Cisplatin/Gemcitabine/Herceptin Encouraging in NSCLC

SAN FRANCISCO—Early results with a regimen of gemcitabine (Gemzar), cisplatin (Platinol), and trastuzumab (Herceptin) in advanced non-small-cell lung cancer (NSCLC) patients overex-pressing HER-2 are encouraging, according to a presentation at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 1307).

The current standard-of-care chemotherapeutic agents used in NSCLC are relatively similar in their ability to improve survival, quality of life, and symptom relief. "So if we can find a way to improve these by adding Herceptin in a practical manner, then patients will benefit," principal investigator Ralph G. Zinner, MD, assistant professor of medicine at M.D. Anderson Cancer Center, told ONI in an interview.

Co-investigator is Roy Herbst, MD, PhD, assistant professor of medicine and cancer biology.

The current phase II study addresses several issues, primarily efficacy vs historical controls. Dr. Zinner said that chemotherapy response rates in three phase III NSCLC trials of the cisplatin/gemcitabine combination have been around 35% (40.6%, 31%, and 40%). "We felt that achieving a 55% response rate by adding Herceptin would be good evidence of benefit," Dr. Zinner stated.

He noted, however, that use of historical controls who did not receive trastuzumab as part of their chemotherapy regimen is complicated by the absence of response data in patients identified as having HER-2 overexpression. This is important, he said, since HER-2 overexpression may predict either better or worse response to standard chemotherapy.

Assessment of HER-2 overexpression was another area of study interest. Dr. Zinner pointed out that fluorescence in situ hybridization (FISH) was not used because in NSCLC (unlike in breast cancer), DNA amplification is not the usual mechanism of overexpression. Through poorly understood mechanisms, within the subset of lung cancer tumor tissues that overexpress HER-2, only a small percentage have such DNA amplification detectable through FISH.

Immunohistochemistry (IHC), however, does detect the HER-2 protein gene product in lung cancer. Dr. Zinner said that preclinical studies have shown antibodies against HER-2 to have antipro-liferative effects even without DNA amplification.

The investigators also looked at evidence for overexpression of HER-2 in serum, based on evidence that truncated HER-2 (soluble in serum) may be a predictor of more severe disease. One potential advantage of a serum assay, should it prove to be an accurate indicator, is that it would allow serial blood draws for measuring response to therapy.

Eligible patients were of Zubrod status 2 or less and were chemotherapy naïve with stage IIIB/IV NSCLC. Left ventricular ejection fraction was 40% or more, and HER-2 status was 1+ or more by IHC or 15 ng/mL or more serum HER-2 shed antigen by ELISA. Dr. Zinner noted that although at the outset, a 2+ criterion for IHC (as in breast cancer) was established, the researchers decided (as have ECOG investigators studying NSCLC) to relax the standard to 1+ or higher.

He mentioned also that although trastuzumab treatment in breast cancer patients has been associated with some congestive heart failure (CHF) in patients with either previous or concurrent doxorubicin therapy or preexisting cardiac dysfunction, the risk of CHF has been low in NSCLC, since eligible patients have good ejection fraction as determined by MUGA scan and are chemotherapy naïve.

The treatment regimen was trastuzumab 2 mg/kg/wk IV, gemcitabine 1,250 mg/m² IV on days 1 and 8, cisplatin 75 mg/m² IV on day 1 every 3 weeks for six cycles, followed by maintenance with trastuzumab 2 mg/kg/wk IV until disease progression.

The researchers screened 279 patients by IHC, with 25% being 1+ or higher; 192 were screened using serum, with 10% positive by the serum criterion. A weak correspondence was revealed between elevated IHC and elevated serum HER-2. Also, pharmacokinetic evaluation in seven patients showed no effect of trastuzumab on gemcitabine clearance.

Out of a target of 48 patients, 18 had been treated at the time of the ASCO presentation, with 14 evaluable (median age 60, 8 female). Dr. Zinner reported partial responses in eight patients (57%), with stable disease in four (28%) and progression in two (14%). Five patients continue to receive the regimen. Maintenance therapy durations are, to date, 8 to 80+ weeks. Median time to progression is 32 weeks.

Grade 3 and 4 toxicities include neutropenia (4 and 3 patients, respectively); thrombocytopenia (5 and 1 patients); anemia (1 grade 3); fatigue (2 grade 3); and nausea (1 grade 3). During maintenance, there was no toxicity greater than grade 1. Ejection fraction did not decrease by 10% or more from baseline or fall below 40% in any patient.

Dr. Zinner concluded: "This regimen is well tolerated with no detected additional toxicity from the inclusion of Herceptin. Response rates and median time to progression are encouraging, but there are few patients. Since maintenance Herceptin causes minimal toxicity with prolonged treatment, time to progression and survival will be critical end-points."