Comparative profile of cutaneous adverse events: BRAF/MEK inhibitor combination therapy versus BRAF monotherapy in melanoma

Abstract

Background BRAF and MEK inhibitors frequently cause cutaneous adverse events. Objective To investigate the cutaneous safety profile of BRAF inhibitors versus BRAF- and MEK-inhibitor combination regimens. Methods We performed a retrospective cohort study, collecting data from 44 melanoma patients treated either with BRAF inhibitors (vemurafenib or dabrafenib) or BRAF- and MEK- inhibitor combination regimens (vemurafenib+cobimetinib or dabrafenib+trametinib). Patient characteristics, as well as the occurrence and severity of cutaneous adverse events are described. Results The development of cutaneous adverse events was significantly less frequent (p=0.012) and occurred after longer treatment time (p=0.025) in patients treated with BRAF- and MEK-inhibitor combination regimen compared to patients treated with BRAF inhibitor monotherapy. Among patients who received both BRAF inhibitor treatment and the combination of BRAF- and MEK-inhibitor at different time points during their treatment course, the development of squamous cell carcinoma or keratoacanthoma was significantly less frequent when they received the combination regimen (p=0.008). Patients receiving vemurafenib developed more cutaneous adverse events (p=0.001) and in particular more photosensitivity (p=0.010) than patients who did not. Limitations Limited number of patients. Conclusion Combination regimen with BRAF- and MEK-inhibitors shows fewer cutaneous adverse events and longer cutaneous adverse event-free interval compared to BRAF inhibitor monotherapy.

Development of Cutaneous Toxicities During Selective Anti-BRAF Therapies: Preventive Role of Combination with MEK Inhibitors

“…Similar to previous reports, single-drug treatment demonstrated a higher frequency and earlier appearance of NMSC-including or not including AK, than combined treatment (7)(8)(9)(10)(11). Indeed all SCCs were presented under this regime.…”

“…Importantly, our study found that combined therapy did not prevent PPK. Acneiform eruption/folliculitis was more frequent in our series and significantly seen in males (8,(10)(11)(12). Interestingly, gender was not related to any other specific toxicity.…”

“…Our study supports the fact that photosensitivity occurs during the early stages of BRAF inhibitor treat ments and, notably, demonstrates that combination with MEK inhibitors does not prevent photosensitivity. Despite the small sample size with dabrafenib in our series, which is a limitation of our study, there appears to be no difference in photosensitivity between the 2 selective BRAF inhibitors (8)(9)(10)(11).…”

“…Trametinib is one of these MEK inhibitors. Skin toxicities from BRAF inhibitors, such as photosensitivity, palmoplantar keratoderma (PPK) and keratosis pilaris (KP), have been reported (4,(6)(7)(8)(9)(10)(11). Also, non-melanoma skin cancers (NMSC) are considered one of the most significant sideeffects (3,11).…”

Overcoming resistance to BRAF inhibitors

“…Despite slight differences on clinical endpoints both combinations provide equally evident benefit, and as previously mentioned have now become the standard of care for BRAF mutant melanomas (92,93). Combinations of BRAF and MEK targeting drugs provide further clinical benefits as the occurrence of cutaneous adverse events such as squamous cell carcinoma or keratoacanthoma is significantly diminished (94), positively impacting on patient's healthrelated quality of life (95,96).…”