Patricia Stephenson

Trastuzumab in the Treatment of Advanced Non-Small-Cell Lung Cancer: Is There a Role? Focus on Eastern Cooperative Oncology Group Study 2598

PURPOSE Multiple non-small-cell lung cancer (NSCLC) cell lines and 20% to 50% of pathologic specimens express HER-2/neu, the target of trastuzumab, and HER-2/neu expression has proven to be an independent, unfavorable prognostic factor in resected patients with NSCLC. Trastuzumab, in vitro, has demonstrated growth-inhibiting synergy with platinating agents, and additivity with paclitaxel. The Eastern Cooperative Oncology Group therefore launched a phase II study evaluating combination carboplatin, paclitaxel, and trastuzumab in patients with advanced NSCLC. MATERIALS AND METHODS Eligibility stipulated the following: measurable tumor, HER-2/neu positivity (1+ to 3+ by Herceptest [Dako Corp, Carpinteria, CA], confirmed by central review), Eastern Cooperative Oncology Group PS 0 to 1, adequate marrow, hepatic and renal function, and left ventricular ejection fraction >or= 45%. Patients received paclitaxel 225 mg/m(2)/3 hours, and carboplatin (area under the curve, 6) every 3 weeks, and trastuzumab 4 mg/kg intravenously on day 1, then 2 mg/kg weekly for <or= 1 year. RESULTS Between August 1999 and May 2000, 139 patients were screened; seven specimens (5%) were indeterminate. Fifty patients (36%) were HER-2/neu negative, 38 (27%) were HER-2/neu 1+, 31 (22%) were 2+, and 13 (9%) were 3+. Fifty-six patients were enrolled; 53 were eligible (22 [42%] were 1+, 23 (43%) were 2+, and eight (15%) were 3+). Thirteen (24.5%) of 52 assessable patients (95% CI, 13.8 to 38.3) responded. The incidence of grade >or= 3 neutropenia and thrombocytopenia was 57% (34%) and 16% (2%), respectively. Asymptomatic grade <or= 2 reduction in left ventricular ejection fraction occurred in 7%. Other nonhematologic toxicities, including nausea, fatigue, arthralgias, and peripheral sensory neuropathy, were mild to moderate and matched those expected with carboplatin and paclitaxel alone. Eighteen patients (35%) received maintenance trastuzumab. Median progression-free survival was 3.3 months; median survival was 10.1 months, and 1-year survival rate was 42%. CONCLUSION Combination paclitaxel, carboplatin, and trastuzumab is feasible. Toxicity appears no worse than cytotoxic therapy alone. Overall survival is similar to historical data using carboplatin and paclitaxel alone. However, patients with 3+ HER-2/neu expression did well in contrast to historical data suggesting potential benefit for trastuzumab in this rare subset of NSCLC. Critical assessment of trastuzumabs role in advanced NSCLC will require phase III trials.

Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: A phase I dose-escalation study

PURPOSE To determine the maximum tolerated dose (MTD) of sunitinib plus gemcitabine/cisplatin for first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). Safety, pharmacokinetics, and antitumor activities were evaluated. METHODS Patients ≥18 years with Eastern Cooperative Oncology Group performance status 0/1 and stage IIIB/IV NSCLC were included in this open-label, multicenter, dose-escalation phase I study. Treatment was administered in 3-week cycles: oral sunitinib 37.5 or 50mg/day intermittently (Schedule 2/1: 2 weeks on treatment, 1 week off treatment) or 25mg continuous daily dosing (CDD) schedule with intravenous infusions of gemcitabine (1000 or 1250 mg/m(2) days 1, 8) and cisplatin (80 mg/m(2) day 1). RESULTS A total of 28 evaluable patients were assigned to four dose levels. Most adverse events (AEs) on the Schedule 2/1 MTD were mild to moderate. Dose delays due to myelosuppression occurred on both schedules, limiting treatment to a median of four cycles. Four of 18 evaluable patients (22%) on Schedule 2/1 and 1 of 6 patients (17%) on the CDD schedule had confirmed partial responses. CONCLUSIONS The MTD was identified as sunitinib 37.5mg (Schedule 2/1), gemcitabine 1250 mg/m(2), and cisplatin 80 mg/m(2), with most AEs being mild to moderate. However, frequent dose delays due to myelosuppression occurred. There was evidence of antitumor activity with this combination.

EGFR Dinucleotide Repeat Polymorphism as a Prognostic Indicator in Non-small Cell Lung Cancer

Background: The epidermal growth factor receptor (EGFR) has been implicated in tumor growth and progression. Intron 1 of the EGFR gene contains a polymorphic simple sequence repeat (SSR) of 14 to 21 CA dinucleotides, the length of which correlates inversely with the level of EGFR transcription. The authors hypothesized that a shorter length of tumor SSR would be associated with poorer survival in patients with non-small cell lung cancer (NSCLC). Methods: Patients enrolled in Eastern Cooperative Oncology Group E3590 (a randomized, prospective trial of adjuvant therapy following resection of stages II and IIIa NSCLC) were randomized to radiation or radiation plus chemotherapy. Genomic DNA extracted from resected tumors was amplified for EGFR intron 1 by polymerase chain reaction and sequenced in a 3730XL DNA analyzer. Results: One hundred fifty-seven primary tumors were sequenced, 106 (68%) of which were heterozygous for intron 1. The most common genotypes were allele lengths of 17/19 dinucleotides (17.8%), 17/18 (11.4%), and 19/19 (11.4%). Allele status (homozygous versus heterozygous) did not correlate with race, gender, weight, performance status, histology, stage, or survival. Shorter allele length (≤18 versus >18 CA dinucleotide repeats) was associated with squamous cell histology (p = 0.03). Allele sum of greater than 35 was associated with improved overall survival (log-rank p = 0.03, hazard ratio = 0.66). Conclusion: This is the first study to characterize the EGFR intron 1 SSR polymorphism in NSCLC. Tumors were most commonly heterozygous for SSR length. Squamous histology was associated with a shorter SSR. Longer sequences are associated with improved survival.

A Phase II trial of cisplatin plus WR-2721 (amifostine) for metastatic breast carcinoma: an Eastern Cooperative Oncology Group Study (E8188).

Cisplatin has minimal antitumor activity when used as second‐ or third‐line treatment of metastatic breast carcinoma. Older reports suggest an objective response rate of 8% when 60–120 mg/m2 of cisplatin is administered every 3–4 weeks. Although a dose–response effect has been observed with cisplatin, the dose‐limiting toxicities associated with cisplatin (e.g., nephrotoxicity, ototoxicity, and neurotoxicity) have limited its use as a treatment for breast carcinoma. WR‐2721 or amifostine initially was developed to protect military personnel in the event of nuclear war. Amifostine subsequently was shown to protect normal tissues from the toxic effects of alkylating agents and cisplatin without decreasing the antitumor effect of the chemotherapy. Early trials of cisplatin and amifostine also suggested that the incidence and severity of cisplatin‐induced nephrotoxicity, ototoxicity, and neuropathy were reduced.

CYP3A5*3 and CYP3A4*1B polymorphisms are associated and more frequent in NSCLC tumors than in normal volunteers

2016 Background:. CYP3A4 and CYP3A5 are monooxygenases that metabolize tobacco, endogenous steroids, and numerous anti-cancer agents. The CYP3A4*1B polymorphism leads to increased promotor activity and is associated with small cell lung cancer. The CYP3A5*3 polymorphism causes decreased protein levels and is associated with an increased risk for non small cell lung cancer (NSCLC). METHODS Genomic DNA isolated from primary lung tumor and matched normal nodes from subjects with NSCLC enrolled in E3590 and from peripheral blood mononuclear cells from normal volunteers was evaluated for six CYP3A4/5 polymorphisms by pyrosequencing. Samples were designated as wild-type (WT), heterozygote or homozygous variant for each of the polymorphisms, and differences were evaluated by Chi square analysis and exact binomial confidence intervals were computed for proportions. RESULTS There were 187 primary tumors with 51 matched nodes and 95 normal volunteers analyzed. Homozygous polymorphisms in CYP3A4/*1B were identified in 2.9% of the tumors, 0.2% of the matched normal nodes and 0% of the normal volunteers. Homozygous polymorphisms in CYP3A5/*3 were identified in 5% of the tumors, 2% of the matched normal nodes and 0% of the normal volunteers. Polymorphisms in CYP3A4/*1B and CYP3A5/*3 were significantly associated (p=0.0001) and both polymorphisms were more common in tumors than in normal volunteers (CI 0.01-0.067 for CYP3A4/*1B, and 0.021-0.105 for CYP3A5/*3). CONCLUSIONS The CYP3A5*3 and 4*1B polymorphisms are associated and occur more frequently in tumors from individuals with NSCLC than in the normal population. Individuals with the CYP3A5*3/4*1B genotype are expected to have high levels of CYP3A4 activity and very little CYP3A5 activity, which may be important in the metabolism of carcinogens such as tobacco smoke and the biotransformation of numerous anti-cancer agents. [Figure: see text] No significant financial relationships to disclose.

EGFr dinucleotide repeat polymorphism in non-small cell lung cancer

9585 Background: Intron 1 of the epidermal growth factor receptor (EGFr) gene contains a polymorphic simple sequence repeat (SSR) of 14-21 CA dinucleotides, which regulates the transcription and expression of EGFr. In breast cancer, the length of these repeats is inversely related to EGFr expression. In breast and colorectal cancer, the most common genotype was heterozygous for 16 and 20 repeats. We evaluated the distribution of the (CA)n repeats in non-small cell lung cancer (NSCLC). METHODS Genomic DNA isolated from primary lung tumor and matched normal nodes samples from ECOG 3590 study were analyzed. Extracted DNA was amplified for EGFr intron1 by PCR and sequenced in a 3730XL DNA analyzer. RESULTS 157 primary tumors and 72 nodes were sequenced. 105 (67%) tumor samples were heterozygous for intron 1. There was no significant association between homozygous or heterozygous status with baseline characteristics such as race, gender, weight, performance status, histology, and stage or survival. The commonest genotype was heterozygous with allele lengths of 17/19 dinucleotides (17.8%), followed closely by 17/18 (11.4%) and homozygous 19 (11.4%) (Table1). SSR length of 18 or less dinucleotide repeats was associated with squamous cell histology (p=0.03). SSR length did not correlate with survival (p=0.20) . CONCLUSIONS This is the first study to assess the EGFr SSR polymorphism in NSCLC. The commonest genotype for SSR length in NSCLC differs from breast and colon cancer. There is no significant correlation between allele status and length of the SSR with survival. Tumors with a shorter SSR were associated with squamous histology. [Figure: see text] No significant financial relationships to disclose.