PMID- 36922935
OWN - NLM
STAT- MEDLINE
DCOM- 20230731
LR  - 20230731
IS  - 2767-9764 (Electronic)
IS  - 2767-9764 (Linking)
VI  - 2
IP  - 9
DP  - 2022 Sep
TI  - Real-world Validation of TMB and Microsatellite Instability as Predictive 
      Biomarkers of Immune Checkpoint Inhibitor Effectiveness in Advanced 
      Gastroesophageal Cancer.
PG  - 1037-1048
LID - 10.1158/2767-9764.CRC-22-0161 [doi]
AB  - Patients with advanced gastroesophageal cancer (mEG) and tumor mutational burden 
      >/=10 mut/Mb (TMB >/= 10) have more favorable outcomes on immune checkpoint inhibitor 
      (ICPI) monotherapy compared with chemotherapy in subgroup analyses of randomized 
      controlled trials. We sought to evaluate the robustness of these associations in 
      real-world settings where patients and practices are more diverse. A total of 362 
      2 L and 692 1 L patients, respectively received ICPI (n = 99, 33) or chemotherapy 
      (n = 263, 659) across approximately 280 U.S. academic or community-based cancer 
      clinics March 2014-July 2021. Deidentified data were captured into a real-world 
      clinico-genomic database. All patients underwent Foundation Medicine testing. 
      Time to next treatment (TTNT) and overall survival (OS) comparing ICPI versus 
      chemotherapy were adjusted for treatment assignment imbalances using propensity 
      scores. 2L: TMB >/= 10 had more favorable TTNT [median 24 vs. 4.1 months; HR: 0.19; 
      95% confidence interval (CI): 0.09-0.44; P = 0.0001] and OS (median 43.1 vs. 6.2 
      months; HR: 0.24; 95% CI: 0.011-0.54; P = 0.0005), TMB < 10 did not (P > 0.05). 
      1L: TMB >/= 10 had more favorable TTNT (not reached vs. median 4.1 months; HR: 
      0.13; 95% CI: 0.03-0.48; P = 0.0024) and OS (not reached vs. median 17.1 months; 
      HR: 0.30; 95% CI: 0.08-1.14; P = 0.078), TMB < 10 had less favorable TTNT (median 
      2.8 vs. 6.5 months; HR: 2.36; 95% CI: 1.25-4.45; P = 0.008) and OS (median 4.5 
      vs. 13.1 months; HR: 1.82, 95% CI: 0.87-3.81; P = 0.11). TMB >/= 10 robustly 
      identifies patients with mEG with more favorable outcomes on 2 L ICPI monotherapy 
      versus chemotherapy. 1 L data are more limited, but effects are consistent with 
      2L. SIGNIFICANCE: Using real-world data, we sought to evaluate robustness of 
      these clinical associations using the same assay platform and biomarker cut-off 
      point used in both clinical trials and pan-tumor CDx approvals for later 
      treatment lines. TMB >/= 10 robustly identified patients with mEG with more 
      favorable outcomes on ICPI monotherapy versus chemotherapy and suggests this 
      subset of patients could be targeted for further trial development.
CI  - (c) 2022 The Authors; Published by the American Association for Cancer Research.
FAU - Graf, Ryon P
AU  - Graf RP
AUID- ORCID: 0000-0002-8065-4148
AD  - Foundation Medicine, Cambridge, Massachusetts.
FAU - Fisher, Virginia
AU  - Fisher V
AD  - Foundation Medicine, Cambridge, Massachusetts.
FAU - Creeden, James
AU  - Creeden J
AUID- ORCID: 0000-0001-5863-133X
AD  - Foundation Medicine, Cambridge, Massachusetts.
FAU - Schrock, Alexa B
AU  - Schrock AB
AD  - Foundation Medicine, Cambridge, Massachusetts.
FAU - Ross, Jeffrey S
AU  - Ross JS
AUID- ORCID: 0000-0001-8494-2596
AD  - Foundation Medicine, Cambridge, Massachusetts.
AD  - Upstate Medical University, Syracuse, New York.
FAU - Nimeiri, Halla
AU  - Nimeiri H
AD  - Foundation Medicine, Cambridge, Massachusetts.
FAU - Oxnard, Geoffrey R
AU  - Oxnard GR
AUID- ORCID: 0000-0003-1054-8240
AD  - Foundation Medicine, Cambridge, Massachusetts.
FAU - Klempner, Samuel J
AU  - Klempner SJ
AUID- ORCID: 0000-0002-4062-0808
AD  - Department of Medicine, Division of Hematology-Oncology, Massachusetts General 
      Hospital, Boston, Massachusetts.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220921
PL  - United States
TA  - Cancer Res Commun
JT  - Cancer research communications
JID - 9918281580506676
RN  - 0 (Immune Checkpoint Inhibitors)
RN  - 0 (Biomarkers, Tumor)
MH  - Humans
MH  - Immune Checkpoint Inhibitors/pharmacology
MH  - Microsatellite Instability
MH  - Mutation
MH  - *Carcinoma, Non-Small-Cell Lung/drug therapy
MH  - *Lung Neoplasms/drug therapy
MH  - Biomarkers, Tumor/genetics
MH  - *Stomach Neoplasms/drug therapy
MH  - *Esophageal Neoplasms/drug therapy
PMC - PMC10010289
COIS- R.P. Graf reports personal fees from Foundation Medicine, Inc during the conduct 
      of the study; personal fees from Epic Sciences outside the submitted work; in 
      addition, R.P. Graf has a patent to Planned pending. V. Fisher reports grants 
      from Roche outside the submitted work. J. Creeden reports other from Foundation 
      Medicine, Inc outside the submitted work. A.B. Schrock reports personal fees from 
      Foundation Medicine and Roche during the conduct of the study. J.S. Ross reports 
      personal fees from Foundation Medicine outside the submitted work. H. Nimeiri 
      reports other from Foundation Medicine outside the submitted work. G.R. Oxnard 
      reports personal fees from Foundation Medicine and Roche during the conduct of 
      the study. S.J. Klempner reports personal fees from Merck, Bristol Myers Squibb, 
      Astellas, Daiichi-Sankyo, AstraZeneca, Sanofi-Aventis, Exact Sciences, Eli Lilly; 
      other from Nuvalent and Turning Point Therapeutics outside the submitted work. No 
      other disclosures were reported.
EDAT- 2023/03/17 06:00
MHDA- 2023/03/17 06:01
PMCR- 2022/09/21
CRDT- 2023/03/16 02:14
PHST- 2022/04/14 00:00 [received]
PHST- 2022/06/27 00:00 [revised]
PHST- 2022/08/15 00:00 [accepted]
PHST- 2023/03/16 02:14 [entrez]
PHST- 2023/03/17 06:00 [pubmed]
PHST- 2023/03/17 06:01 [medline]
PHST- 2022/09/21 00:00 [pmc-release]
AID - CRC-22-0161 [pii]
AID - 10.1158/2767-9764.CRC-22-0161 [doi]
PST - epublish
SO  - Cancer Res Commun. 2022 Sep 21;2(9):1037-1048. doi: 
      10.1158/2767-9764.CRC-22-0161. eCollection 2022 Sep.