Author of

• 36336

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  P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Targeted Therapy - Clinically Focused
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 36427

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    P76.73 - MARIPOSA: Randomized Phase 3 Study of First-line Amivantamab + Lazertinib vs Osimertinib vs Lazertinib in EGFR-mutant NSCLC (ID 3374)

    00:00 - 00:00  |  Presenting Author(s): S. Martin Shreeve
    • Abstract
    • Slides

    Introduction
    

    Amivantamab (JNJ-61186372) is an epidermal growth factor receptor (EGFR)-MET bispecific antibody with immune-cell directing activity that targets activating and resistance EGFR and MET aberrations. Lazertinib is a 3^rd-generation tyrosine kinase inhibitor (TKI) with efficacy against activating EGFR mutations, T790M, and central nervous system lesions (Ahn Lancet Oncol 20(12):P1681; Kim JTO 38;no.15_suppl:9571). The low rates of EGFR-related toxicities observed with lazertinib support combination approaches with other anti-EGFR molecules. Preclinical studies with the combination of amivantamab and lazertinib have shown synergistic inhibition of tumor growth. In the ongoing CHRYSALIS phase 1 study (NCT02609776), amivantamab demonstrated antitumor activity both as monotherapy, and in combination with lazertinib, in patients with diverse EGFR-mutant non-small cell lung cancer (NSCLC), and in both treatment-naïve and osimertinib-relapsed disease, with a tolerable safety profile. The objective of this phase 3 randomized study is to assess the efficacy of the combination of amivantamab and lazertinib, as compared with single-agent osimertinib, as first-line therapy in patients with advanced EGFR-mutant NSCLC.

    Methods
    

    The multicenter, global MARIPOSA study (NCT04487080) will open in 262 sites in 27 countries. Eligible patients will have locally advanced or metastatic EGFR-mutant NSCLC not amenable to curative therapy, Exon19del or L858R mutation, measurable disease, and be treatment-naïve for advanced disease. Patients with asymptomatic or previously treated and stable brain metastases are eligible. Key exclusion criteria include prior systemic treatment for locally advanced or metastatic disease, history of leptomeningeal disease, interstitial lung disease, and prior treatment with an EGFR TKI. Approximately 1000 patients will be randomly assigned 2:2:1 to receive amivantamab + lazertinib (n~400), osimertinib (n~400), or lazertinib (n~200). Randomization will be stratified by mutation type (Exon19del vs L858R), race (Asian vs non-Asian), and history of brain metastases (present vs absent).

    Patients in the combination arm will receive open-label treatment with amivantamab (1050 mg [1400 mg, patients ≥80 kg] intravenously once weekly for the first 4 weeks, every 2 weeks thereafter) + lazertinib (240 mg oral daily). Patients in the single-agent osimertinib and lazertinib arms will receive double-blind treatment (80 mg or 240 mg oral daily, respectively).

    The primary endpoint of the study is progression-free survival (PFS) based on blinded independent central review according to RECIST v1.1. To assess the contribution of amivantamab to the efficacy of the combination, comparison of the combination and monotherapy lazertinib arms will also be performed. Secondary endpoints include overall survival, objective response rate, duration of response, PFS after first subsequent therapy, time to symptomatic progression, and intracranial PFS. Safety assessments will include monitoring adverse events and laboratory abnormalities.

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• 36555

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  P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Targeted Therapy - Clinically Focused
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 36574

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    P86.12 - Cardiac Safety Assessment of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer (ID 1247)

    00:00 - 00:00  |  Author(s): S. Martin Shreeve
    • Abstract
    • Slides

    Introduction
    

    Lazertinib (YH25448, JNJ-73841937) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. The recommended phase 2 dose was determined to be 240 mg once daily (QD) in Korean patients based on the results of a first-in-human study in patients with advanced, EGFR-mutated non-small cell lung cancer at doses of 20-320 mg QD. The objective of this evaluation was to assess lazertinib cardiac safety in these patients.

    Methods
    

    The electrocardiogram (ECG) assessments (absolute and change from baseline QTcF) were performed in an ongoing phase 1/2 lazertinib pharmacokinetics, safety and efficacy study. A total of 224 patients [1^st (n=43) and 2^nd (n=181) line therapy, 20-320 mg QD dose] with baseline and postdose ECG assessments (in triplicates) along with time-matched plasma concentration data were included in exposure-QTcF analysis using linear regression. The left ventricular ejection fraction (LVEF) was assessed using an echocardiogram or multiple gated acquisition (MUGA) scan at baseline and every 12 weeks.

    Results
    

    Of 224 evaluable patients, no post-treatment QTcF values >500 ms were reported during the study; 26 (11.6%) patients had a post-baseline QTcF >450 ms including 3 (1.3%) patients with QTcF >480 ms. Of the 221 patients with baseline QTcF confirmed by central assessment, 22 (10.0%) patients had >30 to 60 ms increase and 1 (0.5%) had >60 ms increase in QTcF from baseline. Of the 121 patients at 240 mg, 10 (8.3%) patients had a post-baseline QTcF >450 ms including 1 (0.8%) patient with QTcF >480 ms. There were no clinical symptoms of QTc prolongation observed in any of the patients. At clinically relevant (240 mg QD dosing) plasma steady state C_max (maximum plasma concentration) of 517.15 (43% coefficient of variation) ng/mL, the upper bound of the two-sided 90% confidence interval for change from baseline QTcF was estimated to 3.9 ms (low concern category). The exposure-QTcF assessment-based prediction suggests that a 2.5-fold and 4.8-fold higher than 517.15 ng/ml plasma concentration would be required to cause the upper bound of two-sided 90% confidence interval for the change from baseline in QTcF of ~10 ms (increasing concern category) and QTcF of ~20 ms (definite concern category), respectively. These results are in line with in vitro (hERG assay), ex-vivo (isolated perfused rabbit heart) and in vivo (instrumented male beagle dogs) preclinical findings. Of 224 patients, no treatment emergent adverse event related with heart failure or clinically meaningful decrease of LVEF was reported.

    Conclusion
    

    Taken together, preclinical and clinical cardiac safety assessment findings suggest that lazertinib has no clinically relevant effect on QT interval and LVEF. Time-matched plasma concentration and QTcF read-outs as well as LVEF assessments will continue to be collected in all ongoing as well as future lazertinib clinical studies to further confirm that lazertinib has no/minimal cardiac safety risk.

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