[Interview] 'Speed and strategy determine fate of new cancer drugs in phase 1 trials'

As phase 1 clinical trials for cancer drugs evolve into a stage for designing treatment strategies, the boundary between research and treatment remains blurred in clinical practice.

With the rise of combination therapies and intensifying global competition, phase 1 trial design and execution are becoming more complex. The roles of individual countries are also shifting.

Korea Biomedical Review met with Professor Lee Keun-wook of Seoul National University Bundang Hospital (SNUBH). The interview focused on the significance of phase 1 clinical trials for cancer drugs, recent changes, and challenges in the domestic environment.

Professor Lee Keun-wook of the Department of Medical Oncology at Seoul National University Bundang Hospital discussed the fundamental significance of phase 1 clinical trials for anticancer drugs and other related issues during a recent interview with Korea Biomedical Review. (KBR photo)

Question: There is still a perception that phase 1 trials represent “uncertain treatment.” How are they actually defined in clinical practice?

Answer: Phase 1 anticancer drug trials begin before a drug’s efficacy, side effects, and optimal dosage are known. Often conducted in humans for the first time, these studies begin without knowing the drug’s exact actions in the body. This high uncertainty requires careful explanation to patients.

However, phase 1 anticancer drug trials cannot be simplified into a single category. When a completely new drug is administered as monotherapy, the trial often targets patients who no longer have standard treatment options. In the absence of alternative treatments, patients participate in clinical trials in the hope of a new treatment.

If more positive effects than expected are confirmed, the drug may advance to a later stage of treatment. Phase 1 trials may then proceed as combination therapy with standard treatments. In such cases, the focus expands beyond safety assessment and anticipates better efficacy than existing treatments.

It is repeatedly emphasized that, formally, phase 1 clearly constitutes research and that clinical trials are not treatments. However, in clinical trials involving cancer patients, both patients and medical staff participate on the premise of therapeutic potential. Ultimately, phase 1 of anticancer drug trials can be viewed as a stage where the meaning of “treatment” coexists alongside the essence of “research.”

Q: We’ve heard that phase 1 clinical trials have changed recently as combination therapy has become the standard of care.

A: Combination therapy is now the standard in cancer treatment, and phase 1 clinical trials have undergone significant changes. Previously, phase 1 aimed to confirm safety and the maximum tolerated dose. Now, efficacy is often explored from the early stages.

Designs that confirm efficacy in certain cancer types or patient subgroups, using dose-expansion cohorts after dose escalation, are now widespread. Pharmaceutical companies use this strategy to demonstrate a drug’s potential early.

Institutional and national roles differ in this process. The dose-escalation phase is most experimental and challenging. Global pharmaceutical companies entrust it only to select reliable institutions. Previously, these trials mainly occurred in the United States, with limited work at overseas institutions.

In the dose-expansion phase, Asian countries, including Korea, play a larger role depending on the cancer type. For diseases with high prevalence in East Asia, such as gastric cancer or EGFR-mutated lung cancer, Korea has become a key country for clinical trial conduct.

During these dose-expansion phases, it is not uncommon for patients to experience meaningful therapeutic responses. Even in early-stage clinical trials, the significance of phase 1 is increasingly evident, as it can offer patients a tangible treatment option.

Q: What is Korea’s role in the process of determining and scaling up doses in phase 1 clinical trials?

A: Phase 1 clinical trials require high expertise, especially during dose determination. This area is difficult to enter, as it demands responses to unexpected adverse effects and a strong understanding of the protocol.

While not all Korean hospitals can conduct this phase, a growing number of large hospitals in the Seoul metropolitan area are participating in the dose-escalation phase of global new drug development. This indicates that Korea’s capabilities in conducting early-phase clinical trials are being recognized to some extent globally.

Korea shows strengths in the dose-expansion phase, with rapid patient enrollment. It is also easier to conduct trials for specific cancer types. These advantages make Korea crucial in global development strategies.

Ultimately, it can be concluded that Korea has established itself as a country capable of making meaningful contributions in both the dose-escalation and expansion phases, moving beyond mere participation in phase 1 clinical trials.

Professor Lee Keun-wook (KBR photo)

Q: Can you share a specific example of how the speed of clinical progress, like patient enrollment, is important based on your experience?

A: A representative example is “zanidatamab,” an HER2-targeted therapy. We participated in the initial phase 1 stage. Early responses exceeded expectations, so development expanded rapidly. The drug has since advanced to phase 3 trials, raising the possibility it could become a standard treatment.

Another example is Tevimbra (tislelizumab), an immunotherapy drug. Complete remission was seen in metastatic gastric cancer patients who had not responded to previous treatments. These cases show that phase 1 clinical trials can offer real treatment opportunities.

However, not all phase 1 trials succeed. Some developments halt due to side effects, despite promising efficacy. Many others fall behind as competitors develop drugs more quickly.

In phase 1, both the drug’s potential and the development timeline are crucial. Even an excellent drug will fall behind if clinical progress is delayed.

Q: From the perspective of homegrown new drug development, what is the significance of phase 1 clinical trials, and what challenges do they present?

A: Phase 1 clinical trials are critical for evaluating a drug’s potential and shaping development strategies. However, Korea lacks experience in early-stage clinical trials.

For this reason, it is crucial to work closely with clinical researchers from the start to design the study together. Instead of relying only on preclinical data, strategies should be made in the context of actual patient care.

Managing expectations is also important. Phase 1 trials can only confirm preliminary signals, but companies and investors often expect too much. This leads to cases where development stops or changes direction without enough validation.

Funding is another major issue. Korean biotech companies have limited financial resources, making it difficult to scale long-term clinical trials. This shows the gap between the goal of phase 1 trials and real industry conditions.

Q: How would you assess Korea’s competitiveness in the global clinical environment?

A: Korea is recognized for high-quality clinical trial execution. However, cost competitiveness has declined, and now quality is the main competitive factor.

China is quickly catching up, using its large patient pool and faster speed. For global pharmaceutical companies, this means Korea could lose its place as a preferred country.

In particular, regulatory rigidity poses a significant risk. For example, there have been cases in which protocols approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) have nevertheless been restricted in Korea. If such situations persist, Korea could be excluded from global clinical trials. After all, stakeholders need a balanced approach that recognizes clinical trials not only as research but also as part of the treatment and industrial infrastructure.

Q: What areas need improvement in terms of medical infrastructure and the research environment?

A: Clinical trial competitiveness relies on more than just regulations. The workforce structure presents the biggest problem. A shortage of essential medical staff directly affects clinical trial operations.als.

Furthermore, sustaining challenging clinical research is difficult in a system where medical staff face excessive legal burdens. Clinical trials inherently involve the possibility of adverse effects. Yet one incident can sometimes place an excessive burden on staff.

Time constraints and workload are also issues. Given the nature of clinical trials, which require thorough explanations and communication with patients, an environment where medical staff can focus on both patient care and research is essential.

Q: What message would you like to convey to patients considering participation in clinical trials?

A: Clinical trials are designed based on rigorous scientific evidence and procedures. They proceed only after thorough preclinical validation and are approved following a comprehensive review.

Furthermore, since there are various types of clinical trials, it is important for patients to listen carefully to their healthcare providers’ explanations and understand the nature of the trial. Recent informed consent forms are also very detailed, so patients need to fully familiarize themselves with the content before making a decision.

If patients make decisions based on accurate information rather than vague anxiety, clinical trials can provide meaningful treatment opportunities.