A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma

Abstract

Purpose: Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody-drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Le(y)) antigen, conjugated to doxorubicin. Le(y) is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Le(y)-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients.

Experimental design: Sixty-two patients with recurrent or metastatic NSCLC expressing Le(y), one or two prior chemotherapy regimens, and PS< or =2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life.

Results: Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A.

Conclusions: SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.

Fig. 1

Survival (top) and progression-free survival (bottom) were followed for the 40 subjects on Arm A and the 19 subjects on Arm B who received at least one dose of study drug. Seven patients (18%) in Arm A and three patients (16%) in Arm B were censored for survival. Median survival was 31.4 weeks (range 1.7–102.3+ weeks) in Arm A and 25.3 weeks (8.4–108.6+ weeks) in Arm B. Three subjects in Arm A (8%) and no subjects in Arm B were censored for PFS. The median PFS was 10.9 weeks in Arm A and 7.0 weeks in Arm B. The 1-year progression-free survival probability was 11% in Arm A and 0% in Arm B.

Fig. 2

Mean quality of life scores at baseline, beginning of Course 2, and at end of study, as assessed using the FACT-L lung cancer subscale (top), FACT-L total score (middle), and FACT-taxane total score (bottom). Bars show standard deviations.

Fig. 3

Symbols represent actual serum levels of cBR96 (blue) and doxorubicin (red) from patients treated with 200 mg/m² of SGN-15. The lines represent model predicted serum levels of cBR96 (blue) and doxorubicin (red) generated using WinNonlin. The model predicted clearance values were 9 mL/h/m² for cBR96 and 1900 mL/h/m² for doxorubicin. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)