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New primary malignant tumors, including cutaneous and non-cutaneous malignancies, may occur with cobimetinib use.
In Trial 1, the following cutaneous malignancies or precancerous lesions occurred in the cobimetinib plus vemurafenib group and the vemurafenib alone group, respectively:
Cutaneous squamous cell carcinoma (cSCC) or keratoacanthoma: 6% vs. 20%
Basal cell carcinoma (BCC): 4.5% vs. 2.4%
Second primary melanoma: 0.8% vs. 2.4%
Among patients receiving cobimetinib plus vemurafenib, the median time to first detection of cSCC/keratoacanthoma was 4 months (range: 2–11 months), and the median time to detection of BCC was 4 months (range: 27 days–13 months). The onset times of second primary melanoma in two patients were 9 months and 12 months, respectively.
Dermatological evaluations should be performed before initiating treatment and every 2 months during treatment. Suspected cutaneous lesions should be managed with excision and dermatopathological assessment. Dose adjustment of cobimetinib is not recommended. Skin monitoring should be conducted for 6 months after discontinuing the combined treatment of cobimetinib and vemurafenib.
Based on its mechanism of action, vemurafenib may promote the growth and development of malignant tumors. In Trial 1, non-cutaneous malignancies occurred in 0.8% of patients in the cobimetinib plus vemurafenib group and 1.2% of patients in the vemurafenib alone group.
When cobimetinib is administered in combination with vemurafenib, monitor patients for signs or symptoms of non-cutaneous malignancies.
Bleeding, including major bleeding defined as symptomatic bleeding in critical areas or organs, may occur with cobimetinib.
In Trial 1:
The incidence of Grade 3–4 bleeding was 1.2% in patients receiving cobimetinib plus vemurafenib and 0.8% in those receiving vemurafenib alone.
The incidence of bleeding (all grades) was 13% in the cobimetinib plus vemurafenib group and 7% in the vemurafenib alone group.
The incidence of cerebral hemorrhage was 0.8% in the cobimetinib plus vemurafenib group, with no cases reported in the vemurafenib alone group.
Compared with patients receiving vemurafenib alone, those receiving cobimetinib plus vemurafenib also had higher incidences of gastrointestinal bleeding (3.6% vs. 1.2%), genital bleeding (2.0% vs. 0.4%), and hematuria (2.4% vs. 0.8%).
In Trial 2 (patients with histiocytic neoplasms), 19% of patients experienced bleeding events (all Grade 1 severity).
For Grade 3 bleeding events, withhold cobimetinib. If improvement to Grade 0 or 1 occurs within 4 weeks, resume cobimetinib at a lower dose level. For Grade 4 bleeding events and any Grade 3 bleeding events that do not improve, discontinue cobimetinib.
Cardiomyopathy, defined as symptomatic or asymptomatic left ventricular ejection fraction (LVEF) reduction, may occur with cobimetinib. The safety of cobimetinib in patients with a baseline LVEF below the institutional lower limit of normal (LLN) or below 50% has not been established.
In Trial 1:
LVEF reduction was assessed via echocardiogram or multigated acquisition (MUGA) scan at baseline, Week 5, Week 17, Week 29, Week 43, and every 4–6 months thereafter during treatment.
LVEF reduction of Grade 2 or 3 occurred in 26% of patients receiving cobimetinib plus vemurafenib and 19% of those receiving vemurafenib alone.
The median time to first onset of LVEF reduction was 4 months (range: 23 days–13 months).
Among patients with LVEF reduction, 22% required treatment interruption and/or dose reduction, and 14% required permanent discontinuation.
In patients receiving cobimetinib, 62% had LVEF reduction recover to above the LLN or within 10% of the baseline value, with a median recovery time of 3 months (range: 4 days–12 months).
In Trial 2 (patients with histiocytic neoplasms):
8% of patients experienced Grade 2 LVEF reduction, and 12% experienced Grade 3–4 events.
The median time to first onset of LVEF reduction was 29 days (range: 22 days–114 days).
All patients with LVEF reduction required dose interruption and/or reduction, with no permanent discontinuation needed.
60% of patients receiving cobimetinib had LVEF reduction recover to above the LLN or within 10% of the baseline value, with a median recovery time of 31 days (range: 13 days–126 days).
Assess LVEF before initiating treatment, 1 month after treatment initiation, and every 3 months thereafter until cobimetinib is discontinued. Manage left ventricular dysfunction events through treatment interruption, dose reduction, or discontinuation. For patients restarting cobimetinib after dose reduction or interruption, assess LVEF approximately at Week 2, Week 4, Week 10, Week 16, and as clinically indicated.
Severe rash and other cutaneous reactions may occur with cobimetinib.
In Trial 1:
Grade 3–4 rash occurred in 16% of patients receiving cobimetinib plus vemurafenib and 17% of those receiving vemurafenib alone, including Grade 4 rash in 1.6% of the combination group and 0.8% of the monotherapy group.
The incidence of rash leading to hospitalization was 3.2% in the cobimetinib plus vemurafenib group and 2.0% in the vemurafenib alone group.
The median time to onset of Grade 3 or 4 rash events in patients receiving cobimetinib was 11 days (range: 3 days–2.8 months).
Among patients with Grade 3 or 4 rash events, 95% achieved complete resolution, with a median resolution time of 21 days (range: 4 days–17 months).
In Trial 2 (patients with histiocytic neoplasms), 81% of patients experienced rash events (all Grade 1–2 severity).
Withhold, reduce the dose of, or discontinue cobimetinib for severe cutaneous reactions.
Ocular toxicity, including serous retinopathy (fluid accumulation under the retinal layers), may occur with cobimetinib.
In Trial 1:
Ophthalmic examinations, including retinal assessment, were performed regularly before and during treatment.
Symptomatic and asymptomatic serous retinopathy was identified in 26% of patients receiving cobimetinib plus vemurafenib. Most of these events were reported as chorioretinopathy (13%) or retinal detachment (12%).
The time to first onset of serous retinopathy events ranged from 2 days to 9 months, and the reported duration of serous retinopathy ranged from 1 day to 15 months.
One patient in each group developed retinal vein occlusion.
In Trial 2 (patients with histiocytic neoplasms), 4% of patients experienced Grade 2 retinopathy, and 4% experienced Grade 3 retinal vascular disease.
Perform regular ophthalmic evaluations and additional examinations whenever patients report new or worsening visual disturbances. If serous retinopathy is diagnosed, withhold cobimetinib treatment until visual symptoms improve. Manage serous retinopathy through treatment interruption, dose reduction, or discontinuation.
Hepatotoxicity may occur with cobimetinib.
In Trial 1, the incidences of Grade 3 or 4 liver laboratory abnormalities in patients receiving cobimetinib plus vemurafenib versus those receiving vemurafenib alone were:
Alanine aminotransferase (ALT): 11% vs. 5%.
Aspartate aminotransferase (AST): 8% vs. 2.1%.
Total bilirubin: 1.6% vs. 1.2%.
Alkaline phosphatase (ALP): 7% vs. 3.3%.
One patient (0.4%) in the cobimetinib plus vemurafenib group developed concurrent ALT elevation >3 times the upper limit of normal (ULN) and bilirubin elevation >2 times ULN (without significant ALP elevation >2 times ULN), while no such cases were reported in the vemurafenib monotherapy group.
In Trial 2 (patients with histiocytic neoplasms), 9% of patients receiving cobimetinib experienced Grade 3 or 4 AST elevation, and 5% experienced Grade 3 or 4 ALT elevation.
Monitor liver laboratory tests before initiating cobimetinib treatment, monthly during treatment, or more frequently as clinically needed. Manage Grade 3 and 4 liver laboratory abnormalities by withholding, reducing the dose of, or discontinuing cobimetinib.
Rhabdomyolysis may occur with cobimetinib.
In Trial 1:
Grade 3 or 4 creatine phosphokinase (CPK) elevation (including asymptomatic elevation above baseline) occurred in 14% of patients receiving cobimetinib plus vemurafenib and 0.5% of those receiving vemurafenib alone.
The median time to first onset of Grade 3 or 4 CPK elevation in the combination group was 16 days (range: 12 days–11 months), and the median time to complete resolution was 15 days (range: 9 days–11 months).
3.6% of patients in the cobimetinib plus vemurafenib group had serum CPK elevation >10 times the baseline value concurrent with serum creatinine elevation ≥1.5 times the baseline value, compared with 0.4% in the vemurafenib alone group.
Obtain baseline serum CPK and creatinine levels before initiating cobimetinib treatment, regularly during treatment, and as clinically indicated. If CPK elevation occurs, assess for signs and symptoms of rhabdomyolysis or other causes. Treatment interruption or discontinuation of cobimetinib may be required based on the severity of symptoms or CPK elevation.
In Trial 2 (patients with histiocytic neoplasms), 27% of patients experienced Grade 2 CPK elevation, and 27% experienced Grade 3–4 CPK elevation.
FDA，2023.05
Lucius Pharmaceuticals (Lao) LTD. (Lucius Pharmaceuticals), with its manufacturing campus in Laos located in the capital city of Vientiane in 2020, officially begins its great journey to make effective and affordable medicines available to people in need around the world...More
Lucius Pharmaceutical Co., Ltd., was established in 2020 in Vientiane, the capital of Laos. It aims to offer safe, effective, and affordable medicines globally. With a factory spanning 25,000 square meters, the company manufactures 200+ generic drugs in diverse therapeutic fields.
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