Assessment Of Progression-free Survival Research Articles

A randomized double-blind phase II study of the combination of oral WX-671 plus capecitabine versus capecitabine monotherapy in first-line HER2-negative metastatic breast cancer (MBC).

508 Background: uPA and its inhibitor PAI-1 play a key role in tumor invasion, metastasis and tumor growth. uPA and PAI-1 are biomarkers validated at highest level of evidence in breast tumors and are recommended for clinical decision making by ASCO. WX-UK1 is a competitive inhibitor of uPA with an inhibition constant in the submicromolar range. WX-671 (upamostat) is an oral prodrug of WX-UK1. Methods: Female patients aged >18, with HER2 negative MBC were randomized in a double-blind fashion to receive upamostat (200 mg orally daily for 21 days) plus C (1000 mg/m2 orally twice daily for 14 days) vs. C (same regimen) in 3 week treatment cycles until progressive disease or unacceptable toxicity. 132 from five countries were enrolled. The primary objective was to evaluate the efficacy of the combination of upamostat and C compared to C alone by assessment of progression free survival (PFS). The study also evaluated the objective response rate and safety as well as pharmacokinetics (PK). Efficacy was evaluated by RECIST by independent central read. Results: Median treatment duration was 8 cycles in both arms. In the total study population (intent to treat; ITT) upamostat led to an increase of median PFS from 7.5 months (95% CI: 4.2; 12.8) in the control group to 8.3 months (95% CI: 5.6; 9.6) in the combination therapy. An unexpectedly high rate (50%) of study patients presented within their first two years after initial diagnosis. In patients who had received prior adjuvant chemotherapy, PFS improved from 4.3 months (95% CI: 2.6; 9.7) in the C alone group to 8.3 months (95% CI: 5.6; 10.9) in the upamostat plus C group. The overall response rate was higher in the combination group compared to C alone (20% vs. 12% at Week 24). PK analysis demonstrated no drug-drug interactions between upamostat and C. The combination therapy was safe and well tolerated. Conclusions: This is the first proof of efficacy of an anti-uPA therapy in breast cancer. The heterogeneity of the patients in this study may underestimate the potential treatment effects of upamostat. Additional subset analyses will be presented. Future biomarker-stratified strategies may reveal better efficacy. Clinical trial information: NCT00615940.

Cabazitaxel (Cbz) versus topotecan in patients (pts) with small cell lung cancer (SCLC) that has progressed during or after first-line treatment with platinum-based chemotherapy: A randomized phase II study.

TPS7609 Background: Approximately 12–15% of pts with lung cancer have SCLC. Although first-line platinum-based chemotherapy regimens may be effective, pts often experience rapid relapse and develop systemic metastases. Median survival after SCLC relapse varies from 13 to 35 weeks. As such, there is a substantial unmet need for more effective second-line treatments. Clinical studies suggest that taxanes are effective in relapsed SCLC, and Cbz, a next-generation taxane, has shown efficacy in the second-line treatment of taxane-resistant tumors (de Bono JS, et al. Lancet 2010;376: 1147–54; Pivot X, et al. Ann Oncol 2008;19:1547–52). Assessment of Cbz treatment for SCLC is therefore warranted. Methods: This is a multinational, open-label Phase II study (NCT01500720) in pts with confirmed, measurable, locally advanced or metastatic SCLC whose disease has progressed during/after first-line platinum-based chemotherapy. Pts aged ≥ 18 years with ECOG performance status ≤ 1 are eligible, but those with > 1 prior chemotherapy regimen or prior topotecan or taxane use are excluded. Pts are randomized 1:1 to receive IV Cbz 25 mg/m2 (Day 1 Q3W) or IV topotecan 1.5 mg/m2 (Days 1–5 Q3W). Pts are divided into chemo-sensitive and chemo-refractory subgroups, while stratification is based on the presence of brain metastases (yes vs no) and by lactate dehydrogenase plasma concentration (≤ or > upper limit). Pts will be treated until disease progression, unacceptable toxicity or withdrawal of consent. The primary objective is assessment of progression-free survival (PFS). Secondary objectives include assessment of other efficacy endpoints (proportion of pts free of disease progression at 12 weeks, tumor response and overall survival), safety and health-related quality of life. A centralized imaging review process is being used to independently review tumor measurements. Planned enrollment is 172 pts (to provide 80% power for PFS analysis). The first pt was enrolled in March 2012. By December 2012, 91 pts had been randomized in 38 sites. Clinical trial information: NCT01500720.

Comparative efficacy of everolimus versus fulvestrant for hormone-receptor–positive (HR+) advanced breast cancer (ABC) following progression/recurrence after first-line treatment: A network meta-analysis.

e11602 Background: Everolimus (EVE), an oral mammalian target of rapamycin (mTOR) inhibitor, is approved in combination with exemestane (EXE) to treat postmenopausal women (PMW) with HR+, human epidermal growth factor receptor-2–negative (HER2–) ABC that progressed after nonsteroidal aromatase inhibitor therapy. Fulvestrant (FUL), an estrogen receptor antagonist, is another treatment option for PMW previously treated with endocrine therapy. However, the comparative efficacy of EVE + EXE vs FUL is unknown. Methods: Six randomized, controlled trials in HR+, HER2–ABC patients were identified by systematic literature review (Cochrane library, National Horizon Scanning Centre, and NICE Web sites) that formed a network permitting indirect comparisons of EVE + EXE or EVE + tamoxifen (TAM) vs FUL: BOLERO-2, CONFIRM, EFECT, Paridaens (2008), SoFEA, and TAMRAD. All 6 trials had EXE, TAM, or FUL 250 mg as the common comparator to form the network. Relative efficacy of EVE and FUL was obtained using a Bayesian network meta-analysis based on these 6 trials. The primary endpoint was local assessment of progression-free survival (PFS) or time to progression (TTP). The hazard ratio (HR) of EVE + EXE relative to FUL and its 95% credible intervals (CrI) were calculated. Evidence of a difference between treatments is suggested by the 95% CrI not including 1. A HR <1 indicates that the hazard rate is higher in the comparator group and that the treatment is more effective. Results: EVE + EXE was found to be more efficacious for PFS/TTP than FUL 250 mg (HR = 0.47; 95% Crl, 0.38-0.58) and more efficacious than FUL 500 mg (HR = 0.59; 95% Crl, 0.45-0.77). EVE + TAM was found to be numerically better for PFS/TTP than FUL 250 mg (HR = 0.65; 95% Crl, 0.40-1.04) and numerically better than FUL 500 mg (HR = 0.81; 95% Crl, 0.49-1.33). Conclusions: The indirect evidence from this analysis suggests that EVE in combination with EXE is more efficacious than FUL 250 and 500 mg in PMW with HR+, HER2– ABC that progresses after endocrine therapy. These data should be interpreted with caution as there is no randomized trial that directly compares EVE + EXE vs FUL.

Abstract 3542: Effects of single nucleotide polymorphisms on treatment outcomes and toxicity in patients treated with sunitinib for biliary tract and gastric cancers.

Abstract BACKGROUND: We analyzed the efficacy and toxicity profile of sunitinib according to single nucleotide polymorphisms (SNPs) of VEGFA and KDR among the patients with gastric or biliary tract cancer. METHODS: We examined 8 known SNPs of VEGFA and 5 SNPs of KDR among patients with gastric or biliary tract cancer who were treated with sunitinib in our two previous phase II studies. We assessed progression free survival (PFS), overall survival (OS), and toxicity and their relationships to these SNPs. RESULTS: A total of 63 patients were evaluable. Among candidate SNPs, rs2010963, rs833068, and rs1870377 were associated with poor PFS (P = .009, .002, and .029, respectively), while rs1870377 and rs7692791 were associated with poor OS (P = .001 and 0.03, respectively). Multivariate analysis showed that only rs1870377 had significant effects on both PFS and OS. Toxicity evaluation indicated that rs1531289 was associated with grade 3-4 anemia. (P = .03). CONCLUSIONS: Certain SNPs of KDR may affect treatment outcome and toxicity of patients treated with sunitinib. Citation Format: Chi Hoon MAENG, Jun Ho Lee, Jeeyun Lee, Jung Yong Hong, Moon Ki Choi, Young Saing Kim, Hyun Ae Jung, Joon Oh Park, Se Hoon Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim. Effects of single nucleotide polymorphisms on treatment outcomes and toxicity in patients treated with sunitinib for biliary tract and gastric cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3542. doi:10.1158/1538-7445.AM2013-3542

1301 POSTER Assessment of Progression-free Survival as a Surrogate Endpoint for Overall Survival in Patients With Metastatic Renal Cell Carcinoma

1301 POSTER Assessment of Progression-free Survival as a Surrogate Endpoint for Overall Survival in Patients With Metastatic Renal Cell Carcinoma

The role of 18F‐FDG PET/CT imaging in Waldenstrom macroglobulinemia

Disease assessment in WM is dependent on the quantification of the IgM monoclonal protein and percent involvement of the bone marrow. There is a need for imaging studies that objectively measure tumor load in these patients. In this study, we sought to examine the role of combined FDG-PET/CT imaging in the detection of tumor load and in the assessment of response to therapy. Thirty-five patients were enrolled on a prospective study using bortezomib and rituximab therapy and were included in this study because they completed a pre- and post-treatment FDG-PET/CT imaging at one facility (12 newly diagnosed and 23 relapsed/refractory). The use of combined FDG-PET/CT imaging showed positive findings in 83% of patients with WM, unlike prior studies using conventional imaging that indicate that only 20% of patients have lymphadenopathy or hepatosplenomegaly. Moreover, 43% of patients had abnormal bone marrow uptake on FDG-PET imaging that can potentially help in the assessment of their tumor load, especially with heterogenous sampling of the bone marrow. There was no statistical correlation between EORTC response criteria for FDG-PET/CT and response by monoclonal protein. This is the first study to examine the role of FDG-PET/CT imaging in WM. Future studies should examine the role of FDG-PET/CT in conjunction with monoclonal protein response in the assessment of progression-free survival in patients with WM.

Phase II trial of sorafenib in esophageal (E) and gastroesophageal junction (GEJ) cancer: Response observed in adenocarcinoma.

41 Background: Sorafenib is a tyrosine kinase inhibitor targeting VEGFr, PDGFr, Raf and other pathways. Encouraging response and survival were observed in a phase II trial combining sorafenib with chemotherapy in GE cancer (J Clin Oncol 27:2947;2010). We are studying single agent sorafenib in a phase II trial with the primary endpoint to assess progression free survival (PFS). Secondary endpoints include response and therapy tolerance. Methods: Patients (pts) with measurable metastatic E and GEJ cancer with no more than 3 prior chemotherapy regimens were treated with sorafenib 400 mg BID. CT scans were performed monthly for the first 2 months, then every 2 months. Results: Sixteen of 35 pts have been accrued and 14 are currently evaluable. 13 male, 3 female, median KPS 80%, age 58, GEJ 7, E 9, squamous 2, adenocarcinoma (AC)14. An ongoing complete response (11+ months) was observed in a pt with biopsy proven metastatic neck lymphadenopathy (E primary AC, recurrence after prior chemoradiotherapy and surgery). A second pt (GEJ AC) had protracted stable disease in bulky celiac node disease (15+ months). Grade 3 toxicity was limited to skin rash (1 pt), hand foot reaction (1 pt), and fatigue (1 pt). Only 3 of 14 pts (21%) had early disease progression at 2 months or less. Median PFS 4 mos, 4 patients (29%) continue on therapy for more than 7 months. The majority of tumors tested positive for phospho-erk by immunohistochemistry (11/14, 79%). Conclusions: The observation of a durable complete response and protracted stable disease to sorafenib in E cancer is remarkable. Further accrual continues to define PFS. Supported by a grant from Bayer. [Table: see text]

Neoadjuvant chemotherapy in ovarian, primary peritoneal and tubal carcinoma: can imaging results prior to interval debulking predict survival?

ObjectiveTo assess whether there is an association between improvement of computed tomography imaging results prior to interval debulking with survival in patients treated by neoadjuvant chemotherapy.MethodsThe clinical and outcome data of all advanced ovarian, primary peritoneal and tubal carcinoma patients who after diagnosis had neoadjuvant chemotherapy and underwent interval debulking during the period 2000-2010, were abstracted. Results of computed tomography imaging at diagnosis and prior to interval debulking were compared. Two parameters were assessed: the change of the size and number of abnormal findings and the change in the amount of ascites. CA-125 level response was also calculated. An assessment of progression free survival and of survival by the Kaplan-Meier method was made according to the change in computed tomography imaging results and according to response of CA-125 levels.ResultsThe median progression free survival and the median survival of the 37 study group patients were 7.9 and 49.2 months respectively. No significant difference in progression free survival and survival was observed between patients with marked improvement in the computed tomography results and those with less desirable results (7.93 vs. 7.23 months respectively, p=0.89; 45.8% vs. 52.5% months respectively, p=0.95). There were also no statistically significant difference according to CA-125 level response.ConclusionIt seems that neither improvement in imaging results nor CA-125 level response can predict the survival of ovarian carcinoma patients prior to interval debulking after neoadjuvant chemotherapy.

Lapatinib combined with letrozole vs. letrozole alone for front line postmenopausal hormone receptor positive (HR+) metastatic breast cancer (MBC): first results from the EGF30008 Trial.

Abstract Abstract #46 Background: Cross-talk between growth factor and steroid receptor pathways has been implicated in endocrine resistance in breast cancer. Combining EGFR/HER2-targeted therapy with aromatase inhibitors for HR+ postmenopausal breast cancer may enhance endocrine responsiveness and delay the onset of resistance. EGF30008 is a double-blind, placebo-controlled, first-line phase III trial to explore the benefit of letrozole with/without lapatinib, an oral dual tyrosine-kinase inhibitor of HER2 and EGFR, in patients (pts) with HR+ postmenopausal MBC.
 Methods: 1286 postmenopausal women with HR+ untreated MBC from 212 international centers were randomized to once daily treatment with letrozole 2.5 mg and lapatinib 1500 mg or letrozole and placebo. Pts were stratified according to presence of visceral vs bone only disease and time since completion of prior adjuvant endocrine tamoxifen therapy (<6 mo or ≥6 mo/never received). 219 pts were HER2+ (IHC 3+ and/or FISH amplified). The primary endpoint of the study was investigator assessed progression free survival (PFS) in the HR+ HER2+ population, and secondarily in the overall ITT population in closed hierarchical testing procedure. Additional secondary endpoints included overall survival, overall response rate, clinical benefit rate, time to and duration of response, and safety of letrozole with/without lapatinib.
 Results: Median PFS in the HER2+ population was significantly increased from 3.0 months (mos) in the letrozole group to 8.2 mos in the lapatinib\letrozole group [Hazard Ratio (95% CI)=0.71(0.53,0.96), stratified log rank p=0.019]. Median PFS in the ITT population increased from 10.9 mos to 11.9 mos, respectively [Hazard Ratio (95% CI)=0.86 (0.76,0.98), stratified log rank p=0.026]. In a pre-planned Cox regression analysis exploring stratification and well known baseline prognostic factors in the HER2+ population, a significant benefit was confirmed [Hazard Ratio (95% CI)=0.65 (0.47-0.89), p=0.008]. In the ITT population, 952 tumor samples were centrally confirmed as HER2 negative. In this group, the Cox regression model after retaining treatment group identified ECOG status, prior adjuvant tamoxifen therapy stratification, number of metastatic sites, and baseline serum HER2 ECD as having a significant impact on PFS [Hazard Ratio (95% CI)=0.77(0.64,0.94), p=0.010].
 Overall response rate (ORR) in the HER2+ population was significantly increased from 14.8% to 37.9% in the combination group [Odds Ratio = 0.4 (0.2, 0.9), p=0.021], with a clinical benefit rate (CBR) improvement from 28.7% to 48.7% [Odds Ratio = 0.4 (0.2,0.8), p=0.003]. There was no difference in ORR or CBR in the HER2 negative population. With 41% of pts still being followed, an overall survival trend was noted in the HER2+ group [Hazard ratio (95% CI) = 0.77 (0.52, 1.14), p=0.185]. The combination of letrozole and lapatinib was well tolerated and no new safety issues were identified.
 Conclusion: This is the largest clinical trial to test whether combined endocrine and targeted EGFR/HER2 inhibition enhances endocrine responsiveness in HR+ MBC. Lapatinib significantly improved the clinical efficacy of an aromatase inhibitor in pts with known HR+ HER2+ MBC, and identified a subset of HR+ HER2-negative that may also benefit. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 46.

Sorafenib plus interferon-α2b (IFN) as first-line therapy for advanced renal cell carcinoma (RCC): SWOG 0412

4525 Background: Sorafenib is a RAF and multiple receptor tyrosine kinase inhibitor active in RCC. IFN has modest activity in RCC and has immunologic, anti-angiogenic, and anti-proliferative effects. Sorafenib and IFN may simultaneously target anti-angiogenic and MAP kinase pathways, providing the basis for this phase II combination study. Methods: Eligible patients (pts) had metastatic or unresectable RCC with a clear cell component, no prior systemic therapy, performance status 0–1, measurable disease. Treatment: IFN 10 x 106 IU s.c. 3x/week and sorafenib 400 mg p.o. BID. Response assessment was performed q8 weeks. This was a single-stage trial with a planned sample size of 55. Primary endpoint was RECIST response rate. Results: Of 67 registered pts, 58 are eligible & evaluable. Pt characteristics: median age 61 years (42–84), male:female (40:18), prior nephrectomy 86%. MSKCC prognostic categories (42 pts) were good:intermediate:poor (28%:67%:5%). With a median follow-up of 6.5 months, 79% (46/58) of pts are alive, 41% (24/58) remain on treatment. Assessment of progression-free survival is premature. Overall response rate (53 pts) is 19% (95% CI: 9%, 32%) with CR 2% and PR 17% (9% confirmed, 8% unconfirmed). Toxicities affecting >50% of subjects were: fatigue, anorexia, diarrhea, nausea, rigors/chills, fever, anemia, leukopenia. Most common Grade 3+ toxicities were fatigue (24%), leukopenia (10%), anorexia (6%), diarrhea (6%), hyponatremia (6%). All pts experienced some toxicity, with 36 (62%) experiencing at least one Grade 3+ toxicity. Hand-foot syndrome, a common side effect of sorafenib, was seen in only 10% of pts. Conclusions: The overall response rate of 19% for the combination of sorafenib and IFN in advanced RCC is greater than expected with either IFN or sorafenib alone. Toxicity is typical of IFN and notable for minimal hand-foot syndrome. Further studies with this combination are warranted. [Table: see text]

Phase II trial of the mTOR inhibitor everolimus (RAD-001) in metastatic melanoma

8043 Background: Mammalian target of rapamycin (mTOR) is a serine-threonine kinase that regulates the production vascular endothelial growth factor (VEGF) and cell growth and proliferation. Inhibitors of mTOR have anti-mitotic and anti-angiogenic effects in various cancers (including melanoma). Everolimus (RAD-001), an orally administered inhibitor of mTOR, is well tolerated at a dose of 30 mg/week. We conducted a phase II study to evaluate the role of RAD-001 in treating patients with metastatic melanoma (MM). Methods: A 2 stage, phase II multi-institutional trial was conducted in patients with MM to assess progression free survival (PFS) rate at 16 weeks was at least 50% against the alternative it was at most 30%. Data about expected baseline PFS were derived from historical controls. Each cycle was 8 weeks in duration. Inclusion criteria: measurable disease, ECOG performance score (PS) of 0–2. Exclusion criteria: presence of intracranial metastases, concurrent use of inducers of cytochrome 3A4 and abnormal hepatic, renal or bone marrow function. Correlative studies included changes pharmacodynamic endpoints to evaluate effect of therapy on signaling pathways. Results: 24 patients with MM were enrolled. Median age was 56 years (33–79), 21 (88%) had at 2 or more sites of metastatic disease. Most (75%) had stage M1c, with 13% each having 1a and 1b disease. PS was 0, 1 and 2 in 58, 38% and 4%, resp. All but 9 had received previous therapy for MM. Planned interim analysis was done after 20 patients were enrolled. Of these, 7 (i.e., 35%) were PF at 16 weeks, which exceeded the decision rule for restarting accrual. No patient had an objective response; all 7 had stable disease. There were no grade 3 toxicities. Grade 2 toxic events (at least possibly related to therapy) were: fatigue (17%), diarrhea (8%) and anemia (8%). Patients had a clinically relevant benefit, with the median PFS for all 24 patients of 3 months. Median overall survival was not reached. Three patients continue on therapy. RAD-001 treatment resulted in changes in serum VEGF levels. Conclusion: Interim analysis after enrollment of 20 patients suggests that RAD-001 is well tolerated and has sufficient anti-tumor activity in MM to warrant the opening of enrollment to the second stage of this trial. Further accrual is planned. No significant financial relationships to disclose.

Combination of temozolomide (TMZ) and irinotecan (CPT-11) showed enhanced activity for recurrent malignant gliomas: A North American Brain Tumor Consortium (NABTC) phase II study

1521 Background: TMZ, an oral alkylating agent is active in recurrent malignant glioma. CPT-11, a topoisomerase I inhibitor, has also been shown to have modest activity in recurrent malignant glioma. A phase I study by NABTC has demonstrated the safety of combining TMZ and CPT-11 in a q2-week schedule and established the MTD of CPT-11 at 500 mg for patients receiving p450 enzyme inducing anticonvulsant (Group B). This phase II study is to further establish the efficacy of this combination in pts with recurrent malignant glioma. Methods: This is a multicenter phase II trial. All pts had documented recurrent GBM or Anaplastic Gliomas (AA, AO, AOA). TMZ was given at 150 mg/m2/d x 5, q 28d. For pts not receiving p450 enzyme inducing anticonvulsant (Group A), CPT-11 was given at 200 mg/m2, q2-wk, while 500 mg/m2 q2-wk, was given to Group B pts. Results: 51 GBM and 17 AG pts were entered into the study (50 Group A, 18 Group B). Demographic and preliminary outcome data are listed in the table below. Response data (not yet centrally reviewed) was available in 57 pts (44 GBM, 13 AG). Follow-up data were available in 43 pts (32 GBM, 11 AG) to assess progression free survival at 6 months (PFS6). No unusual toxicities were encountered. Most common toxicities include Leukopenia, thrombocytopenia, diarrhea, nausea, and vomiting. Conclusions: The combination of TMZ and CPT-11 in this schedule is active and tolerable. The response rate and PFS6 for GBM pts were better than single agent TMZ or CPT-11 for recurrent GBM, while that for AG were the same as single agent. A phase II study with this combination for newly diagnosed GBM is ongoing by the Radiation Therapy Oncology Group. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Pfizer, Pharmacia, Schering-Plough EMD, Genentech, Novartis, Pfizer, Schering-Plough Genentech, Novartis, Pfizer, Schering Plough