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Phase II Trial of Cabozantinib Plus Erlotinib in Patients With Advanced Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer With Progressive Disease on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy: A California Cancer Consortium Phase II Trial (NCI 9303).

ABSTRACT: Introduction: Mesenchymal epidermal transition and vascular endothelial growth factor pathways are important in mediating non-small cell lung cancer (NSCLC) tumorigenesis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. We hypothesized that treatment with cabozantinib plus erlotinib in EGFR mutation-positive NSCLC following progression on EGFR TKI therapy may allow tumors to overcome this resistance or restore sensitivity to therapy regardless of T790M status. Methods: Patients with advanced NSCLC, known EGFR mutation and progressive disease on an EGFR TKI immediately prior to enrollment without intervening therapy were enrolled. Patients received erlotinib 150 mg and cabozantinib 40 mg daily. The primary endpoint was evaluation of efficacy by objective response rate. Secondary endpoints included assessment of progression free survival (PFS), overall survival, change in tumor growth rate, safety and toxicity, and the evaluation of specific EGFR mutations and MET amplification in pre-treatment tissue and plasma. Results: Thirty-seven patients were enrolled at 4 centers. Four patients had partial response (10.8%) and 21 had stable disease (59.5%). A greater than 30% increase in tumor doubling time was observed in 79% of assessable patients (27/34). Median PFS was 3.6 months for all patients. Diarrhea (32%) was the most common grade 3 adverse event; 3 patients had asymptomatic grade 4 elevation of amylase and lipase. Conclusions: Combination erlotinib and cabozantinib demonstrates activity in a highly pretreated population of patients with EGFR mutation and progression on EGFR TKI. Further elucidation of beneficial patient subsets is warranted. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01866410.

SUBMITTER: Reckamp KL

PROVIDER: S-EPMC6421302 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Phase II Trial of Cabozantinib Plus Erlotinib in Patients With Advanced Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer With Progressive Disease on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy: A California Cancer Consortium Phase II Trial (NCI 9303).

Reckamp Karen L KL Frankel Paul H PH Ruel Nora N Mack Philip C PC Gitlitz Barbara J BJ Li Tianhong T Koczywas Marianna M Gadgeel Shirish M SM Cristea Mihaela C MC Belani Chandra P CP Newman Edward M EM Gandara David R DR Lara Primo N PN

Frontiers in oncology 20190311

Introduction: Mesenchymal epidermal transition and vascular endothelial growth factor pathways are important in mediating non-small cell lung cancer (NSCLC) tumorigenesis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. We hypothesized that treatment with cabozantinib plus erlotinib in EGFR mutation-positive NSCLC following progression on EGFR TKI therapy may allow tumors to overcome this resistance or restore sensitivity to therapy regardless ...[more]

PMID: 30915273

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Project description:PurposeGiven the pivotal role of epidermal growth factor receptor (EGFR) inhibitors in advanced EGFR-mutant non-small-cell lung cancer (NSCLC), we tested adjuvant erlotinib in patients with EGFR-mutant early-stage NSCLC.Materials and methodsIn this open-label phase II trial, patients with resected stage IA to IIIA (7th edition of the American Joint Committee on Cancer staging system) EGFR-mutant NSCLC were treated with erlotinib 150 mg per day for 2 years after standard adjuvant chemotherapy with or without radiotherapy. The study was designed for 100 patients and powered to demonstrate a primary end point of 2-year disease-free survival (DFS) greater than 85%, improving on historic data of 76%.ResultsPatients (N = 100) were enrolled at seven sites from January 2008 to May 2012; 13% had stage IA disease, 32% had stage IB disease, 11% had stage IIA disease, 16% had stage IIB disease, and 28% had stage IIIA disease. Toxicities were typical of erlotinib; there were no grade 4 or 5 adverse events. Forty percent of patients required erlotinib dose reduction to 100 mg per day and 16% to 50 mg per day. The intended 2-year course was achieved in 69% of patients. The median follow-up was 5.2 years, and 2-year DFS was 88% (96% stage I, 78% stage II, 91% stage III). Median DFS and overall survival have not been reached; 5-year DFS was 56% (95% CI, 45% to 66%), 5-year overall survival was 86% (95% CI, 77% to 92%). Disease recurred in 40 patients, with only four recurrences during erlotinib treatment. The median time to recurrence was 25 months after stopping erlotinib. Of patients with recurrence who underwent rebiopsy (n = 24; 60%), only one had T790M mutation detected. The majority of patients with recurrence were retreated with erlotinib (n = 26; 65%) for a median duration of 13 months.ConclusionPatients with EGFR-mutant NSCLC treated with adjuvant erlotinib had an improved 2-year DFS compared with historic genotype-matched controls. Recurrences were rare for patients receiving adjuvant erlotinib, and patients rechallenged with erlotinib after recurrence experienced durable benefit.

Project description:PurposePatritumab deruxtecan, or HER3-DXd, is an antibody-drug conjugate consisting of a fully human monoclonal antibody to human epidermal growth factor receptor 3 (HER3) attached to a topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavable linker. We assessed the efficacy and safety of HER3-DXd in patients with epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC).MethodsThis phase II study (ClinicalTrials.gov identifier: NCT04619004) was designed to evaluate HER3-DXd in patients with advanced EGFR-mutated NSCLC previously treated with EGFR tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy (PBC). Patients received HER3-DXd 5.6 mg/kg intravenously once every 3 weeks or an uptitration regimen (3.2 → 4.8 → 6.4 mg/kg). The primary end point was confirmed objective response rate (ORR; RECIST 1.1) by blinded independent central review (BICR), with a null hypothesis of 26.4% on the basis of historical data.ResultsEnrollment into the uptitration arm closed early on the basis of a prespecified benefit-risk assessment of data from the phase I U31402-A-U102 trial. In total, 225 patients received HER3-DXd 5.6 mg/kg once every 3 weeks. As of May 18, 2023, median study duration was 18.9 (range, 14.9-27.5) months. Confirmed ORR by BICR was 29.8% (95% CI, 23.9 to 36.2); median duration of response, 6.4 months; median progression-free survival, 5.5 months; and median overall survival, 11.9 months. The subgroup of patients with previous osimertinib and PBC had similar outcomes. Efficacy was observed across a broad range of pretreatment tumor HER3 membrane expression levels and across diverse mechanisms of EGFR TKI resistance. In patients with nonirradiated brain metastases at baseline (n = 30), the confirmed CNS ORR by BICR per CNS RECIST was 33.3% (95% CI, 17.3 to 52.8). The safety profile (National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) was manageable and tolerable, consistent with previous observations.ConclusionAfter tumor progression with EGFR TKI therapy and PBC in patients with EGFR-mutated NSCLC, HER3-DXd once every 3 weeks demonstrated clinically meaningful efficacy with durable responses, including in CNS metastases. A phase III trial in EGFR-mutated NSCLC after progression on an EGFR TKI is ongoing (HERTHENA-Lung02; ClinicalTrials.gov identifier: NCT05338970).

Project description:PurposeThis randomized, open-label trial compared dacomitinib (PF-00299804), an irreversible inhibitor of human epidermal growth factor receptors (EGFR)/HER1, HER2, and HER4, with erlotinib, a reversible EGFR inhibitor, in patients with advanced non-small-cell lung cancer (NSCLC).Patients and methodsPatients with NSCLC, Eastern Cooperative Oncology Group performance status 0 to 2, no prior HER-directed therapy, and one/two prior chemotherapy regimens received dacomitinib 45 mg or erlotinib 150 mg once daily.ResultsOne hundred eighty-eight patients were randomly assigned. Treatment arms were balanced for most clinical and molecular characteristics. Median progression-free survival (PFS; primary end point) was 2.86 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (hazard ratio [HR] = 0.66; 95% CI, 0.47 to 0.91; two-sided P = .012); in patients with KRAS wild-type tumors, median PFS was 3.71 months for patients treated with dacomitinib and 1.91 months for patients treated with erlotinib (HR = 0.55; 95% CI, 0.35 to 0.85; two-sided P = .006); and in patients with KRAS wild-type/EGFR wild-type tumors, median PFS was 2.21 months for patients treated with dacomitinib and 1.84 months for patients treated with erlotinib (HR = 0.61; 95% CI, 0.37 to 0.99; two-sided P = .043). Median overall survival was 9.53 months for patients treated with dacomitinib and 7.44 months for patients treated with erlotinib (HR = 0.80; 95% CI, 0.56 to 1.13; two-sided P = .205). Adverse event-related discontinuations were uncommon in both arms. Common treatment-related adverse events were dermatologic and gastrointestinal, predominantly grade 1 to 2, and more frequent with dacomitinib.ConclusionDacomitinib demonstrated significantly improved PFS versus erlotinib, with acceptable toxicity. PFS benefit was observed in most clinical and molecular subsets, notably KRAS wild-type/EGFR any status, KRAS wild-type/EGFR wild-type, and EGFR mutants.

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Phase II Trial of Cabozantinib Plus Erlotinib in Patients With Advanced Epidermal Growth Factor Receptor (EGFR)-Mutant Non-small Cell Lung Cancer With Progressive Disease on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy: A California Cancer Consortium Phase II Trial (NCI 9303).

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