Blood tumor mutational burden (bTMB) and tumor PD-L1 as predictive biomarkers of survival in MYSTIC: First-line durvalumab (D) ± tremelimumab (T) versus chemotherapy (CT) in metastatic (m) NSCLC.

9016 Background: MYSTIC, an open-label, Ph3 trial of first-line D (anti-PD-L1) ± T (anti-CTLA-4) vs platinum-based CT, showed an improvement in OS with D vs CT in pts with tumor cell PD-L1 expression ≥25% (PD-L1 TC ≥25%; HR 0.76 [97.54% CI 0.56–1.02], p = 0.036). Exploratory analyses showed bTMB was a predictive biomarker for OS with D±T vs CT. We report further exploratory analyses of OS according to PD-L1 and bTMB. Methods: Immunotherapy/CT-naïve pts with mNSCLC were randomized (1:1:1) to D, D+T or CT. bTMB levels (mut/Mb) were evaluated with the GuardantOMNI platform (Guardant Health), and PD-L1 TC expression with the VENTANA PD-L1 (SP263) IHC assay. Results: D improved OS vs CT in pts with PD-L1 TC ≥25% across bTMB levels (PD-L1 TC ≥25%/bTMB≥20 HR 0.79 [95% CI 0.45, 1.39]; PD-L1 TC ≥25%/bTMB < 20 HR 0.64 [95% CI 0.45, 0.90]). In contrast, D+T improved OS vs CT in pts with bTMB≥20 across different PD-L1 TC expression levels (Table; PD-L1 TC ≥25%/bTMB≥20 HR 0.44 [95% CI 0.23, 0.84]; PD-L1 TC < 1%/bTMB≥20 HR 0.42 [95% CI 0.17, 0.97]). Additional cutoffs and outcomes in subgroups defined by both biomarkers will be presented. Conclusions: These exploratory analyses from MYSTIC support PD-L1 TC expression as an appropriate predictive biomarker for OS with D vs CT, while suggesting bTMB as a predictive biomarker for OS with D+T in mNSCLC. These biomarkers appear to be independent and both may be important for mNSCLC treatment decisions. Interpretation of these data may be limited by small sample sizes; further investigations are warranted. Clinical trial information: NCT02453282. [Table: see text]

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B-F1RST: Assessment of novel blood-based biomarkers in patients with first-line advanced or metastatic NSCLC receiving atezolizumab monotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.tps9103 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. TPS9103-TPS9103

Author(s):

Edward S. Kim ◽

Mark A. Socinski ◽

Shaker R. Dakhil ◽

Niklas J. Mackler ◽

Nadeem Ikhlaque ◽

...

Keyword(s):

Clinical Trial ◽

Locally Advanced ◽

Predictive Biomarkers ◽

The United States ◽

Phase Iii ◽

First Line ◽

Open Label ◽

Eligibility Criteria ◽

Metastatic Nsclc ◽

Cell Immunity

TPS9103 Background: The anti–PD-L1 monoclonal antibody atezolizumab inhibits the interaction of PD-L1 with its receptors PD-1 and B7.1, thereby restoring T-cell immunity. In the Phase III OAK study, patients with previously treated advanced NSCLC had improved mOS in the atezolizumab arm (13.8 mo) vs the docetaxel arm (9.6 mo) (HR 0.73 [95%CI: 0.62, 0.87]; P= 0.0003), irrespective of PD-L1 expression or histology. A Phase III clinical trial of atezolizumab monotherapy for first-line, PD-L1–selected patients with NSCLC is underway; however, first-line atezolizumab monotherapy for NSCLC treatment in a biomarker-unselected population has not yet been investigated. Current assays to measure PD-L1 expression by IHC require tumor biopsies, which can be difficult to obtain in some patients. Novel blood-based biomarkers will be evaluated retrospectively in B-F1RST (Blood-First-Line Ready Screening Trial) in patients receiving atezolizumab monotherapy in first-line NSCLC. Methods: A Phase II, open-label, single-arm study, B-F1RST (NCT02848651), will evaluate the efficacy and safety of atezolizumab in PD-L1–unselected patients with first-line locally advanced or metastatic NSCLC. Eligibility criteria include stage IIIB-IVB NSCLC, ECOG PS 0-1, measurable disease per RECIST v1.1 and adequate hematologic and end-organ function. Exclusion criteria include the presence of EGFRmutations or ALKfusions, active CNS metastases and prior immunotherapy for NSCLC. Patients will receive atezolizumab 1200 mg IV q3w until disease progression or loss of clinical benefit. Prospective collection of blood samples is mandatory; collection of tissue biopsies is optional. The co-primary endpoints of the study are investigator-assessed ORR per RECIST v1.1 for the efficacy objective and PFS per RECIST v1.1 for evaluating blood-based predictive biomarkers for atezolizumab efficacy, including mutation status. Approximately 150 patients will be enrolled at 25 or more centers in the United States. Clinical trial information: NCT02848651.

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Tumor mutational burden assessment in non-small-cell lung cancer samples: results from the TMB2 harmonization project comparing three NGS panels

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001904 ◽

2021 ◽

Vol 9 (5) ◽

pp. e001904

Author(s):

Javier Ramos-Paradas ◽

Susana Hernández-Prieto ◽

David Lora ◽

Elena Sanchez ◽

Aranzazu Rosado ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Predictive Value ◽

Predictive Biomarker ◽

Small Cell ◽

Small Cell Lung ◽

Mutational Burden ◽

Reproducibility Study ◽

Tumor Mutational Burden

BackgroundTumor mutational burden (TMB) is a recently proposed predictive biomarker for immunotherapy in solid tumors, including non-small cell lung cancer (NSCLC). Available assays for TMB determination differ in horizontal coverage, gene content and algorithms, leading to discrepancies in results, impacting patient selection. A harmonization study of TMB assessment with available assays in a cohort of patients with NSCLC is urgently needed.MethodsWe evaluated the TMB assessment obtained with two marketed next generation sequencing panels: TruSight Oncology 500 (TSO500) and Oncomine Tumor Mutation Load (OTML) versus a reference assay (Foundation One, FO) in 96 NSCLC samples. Additionally, we studied the level of agreement among the three methods with respect to PD-L1 expression in tumors, checked the level of different immune infiltrates versus TMB, and performed an inter-laboratory reproducibility study. Finally, adjusted cut-off values were determined.ResultsBoth panels showed strong agreement with FO, with concordance correlation coefficients (CCC) of 0.933 (95% CI 0.908 to 0.959) for TSO500 and 0.881 (95% CI 0.840 to 0.922) for OTML. The corresponding CCCs were 0.951 (TSO500-FO) and 0.919 (OTML-FO) in tumors with <1% of cells expressing PD-L1 (PD-L1<1%; N=55), and 0.861 (TSO500-FO) and 0.722 (OTML-FO) in tumors with PD-L1≥1% (N=41). Inter-laboratory reproducibility analyses showed higher reproducibility with TSO500. No significant differences were found in terms of immune infiltration versus TMB. Adjusted cut-off values corresponding to 10 muts/Mb with FO needed to be lowered to 7.847 muts/Mb (TSO500) and 8.380 muts/Mb (OTML) to ensure a sensitivity >88%. With these cut-offs, the positive predictive value was 78.57% (95% CI 67.82 to 89.32) and the negative predictive value was 87.50% (95% CI 77.25 to 97.75) for TSO500, while for OTML they were 73.33% (95% CI 62.14 to 84.52) and 86.11% (95% CI 74.81 to 97.41), respectively.ConclusionsBoth 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.

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The prognostic impact of tumor mutational burden (TMB) in the first-line management of advanced non-oncogene addicted non-small-cell lung cancer (NSCLC): a systematic review and meta-analysis of randomized controlled trials

ESMO Open ◽

10.1016/j.esmoop.2021.100124 ◽

2021 ◽

Vol 6 (3) ◽

pp. 100124

Author(s):

A. Galvano ◽

V. Gristina ◽

U. Malapelle ◽

P. Pisapia ◽

F. Pepe ◽

...

Keyword(s):

Lung Cancer ◽

Meta Analysis ◽

Small Cell ◽

Controlled Trials ◽

Prognostic Impact ◽

Small Cell Lung ◽

First Line ◽

Randomized Controlled ◽

Mutational Burden ◽

Tumor Mutational Burden

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Harnessing biomarkers of response to improve therapy selection in esophago-gastric adenocarcinoma

Pharmacogenomics ◽

10.2217/pgs-2020-0090 ◽

2021 ◽

Author(s):

Caroline YK Fong ◽

Ian Chau

Keyword(s):

Patient Outcomes ◽

Tumor Heterogeneity ◽

Systemic Treatment ◽

Predictive Biomarkers ◽

Predictive Biomarker ◽

Molecular Characteristics ◽

Precision Oncology ◽

First Line ◽

Clinical Strategies ◽

Line Chemotherapy

Advanced esophago-gastric (OG) adenocarcinomas have a high mortality rate and new therapeutic options are urgently required. Despite recent advances in understanding the molecular characteristics of OG cancers, tumor heterogeneity poses a challenge in developing new therapeutics capable of improving patient outcomes. Consequently, chemotherapy remains the mainstay of systemic treatment, with the HER2 being the only predictive biomarker routinely targeted in clinical practice. Recent data indicate that immunotherapy will be incorporated into first-line chemotherapy, but further research is required to refine patient selection. This review will summarize the clinical strategies being evaluated to utilize our knowledge of predictive biomarkers with reference to novel therapeutics, and discuss the barriers to implementing precision oncology in OG adenocarcinoma.

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Combining radiation therapy with anti-PD-1 for patients with advanced hepatocellular carcinoma: An open-label, single-center, single-arm clinical study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16117 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16117-e16117

Author(s):

Jian-Xu Li ◽

Ting-Shi Su ◽

Xiao-Feng Lin ◽

Yi-Tian Chen ◽

Shi-Xiong Liang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Clinical Trial ◽

Radiation Therapy ◽

Clinical Study ◽

Cancer Staging ◽

Advanced Hepatocellular Carcinoma ◽

Single Center ◽

Open Label ◽

Grade 3 ◽

Clinical Trial Information

e16117 Combining radiation therapy with anti-PD-1 for patients with advanced hepatocellular carcinoma: an open-label, single-center, single-arm clinical study Jian-Xu Li, Ting-Shi Su, Xiao-Feng Lin, Yi-Tian Chen, Shi-Xiong Liang, Bang-De Xiang; Guangxi Medical University Cancer Hospital, Nanning, China Abstract Research Funding: Jiangsu Hengrui Pharmaceuticals Co., Ltd., Shanghai, China. Guangxi Medical and Health Appropriate Technology Development and Application Project (No. S2019039), Guangxi, China. Background: Based on the results of recent studies, the PD-1 monoclonal antibodies have been approved to treat the patients with advanced hepatocellular carcinoma (HCC) by the FDA. Radiation therapy (RT) can enhance responsiveness to PD-1 monoclonal antibody by potential mechanisms. A phase Ⅱa study was conducted to assess the safety and the efficacy of combining RT with anti-PD-1 for patients with advanced hepatocellular carcinoma. Methods: Patients with advanced HCC were eligible. Stereotactic body radiation therapy (SBRT) were adopted, and the dose of radiation were Dt-PGTV 30-50 Gy/10fractions. Camrelizumab (200mg) were given intravenously every 3 weeks since the first day of RT until disease progression, or intolerable toxicity. Adverse events (AEs) and objective response rate (ORR) were summarized to assess the safety and efficacy. Results: From April 2020 to November 2020, 17 patients were enrolled (median age 54, range 32-69). 15 (88%) patients were male. 14 (82%) had ECOG performance score of 0. All the patients had Child-Pugh score A. 16 patients staged as Barcelona Clinic Liver Cancer staging C or China Liver Cancer staging Ⅲ. Extrahepatic metastases were identified in 11 (65%) patients. 13 (77%) patients were Hepatitis B virus infected. 15 (88%) patients had previously 2 lines or more chemotherapy. 9 (53%) patients had Alpha-fetoprotein level≥400 ng/ml. The ORR was 47%. The best response assessed by RECIST 1.1 was partial response (8 patients). Four patients had grade 3 immune-related adverse events (irAEs), including increased aspartate aminotransferase and alanine transaminase (n =1)，decreased hemoglobin (n =1)，decreased platelet count (n =1)，decreased neutrophil count (n =1). All grade 3 irAEs were mitigated with proper treatment. None treatment-related deaths occurred. Conclusions: In this study, RT combined with anti-PD-1 had an acceptable safety profile and indicated an effective treatment option in patients with unresectable HCC. Clinical trial information: NCT04193696. Clinical trial information: NCT04193696.

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Update results from ALTER-C-001: Efficacy and safety of anlotinib plus XELOX regimen as first-line treatment followed by maintenance monotherapy of anlotinib for patients with mCRC-A single-arm, multicenter, phase Ⅱ clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e15550 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e15550-e15550

Author(s):

Jin Yan ◽

Yunwei Han ◽

Li Zhang ◽

Yongdong Jin ◽

Hao Sun

Keyword(s):

Clinical Trial ◽

Adverse Events ◽

Performance Status ◽

Phase Iii ◽

Line Treatment ◽

First Line ◽

Open Label ◽

Ecog Performance Status ◽

Multicenter Phase ◽

First Line Treatment

e15550 Background: The combination of anti-VEGF or anti-EGFR targeted drugs with chemotherapy is the standard first-line therapy for metastatic colorectal cancer (mCRC), and the followed maintenance treatment is an optional approach to balance the efficacy and toxicity. However, studies regarding the maintenance strategies based on antiangiogenic TKIs are limited currently. Anlotinib, a novel oral multi-target TKI which can inhibit both tumor angiogenesis and tumor cell proliferation simultaneously, substantially prolonged the PFS with manageable toxicity for refractory mCRC in the phase III ALTER0703 clinical trial. Here we report an update on the effectiveness and safety of anlotinib plus XELOX as first-line treatment followed by anlotinib monotherapy for mCRC. Methods: In this open label, single-arm, multicenter phase II clinical trial, 53 mCRC patients without prior systemic treated, aged 18-75 and an ECOG performance status of 0 or 1 were planned to recruit. Eligible patients received capecitabine (1000 mg/m2, po, d1-14, q3w) and oxaliplatin (130 mg/m2, iv, d1, q3w) plus anlotinib (10mg, po, d1̃14, q3w) treatment for 6 cycles. After 6 cycles of inducing therapy, patients would receive anlotinib (12mg, po, d1̃14, q3w) as maintenance therapy until disease progression or intolerable adverse events (AEs). The primary endpoint was PFS; Secondary endpoints included ORR, DCR, DOR and safety. Results: By the data analysis cutoff date of January 22, 2021, a total of 18 patients were enrolled, of which 12 patients were available for efficacy assessment. In best overall response assessment, there were 50.0% PR (6/12), 33.3% SD (4/12) and 16.7% PD (2/12). The ORR was 50.0% (95% CI, 21.1-78.9%) and DCR was 83.3% (95% CI, 51.5-97.9%). The longest duration of treatment was 8.8 months and the response was still ongoing. The median PFS was not reached. The most common treatment related adverse events (TRAEs) of any grade (≥20%) were leukopenia, hypertension, neutropenia, diarrhea, fatigue, hypertriglyceridemia. Grade 3/4 TRAEs included hypertension (22.2%), hypertriglyceridemia (11.1%), lipase elevated (11.1%) and neutropenia (5.6%). No grade 5 AEs occurred. Conclusions: The update results suggested that anlotinib combined with XELOX as first line regimen followed by anlotinib monotherapy showed promising anti-tumor activity and manageable safety for patients with mCRC. And the conclusions needed to be confirmed in trials continued subsequently. Clinical trial information: ChiCTR1900028417.

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From Tumor Mutational Burden to Blood T Cell Receptor: Looking for the Best Predictive Biomarker in Lung Cancer Treated with Immunotherapy

Cancers ◽

10.3390/cancers12102974 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2974

Author(s):

Andrea Sesma ◽

Julián Pardo ◽

Mara Cruellas ◽

Eva M. Gálvez ◽

Marta Gascón ◽

...

Keyword(s):

Lung Cancer ◽

T Cell ◽

T Cell Receptor ◽

Checkpoint Inhibitors ◽

Predictive Biomarker ◽

Cell Receptor ◽

Mutational Burden ◽

Tcr Repertoire ◽

Tumor Mutational Burden ◽

Tumor Immunogenicity

Despite therapeutic advances, lung cancer (LC) is one of the leading causes of cancer morbidity and mortality worldwide. Recently, the treatment of advanced LC has experienced important changes in survival benefit due to immune checkpoint inhibitors (ICIs). However, overall response rates (ORR) remain low in unselected patients and a large proportion of patients undergo disease progression in the first weeks of treatment. Therefore, there is a need of biomarkers to identify patients who will benefit from ICIs. The programmed cell death ligand 1 (PD-L1) expression has been the first biomarker developed. However, its use as a robust predictive biomarker has been limited due to the variability of techniques used, with different antibodies and thresholds. In this context, tumor mutational burden (TMB) has emerged as an additional powerful biomarker based on the observation of successful response to ICIs in solid tumors with high TMB. TMB can be defined as the total number of nonsynonymous mutations per DNA megabases being a mechanism generating neoantigens conditioning the tumor immunogenicity and response to ICIs. However, the latest data provide conflicting results regarding its role as a biomarker. Moreover, considering the results of the recent data, the use of peripheral blood T cell receptor (TCR) repertoire could be a new predictive biomarker. This review summarises recent findings describing the clinical utility of TMB and TCRβ (TCRB) and concludes that immune, neontigen, and checkpoint targeted variables are required in combination for accurately identifying patients who most likely will benefit of ICIs.

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