By Matthew Cunningham, Managing Partner
In oncology, the language used to frame innovation matters. Terms like “next-generation,” “second-generation,” and even “third-” or “fourth-generation” are used to imply progress—but they also influence how products are perceived by providers, payers, and investors.
The use of these terms is not just siloed to post-launch marketing —it’s growing significantly in the scientific literature.
Framing Innovation: A Growing Trend in Scientific Literature
A PubMed analysis* of over 18,000 therapeutic-focused publications from 2010 to 2024 shows that title references to “next-generation,” “second-generation,” “third-generation,” and “fourth-generation” have all increased significantly.
While the analysis spans multiple therapeutic areas, this trend is highly relevant for oncology, where generational labels can carry implications for market positioning, payer coverage, and trial design. While “next-generation” remains the most commonly used term, recent years show a sharp uptick in “third-” and “fourth-generation” verbiage—signaling deeper class maturity.
What Does “Next-Generation” Actually Mean?
While ordinal generations (e.g., second, third, fourth) typically represent the ability to overcome a resistance mechanism or have clean clinical superiority, the term “next-generation” lacks consensus or regularity definition. In practice, it’s often used to indicate one or more of the following:
- Mechanistic refinement (e.g. increased selectivity, novel binding)
- Activity in resistant disease
- Improved safety/tolerability
- Operational benefits (e.g. subcutaneous vs. IV, fewer doses)
The question arises, how much better is “next”? The answer many times depends on who you are asking and in what context.
Clear-Cut Examples
For many “next gen” oncology therapies, the label is non-controversial and represents a legitimate leap forward in standard of care. Examples such as Tagrisso (third-generation EGFR-TKI) Brukinsa / Calquence (second-generation BTK inhibitors) and Enhertu (next-generation ADC) clearly moved standard of care forward and had mechanistic rationale for improvement over prior generations.
Future-State Murkiness and Strategic Tradeoffs
Calling a therapy “next-generation” does more than signal innovation—it anchors the product within the same mechanistic class as its predecessor. In novel modalities like bispecifics, cell therapies, or modular immunotherapies, it becomes much harder to define what “next-generation” actually means. Mechanisms of action are more complex, targets are often novel or combinatorial, and the biology may not map cleanly onto earlier standards of care. In these cases, generational language can blur the line between true class evolution and mechanistic reinvention.
Once a product is positioned as the next generation of an existing therapy, it’s naturally evaluated in direct comparison to what came before—not just by providers, but by payers as well. Even when clinical differentiation is well-established, payers may still look to manage the class as a whole, either through direct management, or pricing and contracting pressure.
This tension will become even more pronounced in the red-hot field of PD-(L)1 bispecifics. Describing these bispecifics as “next-generation checkpoint inhibitors” may sound progressive, but it implies some degree of class continuity vs. an entirely novel therapeutic. As immunotherapies such as Keytruda & Opdivo approach biosimilar entry & IRA pressure, maximizing the differentiation of bispecifics can help insulate from inevitable pricing & payer management pressures in the PD-L1 class.
As more complex oncology therapies enter the market, navigating the balance between innovation and class inheritance will only grow in importance within manufacturer positioning & differentiation strategies.
