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‘Ibrance’ opens new horizon as the lead CDK4/6 inhibitor
by Oct 14, 2021 05:38am
The breast cancer treatment ‘Ibrance (palbociclib)’ was what established Pfizer Korea as the ‘anticancer drug power’ in Korea. The company had other excellent anticancer drugs such as ‘Xalkori,’ and ‘Sutene,’ but none had received as much spotlight as Ibrance. As the ‘first CDK4/6 inhibitor,’ and ‘the first new breast cancer drug in 50 years,’ Ibrance had quickly rose to the ranks and became a blockbuster drug. ◆ The first CDK4/6 inhibitor, unrivaled status despite controversy Ibrance selectively inhibits Cyclin-dependent kinases (CDK) 4/6 that regulate cell division and cell growth to block the proliferation of tumor cells. Lilly’s Verzenio (abemaciclib),’ and Novartis’s ‘Kisqali (ribociclib)’ belong to CDK4/6 inhibitor class drugs. Among these drugs, Ibrance is the first drug in its class, the ‘first-in-class’ CDK 4/6 inhibitor. Ibrance is indicated for the treatment of breast cancer in combination with an aromatase inhibitor as first-line endocrine therapy in postmenopausal women or combination with fulvestrant in pre-and post-menopausal women with disease progression following endocrine therapy. For a year Ibrance was launched in Korea in August 2016, the field was full of expectations, disappointment, longing, and appeals. The introduction of a new drug with a new mechanism of action was blissful news. In particular, the patient population for Ibrance was wider than other drugs, as it targeted f hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, which accounts for 60% of all breast cancers. These patients had to use anti-hormonal drugs such as aromatase inhibitors or chemotherapy, which had many systemic side effects if not managed until Ibrance appeared. Before the introduction of Ibrance, this patient group had to use antihormonal therapy such as aromatase inhibitors, and if their condition was not managed with such therapies, use chemotherapy, which had many systemic side effects Korea was the fifth country to approve the drug. In December of the same year, the drug's efficacy and safety in Asian patients were verified through a clinical trial and rose as the drug that could change the breast cancer treatment paradigm. The National Comprehensive Cancer Network’s ‘Category 1’ recommendation of CDK4/6 inhibitors as combination therapy for the treatment of HR+/HER2- advanced/metastatic breast cancer had also contributed greatly to establishing the drug as standard care in breast cancer. However, Ibrance did not immediately rise and become the star after its release. The drug had suffered receiving reimbursement due to its high drug price, costing over ₩5 million per month. In particular, 2017 was the time when many high-price anticancer drugs were introduced and rejected reimbursement, and Pfizer Korea was put at a difficult price due to its difficulty in demonstrating cost-effectiveness, and the issue that Ibrance was more expensive in Korea than abroad. The Health Insurance Review and Assessment Service recognized Ibrance’s feasibility of reimbursement in July 2017, after rounds of review. However, the approval left much to be desired among patients because the reimbursement was only allowed as first-line endocrine therapy in postmenopausal women in combination with letrozole. Its use as second-line therapy in combination with fulvestrant was non-reimbursed, and premenopausal patients, which are much more prevalent in the East than in the West, were unable to receive the reimbursement benefit at all. The 2nd-line reimbursement of Ibrance+fulvestrant was only approved last July, 4 years after Ibrance’s approval. In addition, the fact that the drug was reimbursed at the same time with the CDK4/6 class latecomer Verzenio, left much to be desired for Ibrance. However still, Ibrance is fully exerting its strength as the ‘first’ introduced to its market. Among the three products in the CDK4/6 market, Ibrance has been dominating the market as the second drug, Verzenio, was approved in Korea three years later than Ibrance, in May 2019. The third CDK4/6 inhibitor Kisqali was approved 5 months after Verzenio, in October 2019 and listed for reimbursement in November last year. 자료: 아이큐비아 Ibrance raised annual sales of ₩40 billion in three years in the competitor-free market. According to the market research institution IQVIA, sales of Ibrance, which was ₩6.6 billion in 2017, surged 283% in 2018 to reach ₩25.3 billion after being listed for reimbursement. Then, sales rose 73% again to record ₩43.7 billion in 2019. Last year, Ibrance sold around ₩60 billion and is expected to sell near ₩70 billion this year. Compared to Ibrance’s quarterly sales, which is around ₩15 billion, Verzenio’s sold ₩3 billion, and Kisqali sold mid-₩1 billion range. ◆Three-way competition starts now… data will decide the winner With all three products now approved for reimbursement, the competition is finally in full pace. Of course, the other two drugs have a long way to go because they need to break down the solid position held by Ibrance in the market. Therefore, the latecomer drugs are betting in areas where Ibrance has not reached, as preoccupying new areas is easier than breaking down Ibrance's established position. The attempt will also support the expansion of the overall CDK4/6 inhibitor market amid the increased introduction of new-class drugs. One of the areas being targeted is early breast cancer. Despite its strength in metastatic breast cancer, Ibrance did not show as a good result in early breast cancer. In both the PALLAS study that tested Ibrance+endoctrine therapy as adjuvant therapy in hormone receptor-positive (HR+)/HER-2 negative (HER2-) metastatic breast cancer and the PENELOPE-B study that tested Ibrance+endoctrine therapy after neoadjuvant chemotherapy, Ibrance did not show a difference in invasive disease-free survival (iDFS) compared to placebo (primary endpoint). Pfizer believed the high early discontinuation rate due to the strict dose restriction and the short period of administration had an effect. On the other hand, Verzenio achieved its primary endpoint in a median follow-up period of 15.5 months as adjuvant therapy, suggesting the potential for scope expansion. Of course, whether using CDK4/6 inhibitor as adjuvant therapy in early breast cancer patients is more beneficial, remains a question that needs to be addressed. Kisqali can be used in combination with an aromatase inhibitor as first-line endocrine therapy in pre/perimenopausal women that cannot use Ibrance, and therefore may resolve the unmet needs of Ibrance. Also, Kisqali has demonstrated the longest overall survival period among all drugs, threatening Ibrance’s sole lead in the market.