Recently, Pfizer announced positive results from its proprietary, highly selective CDK4 inhibitor, Atirmociclib, in the Phase 2 clinical trial (FOURLIGHT-1) for the treatment of previously treated HR+/HER2- advanced or metastatic breast cancer.

Based on this positive result, Pfizer believes that Atirmociclib has the potential to become the next blockbuster product in breast cancer treatment , and also gives confidence to other CDK4 inhibitors in development.

01

Next-generation CDK inhibitors

Breast cancer is a common malignant tumor in women, most of which belong to the hormone receptor positive (HR+)/human epidermal growth factor receptor 2 (HER2-) subtype.

The rise of CDK4/6 inhibitors has brought a breakthrough in precision treatment of this subtype of breast cancer, shifting the treatment modality for HR+/HER2- breast cancer patients from single-drug endocrine therapy to a combination of endocrine and targeted therapy. Currently, CDK4/6 inhibitors combined with endocrine therapy have become the standard treatment for HR+/HER2- advanced breast cancer, unanimously recommended by authoritative guidelines both domestically and internationally.

However, CDK4/6 inhibitors commonly cause dose-limiting hematological adverse reactions such as neutropenia, and with the widespread use of these drugs, drug resistance is becoming increasingly prominent.

Therefore, developing a new generation of CDK inhibitors with higher selectivity and lower toxicity has significant clinical value.

Studies have found that tumors highly dependent on CDK4 (such as HR+/HER2- breast cancer, prostate cancer, and Ewing sarcoma) are generally not dependent on CDK6. Furthermore, knocking out CDK4 alone does not affect human bone marrow-derived cells, while knocking out CDK6 alone or simultaneously knocking out both CDK4 and CDK6 reduces the number of human bone marrow-derived cells, indicating that CDK6 plays a crucial role in hematopoiesis. Therefore, developing highly selective CDK4 inhibitors may be a better solution for tumor types highly dependent on CDK4.

Pfizer's Atirmociclib has a higher affinity and selectivity for CDK4 . Compared with the existing CDK4/6 inhibitor palbociclib, it improves CDK4 target coverage and efficacy while reducing CDK6 inhibition and minimizing the impact on neutrophils.

The data from the FOURLIGHT-1 study released this time validates the clinical feasibility of the above theoretical assumptions.

This study was an open-label, randomized, multicenter phase 2 clinical trial that enrolled 264 patients to evaluate the efficacy and safety of atirmociclib plus fulvestrant versus fulvestrant or everolimus plus exemestane in adult patients with HR+/HER2- advanced or metastatic breast cancer whose disease had progressed after CDK4/6 inhibitor therapy.

The results showed that the combination therapy with Atirmociclib demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint of PFS (HR=0.60, p=0.0007) , which was superior to the control group.

In all pre-specified subgroups, including performance status, menopausal status, presence of visceral metastases, duration of previous CDK4/6 inhibitor treatment, and type of previous CDK4/6 inhibitor, PFS results remained consistent.

Meanwhile, Atirmociclib has a manageable safety profile and is well-tolerated, with only 6.4% of patients discontinuing treatment due to treatment-emergent adverse events (TEAEs) . Its safety profile is consistent with previous studies, and no new safety signals were identified.

Although overall survival (OS) data are still immature, the significant prolongation of progression-free survival (PFS) in later-line treatment is sufficient to demonstrate its clinical value. This indicates that even if patients have developed resistance to first-generation CDK4/6 inhibitors, the use of highly selective CDK4 inhibitors remains effective.

Besides Pfizer, companies such as BeiGene, Hengrui Medicine, Anrui Biotech, and Roche have also entered the CDK4 inhibitor market.

BeiGene plans to initiate a Phase 3 clinical trial in the first half of this year for its CDK4 inhibitor BGB-43395 as a first-line treatment for HR+/HER2- metastatic breast cancer , which is expected to become the second drug targeting the same target to enter the registration clinical stage.

BGB-43395 performed well in GLP toxicology studies, with no significant neutropenia or gastrointestinal toxicity observed. Furthermore, in the MCF-7 proliferation assay, BGB-43395 exhibited an inhibitory efficacy of 126 nM (IC₅₀), stronger than Atirmociclib, demonstrating superior therapeutic efficacy.

Hengrui Medicine 's highly selective CDK4 inhibitor HRS-6209 is currently in Phase 1/2 clinical trials. This drug can inhibit the CDK4/cyclin D complex and downstream signaling, inducing tumor cells to arrest in the G1 phase, thereby exerting an anti-tumor effect.

Allorion 's CDK4 inhibitor is also undergoing Phase 1/2 clinical trials.

In 2024, Anrui Biotech entered into a collaboration agreement with Avenzo Biotech, granting Avenzo the global (excluding Greater China) development and commercialization rights to Anrui Biotech's CDK2 selective inhibitor ARTS-021 (AVZO-021), and an exclusive option for the CDK4 inhibitor ARTS-023 (AVZO-023). In return, Anrui Biotech received an upfront payment of $40 million, potential milestone payments of up to $1 billion, and sales royalties. AVZO-023 is currently in Avenzo's pipeline.

Roche added a Phase I clinical trial of its CDK4 inhibitor RG6795 for the treatment of HR+/HER2- breast cancer.

02

A key piece of the puzzle in Pfizer's oncology pipeline
In 2015, Pfizer secured the world's first marketed CDK4/6 inhibitor, Ibrance (palbociclib). Sales of the drug peaked at $5.437 billion in 2021.

However, the CDK4/6 market quickly became crowded, and currently there are 9 CDK4/6 inhibitors and 1 CDK2/4/6 inhibitor approved for marketing worldwide.

In 2024, Eli Lilly's Verzenios (abecical) surpassed Ibrance in sales, becoming the new leader in the CDK4/6 inhibitor market. Furthermore, Ibrance's US patent expires in 2027.

Therefore, the next-generation CDK4 inhibitor Atirmociclib has become a key piece of the puzzle for Pfizer in defending its position in breast cancer.

Currently, the Fourlight-1 study has met its primary endpoint, demonstrating that Atirmociclib has the potential to outperform existing CDK4/6 inhibitors in the treatment of HR-positive breast cancer.

It is worth noting that Pfizer is not content with second-line treatment and has set its sights on earlier treatment options .

Pfizer initially designed the Fourlight-1 study as a phase 3 clinical trial. However, last year Pfizer readjusted its strategy, changing the study to a phase 2 trial and reducing the enrollment target from 500 to 333 participants, with 264 ultimately enrolled.

Pfizer made this adjustment at the same time it launched a Phase 3 clinical trial (FOURLIGHT-3) for first-line advanced or metastatic breast cancer patients, with an enrollment of over 1,000 participants . This will be a crucial battleground for Atirmociclib to directly compete with approved CDK4/6 inhibitors.

FOURLIGHT-3 was an interventional, open-label, randomized, multicenter phase 3 clinical trial designed to compare the efficacy of combination therapy with atirmociclib versus combination therapy with a CDK4/6 inhibitor. The control group of CDK4/6 inhibitors included Eli Lilly's Verzenio, Novartis' Kisqali, and Pfizer's Ibrance.

In addition, the results of a phase 2 study of Atirmociclib for neoadjuvant therapy in early breast cancer are also about to be released.

Oncology is one of Pfizer's four core therapeutic areas following its organizational restructuring and strategic focus, and it is also a top priority for Pfizer's research and development.

In this field, Pfizer focuses on small molecule drugs, ADCs, bispecific antibodies, and other immunotherapies. The company previously acquired Seagen for $43 billion, gaining an early advantage in the ADC market; at the same time, it has been aggressively expanding its external pipeline to strengthen its product portfolio, covering various technologies such as bispecific antibodies, ADCs, small molecules, and AI.

Other potential pipeline drugs include SSGJ-707, a PD-1/VEGF bispecific antibody acquired from 3SBio; Sigvotatug vedotin, an ADC drug targeting integrin β6 (IB6); and SGN-PDL1V, an ADC drug targeting PD-L1. The company anticipates launching more than eight potential blockbuster innovative oncology drugs by 2030.

03

Conclusion
The advent of CDK4/6 inhibitors ushered in a new era of targeted therapy combined with endocrine therapy for HR+/HER2- breast cancer. Now, next-generation highly selective CDK4 inhibitors, with their dual advantages of high efficacy and low toxicity, are poised to reshape the landscape of breast cancer treatment once again.

Currently, Pfizer has taken the lead in initiating a registration clinical trial for Atirmociclib as a first-line treatment for HR+/HER2- breast cancer, and it is expected to replicate the success of palbociclib and become the next blockbuster drug in the field of breast cancer.

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