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Second-line Treatment of Non-Small Cell Lung Cancer: Focus on the Clinical Development of Dacomitinib.

ABSTRACT: Dacomitinib is a second-generation, irreversible, covalent pan-HER tyrosine-kinase inhibitor (TKI). It showed potent EGFR signaling inhibition in experimental models, including first-generation TKI-resistant non-small cell lung cancer (NSCLC) cell lines. This preclinical efficacy did not translate into clinically meaningful treatment benefits for advanced, pretreated, molecularly unselected NSCLC patients enrolled in two parallel phase III trials. Dacomitinib and erlotinib showed overlapping efficacy data in chemotherapy-pretreated EGFR wild-type (WT) patients in the ARCHER 1009 trial. Similarly, it failed to demonstrate any survival benefits as compared to placebo in EGFR WT subsets progressing on chemotherapy and at least one previous first-generation TKI (erlotinib or gefitinib) in the BR.26 trial. In the case of EGFR-mutant NSCLCs, a pooled analysis of the ARCHER 1009 and ARCHER 1028 trials comparing the efficacy of dacomitinib vs. erlotinib in chemotherapy-pretreated, EGFR TKI-naïve patients showed a trend to a longer progression-free survival (PFS) and overall survival in favor of dacomitinib that did not reach statistical significance, with a higher rate of treatment related adverse events (mainly skin rash, paronychia, and gastrointestinal toxicities). On the other hand, the clinical activity in patients with EGFR-mutant NSCLCs with acquired TKI resistance that were included in phase II/III trials was equally poor (response rate <10%; PFS 3-4?months). Therefore, with the results of the ARCHER 1050 trial (NCT01774721) still pending, the current clinical development of dacomitinib is largely focused on EGFR-mutant, TKI-naïve patients. Here, we review the most relevant clinical data of dacomitinib in advanced NSCLC. We discuss the potential role of dacomitinib in pretreated EGFR WT and EGFR-mutant (TKI-naïve and TKI-resistant) patients. Finally, we briefly comment the available clinical data of dacomitinib in HER2-mutant NSCLC patients.

SUBMITTER: Zugazagoitia J

PROVIDER: S-EPMC5380728 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Second-line Treatment of Non-Small Cell Lung Cancer: Focus on the Clinical Development of Dacomitinib.

Zugazagoitia Jon J Díaz Asunción A Jimenez Elisabeth E Nuñez Juan Antonio JA Iglesias Lara L Ponce-Aix Santiago S Paz-Ares Luis L

Frontiers in medicine 20170405

Dacomitinib is a second-generation, irreversible, covalent pan-HER tyrosine-kinase inhibitor (TKI). It showed potent EGFR signaling inhibition in experimental models, including first-generation TKI-resistant non-small cell lung cancer (NSCLC) cell lines. This preclinical efficacy did not translate into clinically meaningful treatment benefits for advanced, pretreated, molecularly unselected NSCLC patients enrolled in two parallel phase III trials. Dacomitinib and erlotinib showed overlapping eff ...[more]

PMID: 28424775

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Project description:Systemic treatment of advanced non-small cell lung cancer (NSCLC) has undergone remarkable changes in the last decade, with the introduction of targeted therapies and immunotherapy. The identification of activating mutations in the epidermal growth factor receptor (EGFR) gene (deletions in exon 19 [Del19] and point mutation L858R in exon 21) has been the first important step toward molecularly guided precision therapy in lung cancer. Several randomized trials comparing EGFR tyrosine kinase inhibitors (TKIs) (gefitinib, erlotinib, and afatinib) to standard chemotherapy in first-line treatment of advanced EGFR-mutant NSCLC showed significant improvement in progression-free survival (PFS) and in response rate, with lower rates of adverse events (AEs) and better symptom control. However, none of these trials showed significant improvement in overall survival (OS). Despite impressive responses with EGFR-TKI, disease invariably progresses after 9 to 13 months, due to acquired resistance. Dacomitinib is a potent, irreversible, highly selective, second-generation EGFR-TKI, which inhibits the signaling from both heterodimers and homodimers of all the members of the human epidermal growth factor receptor (HER) family. Here, we review the clinical development of dacomitinib from phase I to phase III, with particular attention to its toxicity and on its activity on T790M mutation. Then, we critically examine the results of ARCHER 1050, a study that was crucial for Food and Drug Administration (FDA) approval. ARCHER 1050 was the first randomized phase III study comparing dacomitinib with gefitinib, in first-line treatment of patients with advanced EGFR-mutated NSCLC. Dacomitinib was superior to gefitinib in terms of primary end-point (14.7 vs 9.2 months) and OS (34.1 vs 26.8 months). The incidence of diarrhea, skin rash, mucositis and, consequently, dose reductions was higher with dacomitinib, while hepatic toxicity was higher with gefitinib. Dacomitinib constitutes one of the standard first-line options in patients with advanced EGFR-mutated NSCLC.

Project description:BackgroundLimited data are available for the combination regimen of anti-programmed cell death protein 1 (PD-1) inhibitor and anti-angiogenic agents as second-line therapy for the treatment of patients with advanced non-small cell lung cancer (NSCLC), especially in patients with squamous NSCLC. This study assessed the efficacy and safety of camrelizumab plus apatinib (a vascular endothelial growth factor receptor 2 inhibitor) as second-line treatment in patients with advanced squamous NSCLC.MethodsIn the Cohort 3 from a phase II dose-expansion trial, patients with advanced non-central squamous NSCLC who were immunotherapy naïve and had failed prior first-line platinum-based chemotherapy received 200 mg of camrelizumab intravenously every 2 weeks plus oral apatinib at the recommended dose of 250 mg once daily. The primary endpoint was objective response rate (ORR) assessed by the investigators as per the Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1.ResultsCohort 3 was prematurely terminated because of slow accrual after 25 patients with advanced squamous NSCLC had been enrolled between 10 October 2018, and 3 March 2019. At the data cutoff date of 12 June 2020, the median follow-up was 13.3 (range, 1.6 to 19.2) months. Among all 25 participants, the ORR was 32.0% (95% CI: 14.9% to 53.5%), the clinical benefit rate was 44.0% (95% CI: 24.4% to 65.1%), and the disease control rate (DCR) was 84.0% (95% CI: 63.9% to 95.5%). Median progression-free survival (PFS) was 6.0 (95% CI: 3.5 to 8.1) months, and median overall survival (OS) was 13.3 (95% CI: 6.4 to 18.8) months. Furthermore, clinical benefits from this combination regimen were evident across all tumor PD ligand 1 (PD-L1) expression subgroups. The most common treatment-related adverse events (TRAEs) of grade 3 or higher were hypertension (44.0%) and palmar-plantar erythrodysesthesia (16.0%). As reported by the investigators, 3 participants (12.0%) died due to TRAEs (interstitial pneumonia, hemorrhage, and unknown reason; n=1 each, 4%).ConclusionsCamrelizumab plus apatinib as second-line therapy showed satisfactory antitumor activity in patients with non-central squamous NSCLC, regardless of tumor PD-L1 expression. Camrelizumab plus apatinib had a manageable safety profile in this patient population, and the toxic reactions observed were generally consistent with those in previously reported studies. Interstitial pneumonia and hemorrhage are important risks requiring careful monitoring and prompt intervention.

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Dataset Information

Second-line Treatment of Non-Small Cell Lung Cancer: Focus on the Clinical Development of Dacomitinib.

Publications

Second-line Treatment of Non-Small Cell Lung Cancer: Focus on the Clinical Development of Dacomitinib.

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