Amivantamab Plus Lazertinib May Be a Future Treatment Option for NSCLC

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Targeting biomarkers in patients with non­–small cell lung cancer [NSCLC] continues to be a major avenue of development for combination therapy with long-term results showing the response durability of amivantamab [Rybrevant] and lazertinib [Leclaza] in patients with EGFR-mutated NSCLC, according to data published in the Journal of Clinical Oncology.¹

These data come from the long-term follow up of the phase 1 CHRYSALIS study [NCT02609776], which looked at 20 treatment-naive patients with NSCLC, whose disease harbored an EGFR mutation, on 1050 mg (1400 mg if ≥ 80 kg) of amivantamab and 240 mg of lazertinib. Initial results from this study showed a 100% overall response rate [ORR] for these patients with all of them achieving a partial response on the combination therapy.² However, any discussion on long-term results was limited due to the shorter follow up.

At the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting, a long-term follow-up analysis with a median of 33.6 months of follow up, was presented to show that the 100% ORR was maintained. The median duration of treatment was 33.5 months and data showed that 10 patients (50%) remained progression free and were continuing treatment while 2 patients (10%) were being treated with the combination beyond progression. Other median efficacy endpoints were not reached, but a landmark progression-free survival [PFS] rate was estimated to be 85% at 12 months, 65% at 24 months, and 51% at 36 months.

No new safety signals were reported, but 10 patients who discontinued treatment still gave circulating tumor (ct) DNA samples before the end of treatment. Looking at these ctDNA samples, the researchers saw that among a few patients some new mutations formed.

In an interview with Targeted Oncology^TM, Se-Hoon Lee, MD, an oncologist at the Samsung Medical Center in Seoul, Korea, discussed the highlights of these data from his presentation at ASCO and where he sees the field of targeted oncology heading.

Targeted Oncology: What is your focus of research in this space?

Lee: This is the era of targeted therapy and immuno-oncology. I'm conducting translational research for [patients with] lung cancer, especially focused on immuno-oncology or targeted therapy such as [targeting the] EGFR mutation. In Asia, EGFR mutations have very high prevalence [among patients with] lung cancer.³

What were the results of the CHRSYALIS trial?

In the CHRSYALIS trial, we looked at the first line treatment for treatment naive patients with amivantamab and lazertinib for patients with EGFR-NSCLC.¹ [This research was] reported in a previous academic meeting, [which showed an] objective response rate of 100%. [It was a smaller patient population, but] a 100% response rate was fascinating. [However], for every clinician their concern is about the long term follow up of the research. So, after nearly 3 years [of follow up] the ORR was still 100%, and half of the patients remain disease free and alive. So, this is also happy news for patients with EGFR-mutated NSCLC.

After a median treatment duration of 3 years, 8 patients still progressed on the combination of amivantimab plus lazertinib. Four patients had ctDNA re-emergence at the end of the trial and 2 patients had new mutations observed. These included 1 patient with a PIK3CA E542K/545K amplification and another with a CCNE1 amplification.

What are the next steps after this trial?

The median PFS was not reached, because about half of patients remain disease free. So, we are waiting for the results of the [MARIPOSA (NCT04487080)] phase 3 trial, [which is looking at] amivantamab and lazertinib vs osimertinib [Tagrisso].⁴ We do know that the median PFS of EGFR-associated TKIs is around 2 years, but this regimen could be nearly 3 years of PFS, and hopefully over 3 years.... In the meantime, we are expecting the end the phase 3 trial, but our study also reported [ctDNA results of these patents].¹ So, among 20 patients 18 patients provided [ctDNA samples], and among those 18 patients, 15 patients had [something cleared on day 1 of their cycles].

What do you see as the future of treatment for these patients?

In the future, we are expecting that even a small portion of patients can reach a better long-term survival without compromising their quality-of-life. Yeah. So, [of course we're waiting for the phase 3 [Main trial], but we are also waiting for [more results from the] FLAURA2 [NCT04035486] study of osimertinib plus chemotherapy.⁵ Many clinicians are expecting good [results from either trial], but we are still concerned about toxicity issues with combination treatment. In the near future, we are expecting we can have a therapy tailored to the patient [depending on their treatment factors and how they respond to these therapies].

_References:

_{1. Lee Se-Hoon, Cho B, Han Ji-Huan, et al. Amivantamab and lazertinib in treatment-naïve EGFR-mutated advanced non–small-cell lung cancer (NSCLC): Long-term follow-up and ctDNA results from CHRYSALIS. J Clin Oncol. 2023;41(16):9134-9134. doi: 10.1200/JCO.2023.41.16_suppl.9134}

_{2. Cho B, Lee Se-Hoon, Han J-Y, et al. Amivantamab and Lazertinib in Treatment-Naive EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC). J Thorac Oncol. 2022;17(9):S126-S126. doi:10.1016/j.jtho.2022.07.210}

_{3. Melosky B, Kambartel K, Häntschel M, et al. Worldwide Prevalence of Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer: A Meta-Analysis. Mol Diagn Ther. 2022;26(1):7-18. doi:10.1007/s40291-021-00563-1}

_{4. Cho BC, Felip E, Hayashi H, et al. MARIPOSA: phase 3 study of first-line amivantamab + lazertinib versus osimertinib in EGFR-mutant non-small-cell lung cancer. Future Oncol. 2022;18(6):639-647. doi:10.2217/fon-2021-0923}

_{5. Planchard D, Feng P-H, Karaseva N, et al. Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study. ESMO Open. 2021;6(5):100271. doi:10.1016/j.esmoop.2021.100271}