New Indication Approval for Ribociclib: A Game Changer for CDK4/6 Inhibitors

Recently, the FDA officially approved Novartis's ribociclib, in combination with aromatase inhibitors (AI), for the adjuvant treatment of hormone receptor-positive (HR+)/ human epidermal growth factor receptor 2-negative (HER2-) early breast cancer (EBC) patients with high recurrence risk in Phases II and III. This approval extends not only to patients with lymph node metastasis (N+) but also to those with no lymph node metastasis (N0) who are at high risk of recurrence.

As a CDK4/6 inhibitor (CDK4/6i), ribociclib's new indication nearly doubles the population eligible for CDK4/6i adjuvant therapy. This marks a significant milestone in the treatment of early-stage breast cancer. What impact will this development have on the competitive landscape for CDK4/6i?

CDK4/6i R&D Status

CDK4/6i (cyclin-dependent kinases 4 and 6) are important regulators of the cell cycle, a group of serine/threonine protein kinases that catalyze serine/threonine protein phosphorylation and cooperate with cyclins to drive the cell cycle. CDK forms heterodimers when combined with cyclins, and these cyclin-CDK complexes push the progression and transition of the cell cycle phases through CDK activity and substrate phosphorylation.

Given the high expression levels of CDK4/6 in tumors, overexpression can promote the G1/S transition through the phosphorylation of Rb, thereby fostering tumorigenesis. Research has shown that knocking out CDK4/6 genes can inhibit tumor cell growth without affecting normal cells, making CDK4/6 an attractive clinical target, especially in the field of breast cancer. 

Currently, five CDK4/6i have been approved globally: Pfizer's Palbociclib, Novartis's Ribociclib, Eli Lilly's Verzenio, Hengrui Pharmaceuticals's Dalpiciclib, and Simcere Pharmaceutical/G1 Therapeutics' Trilaciclib. Among these, Trilaciclib's indication is for preventing myelosuppression caused by chemotherapy in small cell lung carcinoma (SCLC), whereas the others are primarily indicated for breast cancer.

The CDK4/6i market is dominated by Pfizer, Novartis, and Eli Lilly. With this recent approval, Ribociclib has significantly impacted the market dynamics, particularly affecting Verzenio.

Ribociclib vs. Verzenio: Which Comes Out on Top?

Novartis's ribociclib (marketed as Kisqali) first received FDA approval in March 2017 for use in combination with an aromatase inhibitor (AI) as a first-line treatment for HR+/HER2- locally advanced or metastatic breast cancer in postmenopausal women.

Later, Ribociclib obtained FDA approval for the treatment of HR+/HER2- advanced or metastatic breast cancer in both premenopausal and postmenopausal women, becoming the first CDK4/6 inhibitor to be approved for use in combination with AI in these populations.

Recently, Novartis published data from the Phase III NATALEE trial, evaluating Ribociclib plus endocrine therapy for adjuvant treatment of HR+/HER2- early breast cancer. This study enrolled 5,101 patients with Phases II-III HR+/HER2- early breast cancer, who were randomized 1:1 to receive either Ribociclib plus endocrine therapy or endocrine therapy alone.

After the latest four-year follow-up, the study confirmed the sustained iDFS (invasive disease-free survival) benefit for Phase II-III patients in the ribociclib arm compared to the control. Specifically, after a median follow-up of 44.2 months, the absolute iDFS benefit in the intent-to-treat (ITT) population was 4.9% (88.5% vs. 83.6%, HR = 0.715, P<0.0001). Furthermore, the four-year iDFS benefit increased by 4.3% in the Phase II subgroup and by 5.1% in the high-risk N0 subgroup when treated with ribociclib plus endocrine therapy.

Based on these results, the FDA granted approval for Ribociclib plus AI for adjuvant treatment in Phase II-III HR+/HER2- EBC patients with high recurrence risk, covering both N+ and high-risk N0 patients.

This approval has extended Ribociclib's indication in early-stage breast cancer beyond that of Eli Lilly's Verzenio. Approved in 2017 for HR+/HER2- advanced or metastatic breast cancer, Verzenio was later approved in 2021 for combination therapy with endocrine therapy for HR+/HER2-, node-positive EBC patients at high risk of recurrence, initially requiring a Ki-67 proliferation index of ≥20%. The Ki-67 requirement was later removed.

With its expanded indication in breast cancer, Verzenio held a strong position in early-stage breast cancer treatment, achieving a global sales figure of USD 3.863 billion in 2023 with USD 2.38 billion in sales in the first half of the year. Now, with Ribociclib's approval for N0 EBC patients, its indication has expanded further, potentially impacting Verzenio's market share.

CDK4/6i Market Landscape Facing Reshuffle

As mentioned earlier, there are currently five approved CDK4/6i, with Dalpiciclib and Trilaciclib still relatively new to significantly contribute to sales. The main players in the CDK4/6i market are Palbociclib, Ribociclib, and Verzenio.

As the first globally approved CDK4/6i in 2015 for HR+/HER2- advanced breast cancer, palbociclib was initially granted accelerated approval. It was later approved for second-line treatment with Fulvestrant and first-line treatment with an AI. Within five years on the market, Palbociclib's sales exceeded USD 5 billion, with high market expectations.

However, Palbociclib's heyday was short-lived, as Verzenio and Ribociclib rapidly gained ground. Starting in 2023, Palbociclib's sales began to decline.

Moreover, with its core patent expiring in China in 2023, Palbociclib faced competition from generics. In 2020, Qilu Pharmaaeutical's Palbociclib capsules were approved in China as the first generic drug. Subsequently, Hansoh Pharma and Shanxiang Pharma also obtained approvals for Palbociclib capsule generics, with Simcere Pharmaceutical and Aosaikang also actively entering this market.   

In the Palbociclib tablet market, CSPC Pharmaceutical Group obtained the first generic drug approval in June 2024, while Chiatai Tianqing and Qilu Pharmaceutical are also active in this area.

With the morbidity rate of breast cancer rivaling lung cancer, the market potential for CDK4/6 inhibitors in this therapeutic area is immense, making it a battleground for major pharmaceutical companies. Reports indicate that in 2023, the combined sales of Pfizer, Novartis, and Eli Lilly's CDK4/6 inhibitors alone reached USD 10.796 billion. With new indications and more generics entering the market, the CDK4/6i competitive landscape is set for a major reshuffle.

Reference:

1. Novartis announcement

2.Morrison L, Loibl S, Turner NC. The CDK4/6 inhibitor revolution - a game-changing era for breast cancer treatment. Nat Rev Clin Oncol. 2024 Feb;21(2):89-105. doi: 10.1038/s41571-023-00840-4. Epub 2023 Dec 11. PMID: 38082107.

3. Hui Xue, et al. Research Progress on the Mechanism of Resistance to CDK4/6 Inhibitors. Journal of Modern Oncology, 2022, 30(17):  3225-3230.

4.CDK4/6 inhibitor resistance mechanisms and treatment strategies. DOI: 10.3892/ijmm.2022.5184.