Beyond the dose-limiting toxicity period: Dermatologic adverse events of patients on phase 1 trials of the Cancer Therapeutics Evaluation Program.

BACKGROUND: Dermatologic adverse events (AEs) can be key determinants of overall drug tolerability and of the maximum tolerated and recommended phase 2 doses in phase 1 trials. The authors present the largest dedicated analysis of dermatologic AEs on phase 1 trials to date. METHODS: Data from a prospectively maintained database of patients with solid tumors who were enrolled onto Cancer Therapeutics Evaluation Program (CTEP)-sponsored phase 1 trials of cytotoxic or molecularly targeted agents (MTAs) from 2000 to 2010 were analyzed. Cumulative incidence, site, and type of drug-related dermatologic AEs were described and compared. The timing of worst drug-related dermatologic AEs was summarized. RESULTS: In total, 3517 patients with solid tumors and 6165 unique, drug-related dermatologic AEs were analyzed, including 1545 patients on MTA-only trials, 671 on cytotoxic-only trials, and 1392 on combination MTA and cytotoxic trials. Of 1270 patients who had drug-related dermatologic events, the timing of the worst AE was as follows: 743 (cycle 1), 303 (cycle 2), and 224 (cycle 3 or later). Although the cumulative incidence of grade ≥3 drug-related AEs increased to 2.4% by cycle 6, it was only 1.6% at the end of cycle 1. The cumulative incidence of drug-related AEs was highest in patients who received MTA-only therapy (P < .001) and differed by dose level (P < .001). In patients who received MTA-only therapy, drug-related AEs were most common for combination kinase inhibitor-containing therapy (P < .001). CONCLUSIONS: A substantial proportion of drug-related dermatologic AEs occur after the traditional dose-limiting toxicity monitoring period of phase 1 clinical trials. Future designs should account for late toxicities.

Incidence and risk of xerosis with targeted anticancer therapies.

BACKGROUND: Many targeted therapies used in the treatment of cancer can lead to the development of xerosis, but the incidence and relative risk of xerosis have not been ascertained. OBJECTIVE: We conducted a systematic review and metaanalysis of clinical trials, to ascertain the incidence and risk of developing xerosis after taking anticancer drugs. METHODS: The PubMed (1966-October 2013), Web of Science (January 1998-October 2013), and American Society of Clinical Oncology abstracts (2004-2013) databases were searched for clinical trials of 58 targeted agents. Results were calculated using random or fixed effects models. RESULTS: The incidences of all- and high-grade xerosis were 17.9% (95% confidence interval [CI]: 15.6-20.4%) and 1.0% (95% CI: 0.9-1.5%), respectively. The risk of developing all-grade xerosis was 2.99 (95% CI: 2.0-4.3), and it varied across different drugs (P < .001). LIMITATIONS: The reporting of xerosis may vary among clinicians and institutions, and the incidence may be affected by age, concomitant medications, comorbidities, and underlying malignancies or skin conditions. CONCLUSION: Patients receiving targeted therapies have a significant risk of developing xerosis. Patients should be counseled and treated early for this symptom to prevent suboptimal dosing and quality of life impairment.

A systematic review of patient-reported outcome instruments of dermatologic adverse events associated with targeted cancer therapies.

PURPOSE: Dermatologic adverse events (dAEs) in cancer treatment are frequent with the use of targeted therapies. These dAEs have been shown to have significant impact on health-related quality of life (HRQoL). While standardized assessment tools have been developed for physicians to assess severity of dAEs, there is a discord between objective and subjective measures. The identification of patient-reported outcome (PRO) instruments useful in the context of targeted cancer therapies is therefore important in both the clinical and research settings for the overall evaluation of dAEs and their impact on HRQoL. METHODS: A comprehensive, systematic literature search of published articles was conducted by two independent reviewers in order to identify PRO instruments previously utilized in patient populations with dAEs from targeted cancer therapies. The identified PRO instruments were studied to determine which HRQoL issues relevant to dAEs were addressed, as well as the process of development and validation of these instruments. RESULTS: Thirteen articles identifying six PRO instruments met the inclusion criteria. Four instruments were general dermatology (Skindex-16©, Skindex-29©, Dermatology Life Quality Index (DLQI), and DIELH-24) and two were symptom-specific (functional assessment of cancer therapy-epidermal growth factor receptor inhibitor-18 (FACT-EGFRI-18) and hand-foot syndrome 14 (HFS-14)). CONCLUSIONS: While there are several PRO instruments that have been tested in the context of targeted cancer therapy, additional work is needed to develop new instruments and to further validate the instruments identified in this study in patients receiving targeted therapies.

Ado-trastuzumab emtansine-associated telangiectasias in metastatic breast cancer: a case series.

Treatment of HER2-positive metastatic breast cancer with ado-trastuzumab emtansine (T-DM1), a novel antibody-drug conjugate, has resulted in both improved progression-free and overall survival. Recognition and treatment of diverse adverse events related to T-DM1 is critical for safety and tolerability. The most frequent adverse events with T-DM1 include fatigue, diarrhea, anemia, elevated transaminases, and mild-to-moderate hemorrhagic events, which are thought to be related to induced thrombocytopenia. Here, we present five case series of cutaneous and mucosal telangiectasias, definitely related to T-DM1. The development of telangiectasias represents a newly recognized adverse effect of T-DM1. We provide description and timing of the telangiectasias and review the mechanisms that may explain the formation of these vascular lesions in association with T-DM1. Further, we describe associated bleeding events and propose that induced telangiectasias could represent an additional cause of T-DM1-associated hemorrhage.

Autoimmune Bullous Skin Disorders with Immune Checkpoint Inhibitors Targeting PD-1 and PD-L1.

Monoclonal antibodies (mAb) targeting immune checkpoint pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) may confer durable disease control in several malignancies. In some patients, immune checkpoint mAbs cause cutaneous immune-related adverse events. Although the most commonly reported cutaneous toxicities are mild, a subset may persist despite therapy and can lead to severe or life-threatening toxicity. Autoimmune blistering disorders are not commonly associated with immune checkpoint mAb therapy. We report a case series of patients who developed bullous pemphigoid (BP), an autoimmune process classically attributed to pathologic autoantibody formation and complement deposition. Three patients were identified. Two patients developed BP while receiving the anti-PD-1 mAb nivolumab, and one while receiving the anti-PD-L1 mAb durvalumab. The clinicopathologic features of each patient and rash, and corresponding radiologic findings at the development of the rash and after its treatment, are described. Patients receiving an anti-PD-1/PD-L1 mAb may develop immune-related BP. This may be related to both T-cell- and B-cell-mediated responses. Referral to a dermatologist for accurate diagnosis and management is recommended. Cancer Immunol Res; 4(5); 383-9. ©2016 AACR.

Analysis of BRAF and NRAS Mutation Status in Advanced Melanoma Patients Treated with Anti-CTLA-4 Antibodies: Association with Overall Survival?

Ipilimumab and tremelimumab are human monoclonal antibodies (Abs) against cytotoxic T-lymphocyte antigen-4 (CTLA-4). Ipilimumab was the first agent to show a statistically significant benefit in overall survival in advanced melanoma patients. Currently, there is no proven association between the BRAFV600 mutation and the disease control rate in response to ipilimumab. This analysis was carried out to assess if BRAFV600 and NRAS mutation status affects the clinical outcome of anti-CTLA-4-treated melanoma patients. This is a retrospective multi-center analysis of 101 patients, with confirmed BRAF and NRAS mutation status, treated with anti-CTLA-4 antibodies from December 2006 until August 2012. The median overall survival, defined from the treatment start date with the anti-CTLA-4. Abs-treatment to death or till last follow up, of BRAFV600 or NRAS mutant patients (n = 62) was 10.12 months (95% CI 6.78-13.2) compared to 8.26 months (95% CI 6.02-19.9) in BRAFV600/NRASwt subpopulation (n = 39) (p = 0.67). The median OS of NRAS mutated patients (n = 24) was 12.1 months and although was prolonged compared to the median OS of BRAF mutated patients (n = 38, mOS = 8.03 months) or BRAFV600/NRASwt patients (n = 39, mOS = 8.26 months) the difference didn't reach statistical significance (p = 0.56). 69 patients were able to complete 4 cycles of anti-CTLA-4 treatment. Of the 24 patients treated with selected BRAF- or MEK-inhibitors, 16 patients received anti-CTLA 4 Abs following either a BRAF or MEK inhibitor with only 8 of them being able to finish 4 cycles of treatment. Based on our results, there is no difference in the median OS in patients treated with anti-CTLA-4 Abs implying that the BRAF/NRAS mutation status alone is not sufficient to predict the outcome of patients treated with anti-CTLA-4 Abs.

Current options and future directions in the systemic treatment of metastatic melanoma.

Systemic treatment options for metastatic melanoma have historically been limited, with conventional cytotoxic chemotherapies demonstrating only modest benefit. Recent advances, however, have dramatically changed the treatment landscape and can be considered in 2 general categories: immunotherapeutic approaches that enhance antitumor immunity, and targeted therapeutic approaches that block oncogenic driver mutations. Immunotherapy with antibodies that block cytotoxic T-lymphocyte antigen 4 and programmed death-1 receptor can result in durable responses in a subset of patients. These treatments may be considered for patients irrespective of their mutational status, and ongoing research continues to investigate biomarkers associated with clinical outcomes. Side effects of these agents result from immune-mediated reactions involving various organ sites and can include: diarrhea, rash, hepatitis, and endocrinopathies. For patients whose melanoma harbors a BRAF mutation, targeted therapy with BRAF and MEK inhibitors has the potential for rapid tumor regression in the majority of patients, and some patients with KIT mutations can also respond to appropriately targeted therapy. Unfortunately, most patients' responses to targeted agents are transient with disease progression ultimately ensuing owing to the emergence of a number of mechanisms of resistance. This review begins with a description of the traditional agents used to treat metastatic melanoma, then focuses on the mechanism of action, toxicity profile, and efficacy data for the recently approved immunotherapeutic and targeted therapeutic agents. Novel approaches in clinical development are also included because expectations are high that these new agents will ultimately have an important role in the treatment of advanced melanoma.

A rare case of primary rhabdoid melanoma of the urinary bladder treated with ipilimumab, an anti-CTLA 4 monoclonal antibody.

Primary melanoma of the urinary bladder is a rare subentity of melanoma. The same applies for melanoma of the rhabdoid histopathologic phenotype. A female patient was initially diagnosed with melanoma of unknown origin caused by macroscopic lymph node metastasis in the left inguinal and parailiacal regions. Because of the extent of the disease, radical surgery could not be performed. The patient underwent systemic chemotherapy with dacarbazine, followed by the experimental compound tasisulam. Upon sudden macrohematuria, cystoscopy showed a large infiltrating tumorous structure located on the left side of the urinary bladder. Clinically, the amelanotic tumor showed endophytic growth into the lumen; on the histopathological specimen, the growth pattern was partially undermining the urothelium, which is commonly observed in primary melanoma of the urinary bladder. Cytologically, the tumor cells were classified as rhabdoid melanoma, a very rare variant of melanoma, which is commonly amelanotic and expresses S100, vimentin and Ncam. Mutational analysis showed positive results for BRAF V600E. After detecting the primary melanoma, the patient received anti-CTLA4 antibody treatment with 3 mg/kg ipilimumab, through which a partial response was achieved. Past computed tomography scans should be re-evaluated for suspicious lesions, and cystoscopy should be included in the clinical workup if the pattern of metastasis is congruent with the drainage sites of the urinary bladder.

Cryptogenic organizing pneumonia due to amiodarone: long-term follow-up after corticosteroid treatment.

Cryptogenic organizing pneumonia (formerly known as bronchiolitis obliterans organizing pneumonia) is a clinicopathological entity with characteristical radiographic findings such as bilateral, asymmetrical, sometimes migrating, patchy infiltrates in chest radiograph and ground-glass opacities in computed tomography. The disease has been observed in the context of gastrointestinal disorders, certain lung infections, autoimmune-mediated diseases (such as Wegener granulomatosis), inhalation of toxic fumes, bone marrow transplantation and administration of drugs. The benzofuran amiodarone, a commonly used antiarrythmic drug for atrial fibrillation, can exhibit several pulmonary adverse effects, amongst them cryptogenic organizing pneumonia as a rarely diagnosed and published one. We report a case of cryptogenic organizing pneumonia secondary to amiodarone treatment, its clinical course with significant improvement of clinical symptoms within a few days after discontinuation of amiodarone treatment and administration of corticosteroids. Also the infiltrations found in chest X-ray and computed tomography responded well and showed remarkable resolution tendency quickly. During 5 months of corticoid therapy pulmonary abnormalities gradually resolved almost completely and remained equal during the 8 months follow-up after corticoid termination.