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Evidence-Based Oncology October 2019

Medical World News

AJMC Staff
Managed care and clinical updates in cancer treatment.

New Liquid Biopsy Test Identifies Patients Who May Respond to Immune Checkpoint Blockade

A liquid biopsy test, developed by Personal Genome Diagnostics, was shown to possibly detect microsatellite instability (MSI) and tumor mutational burden (TMB), which may help determine which patients are likely to respond to immune checkpoint inhibitors, according to a September study published in the journal Clinical Cancer Research.1

In May 2017, the FDA approved the immune checkpoint inhibitor pembrolizumab, sold as Keytruda, for patients with unresectable or metastatic tumors that tested high for MSI (MSI-H) or mismatch repair deficiency (dMMR).Although this approval addressed the treatment of MSI-H or dMMR in these patients, detecting these conditions can be difficult.

Current MSI detection processes include tissue biopsies and technologies such as polymerase chain reaction–based amplification or next-generation sequencing. These approaches have been found to be complicated and contain sensitivity limitations, which can exclude patients whose tumor samples lack enough tissue for accurate testing. 

Study coauthors Andrew Georgiadis, MS, a scientist at Personal Genome Diagnostics, and Dung Le, MD, associate professor of oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, sought to evaluate the sensitivity and specificity of a liquid biopsy test that would help create an alternative for MSI detection and cater to patients affected by these complications. “A liquid biopsy test assessing MSI could reach a larger subset of patients, such as those where tissue is limited or where there are safety concerns around additional surgical intervention,” Georgiadis said.

The study included 61 patients with metastatic cancer and 163 plasma samples from healthy subjects. Investigators developed a 98 kb pan-cancer 58-gene panel, then employed a multifactorial error-correction method and a novel peak-finding algorithm to identify MSI frameshift alleles in the study group’s cell-free DNA. As the authors explained, MSI can be detected by measuring the length of altered microsatellite sequences in tumor DNA compared with normal DNA:

• Investigators flagged certain sequence data for error correction, then subjected data to the peak-finding algorithm that identified instability in the loci.

• If 20% or more of loci contained MSI, samples were classified as MSI-H. The liquid biopsy test produced a specificity of greater than 99% and a sensitivity of 78%, which speaks to its prowess for identifying MSI levels in patients.

Investigators then tested for TMB, in which next-generation sequencing data were processed, and variants were identified using VariantDx software. The threshold for identifying a high TMB in the analyzed tumors was set at 5 mutations in the targeted plasma panel. The liquid biopsy test produced similar results toward TMB to that of MSI as a specificity of greater than 99% was achieved, although the liquid biopsy’s sensitivity was lower, at 67%. The VariantDx test identified MSI-H in 18 of the 23 MSI-H patients (78.3%) and correctly detected the 6 microsatellite stable cases.

For patients treated with programmed cell death protein-1 blockade, a type of immune checkpoint blockade, MSI and high TMB levels in pretreatment plasma predicted progression-free survival (hazard ratios, 0.21 and 0.23; P = .001 and .003), the investigators found.

Le emphasized the potential of the liquid biopsy test to enhance MSI-H detection in more at-risk patients who can benefit from the immune checkpoint blockade. “If tests become more accessible, less expensive, and require fewer resources such as tissue acquisition and pathology resources, more patients could be tested,” Le said.

Study limitations included the small population of cancer patients analyzed. The authors noted that further research on a broader range of tumor types is warranted to confirm their results. 

References

1. Georgiadis A, Durham JN, Keefer LA, et al. Noninvasive detection of microsatellite instability and high tumor mutation burden in cancer patients treated with PD-1 blockade [published online September 10, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-1372.

2. FDA approves first cancer treatment for any solid tumor with a specific genetic feature [press release]. Silver Spring, MD: FDA Newsroom; May 23, 2017. www.fda.gov/news-events/press-announcements/fda-approves-first-cancer-treatment-any-solid-tumor-specific-genetic-feature. Accessed September 11, 2019.

 

Study Explores Brentuximab Vedotin Efficacy in Patients Expressing High CD30 Levels

Brentuximab vedotin (BV) performed acceptably in patients with high-CD30–expressing non-Hodgkin lymphoma (NHL), according to recent study results. Investigators sought to find out which patients will most likely benefit from using the agent.

The phase 2 trial enrolled relapsed or refractory high-CD30–expressing NHL, with BV administered intravenously at 1.8 mg/kg every 3 weeks. The primary end point was a disease control rate of more than 40%, consisting of complete response (CR), partial response (PR), or stable disease. BV, sold as Adcetris, has several FDA approvals, including for use in combination with chemotherapy for adults with certain types of peripheral T-cell lymphoma (PTCL) and for the treatment of adults with previously untreated stage III or IV classical Hodgkin lymphoma (HL), systemic anaplastic large cell lymphoma (ALCL) after failure of at least 1 prior multiagent chemotherapy regimen, and primary cutaneous anaplastic large cell lymphoma or CD30-expressing mycosis fungoides (MF).

The efficacy of BV was previously evaluated in various subtypes of NHL, including diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, PTCL, MF, and various cutaneous T-cell lymphomas. These studies enrolled patients with a wide range of CD30 expression levels, and their response rates were unrelated to the CD30 expression level of tumor cells.

High CD30 expression was defined as 30% or greater tumor cells positive for CD30 by immunohistochemistry. CD30 is uniformly expressed in HL and ALCL. The purpose of the study was to determine the overall disease control rate from BV administration among heavily pretreated relapsed or refractory patients with various subtypes of NHL, other than ALCL and HL. Because the study sample was based on CD30-positive tumor cells being equal to or greater than 30%, regardless of histologic subtype, patients with various subtypes of NHL, from DLBCL to MF, could enroll. High-CD30–expressing NHL patients (n = 33) were enrolled, except for those with ALCL.

The disease control rate was 48.5% (16 of 33), including 6 CRs and 6 PRs; 6 patients (4 CRs, 2 PRs) maintained their response over 16 completed cycles. Response to BV and survival were not associated with CD30 expression levels. Over a median of 29.2 months of follow-up, the median progression-free and overall survival rates were 1.9 months and 6.1 months, respectively. The most common adverse events were fever (39%), neutropenia (30%), fatigue (24%), and peripheral sensory neuropathy (27%).

In a post hoc analysis for the association of multiple myeloma oncogene 1 (MUM1) on treatment outcome, MUM1-negative patients showed a higher response (55.6%; 5 of 9) than MUM1-positive patients (13.3%; 2 of 15). BV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles, the researchers said, especially in MUM1-negative patients. 

Reference

Kim SJ, Yoon DH, Kim JS, et al. Efficacy of brentuximab vedotin in relapsed or refractory high-CD30–expressing non-Hodgkin lymphomas: results of a multicenter, open-labeled phase II trial [published online August 13, 2019]. Cancer Res Treat. doi: 10.4143/crt.2019.198.

 

New Treatment Can Benefit Patients With MM Refractory to Multiple Other Therapies

Patients with multiple myeloma (MM) whose disease is refractory to available treatments may have better a better response if they are treated with selinexor plus dexamethasone, according to a study published in the New England Journal of Medicine.1

Investigators from Mount Sinai found that patients taking the oral combination therapy saw a response within 2 months. Selinexor causes cancer cells to die by blocking the export of the cells’ protein and messenger RNA to the cytoplasm. “This study is meaningful for patients with multiple myeloma who haven’t had success on multiple other therapies,” the study’s first author Ajai Chari, MD, director of clinical research in the multiple myeloma program at the Tisch Cancer Institute at Mount Sinai, said in a statement. “An increasing number of patients have resistance to the standard drugs used in the treatment of multiple myeloma, and the overall survival in these patients is short, sometimes less than 3 months.”

Patients in the STORM Part 2 study had MM and had been treated previously with bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, glucocorticoids, and an alkylating agent. The patients had disease progression during treatment or within 60 days after completing treatment or had less than a 25% response to therapy. A total of 122 patients were included, with a median age of 65.2 years and a median disease duration of 6.6 years. The vast majority of patients (118; 97%) discontinued the treatment, with the most common reasons being disease progression and adverse events (AEs). However, 5 patients (4%) continued to receive treatment at the last date of follow-up, and another 34 (28%) discontinued treatment and remained in follow-up for long-term survival.

Approximately one-fourth (26%) of patients had a partial response (PR) or better. Of those, 2 patients had stringent complete responses, 6 had very good PRs, and 24 had PRs. However, 48 patients (39%) had stable disease and 26 (21%) had progressive disease or disease that could be not evaluated. The researchers found that the median progression-free survival was 3.7 months and the median overall survival (OS) was 8.6 months. Patients with a minimal response or better had a median OS of 15.6 months. Thrombocytopenia was the most common AE, occurring in 73% of the patients, followed by nausea in 72% and anemia in 67%. Thrombocytopenia was also the most common grade 3 or 4 AE (59%). AEs considered to be related to selinexor or dexamethasone led to 18% of patients discontinuing treatment. The authors reported that 16 patients died during the study from disease progression and another 12 from an AE, including 2 cases that were considered to be related to treatment.

“This study proved that a novel, first-in-class drug with a new mechanism of action can kill a patient’s cancer cells,” said the study’s senior author, Sundar Jagannath, MBBS, director of the multiple myeloma program and a professor of medicine (hematology and medical oncology) at the Tisch Cancer Institute. “This proved that the drug worked in patients who had exhausted every other treatment and who would have been placed on hospice care otherwise.” 

Reference

 
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