How CDK4/6 Inhibitors Are Changing the Cancer Treatment Paradigm?

In the rapidly evolving landscape of cancer therapy, one class of drugs is making waves for its game-changing impact: CDK4/6 inhibitors. These revolutionary agents are rewriting the narrative for treating cancers driven by uncontrolled cell division, particularly hormone receptor-positive, HER2-negative breast cancers. By targeting the critical regulators of the cell cycle, CDK4/6 inhibitors strike at the very heart of cancer’s relentless growth, offering new hope to patients and clinicians alike. With promising data, innovative combinations, and expanding indications, CDK4/6 inhibitors are spearheading a new oncology era—where science meets precision for truly transformative care.

CDK4/6 Inhibitors: Target Patient Pool Analysis

Around 20% of patients with advanced disease fail to respond to CDK4/6 inhibitors, and all eventually develop resistance. Patients with resistant disease face a poor prognosis, with limited treatment options that often come with significant side effects. 

In 2023, there were approximately 475K new cases of HR+/HER2– breast cancer across the 7MM, according to DelveInsight’s assessment in Metastatic HR+/HER2− Breast Cancer Market Report. Additionally, about 80% of small-cell lung cancer (SCLC) cases occurred in individuals aged 65 or older, aligning with the median diagnosis age of 71 years.

In Germany, breast cancer incidence is projected to increase due to an aging population and changes in reproductive behaviors. These include more women remaining childless, delayed motherhood, decreased breastfeeding rates, and lifestyle changes such as shifts in diet and physical activity.

CDK4/6 inhibitors were first approved for metastatic cases, accounting for approximately 6% of de novo metastatic instances and 30% of patients transitioning from localized or regional stages to metastatic disease. Previously, Lilly’s VERZENIO was the sole option for high-risk early-stage patients, but as of September 2024, Novartis’ KISQALI has also entered this space.

CDK4/6 Inhibitors: Cornerstone Treatment Option for Breast Cancer

There are three FDA-approved CDK4/6 inhibitors for the treatment of breast cancer: IBRANCE (Pfizer), VERZENIO (Eli Lilly), and KISQALI (Novartis). VERZENIO, a daily pill typically taken alone, primarily targets CDK4 over CDK6. IBRANCE and KISQALI, which target both CDK4 and CDK6, are used alongside hormonal therapy. In Japan, palbociclib was approved in 2017 for unresectable or recurrent breast cancer, while abemaciclib was approved in 2018 for advanced HR+/HER2− breast cancer. There’s potential for expanding the use of CDK4/6 inhibitors beyond HR+/HER2− advanced breast cancer. Additionally, COSELA, another CDK4/6 inhibitor, was approved for extensive-stage small-cell lung cancer. 

When combined with endocrine therapy, CDK4/6 inhibitors have become the preferred first-line palliative treatment for HR+/HER2− advanced breast cancer. In 2015, IBRANCE (palbociclib) was the first CDK4/6 inhibitor approved by the FDA for HR+/HER2− breast cancer. Its approval extended to use with aromatase inhibitors (AIs) as initial treatment for postmenopausal women or men, and in combination with fulvestrant for patients whose cancer progressed after prior endocrine therapy. 

This approval followed promising results from the Phase II PALOMA-1 trial, where palbociclib outperformed letrozole alone as the initial therapy for patients with advanced breast cancer who had not previously received endocrine therapy. Palbociclib showed manageable side effects and improved quality of life when used in combination therapy compared to endocrine monotherapy.

KISQALI, a CDK4/6 inhibitor approved by the FDA for the treatment of HR+/HER2- metastatic breast cancer in adults. It is authorized for use alongside an aromatase inhibitor as the initial endocrine therapy or with fulvestrant as the first treatment, as well as following disease progression on endocrine therapy in postmenopausal women or men. In December 2018, the European Commission (EC) expanded KISQALI’s approval, following its initial FDA approval in 2017.

Additionally, in September 2024, Novartis’ NATALEE trial extends the use of KISQALI to include node-negative patients, broadening its potential to treat a larger group of breast cancer patients. In contrast, while VERZENIO enjoys the advantage of being a first mover in node-negative patients, it recently failed to show significant benefits in prostate cancer. As Novartis looks to compete with VERZENIO in the adjuvant breast cancer setting, it is also exploring KISQALI’s use in pediatric patients with relapsed or refractory neuroblastoma. 

In terms of sales, VERZENIO’s revenue nearly doubled from 2020 to 2022, largely due to its success in early-stage breast cancer. KISQALI’s global sales rose significantly, driven by its demonstrated overall survival benefit. However, despite being a leader in the CDK4/6 inhibitor class, IBRANCE saw a decline in sales, mainly due to reduced global demand, competitive pressures, fewer international clinical trial purchases, and planned price cuts in select developed markets.

Promising CDK4/6 Inhibitors in the Pipeline

There is promising potential for expanding CDK4/6 inhibitor applications beyond HR+/HER2− advanced breast cancer. Patients who develop resistance to combined CDK4/6 inhibitors and endocrine treatments often switch to conventional chemotherapy due to disappointing outcomes with single-agent fulvestrant.

Major companies are actively working on developing CDK4/6 inhibitors for a range of conditions, such as prostate cancer, breast cancer, and lung cancer. This emerging class of agents holds significant promise for future advancements. As ongoing studies progress in the coming years, we can expect a deeper understanding of CDK4/6 inhibitors and their role in cancer treatment to be better defined.

Trilaciclib (G1 Therapeutics), SPH4336 (Shanghai Pharma Biotherapeutics), Lerociclib (G1 Therapeutics and Pepper bio), Narazaciclib + Letrozole (Traws Pharma), PRT3645 (Prelude Therapeutics) Euthare-155008 (Shengke Pharmaceuticals), and others are the emerging CDK4/6 inhibitors being investigated in early stage (Phase II and I) for several indications.

The anticipated launch of these emerging therapies are poised to transform the CDK4/6 inhibitors market landscape in the coming years. As these cutting-edge therapies continue to mature and gain regulatory approval, they are expected to reshape the CDK4/6 inhibitors market landscape, offering new standards of care and unlocking opportunities for medical innovation and economic growth.

Key Highlights of CDK4/6 Inhibitors at ASCO 2024

At the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, several key developments regarding CDK4/6 inhibitors in cancer treatment were highlighted:

CDK4/6 Inhibitors: What Lies Ahead?

CDK4/6 inhibitors, a class of targeted therapies, have made significant strides in oncology, particularly in the treatment of hormone receptor-positive, HER2-negative breast cancer. These inhibitors work by blocking cyclin-dependent kinases 4 and 6, which are essential for the progression of the cell cycle. By halting cell division, CDK4/6 inhibitors prevent cancer cells from proliferating, leading to tumor shrinkage and prolonged progression-free survival in patients. The approved therapies in this class, such as palbociclib, ribociclib, and abemaciclib, have shown clinical efficacy and are increasingly being used in combination with hormonal therapies, offering new hope for patients with advanced breast cancer. However, challenges such as resistance mechanisms, optimal combination strategies, and side effects like neutropenia and fatigue remain to be fully addressed.

The market for CDK4/6 inhibitors is projected to experience substantial growth in the near future, primarily driven by the rising prevalence of HR+/HER2 breast cancer, which is the main condition treated with these inhibitors. CDK4/6 inhibitors have become a well-established treatment class, with all three approved drugs achieving blockbuster status. Additionally, numerous new therapies are currently undergoing clinical trials, while the existing approved drugs are preparing for label expansions.

Looking ahead, the future of CDK4/6 inhibitors lies in expanding their use beyond breast cancer. Ongoing research is exploring their potential in other malignancies, such as lung cancer, ovarian cancer, and even certain hematologic cancers, where deregulation of the cell cycle plays a crucial role in disease progression. Additionally, the combination of CDK4/6 inhibitors with immunotherapies or other novel agents is being investigated to overcome resistance and enhance their therapeutic efficacy. Moreover, personalized medicine approaches are expected to play a pivotal role in determining the most effective use of these inhibitors, as biomarkers and genetic profiling may help identify which patients will benefit most. As the landscape of cancer treatment continues to evolve, CDK4/6 inhibitors are likely to remain a cornerstone of targeted therapies, with ongoing innovations paving the way for broader applications and improved patient outcomes.