N0321: A phase II study of bortezomib, paclitaxel, carboplatin (CBCDA), and radiotherapy (RT) for locally advanced non-small cell lung cancer (NSCLC)

7073 Background: In preclinical studies, combinations of bortezomib and RT result in synergistic tumor killing (Cancer Chemother Pharmacol. 2007;59:207-15). Our group reported the results from the phase I portion of this study previously (J Clin Oncol. 200;28 (suppl; abstr 7085)). Based on these data, we undertook a phase II study of bortezomib in combination with paclitaxel/CBCDA and RT. Methods: Based on results from our previously reported phase I trial, systemic therapy included bortezomib (1.2 mg/m² IV days 1,4,8,11), paclitaxel (175 mg/m² IV day 2), and carboplatin (CBCDA; AUC=6 day 2) given every 3 weeks for 2 cycles. Thoracic radiotherapy (RT) included 60Gy/30 daily fractions starting day 1. The primary endpoint was the 12-month survival rate. If 41 or more of these 60 patients (68%) were alive at least 12 months after study entry, the trial would be deemed as positive and further study would be warranted. Results: 27 pts were enrolled to the phase II portion: M/F=17/10; stage IIIA/IIIB=13/14; ECOG PS 0/1=9/18; and median age: 58 (range 43-79). 18 pts (67%) completed therapy per protocol. At a planned interim analysis, 23 of 26 evaluable patients (88.5%, 95% CI: 70-98%) survived for at least 6 months, which exceeded the boundary of 21 or more needed to continue to full accrual. This trial could have continued per protocol, but was closed early due to slow accrual. With a median follow-up of 15.0 months in the 17 patients still alive, the 12-month survival rate was 71% (95% CI: 49 – 85). The median OS was 19 months (95% CI: 11 – no upper). Grade 3 or higher adverse events (regardless of attribution) were reported in 22 (82%) patients. Grade 4/5 adverse events were reported in 15 (56%) patients. There was one grade 5 event (pneumonitis). The most common (5 or more patients) grade 3/4 adverse events were fatigue (22%), leukopenia (63%), neutropenia (67%), and thrombocytopenia (44%). Conclusions: The addition of bortezomib resulted in high levels of severe hematologic toxicity, but also demonstrated evidence of activity with a 12-month survival rate of 71% and a median OS of 19 months. Further testing of this regimen in a larger study appears warranted.