Leclaza demonstrates efficacy as combo therapy in NSCLC

Will it serve as a green light for its FDA approval as a combination therapy in the US?

Demonstrated improved survival in high-risk groups that have specific biomarkers

Anti-tumor effect confirmed in patients with uncommon mutations, including G719X, L861Q, and S768I

Clinical data demonstrating the efficacy of the Leclaza and Rybrevant combination in lung cancer will be presented at the upcoming American Society of Clinical Oncology (ASCO) Annual Meeting.

 

An abstract published for the ASCO 2024 Annual Meeting (ASCO 2024), a five-day conference that is set to start on the 31st, confirmed the additional efficacy of the combination therapy.

 

In addition to the primary endpoint results for the combination announced last year, the abstract confirmed the drug’s efficacy in rare types of mutations, giving the combination a green light for its entry into the global new drug market.

 

Johnson & Johnson (J&J), which holds the global rights to both treatments, filed for the combination’s approval as a first-line treatment for EGFR-positive NSCLC to the U.S.

 

Food and Drug Administration (FDA) last December.

 

According to industry sources on the 25th, abstracts of the results of the Phase III MARIPOSA follow-up study of Leclaza and Rybrevant were released on the 25th.

 

Leclaza is Yuhan Corp’s treatment for non-small cell lung cancer that targets the epidermal growth factor receptor (EGFR) mutations exon 19 deletion and exon 21 (L858R).

 

The company has been testing the drug’s potential in combination with Rybrevant, Janssen's EGFR exon 20 mutation-targeting NSCLC drug, in NSCLC.

 

The MARIPOSA trial evaluated Leclaza and Rybrevant’s efficacy in patients with EGFR-positive locally advanced or metastatic NSCLC.

 

Results that were presented last year showed that the combination improved overall survival (OS) and reduced the risk of disease progression and death by 30% compared with Tagrisso.

 

At the upcoming ASCO meeting, the results of a subgroup analysis that evaluated the combination’s efficacy in high-risk groups, including patients with TP53 mutation, circulating tumor DNA (ctDNA), and brain or liver metastases, will be presented.

 

TP53 mutations are present in various cancers, including lung and liver cancers, and the inactivation of TP53 is known to be associated with malignant lung cancer.

 

636 patients with treatment-naïve EGFR-positive exon 19 del or exon 21 mutated NSCLC enrolled in the study.

 

Based on an analysis of 636 evaluable patients, patients treated with Leclaza+Rybrevant achieved a median progression-free survival (PFS) of 18.2 months in patients with TP53-mutated NSCLC, which was longer than the 12.9 months achieved with Tagrisso monotherapy.

 

In patients with detectable ctDNA at baseline, PFS was 20.3 months in the Leclaza+Rybrevant group, compared with 14.8 months in the Tagrisso monotherapy group.

 

In patients with liver metastases, PFS was 18.2 months with the Leclaza+Rybrevant group versus 11.0 months with the Tagrisso monotherapy group.

 

The researchers said, “Given that this high-risk biomarker population accounts for up to 85% of all EGFR-positive NSCLC patients, we believe that the Leclaza+Rybrevant combination may play an important role as a standard of care in first-line NSCLC.” Leclaza+Rybrevant demonstrates efficacy in rare-mutated types of lung cancer as well

Yuhan Corp’s Leclaza and Janssen’s Rybrevant

The Leclaza and Rybrevant combination also demonstrated efficacy in NSCLC harboring atypical mutations in the CHRYSALIS-2 study.

 

The CHRYSALIS-2 study was initiated to identify biomarkers that are associated with higher response rates to the Leclaza+Rybrevant combination therapy.

 

The Cohort C study that was presented this time evaluated the potential of the Leclaza+Rybrevant combination in treating NSCLC harboring atypical EGFR-positive mutations, excluding exon 20 insertion mutations (S768I, L861Q, and G719X).

 

Cohort C of the CHRYSALIS-2 study enrolled patients with atypical EGFR mutations, excluding exon 20 insertion mutations, who were treatment-naïve or had two or fewer prior lines of therapy, which may have included a 1st/2nd-generation EGFR TKI.

 

The median age was 64 years, and 68% of the patients were Asian.

 

The most common mutations were G719X (54%), L861Q (24%), and S768I (22%).  As of December 14, 2023, at a median 13.8 months of follow-up, the ORR was 51% in the treatment-naïve subset.

 

The ORR for patients harboring solitary mutations at G719 (n = 13), L861 (n = 8), and S768 (n = 2) was 54%, 63%, and 100%, respectively.

 

Among patients treated with prior Giotrif, the ORR was 45%.

 

Up to now, the only drugs that have shown an effect in EGFR-positive variants, including G719X, L861Q, and S768I, have been Boehringer Ingelheim's Giotrif and AstraZeneca's Tagrisso.

 

In this area that lacked treatment options, the combination of Leclaza and Rybrevant showed efficacy against rare EGFR-positive mutations, paving the way for the combination to become the standard of care for NSCLC.

 

The details of the clinical results from the CHRYSALIS-2 cohort will be presented at the ASCO Abstract Session by Dr.

 

Byoung Cheol Cho, Director of the Lung Cancer Center at Yonsei University Cancer Hospital.