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ESMO Data Shed Light on Activity of Janssen's Rybrevant-Leclaza Combo in EGFR-Mutated NSCLC

NEW YORK – During back-to-back presentations at the European Society for Medical Oncology Congress on Sunday, Janssen Pharmaceuticals shared data suggesting the ability of its EGFR-MET bispecific antibody amivantamab (Rybrevant) to benefit a broader subset of EGFR-mutated non-small cell lung cancer patients when combined with lazertinib (Leclaza), a third-generation EGFR inhibitor.

In May of this year, based on results from the Phase I CHRYSALIS study, the US Food and Drug Administration granted accelerated approval to amivantamab monotherapy as a post-chemotherapy, second-line treatment for NSCLC patients whose tumors harbor the EGFR exon 20 mutation. The agency also approved Guardant Health's liquid-based next-generation sequencing test, Guardant360 CDx, as a companion diagnostic to identify patients eligible for the drug.

Although the FDA granted accelerated approval to amivantamab as a single-agent therapy based on data from CHRYSALIS, the trial also included an additional cohort of patients who received the combination of amivantamab and lazertinib, which Janssen developed with South Korean firm Yuhan and was approved in that country this year. Lazertinib does not have FDA approval yet.

Lazertinib, similar to AstraZeneca's third-generation anti-EGFR inhibitor osimertinib (Tagrisso), is designed to target EGFR T790M mutations so as to mitigate the resistance that many NSCLC patients develop following earlier-generation EGFR inhibitors. Another feature lazertinib shares with osimertinib is that it has been designed to penetrate the blood-brain barrier and hopefully will bring added benefit to patients with NSCLC tumors that have metastasized to the brain.

According to Natasha Leighl, leader of the Princess Margaret Cancer Centre's thoracic medical oncology group who presented the results of the analysis during the ESMO Congress, the rationale to combine amivantamab and lazertinib has to do with the different EGFR domains the two agents target.

"Preclinical studies suggest that targeting both the extracellular [or external, with amivantamab] and catalytic [or internal, with lazertinib] domains of EGFR can lead to anti-tumor synergy," Leighl said, explaining that the two cohorts in the CHRYSALIS study — one receiving amivantamab monotherapy and another receiving the amivantamab-lazertinib combination — allows researchers to explore the therapeutic contribution of the two drugs.

Importantly, the CHRYSALIS study included multiple patient cohorts stratified by both specific types of EGFR and MET biomarkers and by prior treatment lines. This analysis zeroed in on patients who had experienced disease progression following prior treatment with osimertinib.

Among 121 patients who received the amivantamab monotherapy — 85 percent of whom were confirmed to have EGFR- and MET-based resistance mutations — the overall response rate was 19 percent, including 23 patients with confirmed partial responses. Among 45 patients in the amivantamab-lazertinib combination therapy cohort — of whom 38 percent were confirmed to have EGFR- and MET-based resistance mutations — the overall response rate was 36 percent, including one complete response and 15 partial responses.

The median duration of response was 5.9 months among the monotherapy-treated patients versus 9.6 months with the combination. The median progression-free survival times among the monotherapy and combination therapy groups were 4.1 months and 4.9 months, respectively.

"Responses with the combination were earlier and deeper," Leighl noted, pointing out that fewer patients in the combination cohort went on to develop central nervous system metastases. Patients tolerated the monotherapy and combination treatment well and no unexpected side effects emerged in the study.

There are also indications in the trial that the addition of lazertinib to amivantamab is better at overcoming resistance driven by EGFR and MET mutations than amivantamab alone. The response rate among amivantamab-treated patients with these resistance mutations was 18 percent but was 47 percent in those receiving the combination regimen.

"The combination of amivantamab and lazertinib after osimertinib has higher activity and response duration compared to amivantamab monotherapy, with the potential for improved intracranial protection," Leighl said in the conclusion of her presentation, explaining further in a statement that the findings "provide insight into a potential new treatment approach for patients whose lung cancer has progressed on standard treatment."

Since CHRYSALIS is an early-phase study rather than a randomized-controlled clinical trial, additional research is needed to prove the relative benefit of the combination. This is especially true in light of the fact that combination therapy tends to be associated with increased financial toxicity versus single-agent treatment. The question also remains as to how the two Janssen agents would hold up against osimertinib in a head-to-head comparison.

With regard to the latter question, Leighl pointed out that Janssen is currently conducting the Phase III MARIPOSA study comparing the amivantamab-lazertinib combination directly with osimertinib in advanced, EGFR-mutated NSCLC patients who have not received any prior treatment. Osimertinib is already FDA-approved as a first-line treatment for metastatic NSCLC patients whose tumors harbor common EGFR mutations and the T790M resistance mutation.

In a separate ESMO presentation following the CHRYSALIS analysis, Catherine Shu, a thoracic oncologist at Columbia University's Irving Comprehensive Cancer Center, presented preliminary results from the Phase I/Ib CHRYSALIS-2 study, shedding further light on the benefit of the amivantamab-lazertinib combo.

Shu presented results from two cohorts, stratified according to the prior treatment patients had received. Cohort A — which investigators called the target population — included patients who had experienced disease progression after first- or second-line osimertinib treatment, then platinum-based chemotherapy. In this cohort, patients had received a median of three prior therapies. The other cohort researchers analyzed comprised a more heavily pretreated group, who had a median of four prior lines of therapy but were not restricted in the types of treatments they received. Beyond their treatment histories, the two groups shared similar demographic and disease characteristics.

Among 29 efficacy-evaluable patients in the target population, the overall response rate with the amivantamab-lazertinib combination was 41 percent, and the clinical benefit rate — defined as complete response, partial response, or stable disease for at least 11 weeks — was 69 percent. Eight out of 12 patients who responded to the combination, as well as five out of 12 patients who had stable disease following the combination, remain on treatment today.

Among 47 efficacy-evaluable patients in the more heavily pretreated cohort, on the other hand, the overall response rate with the combination treatment was 21 percent and the clinical benefit rate was 51 percent. All 10 patients who responded to the combination regimen in this cohort remain on treatment, and 10 out of 26 patients who had stable disease also remain on treatment.

Notably, Shu drew a comparison between the response rates in both of these groups and a previously reported 36 percent response rate observed from a CHRYSALIS cohort of patients who had received the amivantamab-lazertinib combination following osimertinib, but no intervening chemotherapy. In comparison to the response rates in this study, the CHRYSALIS-2 target population fared better, while the more heavily pretreated cohort fared worse. 

What this suggests, Shu noted, is that adding intervening chemotherapy after osimertinib before amivantamab-lazertinib may not negatively impact the combination's activity, whereas adding additional targeted therapies — which was commonly the case in the heavily pretreated group — might indeed diminish patients' ability to respond to the combination treatment.

As the data in both CHRYSALIS trials as well as MARIPOSA mature, Janssen is amassing data on the amivantamab-lazertinib combination that can potentially broaden the eligible patient population to beyond the EGFR exon 20 insertion mutation-positive subgroup eligible for amivantamab monotherapy.

"The approval of [amivantamab] as a monotherapy was a pivotal moment in the treatment of patients with difficult-to-treat NSCLC with EGFR exon 20 insertion mutations," Sylvie Laquerre, Janssen R&D's VP and disease area leader in solid tumor targeted therapies, said in a statement on Sunday. "This new analysis builds on the established safety and efficacy profile of [amivantamab], showing its value for a broader group of patients with EGFR mutations when combined with lazertinib. Janssen is committed to evaluating the potential of these treatments."