New targets and new mechanisms in lung cancer.

With the advent of the importance of histology in non-small-cell lung cancer (NSCLC) and the development of targeted agents that work on newly found mutations, the field of lung cancer therapy has greatly changed. In addition to new uses of chemotherapeutics and targeted agents, the possibilities of immunotherapy are also being explored. This review will describe the well-known use of vascular endothelial growth factor (VEGF) antibodies; the current uses of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors; newer agents being used against MET, fibroblast growth factor receptor (FGFR), and other intracellular targets; insights regarding the field of immunotherapy in lung cancer; and finally, newer developments in chemotherapy.

Identifying potentially inappropriate medication (PIM) use in geriatric oncology.

The median number of medications taken by adults aged 65 and older is four, but may be higher in older adults with cancer. A high number of prescribed medications increases risk for adverse drug reactions (ADRs), drug-drug interactions, drug-disease interactions, and overall healthcare utilization, emphasizing the need for frequent review of medications. There are many tools available to help the health care team assess medication appropriateness; however, none of the currently available tools have been validated in the geriatric oncology population. Older adults with cancer are at increased risk for ADRs and potentially inappropriate medications (PIMs) given the common need for multiple medications to manage cancer and cancer-related symptoms. Frequently used PIM identification tools, such as the American Geriatrics Society's (AGS) Beers criteria, often identify medications as "potentially inappropriate", although many of these medications are considered necessary to provide adequate supportive care in older patients with cancer. There are currently no specific guidelines to help direct application of available tools. This review summarizes literature available on the use of PIM identification tools in geriatric oncology and highlights a theoretical case and proposed medication management strategy, which combines the use of objective review with Beer's criteria and clinical judgement with the Medication Appropriateness Index (MAI). This two-pronged approach can serve to identify PIMs while recognizing factors unique to the geriatric oncology population.

Palbociclib in Patients With Non-Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non-small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported. METHODS: Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon's two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting. CONCLUSION: Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population.

nab-Paclitaxel-Based Therapy in Underserved Patient Populations: The ABOUND.70+ Study in Elderly Patients With Advanced NSCLC.

The phase 4 ABOUND.70+ trial assessed the safety and efficacy of nab-paclitaxel/carboplatin continuously or with a 1-week break between cycles in elderly patients with advanced non-small cell lung cancer (NSCLC). Patients ≥70 years with locally advanced/metastatic NSCLC were randomized 1:1 to first-line nab-paclitaxel days 1, 8, 15 plus carboplatin day 1 of a 21-day cycle (21d) or the same nab-paclitaxel/carboplatin regimen with a 1-week break between cycles (21d + break; 28d). The primary endpoint was the percentage of patients with grade ≥ 2 peripheral neuropathy (PN) or grade ≥ 3 myelosuppression. Other key endpoints included progression-free survival (PFS), overall survival (OS), and overall response rate (ORR). A total of 143 patients were randomized (71 to 21d, 72 to 21d + break). The percentage of patients with grade ≥ 2 PN or grade ≥ 3 myelosuppression was similar between the 21d and 21d + break arms (76.5 and 77.1%; P = 0.9258). Treatment exposure was lower in the 21d arm compared with the 21d + break arm. Median OS was 15.2 and 16.2 months [hazard ratio (HR) 0.72, 95% CI 0.44-1.19; P = 0.1966], median PFS was 3.6 and 7.0 months (HR 0.48, 95% CI 0.30-0.76; P < 0.0019), and ORR was 23.9 and 40.3% (risk ratio 1.68, 95% CI 1.02-2.78; P = 0.0376) in the 21d and 21d + break arms, respectively. In summary, the 1-week break between treatment cycles significantly improved PFS and ORR but did not significantly reduce the percentage of grade ≥ 2 PN or grade ≥ 3 myelosuppression. Overall, the findings support the results of prior subset analyses on the safety and efficacy of first-line nab-paclitaxel/carboplatin in elderly patients with advanced NSCLC.

Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC).

In many cancers, including non-small cell lung cancer (NSCLC), tumor angiogenesis pathways have been identified as important therapeutic targets. Angiogenesis is essential in the process of primary tumor growth, proliferation and metastasis. One of the best characterized group of protein factors for angiogenesis include the members of the vascular endothelial growth factor (VEGF) family, consisting of VEGF-(A-D), and placenta growth factor (PIGF). Targeting tumor angiogenesis has been approached through two primary methods, monoclonal antibodies that block VEGF-vascular endothelial growth factor receptor (VEGFR) binding or small molecule tyrosine kinase inhibitors (TKIs) that inhibit the downstream VEGFR mediated signaling. Many TKIs inhibit multiple pro-angiogenic and pro-proliferative pathways such as the mitogen activated protein (MAP) kinase pathway. Bevacizumab and ramucirumab, monoclonal antibodies targeting VEGF and the VEGFR, respectively, have each led to improvements in overall survival (OS) for NSCLC when added to standard first and second line chemotherapy, respectively. Small incremental gains seen with both bevacizumab and ramucirumab may be further improved upon by incorporating novel agents and treatment strategies, and many additional trials are ongoing.

Clinical implementation of soluble EGFR (sEGFR) as a theragnostic serum biomarker of breast, lung and ovarian cancer.

Signal transduction pathways regulated by the EGFR/ERBB/HER proto-oncogene family and receptor tyrosine kinases encoded by these genes are known to become dysregulated during cellular transformation and carcinogenesis. Consequently, biologically targeted antibodies and tyrosine kinase inhibitors directed toward EGFR/ErbB1/HER1 (eg, cetuximab, erlotinib and gefitinib) and ErbB2/HER2 (eg, trastuzumab), and more recently toward ErbB3/HER3 and ErbB4/HER4, are being investigated as therapeutic agents for treating patients with EGFR/ERBB/HER proto-oncogene-driven malignancies. The accurate selection of patients who will respond efficaciously to these agents a priori is a medical challenge. Understanding the clinical utility of soluble EGFR/ErbB/HER (ie, sEGFR/sErbB/sHER) isoforms, which are present in circulatory fluids, as theragnostic cancer biomarkers is an emerging area of contemporary biomedical investigation. This feature article reviews the literature regarding the clinical utility of serum sEGFR/sErbB1/sHER1 in breast, lung and ovarian cancer, and discusses the potential role of sEGFR in predicting and monitoring therapeutic responsiveness, as well as disease recurrence, and/or predicting disease outcome in patients treated with specific small-molecule, hormonal or biotherapeutic drug regimens. Well-designed translational research studies are needed to validate sEGFR as a theragnostic biomarker further and to achieve routine clinical implementation.