Lazcluze (lazertinib)

P2, N=150, Active, not recruiting, Myung-Ju Ahn | Trial completion date: Jul 2025 --> Dec 2026 | Trial primary completion date: Mar 2025 --> Mar 2026

In participants with atypical EGFR-mutated advanced NSCLC, amivantamab-lazertinib demonstrated clinically meaningful antitumor activity with no new safety signals.

In the ITT population, we found no differences in OS between amivantamab-lazertinib and osimertinib-chemotherapy, despite a slightly higher PFS of the latter. Osimertinib-chemotherapy could be more effective in patients with CNS metastases, without liver metastases, and EGFR L858R mutation, however we could not compare OS in these subgroups. Due to the indirect nature of the comparison and the limitation of the methods our results are not definitive, but rather hypothesis-generating. Other factors must be considered in the choice of the treatment, including patient's characteristics, the safety profile of the combinations, and center's facilities and expertise.

This NMA revealed that cases with EGFR-mutated NSCLC may benefit from different first-line treatment regimens according to their clinicopathological characteristics. On the whole, osimertinib plus CT and amivantamab plus lazertinib emerged as the most noticeable treatment modalities for such cases. (PROSPERO ID: CRD42024506995).

Overall, the estimated time toxicity was 1.03 days for the osimertinib-only group (FLAURA), 3.635 days for the osimertinib plus chemotherapy group (FLAURA2), and 6.425 days for the amivantamab plus lazertinib group (MARIPOSA). Our findings highlight a significant increase in healthcare burden with combination strategies compared to osimertinib monotherapy, underscoring the need for further research to balance time toxicity with the benefits of survival associated with each regimen.

In the network meta-analysis (NMA), amivantamab plus lazertinib plus chemotherapy (amiva-lazer-chemo) yielded the highest PFS (surface under the cumulative ranking curve [SUCRA]: 0.88; hazard ratio [HR] vs chemotherapy, 0.44; 95% CI, 0.32-0.61), followed by AK112 plus chemotherapy (SUCRA: 0.79; HR, 0.46; 95% CI, 0.32-0.67). Combination therapy with anti-angiogenic agents also represents a viable treatment strategy for this patient population. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024565403.

Osimertinib (HR, 0.90; 95% CrI, 0.83-0.99) and lazertinib (HR, 0.89; 95% CrI, 0.79-1.00) showed overall survival benefits over first-gen TKIs. Furmonertinib, aumolertinib, and osimertinib had lower rates of severe treatment-related adverse events (TRAEs), while befotertinib exhibited the highest risk of grade ≥3 TRAEs (RR, 3.96; 95% CrI, 2.35-7.17). This study is the first head-to-head comparison of third-gen EGFR-TKIs using a Bayesian network meta-analysis, offering critical insights into efficacy and safety. Our results support personalized selection of third-gen EGFR TKIs for patients with advanced EGFR-mutated NSCLC, particularly for subpopulations with CNS metastases or different mutation subtypes.

Lazertinib plus pemetrexed demonstrated promising intracranial efficacy, OS benefits, and improved quality of life, highlighting its potential as a treatment option for EGFR-mutant NSCLC and LM, particularly in previously treated patients.

Our findings support the feasibility of individualized lazertinib dosing based on GSTM1 status to reduce toxicity and healthcare costs without compromising effective exposure.

Two recent phase III trials, FLAURA2 and MARIPOSA, demonstrated that first-line intensification-through osimertinib plus chemotherapy or amivantamab-lazertinib-significantly prolongs overall survival compared to osimertinib alone. Careful patient selection, improved toxicity management, and integration of QoL measures will be critical to ensure that the survival advantage demonstrated in trials can translate into true benefit in routine clinical practice. Future research should focus on identifying robust clinical and molecular markers to guide personalized treatment decisions.

Amivantamab+lazertinib has anti-tumor activity in patients with EGFR-mutant lung cancers who develop new or progressing brain or leptomeningeal metastases. This trial demonstrates the feasibility of including patients with LMD in prospective clinical trials.

P2, N=520, Recruiting, Janssen Research & Development, LLC | N=390 --> 520