Concerns over Leclaza's sluggish secondary indicators

[ESMO Asia 2022] Leclaza Non-small cell lung cancer 1st phase 3 results

PFS over 20 months

proves its superior effectiveness in Real World

Yuhan Corporation's new anti-cancer drug Leclaza is expected to not significantly improve the overall survival period (OS), which is a secondary indicator, in the global phase 3 (LASER301) clinical trial

This is in contrast to the significant improvement in the primary indicator, the progression-free survival period (PFS).

 

We cannot rule out the possibility that a similar situation to Tagrisso, whose effectiveness was questioned by the Asian OS, will be reproduced.

 

The global clinical director (PI) explains that it is not easy to secure statistical significance due to the relatively high ratio of crossover converted to third-generation treatments due to confirmed resistance mutations among control patients.

 

Cho Byung-chul, a professor of oncology at Yonsei Severance Hospital, who oversees LASER301 clinical trials, said at a press conference held in Singapore on the 3rd (local time), "Leclaza failed to meet the statistical significance of OS improvement because there was a high crossover rate of about 40 percent," adding, "There is no room for resistance change now."

Professor Cho Byung-chul (left) and Professor Ross Su (right) explain the clinical results of phase 3 of Leclaza

LASER301 is a global study that confirmed the effectiveness and safety of the first-generation treatment "Iressa" when Leclaza was used as the first treatment for EGFR-mutated non-small cell lung cancer patients.

 

The first evaluation index was the progression-free survival period (PFS), and Leclaza recorded a 20.6-month PFS, which reduced the risk of disease progression and death by 55% compared to the control group, demonstrating high improvement.

 

OS, the secondary indicator, has 29% data maturity, and sufficient data has not been collected.

 

However, the survival rate of Leclaza at 18 months after administration was not statistically significant compared to the control group (p=0.116).

 

At the time of 29% of data collection, 25% (49) of the Leclaza group died, and 32% (64) of the control group died.

 

Looking at the trend of the graph of the total survival period released on this day, the survival rate of the Leclaza group and the control group becomes almost similar from 27 months after administration.

 

The final OS data will be released at the end of next year.

 

Leclaza phase 3 clinical overall survival graph (29% maturity).

 

(Source: ESMO)

Professor Cho explained that the high rate of crossover in the control group that received the first-generation treatment affected Leclaza's OS.

 

Crossover refers to allowing patients classified as control groups to take other treatments at an ethical level if they do not see treatment effects due to resistance during the administration of control drugs.

 

In phase 3 clinical trials, 24% (47) of 197 control groups changed the treatment to Leclaza through crossover.

 

12% (24) stopped clinical trials and administered other treatments.

 

A total of 71 people (36%) stopped administering control drugs and switched to third-generation treatments.

 

Tagrisso, the first 3rd generation EGFR formulation conducted earlier, was also affected by the OS by allowing crossover at the time of phase 3 clinical trials.

 

Tagrisso Japan Real World Data The 40.9-month OS dispelled concerns caused by phase 3 data (Source: ESMO)

Tagrisso demonstrated OS improvement over controls but failed to improve OS in Asian subgroups (HR=0.995).

 

At that time, 85 (31%) of 277 patients in the clinical control group stopped administering first and second-generation treatments and received Tagrisso as a follow-up treatment, which caused "data bias." Because of this, Tagrisso's effectiveness was questioned by Asians.

 

Concerns have been raised that Tagrisso's OS benefits are unclear in Asians.

 

Tagrisso has also been pointed out as the main reason why it has not been listed on the domestic primary benefit so far.

 

The effectiveness of Tagrisso is being proven in clinical practice.

 

According to the recently released Real World data in Japan, Tagrisso recorded an OS of 40.9 months for more than three years.

 

About 90% of EGFR-mutated non-small cell lung cancer patients in the United States and Europe as well as Japan are being treated with Tagrisso in the first round.

 

Leclaza was also influenced by the clinical environment where the diagnosis of T790M mutations, the first and second generations of resistant mutations, became active.

 

Professor Cho said, "At the time of phase 3 of Tagrisso, the T790M mutation itself was unfamiliar.

 

Naturally, the diagnosis was not active.

 

However, now, follow-up treatments have emerged and T790M tests are being actively conducted.

 

Because of this, nearly 40% of patients were crossover.

 

In other words, as resistance diagnosis was actively conducted, more patients were found to receive follow-up treatment.

 

He added, "Leclaza's higher OS effect was observed when analyzed by applying the IPCW (Inverse Probability of Sensing Weight) technique." The IPCW technique refers to an analysis that minimizes "bias" by correcting crossover patient data.

 

Professor Cho said, "I don't think the failure of OS to secure statistical significance will lead to concerns over the Leclaza effect." Ross A.

 

Soo, a professor at the National Cancer Center in Singapore, also said, "It is still too early to evaluate OS, and the effectiveness of individual drugs can be confirmed by PFS indicators, and OS is an indicator of the entire treatment, including follow-up treatment."