New Drug Review: FDA Approves Lazertinib Combination Therapy for Non–Small Cell Lung Cancer

In August 2024, the FDA approved lazertinib (Lazcluze) in combination with amivantamab-vmjw (Rybrevant), a bispecific EGFR-directed and MET receptor–directed antibody, as a first-line treatment for locally advanced or metastatic non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R substitution mutations.^1-3 Lazertinib is a selective kinase inhibitor of EGFR, inhibiting EGFR exon 19 deletions and exon 21 L858R substitution mutations at lower concentrations than wild-type EGFR.^1,3

A lazertinib combination therapy was approved in August 2024 as a first-line treatment for locally advanced or metastatic non-small cell lung cancer. | image credit: Sergey Nivens / stock.adobe.com

Efficacy

In the phase 3, randomized, multicenter MARIPOSA trial (NCT04487080), 1074 participants were randomly assigned 2:2:1 to receive either 240 mg oral lazertinib once daily plus either 1050 mg or 1400 mg intravenous amivantamab once weekly for 4 weeks, then every 2 weeks after week 5 (n=429; dosing based on body weight); 80 mg oral osimertinib (Tagrisso) monotherapy once daily (n=429); or 240 mg oral lazertinib monotherapy once daily, an unapproved treatment regimen for NSCLC.^1,4,5

Participants were stratified by EGFR mutation type, Asian race, and history of brain metastasis.⁴ Overall, 40% of participants had exon 21 L858R substitution mutations, and 60% of patients had tumors with an exon 19 deletion.¹

The primary study outcome was progression-free survival (PFS). At a median follow-up of 22 months, the results showed statistically significant improvement in PFS among participants receiving lazertinib plus amivantamab vs osimertinib alone, with a 30% reduction of disease progression or death.^1,5 Secondary efficacy outcomes included overall survival (OS), overall response rate (ORR), and duration of response (DOR). ORR and DOR were similar among the 2 comparators, with the combination group showing a slightly higher statistically significant ORR.⁵ Although OS outcomes have not matured, they show a trend favoring combination therapy.⁵ Lazertinib plus amivantamab shows promise in extending the duration of PFS among the study population.

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Safety

The most common adverse reactions (≥ 20%) occurring in patients receiving lazertinib plus amivantamab were rash, skin toxicity, nail toxicity, infusion-related reactions, stomatitis, edema, venous thromboembolism (VTE), paresthesia, and COVID-19 infections.¹ Nearly half of participants experienced serious adverse reactions, including VTEs, pneumonia, rash, and interstitial lung disease/pneumonitis.¹ Fatal adverse reactions occurred in 7% of patients.¹

Overall, 42% of patients reduced their dose of lazertinib due to adverse reactions, primarily rash and nail toxicity¹; 21% of patients permanently discontinued treatment due to respiratory adverse events, rash, VTE, or death.

Patients should begin anticoagulation therapy for VTE prophylaxis and continue for at least the first 4 months of treatment. If no signs or symptoms of VTE occur during that time, the patient may be taken off anticoagulation. Recurrence of VTEs while on therapeutic anticoagulation requires permanent discontinuation of amivantamab and continuation of lazertinib monotherapy.¹

Dosing and Administration

Recommended lazertinib dosing is 240 mg orally in combination with intravenous amivantamab.¹ If a lazertinib dose is missed, it can be administered within 12 hours of its due time; otherwise, the missed dose should be skipped. If vomiting occurs, the next dose should be administered at its regularly scheduled time.

There are no dosing adjustments for hepatic or renal impairment; however, it has not been studied in severe impairment. Dose reductions are recommended for severe adverse reactions. Initial dose reduction should be to 160 mg daily, then to 80 mg daily if further reduction is required. If additional dose reductions are required, the medication should be discontinued. As a CYP3A4 substrate, concomitant use of moderate to strong CYP3A4 inducers should be avoided.¹

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References

1. LAZCLUZE [package insert]. Horsham, PA Janssen Biotech, Inc.; 2024. Accessed November 4, 2024.

2. RYBREVANT [package insert]. Horsham, PA Janssen Biotech, Inc.; 2021. Accessed November 4, 2024.

3. FDA approves lazertinib with amivantamab-vmjw for NSCLC. FDA. August 20,2024. Accessed November 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-lazertinib-amivantamab-vmjw-non-small-lung-cancer

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. Cho BC, Felip E, Spira AI, et al. Amivantamab plus lazertinib vs osimertinib as first-line treatment in patients with EGFR-mutated, advanced non-small cell lung cancer (NSCLC): Primary results from MARIPOSA, a phase III, global, randomized, controlled trial. Ann Oncol. 2023;34(S2):S1306-S1306. doi: 10.1016/j.annonc.2023.10.062