The developer of South Korean-made lung cancer new drug Leclaza (lazertinib), Professor Cho Byoungchul at Yonsei Cancer Center compared his dramatic five-year journey of seeking South Korea’s Ministry of Food and Drug Safety (MFDS) approval on the drug as a movie production; discovering the candidate substance was a casting call, clinical finding presentation was a premiere and lastly, the authorization was the grand opening.

Based on a young director’s unique perspective and passion, a work worthy of the global spotlight was complete. In the end, the drug was licensed out to a global pharmaceutical company and won the South Korean health authority’s clearance. Like how a nameless director emerges as an international star director, Professor Cho is now a principal investigator (PI) of global clinical trial backed by his performance so far.

#"Lazertinib was my destiny, it would be a role model for developing a new drug"

Lazertinib he developed is a third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that highly selectively targets EGFR T790M mutation.

Recently, MFDS has authorized lazertinib, with condition to provide further clinical evidence, as a treatment in EGFR T790M mutation-positive patients with locally advanced or metastatic non-small cell lung cancer (NSCLC).

Professor Cho Byoungchul has been leading the development and clinical studies of lazertinib from the time when Yuhan Corporation licensed in the candidate medicine from a South Korean bio venture Oscotec at the pre-clinical phase in 2015. The professor said it like he was destined to encounter the candidate medicine at an early stage.

Professor Cho reminisced and commented, “I was offered to lead the clinical trial, when the drug was still a candidate medicine in 2012, but I had to turn it down because the lab was too small and the company offering the job could not afford the entire project. But in 2015, I visited Yuhan Corporation’s central R&D lab invited by Professor Nam Soo Yeon, and I thought it was a destiny to receive the clinical study offer again there. For five years then on, I put my everything into the research and the result is now out finally.”

Besides the romantic metaphor, the professor faced a number of challenges to this date. The biggest shake-up of the new drug development process was the news of a competing drug obtaining the National Health Insurance (NHI) reimbursement in South Korea.

After receiving the market authorization in May 2016, another third-generation EGFR TKI Tagrisso (osimertinib) by AstraZeneca was listed for reimbursement in December 2017, with a second-line treatment indication lazertinib was also targeting for.

Currently, AstraZeneca is negotiating with South Korean health authority like the Health Insurance Review and Assessment Service (HIRA) to expand Tagrisso’s reimbursement as a first-line therapy. Basically, when lazertinib was trying out for the South Korean market, the competitor was already working on indication expansion from second-line to first-line.

Professor Cho confessed the devastating year 2017, when Tagrisso got the NHI benefit, demotivated him the most.

“I remember experiencing the biggest challenge in the clinical studies as Tagrisso received the NHI reimbursement. Our registration for clinical participants was excruciating. I was deeply concerned that the company would lose its motivation in the pipeline. Lazertinib’s Phase I only started when the competitor was conducting a Phase III, and so many were pessimistic that the drug development was too late already,” he elaborated.

"Lazertinib’s global clinical study to confirm efficacy and safety as a first-line treatment”

Currently, lazertinib is in process of conducting a global Phase III trial (LASER301) to overcome the limitation of the conditional approval.

The Phase III trial aims to evaluate the potential of lazertinib as a first-line treatment in 380 patients with EGFR mutation-positive NSCLC. At the moment, 27 hospitals, including Severance Hospital, Samsung Medical Center, Seoul National University Hospital, Seoul St. Mary's Hospital and Seoul Asan Medical Center, are participating in the clinical trial.

Also, the drug is conducting another Phase III trial as a combination therapy with a bispecific antibody anticancer treatment amivantamab developed by a multinational pharmaceutical company Janssen.

# Professor Cho explained, “Lazertinib’s efficacy and safety have to be confirmed as a first-line treatment. It would be directly compared against a first-generation Iressa (gefitinib). We also have to conduct a head-to-head clinical trial comparing lazertinib plus amivantamab combination therapy against Tagrisso to confirm progression-free survival (PFS).”

He also noted Tagrisso and lazertinib should also step away from a strict competitor relationship, but should rather come together as a mutual relationship to survive in the EGFR TKI market.

He stressed, “I think lazertinib and Tagrisso should be good friends. Global pharmaceutical giants like Pfizer and Novartis have given up on the new drug development for various reasons, but think how unfortunate the lung cancer patients would be to have only one treatment. Considering all lung cancer patients, a wide variety of combination therapy is needed to provide more treatment options.”

At the same time, he was confident to claim lazertinib does not shows notable difference between Asian and non-Asian races, which can be one of toughest challenges to overcome when shooting for the international market.

The professor explained, “Regarding the treatment for advanced or metastatic NSCLCL, EGFR TKI would unlikely to show much difference in Asian and non-Asian races. Already there has been a study done to test the pharmacokinetics in different races, and I do not see much of a difference in efficacy. The ongoing LASER301 study would also give more detailed answer to the question.”

Finally, Professor Cho also gave a personal view on the lazertinib pricing procedure to follow after the conditional approval. He firmly argues there should not be a discount for being a home-grown new drug.

He emphasized, “Considering the level of efficacy and safety lazertinib performs, it should be priced on par with Tagrisso until the Phase III trial outcome is out. Basically, the health authority should not press for a discounted pricing, only because the drug is made in Korea. The people of the country worked on the drug and even a global company licensed out the technology. Based on the new drug development infrastructure in Korea, they should properly acknowledge the value of the drug.”