Can Rivoceranib+Iressa therapy really be a game changer?

This is the title of the press release distributed by HLB on the 9th. "We have confirmed high synergy with the first-generation blockbuster EGFR TKI drug in phase 3 clinical trials," HLB said. "We expect a next-generation treatment due to a complete improvement in one person and PFS."

Rivoceranib (Aptinib) is a targeted anticancer drug targeting endothelial cell growth factor receptor 2 (VEGFR-2), which plays an important role in the tumor development process. It is a plan that combines this with Iressa (Gefitinib), a first-generation EGFR target anti-cancer drug, to create synergy in treatment. The combination of the two drugs is positive. In fact, other VEGFR2 inhibitors "Cyramza" and first-generation EGFR TKI "Tarceva" combined therapy were approved as the first treatment for EGFR mutation non-small cell lung cancer in the U.S. last year.

Let's take a look at the phase III results recently published by developer Jiangsu Hengrui Medicine in the Journal of Thoracic Oncology, a journal of the World Lung Cancer Society.

This study compares Rivoceranib and Iressa combinations with Iressa sole therapy (Iressa+placebo) in patients with EGFR-positive non-small cell lung cancer who have not received existing chemotherapy. EGFR Exxon 19 defect or Exxon 21 L848R variant were deployed one-on-one in both counties. The primary validity indicators are PFSs evaluated by the IRRC, which consists of radiologists, and secondary validity indicators include clinical evaluation PFSs, overall survival periods (OS), and quality of life (QoL).

In the study registered by 313 people, the primary variable, the median progressive survival period (mPFS), was approximately 3.5 months longer than 13.7 months for the combined group and 10.2 months for the single group (HR 0.71, p=0.0189). The 12-month PFS was 53.4% to 35.6%. OS data is immature at the time of analysis. CR was observed in one person.

Grade 3 or higher adverse reactions were higher in the Rivoceranib group, with high blood pressure (46.5%), proteinuria (17.8%), and higher serum ALT in the control group (10.3%), and higher AST (3.2%), but there were no statistical changes in the quality of life between the two groups.

It is true that the combination of Rivoceranib and Iressa therapy in phase 3 demonstrates the significance of effectiveness over Iressa alone therapy. However, considering the results of Tagrisso (Osimertinib), a third-generation targeted drug, which is currently a global standard for treating EGFR-positive non-small cell lung cancer, or Cyramza+Tarceva, the same mechanism, the results are somewhat insufficient to become a "game changer."

Although clinical designs and patients are different, let's refer to the results of FLAURA study, which served as the basis for Tagrisso's acquisition of primary indications. Tagrisso compared Iressa and Tarceva, the first-generation drugs at the time, to patients with EGFR-positive non-small cell lung cancer who have no experience in chemotherapy. mPFS had 18.9 months for Tagrisso and 10.2 months for control (HR 0.46 and p<0.001). The mOS was 38.6 months to 31.8 months.

In response, the U.S. General Cancer Network (NCCN), a global treatment guideline, recommends Tagrisso first for progressive primary treatment. Countries around the world are using Tagrisso as a standard treatment instead of Iressa.

What are the results of the same combination, Cyramza+Tarceva? Cyramza+Tarceva therapy was 19.4 months of mPFS in three-phase RELAY clinical trials, about seven months apart from the control group. The risk of death has been reduced by 40%.

The most important part of the treatment of EGFR-positive non-small cell lung cancer is brain failure. One in five patients will be accompanied by brain metastasis from the time of diagnosis, and the rate of brain metastasis during treatment is also known to reach 44%. Existing 1st and 2nd generation drugs did not have meaningful effects due to low brain barrier penetration rate. Tagrisso demonstrated significant effectiveness in patients with brain metastasis with higher blood-brain barrier penetration than conventional drugs.

The limitation was that patients with brain failure were not included. Lilly, a developer, emphasizes the effects of EGFR Exon 19 defect and Exon 21 mutation, which had relatively lower effects of conventional treatments than patients with brain failure.

Rivoceranib also appears to have not been measured for effects on patients with brain metastasis. Analysis related to brain metastasis is not found in the abstract of the paper.

The encouraging part of this Rivoceranib clinical trial is that the subanalysis has further improved PFS in TP53 Exxon 8 variations. PFS for patients in this group was 15.7 months. However, this is the result of a sub-analysis of only seven out of 157 Rivoceranib combined group, meaning that there is a tendency like this.

The goal of the clinical trial is to confirm its effectiveness as a primary treatment that has never been treated before, and since TP53 Exon 8 mutations are not the main resistance of EGFR TKI, it is unlikely to be an alternative to overcoming anticancer drug resistance. Major variations that cause resistance to EGFR TKI are known as T790M variations (1st to 2nd generation), C797S variations (3rd generation), and MET amplification of Exxon 20.