Phase I study of sunitinib and erlotinib in advanced nonsquamous non-small cell lung cancer.

INTRODUCTION: Erlotinib has prolonged survival in unselected patients with advanced non-small cell lung cancer, whereas sunitinib has yielded promising rates of disease control in previously treated patients. We conducted a dose escalation study of this combination to determine the maximum tolerated dose of sunitinib in combination with a fixed dose of erlotinib and to evaluate the toxicities of this combination. METHODS: Patients with advanced nonsquamous non-small cell lung cancer were treated at two dose levels: sunitinib at either 25 mg or 37.5 mg, with erlotinib 150 mg. Both drugs were given once daily, continuously. RESULTS: Eleven patients enrolled from November 2007 to October 2009. No dose-limiting toxicities occurred. Grade 3/4 adverse events at least possibly related to treatment were seen in seven patients (64%). Six patients (54%) required dose modifications, and three (27%) discontinued study treatment due to toxicity. Rates of grade 3 diarrhea and mucositis exceeded those seen with single-agent erlotinib or sunitinib. One patient (9%) attained a partial response lasting 16.3 months. CONCLUSIONS: Although no dose-limiting toxicities occurred, it is difficult to recommend erlotinib 150 mg and sunitinib 37.5 mg daily as the phase II dose for this combination due to the high rate of adverse events. Because of the overlapping toxicity profile of each agent, this combination was poorly tolerated in our population.

Vorinostat (NSC# 701852) in patients with relapsed non-small cell lung cancer: a Wisconsin Oncology Network phase II study.

INTRODUCTION: Vorinostat is a small molecule inhibitor of histone deacetylase, and has shown preclinical activity in non-small cell lung cancer (NSCLC). METHODS: Patients with relapsed NSCLC were eligible. Patients received oral vorinostat, 400 mg daily. The primary objective was response rate, with the goal of at least one responder in the first 14 evaluable patients, according to the two-stage minimax design. Secondary objectives included time to progression (TTP), overall survival (OS), and safety. RESULTS: Sixteen patients enrolled from January 2006 to April 2007. The median age was 59.5 years. Thirteen patients were female. Two patients were not evaluable for response due to progressive disease within Cycle 1. No objective antitumor responses were seen in the 14 evaluable patients. Eight patients experienced stable disease (median 3.7 months, range 1.4-19.4). Median TTP was 2.3 months (range 0.9-19.4 months), median OS was 7.1 months (range 1.4-30.0+ months), and estimated 1 year OS rate was 19% (SE 10%). One patient died on study from an acute ischemic stroke; this event was deemed possibly related to treatment. Grade 3/4 adverse events possibly related to vorinostat included neutropenia, lymphopenia, fatigue, pulmonary embolus/deep vein thrombosis, dehydration, elevated alkaline phosphatase, and hypokalemia. CONCLUSIONS: No objective antitumor activity was detected with single agent vorinostat in this setting; however, it yields TTP in relapsed NSCLC similar to that of other targeted agents. Further studies in NSCLC should focus on combining vorinostat with other antitumor agents.

Pilot study of gefitinib and fulvestrant in the treatment of post-menopausal women with advanced non-small cell lung cancer.

INTRODUCTION: Estrogen receptor beta (ERbeta) has been detected in non-small cell lung cancer (NSCLC) cell lines and tumor specimens. The ER down-regulator, fulvestrant, blocked estradiol-stimulation of tumor growth and gene transcription in NSCLC preclinical models and showed additive effects with the epidermal growth factor receptor (EGFR) inhibitor gefitinib. The safety and tolerability of combination therapy with the EGFR inhibitor, gefitinib, and fulvestrant was explored. METHODS: Post-menopausal women with advanced NSCLC received gefitinib 250 mg po daily and fulvestrant 250 mg IM monthly. RESULTS: Twenty-two patients were enrolled. Eight patients had adenocarcinoma, six NSCLC-NOS, four squamous cell, and four BAC. Seven patients were never-smokers. Eight patients received > or =2 lines of prior chemotherapy, six received one prior chemotherapy, and eight were treatment-naïve. One patient experienced grade 4 dyspnea possibly related to treatment; all other grade 3/4 toxicities were unrelated to treatment. Twenty patients were evaluable for response: three partial responses (PRs) were confirmed (response rate of 15%, 95% CI: 5-36%). The median progression-free survival (PFS), overall survival (OS), and estimated 1-year OS were 12 weeks (3-112 weeks), 38.5 weeks (7-135 weeks), and 41% (95% CI: 20-62%), respectively. Survival outcomes did not differ by prior lines of therapy. A subset analysis revealed that OS in the eight patients whose tumors exhibited at least 60% ERbeta nuclear IHC staining measured 65.5 weeks, while that of the five patients with ERbeta staining of less than 60% was 21 weeks. One patient with bronchioalveolar carcinoma (BAC) and a PR had an EGFR L858R mutation in exon 21. There was no correlation between ERbeta IHC expression and histology or smoking history. CONCLUSIONS: Combination therapy with gefitinib and fulvestrant in this population was well tolerated and demonstrated disease activity.