Abstract 2314
Background
Immune checkpoint inhibitors (ICIs) elicits durable responses in non–small cell lung cancer (NSCLC), but only a fraction of patients responded. TP53 and ATM co-mutation may lead to genomic instability and hypermutation. However, the prevalence and utility of a TP53/ATM co-mutation as a biomarker to ICIs are not fully understood.
Methods
This was a multiple cohort pooled study, 2020 NSCLC samples from Geneplus Institute, 1031 samples from TCGA, 1567 samples from MSKCC, 853 samples from POLAR/OAK databases were statically analyzed. Next-generation sequencing assays were performed in the Geneplus Institute. Genomic, transcriptomic and clinical data were obtained from the TCGA, MSKCC, POLAR/OAK databases. Comprehensive profiling was performed to determine the prevalence of TP53/ATM co-mutation and correlation with the prognosis and the response to ICIs.
Results
TP53/ATM co-mutation sites were found to be scattered throughout the genes and we did not observe any significant difference in TP53/ATM co-mutated frequency within the histologic subtypes and driver genes. In five independent NSCLC cohorts, TP53/ATM co-mutation contributed to significantly higher tumor mutation burden (TMB) compared to both the sole mutation and both wild type groups. Furthermore, in the MSKCC-IO cohort, a TP53/ATM co-mutation was associated with better OS than sole mutation and both wild type groups, especially in pan-cancer (P=.241, NSCLC and P<.0001, Pan-cancer). Similar results were shown in the POLAR/OAK cohort, the disease control benefit rate, and progression free survival (PFS) and OS were all greater in patients with the TP53/ATM co-mutation compared with the other three groups. GSEA showed that IFN-α response, IFN-γ response, IL6/JAK/STAT3 signaling, and TNF-α signaling pathways had higher levels of activation and there was greater PD-L1 expression in the co-mutated group, compared with solely mutated and both wild type group.
Conclusions
Our findings suggest that patients with TP53/ATM co-mutation comprise a special subgroup of NSCLC patients and correlate with increasing TMB and responses to ICIs. It may have implications for potential predictive biomarker in guiding ICIs immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Jian Ji Pan.
Funding
National Natural Science Foundation of China (Grant No. U1705282).
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
5389 - Two-weekly accelerated BEP (aBEP) regimen as induction chemotherapy (CT) in intermediate and poor prognosis patients (pts) with nonseminomatous germ cell tumors (NSGCT): final results of phase II trial.
Presenter: Alexey Tryakin
Session: Poster Display session 3
Resources:
Abstract
2934 - Differential expression of circulating miR375 and miR371 to detect teratoma and viable germ cell malignancy
Presenter: Lucia Nappi
Session: Poster Display session 3
Resources:
Abstract
3585 - Prognosis of anaemia in disseminated testicular germ cell tumours. On behalf of the Spanish Germ Cell Cancer Group (SGCCG)
Presenter: Esmeralda Garcia Torralba
Session: Poster Display session 3
Resources:
Abstract
2254 - The Effects Of Primary Testicular Tumor Localization On Prognosis In Patients With Nonseminomatous Testis Cancer
Presenter: Birol Yildiz
Session: Poster Display session 3
Resources:
Abstract
4505 - Initial Results of a Phase II study of Nivolumab and Ipilimumab in Metastatic Adrenal Tumors.
Presenter: Matthew Campbell
Session: Poster Display session 3
Resources:
Abstract
3369 - NEMIO: a randomized phase II trial evaluating efficacy and safety of dose dense MVAC (ddMVAC) + durvalumab +/- tremelimumab as neoadjuvant treatment in patients with bladder muscle-invasive urothelial carcinoma
Presenter: Constance Thibault
Session: Poster Display session 3
Resources:
Abstract
2075 - KEYNOTE-866: Phase 3 Study of Perioperative Pembrolizumab (pembro) or Placebo (pbo) in Combination With Neoadjuvant Chemotherapy in Cisplatin (cis)-Eligible Patients (pts) With Muscle-Invasive Bladder Cancer (MIBC)
Presenter: Arlene Siefker-Radtke
Session: Poster Display session 3
Resources:
Abstract
4824 - KEYNOTE-905: A Phase 3 Study of Cystectomy Plus Perioperative Pembrolizumab Versus Cystectomy Alone in Cisplatin (cis)-Ineligible Patients (pts) With Muscle-Invasive Bladder Cancer (MIBC)
Presenter: Matthew Galsky
Session: Poster Display session 3
Resources:
Abstract
2253 - Phase 3 LEAP-011 trial: First-Line Pembrolizumab With Lenvatinib in Patients With Advanced Urothelial Carcinoma Ineligible to Receive Platinum-Based Chemotherapy
Presenter: Yohann Loriot
Session: Poster Display session 3
Resources:
Abstract
4310 - PULSE : A Single Arm Trial Assessing The Activity and Safety of Avelumab Immunotherapy Maintenance among Patients With Locally Advanced or Metastatic Squamous Cell Penile Carcinoma (mSCPC).
Presenter: Noemie Gassian
Session: Poster Display session 3
Resources:
Abstract