Adverse Event Management in Patients with BRAF V600E-Mutant Non-Small Cell Lung Cancer Treated with Dabrafenib plus Trametinib

Abstract

Therapies for advanced non‐small cell lung cancer (NSCLC) continue to become more sophisticated. Chemotherapeutics are giving way to newer approaches such as immune checkpoint inhibitors and targeted therapies for greater efficacy and improved outcomes. Dabrafenib plus trametinib combination therapy was first approved for the treatment of metastatic melanoma harboring the BRAF V600‐mutation in 2014. In 2017, the U.S. Food and Drug Administration approved the combination for patients with NSCLC with the same mutation based on an ≈ 65% response rate and median progression‐free survival of 10–11 months. BRAF mutations are a high‐frequency event in melanoma (≈ 50%), whereas the overall incidence in lung cancer is ≈ 2%, but similar in number, because of the high incidence of the disease. As a new approach in NSCLC treatment, dabrafenib plus trametinib has a unique toxicity profile that is likely unfamiliar to care providers in thoracic and general oncology who have not used the combination to treat patients with melanoma. Common adverse events such as pyrexia, fatigue, and nausea, as well as a range of less frequent cutaneous, ocular, and hemorrhagic events, can be observed during treatment with dabrafenib plus trametinib. Previous experience in metastatic melanoma revealed that these events can be effectively managed to improve patient quality of life and reduce unnecessary drug discontinuation. The aim of this review is to summarize treatment guidelines, along with key insights obtained from previous clinical‐trial and real‐world experience in patients with metastatic melanoma, to properly manage toxicities associated with dabrafenib plus trametinib for NSCLC. Implications for Practice The combination of dabrafenib plus trametinib has demonstrated substantial clinical activity in patients with BRAF V600E‐mutant non‐small cell lung cancer, leading to U.S. Food and Drug Administration approval. Although the combination has a manageable safety profile, many toxicities associated with the regimen may not be familiar to thoracic specialists or general oncologists. Extensive clinical experience with the combination in patients with metastatic melanoma has provided a wealth of strategies to identify and manage adverse events associated with dabrafenib plus trametinib. These can be used by medical oncologists to enhance early recognition of toxicities and facilitate effective management, thereby improving quality of treatment for patients.

SRC and MEK Co-inhibition Synergistically Enhances the Anti-tumor Effect in Both Non-small-cell Lung Cancer (NSCLC) and Erlotinib-Resistant NSCLC

“…Studies found that trametinib has a strong activity in cases of BRAF mutation and its combination with dabrafenib has demonstrated substantial clinical activity in patients with the BRAF V600E mutant. That combination is now a standard treatment in the first-line setting (48, 49), although adverse events need to be managed (50). Here, we have studied, for the first time, the combination of trametinib and bosutinib in EGFR-mutant NSCLC, which is a well-characterized and commonly observed type of NSCLC.…”

Advances in anti-BRAF therapies for lung cancer

“…Of the 58 patients bearing V600 mutation, the ORR to BRAFi monotherapy and combined BRAFi/MEKi treatment was 27% (6/22) and 56% (20/36), respectively, whereas PFS was 3.7 and 8.0 months, respectively (p = 0.002) [87]. The DESCRIBE II trial has evaluated the effectiveness of BRAFi dabrafenib and trametinib in the treatment of BRAF V600 -mutated metastatic melanoma patients, in a compassionate use setting [88]. This retrospective trial showed substantial clinical activity with dabrafenib plus trametinib in patients with unresectable or metastatic melanoma, similar to what has been assessed in previous prospective controlled trials [89][90][91].…”

“…The DESCRIBE II trial has evaluated the effectiveness of BRAFi dabrafenib and trametinib in the treatment of BRAF V600 -mutated metastatic melanoma patients, in a compassionate use setting [ 88 ]. This retrospective trial showed substantial clinical activity with dabrafenib plus trametinib in patients with unresectable or metastatic melanoma, similar to what has been assessed in previous prospective controlled trials [ 89 – 91 ].…”

Diverse landscape of dermatologic toxicities from small‐molecule inhibitor cancer therapy

“…112 The significance of dermatologic toxicities is highlighted by the growing number of consensus reports and opinions associated with the prevention, identification, and management of these conditions. 61,103,[329][330][331][332] These recommendations also emphasize the importance of early engagement of dermatologists/ dermatopathologists as part of the multidisciplinary team caring for cancer patients. [333][334][335] In conclusion, increased awareness of the diverse morphologic types of dermatologic toxicities associated with Nibs and a deeper insight into the mechanisms behind the spectrum of distinct and overlapping adverse reactions is critical for patient care in the era of "oncodermatology" and "oncodermatopathology."…”