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Tumor burden as measured by cell free DNA

A PD-L1, cancer technology, applied in the direction of anti-tumor drugs, measuring devices, microbial measurement/inspection, etc., can solve the problems that cannot be effectively eliminated

Inactive Publication Date: 2020-03-24
免疫医疗有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Under normal conditions, cell-free DNA (cfDNA) is only observed in low amounts in the blood, but they are not effectively cleared in response to the onset of strenuous exercise, inflammation or disease

Method used

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  • Tumor burden as measured by cell free DNA
  • Tumor burden as measured by cell free DNA
  • Tumor burden as measured by cell free DNA

Examples

Experimental program
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example

[0136] Materials and methods

[0137] Patient samples. Plasma Samples Obtained from Patients Enrolled in a Phase 1 / 2 Clinical Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of an Anti-PD-L1 Antibody (Durvalumab) in Subjects with Advanced Solid Tumors . Plasma samples from 28 patients with lung cancer (non-small cell lung cancer) and 29 patients with bladder cancer were obtained during patient screening before treatment (Durvalumab at 10.0 mg / kg) and were obtained at It was reacquired at week 8 after 4 treatment doses (given at week 6).

[0138] ctDNA assay / NGS. Next-generation sequencing and ctDNA testing were performed using the Guardant360 Gene Panel (Guardant Health, Inc., Redwood City, CA). The panel includes 73 genes and provides mutant allele frequencies for each detected SNV, indel, and fusion, and copy number for each detected amplification.

example 1

[0139] Example 1: Reduced ctDNA mean variant allele frequencies observed in reactive NSCLC patients

[0140] Analysis of patient samples confirmed that ctDNA was detectable in cell-free DNA isolated from plasma. Analysis of samples obtained from 116 patients during screening identified variants in 96% of samples (111 / 116), with several variants frequently observed, including TP53 (69% of samples), PIK3CA (29% of samples), EGFR (28% of samples), KRAS (24% of samples) and CDKN2A (16% of samples). see figure 1 .

[0141] Changes in mean variant allele frequency (VAF) over the course of treatment correlated with disease progression. After 4 doses / treatment, responding patients (PR) had significantly reduced (-1.6%, p=0.008) ctDNA VAF, while non-responders had an observable increase in mean VAF (+1.4%, p=0.05). see figure 2 , which included SNVs and indels with an allele frequency ≥0.3% at screening, and depicts the probability of PFS and probability of OS for patients who e...

example 2

[0145] Example 2: Reduced ctDNA mutational burden observed in reactive NSCLC patients

[0146] In addition to the reduction in mean VAF discussed in Example 1, after 8 weeks of treatment, when compared to non-responding (PD / SD) patients (mean difference +1.6, p=0.036, ci(95%)=0.1,3.1) , Responsive patients (PR) exhibited a significant reduction in mutation burden as determined by total mutation counts (mean difference -5.3, p=0.037, and ci (95%)=-10.2, -0.4). see Figure 4 , which plots the total mutation counts at screening (pre-dose) and after dose 4 at week 6 (post-dose).

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Abstract

Disclosed are methods for treating cancer (e.g., solid tumor cancers, lung cancer, bladder head and neck cancer) with an anti-PD-Ll antibody in a patient identified as being responsive to anti- PD-Llantibody therapy by detecting a mutation in one or more disclosed circulating tumor DNA (ctDNA) markers. Also disclosed are methods for determining the efficacy of anti-PD-Ll therapeutic antibody treatment in a patient having lung cancer or bladder cancer comprising detecting variant allele frequency in ctDNA in plasma samples and determining the difference of the variant allele frequency in ctDNAbetween the first and at least second plasma samples, wherein a decrease in the variant allele frequency in the at least second plasma sample relative to the first plasma sample identifies the anti-PD-Ll antibody treatment as effective. The disclosure also provides methods of identifying a subject having a cancer responsive to a therapy comprising an anti-PD-Ll antibody by detecting the expression of a mutation in one or more circulating tumor DNA (ctDNA) markers.

Description

Background technique [0001] Despite consistent therapeutic advances, such as immunophysiological therapies, cancer remains a leading cause of death. Assessment of a patient's response to therapeutic intervention can be slow and is usually determined by measuring changes in tumor size several months after initiation of treatment. The application of next-generation sequencing (NGS) technologies in the diagnosis, prognosis, and treatment of cancer allows for more rapid and patient-specific assessment of disease state and treatment options. Under normal conditions, cell-free DNA (cfDNA) is only observed in low amounts in the blood, but they are not effectively cleared in response to strenuous exercise, inflammation or the onset of disease. For example, circulating DNA derived from cancer cells represents a unique and measurable component of cfDNA in cancer patients. Circulating tumor DNA (ctDNA) fractions of cfDNA can be used to classify tumors and cancer diseases, such as strat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/395A61P35/00C12Q1/6886G01N33/574
CPCA61P35/00A61K2039/55C12Q2600/156C07K16/2827C12Q1/6886A61K2039/505C12Q2600/106C07K2317/21A61K2039/545
Inventor B.希格斯K.拉纳德C.拜斯P.布罗豪恩M.库齐奥拉R.拉加
Owner 免疫医疗有限责任公司
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