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Dermatoses of Pregnancy
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Hannah J. Anderson, Dana Correale, Jason B. Lee
The treatment of melanoma is primarily surgical. After the initial diagnostic biopsy, excision of the primary lesion with 0.5–2 cm margins, depending on tumor thickness, is recommended [65]. Patients with metastatic melanoma had limited therapeutic options historically, but significant advances in targeted molecular therapy have resulted in several FDA-approved systemic agents. Combined BRAF and MEK inhibitors, such as dabrafenib/trametinib and vemurafenib/cobimetinib, have been approved for patients with metastatic melanoma associated with a BRAFV600_ mutation [85]. Immune checkpoint inhibitors such as ipilimumab, targeting CTLA-4, and nivolumab and pembrolizumab, targeting PD-1, have also been approved for the treatment of metastatic melanoma [86]. Human data on safety of these new targeted therapies during pregnancy is not available. One case of successful delivery of a premature healthy baby exposed to vemurafenib has been reported [87].
Molecular Drivers in Lung Adenocarcinoma: Therapeutic Implications
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Imayavaramban Lakshmanan, Apar Kishor Ganti
Vemurafenib is a selective oral inhibitor of the BRAF V600 kinase, approved for the treatment of BRAF mutated metastatic melanoma. In a prospective study, vemurafenib had a response rate of 42% (95% CI, 20 to 67) in the cohort of patients with NSCLC [44]. The median PFS in these patients was 7.3 months (95% CI, 3.5 to 10.8).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Cobimetinib (CotellicTM) (Figure 6.51) is a MEK inhibitor developed by Exelixis and Genentech (Roche). It is used in combination with the B-RAF inhibitor vemurafenib (ZelborafTM) to treat melanoma. The structure is unusual in containing a four-membered azetidine ring and four halogen atoms. Structure of cobimetinib (CotellicTM).
Long-term vemurafenib therapy in advanced melanoma patients: cutaneous toxicity and prognostic implications
Published in Journal of Dermatological Treatment, 2022
Victor Desmond Mandel, Matelda Medri, Ausilia Maria Manganoni, Laura Pavoni, Francesco De Rosa, Simone Ribero, Flavia Foca, Daniele Andreis, Laura Mazzoni, Serena Magi, Francesca Farnetani, Marco Palla, Paola Ulivi, Ignazio Stanganelli
Among our study population, the incidence of warts/benign squamoproliferative skin lesions was similar to other previously studies (45%), while cuSCCs resulted lower than expected. This may be explained by the frequent dermatological assessments performed during the study period that allowed an early non-excisional treatment (e.g. cryosurgery with liquid nitrogen, topical drug treatment, and photodynamic therapy) of initial hyperkeratotic lesions, which thus not evolved into cuSCCs. Practical information about sun protection and skin surveillance were provided, discussing with patients the increased risk of skin cancer due to vemurafenib in order to make them aware. Moreover, it was taught to each patient and/or their caregiver the importance cutaneous self-examination and how to check the skin periodically at home. Patients who have noticed a new highly suspicious skin lesion can referred to our institution for an examination, after a first evaluation of their general practitioner, taking an appointment in short time (within 7 days). All these measures/recommendations probably reduced the onset of cuSCCs and can also explain the lower cases of photosensitivity in comparison to other studies (31%). All cuSCCs occurred 2–6 months after the beginning of vemurafenib, mainly in areas not exposed to the sun, and in patients with a negative personal history of non-melanoma skin cancer. Instead, the onset of BCCs was observed throughout the duration of treatment and was probably due to the referred personal history of frequent photodamage rather than to the direct effect of the drug or induced phototoxicity.
Atezolizumab plus vemurafenib and cobimetinib for the treatment of BRAF V600-mutant advanced melanoma: from an hypothetic triplet to an approved regimen
Published in Expert Review of Precision Medicine and Drug Development, 2021
Aikaterini Katsandris, Dimitrios C. Ziogas, Maria Kontouri, Stavroula Staikoglou, Helen Gogas
Vemurafenib is a small oral BRAF kinase inhibitor which blocks cellular proliferation and tumor growth by inhibiting kinase activity in melanoma cells harboring certain mutated forms of BRAF, mainly with BRAF V600E mutation. For its melanoma indication in the triplet with cobimetinib and atezolizumab, vemurafenib should be administered for cycle 1 (with cobimetinib only) at a dose of 960 mg every 12 h on days 1 to 21 of a 28-day cycle, followed by 720 mg every 12 h on days 22 to 28 of cycle 1 and from cycle 2 and beyond, together with cobimetinib and atezolizumab at a dose of 720 mg every 12 h until disease progression or unacceptable toxicity. It is usually binding to albumin and α1-acid glycoprotein and its half-life elimination time is 57 h. It is metabolized mainly by CYP3A4 and in lesser degree by P-glycoprotein/ABCB1 and for this reason all clinically relevant drug interactions should be checked. It is excreted in feces (~94%) and in urine (~1%). No dosage adjustment is necessary even in cases with severe renal or hepatic impairment.
Risks of molecular targeted therapies to fertility and safety during pregnancy: a review of current knowledge and future needs
Published in Expert Opinion on Drug Safety, 2021
Elena Lorenzi, Matteo Simonelli, Pasquale Persico, Angelo Dipasquale, Armando Santoro
Considering pregnancy outcomes during or after maternal exposure, little is known about the effect of vemurafenib, which has only been reported in two single-case reports. In the pregnancy described in the first case report [104], vemurafenib was administered at a dosage of 960 mg b.i.d. to a 37-year-old female with metastatic melanoma at 25 weeks of gestation. The authors observed a marked fetal growth restriction, necessitating an emergency cesarean section at a gestational age of 30 weeks due to fetal distress. No congenital malformations were observed. In the second case report [105], vemurafenib was administered at a dosage of 960 mg b.i.d. to a 30-year-old women at gestational age of 22 weeks. After 12 days from starting treatment with vemurafenib, the mother developed a severe skin toxicity (erythema and blisters), which resulted in spontaneous early preterm delivery of twins and maternal death for intracranial hemorrhage after 78 days from the beginning of the therapy. Any malformations have been observed in newborns, but long-term follow-up is required to assess their neurocognitive function.