.4) 5.6 [3.6, 9.2] 44.7 [28.5, 59.5] NE [1.0, NE] 66.7 [33.7, 86.0] 7.9 [5.5, 9.4] 63.4 [46.8, 76.1] Intracranial response M = 28 39.3 [21.5, 59.4] 75.0 [55.1, 89.3] M = 29 27.6 [12.7, 47.2] 82.8 [64.2, 94.2] M = 7 28.6 [3.7, 71.0] 85.7 [42.1, 99.6] M = 33 51.5 [33.5, 69.2] 75.8 [57.7, 88.9] Intracranial response L‡ = 11 9.2 [3.7, NE] 66.7 [28.2, 87.8] L‡ = 8 10.1 [3.8, 17.3] 62.5 [22.9, 86.1] L‡ = 2 NE 100 [100, 100] L‡ = 17 7.5 [5.6, 11.2] 70.6 [43.1, 86.6] Extracranial response (RECIST v1.1) ORR, % [95% CI] DCR, % [95% CI] 31.0 [17.6, 47.1] 69.0 [52.9, 82.4] 42.5 [27.0, 59.1] 92.5 [79.6, 98.4] 41.7 [15.2, 72.3] 66.7 [34.9, 90.1] 61.4 [45.5, 75.6] 72.7 [57.2, 85.0] Median OS, months [95% CI] Estimated 12-month event-free probability, % [95% CI] 24.0 [12.6, NE] 67.4 [50.4, 79.6] NE [16.2, NE] 72.9 [55.5, 84.5] NE [1.0, NE] 75.0 [40.8, 91.2] NE [26.5, NE] 77.9 [61.8, 87.9]
Conclusions
Efficacy of ceritinib, either in pts with or without a prior exposure to crizotinib, as reported in other studies, is confirmed in this study where only pts with active brain metastases were eligible. Safety profile of ceritinib in these pts remain consistent to what was reported earlier.
Clinical trial identification
NCT02336451.
Editorial acknowledgement
Shiva Krishna Rachamadugu, Novartis Healthcare Pvt Ltd, Hyderabad, India.
Legal entity responsible for the study
Novartis Pharmaceuticals Corporation.
Funding
Novartis Pharmaceuticals Corporation.
Disclosure
L.Q. Chow: Advisory / Consultancy, Consultation Honoraria/Review panel: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Lilly/Imclone; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca/MedImmune ; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Incyte; Advisory / Consultancy: Takeda; Research grant / Funding (institution): VentiRx; Advisory / Consultancy: Sanofi-Genzyme; Advisory / Consultancy, Research grant / Funding (institution): Seattle Genetics; Advisory / Consultancy, Research grant / Funding (institution): Dynavax; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy: Synthorx; Research grant / Funding (institution): Alkermes. F. Barlesi: Honoraria (self), Research grant / Funding (institution): AstraZeneca, Bayer; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): Boehringer–Ingelheim; Honoraria (self), Research grant / Funding (institution): Eli Lilly Oncology; Honoraria (self), Research grant / Funding (institution): F. Hoffmann–La Roche Ltd; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self), Research grant / Funding (institution): Merck; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self), Research grant / Funding (institution): Pierre Fabre; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Takeda; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): ACEA; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): MedImmune and Sanofi-Aventis; Non-remunerated activity/ies: Principal Investigator for AstraZeneca, BMS, Merck, Pierre Fabre and F. Hoffmann-La Roche, Ltd, sponsored trials (or ISR). E.M. Bertino: Advisory / Consultancy: Takeda; Speaker Bureau / Expert testimony: Pfizer. M.J. van den Bent: Honoraria (self): Celgene, Agios, Boehringer, BMS, AbbVie ; Research grant / Funding (institution): AbbVie. H. Wakelee: Honoraria (self): Novartis, AstraZeneca; Advisory / Consultancy, NOT compensated: Merck, Takeda, Genentech/Roche: AstraZeneca, Xcovery, Janssen; Research grant / Funding (institution): ACEA Biosciences, Arrys Therapeutics, AstraZeneca/MedImmune, Bayer (under Suki and not me), BMS, Celgene, Clovis Oncology, Exelixis, Genentech/Roche, Gilead, Lilly, Merck, Novartis, Pfizer, Pharmacyclics, Xcovery; Travel / Accommodation / Expenses: AstraZeneca; Officer / Board of Directors: International Association for the Study of Lung Cancer (IASLC). P.Y. Wen: Advisory / Consultancy: Agios, AstraZeneca, Beigene, Eli Lilly, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines, Tocagen; Speaker Bureau / Expert testimony: Merck, Prime Oncology; Research grant / Funding (institution): Agios, AstraZeneca, Beigene, Eli Lilly, Genentech/Roche, Karyopharm, Kazia, MediciNova, Merck, Novartis, Oncoceutics, Sanofi-Aventis, VBI Vaccines. C. Chiu: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda. M. Majem: Advisory / Consultancy: Roche, MSD, AstraZeneca, Boehringer, Tesaro, Takeda, Pierre Fabre; Speaker Bureau / Expert testimony: Roche, BMS, MSD, AstraZeneca, Boehringer Hellsin, Pierre Fabre, Amgen; Research grant / Funding (self): BMS; Travel / Accommodation / Expenses: BMS, MSD, AstraZeneca, Lilly. R. Chiari: Honoraria (self): AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Pfizer, Roche, and Takeda. M. McKeage: Advisory / Consultancy: Novartis, Pfizer; Research grant / Funding (institution): Novartis, Pfizer, Roche. C. Yu: Honoraria (self): Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim ; Advisory / Consultancy: Roche, AstraZeneca, Ono pharma, Boehringer Ingelheim. F.K. Hurtado: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. P. Cazorla Arratia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. Y. Song: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. F. Branle: Honoraria (self), Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. M. Shi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Novartis. D. Kim: Research grant / Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, and Yuhan. All other authors have declared no conflicts of interest.
1479O - Integrated genomic and DNA methylation analyses of non-small cell lung cancer patients with brain metastases (ID 2693)
- Yanjun Xu (Hangzhou, China)
Abstract
Background
Brain metastases (BM), with a dismal prognosis, are a common and lethal complication of non-small cell lung cancer. Recognition of its genomic and epigenomic landscape is very necessary.
Methods
Capture-based targeted sequencing for somatic mutation profiling was performed on 27 treatment-naïve advanced NSCLC patients with paired lung primary and BM lesions using a pane consisting of 520 cancer related genes. DNA methylation analyses was performed on same samples using a DNA methylation panel consisting of 100,000 CpG sites.
Results
Collectively, we identified 370 (291 SNVs+Indels, 78 CNVs and 1 rearrangement) and 574 (245 SNVs+Indels, 327 CNVs and 2 rearrangements) mutations from lung primary lesions and BM, respectively. Among them, 242 mutations were shared; 128 were lung primary-specific and 332 were BM-specific. Among the BM specific mutations, a majority of them (82%, 272/332) were copy number variations (CNVs). Only 16% of CNVs were shared by lung lesions and BM. The concordance for SNVs and indels were much higher-54% between the two sources of tissues. Furthermore, we observed a much higher concordance rate (79%) in TP53 and classic lung cancer driver genes than other genes (p < 0.001), indicating that they might be stem mutations. Next, we performed pathway analysis of genes that were only mutated in BM and revealed an enrichment of genes participating in PI3K-AKT and focal adhesion pathways. Our DNA methylation analysis revealed distinct methylation patterns with 268 blocks that are significantly differentially methylated between primary lung lesions and BM. Among them, 211 blocks were hypermethylated in BM and the remaining 57 blocks were hypermethylated in lung lesions. These blocks were enrichment in genes participating in cell adhesion, Rap1 signaling and calcium signaling pathways.
Conclusions
We revealed diverse somatic mutation and DNA methylation profiles between lung primary lesions and BM. BM had significantly more unique CNVs. A great concordance was observed for classic lung cancer driver genes and TP53. Our study provided a comprehensive view of genomic and DNA methylation profiling for lung primary lesions and BM, paving the avenue for the development of targeted therapies for treating BM.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Invited Discussant 1478O and 1479O (ID 6844)
- Lizza Hendriks (Maastricht, Netherlands)
LBA78 - IMpower110: Interim overall survival (OS) analysis of a phase III study of atezolizumab (atezo) vs platinum-based chemotherapy (chemo) as first-line (1L) treatment (tx) in PD-L1–selected NSCLC (ID 6256)
- David Spigel (Tennessee, TN, United States of America)
Abstract
Background
PD-L1/PD-1 inhibitors (CPI) as monotherapy or combined with platinum-based doublet chemo (± bevacizumab) are 1L tx options in metastatic NSCLC, with choice of agent(s) determined by PD-L1 expression. For patients (pts) who may be ineligible for combination therapy, CPI monotherapy remains an attractive tx choice. IMpower110 evaluated atezo as 1L tx in PD-L1–selected pts independent of tumour histology.
Methods
IMpower110 enrolled 572 chemo-naive pts with stage IV nonsquamous (nsq) or squamous (sq) NSCLC, PD-L1 expression ≥ 1% on TC or IC, measurable disease by RECIST 1.1 and ECOG PS 0-1. Pts were randomised 1:1 to receive atezo 1200 mg IV q3w (Arm A) or platinum-based chemo (Arm B; 4 or 6 21-day cycles). Arm B nsq pts received cisplatin (cis) 75 mg/m2 or carboplatin (carbo) AUC 6 + pemetrexed 500 mg/m2 IV q3w; Arm B sq pts received cis 75 mg/m2 + gemcitabine (gem) 1250 mg/m2 or carbo AUC 5 + gem 1000 mg/m2 IV q3w. Stratification factors were sex, ECOG PS, histology and tumour PD-L1 status. The primary endpoint of OS is tested hierarchically in wild-type (WT; EGFR/ALK-negative) pts (TC3 or IC3 then TC2/3 or IC2/3 then TC1/2/3 or IC1/2/3).
Results
The 3 primary efficacy populations included 554 TC1/2/3 or IC1/2/3 WT pts, 328 TC2/3 or IC2/3 WT pts and 205 TC3 or IC3 WT pts. In the TC3 or IC3 WT population, atezo monotherapy improved median OS by 7.1 mo (HR, 0.595; P = 0.0106) vs chemo (Table); median follow-up was 15.7 mo. The safety population comprised 286 pts in Arm A and 263 pts in Arm B. Treatment-related AEs (TRAEs) and Grade 3-4 TRAEs occurred in 60.5% (Arm A) and 85.2% (Arm B), and 12.9% (Arm A) and 44.1% (Arm B), respectively. LBA78 IC, tumour-infiltrating immune cells; TC, tumour cells. PD-L1 expression was centrally evaluated with the VENTANA SP142 IHC assay. TC3 or IC3 = TC ≥ 50% or IC ≥ 10% PD-L1+; TC2/3 or IC2/3 = TC ≥ 5% or IC ≥ 5% PD-L1+; TC1/2/3 or IC1/2/3 = TC ≥ 1% or IC ≥ 1% PD-L1+. Stratified. Only for descriptive purposes.Median OS Arm A (atezo) Arm B (chemo) HR P value n Months n Months TC3 or IC3 WT 107 20.2 98 13.1 0.595 (0.398, 0.890) 0.0106 TC2/3 or IC2/3 WT 166 18.2 162 14.9 0.717 (0.520, 0.989) 0.0416 TC1/2/3 or IC1/2/3 WT 277 17.5 277 14.1 0.832 (0.649, 1.067) 0.1481
Conclusions
At this interim analysis, IMpower110 met the primary OS endpoint with statistically significant and clinically meaningful improvement in the TC3 or IC3 WT population. The safety profile favoured Arm A, with no new or unexpected safety signals seen.
Clinical trial identification
NCT02409342.
Editorial acknowledgement
Medical writing assistance was provided by Kia C. E. Walcott, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.
Legal entity responsible for the study
F. Hoffmann-La Roche.
Funding
F. Hoffmann-La Roche.
Disclosure
D. Spigel: Research grant / Funding (self): F. Hoffmann-La Roche . F. de Marinis: Research grant / Funding (institution): F. Hoffmann-La Roche. G. Giaccone: Research grant / Funding (institution): F. Hoffmann-La Roche. N. Reinmuth: Research grant / Funding (institution): F. Hoffmann-La Roche; Honoraria (self): BMS, Boehringer, AstraZeneca, MSD, Takeda, Pfizer, Merk. A. Vergnenegre: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: F. Hoffmann-La Roche, BMS, MSD, AstraZeneca. C.H. Barrios: Research grant / Funding (institution): Bristol Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Pfizer, Novartis, Amgen, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Roche/Genentech, Lilly, Sanofi, Taiho Pharmaceutical, Mylan, Merrimack, Merck, Abbvie, Astellas Pharma, Biomarin, Bristol-Myers Squibb, Daiichi Sankyo, Abraxis BioScience, AB Sc. M. Morise: Research grant / Funding (institution): F. Hoffmann-La Roche; Honoraria (self), Speaker Bureau / Expert testimony: Eli Lilly, Chugai, AstraZeneca, Ono, Pfizer, MSD, ; Research grant / Funding (institution): Chugai, AstraZeneca, Pfizer, Merk Serono, Kissei, Taiho, Novartis; Research grant / Funding (institution): Boehringer Ingelheim. E. Felip: Advisory / Consultancy, Speaker Bureau / Expert testimony: ABBVIE; Advisory / Consultancy, Speaker Bureau / Expert testimony: Astra Zeneca; Advisory / Consultancy: BergenBio; Advisory / Consultancy: Blue Print Medicines; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy, Speaker Bureau / Expert testimony: Bristol-Meyers Squibb; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Advisory / Consultancy: Guardant Health; Advisory / Consultancy: Janssen; Advisory / Consultancy, Speaker Bureau / Expert testimony: Medscape; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck KGaA; Advisory / Consultancy, Speaker Bureau / Expert testimony: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy: Prime Oncology; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Advisory / Consultancy: Samsung; Advisory / Consultancy, Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy: Touchtime. Z.G. Andric: Research grant / Funding (institution): F. Hoffmann-La Roche. S. Geater: Research grant / Funding (institution): F. Hoffmann-La Roche. M. Özgüroğlu: Research grant / Funding (institution): F. Hoffmann-La Roche. S. Mocci: Full / Part-time employment: Roche/GNE. M. McCleland: Full / Part-time employment: Roche/GNE. I. Enquist: Full / Part-time employment: Roche/GNE. K.M. Komatsubara: Full / Part-time employment: Roche/GNE. Y. Deng: Full / Part-time employment: Roche/GNE. H. Kuriki: Research grant / Funding (institution): Roche/GNE; Shareholder / Stockholder / Stock options, Full / Part-time employment: Chugai Pharmaceutical. X. Wen: Full / Part-time employment: Roche/GNE. J. Jassem: Speaker Bureau / Expert testimony, Research grant / Funding (institution): F. Hoffmann-La Roche ; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: BMS; Advisory / Consultancy: MSD; Advisory / Consultancy: Takeda. R.S. Herbst: Honoraria (self): Roche/Genentech; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Merck; Honoraria (self), Research grant / Funding (institution): Eli Lilly and Company; Honoraria (self): Abbvie Pharmaceuticals; Honoraria (self): ARMO Biosciences; Honoraria (self): Biodesix; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): EMD Serrano; Honoraria (self): Genmab; Honoraria (self): Halozyme; Honoraria (self): Heat Biologics; Honoraria (self): Infinity Pharmaceuticals; Honoraria (self): Loxo Oncology; Honoraria (self): Merck and Company ; Honoraria (self): Nektar; Honoraria (self): Neon Therapeutics; Honoraria (self): NextCure; Officer / Board of Directors, non-executive/independent: Junshi Pharmaceticals; Honoraria (self): Sanofi; Honoraria (self): Seattle Genetics; Honoraria (self): Shire PLC; Honoraria (self): Spectrum Pharmaceuticals; Honoraria (self): Symphogen; Honoraria (self): Tesaro; Honoraria (self): Tocagen.
LBA79 - Association between tissue TMB (tTMB) and clinical outcomes with pembrolizumab monotherapy (pembro) in PD-L1-positive advanced NSCLC in the KEYNOTE-010 and -042 trials (ID 3570)
- Roy S. Herbst (New Haven, CT, United States of America)
Abstract
Background
In randomized open-label trials, pembro monotherapy demonstrated an OS benefit vs chemo in pts with previously treated (KEYNOTE-010, NCT01905657) or treatment naïve (KEYNOTE-042, NCT02220894), PD-L1 + (TPS ≥1%), advanced NSCLC. Associations between tTMB and efficacy were retrospectively explored in a subset of pts with evaluable tTMB in these trials.
Methods
tTMB was determined by whole exome sequencing of tumor and matched normal DNA. tTMB was evaluable for 253 (24%) pts in KEYNOTE-010 and 793 (62%) pts in KEYNOTE-042. For each study, association of tTMB (continuous log10 scale) with outcomes in each arm was evaluated using Cox proportional hazards models (OS, PFS) and logistic regression (ORR). Statistical significance was determined at the 0.05 level, unadjusted for multiplicity. Clinical utility of tTMB was assessed using a prespecified cutpoint of 175 mut/exome*.
Results
Baseline characteristics of the tTMB evaluable subset and total study population were similar. tTMB was not correlated with TPS (continuous score) in both pembro and chemotherapy (chemo) arms (r < 0.18). tTMB was associated with OS, PFS and ORR for pembro (pembro arms pooled) in KEYNOTE-010 (1-sided p = 0.006, 0.001, 0.009, respectively) and in KEYNOTE-042 (all 1-sided p < 0.001); whereas tTMB was in general not associated with outcomes for chemo. In both trials, improvements in OS, PFS and ORR were generally observed for pembro treated pts with high tTMB ≥175 (Table). LBA79 Cutpoint derived by meta-analysis of TMB and gene expression data from pembro clinical trials across multiple tumor types; pembro 10 mg/kg (Q3W)+pembro 2 mg/kg Q3W; docetaxel 75 mg/m2 Q3W; pembro 200 mg Q3W; platinum-based chemo.TMB ≥175 Mut/exome* TMB <175 Mut/exome* KEYNOTE-010 Pembroa N = 81 Chemob N = 51 Pembroa N = 83 Chemob N = 38 Median OS (95% CI) 14.1 (10.0-19.2) 7.6 (5.0-10.7) 9.3 (8.3-12.5) 7.2 (4.5-14.3) OS HR (95% CI) 0.56 (0.38-0.83) 0.85 (0.56-1.30) Median PFS (95% CI) 4.2 (2.2-10.0) 2.4 (2.1-6.0) 3.7 (2.1-4.5) 3.4 (2.1-7.5) PFS HR (95% CI) 0.59 (0.40-0.87) 1.09 (0.72-1.63) ORR % (95% CI) 23.5 (14.8-34.2) 9.8 (3.3-21.4) 16.9 (9.5-26.7) 21.1 (9.6-37.3) KEYNOTE-042 Pembroc N = 189 Chemod N = 165 Pembroc N = 234 Chemod N = 214 Median OS (95% CI) 21.9 (17.0-26.7) 11.6 (9.9-14.2) 12.0 (9.2-14.8) 12.3 (11.3-16.2) OS HR (95% CI) 0.62 (0.48-0.80) 1.09 (0.88-1.36) Median PFS (95% CI) 6.3 (5.5-8.5) 6.5 (6.2-8.1) 4.1 (3.1-4.3) 6.3 (6.1-8.1) PFS HR (95% CI) 0.75 (0.59-0.95) 1.27 (1.04-1.55) ORR % (95% CI) 34.4 (27.5-41.9) 30.9 (24.0-38.6) 18.8 (14.0-24.4) 22.4 (17.0-28.6)
Conclusions
In this exploratory analysis, associations between higher tTMB levels and improved clinical outcome with pembro monotherapy were observed in pts with PD-L1+ NSCLC. While the results suggest that tTMB may provide additional information regarding the clinical benefit of pembro monotherapy among pts with PD-L1+ NSCLC tumors, the analyses and effect estimates were limited to observational subsets of the randomized cohorts.
Clinical trial identification
KEYNOTE-10 (NCT01905657), originally posted July 23, 2013; KEYNOTE-042 (NCT02220894), originally posted August 20, 2014.
Editorial acknowledgement
Joanne Tomassini of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ USA
Disclosure
R.S. Herbst: Advisory / Consultancy: AbbVie Pharmaceuticals; Advisory / Consultancy: ARMO Biosciences; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly and Company; Advisory / Consultancy: EMD Serrano; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Genmab; Advisory / Consultancy: Heat Biologics; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Loxo Oncology; Advisory / Consultancy, Research grant / Funding (institution): Merck Sharp & Dohme Corp.; Advisory / Consultancy: Nektar; Advisory / Consultancy: NextCure; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Shire PLC; Officer / Board of Directors: Junshi Pharmaceuticals; Advisory / Consultancy: Spectrum Pharmaceuticals; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Tocagen; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Infinity Pharmaceuticals. G. Lopes: Research grant / Funding (institution): MSD; Research grant / Funding (institution): EMD Serono; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Blueprint Medicines; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): GI Therapeutics; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self), Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: ER Squibb Sons, LLC; Travel / Accommodation / Expenses: Janssen; Honoraria (self), Research grant / Funding (self): Merck. D.M. Kowalski: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: MSD; Advisory / Consultancy: Bristol-Myers Squibb. M. Nishio: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Ono Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Chugai Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Taiho Pharmaceutical; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Daiichi Sankyo Healthcare; Advisory / Consultancy: Merck Serono; Research grant / Funding (institution): Astellas. Y. Wu: Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self): Sanofi; Advisory / Consultancy: Merck & Co., Inc.. G. de Castro Junior: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim; Advisory / Consultancy: TEVA; Advisory / Consultancy: Yuhan; Advisory / Consultancy: Merck Serono. P. Baas: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Aldeyra Therapeutics; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Theradex. D. Kim: Research grant / Funding (institution): Alpha Biopharma; Research grant / Funding (institution): AstraZeneca/MedImmune; Research grant / Funding (institution): Hanmi; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Merus; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): ONO Pharmaceuticals; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): TP Therapeutics; Research grant / Funding (institution): Xcovery; Research grant / Funding (institution): Yuhan. M.A. Gubens: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Beyond Spring; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Heron; Advisory / Consultancy: Takeda; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Merck & Co., Inc.; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Roche. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. A. Albright: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. M. Ayers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. A. Loboda: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. G.M. Lubiniecki: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. M.C. Pietanza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc. T.S.K. Mok: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): Clovis Oncology; Research grant / Funding (institution): Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): SFJ Pharmaceuticals; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Xcovery; Honoraria (self), Advisory / Consultancy: Roche/Genentech; Honoraria (self), Leadership role, Shareholder / Stockholder / Stock options: Hutchinson MediPharma; Honoraria (self): Janssen; Honoraria (self): Takeda; Honoraria (self): Fishawack Facilitate Ltd; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: ACEA Biosciences, Celgene, Vertex, geneDecode, OncoGenex, Ignyta, Cirina; Leadership role, Shareholder / Stockholder / Stock options: Sanomics Ltd; Shareholder / Stockholder / Stock options: Cirina; Full / Part-time employment: Chinese University of Hong Kong; Non-remunerated activity/ies, Board of director for ASCO; Track chair for ESMO, ASCO.
LBA80 - Pembrolizumab (pembro) plus platinum-based chemotherapy (chemo) for metastatic NSCLC: Tissue TMB (tTMB) and outcomes in KEYNOTE-021, 189, and 407 (ID 4311)
- Luis Paz-Ares (Madrid, Spain)
Abstract
Background
Pembro + chemo improves efficacy as 1L therapy for metastatic squamous and nonsquamous NSCLC, regardless of PD-L1 TPS. We explored the relationship between tTMB and efficacy in KEYNOTE-021 C and G (nonsquamous; NCT02039674), 189 (nonsquamous; NCT02578680), and 407 (squamous; NCT02775435).
Methods
tTMB was determined by whole-exome sequencing of tumor and matched normal DNA. For each study, the association of tTMB (continuous log10 transformed) with outcomes for pembro + chemo and for chemo was assessed in pts with evaluable tTMB using Cox proportional hazards models (OS, PFS) and logistic regression (ORR); statistical significance was determined at the 0.05 level (no multiplicity adjustment). Clinical utility of tTMB on outcomes was assessed using a prespecified cutpoint of 175 mut/exome. Primary study endpoints were OS and PFS in KEYNOTE-189 and 407 and ORR in 021.
Results
tTMB was evaluable in 48% of treated pts in KEYNOTE-021 C and G, 48% in 189, and 56% in 407. Baseline characteristics and efficacy were similar in the tTMB-evaluable and total populations. tTMB (continuous log10) was not significantly associated with efficacy of pembro + chemo or chemo (minimum P values across studies: 1-sided .072 for ORR, .052 for PFS, and .081 for OS for pembro + chemo; 2-sided .086, .055, and .475, respectively, for chemo). Pembro + chemo improved OS and PFS for tTMB ≥175 and <175 mut/exome in KEYNOTE-189 and 407 (Table). In pembro + chemo–treated pts in KEYNOTE-021 G, ORR (95% CI) was 60.8% (38.5-80.3) in the 23 pts with tTMB <175 and 71.4% (47.8-88.7) in the 21 pts with tTMB ≥175 mut/exome.
Conclusions
In this exploratory analysis, tTMB was not significantly associated with efficacy of pembro + platinum-based chemo or of chemo alone as 1L therapy for metastatic NSCLC, regardless of histology. Pembro + chemo showed survival benefit in the tTMB-high and low subgroups for both squamous and nonsquamous NSCLC. LBA80 Cutpoint derived by meta-analysis of tTMB and gene expression data from pembro clinical trials across multiple tumor types.tTMB ≥175 mut/exomea tTMB <175 mut/exomea KEYNOTE-189 KEYNOTE-407 KEYNOTE-189 KEYNOTE-407 N, pembro + chemo 100 73 107 70 N, chemo 34 89 52 80 OS, HR (95% CI) 0.64 0.74 0.64 0.86 (0.38-1.07) (0.50-1.08) (0.42-0.97) (0.57-1.28) PFS, HR (95% CI) 0.32 0.57 0.51 0.68 (0.21-0.51) (0.41-0.81) (0.35-0.74) (0.48-0.96)
Clinical trial identification
KEYNOTE-021: NCT02039674, originally posted January 17, 2014; KEYNOTE-189: NCT02578680, originally posted October 19, 2015; KEYNOTE-407: NCT02775435, originally posted May 17, 2016.
Editorial acknowledgement
Melanie Leiby of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Legal entity responsible for the study
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.
Funding
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA
Disclosure
L. Paz-Ares: Officer / Board of Directors: Genomica; Honoraria (self): Roche ; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Lilly; Honoraria (self): Novartis; Honoraria (self): Boehringer Ingelheim; Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self): Amgen; Honoraria (self): Sanofi; Honoraria (self): Pharamar; Honoraria (self), Research grant / Funding (institution): Pfizer; Honoraria (self), Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): Celgene; Honoraria (self): Servier; Honoraria (self): Sysmex; Honoraria (self): Incyte; Honoraria (self): Ipsen; Honoraria (self): Adacap; Honoraria (self): Bayer; Honoraria (self): Blueprint; Leadership role: Altum Sequencing. C.J. Langer: Advisory / Consultancy, Research grant / Funding (institution): Merck & Co., Inc.; Advisory / Consultancy: AbbVie; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche/Genentech; Advisory / Consultancy: Takeda; Advisory / Consultancy: Bristol-Myers Squibb. S. Novello: Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Boehringer Ingelheim; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Speaker Bureau / Expert testimony: Bayer; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Takeda; Speaker Bureau / Expert testimony: Pfizer; Speaker Bureau / Expert testimony: Eli Lilly. B. Halmos: Advisory / Consultancy, Research grant / Funding (institution): Merck & Co., Inc.; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Guardant Health; Advisory / Consultancy: Spectrum; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy: Genentech; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Mirati; Research grant / Funding (institution): Takeda. Y. Cheng: Research grant / Funding (institution): MSD. S.M. Gadgeel: Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Xcovery; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novocure; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Takeda; Research grant / Funding (institution): MSD. R. Hui: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Eli Lilly. S. Sugawara: Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Ono Pharmaceutical; Honoraria (self): AstraZeneca; Honoraria (self): Chugai Pharma; Honoraria (self): Nippon Boehringer Ingelheim; Honoraria (self): Eli Lilly; Honoraria (self): Pfizer; Honoraria (self): Novartis; Honoraria (self): Taiho Pharmaceutical; Honoraria (self): Kyowa Hakko Kirin. H. Borghaei: Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck ; Advisory / Consultancy, Travel / Accommodation / Expenses: EMD-Serono; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Genmab; Advisory / Consultancy: Regeneron; Advisory / Consultancy: BioNTech; Advisory / Consultancy: Cantargia AB; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Axiom; Advisory / Consultancy: PharmaMar; Advisory / Consultancy: Takeda; Advisory / Consultancy: Huya Bio; Research grant / Funding (institution): Milennium; Research grant / Funding (institution): Merck/Celgene; Research grant / Funding (institution): BMS/Lilly; Full / Part-time employment: Fox Chase Cancer Center; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly. R. Cristescu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. D. Aurora-Garg: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. A. Albright: Full / Part-time employment: Merck & Co., Inc.. A. Loboda: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J. Kobie: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J. Lunceford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. M. Ayers: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. G.M. Lubiniecki: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. M.C. Pietanza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. B. Piperdi: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. M.C. Garassino: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Takeda; Advisory / Consultancy, Research grant / Funding (institution): Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Lilly; Advisory / Consultancy: Roche; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Novartis; Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): MedImmune.
Invited Discussant LBA78, LBA79 and LBA80 (ID 6848)
- Naiyer Rizvi (New York, NY, United States of America)