TEST:

Oncomine Tumor Mutation Load Assay

Ipi+nivo showed notable efficacy and impressive mDOR in pts with TMB/TML-H tumors across tumor types. Higher TMB/TML correlated with CB, offering further opportunities to refine patient selection.

RNF43mut cases show improved clinical outcomes and stronger antitumour immune responses than RNF43wt cases in MSSPDACs. Moreover, RNF43-mutations were significantly more frequent in MSI-PDACs. Our results underscore the need for deeper understanding of molecular factors modulating the biological behaviour and treatment response of PDACs that can help refining the stratification and optimizing the clinical management of patients.

FL patients harboring t(14; 18) or mutations in genes involved in migration have higher TMB values at diagnosis. Patient stratification based on TMB values allows the identification of a subgroup of FL patients with ≤2.55 mut/Mb with shorter PFS after treatment with frontline ICT. The prognostic usefulness of TMB should also be explored at relapse, in particular in patients receiving novel immunotherapies such as bispecific antibodies and CAR T-cell therapies, that are being approved for relapsed/refractory FL.

TMB-High was associated with decreased risk of progression and with an improved PFS and OS. Furthermore, OCCC with mutations in either ARID1A and/or PIK3CA genes had a significantly impaired prognosis compared to the undetermined subgroup in stage adjusted analyses.

Introduction: Treatment with neoadjuvant nivolumab plus chemotherapy has demonstrated high efficacy in patients with locally advanced non-small-cell lung cancer (NSCLC)... Our data suggest that BRAF pathogenic variants may be a good prognostic factor in locally advance NSCLC patients treated with neoadjuvant chemo-immunotherapy.

In this study, we report preliminary results of potential molecular mechanisms underlying disease progression in patients treated with neoadjuvant nivolumab plus chemotherapy using plasma samples from NADIM and NADIM II cohorts. A total of 10 plasma samples collected upon disease progression from patients included in NADIM or NADIM II trials were analyzed... Acquisition of somatic-copy number alterations in RET, EGFR and FGFR was found in the plasma samples collected upon disease progression in patients treated with neoadjuvant chemoimmunotherapy (NADIM I and II cohorts) which may have important implications for subsequent treatment selection.

In this series of lung neuroendocrine carcinomas, TP53 and RB1 mutations were the most prevalent. No tumors showed H-MSI or dMMR. Only 3 expressed PD-L1.

The study included 51 patients with FL grade 1–3a treated with first line ICT (rituximab, R-CHOP, R-CVP or R-bendamustine). FL patients harboring t(14;18) or mutations in genes of the BCR signaling pathway or involved in migration have higher TMB values at diagnosis. High TMB (≥8 mut/Mb) shows a tendency for longer PFS in FL patients treated with ICT.

Sponsored by Pharmaceutical/Biotech Company, AstraZeneca K.K. Background: Although osimertinib has recently become an option for adjuvant therapy in many countries, biomarkers predicting the efficacy of adjuvant EGFR-TKI and the risk of postoperative recurrence in completely resected NSCLC harboring EGFR mutations have not been fully investigated. This IMPACT-TR study is an exploratory biomarker study for completely resected, EGFR-mutated NSCLC patients who received gefitinib or cisplatin plus vinorelbine (cis/vin) in a phase III IMPACT study (Trial registration number: UMIN000044738... This study suggested that NOTCH1 mutation may be a biomarker to predict poor response to adjuvant gefitinib and CREBBP mutation to predict poor response to cis/vin in patients with completely resected, EGFR-mutated NSCLC. Clinical trial information: UMIN000044738.

Assessment of TMB acquired by EBUS from multiple sites is highly feasible and has the potential to improve accuracy of TMB panels as a companion diagnostic test. We demonstrate similar TMB values across primary and metastatic sites, however 3 out of 10 samples displayed inter-tumoural heterogeneity that would alter clinical management.

Patient-matched FBC and SBC analysis revealed that only a minority of patients exhibited common gene variants between the first and second tumor. Further analysis using larger cohorts preferably using single cell analyses to account for clonality, might better select patients with true recurrences and thereby better inform the decision-making process.

We found that TMB-High is associated with decreased risk of progression and with an improved PFS and OS. Furthermore, a subgroup of OCCC with mutations in either the ARID1A and/or PIK3CA genes had a significantly impaired prognosis compared to the undetermined subgroup in analyses adjusted for stage.

Our results showed that tissue and blood TMB, MAF, and specific tissue mutations were associated to the outcome of MPM patients and could be used as predictive biomarkers. Despite the limitations of this preliminary data, this study opens the door for the application of molecular profiling to identify longer survivors in patients resected MPM.

Conclusions Although we found a wide range of molecular alterations in LR, a minority of patients had concordant mutational profiles between PT and LR. These findings, if confirmed in larger studies, may better guide the choice of therapy after LR excision.

ACC showed less PD-L1 expression in tumor cells and the lowest infiltration of immune cells in both the tumor and stroma compared with other pathological types. These results suggest that the TIME of ACC is the so-called immune desert type, which may in turn explain the mechanisms of the poor response to immune check point inhibitors seen in clinical trials.

Background: Tumor Mutational Burden (TMB), defined as the number of somatic mutations per megabase (mut/Mb), can predict the efficacy of immunotherapy, which led to FDA approval of pembrolizumab for TMB-high (≥10 mut/Mb) tumors... High TMB mostly identifies patients from specific PDAC-subsets such as LTS (MSS) and MSI-high cases. Their microenvironment displays strong anti-tumor immune response, mediated by increased DC counts, which have the capacity to initiate and regulate T cell responses, as well as CD3+CD4+FOXP3-T cells, known to exhibit direct cytotoxicity against tumor cells as well as potentiate the DCs. TMB-high PDACs frequently harbor other actionable alterations, such as defective mismatch repair (MSI) and DNA Damage Response and Repair (ARID1A), as well as ERBB3-alterations.

In 2020, pembrolizumab gained FDA approval for use in advanced solid tumors with TMB ≥10 mutations/megabase (mt/Mb), though consensus guidelines for meaningful treatment thresholds are lacking within and between tumor types... We demonstrated good overall correlation of the OTML assay to the FM/Tempus and TSO panels; however, variation in TMB results led to differing classification of TMB status in 15% of validated samples. Specific therapy-informing thresholds could be impacted by testing platform.

"This study showed that the ddPCR Microsatellite Instability Assay can be used reliably for MSI assessment in colorectal cancer sam- ples and demonstrated a good correlation between MSI and TMB status."

"TMB-H PCs display improved anti-tumour immunity mediated by increased DC numbers, which have the capacity to ini- tiate and regulate T cell responses, and increased counts of CD3+ CD4+FOXP3-T cells, known to exhibit direct cytotoxicity against tumour cells as well as potentiate the DC. Moreover, CD20+ B cells and DC can prime T cells to target tumour cells due to antigen pre- sentation. These results partially explain the improved survival of TMB-H patients and suggest that they might be good candidates for immunotherapy."

Both panels exhibited robust analytical performances for TMB assessment, with stronger concordances in patients with negative PD-L1 expression. TSO500 showed a higher inter-laboratory reproducibility. The cut-offs for each assay were lowered to optimal overlap with FO.

The TMB estimated by OMLA correlated more strongly with the WES-derived TMB comparing with F1 . TMB estimated by OMLA was correlated with PFS and OS in NSCLC patients treated with ICIs . Prospective clinical trials are needed to determine whether TMB estimated by OMLA is a biomarker for ICI.

High TMB was associated with unfavorable clinical outcome in patients with lung adenocarcinoma treated with EGFR-TKIs. Although further large-scaled studies are required, our data suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and may constitute a distinct subgroup warranting tailored therapeutic approach in this clinical setting.