Keytruda is expectedly at the top, not only ranking first among oncology drugs but also at the top of the global drug sales list for the first half of 2024. Since the FDA accelerated its approval for melanoma indications in 2014, ten years have passed. As of June 17, 2024, it has been approved for 40 indications. Opdivo follows closely behind, ranking third. Opdivo was approved for the market around the same time as Keytruda, in 2015, also starting with melanoma as the foundation in the field of oncology, continuously expanding horizontally.

PD-1 therapy represents an epoch-making breakthrough in oncology drugs, killing cancer cells by activating T-cells to achieve the process of self-immunity. This therapy also presents a versatile combination scheme, with chemotherapy, ADCs, small molecule targeted drugs, and even new types of traditional Chinese medicine—all kinds of drugs can be combined, bringing a new imagination to cancer therapy.

In terms of hematologic malignancies, the first to mention is Darzalex, which changed the treatment landscape for multiple myeloma, a CD38 monoclonal antibody that was launched at the end of 2015 and is the world’s first approved CD38 monoclonal antibody. The main expansion of multiple myeloma is from the back line to the front line treatment plan, and Darzalex has quickly covered the treatment of multiple myeloma from the fourth line to the first line in a few years, largely iterating the original traditional small molecule drug lenalidomide, which is No.6 Revlimid on this list.

Johnson & Johnson’s other BTK inhibitor, ibrutinib, is a small molecule inhibitor and is also first in class. Of course, there are many competitors for this drug later on, one of which is Zanubrutinib from BeiGene.

Soon, these two drugs will face the patent cliff. Ibrutinib’s compound patent will expire in 2026, and Darzalex’s patent will expire in 2029. Johnson & Johnson has also been laying out the next era and has once again developed the field of hematologic malignancies with the legendary CAR-T therapy of the legendary biotech.

02 Solid Tumors: Targeted Therapies with Specific Focus

For solid tumors, in addition to PD-1 monoclonal antibodies, most drugs targeting tumor cell markers are specific and may be deeply developed in one or several types of solid tumors.

Today’s blockbusters are mostly the result of the pipeline layout a decade ago, so we can see many monoclonal antibody layouts that were popular at that time, and the targets are also consistent with most of the current frontier bispecific antibodies and ADCs.

The name Tagrisso may be unfamiliar, but its other name is well-known: Osimertinib. The third-generation EGFR-targeting small molecule drug has resolved most of the issues with the first and second generations of targeted drugs, and the treatment lines for this drug have also been rapidly advanced. It has now become the first-line medication for NSCLC indications. Current research pain points are mainly to solve the resistance to osimertinib, which is mainly reflected in the fact that the drug is often used as the head-to-head control group in phase III clinical trials. Recently, the deuterated small molecule from TYK Medicines and the EGFR/c-MET bispecific antibody from Johnson & Johnson are all like this.

Xtandi (enzalutamide) is also a typical masterpiece of the era of small molecule drugs. It was first approved in 2012 and is used to treat prostate cancer because of its specific function of blocking the binding of androgens to receptors. Its more classic therapy is the combination with leuprorelin, which is called androgen deprivation therapy (ADT). However, now, the prostate cancer indication has become a good platform for RDC drugs.

Breast cancer and prostate cancer are rare cancers distinguished by gender in men and women. The incidence of breast cancer ranks second among women. HER2 is a very good target on breast cancer, and clinically, breast cancer is often divided into HER2 negative, HER2 low expression, and HER2 positive. If the target is positive, the available treatment options will be greatly expanded, and Perjeta (pertuzumab) is a representative work of targeted drugs. Clinically, pertuzumab and trastuzumab dual-targeted therapy are often used, both of which are targeting HER2. However, the US patent for trastuzumab has expired in 2019, and now the competitive market for this drug is mainly reflected in biosimilars.

Verzenio (abemaciclib) is another major class of breast cancer: small molecule kinase inhibitors. It inhibits the activity of CDK 4/6, thereby affecting the cell cycle and the proliferation of cancer cells. Of course, the drug also has limitations. CDK4/6 is mainly active in hormone receptor (HR) positive breast cancer, showing significant activity. It mainly targets the type of breast cancer that is HR positive and HER2 negative.

03 New drugs emerge in the market with each generation

Overall, the top-selling oncology drugs we see today on the sales list mostly symbolize the R&D hotspots of the last era, representing a comprehensive cancer treatment matrix constructed by the efforts of the previous generation of researchers. Just like the current R&D personnel who are tackling challenges in therapies such as ADCs, multispecific antibodies, and CAR-T. Each generation has its mission, and the culmination of each generation’s efforts is the extension of cancer patients’ survival periods by several years.

In terms of the HER2 as the target, the ADC drug DS-8201 targeting HER2 has become the new trend-setter, with sales reaching $1.772 billion in the first half of 2024, up from $1.2 billion last year. The drug is not limited to breast cancer; in January 2021, it was approved by the FDA to treat gastric cancer, and its later R&D pipeline also includes non-small cell lung cancer and colorectal cancer.

Speaking of breast cancer indications, the development of Trop2 ADC has brought new hope for the treatment of triple-negative breast cancer. The representative drug is Trodelvy, which was accelerated and approved by the FDA in 2020 based on Phase I/II trials for the treatment of triple-negative breast cancer. Trop2 ADC has also become a new hot entity in the ADC field after HER2, running side by side with nectin-4.

In the field of hematologic malignancies, CAR-T therapy has completely rewritten the treatment landscape of multiple myeloma. The R&D of this therapy is now in a state of intense competition, and the future direction of this competition will mainly focus on autoimmune diseases and solid tumors. CAR-T therapy will bring new hope to the new cancer king in cancer – glioblastoma, which currently still relies on chemotherapy from more than a decade ago, supplemented by the electric field treatment of the past two years.

In the next few years, Legend Biotech’s CAR-T drug Ciltacabtagene Autoleucel may make it to the list, and the key to all this lies in the approval of first-line treatment. If the word on the street about the potential acquisition of Legend Bio is true, it may bring some positive effects to the advancement of Ciltacabtagene Autoleucel indications.

One of the development directions of PD-1 is bispecific antibodies, represented by Akeso Bio, a company whose stock price has recently fluctuated dramatically. AK-104 is a PD-1/CTLA-4 bispecific antibody, and AK112 is a PD-1/VEGF bispecific antibody. AK104 is the first marketed PD-1/CTLA-4 bispecific antibody, and AK112 is the first marketed PD-1/VEGF bispecific antibody. Even from the current perspective, Akeso’s layout of bispecific antibodies is very advanced.

Conclusion: The ranking list is just a review of the last era, and the clinical data of the products in the pipeline represent the competition of this era. The bright past is worth learning from by R&D personnel of later generations and their role and responsibility is to realize the commercialization of today’s cutting-edge technologies.

【Editor’s note】The above content (~7300 words) is a quick translation of a Chinese article (posted on 2024-08-26) by DrugTimes team. To read the original article, please click here. All comments are warmly welcome. Many thanks!