Ribociclib-Induced Cutaneous Adverse Events in Metastatic HR+/HER2- Breast Cancer: Incidence, Multidisciplinary Management, and Prognostic Implication.

BACKGROUND: Ribociclib is approved for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) treatment, in combination with endocrine therapy. Hematological, hepatic, and cardiac adverse events (AEs) emerged from pivotal trials, but little is known about cutaneous adverse events (CAEs). PATIENTS AND METHODS: We report data from a retrospective cohort study of all patients with HR+/HER2- ABC treated with ribociclib at Humanitas Cancer Center between June 2017 and December 2022. We recorded clinical-pathological data, the incidence, and treatment of ribociclib-related CAEs. These were evaluated according to the NCI-CTCAE v5.0 classification. Progression-free survival (PFS) was estimated by Kaplan-Meier method and the log-rank test was used to analyze differences between groups. RESULTS: Thirteen of 91 patients (14.3%) experienced treatment-related CAEs (mean time to the occurrence: 3.9 months). The most frequent CAEs were eczematous dermatitis (53.8%) and maculo-papular reaction (15.4%). Itch was reported by all 13 patients. The grade was G3 in 8 cases, G2 in 4, and G1 in 1. An integrated approach based on ribociclib dose modulation and dermatological interventions (oral antihistamine, moisturized cream, topical, and/or systemic steroids) could prevent ribociclib discontinuation in most patients. At a median follow-up of 20 months, the median PFS was 13 months (range, 1-66) with a better PFS curves for patients experiencing CAEs (P = .04). CONCLUSION: We mapped frequency and types of ribociclib-induced CAEs. An interdisciplinary management of CAEs incorporated into routine care may reduce the rate of drug discontinuation thus potentially contributing to better long-term outcomes.

Sticking to the Rules: Outcome and Success Rate of Guideline-Based Diarrhea Management in Metastatic Breast Cancer Patients Treated with Abemaciclib.

In clinical trials testing abemaciclib in patients with hormone-receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer, diarrhea is a very common adverse event (occurring in approximately 85% of patients, any grade). Nonetheless, this toxicity leads to abemaciclib discontinuation in a small proportion of patients (approximately 2%) thanks to the use of effective loperamide-based supportive therapy. We aimed to determine whether the incidence of abemaciclib-induced diarrhea in real-world trials was higher than the one reported in clinical trials, where patients are highly selected, and to evaluate the success rate of standard supportive care in this setting. We conducted a retrospective, observational, monocentric study including 39 consecutive patients with HR+/HER2- advanced breast cancer treated with abemaciclib and endocrine therapy at our institution from July 2019 to May 2021. Overall, diarrhea of any grade occurred in 36 patients (92%), of whom 6 (17%) had diarrhea of grade ≥3. In 30 patients (77%), diarrhea was associated with other adverse events, including fatigue (33%), neutropenia (33%), emesis (28%), abdominal pain (20%), and hepatotoxicity (13%). Loperamide-based supportive therapy was administered to 26 patients (72%). Abemaciclib dose was reduced in 12 patients (31%) due to diarrhea, and treatment was permanently discontinued in 4 patients (10%). In 58% of patients (15/26), diarrhea was effectively managed with supportive care and did not require abemaciclib dose reduction and/or discontinuation. In our real-world analysis, we observed a higher incidence of diarrhea related to abemaciclib compared to data from clinical trials, and a higher rate of permanent treatment discontinuation due to gastrointestinal toxicity. Better implementation of guideline-based supportive care could help to manage this toxicity.

A Case of Pulmonary Sarcoidosis during First-Line Targeted Therapy with Dabrafenib Plus Trametinib in BRAF V600E-Mutated Metastatic Melanoma.

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) exert a cytotoxic and immune-mediated effect on metastatic melanoma. The immune-mediated mechanism can lead to some adverse events, including panniculitis, erythema, keratitis, vitiligo-like lesions, or, more rarely, sarcoid-like skin reactions. In particular, sarcoidosis-related manifestations during melanoma treatment are characterized mainly by skin involvement and are seldom associated with chest or lymph node lesions. Overall, managing these adverse events can be very challenging from the diagnostic and therapeutic points of view. We present a case of pulmonary sarcoidosis; it is the first without skin involvement and initially only with lung presentation, diagnosed during treatment with BRAFi and MEKi for metastatic cutaneous melanoma. After about 2 years of treatment, with an oncological complete response, a histologically confirmed form of pulmonary sarcoidosis was diagnosed and initially interpreted as tumor progression. Sarcoidosis has always remained asymptomatic. After progression in the thorax and supraclavicular lymph nodes, steroid therapy with prednisone was instituted with total remission of the signs of disease. The targeted therapy has never been interrupted, and the patient still shows a complete response. This clinical case suggests that rare immune-mediated events, such as pulmonary sarcoidosis, should be considered during targeted therapy for metastatic melanoma and not only during treatment with immune checkpoint inhibitors. It also suggests that the interruption of targeted treatment should be accurately considered based on the expected risks or benefits since such immune-mediated events may have low clinical impact.

Tailored Toxicity-Driven Administration of Vismodegib in Patients With Multiple or Locally Advanced Basal Cell Carcinoma: A Pilot Analysis.

In this pilot study, we describe our experience with vismodegib in the treatment of basal cell carcinoma (BCC) and evaluate the feasibility of a tailored toxicity-driven administration of vismodegib in patients with multiple or locally advanced BCC. We retrospectively analyzed the clinical charts of 17 consecutive patients with BCC who were treated with vismodegib. Therapy was started at the usual dosage of 150 mg per day per person, continuously; a rescheduled dosage of 150 mg per day for 4 weeks with a subsequent stop of 2 weeks was allowed during the treatment according to the standard practice of our institution. During treatment, 14 patients with responsive disease presented an adverse event (100% cramps and 20% dysgeusia), therefore, requiring a change in the treatment plan. Overall, in eight out of 17 patients (47% of the overall population), it was possible to re-schedule the treatment by postponing therapy for 2 weeks every 4 weeks. These patients were all still alive at the time of the present analysis and were showing complete response. Adverse events resolved during the first interruption of therapy. The intermittent vismodegib schedule assessed in this pilot series could be beneficial in improving duration of treatment, allowing to maintain a long-term treatment response, even in an elderly and fragile population. Based on these preliminary findings, dedicated studies may be planned to further evaluate an intermittent schedule of vismodegib administration.