[ASCO 2024] New subcutaneous Rybrevant boosts US entry prospects for Leclaza

CHICAGO, Ill. -- By Kim Yun-mi/Korea Biomedical Review correspondent -- A subcutaneous formulation of Janssen's lung cancer drug Rybrevant (amivantamab) has demonstrated pharmacokinetic equivalence to the existing intravenous formulation, while significantly reducing the risk of adverse infusion reactions (IRRs) and venous thromboembolism (VTE).

Korean-made lung cancer drug Leclaza (lazertinib), which Yuhan Corp. hopes to get U.S. FDA approval for in August based on the MARIPOSA study, is expected to benefit from the improved formulation of its companion drug Rybrevant to enter the U.S. market

At the annual meeting of the American Society of Clinical Oncology (ASCO) held from May 31 to June 4 in Chicago, many studies related to the combination of Rybrevant and Leclaza have been highlighted.

These include an analysis of a high-risk group from the phase 3 MARIPOSA study, which is currently under review for U.S. approval for Leclaza, the phase 3 PALOMA-3 study, which evaluated the equivalence and effectiveness of the subcutaneous formulation of Rybrevant, and an analysis of the atypical EGFR mutation cohort from the phase 1b CHRYSALIS-2 study.

1st-line Rybrevant+Leclaza combo shows consistent efficacy in high-risk patients

On May 31, the first day of the event, Professor Enriqueta Felip from the Autonomous University of Barcelona (UAB), Spain, presented the results of her analysis of the effectiveness of Rybrevant+Leclaza combo in the high-risk patient population included in the MARIPOSA study.

EGFR-mutant non-small cell lung cancer (NSCLC) typically has a high-risk patient population with a poor prognosis, including patients with brain metastases (~37 percent) or liver metastases (~16 percent) at diagnosis, co-existing TP53 mutations (~50 percent), and detectable ctDNA in plasma (~70 percent).

The researchers analyzed the effectiveness of first-line treatment with the Rybrevant+Leclaza combo in patients with these high-risk characteristics in the MARIPOSA study.

The MARIPOSA study is a phase 3 trial evaluating the combination of Rybrevant+Leclaza versus AstraZeneca’s Tagrisso (osimertinib) in the first-line treatment of advanced EGFR-mutant NSCLC. In a previously study, first-line treatment with Rybrevant+Leclaza demonstrated a 30 percent reduction in the risk of disease progression or death (HR 0.70) and a prolonged progression-free survival (PFS) benefit compared to Tagrisso monotherapy.

This PFS benefit of the Rybrevant+Leclaza combination was also consistently observed in patients with brain metastases (HR 0.69), liver metastases (HR 0.58), and biomarker-risk patients (HR 0.65 for TP53 mutations, HR 0.68 for baseline ctDNA detection and HR 0.49 for week 9 ctDNA detection).

“The amivantamab plus lazertinib combination significantly improved median PFS compared to osimertinib even in the high-risk subgroup,” said Dr. Felip. “This combination provides significantly better PFS outcomes in patients with high-risk features, making it a promising option that could become a new standard of care in the first-line treatment of EGFR-mutant NSCLC.”

Rybrevant subcutaneous injection reduces dosing time to 5 minutes

In the same session, Dr. Natasha B. Leighl, Princess Margaret Cancer Centre, Canada, presented the first analysis from the PALOMA-3 study, a phase 3 trial evaluating the intravenous versus subcutaneous formulation of Rybrevant in combination with Leclaza in patients with refractory EGFR-mutant NSCLC whose disease had progressed on Tagrisso and chemotherapy.

Originally approved as an intravenous injection, Rybrevant faced challenges, including a dosing time of over four hours and infusion-related reactions (IRRs) reported by 67% of patients.

In response, Janssen initiated the PALOMA program to develop a subcutaneous formulation of  Rybrevant to shorten the dosing time and improve dosing frequency.  Dr. Leighl presented results from one of the studies, PALOMA-3.

The primary endpoint of the study was pharmacokinetic non-inferiority of subcutaneous Rybrevent+Leclaza in comparison with conventional intravenous Rybrevant, with secondary endpoints including objective response rate (ORR), PFS, duration of response (DoR), patient satisfaction survey, and safety. The exploratory endpoint was overall survival (OS).

Results showed that subcutaneous Rybrevant injection with Leclaza demonstrated pharmacokinetic non-inferiority to intravenous Rybrevant. Non-inferiority for objective response rate (ORR) was also met, with more than twice as many patients maintaining a response for six months or longer in the subcutaneous arm (29 percent vs. 14 percent) and a duration of response (DoR) of 11.2 months in the subcutaneous arm vs. 8.3 months in the intravenous arm.

At a median follow-up of seven months, median mPFS was 6.1 months in the subcutaneous arm and 4.3 months in the intravenous arm, which was numerically prolonged, although not statistically significant (HR 0.84, P=0.20).

Notably, the presentation also included exploratory overall survival (OS) data, which showed a statistically significant prolongation of OS with a hazard ratio of 0.62 for intravenous versus subcutaneous injection (P=0.02).

The treatment-related adverse event profile was similar between the two formulations, with few adverse events leading to death in either formulation. However, the incidence of treatment discontinuation clinical events was 9 percent in the subcutaneous group and 12 percent in the intravenous group. 

The most notable was infusion-related reactions (IRRs). The proportion of patients with IRRs was 13 percent in the subcutaneous arm, compared to 66 percent in the intravenous arm, more than five times higher. Grade 4/5 IRRs were not reported in either arm, and most IRRs occurred in the first cycle. There were no IRRs leading to treatment discontinuation in the subcutaneous arm, versus four in the intravenous arm.

Rybrevant+Leclaza effective even in patients with atypical mutations

On the second day of ASCO 2024, Dr. Cho Byoung-chul, director of the Lung Cancer Center at Yonsei Cancer Center, presented the results of an analysis of the CHRYSALIS-2 study's atypical EGFR mutation cohort.

Typically, doctors think of exon19 deletion or exon21 L858R as EGFR mutations, but atypical mutations such as G719X, S768I, and L861Q, including exon20 insertions, are among the less common EGFR mutations.

The problem is that patients with advanced NSCLC with these atypical EGFR mutations have a worse clinical outcome than patients with common types of mutations (Exon19 del, Exon20 L858R). For example, patients with atypical mutations with or without common EGFR mutations had a median progression-free survival of only 10.7 months and 9.4 months, respectively, when treated with the second-generation EGFR TKI Gilotrif (afatinib) or the third-generation agent Tagrisso.

Dr. Cho presented the results of the Cohort C analysis of the CHRYSALIS-2 study, which evaluated the effectiveness of the Rybrevant/Leclaza combination in patients with atypical mutations only.

The combination demonstrated superior anti-tumor activity in patients with advanced NSCLC with atypical mutations. In the treatment-naïve subgroup, the objective response rate (ORR) of the combo was 57 percent, with a median progression-free survival (mPFS) of 19.5 months.

Notably, the Rybrevant plus Leclaza combination demonstrated a Time to Treatment Discontinuation (TTD) of 14.0 months and a two-year survival rate of 79 percent in the first-line setting, which was numerically superior to real-world data (TTD of 3.2 months and two-year OS of 44 percent).

In the previously treated subgroup, the Rybrevant plus Leclaza combination had an ORR of 48 percent and mPFS of 7.8 months.

The safety profile was consistent with previously reported findings, with no new safety indications.

“The Rybrevant and Leclaza combination demonstrated clinically meaningful and durable anti-tumor activity in advanced NSCLC patients with atypical EGFR mutations,” said Dr. Cho.

“This combination is a standard of care option for patients with the broadest spectrum of EGFR mutations, including common EGFR mutations (Exon19 del, L858R), as well as exon20 insertions and atypical mutations.”

Leclaza gains positive outlook ahead of US entry

In a post-presentation interview with Korea Biomedical Review, Dr. Cho commented on the Rybrevant and Leclaza combination therapy studies presented at the conference, saying that they have enhanced their potential in the global market, especially the U.S. market.

“With the PALOMA-3 study, the MARIPOSA treatment has taken wings,” he said. “If the combination of Rybrevant and Leclaza based on the MARIPOSA study is approved in the U.S. in the near future, it is clear that Leclaza will increase its market share in the U.S. as a first-line treatment option.”

In addition, Dr. Cho sees the potential for the Rybrevant/Leclaza combination to be listed as a preferred treatment in the NCCN guidelines for patients with atypical EGFR-mutant NSCLC. While Gilotrif is currently recommended for the treatment of these patients, there is no definitive evidence, such as the cohort analysis from the CHRYSALIS-2 study, that the Rybrevant/Leclaza combination is likely to be recommended as preferred as a result of this study, Cho said.

Janssen is also reportedly planning to expand the indication for the Rybrevant/Leclaza combination in patients with atypical EGFR mutations following approval of the MARIPOSA study, which is currently under review. 

According to industry insiders, the U.S. FDA approval decision for the MARIPOSA study is expected in August.

It will be interesting to see if Leclaza, a Korean cancer drug, will successfully enter the U.S. market this year and accelerate its market share expansion.