Since the development of Iressa (gefitinib), the first epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in the early 2000s, treatment for EGFR-mutated NSCLC has focused on advancing next-generation EGFR TKIs.

Recently, however, there has been a shift in standard care. While EGFR TKI monotherapy has been the norm for the past two decades, new, intensified therapies are emerging that combine EGFR TKIs with chemotherapy or antibody treatments.

Most recently, in April, the Ministry of Food and Drug Safety approved the FLAURA2 treatment strategy, which combines Tagrisso (osimertinib), a third-generation EGFR TKI, with pemetrexed and platinum-based chemotherapy.

Oral TKI monotherapy has made significant strides in convenience and efficacy, yet there is still a need for more intensified treatments. Korea Biomedical Review spoke with Professor Kim Sang-we of Medical Oncology at Asan Medical Center, a leading contributor to the FLAURA2 study, to discuss the ongoing challenges in treating EGFR-mutated NSCLC and the clinical benefits of combining Tagrisso with chemotherapy.

Question: For the past 20 years, EGFR TKI monotherapy has been the standard of care for stage IV EGFR-mutant NSCLC. However, recently, intensified treatments have been developed that add chemotherapy to this regimen, and I'm curious as to why.

Answer: While targeted therapy with EGFR TKIs can lead to good outcomes, in reality, they may not work at all in about 10 percent of patients, and the duration of benefit varies from patient to patient. Even if you have an EGFR mutation, the prognosis and treatment effects vary among patients.

Patients who initially respond to EGFR TKIs but later develop resistance are typically transitioned to subsequent treatments. Currently, those who have received first-line treatment with a third-generation EGFR TKI monotherapy are usually treated with platinum-based chemotherapy. However, about 30 percent of these patients do not even have the chance to receive follow-up treatment. Many of the recent enhanced combinations are specifically designed to address this critical unmet need.

Q: If approximately 30 percent of patients cannot receive follow-up treatment, does that mean that 70% of patients can benefit from EGFR TKI monotherapy alone? Can we identify which patients need more intense combination therapy?

A: As mentioned before, patients with EGFR mutations have variable prognoses and varying responses to EGFR TKIs, so it is not easy to determine which patients are better served by monotherapy or combination therapy. At this point, we can speculate, but it's too early to give a definitive answer. Perhaps next year or the year after, we will have a more concrete answer.

Simply put, we can say that more intense combination therapy is needed in patients whose disease is expected to progress quickly from the start. For example, patients with liver or brain metastases at diagnosis, TP53 gene mutations, or detectable ctDNA are "high-risk" and are more likely to progress quickly. There are also a number of other predictors, such as patients with a high tumor burden.

But predicting them in advance is a challenge. Recently, adding additional combination therapy to patients who have received EGFR TKI monotherapy based on the presence or absence of ctDNA in their blood has been proposed, but exploratory analysis of the FLAURA2 study showed that post-treatment ctDNA clearance did not predict whether patients would benefit from Tagrisso monotherapy or Tagrisso plus chemotherapy. In patients with detectable pre-treatment ctDNA, Tagrisso plus chemotherapy outperformed Tagrisso alone, regardless of whether ctDNA was clear (3 weeks after treatment), but in patients with undetectable pre-treatment ctDNA, there was no meaningful difference in progression-free survival between the two treatment arms.

Toxicity is also an important consideration when deciding whether to use combination therapy in a patient. For example, if an elderly patient can tolerate a combination treatment with the addition of chemotherapy. Patient preference is also important. It's not always easy to go to the doctor every three weeks to get injections. It's up to the doctor to make a judgment call.

Q: A subgroup analysis of the FLAURA2 study showed a significant benefit of adding Tagrisso to chemotherapy in patients with brain metastases at the start of treatment. Would this enhanced combination be effective in patients with brain metastases?

A: Brain metastases in EGFR-mutant lung cancer are more common than in other lung cancers. If the chance of having brain metastases from the start is about 10% in all lung cancer patients, it is about 20% in patients with EGFR mutations. With continued follow-up, this rate is expected to rise to 50% as the disease progresses. Therefore, treatments that can delay and prevent brain metastases in EGFR-mutant lung cancer are of great importance.

Although it is commonly believed that chemotherapy has a low penetration rate across the blood-brain barrier (BBB), patients with brain metastases often have a broken BBB, which can lead to central nervous system (CNS) reactions with conventional chemotherapy alone. As a result, patients with multiple brain metastases are often not treated with whole brain radiotherapy or gamma knife if they are asymptomatic. Regardless of the prevailing concepts, chemotherapy can be effective in patients with brain metastases.

Q: In general, chemotherapy is known to have severe side effects. We are concerned that adding chemotherapy to Tagrisso monotherapy may make it more difficult for patients.

A: Pemetrexed and carboplatin, which were used in the FLAURA2 study, are chemotherapy drugs with fewer side effects. This is why they were chosen as Tagrisso's combination drugs. In addition, local doctors are already accustomed to using these drugs. The ability to combine Tagrisso with familiar and less toxic anticancer drugs is attractive.

Q: Recently, Tagrisso plus anti-cancer chemotherapy was licensed in Korea, paving the way for its use in clinical practice. However, reimbursement remains a challenge.

A: From a patient's and doctor's perspective, it would be great to have insurance coverage, but from a medical policy perspective, the principle of equity must be considered. It will be a matter of insurance finances, and it may be difficult to cover all patients. I would like to see all patients covered like in Japan, but I think there are practical limitations that need to be addressed.