Korea's homegrown Leclaza gains momentum in NSCLC treatment, awaits global expansion

Non-small cell lung cancer (NSCLC) accounts for about 85 percent of all lung cancers, and targeted therapies have become a significant treatment option, especially for patients with EGFR (Epidermal Growth Factor Receptor) mutations.

After the emergence of first—and second-generation EGFR TKIs, third-generation drugs that overcome resistance and provide better therapeutic effects are being introduced rapidly. The third-generation EGFR TKI, Leclaza (lapatinib) of Yuhan Corp., is attracting attention after receiving domestic approval in June 2023 as a first-line treatment.

The homegrown drug has demonstrated excellent efficacy and safety in the first-line treatment of EGFR-mutated NSCLC through the phase 3 LASER 301 trial. In particular, the trial demonstrated a progression-free survival (mPFS) of 20.8 months in Korean patients and an mPFS of 23.3 months in patients with exon 19 deletion mutations.

Since January of this year, health insurance coverage for first-line treatment has significantly reduced the burden on patients. The company is awaiting the outcome of the U.S. Food and Drug Administration (FDA) approval review for the combination therapy with Rybrevant (amivantamab) of Johnson & Johnson, raising expectations for its global expansion.

Korea Biomedical Review spoke with Professor Ahn Jin-seok of the Department of Hematology-Oncology at Samsung Medical Center and Professor Hong Min-hee of the Department of Medical Oncology at Yonsei Cancer Center about Leclaza's clinical performance and current use, its potential for domestic and international use, future strategies for treating NSCLC, and issues related to the reimbursement system.

KBR: It's been about half a year since Leclaza got insurance benefits as a first-line treatment. How is it used in clinical practice in Korea, and what changes have you seen in the prognosis of patients?

Hong: With the reimbursement of third-generation drugs, very few patients are starting treatment with first- or second-generation drugs. Except for patients with rare EGFR mutations, most patients are starting treatment with third-generation drugs.

Ahn: Currently, Tagrisso (osimertinib) of AstraZeneca and Leclaza are used with insurance coverage. Both are good drugs, but Tagrisso tends to be preferred because it is more familiar. Leclaza is struggling as a latecomer. However, when a new drug comes out, many doctors want to try it out. While the pandemic has reduced the number of new patients at large hospitals, expanding coverage to primary care has undoubtedly increased the number of prescriptions.

KBR: Do patients come to you knowing about Leclaza?

Hong: With the development of the internet, patients are more likely to know the name of the drug than in the past. In the past, they used to say, “Please choose a good drug.” Now, they come to us directly mentioning the name of a drug like Leclaza. Since Leclaza was a homegrown drug, the development process was exposed to a lot of media, so the awareness among patients has increased considerably.

KBR: When evaluating the results of LASER 301, the basis for Leclaza's first-line approval and reimbursement, we are curious if the clinical outcomes are reflected in the real world of prescribing.

Hong: One of the most important clinical outcomes we evaluate is progression-free survival (PFS). This is the part that evaluates how long the effect lasts when the drug is used in the first line, but it will take more time for real-world data (RWD) to confirm the expected results from clinical studies fully.

Ahn: We can predict the outcome from previous clinical studies, but it's still too early to see the effects in the real world because we've only been using it as a first-line treatment for less than a year. However, empirically, it will eventually approach the results of clinical studies. The small sample size may initially lead to extreme results, but we should see similar effects in clinical studies over time.

Leclaza's biggest strength is its potent effect on the L858R substitution, and I think this is where the LASER 301 trial (mPFS of 17.8 months in Korean patients) was most meaningful.

KBR: One reason Leclaza is gaining traction is its efficacy in patients with brain metastases. We are curious how you evaluate Korean patients' performance with brain metastases.

Hong: We have seen quite good results in patients with brain metastases. Two to three years ago, when patients with brain metastases came to us, we often considered radiation therapy first and combined it with drug treatment.

Now, however, if the symptoms are not severe, we can start drug treatment right away, and most of them are well controlled. As a result, radiation treatments, such as whole-brain radiation and gamma knife, have been used less frequently.

In the past, when a patient with lung cancer was diagnosed, and it wasn't clear if they had an EGFR mutation, a few steps were taken first. Now, we check for the mutation, and if they have an EGFR mutation, we start them on a drug like Leclaza and see how they do. This improves most patients and dramatically reduces the chance of problems.

KBR: Could you tell us some memorable cases of prescribing Leclaza?

Hong: I remember the first patient I used Leclaza on. She participated in a clinical trial, and her response to the drug was much better than expected. At that time, Tagrisso was not reimbursed, so it was more disappointing that we couldn't use it even though a good treatment was available. However, Leclaza showed excellent results even with a small dose. I had a strong impression that Leclaza was a “go-to” drug.

Ahn: In real life, we often see patients with more than one cancer. Once, I had a patient in her 80s diagnosed with lung cancer and breast cancer. Her lung cancer was EGFR L858R-positive, and her breast cancer was hormone-positive. In the past, she would have had to be treated with chemotherapy for both lung and breast cancer, which would have been difficult for an older adult due to safety concerns. However, the situation is different now. The patient was prescribed Leclaza for her lung cancer and a CDK 4/6 inhibitor for her breast cancer. With targeted therapy options like Leclaza, we can offer patients more options.

KBR: How do you respond to side effects that patients experience when prescribed Leclaza?

Hong: Sometimes, the side effects are slightly different from what we're used to. For example, skin rashes or inflammation around the nails can be managed well because we have much experience with them, but new side effects require a little more attention.

Ahn: Dose adjustments are often made when side effects occur, mainly if side effects include numbness in the hands and feet. In the LASER 301 trial, about 20 percent of patients had to be dose-adjusted. In clinical practice, dose adjustments are slightly more frequent than in studies. Clinical studies are often based on patients who are well, but in the real world, many patients are not, and many patients are elderly, so in our experience, we tend to dose down in elderly or smaller female patients.

In our experience, most patients tolerate reducing the dose or adding a few more medications. Very rarely, a small percentage of patients have difficulty tolerating the medication, and in those cases, we adjust the dose from 240 mg to 160 mg rather than discontinuing the medication altogether. In most cases, the condition stabilizes rather than worsens.

KBR: Does the efficacy remain when the dose is reduced?

Hong: Yes. According to the relevant data, the efficacy does not decrease significantly when the dose is reduced. In our poster at last year's European Society for Medical Oncology Annual Meeting (ESMO 2023), we confirmed that the side effects are transient when the dose is reduced and often recover after a short dose reduction, indicating that the side effects are reversible.

KBR: In the case of numbness in the hands and feet, we understand there are concerns because it is a new side effect.

Ahn: It's a rare side effect in EGFR TKIs but also in ALK inhibitors and other EGFR TKIs.

Hong: Paresthesia has not been reported at all. When I checked again recently, I didn't think it was a side effect of EGFR TKIs, but when I looked at other patients, there were a few cases. Sometimes, patients don't talk about it because it's mild. It's not a completely unheard-of side effect, but it tends to be more prevalent and seems to be more severe with Leclaza compared to other TKIs.

KBR: This month, the U.S. FDA is expected to announce its review of the Leclaza and Rybrevant intravenous combination. How do you think it will impact the domestic prescription market if approved?

Ahn: It could be used by patients for whom cost is not an issue, but Korea's lack of insurance coverage is a barrier. It will likely be delayed until the subcutaneous (SC) version of Rybrevant is introduced. The plan for its introduction is not clear yet.

Hong: In the case of Tagrisso, even if you use a combination therapy and then use Tagrisso alone without chemotherapy if the combination therapy is not covered, it will remain unreimbursed. Once it goes off-benefit, it stays off-benefit, so you have to decide carefully. This may be possible for patients for whom cost is not an issue, but this is rarely the case.

KBR: So what was your assessment of the phase 3 data for the combination of Leclaza and Rybrevant SC presented at the American Society of Clinical Oncology Annual Meeting (ASCO 2024) in June?

Hong: First, it's important to note that dosing efficacy was demonstrated. Secondly, as a biologic, when administered intravenously, Rybrevant can cause infusion-related reactions (IRRs), including fever, skin rash, and shortness of breath. These side effects can be quickly resolved with antihistamines or steroids, but the subcutaneous (SC) route has rarely seen these side effects. The RWD shows that SC has fewer side effects and more positive data, so it's more likely to be switched to SC.

Even if the data is the same, the only thing that can change is the convenience of administration, so if it's positive in all aspects, it will likely be switched to subcutaneous injection. However, it is still uncertain when this will be applied in Korea. There is no reimbursement for combination therapy in Korea, and it is unclear when the subcutaneous injection system will be introduced.

KBR: How do you assess Leclaza's future potential in terms of versatility?

Ahn: Tagrisso was launched earlier by a global company, so it already has a wealth of clinical data for various indications, such as stage 3 EGFR NSCLC with adjuvant therapy or cancer chemoradiotherapy (CCRT). As a latecomer, it may be challenging for Leclaza to expand its indications. On a positive note, however, the company has some ground to make up with the LAZER 301 clinical data. The ongoing combination with Rybrevant and treatments, such as Rybrevant SC, has the potential to be a breakthrough.

KBR: The development of fourth-generation EGFR TKI lung cancer therapies has been active in recent years. What unmet needs should these upcoming therapies address?

Hong: Fourth-generation drugs mainly target the C797S mutation, which is a significant resistance in third-generation EGFR TKIs. The drugs attempt to inhibit this mutation, but the published data has not been impressive. If a fourth-generation drug is developed, the question is whether it will be enough to keep up with the mutation or whether it is more important to prevent resistance from developing in the first place. The latter is more important, but it is also a challenge.

Ahn: I agree. The fourth-generation drugs under development target multiple resistance mechanisms but only target a fraction of the total resistance. They are still in the early stages and have yet to show impressive results, and even if they are successful, their role is likely to be limited. Because third-generation drugs are so potent, third-generation monotherapies still address a significant unmet need. However, strategic considerations need to be made about using more potent therapies in certain patients early on or waiting for resistance to develop.

KBR: After Leclaza's coverage as a first-line treatment, are there any improvements that need to be made, especially in terms of access to treatment and challenges faced by patients and healthcare providers?

Hong: Currently, it is difficult to get reimbursement for third-generation therapies unless you are a stage 4 patient. In some cases, patients with advanced stage 3 are not eligible because they don't meet the reimbursement criteria, even though they are no different from stage 4 patients. This is about 2-3 percent of all patients. This problem also applies to immuno-oncology drugs.

Ahn: The criteria for evaluating the response to anticancer drugs conducted by the KFDA have become more stringent in recent years. The cuts have increased accordingly, and I would like more flexibility in evaluating clinicians' judgment. In theory, stage 3 patients are supposed to receive CCRT. However, CCRT may not be used in older patients or those with reduced lung function due to the increased risk of adverse events. Given the inferior prognosis of patients with EGFR mutations, especially when CCRT is given alone, it is unfortunate that many patients in stage 3, which is equivalent to stage 4, are not eligible for third-generation therapies.

KBR: What else needs to be improved in the lung cancer treatment landscape?

Hong: To be eligible for benefits, patients must pass an EGFR test using nationally recognized standards. Generally, this is either PCR (polymerase chain reaction) or NGS (next-generation sequencing) testing. However, these domestic standards are relatively rigid and lack flexibility. Even if a blood test from abroad detects the EGFR mutation, some patients cannot receive benefits if they do not meet the domestic standards.

Ahn: If the test results are recognized overseas, they can be considered meeting global standards. However, some patients cannot receive treatment because they do not meet domestic standards. For example, blood tests at Guardant Health or Foundation Medicine are representative. In Korea, laws and systems are often interpreted literally, leading to rigid results, which is unfortunate because they do not align with global standards.

KBR: Leclaza is a homegrown drug developed with Korean technology. What are your expectations and impressions now that it is about to expand overseas?

Hong: Leclaza was developed by Korean doctors in the preclinical stage. In a word, it feels like a drug that we have cultivated ourselves. Even after the product is approved, researcher-led clinical trials are active.

Ahn: Unfortunately, Korean pharmaceutical companies have to license out to Big Pharma because they don't have the capital to enter the global market directly. However, Leclaza has set a good example and paved the way for other Korean pharmaceutical companies to go global. The Korean pharmaceutical industry will expand its influence, starting with Leclaza, and one day, it will be able to take charge of blockbuster drugs from start to finish.