A phase II open-label, multicentre study to assess the anti-tumour activity of afatinib in patients with activating epidermal growth factor receptor mutation (EGFRm) from circulating tumour DNA (CtDNA)

Abstract Background Larotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This open-label, phase 1b study is aimed to evaluate the efficacy, safety of larotinib in patients with advanced esophageal squamous cell carcinoma (ESCC) with EGFR overexpression or amplification pretreated with one or more system regimens, and to recommend an appropriate dose for its further study. Methods Patients received larotinib orally at 3 doses (250, 300, 350 mg), once daily. Clinical response was evaluated every 8 weeks according to RECIST v1.1 criteria by both investigators and independent radiology review (IRC). Results 81 patients were enrolled. The investigator-assessed overall response rate (ORR) was 13.7% (10/73), all responses were observed in the 350 mg group of which ORR up to 20.0% (10/50), with 10 of them having EGFR overexpression and 4 having EGFR amplification. Per IRC assessment, ORR for all patients and 350 mg group were 13.9% (10/72) and 16.3% (8/50). In the 350 mg group, median overall survival (OS) and progression-free survival (PFS) were 8.0 (95% CI 4.9–10.2) months and 3.4 (95% CI 2.4–3.7) months, respectively. The most common treatment-related adverse events (TRAEs) were diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome, elevated AST/ALT, vomiting, similarly with other EGFR TKIs. Conclusions Larotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression. Trial registration This trial was retrospectively registered on 25/03/2019, NCT03888092. https://clinicaltrials.gov/ct2/show/NCT03888092.

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Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER)

Annals of Oncology ◽

10.1016/j.annonc.2019.10.018 ◽

2020 ◽

Vol 31 (2) ◽

pp. 228-235 ◽

Cited By ~ 7

Author(s):

M. Moehler ◽

A. Maderer ◽

P.C. Thuss-Patience ◽

B. Brenner ◽

J. Meiler ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Squamous Cell Cancer ◽

Cell Cancer ◽

Growth Factor Receptor ◽

Phase Iii ◽

Open Label ◽

Receptor Inhibition ◽

Epidermal Growth

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Phase III randomized, open label study (ARCHER 1050) of first-line dacomitinib (D) versus gefitinib (G) for advanced (adv) non-small cell lung cancer (NSCLC) in patients (pts) with epidermal growth factor receptor (EGFR) activating mutation(s).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.tps8123 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. TPS8123-TPS8123 ◽

Cited By ~ 5

Author(s):

Tony Mok ◽

Kazuhiko Nakagawa ◽

Rafael Rosell ◽

Yi Long Wu ◽

Carl Trygstad ◽

...

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Phase Ii ◽

Growth Factor Receptor ◽

Phase Iii ◽

Open Label ◽

Exon 19 Deletion ◽

Epidermal Growth ◽

Exon 19

TPS8123 Background: D is an orally available, potent and selective irreversible small molecule inhibitor of all catalytically active members of the HER (human epidermal growth factor receptor) family tyrosine kinases that has shown activity in preclinical studies on EGFR mutant cell lines, including those resistant to G. In a phase II trial of NSCLC pts who received 1st-line D, 75.6% of 45 pts with confirmed EGFR exon 19 or 21 sensitizing mutations (m) experienced a partial response (PR). The median progression-free survival (PFS) was 18.2 mo, and the PFS rate at 1 yr was 76.5% (preliminary data; Mok et al APLCC 2012). Methods: Based on the phase II data, a phase III randomized, open label trial (ARCHER 1050; NCT01774721) was designed to compare the efficacy of 1st line D with G in pts with adv EGFR m-positive NSCLC. Eligible pts (N=440) have pathologically confirmed stage IIIB/IV NSCLC with at least one activating EGFR m, either exon 19 deletion or exon 21 L858R m. Concurrent m in exon 20 T790M is permitted. Pts must have radiologically measurable disease, ECOG PS 0–1 and no prior systemic therapy. Pts will be randomized (1:1) to receive D 45 mg or G 250 mg orally once daily. The primary endpoint is PFS by Independent Radiologic Review. Secondary endpoints include PFS by investigator assessment, overall survival (OS), OS at 30 mo, best overall response, duration of response, and safety and tolerability. Pt-reported outcomes (HRQoL and disease/treatment-related symptoms) were also assessed. Randomization will be stratified by race (Japanese vs mainland Chinese vs other East Asian vs nonEEast Asian), and EGFR m status (exon 19 deletion vs exon 21 L858R m). A minimum of 268 PFS events is required for 90% power to detect a PFS improvement of ≥50% in D vs G recipients using the intent-to-treat (ITT) analysis population (HR ≤0.667). A significant (0.025 significance level) 1-sided stratified log-rank test for PFS at the final PFS analysis will be indicative of a positive study outcome. An interim analysis is planned to assess safety and whether early discontinuation of the trial is required for futility. Clinical trial information: NCT01774721.

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Larotinib in Patients with Advanced and Previously Treated Esophageal Squamous Cell Carcinoma with Epidermal Growth Factor Receptor Overexpression or Amplification: An Open-Label, Multicenter Phase 1b Study

10.21203/rs.3.rs-517047/v1 ◽

2021 ◽

Author(s):

Jianming Xu ◽

Lianke Liu ◽

Rongrui Liu ◽

Yuxian Bai ◽

Yulong Zheng ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Growth Factor Receptor ◽

Open Label ◽

Phase 1B ◽

Epidermal Growth

Abstract PurposeLarotinib is a new first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. This open-label, phase 1b study is aimed to evaluate the efficacy, safety of larotinib in patients with advanced esophageal squamous cell carcinoma (ESCC) with EGFR overexpression or amplification pretreated with one or more system regimens, and to recommend appropriate dose for its further study.MethodsPatients received larotinib orally at 3 doses (250, 300, 350 mg), once daily. Clinical response was evaluated every 8-weeks according to RECIST v1.1 criteria by both investigators and independent radiology review (IRC).Results81 patients were enrolled. The investigator-assessed overall response rate (ORR) was 13.7% (10/73), all responses were observed in the 350 mg group of which ORR up to 20.0% (10/50), with 10 of them having EGFR overexpression and 4 having EGFR amplification. Per IRC assessment, ORR for all patients and 350 mg group were 13.9% (10/72) and 16.3% (8/50). In the 350 mg group, median overall survival (OS) and progression-free survival (PFS) were 8.0 (95% CI, 4.9–10.2) months and 3.4 (95%CI, 2.4–3.7) months, respectively. The most common treatment-related adverse events (TRAEs) were diarrhea, rash and palmar-plantar erythrodysesthesia syndrome, elevated AST/ALT, vomiting, similarly with other EGFR TKIs.ConclusionLarotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression.Trial registrationNCT03888092, registered on March 25, 2019, retrospectively registered. https://clinicaltrials.gov/ct2/show/NCT03888092

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