The oncologist
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On August 5, 2016, the U. S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme Corp., Kenilworth, NJ) for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy. ⋯ Clinically significant immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders. The benefit-risk profile of pembrolizumab was considered acceptable in this patient population. As a condition of accelerated approval, Merck is required to conduct a confirmatory trial; this trial, KEYNOTE-040, is ongoing.
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Randomized Controlled Trial Multicenter Study
Palbociclib in Combination With Fulvestrant in Women With Hormone Receptor-Positive/HER2-Negative Advanced Metastatic Breast Cancer: Detailed Safety Analysis From a Multicenter, Randomized, Placebo-Controlled, Phase III Study (PALOMA-3).
Palbociclib enhances endocrine therapy and improves clinical outcomes in hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Because this is a new target, it is clinically important to understand palbociclib's safety profile to effectively manage toxicity and optimize clinical benefit. ⋯ Treatment with palbociclib in combination with fulvestrant was generally safe and well-tolerated in patients with hormone receptor (HR)-positive metastatic breast cancer. Consistent with the drug's proposed mechanism of action, palbociclib-related neutropenia differs in its clinical time course, patterns, and consequences from those seen with chemotherapy. Neutropenia can be effectively managed by a dose reduction, interruption, or cycle delay without compromising efficacy. A significant efficacy gain and a favorable safety profile support the consideration of incorporating palbociclib into the routine management of HR-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer.
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Randomized Controlled Trial Multicenter Study
A Randomized Controlled Trial of a Nurse-Led Supportive Care Package (SurvivorCare) for Survivors of Colorectal Cancer.
Colorectal cancer (CRC) and its treatments can cause distressing sequelae. We conducted a multicenter randomized controlled trial aiming to improve psychological distress, supportive care needs (SCNs), and quality of life (QOL) of patients with CRC. The intervention, called SurvivorCare (SC), comprised educational materials, needs assessment, survivorship care plan, end-of-treatment session, and three follow-up telephone calls. ⋯ Some survivors of colorectal cancer report distressing effects after completing treatment. Strategies to identify and respond to survivors' issues are needed. In a randomized controlled trial, the addition of a nurse-led supportive care package (SurvivorCare) to usual post-treatment care did not impact survivors' distress, quality of life, or unmet needs. However, patients receiving the SurvivorCare intervention were more satisfied with survivorship care. Factors for consideration in the design of subsequent studies are discussed.
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Randomized Controlled Trial Multicenter Study
FDA Approval Summary: Nivolumab for the Treatment of Metastatic Non-Small Cell Lung Cancer With Progression On or After Platinum-Based Chemotherapy.
: On October 9, 2015, the U.S. Food and Drug Administration expanded the nivolumab metastatic non-small cell lung cancer (NSCLC) indication to include patients with nonsquamous NSCLC after a 3.25-month review timeline. Approval was based on demonstration of an improvement in overall survival (OS) in an international, multicenter, open-label, randomized trial comparing nivolumab to docetaxel in patients with metastatic nonsquamous NSCLC with progression on or after platinum-based chemotherapy. The CheckMate 057 trial enrolled 582 patients who were randomized (1:1) to receive nivolumab or docetaxel. Nivolumab demonstrated improved OS compared with docetaxel at the prespecified interim analysis with a hazard ratio (HR) of 0.73 (p = .0015), and a median OS of 12.2 months (95% CI: 9.7-15.0 months) in patients treated with nivolumab compared with 9.4 months (95% CI: 8.0-10.7 months) in patients treated with docetaxel. A statistically significant improvement in objective response rate (ORR) was also observed, with an ORR of 19% (95% CI: 15%-24%) in the nivolumab arm and 12% (95% CI: 9%-17%) in the docetaxel arm. The median duration of response was 17 months in the nivolumab arm and 6 months in the docetaxel arm. Progression-free survival was not statistically different between arms. A prespecified retrospective subgroup analysis suggested that patients with programmed cell death ligand 1-negative tumors treated with nivolumab had similar OS to those treated with docetaxel. The toxicity profile of nivolumab was consistent with the known immune-mediated adverse event profile except for 1 case of grade 5 limbic encephalitis, which led to a postmarketing requirement study to better characterize immune-mediated encephalitis. ⋯ Based on the results from the CheckMate 057 clinical trial, nivolumab represents a new treatment option for patients requiring second-line treatment for metastatic non-small cell lung cancer. The role of nivolumab in patients with sensitizing epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) alterations is less clear. Until dedicated studies are performed to better characterize the role and sequence of programmed cell death 1 (PD-1) therapy, patients with EGFR or ALK alterations should have progressed on appropriate targeted therapy before initiating PD-1 inhibitor therapy. Some patients whose tumors lack programmed cell death ligand 1 (PD-L1) expression also appear to have durable responses. The U.S. Food and Drug Administration granted approval to Dako's PD-L1 test, PD-L1 IHC 28-8 pharmDx, which the applicant claimed as a nonessential complementary diagnostic for nivolumab use.
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Multicenter Study
FDA Approval Summary: Pembrolizumab for the Treatment of Patients With Metastatic Non-Small Cell Lung Cancer Whose Tumors Express Programmed Death-Ligand 1.
: On October 2, 2015, the U.S. Food and Drug Administration (FDA) granted accelerated approval for pembrolizumab, a breakthrough therapy-designated drug, for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express programmed death-ligand 1 (PD-L1), as determined by an FDA-approved test, and who have disease progression on or after platinum-containing chemotherapy or targeted therapy against anaplastic lymphoma kinase or epidermal growth factor receptor, if appropriate. This indication was approved concurrently with the PD-L1 immunohistochemistry 22C3 pharmDx, a companion diagnostic test for patient selection based on PD-L1 tumor expression. The accelerated approval was granted based on durable objective response rate (ORR) and an acceptable toxicity profile demonstrated in a multicenter, open-label trial enrolling 550 patients with metastatic NSCLC. The efficacy population comprised 61 patients with tumors identified as strongly positive for PD-L1, and the confirmed ORR as determined by blinded independent central review was 41% (95% confidence interval: 28.6%, 54.3%); all were partial responses. At the time of the analysis, responses were ongoing in 21 of 25 patients (84%), with 11 patients (44%) having response duration of ≥6 months. The most commonly occurring (≥20%) adverse reactions included fatigue, decreased appetite, dyspnea, and cough. The most frequent (≥2%) serious adverse drug reactions were pleural effusion, pneumonia, dyspnea, pulmonary embolism, and pneumonitis. Immune-mediated adverse reactions occurred in 13% of patients and included pneumonitis, colitis, hypophysitis, and thyroid disorders. The accelerated approval regulations describe approval of drugs and biologic products for serious and life-threatening illnesses based on a surrogate endpoint likely to predict clinical benefit. Under these regulations, a confirmatory trial or trials is required to verify and describe the benefit of pembrolizumab for patients with metastatic NSCLC. ⋯ This report presents key information on the U.S. Food and Drug Administration (FDA) accelerated approval of pembrolizumab for the treatment of patients with metastatic non-small cell lung cancer whose tumors express programmed death-ligand 1, as determined by an FDA-approved test, and who have disease progression on or after platinum-containing chemotherapy or targeted therapy against anaplastic lymphoma kinase or epidermal growth factor receptor, if appropriate. The report discusses the data supporting the approval decision, specifically highlighting the incorporation of a companion diagnostic in the key study and the optimal dose of pembrolizumab.