Combination Therapies May Be the Future of Oncology – How Can We Navigate Development Challenges Today?

The field of oncology is experiencing a proliferation of cancer therapies. In 2024 alone, the U.S. Food and Drug Administration (FDA) issued more than 60 oncology approvals, including 11 for first-in-class therapeutics.1 This diverse array of increasingly specialized treatments is reshaping the oncology market and ushering in a more diversified era of cancer treatment. Moreover, the landscape has shifted from SoC chemotherapies and radiation therapies to combinations of these with agents that include but are not limited to molecular targeted treatments and radiopharmaceuticals with synergistic effects.

Indeed, combination oncology therapies have become a key strategy for enhancing treatment efficacy, combating drug resistance and extending patient survival. The investment in combination therapies is projected to continue and according to an ICON survey of over 100 oncology developers, about two thirds (68%) are actively developing a combination therapy, and nearly half of respondents (48%) expect that most cancer patients will undergo combination therapy in the future.

However, combination therapies also introduce unique challenges during therapeutic development. In the ICON survey, developers of combination therapies reported challenges with protocol design and regulatory alignment more often than those developing monotherapies. Furthermore, respondents frequently co-identified challenges with finding experienced partners, designing trials with non-traditional designs (i.e., adaptive trials), and managing regulatory requirements and large amounts of data.

In this article, we provide an overview of common ways oncology therapies are combined to achieve synergistic effects, and considerations that oncology developers should employ to de-risk combination therapy development.

Synergy through immune response activation

Approval of therapies in combination with immune checkpoint inhibitors (ICI), small molecules and with anti-angiogenic therapies have become especially common in the past few years. These combination therapies have demonstrated synergistic effects on treatment efficacy across diverse therapeutic modalities. At a high level, ICIs, small molecule inhibitors and anti-angiogenic therapies undermine common cancer resistance mechanisms that help prevent an effective anti-cancer response, and demonstrate complementary mechanisms of action with therapies that directly target cancer cells [2].

For example, anti-angiogenic therapies block the growth of blood vessels that supply tumors with oxygen and nutrients. Additionally, when an abnormal vasculature forms around a tumor, it creates physical barriers that are difficult for immune cells to penetrate, and actively suppresses the anti-cancer immune response. Therefore, when administered in combination with other treatment approaches, anti-angiogenic therapies can make it easier for the combination therapies to penetrate the tumor and boost their effectiveness [3]. The combination of anti-angiogenic drugs with other treatment modalities has become part of the first-line treatment regimens for specific cancer patient subgroups, including non-small cell lung cancer [2].

Another way cancers evade a targeted immune response is by co-opting immune checkpoint mechanisms that help prevent autoimmune damage. ICIs work by blocking immune checkpoints that would otherwise suppress the immune response against cancer cells [4]. When ICI’s work alone, they rely on a patient’s immune response to successfully target the cancer once immune checkpoints have been blocked. But, when ICIs are combined with therapies that promote a targeted immune response – such as CAR T-cell therapies and mRNA cancer vaccines, they can work synergistically to be more effective than either therapy alone.

The synergistic effect of ICIs and targeted immunotherapies was recently demonstrated in the Phase 2b study of a personalized mRNA vaccine in combination with Keytruda (Pembrolizumab), which targets the immune checkpoint protein PD-1, in patients with stage 3 or 4 melanoma who had a high risk of recurrence following complete resection. When compared against treatment with Keytruda alone, patients who received the combination therapy had a 49% reduced risk of recurrence or death and a 62% reduced risk of distant metastasis [5].

ICIs have also demonstrated synergistic efficacy with older treatment approaches like chemotherapy and radiation therapy. In 2024 alone, Keytruda was approved in combination with chemoradiotherapy to treat patients with stage III-IVA cervical cancer, and was separately approved in combination with chemotherapy to treat patients with stage III-IVA cervical cancer [6].

Synergy through a multi-pronged attack

Other approaches to combination therapy directly attack cancer in different ways, increasing the lethality of the attack, and making treatment resistance less likely. This approach has drawn increasing attention because of the potential for synthetic lethality, which occurs when inhibiting one molecular target in isolation has little impact on cancer survival, but inhibiting two interdependent targets results in pronounced cell death [7].

A common way to employ this strategy is through the combination of small molecule inhibitors, which target common molecular mechanisms in a cancer, like a mutated DNA-repair protein, with other treatment modalities. One good illustration of this is a small molecule inhibitor combination therapy that was granted accelerated approval by the FDA in 2024: the small molecule inhibitor adagrasib in combination with the monoclonal antibody cetuximab for KRAS G12C-mutated colorectal cancer [8].

Adagrasib is an inhibitor of the KRAS G12C protein, which causes colorectal cancer cells to grow uncontrollably. However, there are many mechanisms of resistance to KRAS inhibition, which often makes treatment response to adagrasib short-lived [9]. For example, preclinical evidence suggests activation of another protein, EGFR, can also drive tumor growth through the same molecular pathway. Recently, an expansion cohort trial has demonstrated that blocking EGFR with the monoclonal antibody cetuximab, while simultaneously inhibiting KRAS G12C with adagrasib results in an improved drug response rate (46% vs 19%) and decreased the percentage of grade 3 or 4 adverse reactions (34% vs 16%), compared to adagrasib monotherapy [10].

Navigating development challenges and opportunities for combination therapies

Combination approaches to emerging therapies are so promising that some oncologists suggest finding highly effective combinations of existing therapies may have more clinical benefit to patients than developing next-generation monotherapies [11]. However, combination therapies also face shortcomings and unique challenges during clinical development and commercialization.

In instances, the entry criteria for a combination therapy of a drug are often stricter than for the monotherapy of that same drug. For example, the hormone treatment enzalutamide was approved for people with castration-resistant prostate cancer in 2018 [12]. But, in 2023, a combination of enzalutamide with talazoparib, the small molecule inhibitor of a DNA repair protein, was approved specifically for the treatment of patients with metastatic, HRR gene-mutated, castration-resistant prostate cancer [13]. As a consequence of stricter entry criteria, combination therapies may face more challenges with lengthy enrollment periods during development, and with a smaller number of patients eligible for the treatment following approval. The number of patients who can access a combination therapy may be further restricted by cost limitations, as combination therapies increase drug costs for patients.

Additionally, combination therapies have an increased potential for adverse drug reactions. The combined use of different drugs may not always be compatible, and combination therapy could increase the frequency of adverse events from drug-drug interactions [2]. Assessing the potential for adverse drug interactions – along with the potential for synergistic efficacy – is, therefore, a crucial first step when selecting an appropriate combination of therapies in preclinical and early clinical development.

With the number of potential therapy combinations rising exponentially, it is becoming increasingly difficult to identify optimal cancer drug combinations. Here, advancements in high-throughput screening, supported by artificial intelligence (AI), are proving essential to the identification and selection of optimal cancer drug combinations. Researchers are also working on AI-driven frameworks for predicting synthetically lethal combination therapies and clarifying associated biological processes [7].

Once developers have selected an optimal therapeutic combination, they should then employ sensitive, model-based methods of dose determination. Traditional methods of rule-based dose selection, which were originally developed to identify the optimal tolerable dose for toxic chemotherapies, are not appropriate for dose selection of combination therapies. Instead, developers should employ dose selection protocols that will identify the optimal biological doses of both therapies by accounting for toxicity and efficacy.

Careful dose determination is especially important because some drugs may be more potent in combination, meaning the optimal biological dose of a monotherapy drug may be higher than when the same drug is administered in combination. In such cases, being able to lower the dose of a drug that has toxic side effects could actually improve the safety profile of a combination therapy, when compared to the monotherapy.

The unique considerations for biomarker development of combination therapies is also worth noting. Given the elevated risk of adverse events from drug-drug interaction, biomarkers that predict a patient’s response to treatment are essential to identifying patients who will most benefit from a combination approach. Additionally, biomarkers and biomarker thresholds used in a monotherapy outcomes assessment may need to be redefined when that therapy is used in combination to accurately describe a patient’s treatment response.

Get support from an experienced partner

As a diverse, sophisticated and crowded therapeutic oncology landscape drives complexity in clinical development and commercialization, the experience embodied in collaborating with partners, vendors and trial sites can make the difference between insurmountable challenges and successful clinical development. Learn more about de-risking clinical development as the oncology landscape shifts in ICON’s whitepaper and survey report. Search “precision medicines oncology whitepaper ICON.”

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