Months For Docetaxel Research Articles

Anlotinib plus docetaxel vs. docetaxel alone for advanced non-small-cell lung cancer patients who failed first-line treatment: A multicenter, randomized phase II trial

ObjectivesGiven the modest efficacy of docetaxel in advanced non-small cell lung cancer (NSCLC), this study assesses the therapeutic potential and safety profile of anlotinib in combination with docetaxel compared to docetaxel monotherapy as a second-line therapy for patients with advanced NSCLC. Materials and MethodsIn this phase II study, patients with advanced NSCLC experiencing failure with first-line platinum-based regimens were randomized in a 1:1 ratio to receive either anlotinib plus docetaxel or docetaxel alone. Primary endpoint was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety as secondary endpoints. ResultsA total of 83 patients were randomized. The combination of anlotinib and docetaxel significantly extended median PFS to 4.4 months compared to 1.6 months for docetaxel alone (hazard ratio [HR] = 0.38, 95 % confidence interval [CI]: 0.23–0.63, P = 0.0002), and also demonstrated superior ORR (32.5 % vs. 9.3 %, P = 0.0089) and DCR (87.5 % vs. 53.5 %, P = 0.0007). Median OS was observed at 12.0 months in the combination group vs. 10.9 months in the monotherapy group (HR = 0.82, 95 % CI: 0.47–1.43, P = 0.4803). For patients previously treated with immunotherapy, the median PFS was notably longer at 7.8 vs. 1.7 months (HR = 0.22, 95 % CI: 0.09–0.51, P = 0.0290). The incidence of grade ≥ 3 treatment-related adverse events, predominantly leukopenia (15.0 % vs. 7.0 %) and neutropenia (10.0 % vs. 5.0 %), was manageable across both groups. ConclusionAnlotinib plus docetaxel offers a viable therapeutic alternative for patients with advanced NSCLC who failed first-line platinum-based treatments.

An analysis to inform the timing of docetaxel use leveraging data from the United States Veterans Administration on patients with metastatic castration-sensitive prostate cancer (mCSPC).

5085 Background: Every oncologist caring for patients(pts) with a diagnosis of mCSPC at some point finds themselves deciding whether to use docetaxel (DOCE) in 1st line or later, a difficult selection often based on perceived tolerability. In1st line mCSPC, both novel hormonal therapies (NHTs) and DOCE have been shown effective, with direct comparisons lacking. We conducted the present analysis to help address this issue. Methods: All pts with mCSPC diagnosis in the VA Corporate Data Warehouse (CDW) who received either DOCE or NHT (abiraterone or enzalutamide) in the mCSPC setting and the converse after disease progression to castrate-resistant prostate cancer (mCRPC) were eligible for comparison. The cohort date range was from 7/2015 to 6/2022. We then created two arms — DOCE 1st and DOCE later — matched 1:1 exactly for age, race, total lines of therapy received, PSA at diagnosis, Gleason score (GS), Charlson comorbidity index (CI) excluding cancer diagnosis, and rurality. Results: 580 pts met study eligibility, with two 147 patient cohorts identified for matched analysis. Median age was 69 (64-73) and 70 (65-73) for the DOCE 1st and DOCE later cohorts, respectively. In both cohorts, 66%/31% were white/black. Starting PSA was <20/≥20 in 36%/64%. 60% had GS≥8. CI was <5/≥5 in 80%/20%. 2/≥3 total lines of therapy had been given to 32%/68%. Urban/rural distribution was 74%/26%. Median follow up of 30.2/23.7 months for DOCE 1st/DOCE later, reflects DOCE approval in mCSPC two years before approval of NHTs. Median OS were 37.9/31.6 months for DOCE 1st/DOCE later, [HR 0.65 (0.48-0.89), p=0.012], with HRs when comparing those from each cohort with GS≥8 or with starting PSA≥20, of 0.7 (0.47-1.05), p=0.018 for GS≥8, and 0.48 (0.32-0.73) p=0.001 for starting PSA≥20, both in favor of DOCE 1st. Duration of abiraterone treatment was greater in DOCE later with values of 284 (160-460) and 153 (90-286) days, p<0.0001 for DOCE later and DOCE 1st, respectively. Durations of DOCE treatment was statistically insignificant between cohorts at 135 (94-141) and 93 (51-177) days, p=0.35 for DOCE 1st and DOCE later, respectively. Surprisingly, time to mCRPC, defined as time from diagnosis to 1st mCRPC therapy, was longer but not statistically significant for DOCE later than for DOCE 1st, with durations of 23.7 and 20.3 months, respectively, p=0.23. Conclusions: Our data in US Veterans suggest the strategy of using DOCE upfront in those with mCSPC followed by a NHT on progression results in superior OS compared with DOCE later in mCRPC, especially in men with PSA≥20 as a surrogate for high volume disease. Concordant with data from CHAARTED and STAMPEDE arm C where single agent ADT was the reference and ADT + DOCE emerged as the SOC for high volume or high-risk disease, the 6.3-month survival difference between strategies in this analysis argues for consideration of a prospective comparative study.

Management of de novo metastatic hormone-sensitive prostate cancer: A comprehensive report of a single-center experience.

Upfront docetaxel or novel hormonal agents (NHA) such as abiraterone and enzalutamide have become the standard of care for metastatic hormone sensitive prostate cancer (mHSPC). We evaluated real-world management of patients treated with these agents at a single center. Patients with de novo mHSPC treated with upfront docetaxel or an NHA between January 2014 and April 2019 at Mount Sinai Health System were included. We evaluated time to next treatment (TTNT), PSA progression free survival (PFS) and overall survival (OS) after initial treatment with these drugs. Kaplan Meier method and multivariable Cox proportional hazards models were used for analysis. We additionally assessed the prognostic value of post-treatment PSA. We identified 94 de novo mHSPC patients; 52 and 42 treated with upfront docetaxel and NHAs, respectively. NHAs were associated with a median TTNT of 20.7 months compared to 10.1 months with docetaxel (log-rank p = 0.023). We also observed median PSA PFS of 19 months for NHAs and 13.2 months for docetaxel (p = 0.069). However, OS between the two treatment groups was unchanged. Among docetaxel treated patients, TTNT was shorter among those with high metastasis burden (9.63 vs 25.5 months, p = 0.026) which was not observed among NHA treated patients (25.1 vs 20.7 months, p = 0.79). Regardless of treatment, lower post-treatment PSA levels were associated with improved TTNT (58.95 vs. 11.57 vs. 9.4 months for PSA ≤0.2, 0.2-0.4, >0.4ng/ml, respectively; p<0.001). Real world data demonstrated a shorter duration of treatment with docetaxel than NHAs, reflecting the time-limited nature of docetaxel regimens compared to the treat-till-progression approach of NHAs. While TTNT was generally longer for NHAs than docetaxel, some docetaxel-treated patients achieved significant periods of time off treatment. In addition, the depth of PSA response following combination treatment may hold prognostic value for mHSPC outcomes.

Targeting resistant prostate cancer with ATR and PARP inhibition (TRAP trial): A phase II study.

TPS254 Background: Inhibition of poly(ADP-ribose) polymerase (PARP) shows promise in prostate cancer, but is limited to the ~20% of men with defects in genes encoding for DNA repair proteins BRCA1, BRCA2 or ATM (homologous recombination defect positive, HRD+). The effect is modest for HRD+ patients with a progression free survival of ~7 months. Pharmacologically simulating genetic DNA repair defects may expand who benefits to homologous recombination defect negative (HRD-) patients and improve HRD+ response. The ataxia telangiectasia and Rad3-related protein (ATR) is ideal with its roles in cell cycle regulation, replication fork resolution and both single and double strand break repair. Preclinical studies on HRD-/HRD+ cell lines support this. We hypothesize co-inhibition of ATR and PARP will respond regardless of HRD status. Methods: TRAP is a prospective, multi-institutional, phase 2 clinical trial testing AZD6738 combined with olaparib in HRD+ and HRD- mCRPC patients. Primary endpoint is the response rate (RR) by RECIST radiographic response or PSA decline ≥50% in 35 HRD- patients, with a secondary objective of RR in 12 HRD+ patients. HRD+ is mono/biallelic loss of ATM or biallelic loss of BRCA1/2. Tissue based sequencing is done unless completed prior in mCRPC, known BRCA germline loss, treating provider deems biopsy unsafe or biopsy fails. Those unable or failing biopsy are designated as HRD-, but BRCA1/2 and ATM are tested via circulating tumor DNA in a commercial test. Eligible patients must progress after ≥1 line of mCRPC therapy. Progression on a second generation anti-androgen (e.g. apalutamide), abiraterone or within 6 months of docetaxel in hormone sensitive disease are eligible. Treatment entails 160 mg PO daily of AZD6738 on days 1-7 and 300 mg PO BID of olaparib on days 1-28 of a 28-day cycle. Statistical analysis will provide RR with 95% binomial confidence intervals. Analysis of tumor specimens, circulating tumor cells and DNA will be performed for predictors of response and acquired resistance. The study is at four sites in the US, participates in the Prostate Cancer Clinical Trials Consortium, LLC, is managed by the University of Michigan and funded by AstraZeneca. Clinical trial information: NCT03787680.

P2.01-20 Anlotinib vs. Docetaxel in Advanced Non-Squamous NSCLC (EGFR Wild-Type) After Progression on Platinum-Based Chemotherapy: A Trial Protocol

Anlotinib, an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, showed significantly longer overall survival in a phase 3 trial. In the multi-center, open-label, randomized controlled ALTER-L023 trial, we compared anlotinib with docetaxel as second-line treatment in patients with advanced non-squamous EGFR wild-type non-small cell lung cancer (NSCLC) previously given platinum-based doublet chemotherapy. This multi-center, open-label, randomized controlled ALTER-L023 trial was conducted at 10 hospitals in China. Eligible patients with previously treated non-squamous EGFR wild-type NSCLC were randomly assigned (1:1) to receive anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or docetaxel (75mg/m2, on day 1 of a 21-day cycle) till progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), that was defined as the time from randomization to disease progression or death. The secondary endpoints included objective response rate, disease control rate, duration of response and safety. Based on a two-sided log-rank test at 5% significance level, a power of 80% and a median PFS of 6 months for anlotinib versus 3 months for docetaxel, the simple size was estimated at 77 patients. Allowing for 15% dropouts, the sample size was set at 88 patients (44 patients in both groups). Clinical trial information: NCT03703596 Section not applicable Section not applicable

An exploratory analysis of bone scan lesion area (BSLA), circulating tumor cell (CTC) change, pain reduction, and overall survival (OS) in patients (pts) with castration-resistant prostate cancer (CRPC) treated with cabozantinib (cabo): Updated results of a phase II nonrandomized expansion (NRE) cohort.

5026 Background: The results of 144 pts with metastatic CRPC treated in a phase II NRE cohort with daily cabo 100 mg and 40 mg starting doses have been previously reported. Substantial rates of bone scan improvement, reductions in CTC counts and pain relief were observed. To better understand the implication of these effects, the association with OS was explored. Methods: Relevant baseline variables (LDH, BSLA, visceral disease, pain, hemoglobin, CTCs) and post-treatment changes at week 6: ≥30% reduction in BSLA using computer-aided assessment, CTC conversion (&gt;5 vs. 4 or less/7.5 ml of blood), and pain intensity (7 day averaged worst pain score; BPI scale; using an IVR system) were associated with OS in 144 CRPC pts with bone metastasis who progressed within 6 months of docetaxel (D) treatment (≥225 mg/m2) in either bone or soft tissue. Median OS was compared between responders and non-responders for each of the above outcomes categories using a Cox proportional hazard model. The findings were examined further after adjusting for significant baseline covariates selected from a stepwise Cox regression model. Results: See Table. Conclusions: Recognizing the limitations of associating response with survival, this retrospective analysis of decreases in BSLA, CTC conversions and reductions in pain intensity support further study in ongoing phase III trials. Clinical trial information: NCT00940225. [Table: see text]

Nab-Paclitaxel for first-line treatment of patients with metastatic breast cancer and poor prognostic factors: a retrospective analysis

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) has demonstrated clinical benefit in metastatic breast cancer (MBC) in a randomized phase III trial versus paclitaxel (CA012; N = 454) and in a randomized phase II trial versus docetaxel (CA024; N = 300). This retrospective analysis examines whether patients with poor prognostic factors demonstrate similar outcomes to the intent-to-treat (ITT) populations in these trials. This retrospective analysis evaluated the efficacy and safety of previously untreated patients with MBC with the following poor prognostic factors: visceral dominant metastases and short disease-free interval (DFI; ≤2 years). In CA012 (n = 186 first-line patients), nab-paclitaxel demonstrated a significantly higher overall response rate (ORR) versus paclitaxel in patients with visceral dominant metastases (42 vs. 23 %; P = 0.022), whereas the higher ORR for nab-paclitaxel in patients with a short DFI (43 vs. 33 %; P = NS) was not statistically significant. In CA024, a significantly higher ORR for nab-paclitaxel 150 mg/m2 versus docetaxel was observed in patients with visceral dominant metastases (76 vs. 37 %; P < 0.001). No significant differences in ORR were observed in patients with a short DFI. Although progression-free survival (PFS) and overall survival showed trends similar to ORR, statistical significance was only achieved for comparisons of PFS in patients with visceral dominant metastases in CA024 (13.1 months for nab-paclitaxel 150 mg/m2 vs. 7.8 months for docetaxel [P = 0.019] and 7.5 months for nab-paclitaxel 100 mg/m2 [P = 0.010]). Safety results were similar to previous reports of the ITT populations. nab-Paclitaxel demonstrated similar efficacy in patients with poor prognostic factors as in the ITT populations of these two trials. In each trial, ORR was significantly higher for nab-paclitaxel versus the comparator taxane among patients with visceral dominant metastases.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-013-2447-8) contains supplementary material, which is available to authorized users.

Abstract P1-12-07: A Retrospective Analysis of nab-Paclitaxel as First-Line Therapy for Metastatic Breast Cancer Patients With Poor Prognostic Factors

Abstract Background: Solvent-based taxanes have demonstrated activity in metastatic breast cancer (MBC) patients with poor prognostic factors, an important subset of patients with aggressive disease who require special consideration in treatment optimization. nab-Paclitaxel has been compared with solvent-based (sb-) paclitaxel in a randomized phase III trial (CA012; N = 454) and docetaxel in a randomized phase II trial (CA024; N = 300) for the treatment of MBC, revealing a favorable clinical benefit for nab-paclitaxel in both intent-to-treat (ITT) populations. This retrospective analysis examines whether the safety and efficacy of nab-paclitaxel observed in these trials are maintained in patients with poor prognostic factors. Methods: This retrospective analysis evaluated safety and efficacy of the first-line treatment of patients with MBC with the poor prognostic factors of visceral dominant metastases (dominant metastatic lesion localized to visceral tissue [ie, not in bone or soft tissues]) and early disease recurrence (≤ 2 years after completing neoadjuvant or adjuvant treatment) in the CA012 and CA024 trials. Results: In CA012 (n = 186 first-line patients), nab-paclitaxel 260 mg/m2 every 3 weeks (q3w) demonstrated a higher overall response rate (ORR) vs sb-paclitaxel 175 mg/m2 q3w in patients with visceral dominant metastases (42% vs 23%, P = .022) and in patients with early disease recurrence (43% vs 33%, P = not significant [NS]). In CA024 (n = 300 first-line patients), significantly higher ORRs for nab-paclitaxel at 100 mg/m2 (63%, P = .002) and 150 mg/m2 (76%, P &amp;lt; .001) the first 3 of 4 weeks (qw 3/4) vs docetaxel 100 mg/m2 q3w (37%) were observed in patients with visceral dominant metastases. The difference in ORR in this subgroup between nab-paclitaxel 300 mg/m2 q3w (44%, P = NS) and docetaxel 100 mg/m2 q3w was not statistically different. As in CA012, the differences in ORR among patients with early disease recurrence in CA024 were not statistically significant (35% to 64% for the nab-paclitaxel arms vs 21% for the docetaxel 100 mg/m2 q3w arm, all P = NS). Progression-free survival (PFS) and overall survival (OS) showed trends similar to that of ORR in both trials. Statistical significance was only achieved for median PFS in CA024 among patients with visceral dominant metastases (13.1 months for nab-paclitaxel 150 mg/m2 qw 3/4 vs 7.5 months for nab-paclitaxel 100 mg/m2 qw 3/4 [P = .010] and vs 7.8 months for docetaxel 100 mg/m2 q3w [P = .019]). Safety results were similar to those of previous reports for the ITT populations; in CA024, the lowest rates of neutropenia, sensory neuropathy, and fatigue were observed with nab-paclitaxel 100 mg/m2 qw 3/4 in both patient subgroups. Conclusions: nab-Paclitaxel showed similar efficacy in patients with poor prognostic factors to that in the ITT populations of these 2 trials. In each trial, consistent trends in favor of nab-paclitaxel were observed for ORR, PFS, and OS vs a solvent-based taxane in the specified poor prognostic factor subgroups. No new safety signals were observed. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-12-07.

Metastatic NSCLC: Treatment patterns, outcomes, and costs of newer agents.

7606 Background: New therapies for metastatic NSCLC have improved survival in clinical trials. The increased cost of these agents has led to variable drug funding and treatment across jurisdictions. Here we review patterns, real-world outcomes and costs of metastatic NSCLC treatment in the province of Ontario. Methods: All patients diagnosed with metastatic NSCLC from 2005-2009 were identified from the Ontario Cancer Registry with demographic, histologic and mortality data. Treatment records from the Ontario New Drug Funding Program and centralized treatment database were linked. Statistical analysis involved Wilcoxon rank sum, Kruskal-Wallis, Cochran-Armitage trend and likelihood ratio tests where appropriate. Results: 8113 metastatic NSCLC patients were identified. The median age was 68; 39% had adenocarcinoma, 14% squamous carcinoma and 43% histology not otherwise specified. Most were treated in regional cancer centers (92%). The majority (76%) did not receive systemic therapy; 23% received first-line chemotherapy, most commonly platinum doublets. More patients received systemic therapy over time (19% in 2005 v 26% in 2009, p &lt;0.0001). Older patients (p &lt;0.0001) and those with squamous histology (p &lt;0.0001) were less likely to receive systemic therapy. Center of diagnosis did not affect the likelihood of treatment (p=0.46). The median time from diagnosis to death was significantly greater among patients selected to receive chemotherapy (9.3 v 3.2 months, p &lt;0.0001), and with cisplatin/gemcitabine compared to other doublets (10.7 v 8.2 months, p=0.004). 31% of treated patients received second-line chemotherapy, predominantly with docetaxel (52%) or pemetrexed (41%). Pemetrexed use increased significantly over time (8% in 2005 v 71% in 2009, p&lt;0.0001), as did the mean drug cost of second-line therapy ($5939/patient in 2005 v $10,057 in 2009). A longer median survival was also seen with pemetrexed in adenocarcinoma (17.9 v 15.2 months for docetaxel, p =0.02). Conclusions: Most metastatic NSCLC patients do not undergo systemic treatment. First- and second-line treatment outcomes in this population-based study were similar to clinical trials, confirming better outcomes with new agents at greater cost.

The Qualification of Docetaxel or Erlotinib for Second-Line Therapy Should Be Based on Clinical and Molecular Predictive Factors

Background: We evaluated the effectiveness of docetaxel or erlotinib in second-line treatment of non-small cell lung cancer (NSCLC) and focused on the impact of predictive factors on the outcome of therapy. Methods: 204 patients with progressive disease after platinum-based therapy were enrolled: 102 received an infusion of 75 mg/m² of docetaxel and 102 received 150 mg of erlotinib orally. Results: Response rate (RR) was 6.9 and 8.8% for docetaxel and erlotinib, respectively. Progression-free survival (PFS) was 1.2 months for docetaxel and 1.6 months for erlotinib (hazard ratio, HR = 1.2, p = 0.17). Overall survival was 5.5 versus 7 months for docetaxel and erlotinib, respectively (HR = 1.35, p = 0.06). Using Cox regression, we found clinical factors (performance status and weight loss) with predictive values for RR and PFS in second-line-treated patients. Prior radiotherapy, smoking status and EGFR mutation might help to predict outcome of erlotinib treatment and βIII-tubulin mRNA expression that of docetaxel, but histopathological diagnosis did not have any predictive value. Conclusions: Erlotinib and docetaxel show similar efficacy in the treatment of NSCLC. The application of predictive factors may facilitate qualification for second-line treatment with both drugs.

Cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC): Interim safety and quality-of-life (QOL) data from the U.K. early access program (NCT01254279).

44 Background: Cabazitaxel, a tubulin-binding taxane, improved survival in mCRPC in the TROPIC trial. Notable toxicities were neutropenia and diarrhoea. We report interim safety and QOL data from a single arm multicentre open label study providing early access to cabazitaxel in the UK. Methods: Patients recruited from 12 centres received cabazitaxel 25mg/m2 intravenously every 3 weeks and prednisolone 10mg daily. Safety assessments were performed before each cycle. Patients completed the EQ-5D questionnaire and health state visual analogue scale (VAS) at baseline and at alternate cycles. Patients recruited before March 31st 2011 are included in the safety analysis. QOL data collected before July 31st 2011 at baseline (n=62), cycle 2 (n=50) and cycle 4 (n=26) are included. Results: Median age was 68 years; 24% were aged over 75 years. 93% had bone metastases. 50% had experienced disease progression during or within 3 months of docetaxel and the remaining 50% within 3-6 months. A median of 3 cycles of cabazitaxel were completed with 99% relative dose intensity. 83% continued cabazitaxel at the time of safety analysis. 7 patients stopped before completing the full course, 5 of these were due to disease progression. One treatment related death occurred within 30 days of the last cabazitaxel infusion (2.4%). 85% of patients received granulocyte-colony stimulating factor prophylaxis from cycle 1. The proportion of patients reporting no pain or discomfort increased between baseline, cycle 2 and cycle 4 (22.6% to 38% to 50%). Anxiety and depression, mobility and self-care scores from EQ-5D were stable. Median VAS health state increased from baseline (75%) to cycle 4 (79%). Conclusions: Improvements in pain control and health states were reported during early stages of cabazitaxel treatment. Other EQ-5D QOL measures were stable. Severe toxicity was rare. Results will be updated from final analysis in late 2011. [Table: see text]

129 Cabazitaxel for metastatic castration resistant prostate cancer (mCRPC): Interim safety and quality of life (QOL) data from the UK early access programme

44 Background: Cabazitaxel, a tubulin-binding taxane, improved survival in mCRPC in the TROPIC trial. Notable toxicities were neutropenia and diarrhoea. We report interim safety and QOL data from a single arm multicentre open label study providing early access to cabazitaxel in the UK. Methods: Patients recruited from 12 centres received cabazitaxel 25mg/m2 intravenously every 3 weeks and prednisolone 10mg daily. Safety assessments were performed before each cycle. Patients completed the EQ-5D questionnaire and health state visual analogue scale (VAS) at baseline and at alternate cycles. Patients recruited before March 31st 2011 are included in the safety analysis. QOL data collected before July 31st 2011 at baseline (n=62), cycle 2 (n=50) and cycle 4 (n=26) are included. Results: Median age was 68 years; 24% were aged over 75 years. 93% had bone metastases. 50% had experienced disease progression during or within 3 months of docetaxel and the remaining 50% within 3-6 months. A median of 3 cycles of cabaz...

Double-Blind, Placebo-Controlled, Randomized Phase 2 Study of the Proapoptotic Agent AT-101 Plus Docetaxel, in Second-Line Non-small Cell Lung Cancer

AT-101 is an inhibitor of Bcl-2 family proteins including Bcl-2, Bcl-xL, Mcl-1, and Bcl-w. In vivo and in vitro studies have exhibited broad activity of AT-101, including synergy with docetaxel in non-small cell lung cancer tumor models. We conducted a prospective, randomized (1:1), double-blind, placebo-controlled phase 2 study. Eligible patients must have received one prior chemotherapeutic regimen for advanced or metastatic non-small cell lung cancer and may also have received therapy with an epidermal growth factor receptor inhibitor. Patients received AT-101 (40 mg b.i.d. × 3 days) or placebo in combination with docetaxel (75 mg/m on day 1) every 21 days. The primary endpoint was progression-free survival (PFS) as determined by independent review; other endpoints include overall survival and PFS by investigator determination. Approximately 102 patients were planned to provide 70 events (80% power, hazard ratio [HR] of 0.6, one-sided alpha of 0.1). : One hundred six patients were assigned to treatment and 105 patients received at least one dose of AT-101 or placebo. Baseline factors were balanced between treatment groups: median age 59 years; 77% men, and 79% current or former smokers. Ninety-three percent of patients had distant metastatic disease at randomization and 56% squamous histology. The most frequently reported adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). No statistically significant differences in serious adverse events were observed between AT-101 and placebo; grade 1/2 headaches appeared more frequently with AT-101 (9% versus 0%) and neutropenia was reported more frequently in the docetaxel plus placebo arm compared with docetaxel plus AT-101 (17% versus 8%). Unlike trials with continuous daily dosing of AT-101, no cases of small bowel obstruction were reported. The response rate and median PFS were not different between the arms by independent review, PFS 7.5 weeks for docetaxel plus AT-101 and 7.1 weeks for docetaxel plus placebo arms (HR, 1.04; p = 0.57). The median overall survival was 7.8 months for docetaxel plus AT-101 versus 5.9 months for docetaxel plus placebo (HR, 0.82; p = 0.21). The primary endpoint of improved PFS for AT-101 plus docetaxel was not met. AT-101 plus docetaxel was well tolerated with an adverse event profile indistinguishable from the base docetaxel regimen. AT-101 is the first oral, pan Bcl-2 family inhibitor to exhibit a possible survival benefit in a randomized study.

Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Time to Step Out of the Limelight

Chemotherapy Agents in Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer: Time to Step Out of the Limelight

Poxviral-Based Prostate-Specific Antigen Vaccine in Prostate Cancer

TO THE EDITOR: In the March 1, 2010, issue of Journal of Clinical Oncology, Kantoff et al reported the results of a phase II randomized trial of a poxviral-based prostate-specific antigen vaccine (PROSTVAC) in metastatic castration-resistant prostate cancer. Eighty-two patients received PROSTVAC and 40 received control vectors. The primary end point was progression-free survival, which was similar in both groups (hazard ratio, 0.884; 95% CI, 0.568 to 1.375; P .6), but overall survival (OS) favored PROSTVAC arm (25.1 v 16.6 months). The authors conclude that PROSTVAC immunotherapy is associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS. Although these data merit further exploration, we have concerns about whether both study arms are comparable. First, the difference in median age (71.6 v 79 years), percentage of lymph node involvement only (9.8% v 0%), and median survival estimated by Halabi nomogram may favor the PROSTVAC arm. Second, as Kantoff et al point out, the lack of treatment data after initial progression limits the interpretation of the survival result. PROSTVAC plus subsequent treatment improved in 3 months the survival predicted by Halabi. In the control arm, OS is reduced by 4 months as estimated by the Halabi nomogram. Half of the patients in the control arm received PROSTVAC as second-line treatment. An interesting question is whether a higher percentage of patients in the PROSTVAC arm received second-line docetaxel, obtaining a benefit in survival. Third, Kantoff et al mentioned that only docetaxel has been shown to affect survival in metastatic prostate cancer, by approximately 3 months. In the TAX 327 study, an OS of 19.2 months was reported in the every-3-weeks docetaxel arm. Nevertheless, patients included in the TAX 327 had an disfavorable prognosis when compared with the PROSTVAC study. Patients in TAX 327 were more symptomatic with a higher median prostate-specific antigen, Eastern Cooperative Oncology Group performance status of 2 was permitted, and 30% of patients had a Gleason score of 8 to 10. In a retrospective subanalysis of 110 minimally symptomatic patients, Berthold et al reported an OS of 28.4, 25.9, and 22 months for docetaxel every 3 weeks, docetaxel every week, or mitoxantrone, respectively. These differences did not reach statistical significance as a result of the small number of patients, and the results should be interpreted with caution. These data suggest than docetaxel should offer similar results to PROSTVAC in this population and should be the control arm in a phase III study. We agree with Kantoff et al that their findings are regarded as hypothesis generating, but OS data should be interpreted with caution in the absence of treatment information after progression to PROSTVAC or placebo.

Future role of bevacizumab in breast cancer

In the past years, anti-angiogenic therapies have rapidly developed for many solid tumors, including breast cancer. The first phase III trial of bevacizumab in combination with capecitabine versus capecitabine alone was conducted in 462 patients with MBC previously treated with antracycline or taxane: although the addition of bevacizumab did not improve PFS, there was an absolute increase of approximately 11% in ORR (20 vs 9%; P = 0.001) [1]. In the E2100 trial the addition of bevacizumab to first-line weekly paclitaxel resulted in doubling of both the objective RR (36.9 vs 21.2%; P < 0.0001) and median PFS (11.8 vs 5.9 months; P < 0.0001), compared with paclitaxel alone in more than 700 HER2-negative MBC patients, although there was no impact on OS [2]. These findings were corroborated by more complete analyses for regulatory purpose and confirmed by IRF. The AVADO phase III trial compared bevacizumab with placebo in combination with docetaxel as first-line chemotherapy for patients with HER2-negative locally recurrent breast cancer or MBC, showing a significant improvement in PFS (8.8 months for bevacizumab 15 mg/kg vs 8 months for docetaxel; P < 0.0001) [3]. These results have led to the development of multiple phase III trials of bevacizumab in combination with chemotherapy agents in first-line MBC, along with trials investigating the addition of bevacizumab to other anticancer therapies such as trastuzumab and endocrine agents. To date no predictive biomarkers for benefit from bevacizumab have been identified; several ongoing trials incorporate molecular studies with the aim of targeting the correct subset of patients (such as triple-negative patients) for bevacizumab therapy. Clinical trials are underway to evaluate the use of bevacizumab in the adjuvant and neoadjuvant setting. The BEATRICE phase III trial will assess the benefit of adding bevacizumab to standard adjuvant chemotherapy (anthracycline ± taxane or taxane only) in triple-negative early breast cancer. The addition of bevacizumab to adjuvant chemotherapy (docetaxel/carboplatin or docetaxel–FEC) and trastuzumab will be studied in a further phase III trial (BETH) in patients with HER2-positive breast cancer. Other phase III adjuvant trials are evaluating the addition of bevacizumab to standard chemotherapy in HER2-negative and in node-positive or high-risk breast cancer. The NSABP B-40 ongoing phase III trial will evaluate the addition of bevacizumab to either neoadjuvant docetaxel, docetaxel plus capecita-bine or docetaxel plus gemcitabine followed by doxorubicin plus cyclophosphamide in patients with operable breast cancer. The phase III GeparQuinto trial will evaluate the integration of bevacizumab, everolimus and lapatinib into current neoadjuvant regimens [4]. Bevacizumab will probably have an established role in the treatment of some subgroups of MBC and as adjuvant therapy in early breast cancer; we need to identify which subgroups of patients may specifically benefit from bevacizumab therapy.

Survival and PSA response of patients in the TAX 327 study who crossed over to receive docetaxel after mitoxantrone or vice versa

BackgroundThe TAX 327 study compared 3-weekly docetaxel, weekly docetaxel or 3-weekly mitoxantrone, each with prednisone, for 1006 patients with metastatic hormone-refractory prostate cancer. Survival and symptom control were superior following 3-weekly docetaxel as compared with mitoxantrone. At progression, many patients were treated with the other drug. Here, we provide a retrospective report of survival and prostate-specific antigen (PSA) response after second-line therapy. MethodsThe TAX 327 database provided information about treatment after progression on first-line therapy, and survival has been updated. Investigators were asked to provide information about crossover treatment and serial PSA values. ResultsWe identified 232 crossover patients. Median survival after crossover was 10 months and did not depend on direction of crossover. Data on PSA response are available for 96 patients: PSA response (≥50% reduction) occurred in 15% of 71 men receiving mitoxantrone after docetaxel and in 28% of 25 men receiving docetaxel after mitoxantrone. Median PSA progression-free survival was 3.4 months for mitoxantrone after docetaxel and 5.9 months for docetaxel after mitoxantrone. ConclusionsOne quarter of men received crossover therapy and survival was similar in the crossover groups. The PSA response rate to docetaxel after mitoxantrone was higher than that for mitoxantrone after docetaxel.

Long-term outcome of patients treated with docetaxel for hormone-dependent prostate-specific antigen (PSA) progression after local therapy for prostate cancer

16030 Background: Mechanisms of chemotherapy resistance increase as cancer progresses, and a treatment approach that targets prostate tumors early, before hormonal therapy, may result in an improved outcome. A long-term outcomes analysis of our prior published study (treating patients for up to 8 months of docetaxel) was conducted to determine if the natural history of patients with PSA progression was altered by docetaxel. Methods: Twenty patients treated on our prior study were assessed for long-term follow up at a median of 9.4 years. All patients were followed until PSA progression (increase of 2 ng/mL over nadir) without the introduction of androgen ablation therapy, but may have received androgen ablation prior to radiographic progression (i.e., metastatic disease). One patient was excluded from the current analysis due to stage D1 disease pre-trial. Time to PSA progression, time to radiographic progression, and mortality were assessed. Comparisons were made between responders and non-responders to docetaxel (responders = PSA decrease ≥ 50%). Kaplan-Meier curves were constructed for the time to radiographic progression and mortality data. Results: Nineteen patients were treated on the original study with a mean time to PSA progression after local therapy of 3.3 years and a mean pre-trial PSA doubling time of 186 days. On docetaxel therapy, 8 (42%) of 19 patients demonstrated a decrease in PSA by ≥ 50% for at least 4 weeks. The median time to PSA progression after trial end was 57.5 vs. 20.0 days among PSA responders and non-responders respectively. The median time to radiographic progression from diagnosis of prostate cancer was 56.5 (95% CI: 27.7 to 99.8) vs. 45.3 months (95% CI: 40.3 to 82.5) among PSA responders and non-responders respectively. There were 4 deaths in the follow up period. Conclusions: Although treatment with docetaxel did not appear to alter overall progression in this small study, the trend towards longer time to disease progression in PSA responders suggests activity, and warrants larger studies of chemotherapy in this patient population. No significant financial relationships to disclose.