SINGAPORE -- “The FLAURA2 study is the first to demonstrate progression-free survival (PFS) improvement with a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) plus chemotherapy. I’d say the result was a home run.”

Dr. Pasi A. Jänne of Dana-Farber Cancer Institute in the U.S. said so while commenting on the results of the global phase-3 FLAURA2 study that he led during the World Conference on Lung Cancer (IASLC 2023 WCLC).

The FLAURA2 study showed that adding chemotherapy to Tagrisso (osimertinib) monotherapy used in the first-line treatment of stage 4 EGFR-mutant NSCLC can increase progression-free survival (PFS) by about nine months, joining the plenary session at the IASLC 2023 WCLC.

However, adding chemotherapy can reduce the convenience and adherence of conventional EGFR TKI monotherapy and increase toxicity, reducing patients' quality of life. Therefore, the question of patient selection, including which patients should use the Tagrisso-chemotherapy combination, remains challenging.

On the sidelines of the conference on Sept. 9-12, Korea Biomedical Review met with Dr. Jänne and Professor Lee Se-hoon of the Department of Hematology/Oncology at Samsung Medical Center to explore the clinical implications of the FLAURA2 study data, its key issues, and potential applications in real-world practice.

KBR: How can the results of the FLAURA2 study be applied to real-world clinical practice?

Jänne: The FLAURA2 data confirmed that the Tagrisso-chemotherapy combination is more effective than Tagrisso alone in all patients. We know that some patients benefit from Tagrisso alone, and the addition of chemotherapy increases that benefit by prolonging patients' PFS and the duration of response (DoR).

There are patients generally considered to have a poorer prognosis, such as those with brain metastases and L858R mutations. The FLAURA2 study showed that both subgroups benefited from the Tagrisso-anti-cancer chemotherapy combination, so we believe the combination may apply to these patients.

Further clinical studies and blood ctDNA analysis will be needed to characterize patients who benefit from the combination. We already know from previous studies that patients with negative ctDNA (i.e., ctDNA detected at diagnosis but undetectable three to six weeks after treatment) have a better prognosis. These patients tended to have longer PFS. In the FLAURA2 study, additional analyses will determine if Tagrisso, in combination with chemotherapy, results in earlier ctDNA negativity compared to Tagrisso as monotherapy. We are also investigating whether the resistance mechanisms differ between Tagrisso monotherapy and Tagrisso-chemotherapy combinations by analyzing ctDNA.

Lee: In the U.S., there is a consensus that targeted therapy should be maintained. So, when switching to chemotherapy after using Tagrisso, many clinical trials use a treatment that adds chemotherapy without stopping Tagrisso. However, we cannot use it in Korea outside the scope stipulated by the Health Insurance Review and Assessment Service (HIRA) or the Ministry of Food and Drug Safety (MFDS), so there is a very large unmet need in this area. Some patients need Tagrisso combined with chemotherapy, and we don't even have that opportunity. So, I'm very happy that this FLAURA2 study provides evidence to combine Tagrisso with chemotherapy.

If you ask me about its target patients, I will use it on patients with poor prognostic factors, such as those with L858R, brain metastases, and large-sized tumors. In the original FLAURA study, the median cancer size of the patients was 48 millimeters, and in the FLAURA2 study, it was 57 millimeters. This means that these patients have a high tumor burden. This is very good news for clinicians even without looking at the data because, in this case, the patients are more or less prepared mentally for chemotherapy.

KBR: Suppose you have a patient who failed Tagrisso and is currently on a platinum-based chemotherapy regimen. If you use this chemotherapy for the patient’s first-line treatment, you may have some trouble deciding follow-up treatment.

Jänne: I will approach it the same way I would with Tagrisso monotherapy, first trying to figure out why the resistance developed. Whether it's resistance to Tagrisso or resistance to chemotherapy, we would need to look at the patient's tumor or ctDNA analysis. The treatment options available right now are single-agent chemotherapies already approved for second-line treatment, such as docetaxel. In addition, antibody-drug conjugates (ADCs) and novel therapeutics are being developed. As these new treatment options become available, the range of effective treatment options for use after the Tagrisso-chemotherapy combination therapy will gradually expand.

Lee: There are so many treatment options that we are looking forward to. We're thinking about taxel, but much data is coming out on ADCs. In addition, there are immuno-oncology drugs. Of course, it is known that immuno-oncology is EGFR-resistant, but it is still helpful for some patients. Patients will respond differently if the previous treatment method changes, so immuno-oncology will definitely be an option.

Another benefit we expect to see from the FLAURA2 study is a significant reduction in tumor burden in patients on the Tagrisso-chemotherapy combination. This may change the pattern of disease progression in patients. When resistance develops, it's not a systemic, multi-site deterioration as it used to be, but rather a localized progression, allowing us to proceed with treatments, including radiation or surgery, in these patients. Then, you can expect to see an improvement in overall survival (OS). I'm personally looking at that as well.

KBR: The data suggests that patients with brain metastases are particularly likely to benefit from treatment. This is somewhat surprising because central nervous system activity is not something you would normally expect from chemotherapy.

Jänne: Patients with central nervous system metastases generally have a worse prognosis than patients without metastases. So, stronger therapies may have a greater benefit for these patients.

Although we don't conventionally use chemotherapy for central nervous system metastases, chemotherapy also works in the brain. In particular, patients with brain metastases are more likely to have a broken blood-brain barrier (BBB), so the impact of combination therapy on the central nervous system may be greater than monotherapy. Additional analyses focusing on patients with brain metastases are currently underway.

Lee: There are two possible interpretations of the better effectiveness of the Tagrisso-chemotherapy combination in patients with brain metastases. One is that patients with brain metastases are probably not doing well elsewhere besides the brain, so the effect at these other sites may have been influential. This is a way to understand brain metastases as a bad prognostic factor.

The other view is that the effect on the brain itself may be good. Patients with brain metastases have a broken BBB at the time of diagnosis. In some cases, as they improve with treatment, the BBB partially closes again, so we can assume that the Tagrisso-chemotherapy combination allows both drugs to enter the brain when the BBB is open. In other words, a synergistic environment has been created. Which of the two interpretations prevails will be determined by further analysis.

KBR: Some have raised doubts about extending OS. What is your outlook?

Jänne: The OS data is still immature. It will take more time to see if the OS curve widens.

Lee: We think we must see results in OS in the clinic, which is a little misguided. Clinical trials are designed to prove that the drug is good. In the past, when there were no targeted anticancer drugs and no follow-up treatment options, it was appropriate to look at OS. However, now that more drugs and patients are participating in various trials after disease progression, OS is no longer the concept we originally thought it was. This is why recent trials have PFS as the primary endpoint, meaning that OS does not fully represent the drug's effect that we want to know.

KBR: Later this year, results from the MARIPOSA study, which tested the combination of the third-generation EGFR TKI Leclaza (lazerinib) and the bispecific antibody Rybrevant (amivantamab), will be released. If the results are positive, clinicians will be faced with combining a third-generation EGFR TKI with chemotherapy or a bispecific antibody.

Jänne: We don't have the results yet, but assuming the results are positive, the treatment choice always balances efficacy and side effects. You have to weigh the cost against the magnitude of the benefit to the patient by adding lazertinib and amivantamab. The cost here is not monetary but rather the cost of toxicity. And we would need to see how that cost compares to the Tagrisso-chemotherapy combination. The addition of chemotherapy has a different adverse event profile than the addition of amivantamab, so it would be nice to have a more manageable regimen, depending on patient characteristics. It's hard to be more specific because we haven't seen the data yet. Hopefully, the data will come out soon, and hopefully, it will be positive. It would be great to have more treatment options for patients.

Lee: For physicians, the better the good research data that comes out. We don't have to choose one; we can use it according to the patient's condition. In general, I know that there are differences in side effects. Still, the side effects of chemotherapy have the advantage that medical professionals are familiar with them and can manage them. The combination of pemetrexed and carboplatin is a very well-tolerated treatment, so I'm not too concerned about it. Ultimately, I don't think side effects will be the main issue. It's just a matter of which one you are more comfortable with and confident managing.