Ribociclib and Letrozole Improve Survival in Advanced Breast Cancer

Highlights

• Advanced breast cancer is breast cancer that has spread either locally or to other parts of the body like the brain, bones and liver
• Women with breast cancer often develop resistance to hormonal treatment
• The Mammary ONcology Assessment of LEE011's Efficacy and Safety-2 (MONALEESA-2) trial evaluates the combination of ribociclib and letrozole in the treatment of HR+/HER- advanced breast cancer

An investigational drug, ribociclib, has been found to improve progression-free survival of hormone-receptor positive, human epidermal growth factor receptor-2 negative (HR+/HER2-) advanced breast cancer in Asian women. This finding of a sub-group analysis of the MONALEESA-2 (Mammary ONcology Assessment of LEE011's Efficacy and Safety-2) trial is being presented at the European Society of Medical Oncology 2016 Congress, Singapore. Breast cancer is responsible for numerous deaths among women all over the world. With increased awareness, regular screening and effective treatments, several women diagnosed early go on to lead normal lives.

Unfortunately, breast cancer is still difficult to be completely cured at an advanced stage. Advanced breast cancer includes stage 3 cancer that has spread locally, for example, to the chest wall, skin or local lymph nodes, and stage 4 cancer, that has spread to distant sites like the brain, bones and the liver. Under such circumstances, efforts are made to prevent progression of the cancer and prolong the life of the patient.

Breast cancer is treated with:

• Surgery, which may be just removal of the lump or the entire breast
• Radiation therapy
• Chemotherapy
• Hormone treatment, which is useful for those cancers that are positive for hormone receptors i.e. estrogen and /or progesterone receptors. (ER-positive and/or PR-positive). Hormonal treatments for breast cancer include:
• The estrogen receptor blockers tamoxifen and fulvestrant
• Aromatase inhibitors that reduce production of estrogen which include letrozole, anastrozole and exemestane
• Suppression of ovarian function with either surgical removal or the ovaries, use of LHRH agonists leuprolide or goserelin, or chemotherapy drugs
• Targeted therapy, It is used in the treatment of HER2-positive breast cancers. HER2 or HER2/neu is a protein on breast cancer cells that promotes the growth of the cancer. Medications like trastuzumab, pertuzumab, ado-trastuzumab emtansine and lapatinib act by targeting this protein.

Patients can develop resistance to hormonal treatment, thereby making treatment ineffective. To overcome this problem, ribociclib drug is being tried out.

Ribociclib Drug

Ribociclib belongs to group of drugs called selective cyclin dependent kinase inhibitors. It acts on and inhibits two proteins called cyclin dependent kinase 4 and 6 (CDK4/6), which promote the growth of cancer cells and are responsible for the resistance to drugs like letrozole. By inhibiting the pathway, it possibly prevents the resistance and allows letrozole to be used for a longer period thereby delaying the use of chemotherapy. Palbociclib is a similar drug that is already approved by the FDA in HR+/HER- advanced breast cancers.

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Drug Trial Conducted on Breast Cancer Patients

Ribociclib is being evaluated in the MONALEESA trial that is being conducted in breast cancer patients all over the world. The MONALEESA trial includes the MONALEESA-2, MONALEESA-3, and MONALEESA-7 trials.

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In the MONALEESA-3 trial, the combination of ribociclib and fulvestrant is being tested, while in the MONALEESA-7 trial, ribociclib is being tested for use along with endocrine therapy and goserelin.

The MONALEESA-2 study included 668 patients with HR-positive, HER2-negative advanced breast cancer. Among these, 334 patients received letrozole 2.5 mg/ day and a placebo, while the remaining 334 patients were administered letrozole 2.5 mg/ day plus ribociclib (in a regimen 600 mg /day for three weeks followed by a break for a week). The patients were assessed every 8 weeks for the first year and a half, and then every 12 weekly.

The researchers found that the combined treatment with ribociclib and letrozole increased the progression-free survival of the patients by 44% as compared to letrozole alone. As mentioned above, letrozole is an aromatase inhibitor that reduces the production of estrogen. It is used in postmenopausal women with hormone-positive breast cancer who have early received tamoxifen for 5 years.

A subgroup analysis of the MONALEESA-2 trial in the Asian population is being presented at the European Society of Medical Oncology 2016 Congress, Singapore. The analysis is relevant since the incidence of breast cancer is high in several parts of Asia. Asia accounts for 24% of all breast cancer cases, several of these being in the advanced stages at the time of diagnosis.

The research team found that the combined treatment with ribociclib and letrozole caused a significant improvement in progression-free survival in Asian patients as compared to those who received only letrozole. The safety of the combination was acceptable and similar to that observed in the full population.

Side effects of ribociclib include reduced white blood cell counts (neutropenia / leucopenia) and increase in the levels of liver enzymes. The patient may thus be exposed to additional side effects. However, it could still be useful if the benefits of the combination outweigh the risks.

Ribociclib and letrozole used together may thus provide an alternative to the treatment of HR+/HER2- advanced breast cancer in the Asian patients. However, the cost of the treatment may not support the use of this drug in several parts of Asia.

Further studies to pinpoint patients who would particularly benefit from the new drug, like those with a specific biomarker, could help to better select patients for the treatment.

Novartis, the company manufacturing ribociclib, has been granted Priority Review for the drug, which means that the drug will go through the approval process faster and possibly get approval early.

References:

1. LBA1_PR - 'First-line ribociclib + letrozole in postmenopausal Asian women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): A subgroup analysis from MONALEESA-2' Presented by Yoon-Sim Yap during the Presidential Symposium at ESMO Asia 2016, Singapore.

Source-Medindia