Since the discovery of cyclin-dependent kinases (CDKs), scientists have been trying to target them to disrupt cancer cell division and proliferation. Breast cancer in particular relies on this process to grow. Because of this, the first-generation CDK inhibitors targeting CDK4 and CDK6 have been very successful.

In February 2015, palbociclib, the first CDK4/6 inhibitor developed by Pfizer, was approved for marketing in the United States for the treatment of locally advanced or metastatic breast cancer of HR/HER2-. There are many breast cancer patients, and in 2020, there were more than 2.3 million new breast cancer patients in the world, making it the world's largest cancer type. Based on the large patient size, the sales scale of palbociclib is also considerable. In 2016, the sales of palbociclib in the first full year of marketing reached 2.135 billion US dollars, becoming a well-deserved blockbuster drug. Since then, CDK4/6 inhibitors of Eli Lilly, Novartis, Boling Ingelheim, and Hengrui Pharmaceutical have been approved for marketing one after another. In 2023, the total sales of CDK4/6 inhibitors of Pfizer, Novartis, and Eli Lilly alone will be close to $10 billion. Based on the successful commercial performance of CDK4/6 inhibitors in breast cancer, Nature Reviews Drug Discovery expects CDK4/6 inhibitors to contribute $20 billion by 2029, accounting for 42% of the breast cancer drug sales market share.

However, the CDK4/6 inhibitors that have been marketed are not perfect, and they all have some shortcomings to a greater or lesser extent. First of all, one of the problems that plagues CDK4/6 inhibitors is toxicity. At present, the most common adverse reaction of CDK4/6 inhibitors is neutropenia, with palbociclib and rebociclib occurring in the highest proportion, and grade 3 to 4 neutropenia in 60% to 66%. In addition, bone marrow suppression is the most common toxicity of CDK4/6 inhibitors, occurring in up to 80% of women taking palbociclib or rebociclib and up to 50% when taking abeciclib. These adverse reactions limit the dosing dose of CDK4/6 and affect the clinical application of CDK4/6 inhibitors to a certain extent. Because of this, the research and development of next-generation CDK inhibitors is in full swing.

The potential of CDK inhibitors is not limited to targeting CDK4 and CDK6. There are many members of the CDK family, and 20 different subtypes have been discovered, which can be divided into two categories according to their functions: one type of CDK is involved in cell cycle regulation, such as CDK1, CDK2, CDK4, CDK6, etc.; Another type of CDK is involved in transcriptional regulation, mainly including CDK7, CDK8, CDK9, CDK10, CDK11, etc. Among them, many family members are potential drug targets, and CDK2 is one of the current research hotspots.

Regal Pharmaceutical, which has reached an important cooperation with Roche, has two CDK inhibitors under development in its product line, both targeting CDK2: one is the CDK2/4/6 inhibitor RGT-419B, and the other is the CDK2 inhibitor QR-6401. Similarly, on November 21 last year, BeiGene partnered with Oncent Therapeutics to acquire exclusive global rights to ETX-197, the latter's investigational oral CDK2 inhibitor. It is not surprising that CDK2 has attracted attention, and the key is its huge potential. For example, CDK2 may help address resistance to CDK4/6 inhibitors. As first-line treatment, CDK4/6 inhibitors, whether in combination with aromatase inhibitors or fulvestrant, have 15% to 20% of patients with primary resistance, and almost all patients develop secondary resistance in the later stages of CDK4/6 inhibitor use. Once drug resistance develops, treatment options for patients will be very limited.

It seems that CDK2 is a potential breakthrough. Studies have shown that after CDK4 is suppressed, CDK2 takes over its effects and promotes cancer cell proliferation. Not only will these cancer cells continue to grow, but they may also become resistant to previous CDK inhibitor treatments. These suggests that CDK2 may be one of the mechanisms of CDK4/6 resistance. This has also been initially verified by Pfizer. In the clinical trial, 16 patients with metastatic breast cancer who had received 2 lines of CDK4/6i endocrine monotherapy achieved partial remission and 6 patients achieved stable disease after treatment with PF-07104091, a selective inhibitor of CDK2 developed by Pfizer. Preliminary results show that PF-07104091 has good efficacy in patients with HR/HER2- breast cancer who are resistant to CDK4/6 inhibitors. This means that CDK2 in combination with CDK4/6 may help address drug resistance. RGT-419B, which is developing rapidly in Regel Therapeutics, is also being developed to address resistance to CDK4/6 and other hormone receptor-modulating therapies. Preclinical data show that RGT-419B shows complete inhibition of cancer cell proliferation in ER breast cancer cells resistant to currently approved CDK4/6 inhibitors. In these experiments, RGT-419B was further enhanced in its inhibitory effect on tumor cells when combined with selective estrogen receptor degraders or PI3K signaling pathway inhibitors.

In the face of the huge temptation of the CDK inhibitor market of tens of billions of US dollars, many domestic and foreign pharmaceutical companies have begun to be eager to try. At present, the layout of pharmaceutical companies targeting CDK2 and CDK4/6 has been quite extensive. In China, Chenxin Pharmaceutical, CSPC Pharmaceutical Group, Qilu Pharmaceutical, Tongyuankang Pharmaceutical, etc. are all conducting clinical trials of CDK2/4/6 inhibitors. Overseas, Pfizer's R&D progress is the fastest, and at last year's ASCO conference, Pfizer has announced the Phase 1/2a clinical data of its drug candidate PF-07104091, and is conducting a three-year study. In addition, CDK2 inhibitors such as Incyte's INCB123667 and Blueprint's BLU-222 are also in clinical studies.

Now, with Roche on board, the competition around the new generation of CDK inhibitors will undoubtedly intensify. For biotech companies, there may also be strategic choices to consider while developing better molecules. After all, the entry of big pharma companies can change the competitive landscape at all times. On the one hand, at the heart of a giant like Roche's onboarding program is essentially a deal that leverages its "clinical development strength, manufacturing capabilities and commercial reach" to create more value. In these three areas, biotech does not have an advantage. On the other hand, some large pharmaceutical companies have formed the ability to make ecological breakthroughs in the field of breast cancer. The most typical example is Roche, from HER2 to PI3K targets, Roche led the research and development boom of targeted drugs in the field of breast cancer, and is still pushing this field to a higher level. In other words, the competitiveness of these large pharmaceutical companies in these specific areas will be further strengthened. In the context of the need to do faster and to ensure that commercialization expectations are met, strategic choices may be the most critical.