Gemcitabine combination therapy for non-small cell lung cancer. Mark R. Green, M.D. Univ of California, San Diego Medical Center and UCSD Cancer Center, San Diego, CA 92103-8421

Gemcitabine (2', 2’ difluorodeoxycytidine) is a new pyrimidine antimetabolite with a broad spectrum of activity in preclinical models. Phosphorylated dFdC inhibits DNA synthesis through several mechanisms including direct competition for DNA polymerases o and e and incorporation into DNA with resulting chain termination. Excision of the dFdCMP from DNA by DNA exonuclease is less effective than repair of incorporated AraCMP. Gemcitabine also inhibits ribonucleotide reductase, contributing to depletion of DNA precursor pools and inhibition of DNA excision repair"'. These mechanisms suggest potentially exploitable interactions with currently available cytotoxic agents such as cisplatin.

Preclinical data in both wild type and gemcitabine or cisplatin resistant ovarian cancer cell lines demonstrate schedule dependent synergy for combinations of gemcitabine and cisplatin (Peters, AACR 1994). Similar synergistic interactions between gemcitabine and cisplatin have been demonstrated in a nude mouse model bearing a human lung cancer cell line. In the same nude mouse model additive and synergistic effects were noted for combinations of gemcitabine and vindesine (F. Fujita, in preparation; A. Pedersen, personal communication). In studies of combined dFdC and radiation against two human pancreas cancer cell lines, potent radiation sensitization is demonstrable under non-cytoxic conditions (Lawrence AACR 1994).

Single agent gemcitabine has been tested extensively in non-small cell lung cancerc2'. Using a variety of doses and schedules an aggregate response rate of 19% was observed in over 400 carefully reviewed cases (E. Lilly and Co., 1993). Since completion of these single agent studies, a number of phase I and phase II trials of gemcitabine and cisplatin in NSCLC and one phase II trial of gemcitabine and vindesine in NSCLC have been initiated.

Danish investigators have treated 32 previously untreated NSCLC patients with gemcitabine 1000mg/m2 weekly x 3 every 4 weeks and vindesine 3mg/mz weekly x 7 and then every 2 weeks. (J. Sorensen et al, 1994). Thirty patients were evaluable. There were 7 partial responses and 1 complete response [8/30, 27% (12%-46%)]. Thirteen percent of patients (4/32) experienced grade 3-4 leukopenia, 9% (3/32) grade 3-4 thrombocytopenia, and 13% (4/32) grade 3 hepatic transaminase elevations. One patient (3%) developed chronic renal insufficiency. These investigators concluded that this combination of gemcitabine and vindesine was not obviously more active than gemcitabine alone.

In a phase I study of previously untreated NSCLC patients in the United Kingdom, gemcitabine 1000mg/m2 weekly for 3 weeks was combined with escalating doses of cisplatin given on day 15. Cycles were repeated every 4 weeks. The starting cisplatin dose was 60 mg/m* with subsequent cohorts receiving 75 mg/m2 or 100 mg/m*. All these dose levels of cisplatin were considered acceptable. (A. Dorr, personal communication). An anglo-french phase II trial of the gemcitabine 1000 mg/m* and cisplatin 100 mg/m2 cohort is currently ongoing with a total of 40 patients accrued as of 2/24/94. Nineteen have received at least 2 cycles of treatment and are fully evaluable for response. Seven partial response have been reported thus far (7/19, 36%) with 2 additional patients currently demonstrating disease regression that has not yet reached PR status. (A. Pedersen, personal communication.)

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In a separate phase weekly x 3 and cisplatin patients with previously as shown.

I trial, Canadian investigators are using gemcitabine weekly x 3 with courses repeated every 4 weeks in untreated NSCLC. Dose levels for individual cohorts are

Cohort #l No. Patients Gem/m* CDDP/m' 1 6 1OOOmg 25mg 2 7 1OOOmg 30mg 3 5 1250mg 30mg 4 2 1500mg 30mg

Accrual to this trial is continuing. A phase II trial of the cohort 2 dose and schedule is currently underway in good performance status (KPS 2 70%) patients with measurable or evaluable NSCLC and no prior chemotherapy. Additional data on these trials should be available at the time of the 7th World Conference.

References

1. Grunewald R, et al: J Clin Oncol 10, 406-413, 1992 2. Lilenbaum RC, Green MR: J Clin Oncol 11, 1391-1402, 1993