Dataset Information

Phase 1 study of DS-1205c combined with gefitinib for EGFR mutation-positive non-small cell lung cancer.

ABSTRACT:

Background

Tyrosine kinase inhibitors (TKIs) are effective for the treatment of non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR), but responses are not durable as tumors develop resistance. DS-1205c is a novel, specific, orally bioavailable, small-molecule AXL receptor TKI. In preclinical studies, DS-1205c restored TKI antitumor activity in a TKI acquired-resistance EGFR-mutant NSCLC tumor xenograft model.

Methods

This first-in-human, multicenter, open-label Phase 1 study (registered at ClinicalTrials.gov: NCT03599518) primarily evaluated the safety and tolerability of combination therapy with DS-1205c and gefitinib in Japanese patients with metastatic or unresectable EGFR-mutant NSCLC and tumor progression during treatment with EGFR-TKIs. Patients (n = 20) received DS-1205c monotherapy (200-1200 mg twice daily [BID]) in a 7-day safety monitoring period before combination DS-1205c/gefitinib (250 mg once daily) in 21-day cycles.

Results

The observed common treatment-emergent adverse events (TEAEs) were increased aspartate aminotransferase (35%), increased alanine aminotransferase (30%), rash maculo-papular (30%), and diarrhea (25%). No serious TEAEs were reported. Plasma concentrations and pharmacokinetic parameters of DS-1205a (free form of DS-1205c) were unaffected by concomitant administration of gefitinib. No patient achieved a complete or partial response and 5 patients (25%) had stable disease.

Conclusion

DS-1205c was generally safe and well tolerated at all dose levels, but the safety profile of ≤800 mg BID was more favorable than 1200 mg BID. The recommended dose for dose-expansion cohorts of DS-1205c in combination therapy with gefitinib was 800 mg BID.

SUBMITTER: Goto K

PROVIDER: S-EPMC10067098 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

Phase 1 study of DS-1205c combined with gefitinib for EGFR mutation-positive non-small cell lung cancer.

Goto Koichi K Shiraishi Yoshimasa Y Murakami Haruyasu H Horinouchi Hidehito H Toyozawa Ryo R Takeda Masayuki M Uno Makiko M Crawford Nigel N McGill Joseph J Jimbo Takeshi T Ishigami Masato M Takayama Gensuke G Nakayama Shintaro S Ohwada Shoichi S Nishio Makoto M

Cancer medicine 20230109 6

<h4>Background</h4>Tyrosine kinase inhibitors (TKIs) are effective for the treatment of non-small cell lung cancer (NSCLC) patients with activating mutations of the epidermal growth factor receptor (EGFR), but responses are not durable as tumors develop resistance. DS-1205c is a novel, specific, orally bioavailable, small-molecule AXL receptor TKI. In preclinical studies, DS-1205c restored TKI antitumor activity in a TKI acquired-resistance EGFR-mutant NSCLC tumor xenograft model.<h4>Methods</h4 ...[more]

PMID: 36621830

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Project description:BackgroundThis study aimed to identify independent prognostic factors for overall survival (OS) of patients with advanced non-small cell lung cancer (NSCLC) harboring an activating epidermal growth factor receptor (EGFR) mutation and receiving gefitinib as first-line treatment in real-world practice.Materials and methodsWe enrolled 226 patients from June 2011 to May 2013. During this period, gefitinib was the only EGFR-tyrosine kinase inhibitor reimbursed by the Bureau of National Health Insurance of Taiwan.ResultsThe median progression-free survival and median OS were 11.9 months (95% confidence interval [CI]: 9.7-14.2) and 26.9 months (21.2-32.5), respectively. The Cox proportional hazards regression model revealed that postoperative recurrence, performance status (Eastern Cooperative Oncology Grade [ECOG] ≥2), smoking index (≥20 pack-years), liver metastasis at initial diagnosis, and chronic hepatitis C virus (HCV) infection were independent prognostic factors for OS (hazard ratio [95% CI] 0.3 [0.11-0.83], p = .02; 2.69 [1.60-4.51], p < .001; 1.92 [1.24-2.97], p = .003; 2.26 [1.34-3.82], p = .002; 3.38 [1.85-7.78], p < .001, respectively). However, brain metastasis (BM) at initial diagnosis or intracranial progression during gefitinib treatment had no impact on OS (1.266 [0.83-1.93], p = .275 and 0.75 [0.48-1.19], p = .211, respectively).ConclusionHCV infection, performance status (ECOG ≥2), newly diagnosed advanced NSCLC without prior operation, and liver metastasis predicted poor OS in EGFR mutation-positive advanced NSCLC patients treated with first-line gefitinib; however, neither BM at initial diagnosis nor intracranial progression during gefitinib treatment had an impact on OS.Implications for practiceThe finding that chronic hepatitis C virus (HCV) infection might predict poor overall survival (OS) in epidermal growth factor receptor mutation-positive advanced non-small cell lung cancer (NSCLC) patients treated with first-line gefitinib may raise awareness of benefit from anti-HCV treatment in this patient population. Brain metastasis in the initial diagnosis or intracranial progression during gefitinib treatment is not a prognostic factor for OS. This study, which enrolled a real-world population of NSCLC patients, including sicker patients who were not eligible for a clinical trial, may have impact on guiding usual clinical practice.

Dataset Information

Phase 1 study of DS-1205c combined with gefitinib for EGFR mutation-positive non-small cell lung cancer.

Background

Methods

Results

Conclusion

Publications

Phase 1 study of DS-1205c combined with gefitinib for EGFR mutation-positive non-small cell lung cancer.

Similar Datasets

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