Who Led LECLAZA-RYBREVANT Combination Therapy Clinical Trial and Achieved FDA Approval?

"When coincidences accumulate, they become inevitable. The fact that LECLAZA, which I once crossed paths with, came back to me, and the timing of developing LECLAZA and RYBREVANT together—everything fell into place as if it was destiny. I firmly believe that this miracle will extend the lives of 500,000 patients each year."

In an interview with kormedi.com, MD, PhD. Cho Byoungchul of Yonsei University’s Severance Hospital Yonsei Cancer Center described leading the clinical trials of Yuhan's Leclaza (ingredient: lazertinib) and Janssen's Rybrevant (ingredient: amivantamab) as a "fateful encounter." He emphasized that the opportunities brought by the FDA's approval of the Leclaza-Rybrevant combination therapy on the 20th hold invaluable significance that cannot be measured in monetary terms.

Leading the Clinical Trials of Leclaza, Rybrevant, and Their Combination Therapy

Cho spearheaded the Phase 1, 2, and 3 clinical trials of the Leclaza-Rybrevant combination therapy. Additionally, he led the translational research and clinical trials (Phases 1 through 3) for both Leclaza and Rybrevant individually. This has earned him the title of "Father of Leclaza and Rybrevant."

Leclaza is a treatment for non-small cell lung cancer (NSCLC) targeting mutations in the EGFR (epidermal growth factor receptor). Johnson & Johnson's Rybrevant targets not only EGFR but also MET (mesenchymal-epithelial transition factor) gene mutations.

The combination therapy maximizes the anticancer effect by having Rybrevant block EGFR and MET to inhibit tumor cell signaling, while Leclaza suppresses the activity of tyrosine kinases, enzymes that send signals inside cancer cells.

The global market for EGFR-targeting NSCLC therapies is estimated to be worth over 10 trillion KRW (approximately 7.6 billion USD). Currently, the latest standard treatment for NSCLC is Tagrisso (ingredient: osimertinib) developed by AstraZeneca. The Leclaza-Rybrevant combination therapy has shown to be more effective than Tagrisso in progression-free survival (PFS), fueling high expectations for its market potential. Johnson & Johnson predicts that the combination therapy could generate up to 5 billion USD (approximately 6.6 trillion KRW) in sales by 2025.

With FDA approval, Yuhan is expected to receive about 60 million USD (approximately 82.5 billion KRW) in royalties from Johnson & Johnson, along with a portion of the sales revenue.

"New Drug Trials Expand the Horizon of Cancer Treatment"

The journey to develop a new drug that would offer new hope to lung cancer patients was not without its challenges. As Cho recounted the journey from his first encounter with Leclaza to its FDA approval, his expression reflected a mix of emotions—deeply moved and joyous. Particularly, he spoke of the difficult times when the drug was dismissed at international conferences simply because it was a latecomer. "Only by advancing clinical trials for new drugs can we expand the horizon of treatment options," he stated.

-LECLAZA has become the first FDA-approved cancer drug from Korea. How did you first encounter it?

"It was truly a fateful encounter. In 2013, PhD. Ko Jongung, the CEO of Genosco, came to Korea from the United States because he wanted to test a drug he had developed. At that time, my lab was small, with only 6-7 research nurses, and I couldn't really collaborate. Two years later, after returning from training in Singapore, I received a proposal from MD, PhD. Nam Sooyeon at Yuhan to co-develop a candidate substance. The substance she showed me was the same one I had seen two years earlier. During that time, Yuhan had acquired the candidate substance from Oscotec, Genosco's parent company. My first thought was, 'What is this?' It was a connection I thought had passed, but it came back."

-What were the results of the clinical trials for the LECLAZA-RYBREVANT combination therapy?

"The combination therapy of Leclaza and Rybrevant proved to be more effective than Tagrisso monotherapy. The PFS of the combination therapy was 23.7 months, about 30% better than Tagrisso’s 16.6 months. Most side effects were manageable. The therapy was effective in both Asians and Westerners, with no racial differences."

-There must have been many challenges during the clinical trials.

"When we first started developing Leclaza, I was often told it was too late. The hardest part was the lack of support even from domestic researchers who were certain it wouldn’t succeed. There were internal challenges too, especially when Nam Sooyeon left Yuhan. However, thanks to the perseverance and belief of Yuhan's Chairman Lee Jung-hee and CEO Jo Ukjae, we were able to complete the research. The most difficult part was being disregarded at conferences. Early in the clinical development, Leclaza was treated poorly at international conferences. When I presented the clinical data, it was often dismissed, and I found myself arguing for an hour straight."

"Inspired by Dr. New Il-han... I Embraced LECLAZA as a Mission"

-Despite the difficulties, what motivated you to keep going?

"Honestly, I'm not an extremely diligent or energetic person, but when I have a sense of duty, nothing can stop me. During the research on Leclaza, I happened to learn that Dr. New Ilhan, the founder of Yuhan, established the company to save the people suffering from poverty, hunger, and disease. That statement resonated deeply with me. From then on, I felt it was my duty to repay the country through my research. Leclaza became my mission. After that, I thought of it as my child and developed it with the mindset of breathing life into it. A drug, though inanimate, must have life to save cancer patients. It was very tough, and I lost a lot of hair. Still, I feel proud and grateful, knowing that such an experience in life is rare."

-What does this approval mean for the Korean pharmaceutical and biotech industry?

"Korea has always aspired to be a biotech powerhouse, but it lacked a representative drug. For a drug to be globally recognized, doctors worldwide must prescribe it, and it must ultimately improve the lives of patients globally, relieving them from the pain of disease. Leclaza is the first drug that has the potential to fulfill that hope. It's also significant that we now have an excellent alternative capable of challenging the monopoly in a market that sees 500,000 new patients every year."

-What is the significance from an economic perspective?

"The economic impact is also significant. Tagrisso was recently included in Korea's insurance reimbursement system, and if it were the only option, it would have cost the insurance system billions of KRW annually. However, with Leclaza also covered, the government was able to negotiate prices and prevent financial losses. Additionally, as patients worldwide start using it, revenue will flow into Korea, creating momentum for further growth in the domestic biotech industry. Particularly, the opportunities brought by the combination therapy are of incalculable value."

-Do you think doctors will actively adopt the combination therapy?

"Unfortunately, only 60-70% of patients with stage 4 EGFR lung cancer transition from first-line to second-line treatment. Many patients develop resistance and their condition worsens, preventing them from moving to the next stage. Therefore, to extend overall survival, I believe we must prioritize the use of superior treatments like combination therapy to offer better treatment opportunities."

"LECLAZA Monotherapy Also Has Strong Potential for FDA Approval"

- What is the future potential of LECLAZA?

"Next month, results from a study comparing LECLAZA directly with Tagrisso will be presented at the World Conference on Lung Cancer. In the high-risk group, which accounts for 70% of all EGFR mutations (including liver and brain metastases), LECLAZA monotherapy has shown better efficacy compared to Tagrisso. This data indicates that LECLAZA is also worthy of FDA approval as a monotherapy. Moreover, the LECLAZA-RYBREVANT combination therapy has shown more than double the progression-free survival compared to existing treatments in patients with atypical mutations. Atypical mutations account for 10% of all EGFR mutations, and this combination therapy has proven to be a widely applicable treatment option."

- There was a time when expectations for the LECLAZA-RYBREVANT combination therapy were dampened due to positive results from trials combining Tagrisso with chemotherapy. Can the combination therapy truly challenge Tagrisso's dominance?

"Recent data on the combination therapy of LECLAZA with subcutaneous (SC) RYBREVANT shows that it not only enhances patient convenience but also reduces side effects and improves efficacy, making the Tagrisso-chemotherapy combination less relevant. Intravenous injections require hospital visits every three weeks, with patients waiting for six hours, but this process can be shortened to just five minutes. Notably, I met many influential experts in the U.S. who provided feedback that the 'first-line choice should be the LECLAZA and RYBREVANT (SC) combination therapy.'"

- Lastly, how do you feel now that FDA approval has been granted?

"I am incredibly happy, but it's overwhelming to express that emotion in just a few words. I am filled with gratitude. As I mentioned earlier, a destined encounter is not something that can be forced. But sometimes, it feels as though the heavens are guiding you, saying, 'You were made to pursue this with all your heart.' And because I know that hard work doesn’t always guarantee success, all I feel is deep thankfulness."