Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-analysis of Clinical Trials Leading to FDA Approval

Jardim, Denis Leonardo Fontes; Schwaederlé, Maria; Wei, Caimiao; Lee, John; Hong, David S.; Eggermont, Alexander M.M.; Schilsky, Richard L.; Mendelsohn, John; Lazar, Vladimir; Kurzrock, Razelle

doi:10.1093/jnci/djv253

Cited by 142 publications

(59 citation statements)

References 40 publications

(62 reference statements)

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“…Accumulating evidence suggests that, amongst patients with refractory cancers, a biomarker-based, personalized approach that matches patients with therapies based on specific genomic or protein markers may be able to improve clinical outcome (10–14). Herein, we report the genomic alterations identified in 442 patients with CUP using targeted NGS that evaluated ctDNA from patient plasma.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, patients could potentially be matched to genomically targeted therapy or to immunotherapy or both, as demonstrated by our responding patient who received both a MEK and a checkpoint inhibitor because of the presence of a KRAS and a mismatch repair gene alteration (Figure 4). Previous literature suggests that biomarker-based, matched targeted therapy can improve clinical outcome (10–14). Our current report indicates that the non-invasive liquid biopsy approach merits investigation in next generation clinical trials of cancer of unknown primary.…”

Section: Discussionmentioning

confidence: 99%

“…Amongst refractory malignancies, a biomarker-based (personalized) approach matching patients with drugs has shown efficacy (10–14). Further understanding of the underlying genomic alterations among patients with CUP may also prove useful.…”

Section: Introductionmentioning

confidence: 99%

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Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

et al. 2017

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Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated interrogated 54–70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66%, ≥ 1 characterized alteration(s) excluding variants of unknown significance. TP53-associated genes were most commonly altered (37.8%) followed by genes involved in the MAPK pathway (31.2%), PI3K signaling (18.1%) and the cell cycle machinery (10.4%). Distinct genomic profiles were observed in 87.9% of CUP cases with 99.7% exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of non-invasive liquid biopsies in next-generation clinical trials.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

et al. 2017

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“…Accumulating evidence has suggested that the matched targeted therapy approach can demonstrate better clinical outcomes than a nonmatched approach, but this implies the need to select patients for the relevant aberration. 34–37 Wagner et al 21 showed that responses with MK-8242 (MDM2 inhibitor) were exclusively observed in patients with liposarcoma (RR, 11.1% [three or 27]) whose molecular hallmark includes MDM2 amplification 5 (nonliposarcoma; RR, 0% [zero of 14]). On the other hand, even in a disease such as liposarcoma where > 60% of patients have MDM2 amplification, the RR is relatively low, which may be due to, as mentioned previously, the presence of co-alterations.…”

Section: Discussionmentioning

confidence: 99%

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Kato

Ross

Gay

et al. 2018

JCO Precision Oncology

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Purpose MDM2 amplification can promote tumorigenesis directly or indirectly through p53 inhibition. MDM2 has increasing clinical relevance because inhibitors are under evaluation in clinical trials, and MDM2 amplification is a possible genomic correlate of accelerated progression, known as hyperprogression, after anti–PD-1/PD-L1 immunotherapy. We used next-generation sequencing (NGS) to ascertain MDM2 amplification status across a large number of diverse cancers. Methods We interrogated the molecular profiles of 102,878 patients with diverse malignancies for MDM2 amplification and co-altered genes using clinical-grade NGS (182 to 465 genes). Results MDM2 amplification occurred in 3.5% of patients (3,650 of 102,878). The majority of tumor types had a small subset of patients with MDM2 amplification. Most of these patients (99.0% [3,613/3,650]) had co-alterations that accompanied MDM2 amplification. Various pathways, including those related to tyrosine kinase (37.9% [1,385 of 3,650]), PI3K signaling (25.4% [926 of 3,650]), TP53 (24.9% [910 of 3,650]), and MAPK signaling (23.6% [863 of 3,650]), were involved. Although infrequent, mismatch repair genes and PD-L1 amplification also were co-altered (2.2% [79 of 3,650]). Most patients (97.6% [3,563 of 3,650]) had one or more co-alterations potentially targetable with either a Food and Drug Administration–approved or investigational agent. MDM2 amplifications were less frequently associated with high tumor mutation burden compared with the MDM2 wild-type population (2.9% v 6.5%; P < .001). An illustrative patient who harbored MDM2 amplification and experienced hyperprogression with an immune checkpoint inhibitor is presented. Conclusion MDM2 amplification was found in 3.5% of 102,878 patients, 97.6% of whom harbored genomic co-alterations that were potentially targetable. This study suggests that a small subset of most tumor types have MDM2 amplification as well as pharmacologically tractable co-alterations.

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“…Moreover, in several of the trials using targeted agents alone, response rates were quite low, suggesting the importance of biomarker selection. Indeed, recent large meta-analyses (~70,000 patients) suggest that matched targeted therapy results in improved outcomes, but that targeted therapy without matching often has low or negligible salutary effects [67, 68]. Further, the PFS in phase I trials of mainly matched targeted agents or local therapies in patients with advanced, refractory GBCA and cholangiocarcinoma were similar to that of the first, second, and last-line therapy with FDA-approved agents [3].…”

Section: Overview Of Clinical Trials With Targeted Agentsmentioning

confidence: 99%

Genomics of gallbladder cancer: the case for biomarker-driven clinical trial design

Sicklick

Fanta

Shimabukuro

et al. 2016

Cancer Metastasis Rev

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Background and aims Gallbladder carcinoma is a rare, aggressive malignancy of the biliary tract associated with a poor prognosis. Despite the deployment of targeted therapies that have demonstrated marked survival benefits in many tumor types, traditional cytotoxic chemotherapy has remained the mainstay of treatment for unresectable and metastatic gall-bladder cancer. Methods Systematic review of ongoing and prior clinical studies shows a paucity of biomarker-driven therapeutic trials using targeted agents in gallbladder cancer. In fact, over the past 6 years, of the 38 therapeutic biliary tract protocols listed on clinicaltrials.gov, only 6 (21 %) utilized targeted therapies based upon tumor biomarkers or genomics. Now that we have entered the era of next-generation sequencing and precision medicine, we are beginning to identify common and specific genetic alterations in gallbladder carcinomas. Results A review of the literature reveals alterations in ARID1A, BRAF, CDKN2A/B, EGFR, ERBB2-4, HKN-RAS, PIK3CA, PBRM1, and TP53. Given the widespread use of tumor genomic profiling and the fact that most of the aforementioned alterations are pharmacologically tractable, these observations suggest the potential for new therapeutic strategies in this aggressive malignancy. Conclusions Taken together, further understanding of the genomic landscape of gallbladder cancer coupled with biomarker-driven clinical trials that match therapies to targets are urgently needed.

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Impact of a Biomarker-Based Strategy on Oncology Drug Development: A Meta-analysis of Clinical Trials Leading to FDA Approval

Abstract: Background: In order to ascertain the impact of a biomarker-based (personalized) strategy, we compared outcomes between US Food and Drug Administration (FDA)-approved cancer treatments that were studied with and without such a selection rationale.

Cited by 142 publications

References 40 publications

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary

Analysis ofMDM2Amplification: Next-Generation Sequencing of Patients With Diverse Malignancies

Genomics of gallbladder cancer: the case for biomarker-driven clinical trial design

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