For all the focus on what is entirely new, fast, and transformative, some of the most meaningful innovations in oncology have been catalyzed by the passing of time and the compounding of science—on returning to what we know with sharper tools, deeper insight, and greater intent. This is largely the case because cancer biology is a moving target, both due to the heterogeneity of the disease and our evolving understanding of what makes it tick.
In other words, as our understanding of cancer evolves, adaptability becomes as important as novelty in driving meaningful therapeutic innovation. In an ever-moving biological landscape, therapies already proven to be safe, effective, and mechanistically sound offer a clear strategic advantage, as they can be continuously reinterpreted through the lens of new biological insights, strategically combined, redeployed, reformulated and optimized. Importantly, the value of a therapy is often not determined at the moment of discovery, but through how it is developed, understood, and applied over time.
Innovation beyond discovery: The pembrolizumab story
Few examples make this clearer than the blockbuster immunotherapy drug, pembrolizumab (Keytruda®), the world’s highest-grossing medicine prescribed across more than 40 indications and multiple cancer types.[1]
Pembrolizumab is a humanized monoclonal antibody that emerged from immunology research into how the body keeps its immune system in check. What began as an effort to understand and control autoimmunity ultimately led to a different insight: that releasing those brakes could be harnessed to treat cancer.[2] Pembrolizumab targets programmed cell death protein 1 (PD-1), a protein on T cells that normally restrains immune responses to prevent autoimmunity, but which tumors co-opt to suppress T-cell activity and escape detection. By blocking PD-1, pembrolizumab aims to restore T-cell activity, effectively lifting the natural restraints on the immune system (an approach known as checkpoint inhibition), and enabling the immune system to recognize and attack cancer cells.
But the discovery of a compelling mechanism alone does not create value; after passing through two mergers and acquisitions, pembrolizumab entered Merck’s portfolio in 2009, where it was deprioritized and ultimately slated for out-licensing.[3] This trajectory changed following the publication of a Phase III study demonstrating that checkpoint inhibition could improve survival in unresectable and refractory metastatic melanoma.[4] Not long after, emerging early clinical signals from PD-1 inhibitor, nivolumab, began to suggest this specific pathway could drive meaningful clinical responses, leading to a reassessment of pembrolizumab’s potential.
Even with clinical validation, the eventual value of pembrolizumab was contingent on subsequent development choices. Initial activity in advanced solid tumors emerged from a Phase I study, which was subsequently extended to include melanoma and non-small cell lung cancer (NSCLC) expansion cohorts. But it was the introduction of a companion diagnostic to identify patients most likely to respond that proved decisive to pembrolizumab’s gained advantage and eventual blockbuster success.[3] The introduction of a biomarker for programmed death-ligand 1 (PD-L1), the ligand that binds to the PD-1 receptor on T-cells, enabled the selection of patients whose tumors were more likely to depend on this pathway, enriching for responders and generating more compelling clinical outcomes.
What the pembrolizumab story makes clear is that innovation in oncology is not defined by discovery alone, but by utility: by whether and in which way an insight is translated into meaningful outcomes. Its emergence as a foundational therapy in oncology was not the result of a single breakthrough, but a convergence of factors: timing of validation, the strategic choices that shaped its development, the judgment of those who recognized its potential, and a measure of chance.
None of this was inevitable, a pattern that extends far beyond pembrolizumab. Across oncology, some of the most promising advances have come not from entirely new discoveries, but from rethinking and extending what already exists: combining therapies, redeploying, and reformulating them to unlock new value.
Even immunotherapy, often perceived as a relatively recent breakthrough, is the product of decades of accumulated insight into tumor-immune interactions to the gradual elucidation of checkpoint pathways. In turn, its development and use have created a feedback loop that informs our understanding of cancer biology, bringing into focus how tumors evade immune detection, how responses are shaped by biological context, and why outcomes vary across individuals.[5]
Combination Therapies: Making drugs work better together
The constant dialogue between therapeutic advances and our understanding of cancer biology is perhaps most clearly reflected in the rise of combination regimens, where therapies are strategically paired to mirror and respond to the complexity of the disease. Increasingly, there is a broad consensus across oncology—reflected in the work of leaders in the field, such as James P. Allison and Bert Vogelstein—that targeting a single pathway is rarely sufficient, and that meaningful progress depends on approaches capable of addressing multiple, interacting mechanisms.[6]
Combination approaches are designed with distinct biological objectives in mind. For instance, the advent of monoclonal antibodies over the last decades has enabled a new level of precision in targeting cancer, which, when paired with long-standing of cytotoxic modalities such as chemotherapy or radiotherapy, enable the more selective delivery of cytotoxicity to tumor cells, as seen with antibody-drug conjugates and radioimmunoconjugates. This reflects a broader principle in oncology: therapies once expected to be replaced by newer modalities are instead being redefined, their utility extended and enhanced through combination with more precise targeting mechanisms. What was once the central limitation of cytotoxic therapy (its effectiveness at killing cells but its inability to discriminate between healthy and tumor cells) becomes, in combination strategies, a controllable advantage.[7]
The same principle extends beyond delivery to how therapies are combined to act in concert, enhancing overall efficacy. Increasingly, therapies are combined to target complementary pathways, improving outcomes while overcoming resistance mechanisms or enhancing the depth and durability of response. This is exemplified by the combination of checkpoint inhibitors with chemotherapy, as seen with pembrolizumab-based regimens in lung cancer, where cytotoxic therapy is now understood not only to reduce tumor burden, but also as a mechanism to enhance tumor immunogenicity and overcome immune-resistance, with improvements in overall survival and response rates observed across multiple tumor types. Taken together, these approaches reflect a shift in how innovation is realized, from the discovery of individual agents to the intentional design of therapeutic strategies, where existing and emerging modalities are combined in ways that exploit the underlying biology of the disease and generate synergistic effects that enhance efficacy and durability of response.[8]
Combinations can also involve the use of context-modifying agents that alter the tumor microenvironment or underlying biology, enabling other therapies to act more effectively. Unlike synergistic combinations, where multiple active agents directly contribute to tumor control, these approaches function by creating the conditions within which the activity of a single therapeutic (or more) can be enhanced. This may offer strategic advantages in certain settings, where enhancing the activity of a single agent can achieve meaningful gains in efficacy while avoiding the added toxicity, complexity, and potential drug-drug interactions associated with combining multiple active agents. Such strategies include lymphodepleting chemotherapy prior to CAR-T cell therapy in hematologic malignancies, where chemotherapy is administered not for direct tumor cytotoxicity, but to intentionally deplete competing and suppressive immune cells and enable CAR-T cell expansion and activity, with the timing of administration playing a critical role in shaping this effect. A similar principle underlies emerging approaches such as Helix’s L-DOS47, which modulates the pH of the acidic tumor microenvironment, thereby aiming to alleviate immune suppression and enhance the activity of checkpoint inhibitors in NSCLC.[10]
Beyond composition, the effectiveness of combination strategies is also shaped by timing. A recent, notable example comes from observations that COVID-19 mRNA vaccination may enhance responses to immune checkpoint inhibitors such as pembrolizumab in advanced solid tumors. In a retrospective analysis led by The University of Texas MD Anderson Cancer Center and published in Nature in October 2025, patients with advanced NSCLC and metastatic melanoma who had received an mRNA vaccine within 100 days of initiating checkpoint inhibitor therapy showed significantly improved survival compared to unvaccinated patients or those receiving other vaccines.[11] These findings were subsequently supported in preclinical models, where mRNA-lipid nanoparticle vaccination was shown to restore sensitivity to checkpoint inhibitors in otherwise resistant tumors, driven by innate immune activation rather than antigen specificity. Today, the research group is planning a multicenter, randomized Phase III study to determine whether this effect can be confirmed prospectively.[12]
If combination strategies, spanning precision, synergy, biological priming, and timing, reflect how innovation is realized in making therapies work together, redeployment (or repurposing) reflects a complementary form of innovation: making existing therapies do more than they were originally intended to do.
Redeployment: Known drugs with new therapeutic value
Across oncology, drug redeployment takes multiple forms, each reflecting a way in which existing therapies can acquire new meaning as our understanding of cancer biology evolves.
One of the clearest expressions of innovation through redeployment lies in recognizing that a known mechanism of action can be therapeutically relevant in disease settings beyond those for which a drug was originally developed. The evolution of GLP-1 receptor agonists (including semaglutide [Ozempic®, Wegovy®] and liraglutide [Victoza®, Saxenda®]) illustrates this process at scale, with a class of drugs originally developed for the treatment of type 2 diabetes subsequently redeployed for obesity, demonstrating how a known mechanism can be translated into therapeutic value in a different disease context. As cancer is increasingly understood to be shaped by metabolic dysfunction, therapies targeting these pathways are beginning to gain relevance in oncology.[13]
Aspirin offers one of the most established examples of this principle in oncology. First developed as an analgesic and later widely adopted to reduce the risk of heart attack and stroke, it has since been shown to reduce the risk of colorectal cancer (CRC) in certain populations. Whereas early experimental studies in the 1970s suggested an effect of aspirin on cancer metastasis, its clinical relevance in oncology only became clear decades later, when analyses of large cardiovascular trials revealed reductions in both cancer incidence and metastasis.[14] Subsequent randomized studies in high-risk populations, such as patients with Lynch syndrome, demonstrated a substantial reduction in CRC incidence, and more recent data suggest that aspirin may also reduce recurrence in molecularly defined subgroups of CRC.[15] In certain populations, this evidence has been sufficient to inform clinical guidelines, with low-dose aspirin recommended or actively considered for CRC prevention under defined risk conditions.
In other cases, innovation through redeployment is driven by uncovering novel mechanisms of action that enable existing or even withdrawn therapies to be applied in new settings in fundamentally different ways. Thalidomide, a small molecule drug originally developed as an oral sedative and widely used in the 1950s to treat nausea in pregnant women became associated with one of the greatest tragedies in the history of drug development, after causing an estimated 10,000 infants worldwide to be born with severe birth defects.[16] While the drug was withdrawn in 1961, the later discovery of its immunomodulatory and anti-angiogenic effects ultimately led to the redeployment of thalidomide in oncology, with its approval by the US FDA in 2006 as a co-therapy for the treatment of newly diagnosed multiple myeloma. Still, its clinical utility was limited by dose-related toxicities—constraints that catalyzed the development of a new class of thalidomide analogues, the immunomodulatory drugs (IMiDs), retaining and expanding its mechanistic properties while offering improved efficacy and tolerability.[17] Today, IMiDs represent the cornerstone of multiple myeloma treatment; they enable chemotherapy-free regimens with reduced toxicities and improved therapeutic outcomes across multiple lines of therapy, and have contributed to our understanding of the disease’s underlying biology.[18]
In the case of thalidomide, innovation did not arise from redeployment alone, but from the iterative refinement of the original molecule into a new class of analogues with improved clinical utility. However, improving clinical utility is not confined to the molecule itself; it also extends to how a therapy is iteratively optimized through formulation and dosing—a principle reflected in oncology by the growing use of metronomic strategies with oral agents.
Metronomic therapy refers to the frequent or continuous administration of cancer drugs (usually oral cytotoxic chemotherapies) at low, minimally toxic doses, in contrast to traditional intravenous regimens delivered at the maximum tolerated dose. In this context, reformulation into oral agents becomes a key enabler, allowing therapies to be delivered in sustained, flexible dosing schedules that can also redefine their biological and clinical effects. At conventional intravenous dosing, chemotherapy works primarily by killing rapidly dividing cells. At metronomic doses, however, its anti-angiogenic and immunomodulatory effects work to limit the tumor’s ability to sustain itself and enhance immune recognition and response, all while maintaining continuous pressure on the cancer.[19]
While this approach is not universally applicable across tumor types or disease settings, its relevance continues to expand as our understanding of tumor biology and treatment context continues to evolve.[20] Evidence supporting the use of metronomic chemotherapy is growing, especially in the context of personalized medicine and in palliative care, where sustained activity and improved tolerability are of particular importance.[21]
Innovation Beyond Novelty
Taken together, these examples challenge a persistent assumption in oncology: that innovation must begin with something entirely new. Increasingly, the opposite appears to be true. From checkpoint inhibitors to metronomic chemotherapy, and from GLP-1 receptor agonists to aspirin, progress is often not only driven by the discovery of new molecules, but by the reinterpretation and intentional redeployment of what already exists. What COVID-19 mRNA vaccines have brought into focus—the potential to modulate biological responses through timing, context, and delivery—finds clear parallels in oncology, where similar principles are being explored to enhance the activity and durability of therapies that are already within reach.
In this context, innovation becomes less about singular breakthroughs and more about continuity: about refining, combining, and reimagining therapies in ways that align with an evolving understanding of the disease—a perspective that underpins our own approach to development (explored further here). More broadly, it reflects a shift in how progress is made: not as a one-directional process from discovery to application, but as an ongoing dialogue in which therapies do not simply act on cancer biology but also help to reveal it. In keeping that dialogue open, each intervention becomes both a treatment and a source of insight, continuously informing how we understand and approach cancer. And as cancer biology continues to reveal its complexity, the therapies most likely to shape the future of oncology may not be those that are entirely new, but those that are most effectively understood, adapted, and applied over time.
References:
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2. https://pmc.ncbi.nlm.nih.gov/articles/PMC4856023/
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5. https://pmc.ncbi.nlm.nih.gov/articles/PMC6928196/
6. https://www.onclive.com/view/james-allison-says-rational-combinations-key-to-immunotherapy-success-in-cold-tumors ; https://www.sciencedaily.com/releases/2012/07/120703185815.htm
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13. https://pmc.ncbi.nlm.nih.gov/articles/PMC12578377/
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