Three-Drug Combination May Improve Response Rates in NSCLC Patients

NASHVILLE--Adding gemcitabine (Gemzar) to the widely used combination of paclitaxel (Taxol) and carboplatin (Paraplatin) may increase the response rate in advanced non-small-cell lung cancer (NSCLC), compared with the two-drug combination, a phase I/II study has shown.

The three drugs led to a trend toward a higher overall response rate and increased median and 1-year survival. The incidence of myelotoxicity increased, but was manageable without the use of growth factors in most cases, John D. Hainsworth, MD, director of clinical research, Sarah Cannon-Minnie Pearl Cancer Center, Nashville, reported at an ASCO poster session.

Different Mechanism

The rationale for the study came from evidence that the paclitaxel-carboplatin combination leads to 1-year survival of about 40% and moderate myelosuppression in NSCLC. Gemcitabine also is active in NSCLC and has a different mechanism of action.

"Traditionally in cancer therapy, when you can use combinations of drugs that have different mechanisms of action and use the drugs at a reasonable dose, that sometimes translates into a more effective therapy," Dr. Hainsworth said.

The trial involved 77 patients with stage IIIb or IV NSCLC. The patients had no history of chemotherapy and were not eligible for other combined therapies.

Treatment consisted of paclitaxel at 200 mg/m² on day 1, carboplatin infused to an AUC of 5 on day 1, and gemcitabine at 1,000 mg/m² on days 1 and 8. The regimen was repeated every 21 days for 4 to 10 cycles. For comparison, Dr. Hainsworth and his colleagues used data from a previous trial in which they treated 155 NSCLC patients with paclitaxel and carboplatin.

Response Rates

Of the 71 evaluable patients, the three-drug regimen led to a complete response in 2 patients and a partial response in 32 patients, resulting in an overall response rate of 48%. An additional 25 patients (35%) had disease stabilization.

In contrast, the two-drug combination in the earlier study achieved responses in 37% of patients, and an additional 33% had disease stabilization.

Median survival was 9.5 months with the three drugs vs 8 months in the earlier trial of paclitaxel/carboplatin. One-year survival improved to 45% with the addition of gemcitabine, compared with 40% in the two-drug study.

"Even after adding gemcitabine, we found we could use a full dose of paclitaxel and a slightly lower dose of carboplatin," Dr. Hainsworth said. "In this trial, we used a gemcitabine dose that is reasonably close to a full dose, so we felt that we were getting the drugs into the patients in the way that we wanted."

Compared with the two-drug regimen, the incidence of myelosuppression increased when gemcitabine was added. Grade 3-4 leukopenia occurred in 24% of the courses administered vs 12% with the two-drug regimen; thrombocytopenia occurred in 17% vs 4%, and anemia in 12% vs 4%. Nonhematologic toxicity did not differ markedly between the two- and three-drug combinations.

"The results suggest that the addition of the third drug increases the effectiveness," Dr. Hainsworth said. "It’s not a big improvement, and it could have occurred by chance. The improvement really doesn’t mean much without a randomized trial, but at least we can say that all the survival figures were moving in the right direction. We definitely feel the regimen warrants further evaluation."

The study was conducted in 15 community-based oncology practices, which suggests the results are comparable to those that can be obtained with the combination in the oncology community at large, he added. A randomized clinical trial has already begun and will include the paclitaxel/carboplatin/gemcitabine combination as one of four regimens evaluated in patients with advanced NSCLC.