Regulatory implications of ctDNA in immuno-oncology for solid tumors

Vellanki, Paz J.; Ghosh, Soma; Pathak, Anand; Fusco, Michael; Bloomquist, Erik; Tang, Shenghui; Singh, Harpreet; Philip, Reena; Pazdur, Richard; Beaver, Julia A.

doi:10.1136/jitc-2022-005344

Cited by 22 publications

(11 citation statements)

References 81 publications

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“…28 There is a lack of standardization in pTMB assays across different platforms, and pTMB has not been approved as a biomarker for response to ICIs, in contrast to tissue TMB. 29 Patients without LM had longer intervals from diagnosis to study entry, consistent with better OS observed for this group of patients in this analysis.…”

Section: Discussionsupporting

confidence: 84%

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Chen,

Loree,

Titmuss

et al. 2023

JAMA Netw Open

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ImportanceImmune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair–proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM).ObjectiveTo investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer.Design, Setting, and ParticipantsIn this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments.InterventionDurvalumab plus tremelimumab or best supportive care.Main Outcomes and MeasuresHazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR).ResultsOf 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM.Conclusions and RelevanceIn this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

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Section: Discussionsupporting

confidence: 84%

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Chen,

Loree,

Titmuss

et al. 2023

JAMA Netw Open

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“…Although promising, there are several challenges to using ctDNA to monitor treatment response 114 . One challenge is the amount of ctDNA in the blood can vary widely between patients, and it can be difficult to detect at low levels 112 .…”

Section: Leverage Alternative Methods and Data To Enable Efficient De...mentioning

confidence: 99%

“…27 Although promising, there are several challenges to using ctDNA to monitor treatment response. 114 One challenge is the amount of ctDNA in the blood can vary widely between patients, and it can be difficult to detect at low levels. 112 Additionally, ctDNA may not accurately represent the full spectrum of genetic changes present in the tumor, as the ctDNA may only come from certain tumor subclones.…”

Section: Ctdna: Longitudinal and Mechanistic Model To Inform Dose Opt...mentioning

confidence: 99%

Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development

Gao,

Liu,

Shtylla

et al. 2024

CPT Pharmacom & Syst Pharma

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Project Optimus is a U.S. Food and Drug Administration Oncology Center of Excellence initiative aimed at reforming the dose selection and optimization paradigm in oncology drug development. This project seeks to bring together pharmaceutical companies, international regulatory agencies, academic institutions, patient advocates, and other stakeholders. While there is much promise in this initiative, there are several challenges that need to be addressed, including multi‐dimensionality of the dose optimization problem in oncology, the heterogeneity of cancer and patients, importance of evaluating long‐term tolerability beyond dose‐limiting toxicities, and the lack of reliable biomarkers for long‐term efficacy. Through the lens of Totality of Evidence (ToE) and with the mindset of model‐informed drug development (MIDD), we offer insights into dose optimization by building a quantitative knowledge base integrating diverse sources of data and leveraging quantitative modeling tools to build evidence for drug dosage considering exposure, disease biology, efficacy, toxicity, and patient factors. We believe that rational dose optimization can be achieved in oncology drug development, improving patient outcomes by maximizing therapeutic benefit while minimizing toxicity.

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“…To date, the FDA has approved several ctDNA-based companion diagnostic assays for the safe and effective use of various targeted therapies, mainly in metastatic tumors[ 83 ]. These indications include PCR-based techniques for detecting EGFR or PIK3CA alterations in NSCLC and breast cancer, respectively, as well as the use of next-generation sequencing (NGS) platforms in various cancers, such as metastatic breast, prostate, lung, or ovarian carcinomas.…”

Section: Types Of Determination and Technical Foundationsmentioning

confidence: 99%

Liquid biopsy for gastric cancer: Techniques, applications, and future directions

Díaz del Arco,

Fernández Aceñero,

Ortega Medina

2024

World J Gastroenterol

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After the study of circulating tumor cells in blood through liquid biopsy (LB), this technique has evolved to encompass the analysis of multiple materials originating from the tumor, such as nucleic acids, extracellular vesicles, tumor-educated platelets, and other metabolites. Additionally, research has extended to include the examination of samples other than blood or plasma, such as saliva, gastric juice, urine, or stool. LB techniques are diverse, intricate, and variable. They must be highly sensitive, and pre-analytical, patient, and tumor-related factors significantly influence the detection threshold, diagnostic method selection, and potential results. Consequently, the implementation of LB in clinical practice still faces several challenges. The potential applications of LB range from early cancer detection to guiding targeted therapy or immunotherapy in both early and advanced cancer cases, monitoring treatment response, early identification of relapses, or assessing patient risk. On the other hand, gastric cancer (GC) is a disease often diagnosed at advanced stages. Despite recent advances in molecular understanding, the currently available treatment options have not substantially improved the prognosis for many of these patients. The application of LB in GC could be highly valuable as a non-invasive method for early diagnosis and for enhancing the management and outcomes of these patients. In this comprehensive review, from a pathologist’s perspective, we provide an overview of the main options available in LB, delve into the fundamental principles of the most studied techniques, explore the potential utility of LB application in the context of GC, and address the obstacles that need to be overcome in the future to make this innovative technique a game-changer in cancer diagnosis and treatment within clinical practice.

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Regulatory implications of ctDNA in immuno-oncology for solid tumors

Cited by 22 publications

References 81 publications

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Realizing the promise of Project Optimus: Challenges and emerging opportunities for dose optimization in oncology drug development

Liquid biopsy for gastric cancer: Techniques, applications, and future directions

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