Phase III trial of ZD1839 for advanced non-small-cell lung cancer.

The following is an abstract presented to the Presidential Symposium – a phase III trial of ZD1839 in combination with gemcitabine and cisplatin in chemotherapy-naive patients with advanced non-small-cell lung cancer.

The orally administered SGFR-TKI (epidermal growth factor receptor tyrosine kinase inhibitor) ZD1839, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells has a mode of action distinct from cytotoxic agents.

A phase I feasibility study showed ZD1839 in combination with gemcitabine and cisplatin to have an acceptable tolerability profile and high activity.

This combination was assessed in a randomised, double-blind, placebo-controlled, multicentre trial: ‘Iressa’ NSCLC Trial Assessing Combination Treatment 1 (INTACT 1).

Chemo-naive patients with stage III/IV disease, performance status (PS) 0-2, age over 18 years, were randomised to CT + placebo, CT + 250 mg/d or CT + 500mg/d ZD 1839. CT consisted of 6 cycles gemcitabine 1250 mg/m2 on day 1. Treatment with ZD1839 or placebo could be continued until disease progression.

The primary endpoint was overall survival, with the study powered to detect a 33% increase (equivalent to an absolute increase of 2.3 months).

Secondary endpoints were progression-free survival and time to worsening of symptoms per LCS (Lung Cancer Subscale of the FACT-L).

Other endpoints included symptom improvement, objective tumour response and disease control rate (CR + PR + SD), quality of life and safety.

A total of 1093 pts (MF 805/288; median age 61 [31-85] years, PS 0/1/2unknown: 364/620/105/4, disease stage III(A)/III(B)/IV/unknown: 24/306/757/6, histology adeno/squamous/NOS: 512/328/253) were recruited from 165 sites worldwide.

The three treatment groups were well balanced across all disease and demographic characteristics.

Results

There were no statistically significant differences in overall survival (median [CI] 11.1 [10.1-11.9], 9.9 [8.7-10.8] and [9.9 [8.8-11.4] months for placebo, 250mg and 500mg arms respectively), progression-free survival and time to worsening of symptoms across the three arms. The comparative hazard ratios (HR) between the treatment arms for overall survival were: placebo: 250mg, HR=0.91, (p=0.82). The toxicity profile of ZD1839 combined with CT was comparable to CT alone, with exception of additive, dose dependant diarrhea and skin rash.

Conclusions

ZD1839 in combination with this two-agent chemotherapy regimen for advanced NSCLC did not improve treatment outcomes. However, the combination exhibited an acceptable toxicity profile without worsening of CT-associated toxicities, and, based on the results of monotherapy ZD1839 in refractory NSCLC, further study of ZD1839 is warranted in other settings.