Benefit In Time To Progression Research Articles

Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial

BackgroundCALGB 100104 (Alliance) studied lenalidomide vs. placebo following autologous stem cell transplant (ASCT) for newly diagnosed myeloma patients, demonstrating improved time to progression (TTP) and overall survival (OS), and an increase in second primary malignancies (SPM) for lenalidomide at 34-months median follow-up. Here we report an updated intent-to-treat analysis at 91-months median follow-up.MethodsPatients were eligible if they had active myeloma, had received at most two induction regimens and had achieved stable disease or better in the first 100 days after ASCT. In this phase 3 study, 460 patients were randomised in a double-blind manner to either lenalidomide (n=231) or placebo (n=229) utilizing a permutated-block randomisation with fixed block size. Randomisation was stratified by three factors: normal or elevated β2-microglobulin level at registration (≤2·5 mg/L vs > 2·5 mg/L), prior use or nonuse of thalidomide during induction therapy, and prior use or nonuse of lenalidomide during induction therapy. The starting dose was 10 mg daily, escalated to 15 mg daily after three months. The primary endpoint was TTP (time of progressive disease or death from any cause) using intent-to-treat analysis. After three interim analyses, the study was unblinded at median follow-up of 18 months and 86/128 placebo patients without progressive disease chose to cross over to lenalidomide. This study is registered with ClinicalTrials.gov identifier NCT00114101; new patients are no longer being recruited, but some patients remain on treatment and in follow-up.FindingsThe median TTP for lenalidomide is 57·3 months (95% CI 44·2–73·3) and 28·9 months (95% CI 23·0–36·3) for placebo (hazard ratio (HR): 0·57, 95% CI 0·46–0·71, p<0·0001). The TTP benefit with lenalidomide was observed regardless of whether patients were in a complete response at time of randomisation or whether they had received thalidomide or lenalidomide induction therapy. The most common grade 3–4 adverse events were neutropenia (116 (50%) of 231 patients in the lenalidomide arm and 37 (16%) of 229 patients in the placebo arm) and thrombocytopenia (34 patients (15%) in the lenalidomide arm and 11 patients (4·8%) in the placebo arm. Eighteen haematological (7·8%) and 14 solid tumour (6·1%) SPMs have been diagnosed following randomisation and prior to disease progression in the lenalidomide arm vs. three haematological (1·3%) and nine solid tumour (3·9%) SPMs in the placebo arm. Of the placebo SPMs, three haematological and five of nine solid tumour SPMs were in the crossover subgroup.InterpretationDespite an increase in haematological adverse events and SPMs, lenalidomide maintenance therapy following ASCT significantly improves TTP and can be considered a standard of care.

Sustained Overall Survival Benefit with Lenalidomide Plus Dexamethasone Versus No Treatment in Patients with Smoldering Myeloma at High Risk of Progression to Myeloma: Long Term Analysis

Background: For patients with smoldering multiple myeloma (SMM), the standard of care is observation. However, high-risk patients may benefit from early intervention.Methods: In this phase 3 trial, 119 patients with high-risk SMM were randomized to treatment or observation. The high risk populationwas defined by the presence of both PC_ 10% and MC_ 3g/dl or ifonly one criterion was present, patients must have a proportionof aPC within the total PCBM compartment by immunophenotypingof 95% plus immunoparesis. Patients in the treatment group received nine 4-week induction cycles (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15), followed by maintenance (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle) up to 2 years. The primary end point was time to progression (TTP) to myeloma. Secondary end points were overall survival (OS), response rate and safety.Results: After a median follow-up of 75 months (range: 57-100), there was a 57% reduction in the risk of death for the early treatment with lenalidomide-dexamethasone versus not treatment (hazard ratio, 0.43; 95% confidence interval, 0.2 to 0.9; P=0.02). Median overall survival has not been reached in either group, but 86% and 62% of patients are alive at 6 years in the early treatment and observation arms, respectively (Figure 1). The benefit in TTP is also highly sustained (hazard ratio: 0.24 (95% confidence interval, 0.14 to 0.41; P<0.0001). Progression to MM occurred in 53 out of the 62 patients (86%) in the abstention arm while only 22 out of 57 patients (38%) in the len-dex arm. At the time of progression patients received optimized treatments: bortezomib-based combinations were administered to thirteen out of 22 patients (59%) in the len-dex arm and to 23 out of 53 patients (43%) in the observation arm; lenalidomide-based combinations to 3 out of 22 patients (14%) in the experimental and to 8 out of 53 patients (15%) in the control arm; two out of 22 patients in the len-dex arm (9%) received bortezomib plus immunomodulatory agents whilst 16 out of 53 patients (30%) in the observation group received this combination; four out of 22 patients (18%) and six out of 53 patients (11%) in the len-dex and observation groups, respectively, were treated with chemotherapy; four patients (18%) in the experimental arm and 15 (28%) in the observation groups received an ASCT. Most patients responded to rescue therapies in both arms, resulting in overall response rates of 78% (17/22) and 86% (45/53) in the experimental and control arm, respectively. We compared survival from start of subsequent therapy in the patients population who progressed to active disease; the outcome was similar in both arms: at 6 years, 62% (16/22) of the patients in the len-dex arm remain alive and 49% (31/53) in the observation arm (P=0.50; Fig. 2C). The survival benefit observed was independent of the classification model used for defining high risk SMM ( Mayo Clinic and Spanish model)Conclusion: This long term follow-up analysis confirms that early treatment with lenalidomide-dexamethasone for high-risk SMM translates into a significant benefit in TTP but also in a sustained significant prolongation of the OS. The early exposure to lenalidomide-dexamethasone does not induce more resistant relapses. [Display omitted] DisclosuresMateos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Amgen: Honoraria. De La Rubia:Amgen, Bristol Myers, Celgene, Janssen: Consultancy. Paiva:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Takeda: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; EngMab: Research Funding; Amgen: Honoraria; Binding Site: Research Funding. Oriol:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract P3-07-09: Quantitative p95HER2 protein expression is predictive of trastuzumab response in HER2-positive metastatic breast cancer

Abstract Background: Expression of p95HER2 (p95), a truncated form of the HER2 receptor that lacks the trastuzumab binding site but retains kinase activity, has been reported as a prognostic biomarker for poor outcome in trastuzumab-treated HER2-positive metastatic breast cancer (MBC). However, the ability of p95 to predict trastuzumab benefit has not been demonstrated due to the difficulty in obtaining the appropriate control group, namely HER2+ MBC patients not treated with trastuzumab. In the current study, the predictive value of p95 expression was tested in a cohort comprised of HER2-positive MBC patients treated before the availability of trastuzumab and trastuzumab-treated HER2-positive MBC patients. Methods: The current cohort was derived from 206 HER2-positive MBC patients in the Munich Cancer Registry with a median follow up of 64 months. Cases were divided between those that received trastuzumab (n=115) and those that were treated before the availability of trastuzumab (n=91). Quantitative p95 protein expression was measured in formalin-fixed paraffin-embedded samples using the p95 VeraTag® assay (Monogram Biosciences), which is specific for the active M611 form of p95. Quantitative total HER2 protein expression was measured using the HERmark® assay (Monogram Biosciences). p95 and HERmark cutoffs were pre-specified (Duchnowska, Clin Cancer Res, 20:2805, 2014 and Huang, Am J Clin Pathol, 134:303, 2010). Analyses with p95 were restricted to samples with confirmed HER2 overexpression by HERmark. All hazard ratios (HR) were stratified by estrogen receptor status and grade. Results: Consistent with previous training (Sperinde, Clin Cancer Res, 16:4226, 2010) and validation (Duchnowska, Clin Cancer Res, 20:2805, 2014) datasets, subjects treated with trastuzumab experienced a shorter time to progression (TTP) when p95 expression levels were above the cutoff versus below the cutoff (HR = 3.8, p = 0.019). However, only a trend was observed between p95 expression levels and overall survival (HR = 2.2, p = 0.20), possibly due to a lower frequency of events and relatively small sample size. The predictive value of p95 was assessed by determining the benefit of adding trastuzumab to chemotherapy treatment in subsets below and above the p95 cutoff. As expected, patients with p95 below the cutoff experienced significant benefit in TTP from adding trastuzumab (HR = 0.13, p&amp;lt;0.001), whereas patients with p95 above the cutoff experienced less benefit (HR = 0.70, p=0.47). p95 expression level was predictive of trastuzumab response with an interaction p-value of 0.015. The results for OS were similar, however trastuzumab benefit was less distinct between the two groups (interaction p = 0.18); HR = 0.23, p = 0.0013 below the p95 cutoff versus HR = 0.50, p = 0.14 above the p95 cutoff. Conclusions: In this dataset, quantitative p95 expression was predictive of trastuzumab treatment benefit in MBC. Patients with high p95 expression may be particularly good candidates for dual HER2 blockade, as reported in the NeoALTTO trial (Scaltriti, Clin Cancer Res, 21:569, 2015), or other additional therapies. Citation Format: Sperinde J, Bachmeier B, Weidler JM, Lie Y, Chenna A, Winslow J, Engel J, Schubert-Fritschle G, Sommerhoff C, Petropoulos C, Bates M, Huang W, Nerlich A. Quantitative p95HER2 protein expression is predictive of trastuzumab response in HER2-positive metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-09.

Safety and Efficacy of Maintenance Therapy With a Nonspecific Cytochrome P17 Inhibitor (CYP17i) After Response/Stabilization to Docetaxel in Metastatic Castration-Resistant Prostate Cancer

BackgroundFrontline treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6 to 8 months. Ketoconazole, a nonspecific cytochrome P17 inhibitor (CYP17i), blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg three times daily [t.d.s]) has shown activity in mCRPC after progression to androgen deprivation. The role of a CYP17i after docetaxel treatment in the maintenance setting has been unexplored. MethodsWe identified 38 patients with mCRPC who showed progression to luteinizing hormone releasing–hormone agonists (LHRHa) and who were treated with a median of 7 cycles of frontline three-weekly docetaxel (75 mg/m2) plus prednisone (10 mg/d) and LHRHa. Medical charts of 20 patients who showed no progression to docetaxel were reviewed. After the last docetaxel cycle, 10 patients received LDK maintenance treatment plus prednisone (10 mg/d) and LHRHa, whereas 10 patients received LHRHa alone. TTP was the primary endpoint. ResultsAfter a follow-up of 27 months, disease in all patients receiving LHRHa alone progressed, whereas 8/10 patients progressed to maintenance therapy. Median TTP from docetaxel initiation was 11.5 months (95% confidence interval [CI], 6.3-16.6) for maintenance therapy and 9.2 months (95% CI, 8.5-9.9) for LHRHa alone (P = .047). The maintenance treatment was well tolerated. Only 1 patient experienced a grade 4 adverse event due to a nonsymptomatic pulmonary embolism. ConclusionThis is the first study evaluating a CYP17i for maintenance therapy after docetaxel therapy. We showed a 2-month significant benefit in TTP for patients with mCRPC treated with LDK maintenance therapy after docetaxel, with a favorable toxicity profile. A large prospective randomized study using a CYP17i is warranted.

Abstract P5-16-01: Survival advantage in patients with metastatic breast cancer receiving endocrine therapy plus Sialyl Tn-KLH vaccine: post hoc analysis of a large randomized trial

Abstract Background: A multicenter, double blinded, randomized phase III trial of the therapeutic cancer vaccine STn-KLH was completed in an international cohort of 1,028 women with metastatic breast cancer who had either no evidence of disease or nonprogressive disease following first-line chemotherapy. This trial is registered with ClinicalTrials.gov (No. NCT00003638). The outcomes showed that STn-KLH was safe and relatively well tolerated but had neither a positive nor negative effect on time to progression (TTP) or overall survival (OS) duration in the intent-to-treat population when compared with KLH control alone. The purpose of this post hoc analysis is to explore the potential benefit of combining an antiestrogen with MUC1 vaccines in metastatic breast cancer patients. Methods: The data were further explored to determine if a retrospective, reassigned endocrine subset patient stratification produces subgroups that may have experienced benefit in TTP or survival compared with the phase III trial ITT analysis. Results: Women treated with concomitant endocrine therapy, a pre stratified subset comprising approximately one third of the original study population, achieved a clinical benefit both in terms of TTP and survival compared with women who did not receive endocrine therapy. Moreover, women in the endocrine-treatment subset who mounted a median or greater antibody response (titer &amp;gt;1:320 toward bovine submaxillary mucin) to the STn-KLH vaccine experienced significantly longer median survival than their trial counterparts who mounted a below-median antibody response. Conclusion: Unlike maintenance chemotherapy, with its associated cumulative toxicity, the combination of endocrine and STn-KLH therapy may offer clinical benefit with few adverse effects for women with metastatic breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-16-01.

927P - Time to Progression and Safety Results of a Nonspecific Cytochrome-P 17 Inhibitor after Response/Stabilization to Docetaxel as a Maintenance Strategy in Metastatic Castratation-Resistant Prostate Cancer

ABSTRACT Background The first-line treatment of metastatic castration-resistant prostate cancer (mCRPC) consists of docetaxel-based chemotherapy. The median time to progression (TTP) from chemotherapy initiation is 6-8 months (mo). Ketoconazole is a nonspecific cytochrome-P 17 inhibitor (CYP17i) that blocks adrenal androgen synthesis. Low-dose ketoconazole (LDK), (200 mg, t.d.s) has shown interesting activity in mCRPC after progression to androgen deprivation. The role of a CYP17i in the maintenance setting after response/stabilization to docetaxel has never been studied. Methods Thirty-eight mCRPC patients showing progression to luteinizing-hormone releasing hormone agonists (LHRHa), maintained LHRHa and received a median of 7 cycles of front-line three-weekly docetaxel (75 mg/m2) plus daily prednisone (10 mg). Twenty out of the thirty-eight patients showing no progression to docetaxel were enrolled. After docetaxel, ten patients were assigned to LDK maintenance treatment plus prednisone (10 mg/day) and LHRHa, and ten patients received LHRHa alone. TTP was the primary endpoint. Results After 33 months follow-up, a median TTP from docetaxel initiation was 11.5 months (IC95%: 6.3-16.6) for maintenance therapy and 9.2 months (IC95%: 8.5-9.9) for the control arm p = 0.047). Maintenance treatment was well tolerated with only one patient experiencing a grade 4 adverse event (non-symptomatic pulmonary embolism). Grade 1 and 2 asthenia and hot flashes worsening were the most common toxicities (table). Conclusions This is the first study testing a CYP17i for maintenance therapy after response/stabilization to docetaxel. A more than 2 months significant benefit in TTP with a favorable toxicity profile is observed. A further prospective analysis in a larger series using a CYP17i is warranted. Toxicity profile of maintenance therapy with a CYP17 inhibitor. Grade Toxicity 1 2 3 4 5 Asthenia 3 2 - - - Diarrhea 1 1 - - - Hepatotoxicity 1 1 - - - Hyporexia - 1 - - - Cephalea 1 - - - - Hot flashes 1 4 - - - Fluid Retention 1 2 - - - Pulmonary embolism - - - 1 - Disclosure All authors have declared no conflicts of interest.

Phase III Multicenter Clinical Trial of the Sialyl-TN (STn)-Keyhole Limpet Hemocyanin (KLH) Vaccine for Metastatic Breast Cancer

This double-blind, randomized, phase III clinical trial evaluated time to progression (TTP) and overall survival in women with metastatic breast cancer (MBC) who received sialyl-TN (STn) keyhole limpet hemocyanin (KLH) vaccine. Secondary endpoints included vaccine safety and immune response. The study population consisted of 1,028 women with MBC across 126 centers who had previously received chemotherapy and had had either a complete or a partial response or no disease progression. All women received one-time i.v. cyclophosphamide (300 mg/m(2)) 3 days before s.c. injection of 100 μg STn-KLH plus adjuvant (treatment group) or 100 μg KLH plus adjuvant (control group) at weeks 0, 2, 5, and 9. Subsequently, STn-KLH without adjuvant or KLH without adjuvant was then administered monthly for 4 months, and then quarterly until disease progression, without cyclophosphamide. STn-KLH vaccine was well tolerated; patients had mild to moderate injection-site reactions and reversible flu-like symptoms. Week-12 antibody testing revealed high specific IgG titers and a high rate of IgM-to-IgG seroconversion; the median IgG titers in STn-KLH recipients were 320 (anti-ovine submaxillary mucin) and 20,480 (anti-STn), with no detectable antimucin antibodies in the control group. The TTP was 3.4 months in the treatment group and 3.0 months in the control group. The median survival times were 23.1 months and 22.3 months, respectively. Although STn-KLH was well tolerated in this largest to date metastatic breast cancer vaccine trial, no overall benefit in TTP or survival was observed. Lessons were learned for future vaccine study designs.

The Effect of Bone Marrow Involvement on the Efficacy of Pegylated Liposomal Doxorubicin + Bortezomib Vs Bortezomib Alone in Patients with Relapsed/Refractory Multiple Myeloma

Background: Patients with relapsed/refractory multiple myeloma (RRMM) often have a large tumor burden with significant bone marrow involvement, conferring a poor prognostic feature. Those patients with significant bone marrow involvement may benefit from combination regimens with increased activity. Orlowski et al. reported a phase III randomized trial with pegylated liposomal doxorubicin (PLD) + bortezomib (B) vs. B alone in RRMM, which demonstrated improved time to progression (TTP) with the combination of PLD+B. (Orlowski, JCO 2007) We investigated the effect of bone marrow involvement on overall response rates and time to progression (TTP) of PLD+ B versus B alone in patients with RRMM.Methods: Eligible patients were randomized to bolus IV B 1.3 mg/m2 on days 1, 4, 8, and 11 of each 3-week cycle (n=322) or to the same B regimen plus IV PLD 30 mg/m2 on day 4 (n=324) of each cycle. The subsets of patients with bone marrow involvement and those with >30% involvement were analyzed retrospectively.Results: A total of 379 patients had bone marrow involvement and 349 patients had >30% bone marrow involvement compared with 259 with no bone marrow involvement. Time to disease progression (TTP) and complete response (CR) + partial response (PR) rates for PLD+B vs B alone in patients with or without any bone marrow involvement or >30% bone marrow involvement are listed in the table.PLD+BBP valuebHazard RatiocNo bone marrow involvement, N132127TTP, Median days (95% CI)a251 (212, 282)198 (162, 227)0.01341.69 (1.11, 2.57)Total CR+PR, n/evaluable (%)49/118 (42)43/124 (35)0.2887dAny bone marrow involvement, N188191TTP311 (264, 354)197 (169, 222).00011.91 (1.37, 2.67)Total CR+PR94/183 (51)88/182 (48).5187d>30% bone marrow involvement, N172177TTP276 (221, 415)183 (158, 211).00051.83 (1.30, 2.58)Total CR+PR82/168 (49)69/170 (41).1446da. Based on Kaplan-Meier product-limit estimates.b. Based on stratified Log-rank test.c. A hazard ratio >1 indicates an advantage for PLD+B.d. Cochran-Mantel-Haenszel test controlling for Beta2 microglobulin and response to initial treatment.Regardless of bone marrow involvement or extent of bone marrow involvement, there was a statistically significant benefit in TTP for PLD+B vs. B alone. Safety profiles for the 2 regimens in the subsets of patients with or without bone marrow involvement were consistent with the known toxicities of the 2 agents.Conclusions: These data suggest that the combination of PLD+B is an active salvage therapy and superior to B alone in patients with RRMM, regardless of the presence or extent of bone marrow involvement. Patients with significant bone marrow involvement and associated poor risk due to increased tumor burden may benefit from the addition of PLD.

New aromatase inhibitors (Ais) as 1st-line endocrine therapy (ET) in metastatic breast cancer (MBC): A pooled analysis of 3238 women from 8 phase III trials

602 Background: Some of the new non-steroidal AIs (anastrozole and letrozole) have been registred for the treatment of first line ET for MBC. We previously presented the results of a pooled analysis of AIs in 2nd line ET for MBC (Carlini P, ASCO 2004). In order to assess the benefit in TTP and ORR of all AIs when compared to tamoxifen, we performed a pooled analysis including all phase-III trials with new AIs (letrozole, anastrozole, fadrazole, formestane, exemestane) as 1st-line ET for MBC. Methods: Entry criteria: published/presented phase-III studies evaluating AIs as 1st-line ET in MBC. Randomized phase-II trials were ruled out. Time to progression (TTP) and overall response rate (ORR) were our end-points. Event-based relative risk ratio (RR) and 95% confidence intervals (CI) were derived. Combined effect estimation was computed with a fixed-effect model. An heterogeneity test was applied as well. Results: Eight trials were eligible (3238 pts). Significant benefit in favour of AIs versus tamoxifen were seen in TTP (RR 0.83, 95% CI 0.76–0.90, p<0.001), although significant heterogeneity (p<0.00001). When considering only trials with non-steroidal AIs (6 studies, 2458 pts), a significant benefit in favour of AIs versus tamoxifen were seen in TTP (RR 0.80, 95% CI 0.73–0.89, p<0.001), although significant heterogeneity (p<0.0001). Significant benefit in favour of AIs versus tamoxifen were seen in ORR (RR 1.18, 95% CI 1.06–1.31, p=0.002), although significant heterogeneity (p<0.011). When considering only trials with non-steroidal AIs (6 studies, 2458 pts), a significant benefit in favour of AIs versus tamoxifen were seen in ORR (RR 1.19, 95% CI 1.06–1.36, p=0.005), although significant heterogeneity (p=0.04). Conclusions: When all subgroups were analyzed for TTP and ORR, significant differences were found. AIs in 1st-line ET for MBC seem to add a significant benefit versus tamoxifen. The significant heterogeneity of all outcomes requires a careful evaluation of these results No significant financial relationships to disclose.

Bortezomib vs. dexamethasone in relapsed multiple myeloma: A phase 3 randomized study

6511 Background: Bortezomib (Velcade, Millennium Pharmaceuticals), a novel proteasome inhibitor, is effective in refractory multiple myeloma (MM). For the APEX Study Group we present the interim results of an international, randomized phase 3 study conducted at 95 sites. Methods: Between June 2002 and Oct 2003 669 patients (pt) with relapsed MM previously treated with 1–3 prior therapies were randomized to bortezomib (Vc) (327 pts) 1.3 mg/m2 IV days 1,4,8,11 q 3 weeks for 8 cycles followed by 1.3 mg/m2 IV days 1,8,15,22 q 5weeks for 3 cycles versus dexamethasone (D) (330 pts) 40 mg po days 1–4, 9–12, 17–20 q 5 weeks for 4 cycles followed by 40mg po days 1–4 every 28 days for 3 cycles. The primary endpoint was time to progression (TTP) using EBMT criteria for progressive disease (PD). Secondary endpoints were overall survival (OS), incidence of ≥grade 3 infection and time to skeletal event (TSE). Pt progressing on D were offered Vc on a companion study. Results: Median age was 62 with no apparent differences in baseline characteristics. At the interim analysis (IA) 254 PD events had occurred. Pt receiving Vc demonstrated a highly significant benefit in TTP. Median TTP was 5.7 months (95% CI: 5.0, 7.9) on Vc and 3.6 months (95% CI: 3.2, 4.8) on D (p<0.0001, log-rank test). Overall survival was longer on Vc (p=0.038, log-rank test), with 13 deaths on Vc and 24 on D, but median survival was not reached on either arm. A trend towards a lower incidence of ≥grade 3 infections was also noted with 22 (6.7%) on Vc vs 35 (10.6%) on D (p=0.096, Fisher's exact test). No difference was noted in TSE (p=0.954, log-rank test). No other major safety differences were noted. Following the interim analysis, the Data Monitoring Committee recommended that treatment on the D arm be halted, and patients randomized to D were allowed to receive Vc. Conclusions: At the IA bortezomib was significantly more effective than dexamethasone for patients with relapsed MM. Further evaluation of survival, response duration, response rate, and safety are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals Speaker's Bureau Millennium Pharmaceuticals Millennium Pharmaceuticals Millennium Pharmaceuticals Millennium Pharmaceuticals

Bortezomib vs. dexamethasone in relapsed multiple myeloma: A phase 3 randomized study

6511 Background: Bortezomib (Velcade, Millennium Pharmaceuticals), a novel proteasome inhibitor, is effective in refractory multiple myeloma (MM). For the APEX Study Group we present the interim results of an international, randomized phase 3 study conducted at 95 sites. Methods: Between June 2002 and Oct 2003 669 patients (pt) with relapsed MM previously treated with 1–3 prior therapies were randomized to bortezomib (Vc) (327 pts) 1.3 mg/m2 IV days 1,4,8,11 q 3 weeks for 8 cycles followed by 1.3 mg/m2 IV days 1,8,15,22 q 5weeks for 3 cycles versus dexamethasone (D) (330 pts) 40 mg po days 1–4, 9–12, 17–20 q 5 weeks for 4 cycles followed by 40mg po days 1–4 every 28 days for 3 cycles. The primary endpoint was time to progression (TTP) using EBMT criteria for progressive disease (PD). Secondary endpoints were overall survival (OS), incidence of ≥grade 3 infection and time to skeletal event (TSE). Pt progressing on D were offered Vc on a companion study. Results: Median age was 62 with no apparent differences in baseline characteristics. At the interim analysis (IA) 254 PD events had occurred. Pt receiving Vc demonstrated a highly significant benefit in TTP. Median TTP was 5.7 months (95% CI: 5.0, 7.9) on Vc and 3.6 months (95% CI: 3.2, 4.8) on D (p<0.0001, log-rank test). Overall survival was longer on Vc (p=0.038, log-rank test), with 13 deaths on Vc and 24 on D, but median survival was not reached on either arm. A trend towards a lower incidence of ≥grade 3 infections was also noted with 22 (6.7%) on Vc vs 35 (10.6%) on D (p=0.096, Fisher's exact test). No difference was noted in TSE (p=0.954, log-rank test). No other major safety differences were noted. Following the interim analysis, the Data Monitoring Committee recommended that treatment on the D arm be halted, and patients randomized to D were allowed to receive Vc. Conclusions: At the IA bortezomib was significantly more effective than dexamethasone for patients with relapsed MM. Further evaluation of survival, response duration, response rate, and safety are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Millennium Pharmaceuticals Speaker's Bureau Millennium Pharmaceuticals Millennium Pharmaceuticals Millennium Pharmaceuticals Millennium Pharmaceuticals

Weekly vinorelbine (VIN) vs weekly docetaxel (DOC) for metastatic breast cancer failing anthracyclines. Planned interim analysis of a randomized trial

744 Background: Optimal therapy is controversial for metastatic breast cancer no longer eligible for anthracyclines. VIN and DOC are known active regimens. Methods: Randomized patients (pts) received VIN 30 mg vs DOC 35 mg/m2 weekly x 6 for ≤ 4 cyles of 8 weeks duration. Upon progression, crossing of treatment arms (CTA) was offered. Primary endpoint is time to progression (TTP), others are survival (OS), response, toxicity, and quality of life (not reported here). Analysis at 120 of 240 pts accrued was planned for evaluation of trends. Results: Of 121 pts randomized from 11/98 til 07/03, 112 are currently evaluable, VIN (n=57) vs DOC (n=55). Common risk factors are well balanced. 65 CTA pts had VIN (n=31) or DOC (n=34) as 2nd therapy. Overall median follow-up is 230 days (5–1588). Before or without CTA, VIN pts had a median of 7 doses (1–28) for a TTP of 81 days (CI: 67–99), while DOC pts had a median of 11 doses (2–24) for a slightly longer TTP of 103 days (CI: 98–119), (p= 0.1178, log-rank-test). OS for initial VIN vs DOC was 253 (CI: 173–331) vs 288 days (CI: 231–424), (p= 0.1895, log-rank-test). One year survival was 31% for VIN (CI: 20–46%) vs 44% for DOC (CI: 30–60%). More VIN pts (42%) than DOC pts (18%) had disease progression as best response (p=0.00751, Fisher's exact test, double sided); other responses slightly favored initial DOC (not significant). After CTA, DOC produced more responses (35% vs 3%, p≤ 0.0014, Fisher's exact test, double sided), but again without significant benefit in terms of TTP and OS, respectively. Generally, VIN vs DOC resulted in more treatment delays (76% vs 46%), more leukopenia (61% vs 10%) or neutropenia (43% vs 7%) grade 3/4, but less mucositis/stomatitis (1% vs 8%)-(all p<0.05, Fisher's exact test, double sided). 2/5 VIN pts with severe adverse event (SAE) died of neutropenic sepsis, or pulmonary embolism, respectively. 1/10 DOC pts with SAE died of DIC and multiorgan failure. Conclusion: DOC was more efficient at response and less toxic than VIN, both before and after crossing of treatment arms, but so far with marginal or no benefit at TTP or OS. TTP benefit may become apparent once accrual is complete. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis

Weekly vinorelbine (VIN) vs weekly docetaxel (DOC) for metastatic breast cancer failing anthracyclines. Planned interim analysis of a randomized trial

744 Background: Optimal therapy is controversial for metastatic breast cancer no longer eligible for anthracyclines. VIN and DOC are known active regimens. Methods: Randomized patients (pts) received VIN 30 mg vs DOC 35 mg/m2 weekly x 6 for ≤ 4 cyles of 8 weeks duration. Upon progression, crossing of treatment arms (CTA) was offered. Primary endpoint is time to progression (TTP), others are survival (OS), response, toxicity, and quality of life (not reported here). Analysis at 120 of 240 pts accrued was planned for evaluation of trends. Results: Of 121 pts randomized from 11/98 til 07/03, 112 are currently evaluable, VIN (n=57) vs DOC (n=55). Common risk factors are well balanced. 65 CTA pts had VIN (n=31) or DOC (n=34) as 2nd therapy. Overall median follow-up is 230 days (5–1588). Before or without CTA, VIN pts had a median of 7 doses (1–28) for a TTP of 81 days (CI: 67–99), while DOC pts had a median of 11 doses (2–24) for a slightly longer TTP of 103 days (CI: 98–119), (p= 0.1178, log-rank-test). OS for initial VIN vs DOC was 253 (CI: 173–331) vs 288 days (CI: 231–424), (p= 0.1895, log-rank-test). One year survival was 31% for VIN (CI: 20–46%) vs 44% for DOC (CI: 30–60%). More VIN pts (42%) than DOC pts (18%) had disease progression as best response (p=0.00751, Fisher's exact test, double sided); other responses slightly favored initial DOC (not significant). After CTA, DOC produced more responses (35% vs 3%, p≤ 0.0014, Fisher's exact test, double sided), but again without significant benefit in terms of TTP and OS, respectively. Generally, VIN vs DOC resulted in more treatment delays (76% vs 46%), more leukopenia (61% vs 10%) or neutropenia (43% vs 7%) grade 3/4, but less mucositis/stomatitis (1% vs 8%)-(all p<0.05, Fisher's exact test, double sided). 2/5 VIN pts with severe adverse event (SAE) died of neutropenic sepsis, or pulmonary embolism, respectively. 1/10 DOC pts with SAE died of DIC and multiorgan failure. Conclusion: DOC was more efficient at response and less toxic than VIN, both before and after crossing of treatment arms, but so far with marginal or no benefit at TTP or OS. TTP benefit may become apparent once accrual is complete. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis Aventis