Trends in Target Novelty in Oncology Drug R&D

The discovery of novel targets often presents opportunities to create highly successful classes of anticancer drugs. A prime example is the PD-1/PD-L1 inhibitor class, which achieved total global sales of $55 billion in 2024. Among them, the first-in-class product, pembrolizumab, was approved in 2014 and its sales account for nearly one-fifth of the entire oncology market.

In this context, the authors define "first-in-class" (FIC) as a molecule whose mechanism of action targets a specific pathway for which no drug has yet been approved (or was not approved at the time) for oncology indications. Research findings indicate that the majority of oncology drugs in late-stage development do not possess novel targets, and the proportion of potential first-in-class candidates generally declines as the R&D stages progress.

Commercial Returns of First-in-Class Drugs

An analysis of GlobalData's "Drug Sales and Consensus Forecasts" database shows that although first-in-class drugs account for only 31% of all marketed oncology drugs, they generated $119 billion in global sales in 2024, representing 41% of the total revenue in the oncology field. This demonstrates that drugs with novel targets exhibit a distinct "outsized advantage" in terms of commercial returns.

Target Novelty Typically Decreases with R&D Progression

From the perspective of R&D phases, the highest proportion of potential first-in-class oncology drugs is found in the preclinical stage, reaching 57%. Once entering clinical development (Phases I-III), this proportion drops significantly: Phases I and II are relatively similar at 48% and 49%, respectively; Phase III shows a sharp decline to 34%, falling further to 25% in the pre-registration stage. This trend reflects the higher R&D risks associated with novel targets; compared to candidates targeting established mechanisms, more candidates targeting novel pathways are eliminated during Phase II and Phase III clinical trials.

Figure 1. Trends in oncology drug target novelty. (Cuthbertson J, Paliouras S, Kolesnikova T., 2025)

Target Novelty by Drug Modality

When pursuing R&D around novel targets, companies must first choose between different drug modalities. A common view is that, out of caution regarding R&D risk and capital investment, companies and investors often adopt a strategic preference: either use a relatively mature drug modality to explore a novel target, or experiment with a new drug format on an established target.

An analysis of approved oncology drugs by type reveals significant differences in the proportion of novel targets across drug modalities, ranging from 10% to 70%. It should be noted that some of this variance may be influenced by the small number of approved products in certain categories. For the two most mature drug types-small molecules and antibody therapies (excluding antibody-drug conjugates, ADCs)-the proportions of first-in-class products among approved drugs are 26% and 32%, respectively. At the two extremes, only 10% of gene-modified cell therapies possess novel targets, while this proportion reaches 70% for fusion proteins.

In the R&D pipeline (including preclinical projects), the proportion of target novelty across different drug types is generally concentrated between 40% and 60%. Only two drug types, ADCs and gene-modified cell therapies, have a higher proportion of candidates targeting established targets than novel ones. For ADCs, this trend reflects a mature strategy in R&D practice: building ADCs by optimizing other components based on monoclonal antibodies (mAbs) that have already been clinically validated, thereby developing potential next-generation blockbuster products. Typical examples include the HER2-targeted ADCs trastuzumab emtansine (Kadcyla) and trastuzumab deruxtecan (Enhertu), which improved treatment outcomes for metastatic HER2-positive breast cancer by building on the success of the pioneering mAb drug, trastuzumab (Herceptin).

The Race for First-in-Class

The distribution of R&D resources across different novel targets is uneven. The "Me Too" phenomenon-where multiple biopharmaceutical companies simultaneously develop similar drugs around the same target-often emerges even before any drug for that target has received its first approval. For example, there are currently 42 antibody-based candidates targeting CD137 (also known as 4-1BB) in Phase I-III clinical development. CD137 is a co-stimulatory molecule expressed on the surface of activated immune cells. These candidates include 12 monoclonal antibodies and 30 multispecific antibody candidates. The development of bispecific antibodies and novel target combinations (usually one established target and one novel target) allows for the simultaneous action on two pathways to produce synergistic efficacy. Examples include the combined inhibition of EGFR and MET by amivantamab, or the bridging of cancer cells and T cells via the GPRC5DXCD3 bispecific antibody talquetamab.

Figure 2. Popular novel oncology targets for major modalities. (Cuthbertson J, Paliouras S, Kolesnikova T., 2025)

Regarding small molecules, the novel target currently receiving the most attention is cyclin-dependent kinase 2 (CDK2), with a total of 17 candidates in the clinical pipeline. This reflects a general industry expectation that CDK2 inhibitors are poised to target CCNE1-amplified solid tumors and address drug resistance issues arising in breast cancer patients after treatment with CDK4/6 inhibitors. Notably, CDK4/6 inhibitors themselves are already a successful class that has yielded three blockbuster drugs on the market.

Although some novel targets have candidates advancing to Phase III, and not all early projects succeed in later trials, these targets continue to attract massive early-stage R&D investment. For instance, there are as many as 22 Phase I candidates targeting the innate immune checkpoint protein CD47, more than half of which are novel bispecific antibodies. Their clinical potential is considered possibly superior to earlier monoclonal antibody products.

Compared to other drug modalities, the number of ADCs developed for novel targets is significantly lower. This phenomenon again confirms the strategy of prioritizing mature targets, such as HER2, in ADC R&D. A significant exception is the immune checkpoint CD276 (also known as B7-H3): there are currently 12 ADC candidates targeting this mechanism, three of which have entered Phase III clinical trials. Previous attempts to develop monoclonal antibodies against CD276 all ended in failure, but the potential value of this target in small cell lung cancer and other solid tumors with unmet clinical needs has driven the development of ADC projects.

Conclusion

While first-in-class drugs often generate disproportionately high revenues, "second-in-class" and "third-in-class" candidates also hold substantial commercial value. In disease areas with large patient populations, the market can often accommodate multiple blockbuster drugs. Some companies also continue to mine the potential of established targets through different paths, such as introducing entirely new drug modalities or further improving clinical efficacy and safety while adhering to existing drug formats.

Reference

Cuthbertson J, Paliouras S, Kolesnikova T. Trends in target novelty in oncology R&D. Nature reviews. Drug Discovery, 2025.