Abstract LB012: Efficacy of atezolizumab in the treatment of solid tumors with high tumor mutational burden (TMB): A MyPathway study cohort

2021 ◽  
Author(s):  
John Hainsworth ◽  
Claire F. Friedman ◽  
Razelle Kurzrock ◽  
David R. Spigel ◽  
Howard Burris ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Study Cohort ◽  
Mutational Burden ◽  
Tumor Mutational Burden

scholarly journals The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 666 ◽  
Author(s):  
Evangelos Koustas ◽  
Panagiotis Sarantis ◽  
Athanasios G. Papavassiliou ◽  
Michalis V. Karamouzis
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Epigenetic Alterations ◽  
Primary Resistance ◽  
Cellular Processes ◽  
Mutational Burden ◽  
Number Of Patients ◽  
Tumor Mutational Burden

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.

scholarly journals Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors

2020 ◽  
Vol 10 (12) ◽  
pp. 1808-1825
Author(s):  
Dan Sha ◽  
Zhaohui Jin ◽  
Jan Budczies ◽  
Klaus Kluck ◽  
Albrecht Stenzinger ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Predictive Biomarker ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Clinical response and biomarker analysis of a phase II basket trial of toripalimab, a PD-1 mAb in combination with standard chemotherapy as a first-line treatment for patients with solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15083-e15083
Author(s):  
Chao Ren ◽  
Xiao-Li Wei ◽  
Nong Xu ◽  
Lin Shen ◽  
Guanghai Dai ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Clinical Response ◽  
Solid Tumors ◽  
Squamous Cell ◽  
Line Treatment ◽  
First Line ◽  
Standard Chemotherapy ◽  
Mutational Burden ◽  
Tumor Mutational Burden

e15083 Background: Platinum based chemotherapy is the standard care for 1st line treatment of metastatic gastric adenocarcinoma (GC), esophageal squamous cell carcinoma (ESSC), nasopharyngeal carcinoma (NPC) and head and neck squamous cell carcinoma (HNSCC). Combinations of PD-1 blockade with chemotherapy have shown promising but mixed results in solid tumors. Predictive biomarkers for chemo-immunotherapy combination as 1st line treatment remain undefined. Methods: Patients (n = 60) included in this analysis were four complete cohorts from a multi-center, phase Ib/II trial (NCT02915432) evaluating the safety and activity of toripalimab, a humanized PD-1 antibody in combination with standard chemotherapy for the 1st line treatment of GC, EC, NPC and HNSCC (excluding NPC). Whole exome sequencing (WES), RNA sequencing and immunohistochemistry were performed on tumor biopsy samples. PD-L1 expression and tumor mutational burden (TMB) were evaluated for correlation with clinical efficacy. Results: From Oct 2016 to Feb 2019, 33 GC, 12 ESSC, 12 NPC and 3 HNSCC patients were enrolled and treated with 240mg or 360 mg toripalimab Q3W via IV infusion in combination with Oxaliplatin/Capecitabine (XELOX), Paclitaxel/Cisplatin (PP), Gemcitabine/Cisplatin (GP) and Docetaxel/Cisplatin/5-FU(TPF) respectively. By the data cutoff date of Nov 15, 2019, all patients experienced treatment related adverse event (TRAE). There was one TRAE (heart failure) leading to death. Grade 3-4 TRAEs occurred in 67% patients, mostly attributed to chemotherapy, including 27% neutropenia, 23% thrombocytopenia, 18% leukopenia and 12% anemia. As assessed by investigators according to RECIST v1.1, the ORR/DCR were 54.5%/84.8%, 66.7%/91.7%, 75.0%/83.3% and 33.3%/100% respectively for GC, EC, NPC and HSNCC cohorts. The median duration of response was 8.3, 6.8, 7.7 and 7.1 months respectively. WES showed distinctive patterns of genomic alterations among different cohorts. The clinical response was not correlated with either PD-L1 expression or tumor mutational burden. Conclusions: Toripalimab in combination with chemotherapy as first-line treatments showed promising results for metastatic GC, EC, NPC and HNSCC patients. Two randomized Phase III trials of toripalimab in combination with Paclitaxel/Cisplatin or Gemcitabine/Cisplatin versus chemotherapy alone are ongoing to further evaluate the combination as first-line treatments in metastatic EC and NPC patients. Clinical trial information: NCT02915432 .

Genomic evaluation of tumor mutational burden-high (TMB-H) versus TMB-low (TMB-L) metastatic breast cancer to reveal unique mutational features.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1091-1091
Author(s):  
Sarah Sammons ◽  
Andrew Elliott ◽  
Jeremy Meyer Force ◽  
Nicholas C. DeVito ◽  
Paul Kelly Marcom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Solid Tumors ◽  
Immune Checkpoint ◽  
Metastatic Breast ◽  
Breast Cancers ◽  
Checkpoint Inhibition ◽  
Immune Checkpoint Inhibition ◽  
Mutational Burden ◽  
Tumor Mutational Burden

1091 Background: Tumor mutational burden (TMB) has emerged as an imperfect biomarker of immune checkpoint inhibition (ICI) outcomes in solid tumors. Despite the approval for pembrolizumab in all TMB-high (TMB-H) solid tumors, the optimal clinical approach to TMB-H or hypermutated advanced/metastatic breast cancer (MBC) is unknown with sparse prospective data. We hypothesize that TMB-H MBC will have unique genomic alterations compared to TMB-low (TMB-L) breast cancer that could inform novel therapeutic approaches. Methods: Tumor samples (N = 5621) obtained from patients with MBC were analyzed by next-generation sequencing (NGS) of DNA (592-gene panel or whole exome sequencing) and RNA (whole transcriptome sequencing) at Caris Life Sciences (Phoenix, AZ). TMB was calculated based on recommendations from the Friends of Cancer Research TMB Harmonization Project (Merino et al., 2020), with the TMB-H threshold set to ≥ 10 muts/Mb. IHC was performed for PD-L1 (Ventana SP142 ≥1% immune cells). Deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) was tested by IHC and NGS, respectively. Results: TMB-H was identified in 8.2% (n = 461) of MBC samples, with similar frequencies observed across molecular subtypes (7.8-8.6%, p = 0.85): HR+/HER2- (n = 3087) 7.8%, HR+/HER2+ (n = 266) 8.3%, HR-/HER2+ (n = 179) 7.8%, TNBC (n = 1476) 8.6%. The frequency of TMB-H was significantly increased in lobular (16%) versus ductal (5%) MBC (p < 0.01). TMB-H samples were enriched in genitourinary (42%), soft tissue (20%), and gastrointestinal non-liver (16%) biopsy specimens. Compared to TMB-L tumors, TMB-H tumors exhibited significantly higher mutation rates for TP53 (60 v 52%), PIK3CA (55 vs 31%), ARID1A (34 vs 11%), CDH1 (27 vs 11%), NF1 (22 vs 9%), RB1 (14 vs 5%), KMT2C (12 vs 7%), PTEN (12 vs 7%), ERBB2 (7 vs 2.9%), and PALB2 (3.3 vs 1%) genes (p < 0.05 each). Copy number alteration and fusion rates did not differ between TMB-H and TMB-L breast cancers. PI3K/AKT/MTOR, TP53, Histone/Chromatin remodeling, DNA damage repair (DDR), RAS, and cell cycle pathway alterations were detected in > 25% TMB-H MBCs (p < 0.05 each). dMMR/MSI-High (7.2 vs 0.3%, p < 0.01) and PD-L1 positivity (36 vs 28%, p < 0.05) frequencies were significantly increased in TMB-H tumors. DNA signature analyses including APOBEC and homologous recombination repair deficiency, as well as gene expression profiling to assess immune-related signatures and tumor microenvironment are underway. Conclusions: TMB-H breast cancers contain a unique genomic profile enriched with targetable mutations such as PIK3CA, ARID1A, NF1, PTEN, ERBB2, and PALB2. Concurrent predictive biomarkers of response to immune checkpoint inhibition such as MSI-H and PDL-1 positivity are also more prevalent in TMB-H MBC. These findings suggest novel combination strategies within TMB-H MBC could be explored.

scholarly journals 76P The distribution of tumor mutational burden in IDH-mutant solid tumors

2020 ◽  
Vol 31 ◽  
pp. S270
Author(s):  
Y. lu ◽  
J. Zhang ◽  
F. Wu ◽  
C. Ni ◽  
Y. Wang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Mutational Burden ◽  
Tumor Mutational Burden

Biomarkers of Chinese advanced cancer patients based on real-world data: Actionable genomic alterations and tumor mutational burden.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14280-e14280
Author(s):  
HaiTao Wang ◽  
Huina Wang ◽  
Rongyun Guo ◽  
Mingwei Li ◽  
Yanrui Zhang ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Real World ◽  
Cell Cancer ◽  
Objective Response ◽  
Genetic Alterations ◽  
Cancer Type ◽  
Tumor Type ◽  
Mutational Burden ◽  
Esophagogastric Cancer ◽  
Tumor Mutational Burden

e14280 Background: Biomarkers would enrich patients(pts) with responsiveness to both targeted treatments and immunotherapy which have become a priority. However, molecular heterogeneous in actionable gene alterations and mutational loads need to be explored. In this study, based on a real world setting, Cancer Gene Panel (CGP） analysis was performed in a series samples of Chinese pts with advanced solid tumors, to delineate the landscape of actionable mutations and tumor mutational burden (TMB). Methods: 176 advanced pts were enrolled encompassing 19 common tumor types. All tissue samples were analyzed using next-generation sequencing with Acornmed panel including 808 genes. Results: The frequencies of genetic alterations among the most common driver genes were comparable to those reported by MSK-IMPACT (2018) ( TP53: 51.7% vs 44.8%; APC: 9.7% vs 9.8%; EGFR: 12.5% vs 7.7%; KRAS: 16.5% vs 13.6%; PIK3CA: 4.6% vs 12.0%; VHL: 4.0% vs 6.7%). 58.3% of pts with refractory solid tumors had at least one actionable mutation. Among those pts, 16.7% of them including CDK4, CDK6 or CDKN2A/B could benefit from palbociclib, and 32.1% of them including mTOR, PIK3CA, PTEN or STK11 could benefit from everolimus, and 61.9% of them including BRCA2, ARID1A, MSH1/2/6 or ATM could benefit from olaparib. Across all the specimens, the top 20% of TMB was 17.23 mutations/Mb, with a range of 0-48 mutations/Mb. The top 20% of TMB for each tumor type was 21.67(Bladder cancer), 17.23(Lung cancer), 16.45(Colorectal cancer), 11.04 (Renal cell cancer), 16.25 (Prostate cancer) , 19.70 (Hepatobiliary cancer), 14.78 (Esophagogastric cancer), 7.80 (Pancreatic cancer), 25.31 (undefined tumor) mutations/Mb respectively. Conclusions: This study indicates that most of pts with advanced refractory solid tumors have at least one actionable mutation, and matched therapies may confer clinical benefit. TMB fluctuated wildly across different cancer types, illustrating the unequal objective response rate of immunotherapy across various cancer type. Furthermore, CGP analysis in advanced pan-cancer pts can provide opportunities for targeted therapies and immunotherapy, especially in those with refractory cancer.

Evaluating the clinical, environmental, genetic, and genomic profile of men with early-onset aggressive prostate cancer (PCa).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17517-e17517
Author(s):  
Ahmad Zarzour ◽  
Alicia K. Morgans ◽  
Philip Palmbos ◽  
Borko Jovanovic ◽  
Scott A. Tomlins ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Early Onset ◽  
Fusion Gene ◽  
Age Groups ◽  
Local Therapy ◽  
Germline Mutations ◽  
Primary Objective ◽  
Study Cohort ◽  
Mutational Burden ◽  
Tumor Mutational Burden

e17517 Background: Although PCa incidence has stabilized/decreased in most age groups, the incidence of metastatic disease has increased among men 50-69 years-old. The incidence of fatal PCa has decreased for most age groups, it has remained unchanged in men under 55 years-old. Studies have described genetic abnormalities in aggressive localized or end-stage PCa, but early-onset cases are not included or are under-represented. The primary objective of this study is to characterize the clinical, environmental, genetic and genomic features of high-risk advanced PCa. Methods: Study cohort includes men with PCa ≤ 60 years old with N1 or M1 stage at diagnosis or who develop metastases in 5-years after local therapy. Clinical (race, family history (Hx), environmental exposure), laboratory,/pathology, cell-free DNA germline analysis were collected. Primary/metastatic tumor tissue tested via the Tempus-Xe platform (DNA sequencing, whole transcriptome expression profiling, copy number analysis, comprehensive fusion gene analysis and calculation of tumor mutational burden). We report interim analysis. Results: Study completed accrual with 30 pts. Median age 55 years (41-60), 87% are white, 13% are black, 77% had a family Hx of malignancy in 1-6 family members, including 40% with family hx of PCa. Only 33% had Hx of smoking. Median Gleason score 9. Only 27% had nodal disease, and 73% had metastatic disease at diagnosis. Molecular data are available in 25 pts. Most common germline mutations: BRCA2 (12%), ATM (12%), RB1 (8%), MSH3 (8%) and MYBPC3 (8%). Most common somatic mutations:TP53 (40%), TMPRSS2-ERG fusion (32%), MUC4 (16%), PTEN (12%), C2CD4D (12%), SPOP (12%), OBSCN (12%), MXRA5 (12%), and MYO15A (12%). Microsatellite stability status was available in 15 pts and all were stable. Tumor mutational burden was low in all pts, ranging between 0.7 to 2.7 mutations/megabase. Conclusions: Our preliminary data suggest high rates of germline mutations in early onset lethal PCa. This aggressive subset of disease requires further studying to better characterize the underlying clinical/genomic factors driving this disease.

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