Prognostic and predictive biomarkers with therapeutic targets in nonsmall-cell lung cancer: A 2023 update on current development, evidence, and recommendation.

BACKGROUND: Since the publication of the original work in 2014, significant progress has been made in the characterization of genomic alterations that drive oncogenic addiction of nonsmall cell lung cancer (NSCLC) and how the immune system can leverage non-oncogenic pathways to modulate therapeutic outcomes. This update evaluates and validates the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in NSCLC. DATA SOURCES: We performed a literature search from January 2015 to October 2023 using the keywords non-small cell lung cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, circulating tumor DNA, predictive and prognostic biomarkers, and targeted therapies. STUDY SELECTION AND DATA EXTRACTION: We identified, reviewed, and evaluated relevant clinical trials, meta-analyses, seminal articles, and published clinical practice guidelines in the English language. DATA SYNTHESIS: Regulatory-approved targeted therapies include those somatic gene alterations of EGFR ("classic" mutations, exon 20 insertion, and rare EGFR mutations), ALK, ROS1, BRAF V600, RET, MET, NTRK, HER2, and KRAS G12C. Data for immunotherapy and circulating tumor DNA in next-generation sequencing are considered emerging, whereas the predictive role for PIK3CA gene mutation is insufficient. CONCLUSIONS: Advances in sequencing and other genomic technologies have led to identifying novel oncogenic drivers, novel resistance mechanisms, and co-occurring mutations that characterize NSCLC, creating further therapeutic opportunities. The benefits associated with immunotherapy in the perioperative setting hold initial promise, with their long-term results awaiting.

Current therapies for classic myeloproliferative neoplasms: A focus on pathophysiology and supportive care.

PURPOSE: This article concisely evaluates current therapies that have received regulatory approval for the treatment of classic myeloproliferative neoplasms (MPNs). Pertinent pathophysiology and supportive care are discussed. Emerging therapies are also briefly described. SUMMARY: MPNs are a heterogeneous group of diseases characterized by acquired abnormalities of hematopoietic stem cells (HSCs), resulting in the generation of transformed myeloid progenitor cells that overproduce mature and immature cells within the myeloid lineage. Mutations in JAK2 and other driver oncogenes are central to the genetic variability of these diseases. Cytoreductive therapies such as hydroxyurea, anagrelide, interferon, and therapeutic phlebotomy aim to lower the risk of thrombotic events without exposing patients to an increased risk of leukemic transformation. However, no comparisons can be made between these therapies, as reduction of thrombotic risk has not been used as an endpoint. On the other hand, Janus kinase (JAK) inhibitors such as ruxolitinib, fedratinib, pacritinib, and momelotinib (an investigational agent at the time of writing) directly target the constitutively activated JAK-signal transducer and activator of transcription (JAK-STAT) pathway of HSCs in the bone marrow. Mutations of genes in the JAK-STAT signaling pathway provide a unifying understanding of MPNs, spur therapeutic innovations, and represent opportunities for pharmacists to optimize mitigation strategies for both disease-related and treatment-related adverse effects. CONCLUSION: Treatment options for MPNs span a wide range of disease mechanisms. The growth of targeted therapies holds promise for expanding the treatment arsenal for these rare, yet complex diseases and creates opportunities to optimize supportive care for affected patients.

Sequencing and combination of current small-molecule inhibitors for chronic lymphocytic leukemia: Where is the evidence?

Small-molecule inhibitors have revolutionized the treatment of chronic lymphocytic leukemia (CLL), a landscape once dominated by chemoimmunotherapy (i.e., an anti-CD20 monoclonal antibody in combination with systemic chemotherapy) in fit and unfit individuals. Key challenges include the management of refractory disease as well as the optimization of the therapy sequence. Decreased responsiveness has been observed with prolonged treatment, especially with Bruton tyrosine kinase (BTK) and phosphatidylinositol 3-kinase (PI3K) inhibitors which are given continuously, while venetoclax, an agent that targets dysregulations in intrinsic apoptosis signaling, has a fixed duration when combined with anti-CD20 monoclonal antibodies or BTK inhibitors. Combination therapy aims to synergistically target different oncogenic signaling pathways to abrogate the proliferation of resistant clones and thereby allows for fixed-duration treatments. An advantage of fixed-duration therapy is the potential to decrease financial and drug-induced toxicities. Sequencing of therapies is important to individualize treatment decisions based on factors such as age, comorbidities, tolerability, and patient preferences. However, to date, there are limited data to guide the rational sequencing or combination of these therapies, since conventional chemoimmunotherapy or chemotherapy regimens were used as comparators against these small-molecule inhibitors in trials that led to their regulatory approvals. In this article, we examined and evaluated the current evidence for sequencing versus the combination of small-molecule inhibitors for CLL by conducting comprehensive searches of the United States National Library of Medicine PubMed database, key meeting abstracts, and clinical practice guidelines. We also summarized findings from expert opinions to elucidate best practices for clinical scenarios with limited evidence to guide treatment selection.

Prognostic and predictive biomarkers with therapeutic targets in breast cancer: A 2022 update on current developments, evidence, and recommendations.

OBJECTIVE: To evaluate and validate the recent and emerging data for prognostic and predictive biomarkers with therapeutic targets in breast cancer. DATA SOURCES: A literature search from January 2015 to March 2022 was performed using the key terms breast cancer, clinical practice guidelines, gene mutations, genomic assay, immune cancer therapy, predictive and/or prognostic biomarkers, and targeted therapies. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials, meta-analyses, seminal articles, and published evidence- and consensus-based clinical practice guidelines in the English language were identified, reviewed and evaluated. DATA SYNTHESIS: Breast cancer is a biologically heterogeneous disease, leading to wide variability in treatment responses and survival outcomes. Biomarkers for breast cancer are evolving from traditional biomarkers in immunohistochemistry (IHC) such as estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor type 2 (HER2) to genetic biomarkers with therapeutic implications (e.g. breast cancer susceptibility gene 1/2 [BRCA1/2], estrogen receptor α [ESR1] gene mutation, HER2 gene mutation, microsatellite instability [MSI], phosphatidylinositol 3-kinase catalytic subunit 3Cα [PIK3CA] gene mutation, neurotrophic tyrosine receptor kinase [NTRK] gene mutation). In addition, current data are most robust for biomarkers in immunotherapy (e.g. programmed cell death receptor ligand-1 [PD-L1], microsatellite instability-high [MSI-H] or deficient mismatch repair [dMMR]). Oncotype DX assay remains the best validated gene expression assay that is both predictive and prognostic whereas MammaPrint is prognostic for genomic risk. CONCLUSIONS: Biomarker-driven therapies have the potential to confer greater therapeutic advantages than standard-of-care therapies. The purported survival benefits associated with biomarker-driven therapies should be weighed against their potential harms.

A Promising Future for Precision Epigenetic Therapy for Follicular and Diffuse Large B-Cell Lymphoma?

Epigenetic mechanisms such as DNA hypermethylation or histone deacetylation normally silence gene expression that regulates numerous cellular activities. Germinal center-derived lymphomas such as follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) are characterized by frequent mutations of histone-modifying genes. EZH2 is essential to the formation of germinal center in the secondary lymphoid tissue (eg, lymph nodes and spleen) and is one of the most frequently mutated histone-modifying genes in human lymphomas. EZH2 encodes a histone methyltransferase, mediates transcriptional repression and acts as an oncogene that promotes the development and progression of a variety of human malignancies, including FL and DLBCL. Thus, recurrent mutations in the EZH2 and other non-histone epigenetic regulators represent important targets for therapeutic interventions. Recently, an orally active inhibitor of EZH2, tazemetostat, has received regulatory approval for patients with mutated EZH2 relapsed or refractory FL after ≥2 prior systemic therapies. It is also approved for those with relapsed or refractory FL who have no satisfactory alternative treatment options, regardless of their mutational status of EZH2. Currently, tazemetostat and its combination therapies for patients with relapsed or refractory germinal center-derived lymphomas, as well as frontline therapies for previously untreated patients, are in various phases of clinical investigations. Despite the promise of epigenetic therapies, potential pitfalls such as target selectivity, risk of oncogenic activation, risk of secondary malignancies associated with epigenetic therapies must be carefully monitored. Future applications of epigenetic approach that incorporate clinical and genomic features are needed to determine how individualized treatments can be used for these hematologic malignancies.

Paraneoplastic syndromes: A focus on pathophysiology and supportive care.

PURPOSE: This article aims to increase awareness of, outline pathophysiology for, and offer guidance on supportive care strategies for specific endocrine, neurological, and immunological syndromes associated with paraneoplastic syndromes (PNSs). SUMMARY: PNS refers to remote effects that cannot be attributed to the direct or invasive effects of a malignancy. These syndromes are considered clinically important because they may provide early recognition, diagnosis, and management of the malignancy in a timely manner. Many of their presenting symptoms such as ectopic Cushing's syndrome, hypercalcemia of malignancy (HCM), syndrome of inappropriate secretion of antidiuretic hormone (SIADH), neurological dysfunctions, and paraneoplastic autoimmune thrombocytopenia overlap with those of nonneoplastic disorders, yet their pathogenesis and responses to treatments differ. Management of ectopic Cushing's syndrome due to a PNS consists of treatment of the underlying malignancy and its comorbidities. Drug therapies may include ketoconazole, mitotane, metyrapone, somatostatin analogs, and dopamine agonists. Hypercalcemia may be classified into cases with parathyroid hormone (PTH)-dependent causes or PTH-independent causes such as HCM, in which osteoclast inhibitors may be deployed. Treatments of PNS-mediated SIADH include treatment of the underlying malignancy and strategies to increase serum sodium levels. Amifampridine is now considered the first-line agent for paraneoplastic Lambert-Eaton myasthenic syndrome, whereas steroids, intravenous immune globulin, thrombopoietin receptor agonists (eg, romiplostim, eltrombopag, and avatrombopag), fostamatinib, and rituximab may find their niche in treatment of PNS-mediated autoimmune thrombocytopenia. CONCLUSION: Supportive care for PNSs lends opportunities to pharmacists to add quality, value, and safety.

Optimizing Multidisciplinary Treatment-Related Adverse Effects Detection and Reduction in Patients Undergoing Active Cancer Treatments in Ambulatory Infusion Centers.

PURPOSE: The objective of this study was to describe the implementation of an interdisciplinary supportive care program for treatment-related adverse effects (TRAEs) of patients with cancer in two ambulatory infusion centers affiliated with a major health system. METHODS: A management program of TRAEs was developed on the basis of the collaboration between oncologists, infusion center oncology nurses, and a board-certified oncology clinical pharmacist for patients with cancer in two outpatient infusion centers. Patients received multidisciplinary interventions or oncologist-driven interventions on the basis of their reported symptoms during their cancer treatments. They were followed prospectively at regular intervals for further symptom management interventions. To evaluate this program, a retrospective chart review was performed, and data were collected regarding the number and nature of these TRAEs. The outcomes of their interventions were assessed up to 3 months since initial encounters. Data for patient satisfaction were also collected before and after implementation of the program. RESULTS: A total of 308 patients received 469 interventions initiated either by the multidisciplinary team or by oncologists over a 3-year period. Compared with oncologist-led interventions, multidisciplinary interventions were statistically significant in the number of interventions (P = .004; 95% CI, 17.9 to 36.2) and in reducing occurrences of TRAEs (P = .03; 95% CI, 33.8 to 72.4) such as dermatological toxicities, diarrhea, immune-related adverse effects, mucositis, and nausea or vomiting after 1-month follow-up. Multidisciplinary team captured approximately 40% of TRAEs of all grades that were escalated to oncologists for further management, which led to an overall improvement in management of TRAEs. CONCLUSION: Multidisciplinary care for patients in infusion centers led to improvement in treatment-related toxicities.

Targeting the androgen receptor signaling pathway in advanced prostate cancer.

PURPOSE: This article summarizes current androgen receptor (AR)-directed therapies that have received regulatory approval for the treatment of advanced prostate adenocarcinoma (herein referred to as prostate cancer, PC). SUMMARY: PC is an androgen-dependent malignancy in which ligands including testosterone and dihydrotestosterone bind to AR, initiating androgen-AR complex translocation to the nucleus followed by AR-mediated transcription of target genes. Androgen deprivation therapy (ADT), including gonadotropin hormone-releasing hormone (GnRH) agonists with or without AR antagonists (antiandrogens), GnRH antagonists, or bilateral orchiectomy, forms the backbone of treatment for patients with metastatic castration-naive PC and/or castration-resistant PC (CRPC). ADT is also an option for high-risk, early-stage PC after prostatectomy and/or radiation. While ADT is often very effective as initial therapy, resistance ultimately develops despite suppression of gonadal and/or adrenal androgens, leading to CRPC, which is characterized by mechanisms such as reactivation of the AR signaling pathway, AR gene overexpression, and mutations in the ligand-binding domain of AR that lead to disease progression, resulting in increased symptom burden and ultimately death. However, disease in patients with CRPC is still dependent on androgen signaling, and these patients continue on ADT to maintain a castrate level of serum testosterone. Novel hormonal therapies including agents that target AR directly (eg, AR antagonists) are often added to ADT in this setting. Targeting the AR signaling pathway led to the development of second-generation AR antagonists, examples of which include enzalutamide, apalutamide, and darolutamide. These agents do not exhibit partial agonism, possess a higher affinity for AR, and are postulated to improve survival outcomes relative to their first-generation counterparts for patients with CRPC. Lastly, the emergence of ADT, including second-generation AR antagonists, has led to the development of supportive care for treatment-related adverse effects. CONCLUSION: Major advances have been made in targeting the AR signaling pathway in patients with advanced PC. Further studies are warranted to identify the optimal sequencing of therapies to maximize treatment benefit. Mitigation of treatment-related adverse effects presents new opportunities to advance clinical pharmacy practice.

Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation.

Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [NTRK] fusion genes, and human epidermal growth factor receptor type II [HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.

Targeting the Myeloid Lineages and the Immune Microenvironment in Myelodysplastic Syndromes: Novel and Evolving Therapeutic Strategies.

OBJECTIVE: To discuss the recent and emerging data for novel targeted therapies in myelodysplastic syndromes (MDS). DATA SOURCES: A literature search from January 2015 to June 2021 was performed using the key terms targeted therapies, myelodysplastic syndromes, DNA repair, erythroid differentiation therapy, epigenetic inhibitors, signal transduction inhibitors, and apoptosis-inducing agents. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials and articles in the English language were identified and reviewed. DATA SYNTHESIS: MDS are a heterogeneous group of malignant blood disorders affecting the bone marrow (BM), ultimately leading to BM failure, acute leukemia, and death. Selection of treatment is influenced by the severity of symptoms, cytopenia, cytogenetics, prognostic category, medical fitness, and patient preferences. Although current therapies such as erythropoiesis stimulating agents (ESAs) and hypomethylating agents (HMAs) help improve anemia and reduce transfusion burden, limited treatment options exist when patients experience treatment failure to ESAs or HMA. Recent regulatory approval of luspatercept, which targets the erythroid differentiation pathway, represents a major therapeutic advance in the management of anemia in MDS patients who are refractory to ESAs. Many investigational targeted therapies that aim at the myeloid lineage signaling pathway and the immune microenvironment are in active development. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This nonexhaustive review summarizes and describes the recent data for targeted therapies for MDS. CONCLUSION: The development of novel and investigational therapeutic agents continues to contribute to an improved understanding of tumor biology. The precise therapeutic role and timing of these agents remain to be elucidated.

New Therapeutic Targets and Treatment Options for Thrombotic Microangiopathy: Caplacizumab and Ravulizumab.

OBJECTIVE: To review the efficacy and safety of caplacizumab and ravulizumab for thrombotic microangiopathy. DATA SOURCES: A literature search from January 2011 to May 2020 was performed using the key terms caplacizumab (or ALX-0681), ravulizumab (or ALXN1210), atypical hemolytic uremic syndrome (aHUS), acquired thrombotic thrombocytopenic purpura (aTTP), and thrombotic microangiopathy. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials and articles in the English language were identified and reviewed. DATA SYNTHESIS: aTTP and aHUS are syndromes of thrombotic microangiopathy manifested by excessive platelet aggregation and endothelial cell destruction, with subsequent thrombocytopenia, hemolysis, and multiorgan failure. Current standard therapy for aTTP is therapeutic plasma exchange (TPE) to remove von Willebrand factor (vWF) multimers and anti-ADAMTS13 autoantibodies. As an adjunctive therapy to TPE, caplacizumab inhibits binding of vWF to platelets and prevents new microthrombi formation. It reduces thromboembolic event rate and days of TPE and delays relapse. Headache and epistaxis were the most common adverse events. aHUS develops because of dysregulation of the alternative complement pathway, followed by constitutive activation of complement components that causes thrombosis and end-organ damage. Short-term initial evaluation with ravulizumab, a long-acting complement inhibitor, demonstrates rapid hematological and renal improvement, with sustained complement inhibition and tolerable adverse effects. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review describes the pharmacology, pharmacokinetics, cost consideration, and clinical studies for caplacizumab and ravulizumab for thrombotic microangiopathy. Place of therapy is also discussed. CONCLUSION: Targeted therapies with caplacizumab and ravulizumab are expected to reduce the burden of exacerbation, refractory disease, recurrence, and possibly death for thrombotic microangiopathy.

From oxygen sensing to angiogenesis: Targeting the hypoxia signaling pathway in metastatic kidney cancer.

PURPOSE: This article summarizes examples of current and emerging therapies that target the hypoxia and angiogenesis signaling pathways in the clear cell type of renal cell cancer (RCC), with an emphasis on the hypoxia signaling pathway. SUMMARY: Mammalian cells transduce signals of decreased oxygen to hypoxia inducible factor (HIF), an intracellular heterodimer that mediates the adaptation of normal and tumor cells to oxygen deprivation. HIF is frequently overexpressed in cancer cells and is involved in the transcriptional activation of many genes essential for cell invasion, migration, survival, and angiogenesis (including vascular endothelial growth factor [VEGF]). Moreover, HIF confers resistance to cytotoxic chemotherapy and radiation therapy and is associated with poor prognosis in patients with cancer. Blocking the activity of HIF inhibits the expression of VEGF and oncogenic pathways, resulting in the inhibition of tumor growth. Interestingly, activation of oncogenes and/or inactivation of tumor suppressor genes (eg, the gene encoding von Hippel-Lindau [VHL] tumor suppressor protein) can activate tumorigenesis even with normal levels of oxygen, providing support for the notion that the HIF-VHL-VEGF axis is amenable to targeted therapies for the treatment of RCC. This article highlights the current understanding of the hypoxia signaling pathway and its relevance to RCC development. Pharmacologic agents targeting the hypoxia and angiogenesis signaling pathways are discussed. CONCLUSION: Development of novel therapeutic agents that target the hypoxia and angiogenesis signaling pathways holds promise in the management of metastatic clear cell RCC.

Driving toward precision medicine for B cell lymphomas: Targeting the molecular pathogenesis at the gene level.

Lymphomas are a diverse group of hematologic malignancies that arise from either T cell, B cell or the natural killer cell lineage. B cell lymphomas arise from gene mutations with critical functions during normal B cell development. Recent advances in the understanding of molecular pathogenesis demonstrate that many different recurrent genomic and molecular abnormalities and dysregulated oncogenic regulatory pathways exist for many subtypes of B cell lymphomas, both across and within histological subtypes. Pathogenetic processes such as (1) chromosomal aberrations, for example, t(14;18) in follicular lymphoma, t(11;14) in mantle cell lymphoma, t(8;14) in Burkitt lymphoma; dysregulations in signaling pathways of (2) nuclear factor- κB (NF-κB); (3) B cell receptor (BCR); (4) Janus kinase/signal transducers and transcription activators (JAK-STAT); (5) impaired apoptosis/cell cycle regulation due to mutated, rearranged or amplified MYC, BCL-2, BCL-6 proto-oncogenes; (6) epigenetic aberrations may contribute to pathogenesis. More studies are under way to elucidate the molecular heterogeneity underlying many types of lymphomas that account for variable responses to treatment, generation of subclones and treatment resistance. Although significant research is still needed, targeted therapy promises to provide new options for the treatment of patients with lymphomas. This article provides a non-exhaustive overview on the current understanding on the genetics of pathogenesis of B cell lymphomas and their therapeutic implications.

Current targeted therapies in lymphomas.

PURPOSE: This article summarizes current targeted therapies that have received regulatory approval for the treatment of B- and T-cell lymphomas. SUMMARY: Over the last 20 years, new drug therapies for lymphomas of B cells and T cells have expanded considerably. Targeted therapies for B-cell lymphomas include: (1) monoclonal antibodies directed at the CD20 lymphocyte antigen, examples of which are rituximab, ofatumumab, and obinutuzumab; (2) gene transfer therapy, an example of which is chimeric antigen receptor-modified T-cell (CAR-T) therapy directed at the CD19 antigen expressed on the cell surface of both immature and mature B cells; and (3) small-molecule inhibitors (ibrutinib, acalabrutinib, copanlisib, duvelisib, and idelalisib) that target the B-cell receptor signaling pathway. Of note, brentuximab vedotin is an antibody-drug conjugate that targets CD30, another lymphocyte antigen expressed on the cell surface of both Hodgkin lymphoma (a variant of B-cell lymphoma) and some T-cell lymphomas. Although aberrant epigenetic signaling pathways are present in both B- and T-cell lymphomas, epigenetic inhibitors (examples include belinostat, vorinostat, and romidepsin) are currently approved by the Food and Drug Administration for T-cell lymphomas only. In addition, therapies that target the tumor microenvironment have been developed. Examples include mogamulizumab, bortezomib, lenalidomide, nivolumab, and pembrolizumab. In summary, the efficacy of these agents has led to the development of supportive care to mitigate adverse effects, due to the presence of on- or off-target toxicities. CONCLUSION: The therapeutic landscape of lymphomas has continued to evolve. In turn, the efficacy of these agents has led to the development of supportive care to mitigate adverse effects, due to the presence of on- or off-target toxicities. Further opportunities are warranted to identify patients who are most likely to achieve durable response and reduce the risk of disease progression. Ongoing trials with current and investigational agents may further elucidate their place in therapy and therapeutic benefits.

To do or not to do: A concise update of current clinical controversies in immune checkpoint blockade.

Although programmed death-ligand 1 is currently the best available biomarker for first-line therapy with pembrolizumab for patients with non-small cell lung cancer and is a required companion test approved by the US Food and Drug Administration, programmed death-ligand 1 testing is an option (as a complementary test) for patients treated with nivolumab, atezolizumab, and durvalumab. Programmed death-ligand 1 expression is continuously variable and dynamic in the tumor microenvironment. Due to the complex molecular and cellular interactions involved in immune response, a single biomarker may not be sufficient to predict response to cancer immunotherapy. Integration of multiple tumor, immune response, and genomic parameters is likely to influence the future interpretation of biomarker-based treatment outcomes. This article, in a case-based format, concisely summarizes most up-to-date evidence in answering some commonly seen clinical controversies of cancer immunotherapy, in terms of (i) the predictive value of programmed death-ligand 1 as a biomarker; (ii) whether the use of steroids with checkpoint inhibitors will decrease efficacy of the latter; (iii) selection of patients for cancer immunotherapy based on immune-based response criteria, and (iv) whether the use of influenza vaccine with checkpoint inhibitors is considered safe. Until more robust, long-term prospective clinical data are available, these discussions may serve as a starting point for pharmacists to gain timely and effective management of these realistic issues.

Restoring the switch for cancer cell death: Targeting the apoptosis signaling pathway.

PURPOSE: The relevance of apoptosis to cancer development and pharmacologic agents that target this pathway in selected malignancies are described. SUMMARY: Apoptosis is a tightly regulated biological process mediated by both proapoptotic (i.e., prodeath) and antiapoptotic (i.e., prosurvival) proteins. While apoptosis represents a well-established effector mechanism induced by conventional chemotherapy in many malignancies, the development of apoptosis-based targeted therapy is relatively new. The pharmacologic restoration of apoptotic functions, either by blocking the action of antiapoptotic proteins/regulators (e.g., through investigational therapies such as inhibitors of apoptosis proteins, SMAC [second mitochondria-derived activator of caspases] mimetics, MDM2 [murine double minute 2] antagonists) or by inducing apoptosis (e.g., through investigational agonistic monoclonal antibodies or fusion proteins), holds robust potential for cancer pharmacotherapy. Notably, BH domain 3 (BH3) mimetics, a new class of small molecules that block the action antiapoptotic proteins, are touted a success for apoptosis-based targeted therapy. Venetoclax, a synthetic peptide that belongs to this class of BH3 mimetics, is currently approved by the Food and Drug Administration for the treatment of relapsed/refractory chronic lymphocytic leukemia in patients with 17p deletion as a single agent. This agent has been increasingly used either alone or as part of combination therapy for diverse hematologic malignancies in clinical trials. CONCLUSION: Advances in the understanding of molecular mechanisms of apoptosis have given rise to more-refined targeted therapies for diverse malignancies, with the goal to improve survival outcome while sparing treatment-related toxicities.

Implementation of an integrated computerized prescriber order-entry system for chemotherapy in a multisite safety-net health system.

PURPOSE: The development of a computerized prescriber order-entry (CPOE) system for chemotherapy in a multisite safety-net health system and the challenges to its successful implementation are described. SUMMARY: Before CPOE for chemotherapy was first implemented and embedded in the electronic medical record system of Harris Health System (HHS), pharmacy personnel relied on regimen-specific preprinted order sets. However, due to differences in practice styles and workflow logistics, the paper orders across the 3 facilities were mostly site specific, with varying clinical content. Many of these order sets had not been approved by the oncology subcommittee. In addition, disparities in clinical knowledge and lack of communication contributed to inconsistencies in order set development. Led by medical directors from medical oncology departments at the 3 facilities, pharmacy administrators, and information technology representatives, HHS committed resources to supporting the adoption and use of a CPOE system for chemotherapy. Five practical lessons of broad applicability have been learned: engagement of interprofessional stakeholders, optimization of workflow before CPOE implementation, requirement of verification tool for CPOE, consolidation of protocols, and commitment to ongoing training and support. Evaluation of the CPOE system demonstrated a systemwide reduction in medication errors by 75% (p < 0.05). Satisfaction with the CPOE system varied among sites and was unchanged institutionwide 6 months after the CPOE implementation. CONCLUSION: The development and implementation of CPOE for chemotherapy at a multisite safety-net health system created opportunities to optimize patient care and reduce variations through interprofessional collaborations. Initial evaluation suggested that CPOE reduced the medication-order error rate and improved user satisfaction in 1 of 3 facilities.