Yuhan's 'Reclaza' Continues Combination Use and Also Achieves Clear Victory Over Tagrisso Alone

'Mariposa' Clinical Results Revealed at ESMO
mPFS 18.5 Months, 2 Months Longer Than Tagrisso
Not a Direct Comparison but Meaningful Trend Confirmed

Reclaza and Livribant Combination Therapy is a 'Half Success'
No Clear Improvement Over Tagrisso Yet
Higher Adverse Reaction Rate in Terms of Safety

Yuhan Corporation's non-small cell lung cancer treatment 'Leclaza' (active ingredient: Lazertinib) has decisively outperformed AstraZeneca (AZ)'s standard treatment 'Tagrisso' (Osimertinib). In the first clinical trial including monotherapy arms of both drugs, a trend showing higher efficacy was confirmed.

Yuhan Corporation's non-small cell lung cancer treatment 'Leclaza'
Photo by Yuhan Corporation

On the 23rd (local time) at the '2023 European Society for Medical Oncology (ESMO 2023)' held in Madrid, Spain, the results of the combination clinical trial 'MARIPOSA' of Leclaza and Johnson & Johnson (J&J) Innovative Medicine's (formerly Janssen) targeted antibody therapy 'Rybrevant' (Amivantamab), licensed out by Yuhan Corporation, were revealed through the words of Cho Byung-chul, Director of the Yonsei-Yuhan Lung Cancer Research Institute.

The epithelial growth factor receptor (EGFR) mutation treatment market targeted by the Leclaza-Rybrevant combination therapy has been led by Tagrisso as the standard therapy, with the U.S. National Comprehensive Cancer Network (NCCN) recommending Tagrisso as the preferred regimen. Accordingly, J&J and Yuhan set the Tagrisso monotherapy arm, the existing standard treatment, as the control group in the MARIPOSA trial to directly compete with Tagrisso.

With the abstract of the conference already published revealing the main results of the trial, the on-site presentation included details not contained in the abstract. Among these details, the most attention was drawn to the results of the Leclaza monotherapy arm and the adverse event data of the trial.

AstraZeneca's non-small cell lung cancer treatment 'Tagrisso (active ingredient Osimertinib)'
[Photo by Korea AstraZeneca]

This trial was designed not only to compare the Leclaza-Rybrevant combination group with the Tagrisso monotherapy group but also included the Leclaza monotherapy arm as one of the comparison groups to assess the efficacy of the combination therapy. A total of 1,074 patients participated in the trial, allocated in a 2:2:1 ratio with 429, 429, and 216 patients in each group respectively.

As a result, the median progression-free survival (mPFS) of the Leclaza monotherapy group was 18.5 months, approximately two months longer than the 16.6 months observed in the Tagrisso monotherapy group. Progression-free survival refers to the period during which the cancer does not worsen or recur after treatment. Along with overall survival (OS), it is considered a key indicator for evaluating anticancer drug efficacy.

Previously, Leclaza showed a similar level of mPFS extension effect with 20.6 months in the 'LASER 301' trial conducted for monotherapy approval, compared to Tagrisso's 18.9 months (FLAURA1). However, LASER 301 used the first-generation EGFR tyrosine kinase inhibitor (TKI) 'Iressa' (Gefitinib) as the control group, not Tagrisso, which is already established as the standard therapy among third-generation EGFR TKIs, leading to criticism that it is difficult to confirm superiority over Tagrisso.

Since this trial was primarily designed to confirm the efficacy of the Leclaza-Rybrevant combination therapy, scientifically rigorous analysis comparing Tagrisso and Leclaza monotherapy arms is not appropriate. Nevertheless, the confirmation of a certain trend leaves open the possibility of proving actual differentiation through subsequent clinical trials. Park Byung-guk, a researcher at NH Investment & Securities, commented, "There is no p-value (statistical significance) because it was not a comparison target against Tagrisso," but added, "This is the first case where two monotherapy arms were tested in the same trial, and considering cost-effectiveness, the position of Leclaza monotherapy can also be expanded."

However, the overall MARIPOSA trial showed that the primary efficacy endpoint mPFS was 23.7 months in the combination group, reducing the risk of disease progression and death (hazard ratio) by 30% compared to 16.6 months in the Tagrisso monotherapy group, leading to critiques that it is close to a 'half success.' Since it failed to deliver differentiated results compared to AZ's 'FLAURA 2' trial, which combined Tagrisso with chemotherapy to counter Leclaza, the battle was won but the war's outcome remains uncertain. In FLAURA 2, the Tagrisso-chemotherapy combination showed mPFS of 25.5 months or 29.4 months (according to independent central review committee assessment).

However, the mPFS in the MARIPOSA trial did not surpass that of the FLAURA 2 trial. Although the chemotherapy in FLAURA 2 is a highly toxic regimen, the MARIPOSA combination involves oral Leclaza and Tagrisso, but Rybrevant requires intravenous (IV) administration at a hospital, leading to critiques that there is no significant difference between the two regimens.

Heo Hye-min, a researcher at Kiwoom Securities, who evaluated that the trial "fell short of the market expectation (mPFS over 25 months)," stated, "With a 7-month PFS advantage in the combination therapy, it is difficult to be confident about victory based on PFS alone," adding, "Ultimately, OS is important, but it will take considerable time to assess." Currently, in terms of OS, the interim analysis showed a favorable trend with the combination group having a hazard ratio of 0.80 compared to the Tagrisso monotherapy group, and the second progression-free survival (PFS2), which refers to PFS after second-line treatment following the drug therapy, also showed the combination group reducing risk by 25% compared to Tagrisso, suggesting that if this gap is confirmed, there is a possibility of gaining the upper hand.

In terms of safety, results lagging behind Tagrisso are considered a concern. Grade 3 or higher adverse events occurred in 75% of the combination group compared to 43% in the Tagrisso group, and serious adverse events (SAEs) were also higher at 49% versus 33% in the combination group. The proportion of patients who discontinued all drug administration was also higher in the combination group at 10%, compared to 3% in the Tagrisso group.

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