Initial cohort toxicity evaluation for chemoradiotherapy (CRT) and ZD1839 in stage III non-small cell lung cancer (NSCLC): A CALGB stratified phase II trial

Abstract

7078 Background: ZD1839 (Iressa) is a small molecule inhibitor of the EGFR that has single agent activity in advanced NSCLC and preclinical evidence of being a radiosenitizer. Methods: Patients with stage III NSCLC were assigned to stratum 1 (PS 0–1>5% weight loss or PS 2) or stratum 2 (PS 0–1weight loss < 5%). Patients on both strata received induction paclitaxel (P) 200 mg/m2 and carboplatin (C) AUC of 6 IV every three weeks for 2 cycles as well as ZD1839 250 mg PO/day. Stratum 1 then received RT 200 cGy for 33 fractions (total dose 6600 cGy) and ZD1839 250 mg PO /day. Stratum 2 received the same RT with concurrent ZD1839 250 mg/day, and P 50 mg/m2 plus C AUC of 2 weekly for 7 doses. There was a 2-week break from ZD1839 after RT finished to assess recovery from treatment. Maintenance ZD1839 was started if all toxicities were grade < 2. Initial enrollment was limited to 6 institutions and conference calls were held every 2 weeks. Results: Toxicity and safety of therapy was evaluated for ZD1839 concurrent with RT or CRT, since the safety of ZD1839 as a single agent or with doublet chemotherapy has been demonstrated. Acute grade 3 in-field radiotherapy related toxicity such as esophagitis was not considered a DLT because acute grade 3 in-field toxicity exceeded 33% in co-operative group trials such as RTOG 9410 and CALGB 9431. However a DLT was deemed to have occurred if grade ≥ 3 in-field radiotherapy related toxicity persisted at 90 days follow-up. There were no unexpected toxicities in the patients in stratum 2 (CRT and ZD1839). In the initial cohort of 6 patients in stratum 2, 1 patient had a DLT having missed 3 out of 7 planned doses of CT during RT due to cytopenias, and esophagitis, and had a 2 week delay in completing RT. Among the other five patients in stratum 2, RT was delayed 1 week or less, and ≥ 5 CT doses of 7 planned were delivered during CRT. In the initial cohort of 6 patients in stratum 2, all treatment related toxicities improved to grade ≤ 2 by 4 weeks after the completion of RT. Conclusions: Our data suggests that ZD1839 can be safely administered with CRT. The evaluation of the cohort for stratum 1 is ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis AstraZeneca; Aventis Bristol-Myers Squibb