Promising Results Demonstrated with New Agent for Non-Small-Cell Lung Cancer

January 1, 1995

Preliminary clinical results with gemcitabine, an investigational difluoronucleoside, were presented during scientific sessions organized by the 7th World Conference on Lung Cancer, which was held in Colorado Springs last year. The agent produced

Preliminary clinical results with gemcitabine, an investigationaldifluoronucleoside, were presented during scientific sessionsorganized by the 7th World Conference on Lung Cancer, which washeld in Colorado Springs last year. The agent produced promisingresponse rates in patients with non-small-cell lung cancer (NSCLC),in both single-agent and combination chemotherapy trials.

The research presentations and posters at the meeting focusedon data from completed phase II clinical trials in Europe, Japan,and Canada in which gemcitabine had been given to patients withinoperable NSCLC.

Single-Agent Trials

Two multicenter phase II studies were conducted to determine theclinical efficacy of gemcitabine for the treatment of non-small-celllung cancer. The first study evaluated 151 patients with inoperableNSCLC. Gemcitabine, 1,250 mg/m², was administered as a 30-minuteintravenous infusion once a week for 3 weeks followed by 1 weekof rest. This constituted one treatment cycle.

The results of the trial indicated an overall response rate of22%, which included 3 complete and 30 partial responses. Accordingto the lead investigator, Ulrich Gatzemeier, MD, GrosshansdorfHospital, Germany, this response rate compares favorably withsingle-agent response rates reported in the medical literaturefor other existing drugs used against lung cancer. Similar responserates were reported in two independent Japanese studies enrollinga combined 136 patients with previously untreated NSCLC, of which116 were evaluable at the time. The dosing schedule was comparableto that used in the European study, although the initial gemcitabinedose was 1,000 mg/m², with allowance made for increasingthe dose to 1,250 mg/m², depending on the patients' tolerancelevels during the first cycle. An overall response rate of 23%was reported.

Both studies showed gemcitabine to be generally well tolerated.Overall, the most common side effects reported were neutropeniain the first study and leukopenia, anemia, loss of appetite, andfatigue in the second study. Gemcitabine's "overall mildtoxicities, in particular, modest myelotoxicity, may warrant furtherinvestigation of this drug in combination with other anticanceragents," said lead investigator Yushi Nakai, MD, of the SendaiKousei Hospital in Japan.

Combination Studies

Preliminary results from two phase I combination studies involvinggemcitabine and cisplatin to treat NSCLC were also presented atthe Colorado conference.

One study was conducted to determine the maximum tolerated dosesof a 4-week cycle of gemcitabine and cisplatin when administeredfor 3 weeks, with a 1-week rest period. The starting dose of gemcitabinewas 1,000 mg/m² for 3 weeks. At the next dose level, onlycisplatin was increased to 30 mg/m² per week for 3 weeks.Thereafter, dose escalations were made only for gemcitabine (to1,250 mg/m² and 1,500 mg/m²). At the time of the conference,25 patients (24 eligible) had been entered in the study. The initialpartial response rate for this study was 7 out of 12 patients.

Similar results were reported in a second phase I dose-escalationstudy of gemcitabine in combination with cisplatin, using a differentdosing schedule. In 15 patients, gemcitabine 1,000 mg/m²was administered as a 30-minute IV infusion on days 1, 8, and15 of a 28-day cycle. On day 15, cisplatin was given immediatelyafter gemcitabine administration at the following dose levels:60 mg/m² (3 patients), 75 mg/m² (3 patients), and 100mg/m² (9 patients). For these patients, gemcitabine did notadd to expected cisplatin toxicity. The most commonly noted sideeffects included neutropenia, thrombocytopenia, transient risein liver function tests, nausea, and vomiting. The number of evaluablepatients with response rates was two out of three at the 60-mg/m²cisplatin dose level, none out of three at 75 mg/m², andfour out of four at 100 mg/m².

Based on the findings of these two studies, The Toronto Hospital'sFrances A. Shepherd, MD, one of the lead investigators, said,"The preliminary response data suggest that the gemcitabineand cisplatin [combination] is an active regimen against NSCLC.It is well tolerated and deserves further study in comparisonwith other chemotherapy combinations."

Lung cancers are among the most difficult cancers to treat. Aneffective therapy for advanced NSCLC, which accounts for nearly75% of all lung cancer cases, has been particularly elusive. The5-year survival rate for those with NSCLC stands at less than10%.

Gemcitabine is being tested by Eli Lilly and Company, which hasapplications pending for regulatory approval of this compoundin 19 countries outside the United States for the indication ofnon-small-cell lung cancer. The drug is also being studied forthe treatment of pancreatic cancer in an ongoing US registrationtrial. Data also suggest that gemcitabine may have activity againstother solid tumors, including breast, ovarian, bladder, and prostatecancers. Further studies with these tumors are planned to confirmthe activity of the compound.