In the Literature – August 2015

August 2015, Vol 6, No 7 - In the Literature

In This Article

New Guideline on Using Biomarkers in Treatment Decisions in Metastatic Breast Cancer

The use of biomarkers to help guide treatment decisions is a topic of growing priority within the oncology community. Although multiple literature reviews conclude that using biomarkers in treatment decisions can improve health outcomes in patients with serious diseases, the integrity of the evidence is debatable. In an effort to provide reliable, evidence-based guidelines to practicing ­oncologists on the appropriate use of biomarker assay results to influence decisions about systemic therapy in women with breast cancer, the American Society of Clinical Oncology (ASCO) Expert Panel evaluated the evidence for biomarker use based on the assay’s analytic validity, clinical validity, and clinical utility (Van Poznak C, et al. J Clin Oncol. 2015 Jul 20. Epub ahead of print).

Using systematic reviews, meta-analyses, randomized controlled clinical trials, prospective-retrospective studies, and prospective comparative observational studies, the ASCO Expert Panel based their recommendations on biomarker use to guide treatment decisions on answers to 4 questions. Under what circumstances should metastases be biopsied to test for changes from the primary tumor with respect to endocrine receptor or HER2 status? Which additional tumor markers have demonstrated clinical utility to guide the initiation of systemic therapy or direct selection ­­of a new systemic therapy regimen in women with metastatic breast cancer and with endocrine receptor and HER2 status? Which additional tumor markers have demonstrated clinical utility to guide decisions on whether to switch to a different drug or regimen or to discontinue treatment in this patient population? What are the appropriate assays, timing, and frequency of measurement for tumor markers demonstrating clinical utility?

According to the panel, clinicians should retest for estrogen receptor, progesterone receptor, and HER2 on 1 or more metastases, and if there is disagreement in the results between the primary tumor and metastatic tissues, then oncologists should use estrogen receptor, progesterone receptor, and HER2 results from the metastasis to direct treatment decisions.

In addition, the ASCO panel recommends that decisions about initiating or selecting therapy for metastatic breast cancer should only be based on estrogen receptor, progesterone receptor, and HER2 status, because there is no evidence indicating that the use of additional biomarkers confers improved outcomes.

Furthermore, the panel found no evidence that using additional biomarkers beyond estrogen receptor, progesterone receptor, and HER2 to guide treatment decisions improves outcomes, quality of life, or cost-effectiveness; therefore, changing or discontinuing systemic therapy for metastatic breast cancer should be based on the patient’s goals of care, and on the clinical evaluation of disease progression or response. Nevertheless, carcinoembryonic antigen, cancer antigen 15-3, and cancer antigen 27-29 can be used to contribute to treatment decisions, but they should not be used alone for monitoring the response to therapy.

Because the clinical utility of other biomarkers in metastatic breast cancer has not yet been demonstrated, decisions for systemic therapy should be guided by estrogen receptor, progesterone receptor, and HER2 status. Overall, the panel concludes that further research is needed on the use of biomarkers in women with metastatic breast cancer.

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The Use of CTLA-4 and PD-1/PD-L1 Antibodies in Cancer Therapy

Research demonstrates that antibody therapy with ipilimumab (Yervoy) and pembrolizumab (Keytruda) directed against the immunologic regulators cytotoxic T lymphocyte–associated antigen (CTLA)-4 and PD-1/PD ligand 1 (PD-L1), respectively, is likely to play an important role in the treatment of several cancers including advanced melanoma. In a recent literature review, researchers examined the evidence regarding the preclinical rationale and clinical experience with these antibodies, as well as the unique clinical considerations that are relevant for treating patients with these therapies (Postow MA, et al. J Clin Oncol. 2015;33:1974-1982).

The results from preclinical studies suggest that CTLA-4 is a negative regulator of immunity, and that the antibody blockage of CTLA-4 could result in antitumor immunity. Clinical studies with the CTLA-4 antibody ipilimumab demonstrated improved overall survival in 2 phase 3 clinical trials involving patients with advanced melanoma. In addition, the pooled data from clinical trials with ipilimumab indicated that approximately 20% of patients with advanced melanoma will have long-term survival of at least 3 years, which can reach 10 years. In addition to demonstrating efficacy in the treatment of advanced melanoma, ipilimumab alone and in combination with other agents has demonstrated efficacy in other malignancies, including in pancreatic, prostate, and non–small-cell lung cancers.

Whereas CTLA-4 regulates immune responses early in T-cell activation, PD-1 inhibits effector T-cell activity in the effector phase within tissue and tumors. Phase 1 studies with the PD-1 antibodies nivolumab (Opdivo) and pembrolizumab demonstrated robust response rates in patients with advanced melanoma, non–small-cell lung cancer, renal-cell carcinoma, and other solid tumors. In addition, phase 3 studies in patients with melanoma demonstrated an overall response rate of 32% with nivolumab compared with 11% for chemotherapy.

The recently FDA-approved drug pembrolizumab also demonstrated improved tumor responses in patients with previously treated melanoma. Similar to PD-1, PD-L1 antibodies have demonstrated strong disease responses in early-phase clinical studies involving patients with bladder cancer, head and neck cancer, and gastrointestinal malignancies.

Several clinical considerations are relevant to patients who receive CTLA-4 and PD-1/PD-L1 antibodies, including the use of immune-related response criteria to help capture benefits beyond those captured by standard radiographic response criteria (eg, Response Evaluation Criteria in Solid Tumors), and the immune-related adverse events, including dermatologic, gastrointestinal, and hepatic, that are common in patients who receive CTLA-4 and PD-1/PD-L1 antibodies.

Ongoing research related to CTLA-4 and PD-1/PD-L1 blockade include establishing an optimal dose and dosing schedule; identifying biomarkers associated with disease outcomes; and for­mulating combination regimens with CTLA-4, PD-1/PD-L1, and other anticancer agents to improve outcomes in various malignancies.

“Themes from the experience with CTLA-4 and PD-1/PD-L1 will likely be relevant for investigations of novel immunologic checkpoints in the future,” Postow and colleagues concluded.

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Donepezil Improves Cognitive Function in Patients with Irradiated Brain Tumors

Patients with brain cancer typically undergo brain irradiation (whole or partial) for the treatment of primary and metastatic brain tumors. Brain irradiation adversely impacts neurochemical and morphologic markers for cholinergic neurons, which often results in cognitive impairment, as is manifested by deficits in learning, memory, and mood regulation. Donepezil hydrochloride (Aricept), a reversible acetylcholinesterase, has demonstrated efficacy in patients with a variety of brain impairments, including patients with dementia, traumatic brain injury, multiple sclerosis, and other conditions. A new study investigated the potential impact of donepezil on the cognitive functions in patients with irradiated brain tumors (Rapp SR, et al. J Clin Oncol. 2015;33:­1653-1659).

This randomized, double-blind, placebo-controlled, phase 3 clinical trial by Stephen Rapp, PhD, and colleagues included 198 adults who underwent brain irradiation and received a single daily dose of donepezil 5 mg for 6 weeks, which was increased to 10 mg for 18 weeks if well-tolerated, or a matching placebo.

Cognitive abilities, including memory, attention, language, visuomotor, verbal fluency, and executive functions, were assessed before treatment and after 12 weeks and 24 weeks of treatment. The study’s primary objective was to compare the overall cognitive functioning in patients who received donepezil versus patients who received placebo; the intergroup differences in individual cognitive domains were also evaluated.

Rapp and colleagues reported that although treatment with donepezil did not improve overall cognitive function compared with placebo after 24 weeks of treatment as measured by the overall composite score, the analysis of individual cognitive domains between the 2 groups revealed that donepezil conferred a significant but modest benefit in memory, motor speed, and dexterity versus placebo among patients with irradiated brain tumors.

These results demonstrate that the use of donepezil improves several cognitive functions in this patient population. The benefit was especially pronounced in patients who displayed increased cognitive impairment before brain tumor irradiation.

Rapp and colleagues acknowledged that the cognitive impairment reported in patients with irradiated brain tumors could have resulted from causes other than irradiation, such as radiation therapy, tumor effects, surgery, chemotherapy, or premorbid conditions. In addition, a higher dose of donepezil or a longer treatment duration may impart even greater cognitive benefits than were observed in this study. The impact of donepezil’s measured cognitive benefits on patients’ quality of life will be assessed in future studies.

“With survivorship improving, the identification of effective treatments for the consequences of having and treating primary and metastatic brain tumors is crucial for the protection of patients’ quality of life,” the researchers concluded.

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