Key evidence from clinical trials for cobimetinib

What is cobimetinib?

Cobimetinib is a prescription medicine used to treat melanoma that has spread to other parts of the body, cannot be removed by surgery, and has an abnormality BRAF gene. It should not be used to treat melanoma in patients with a normal or wild type BRAF gene.

In 2015, the United States Food and Drug Administration (FDA) approved cobimetinib (Cotellic ™, Genentech Inc. California, USA) in combination with vemurafenib (a specific BRAF kinase inhibitor) for the treatment of melanoma .

In the same year, the Committee for Medicinal Products for Human Use of the European Medicines Agency issued a positive opinion for the marketing authorization of cobimetinib in the European Union.

Cobimetinib has since received approval for marketing in New Zealand through Medsafe in 2017 for the treatment of melanoma patients.

The FDA approval was based on the results of the Phase III CoBRIM study, which showed that cobimetinib, when used in combination with vemurafenib, reduced the risk of disease worsening or death by about half in melanoma patients.

Key evidence from clinical trials for cobimetinib

The CoBRIM study

CoBRIM was an international, randomized, double-blind, placebocontrolled phase III that evaluated the safety and effectiveness cobimetinib 60 mg once daily plus vemurafenib 960 mg twice daily compared to vemurafenib 960 mg twice daily plus placebo. A total of 495 patients participated in the study, all of whom had not been previously treated. BRAF V600 mutation-positive, unresectable, locally advanced or metastatic melanoma.

The presence of BRAF The V600 mutation was detected using the cobas^®; 407 4800 BRAF V600 mutation test.

• All patients received vemurafenib 960 mg orally twice daily on days 1–28.
• Patients were randomized to receive oral cobimetinib 60 mg or placebo equivalent once daily on days 1 to 21 of each 28-day cycle. Randomization It was stratified by geographic region (North America vs. Europe vs. Australia / New Zealand / others) and disease stage (unresectable stage IIIc, M1a or M1b vs. stage M1c).
• Treatment continued until disease progression, unacceptable. toxicityor withdrawal of consent.
• Patients randomized to placebo were not offered cobimetinib at the time of disease progression.
• The main efficacy outcome was investigator-assessed progression-free survival (PFS) according to RECIST v1.1.
• Secondary end points included PFS by an independent review committee, objective response rate, overall survival, and duration of response.

The efficacy results are summarized in Table 1.

Adverse events - experience in clinical trials (CoBRIM study)

The most common (≥ 20%) Adverse reactions with cobimetinib were:

• Diarrhea
• Photosensitivity reaction
• Nausea
• Pyrexia
• Vomiting

Because clinical trials are conducted under highly variable conditions, the adverse reaction rates seen in clinical trials may not reflect rates seen in practice. In the CoBRIM study, 15% of patients receiving cobimetinib experienced an adverse reaction that resulted in permanent discontinuation of the drug.

The most common adverse reactions that led to permanent drug discontinuation were:

• Liver laboratory abnormalities, defined as increased aspartate aminotransferase (2.4%), increased gamma glutamyltransferase (1.6%) and increased alanine aminotransferase (ALT; 1,6%)
• Eruption (1,6%)
• Pyrexia (1.2%)
• Retinal detachment (2%).

Among the 247 patients who received cobimetinib, adverse reactions resulted in dose interruption or reductions in 55%. The most common reasons for cobimetinib dose reductions or interruptions were:

• Rash (11%)
• Diarrhea (9%)
• Chorioretinopathy Accumulation of fluid under the retina (7%)
• Pyrexia (6%)
• Vomiting (6%)
• Nausea (5%)
• Increased creatine phosphokinase (4.9%).

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of a medicine is important, as it allows continuous monitoring of the benefit / risk balance of the medicine. Healthcare professionals in New Zealand are advised to report any suspected adverse reactions to the New Zealand Center for Pharmacovigilance.

Overdose

There is no experience with cobimetinib overdose in human clinical trials. In the event of a suspected overdose, cobimetinib should be discontinued and supportive care instituted. There is no specific antidote for overdose with cobimetinib.

The New Zealand National Poisons Center should be contacted on 0800 764 766 for advice on managing an overdose.

Cobimetinib - future potential

• New treatments for metastatic melanoma work through different mechanisms to enhance immune response and blockage cellular proliferation.
• Like trametinib, cobimetinib is a MEK inhibitor. MEK1 and MEK2 are tyrosine kinases that interact with BRAF and lead to uncontrolled growth of melanoma cells.
• Clinical trials have shown that the addition of cobimetinib to vemurafenib results in improved survival in melanoma patients harboring the BRAF V600 mutation.
• Overall survival in patients treated with nivolumab and pembrolizumab appears to be higher compared to that achieved with cobimetinib and vemurafenib.
• However, overall survival in patients treated with a combination of vemurafenib and cobimetinib appears to be similar to other available treatment strategies for the treatment of unresectable metastases. evil one melanoma, such as combinations of nivolumab and ipilimumab and dabrafenib with trametinib.
• For PFS, dabrafenib in combination with trametinib and vemurafenib in combination with cobimetinib appeared to have a higher probability of good performance than other available treatment strategies.
• For serious adverse events, pembrolizumab and nivolumab appeared to have a higher probability of fewer serious adverse events than cobimetinib and vemurafenib.
• However, neither of these interventions is cost-effective at maximum pharmacy retail prices, and the budgetary impacts on clinical practice can be substantial.
• The fast tumor response to BRAF / MEK inhibition It is often short-lived as tumors develop resistance to combination therapy.
• New trials are beginning to investigate the addition of a third targeted agent or immunotherapy to increase the durability of response to treatment.