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Lazertinib has good showing in EGFR-mutated advanced NSCLC

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Drug’s CNS potential sets it apart

“[W]hy should anyone care about all these data for lazertinib?” Tejas Patil, MD, and D. Ross Camidge, MD, PhD, asked in a commentary, noting that another third-generation EGFR TKI, osimertinib (Tagrisso), has already received Food and Drug Administration approval for use in this setting and has generally similar activity and tolerability.

“Beyond any potential competitive price advantage that could be introduced after licensing, or idiosyncratic tolerance of one drug over another in individual patients, the real potential advantage of lazertinib might be hiding in plain sight. Specifically, lazertinib’s incompletely explored potential to treat CNS metastases,” they noted.

Although osimertinib appears to have good CNS activity, patients with CNS metastases continue to experience poorer progression-free survival. And even at higher doses causing greater toxicity, CNS penetration of that drug is limited.

“[T]he ideal drug for dedicated CNS dose regimen exploration is one in which the standard dosing has been set in the absence of substantial toxicity and in the absence of any plateauing of pharmacokinetic exposures,” Dr. Patil and Dr. Camidge maintained. And lazertinib appears to fit that bill.

The 44% intracranial response rate “is encouraging but still leaves a substantial amount of important data to be generated,” they contended. Although progression in the CNS was uncommon among patients without CNS metastases at baseline, the longer median progression-free survival at higher doses may indicate better CNS control and support further dose escalation.

“Lazertinib could be one of the pioneer drugs for redefining how we optimally address the CNS in oncology drug development,” they concluded. “Taking full advantage of the early drug-development process to explore the CNS potential of any oncology drug being considered in disease types with a high rate of CNS metastases should be part of a future that we can all look forward to.”

Dr. Patil is instructor of medicine, and Dr. Camidge is professor of medicine, in the division of medical oncology, department of medicine, at the University of Colorado, Anschutz Medical Campus, Aurora.



Lazertinib, an investigational third-generation oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has good safety and antitumor activity in patients with EGFR-mutated advanced non–small cell lung cancer (NSCLC), finds a phase 1/2 trial.

Only about one in six patients experienced a grade 3 or 4 adverse event when given the drug at various doses, according to results reported in The Lancet Oncology.

Meanwhile, 54% of patients achieved a response, with a higher rate seen among those whose tumors were positive versus negative for the T790M resistance mutation. Notably, 44% of the subgroup with brain metastases had an intracranial response.

“[O]ur results show that lazertinib is well tolerated, with responses frequently observed in patients with NSCLC harbouring both activating EGFR mutations and EGFR T790M TKI resistance mutations. Intracranial responses were also frequently seen, indicating effective blood-brain barrier penetration,” wrote senior investigator Byoung Chul Cho, MD, PhD, Cancer Center, Yonsei University College of Medicine, Seoul, South Korea, and coinvestigators.

“Lazertinib has a potential therapeutic role in the treatment of NSCLC harbouring EGFR T790M mutations, either alone or in combination with other drugs,” they concluded.

The trial was conducted in Korea among adults having advanced NSCLC with an activating EGFR mutation who experienced progression after treatment with a first- or second-generation EGFR TKI. All were treated on an open-label basis with lazertinib at dose levels from 20 mg to 320 mg once daily, continuously in 21-day cycles.

Dr. Cho and coinvestigators reported results for 127 patients (38 in a dose escalation cohort and 89 in a dose expansion cohort).

Results showed that there were no dose-limiting toxicities and no dose-dependent increases in adverse events. The leading adverse events were grade 1 or 2 rash or acne (30%) and pruritus (27%). Overall, 16% of patients experienced grade 3 or grade 4 adverse events, most commonly grade 3 pneumonia (3%). Only 3% of patients had treatment-related grade 3 or 4 adverse events, while 5% had treatment-related serious adverse events. None experienced adverse events leading to death or treatment-related death.

On independent central review, 54% of patients overall had an objective response (52% had a partial response, 2% had a complete response). The response rate was 57% in patients with T790M-positive tumors compared with 37% in patients with T790M-negative tumors.

The median duration of response was 15.2 months. With a median follow-up of 11.0 months, the median progression-free survival was 9.5 months for the whole study cohort; it was longer in patients whose tumors were positive versus negative for the T790M resistance mutations (9.7 months vs 5.4 months).

Among evaluable patients with brain metastases, the intracranial response rate was 44%, and median intracranial progression-free survival was not reached.

Dr. Cho disclosed relationships with numerous pharmaceutical companies, including Yuhan Corporation, which funded the trial.

SOURCE: Cho BC et al. Lancet Oncol. 2019 Oct 3. doi: 10.1016/S1470-2045(19)30504-2.

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