Table 3.
Chemotherapy combinations with bortezomib.
| Combination | Study | Dose/schedule | Results | Reference |
|---|---|---|---|---|
| Docetaxel | Bortezomib Plus Docetaxel in NSCLC and Other Solid Tumors: A Phase I California Cancer Consortium Trial | Patients with NSCLC and r solid tumors were enrolled in cohorts of three over six dose levels. Each cycle was 3 weeks and consisted of one docetaxel infusion (day 1) and four bortezomib injections (days 1, 4, 8, and 11) | The MTD was 1.0/75 mg/m2. The combination was well tolerated. Two patients with NSCLC achieved a PR (6%), and seven (19%) patients achieved SD (6 patients with NSCLC) | Lara Jr. et al. 2006 [26] |
| Randomized Phase II Study of Bortezomib Alone and Bortezomib in Combination with Docetaxel in Previously Treated Advanced Nonsmall-Cell Lung Cancer | Patients were assigned to bortezomib 1.5 mg/m2 (arm A) or bortezomib 1.3 mg/m2 plus docetaxel 75 mg/m2 (arm B). A treatment cycle of 21 days comprised four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, docetaxel on day 1 | RORR were 8% in arm A and 9% in arm B. DCR rates were 29% in arm A and 54% in arm B. Median TTP was 1.5 months in arm A and 4.0 months in arm B. One-year survival was 39% and 33%, and OS was 7.4 and 7.8 months in arms A and B, respectively | Fanucchi et al. 2006 [27] | |
| Docetaxel + Cetuximab | Randomized Phase II Trial of Docetaxel Plus Cetuximab or Docetaxel Plus Bortezomib in Patients with Advanced Nonsmall-Cell Lung Cancer and a Performance Status of 2: CALGB 30402 | Docetaxel 30 mg/m2 on days 1, 8, and 15 every 28 days in combination with either cetuximab 400 mg/m2 loading dose followed by 250 mg/m2 weekly (D + C) or bortezomib 1.6 mg/m2 on days 1, 8, and 15 every 28 days (D + B) for up to 4 cycles. Patients with responding or stable disease continued cetuximab or bortezomib until progression | ORR response rates were 13.3% and 10.3% for D + C and D + B, respectively. Median PFS was 3.4 months in the D + C arm and 1.9 months in the D + B arm. 6-month PFS were 27.8% and 13.8% and 5.0 and 3.9 months for median survival, respectively. Grade 3/4 hematologic toxicity was 16% for D + C and 21% for D + B, whereas nonhematologic toxicities were observed in 63% and 44% of patients, respectively. Neither combination met the prespecified PFS end point to justify further research in this setting | Lilenbaum et al. 2009 [28] |
| Carboplatin + Paclitaxel and XRT | Phase I Trial of Carboplatin/Paclitaxel/Bortezomib and Concurrent Radiotherapy followed by Surgical Resection in Stage III Nonsmall Cell Lung cancer | Bortezomib was administered on days 1, 4, 15, and 18 during the 6-week induction chemoradiotherapy. Cohorts of three patients were entered. All patients were to receive consolidation chemotherapy with carboplatin AUC = 6 and paclitaxel 200 mg/m2 | 12 patients in three cohorts were enrolled. The addition of bortezomib was well tolerated, with no unexpected toxicities during the induction phase. However, there were 3 postoperative deaths (two pneumonitis and one from failure of the bronchopulmonary flap). The trial was halted as a consequence of these toxicities | Edelman et al. 2010 [29] |
| Gemcitabine + Cisplatin | A Parallel Dose-Escalation Study of Weekly and Twice-Weekly Bortezomib in Combination with Gemcitabine and Cisplatin in the First-Line Treatment of Patients with Advanced Solid Tumors (Phase I study) | Patients were assigned to increasing doses of bortezomib days 1 and 8 (weekly schedule) or days 1, 4, 8, and 11 (twice-weekly schedule), in addition to gemcitabine 1,000 mg/m2 days 1 and 8 and cisplatin 70 mg/m2 day 1, every 21 days. Maximum of six cycles | Weekly bortezomib 1.0 mg/m2 plus gemcitabine 1,000 mg/m2 and cisplatin 70 mg/m2 is the recommended phase II schedule. Of 34 evaluable patients, 13 achieved PR, 17 SD, and 4 PD | Voortman et al. 2007 [30] |
| Gemcitabine + Carboplatin | The Proteasome Inhibitor Bortezomib in Combination with Gemcitabine and Carboplatin in Advanced Nonsmall Cell Lung Cancer: A California Cancer Consortium Phase I Study | Bortezomib was administered on days 1, 4, 8, and 11, after gemcitabine on days 1 and 8, and carboplatin on day 1 of a 21-day cycle. Three escalating dose levels were evaluated: bortezomib 1.0 mg/m2/gemcitabine 800 mg/m2, bortezomib 1.0 mg/m2/gemcitabine 1000 mg/m2, and bortezomib 1.3 mg/m2/gemcitabine 1000 mg/m2, in combination with carboplatin AUC 5.0 | The MTD was defined as bortezomib 1.0 mg/m2, gemcitabine 1000 mg/m2, and carboplatin AUC 5.0. The most common grade 3/4 toxicities were thrombocytopenia (rarely associated with bleeding), and neutropenia. Nine of 26 patients (35%) achieved PR, and eight patients had SD | Davies et al. 2008 [31] |
| Bortezomib Plus Gemcitabine/Carboplatin As First-Line Treatment of Advanced Nonsmall Cell Lung Cancer A Phase II Southwest Oncology Group Study (S0339) | Stage IIIB/IV NSCLC, performance status 0-1, and no history of brain metastasis received up to six 21-day cycles of gemcitabine 1000 mg/m2, days 1 and 8, carboplatin area under curve 5.0, day 1, and bortezomib 1.0 mg/m2, days 1, 4, 8, and 11 | 114 patients (52% adenocarcinoma, 85% stage IV) OS was 11 months; 1-year and 2-year survival rates were 47% and 19%, respectively. Median PFS was 5 months; 1-year PFS rate was 7%. ORR was 23%, and DCR rate was 68% | Davies et al. 2009 [32] | |
| Pemetrexed | Phase I Study of Two Different Schedules of Bortezomib and Pemetrexed in Advanced Solid Tumors with Emphasis on Nonsmall Cell Lung Cancer | Two separate dose-escalating arms (arm A and arm B) were conducted simultaneously. Patients received pemetrexed on day 1 (D1) (500–600 mg/m2 IV) every 21 days. In arm A, bortezomib was given twice weekly (0.7–1.3 mg/m2 on D 1, 4, 8, and 11). In arm B, bortezomib was given weekly (1.0–1.6 mg/m2 on D 1 and 8) | Of 26 evaluable patients, 2 patients had PR (1 in arm A and 1 in arm B), 13 had SD (7 in arm A and 6 in arm B), and 11 had PD (6 in arm A and 5 in arm B). Of the 16 patients with NSCLC, 2 (12.5%) had PR and 9 had SD, for a DCR of 68.8%. Phase II dose for arm A is pemetrexed 500 mg/m2 and bortezomib 1.3 mg/m2 twice weekly. For arm B, the recommended dose is pemetrexed 500 mg/m2, bortezomib 1.6 mg/m2 weekly | Davies et al. 2007 [33] |
| A Randomized Phase II Study of Bortezomib and Pemetrexed, in Combination or Alone, in Patients with Previously Treated Advanced Nonsmall-cell Lung Cancer | Pemetrexed (500 mg/m2) on day 1 plus bortezomib (1.6 mg/m2) on days 1 and 8 (Arm A) or pemetrexed (500 mg/m2) on day 1 (Arm B) or bortezomib (1.6 mg/m2) on days 1 and 8 (Arm C) of a 21 day cycle | In previously treated NSCLC the addition of bortezomib to pemetrexed was well tolerated but offered no statistically significant response or survival advantage versus pemetrexed alone, while bortezomib alone showed no clinically significant activity | Scagliotti et al. 2010 [34] | |
| Erlotinib | A Randomized Phase II Study of Erlotinib Alone and in Combination with Bortezomib in Previously Treated Advanced NSCLC | Erlotinib 150 mg/d alone (arm A; n = 25) or in combination with bortezomib 1.6 mg/m2, days 1 and 8 (arm B; n = 25) in 21-day cycles | ORR were 16% in arm A and 9% in arm B; DCR were 52 and 45%, respectively. The study was halted at the planned interim analysis due to insufficient clinical activity in arm B. Median PFS and OS were 2.7 and 7.3 months in arm A, and 1.3 and 8.5 months in arm B. Six-month survival rates were 56.0% in both arms; 12-month rates were 40 and 30% in arms A and B, respectively. ORR to erlotinib ± bortezomib was significantly higher in patients with EGFR (50 versus 9% for wild type). Insufficient activity was seen with erlotinib plus bortezomib in patients with relapsed/refractory advanced NSCLC to warrant a phase III study of the combination | Lynch et al. 2009 [35] |
PR: partial response, CR: complete response, ORR: overall response rate, PFS: progression-free survival, OS: overall survival, DCR: disease control rate (CR + PR + SD), MTD: maximum tolerated dose.