Independent Review Facility Research Articles

Concordance between independently and investigator-assessed progression-free survival in CLEOPATRA.

e11055^ Background: In CLEOPATRA, pertuzumab (P) + trastuzumab (T) + docetaxel (D) was compared to placebo (Pla)+T+D in HER2-positive 1st-line MBC. In MBC trials, PFS rather than overall survival is often defined as the primary endpoint as PFS data are available earlier and later-line therapy does not impact results. The primary endpoint in CLEOPATRA, PFS, was assessed by an Independent Review Facility (IRF), with investigator (inv)-assessed PFS as a secondary endpoint. As a measure of consistency and robustness, concordance between IRF- and inv-assessed PFS was analyzed. Methods: PFS was defined as time from randomization to first documented radiographic evidence of progressive disease (PD) or death from any cause within 18 wk of the last IRF tumor assessment. Tumor assessments took place every 9 wk and continued until IRF-confirmed PD. Treatment decisions were solely based on the inv’s assessment of PD. Indicators of concordance between IRF- and inv-assessed PFS included: PFS event by IRF only; PFS event by inv only; PFS event by IRF and inv; no PFS event by IRF and inv. These indicators were assessed at any time on study, within 30 d or within 9 wk. Several pre-specified sensitivity analyses for PFS were also performed. Results: 808 pt were enrolled and central tumor assessments performed for 781 pt. Compliance with the schedule of tumor assessments was generally high and comparable between arms, with >78% of pt undergoing assessments within 7 d of the scheduled visit over the 1st yr. At any time on study, concordance between IRF- and inv-assessed PFS was 85%. Of the 15% discordant cases, an equal proportion was assessed by the IRF as a PFS event but not by the inv and vice versa. Estimates of the median time to PFS event based on IRF and inv assessments were identical, Pla+T+D: 12.4 mo, P+T+D: 18.5 mo (IRF: HR 0.62, P < .0001; inv: HR 0.65, P < .0001). Conclusions: Concordance between IRF- and inv-assessed PFS was high, supporting consistency and robustness of the PFS analyses. The subjective nature of PD and potential for bias were reduced by the double-blind, placebo-controlled study design; RECIST 1.0 criteria; identical schedule of assessments in both arms; IRF review and continuation of tumor assessments until IRF confirmation of PD.

An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.

5508 Background: MTC arises from parafollicular cells of the thyroid gland, accounts for 5-8% of thyroid cancers and represents an unmet medical need. Cabozantinib (cabo) is an oral inhibitor of MET, VEGFR2, and RET. We conducted a phase III study of cabo vs placebo (P) in pts with progressive, unresectable, locally advanced or metastatic MTC. Methods: Eligible pts were required to have documented RECIST progression within 14 months of screening. The primary efficacy measure was progression-free survival (PFS) as assessed by an independent review facility (IRF) using RECIST. Secondary efficacy measures included objective response rate (ORR) and overall survival (OS). The study has 90% power to detect a 75% increase in PFS and 80% power to detect a 50% increase in OS. Tumor assessments occurred every 12 weeks. Crossover between treatment arms was not allowed. Results: Between Sept 2008 and Feb 2011, 330 pts (median age 55 yrs; 67% male; 96% measureable disease; RET mutation status: pos 48%; neg 12%; unknown 39%; prior TKI exposure: yes 21%, no 78%, unknown 2%) were randomized 2:1 to cabo (140 mg free base [175 mg salt form] qd; n=219) or P (n=111). The planned primary PFS analysis included events through the date of the 138th event. As of 15June2011, 44.7% of pts on cabo and 13.5% on P were still receiving study treatment. Statistically significant PFS prolongation of 7.2 mo was observed; median PFS for cabo was 11.2 mo vs 4.0 mo for P (HR 0.28, 95% CI 0.19-0.40, p<0.0001). PFS results favored the cabo group across subset analyses including RET status and prior TKI use. ORR was 28% for cabo vs 0% for P (p<0.0001). An interim analysis of OS (44% of the 217 required events) did not show a difference between cabo and P. The most frequent grade ≥3 adverse events (cabo vs P) were diarrhea (15.9 vs 1.8%), palmar-plantar erythrodysesthesia (12.6 vs 0%), fatigue (9.3 vs 2.8%), hypocalcemia (9.3 vs 0%), and hypertension (7.9 vs 0%). Conclusions: This phase III study met its primary objective of demonstrating substantial PFS prolongation with cabo vs. P in a patient population with MTC and documented progressive disease in need of therapeutic intervention.

Durable remissions with brentuximab vedotin (SGN-35): Updated results of a phase II study in patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

8032 Background: sALCL is a CD30-expressing malignancy comprising ~2-3% of all NHL cases. Brentuximab vedotin consists of an anti-CD30 antibody conjugated by a plasma-stable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Brentuximab vedotin selectively induces apoptotic death of CD30+ cells by binding, internalizing, and releasing MMAE. Methods: A phase II, single-arm, multicenter study evaluated the efficacy and safety of brentuximab vedotin in patients (pts) with relapsed or refractory sALCL. Pts received brentuximab vedotin 1.8 mg/kg q3 weeks (wks) as a 30‐minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per an independent review facility (IRF) according to Cheson 2007. Results: 58 pts were enrolled; 57% were male, median age was 52 yrs (range 14–76 yrs). 72% of pts had ALK negative sALCL. Pts had received a median of 2 (range 1–6) prior systemic therapies. 62% of pts had primary refractory disease, 50% were refractory to their most recent prior therapy, and 22% had never responded to any prior therapy. At the time of primary efficacy analysis, ORR per IRF was 86% (50 of 58 pts) with CRs in 53% of pts (31 of 58). Median duration of objective response had not yet been reached; the duration ranged from 0.3 to 45.3 wks. Of 15 pts with malignant cutaneous lesions at baseline, 14 (93%) had resolution of all lesions; median time to resolution was 4.9 wks. After achieving a remission with brentuximab vedotin, 7 pts received an allogeneic stem cell transplant (SCT) and 7 pts had an autologous SCT. Treatment-related adverse events (AEs) of any grade in ≥15% of pts were peripheral sensory neuropathy (36%), nausea (24%), fatigue (22%), diarrhea (19%), and neutropenia (17%). AEs ≥ Grade 3 in ≥10% of patients were neutropenia (21%); thrombocytopenia (14%), and peripheral sensory neuropathy (10%). No treatment-related Grade 5 events were observed. Conclusions: Brentuximab vedotin induced objective responses in 86% of pts with highly refractory sALCL, including a high proportion of CRs, with manageable AEs. Updated response durability and safety will be presented at the meeting.

Results from a pivotal phase II study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma (HL).

8031 Background: CD30 expression by Reed-Sternberg cells is a defining feature of HL. Brentuximab vedotin comprises an anti-CD30 antibody conjugated by a plasma-stable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Brentuximab vedotin selectively induces apoptotic death of CD30+ cells by binding, internalizing, and releasing MMAE. Methods: A pivotal, phase II, single-arm, multicenter study evaluated the efficacy and safety of brentuximab vedotin in patients (pts) with relapsed or refractory HL after autologous stem cell transplant (SCT). Pts received brentuximab vedotin 1.8 mg/kg q3 weeks (wks) as a 30‐minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per an independent review facility (IRF) according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: 102 pts were enrolled; 53% were female and median age was 31 yrs (range, 15–77 yrs). Pts had received a median of 3.5 (range 1–13) prior cancer-related systemic therapies excluding autologous SCT. 71% of pts had primary refractory disease and 42% had not responded to their most recent prior therapy. The ORR per IRF assessment was 75% (76 of 102 pts), with complete remissions (CRs) in 34% of pts (n=35). At the time of database lock (August 2010), the median duration of follow up from first dose was ~9 months (for responders). The median duration of response for pts with CR per IRF has not yet been reached (range 0.3+ to 61.4+ wks); follow up continues and 6+ months of additional data will be available for presentation. The most common (≥15%) treatment-related adverse events (AEs) of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. AEs ≥ Grade 3 occurring in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. Conclusions: With manageable AEs, single-agent brentuximab vedotin induced objective responses in 75% of pts with relapsed or refractory HL. In this heavily pretreated population, 35 of 102 pts (34%) achieved a durable CR, with more than 65% of pts remaining in CR.

MARIANNE: A phase III, randomized study of trastuzumab-DM1 (T-DM1) with or without pertuzumab (P) compared with trastuzumab (H) plus taxane for first-line treatment of HER2-positive, progressive, or recurrent locally advanced or metastatic breast cancer (MBC).

TPS102 Background: T-DM1 is a unique antibody-drug conjugate (ADC) composed of H, a stable thioether linker, and the highly potent cytotoxic agent DM1 (derivative of maytansine). In a randomized phase II trial, single-agent T-DM1 had comparable efficacy to H + docetaxel in the first-line treatment of HER2-positive locally advanced or MBC. P is the first HER2-directed dimerization inhibitor for the treatment of HER2-positive BC. T-DM1 and P bind to different epitopes on HER2, and have distinct mechanisms of action suggesting that the combination may result in more complete blockade of HER2. T-DM1 + P showed synergistic antitumor effects in preclinical models, and preliminary phase Ib/II trial results showed acceptable tolerability and promising efficacy in patients with MBC. Methods: MARIANNE BO22589 (trial registry #NCT01120184) is the first phase III study to evaluate the combination of a targeted antibody and an ADC for first-line MBC. This systemic chemotherapy-sparing combination has the potential to establish a new treatment paradigm by optimizing efficacy while minimizing toxicity. Patients are randomized 1:1:1 to each arm (T-DM1 arms are blinded for P; H + taxane arm is open-label): H + taxane (H 8 mg/kg loading dose, then 6 mg/kg + docetaxel 75 mg/m2 q3w, or H 4 mg/kg loading dose, then 2 mg/kg + paclitaxel 80 mg/m2 qw); T-DM1 (3.6 mg/kg) q3w + P (840 mg loading dose, then 420 mg) q3w; or T-DM1 + placebo. Key eligibility criteria include centrally-confirmed HER2-positive MBC and no history of cardiopulmonary dysfunction. The primary endpoint is progression-free survival by independent review facility. Secondary endpoints include safety, overall response rate, overall survival, duration of response and quality of life. Enrollment began in July 2010, and as of January 31, 2011, 141 patients have been recruited, well ahead of schedule. Target enrollment is 1092 patients across ~310 sites globally. The independent Data Monitoring Committee which assesses safety data has recently recommended continuation of the study without modification. Brisk completion of accrual and data analyses are eagerly awaited.

CLEOPATRA: A Phase III Evaluation of Pertuzumab and Trastuzumab for HER2-Positive Metastatic Breast Cancer

Introduction Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer have a poor prognosis. Despite proven efficacy with the standard of care, trastuzumab, most patients with HER2-positive metastatic breast cancer (MBC) will eventually progress, requiring further intervention to prolong life. Pertuzumab, a humanized monoclonal antibody, is the first HER2 dimerization inhibitor. It binds to the dimerization site on the HER2 domain and prevents ligand-driven pairing of HER2 with other HER receptors, thus inhibiting tumor cell growth and survival. Combining trastuzumab and pertuzumab therefore provides a more comprehensive blockade of the HER signaling pathways, resulting in greater antitumor efficacy. Study Design CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) is an international, randomized, double-blind, placebo-controlled phase III trial that aims to recruit approximately 800 patients from around 250 centers worldwide. Adults with HER2-positive adenocarcinoma of the breast with locally recurrent or metastatic disease will be randomized (1:1) to receive docetaxel, trastuzumab, and pertuzumab or docetaxel, trastuzumab, and placebo. The primary endpoint of the study is progression-free survival (PFS), based on tumor assessments conducted by an independent review facility. Secondary endpoints include PFS evaluated by investigator assessment, overall survival, objective response rate, duration of response, time to symptom progression, and safety. Data will also be collected to identify biomarkers that may correlate with clinical outcomes. Conclusion The CLEOPATRA study will provide important information about the efficacy and safety of adding pertuzumab to one current standard of care in patients with HER2-positive MBC.

Results of a Pivotal Phase 2 Study of Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma

AbstractAbstract 283 Background:Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the highly potent antimicrotubule agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing tumor cell. In a previous phase 1 study with brentuximab vedotin dosing every third week, 11 of 12 patients (92%) treated at the maximum tolerated dose of 1.8 mg/kg had tumor reductions and 6 of 12 patients (50%) achieved an objective response (complete remission [CR] + partial remission [PR]). Methods:A pivotal, phase 2, single-arm, multicenter study was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory HL post autologous stem cell transplant (ASCT). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. The primary endpoint was the overall objective response rate (ORR) as assessed by an independent review facility according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results:A total of 102 patients with relapsed or refractory HL were treated at 26 study centers. Median age was 31 years (range 15–77) and approximately half of the patients were female (53%). Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 (41%) or 1 (59%). All patients had previously received an ASCT and the median number of prior chemotherapy regimens was 4 (range 1–13). More than 70% of the patients had primary refractory disease, defined as failure to achieve a CR or progression within 3 months of completing frontline therapy. In addition, 39% of patients had lymphoma that was refractory to the most recent salvage therapy excluding ASCT. The median duration of brentuximab vedotin treatment on this study was 27 weeks (range 3–54) and the median number of cycles was 9 (range 1–16). The most common (>15%) treatment-related adverse events (AEs) of any grade were peripheral sensory neuropathy (43%), fatigue (40%), nausea (35%), neutropenia (19%), diarrhea (18%), and pyrexia (16%); most events were Grade 1 or 2. Grade 3 treatment-related AEs reported in >1 patient were neutropenia (14%), peripheral sensory neuropathy (5%), thrombocytopenia and hyperglycemia (3% each), and fatigue (2%). The only Grade 4 treatment-related events were neutropenia (4%), and thrombocytopenia, abdominal pain, and pulmonary embolism (1% each). No related Grade 5 events were observed. 18 patients discontinued treatment due to an AE. Consistent with findings from the phase 1 study, 97 patients (95%) had a reduction in tumor size per investigator assessment. Of the 35 patients who had B symptoms at baseline, 29 (83%) experienced resolution of these symptoms. The median time to B symptom resolution was 3 weeks (range <1–16 weeks). To date, 5 patients have received an allogeneic stem cell transplant as their first therapy after discontinuing treatment in the study; all of these patients remain in follow up. Per protocol, no interim analyses were planned for the primary endpoint of ORR by independent review. Independent assessment of ORR is being conducted and final efficacy results will be presented at the meeting. Conclusions:Brentuximab vedotin was associated with manageable adverse events and, based on investigator assessment, demonstrated encouraging activity in heavily pretreated patients with relapsed or refractory HL. Tumor shrinkage was observed in 95% of patients and the B symptom resolution rate was 83%. Final results of the independent assessment of ORR, as well as duration of response, progression-free survival, and updated safety data, will be presented at the meeting. Disclosures:Chen: Seattle Genetics, Inc.: Research Funding. Off Label Use: This clinical trial uses the investigational drug, brentuximab vedotin (SGN-35). Gopal:Seattle Genetics, Inc.: Research Funding. Smith:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Klasa:Seattle Genetics, Inc.: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Engert:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding.

Baseline (BL) radiographic characteristics and severe pulmonary hemorrhage (SPH) in bevacizumab (BV)-treated non-small cell lung cancer (NSCLC) patients (pt): Results from ARIES, an observational cohort study (OCS).

7619 Background: BV prolongs progression free and overall survival in advanced NSCLC pts. ARIES, a prospective OCS, evaluates BV clinical outcomes in a real world setting. Post hoc analyses from randomized controlled trials suggest location and cavitation as potential risk factors for SPH, a serious and often fatal adverse event (AE). ARIES presents a unique opportunity to independently evaluate BL tumor characteristics and correlate with SPH. Methods: Pts with advanced nonsquamous NSCLC on first-line chemotherapy and BV enrolled. No doses, regimens or assessments were prespecified. Data were collected electronically at BL and quarterly. SPH were reported expeditiously. BL CT scans were requested for all pts and reviewed by an independent review facility (IRF). Results: NSCLC enrollment completed 06/2009. As of 09/2009, 1,970 pts had median follow-up of 9.6 mo. The IRF reviewed BL scans of 1,881 pts; 1,470 (78%) had ≥ 1 BL measurable (meas) tumor (≥ 0.5cm) and 49% (718) were central; 67% had largest tumor size ≥ 3 cm; 14% had cavities and 10% had > 1 cavity. BL tumor characteristics were generally similar across subpopulations (age ≥ 70, PS ≥ 2, pts with CNS mets). Pts with a history (Hx) of hemoptysis (n = 105) had more centrally located tumors, fewer numbers of meas tumor, and larger cavity size. There are 15 (0.8%) reported SPH events to date; 2 pts had no BL CT scan submitted and 2 pts with BL scans had no meas tumor (1 had Hx of hemoptysis). Of the remaining 11 pts with SPH: 8 had central tumors; 1 had cavitation (1.2 cm); 0 were on anticoagulants at BL; largest tumor size ranged from 1.8-11.6cm. There was 1 SPH in pts with ≥ 1 cavity (0.5%) and 8 in pts with central tumors (1.1%). Conclusions: ARIES has the largest series of independently reviewed BL scans from advanced NSCLC pts, providing an opportunity to correlate radiographic factors with outcomes in BV treated pts. Although limited by small numbers, the data suggest that cavitation is not predictive of SPH. Correlation of BL radiographic characteristics with outcomes and risk factor analysis will be presented. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Infinity Pharma AstraZeneca, BIPI, Genentech, Merck Infinity Pharma, Roche Genentech

Independent Review of E2100: A Phase III Trial of Bevacizumab Plus Paclitaxel Versus Paclitaxel in Women With Metastatic Breast Cancer

E2100, an open-label, randomized, phase III trial conducted by the Eastern Cooperative Oncology Group (ECOG), demonstrated a significant improvement in progression-free survival (PFS) and overall response rate (ORR) with paclitaxel plus bevacizumab compared with paclitaxel alone as initial chemotherapy for patients with HER2-negative metastatic breast cancer. An independent, blinded review of radiologic and clinical data was performed, assessing progression and response according to Response Evaluation Criteria in Solid Tumors. In addition, ECOG's investigator assessments were reanalyzed using the same methods applied to the independent review. The primary end point was PFS as assessed by an independent review facility (IRF). The addition of bevacizumab to paclitaxel resulted in a statistically significant improvement in PFS using both the IRF and investigator assessments. Hazard ratios for PFS (0.48, 95% CI, 0.385 to 0.607; P < .0001 for the IRF v 0.42, 95% CI, 0.34 to 0.52; P < .0001 for ECOG investigators) and the improvement in median PFS (11.3 v 5.8 months for the IRF v 11.4 v 5.8 months for ECOG investigators) were similar. Among patients with measurable disease at baseline, the IRF-assessed ORR was significantly higher in patients treated with paclitaxel and bevacizumab (48.9% v 22.2%; P < .0001). The risk of progression was reduced by more than half and the ORR more than doubled with the addition of bevacizumab to weekly paclitaxel in both analyses, confirming a substantial and robust bevacizumab treatment effect. The consistency between the IRF and ECOG analyses validates the original data previously reported by ECOG in this open-label trial.

Development of cavitation while on bevacizumab (BV) therapy in patients (pts) with non-small cell lung cancer (NSCLC): Results from ARIES—A bevacizumab (BV) treatment observational cohort study (OCS)

e19045 Background: BV (Avastin), an anti-VEGF monoclonal antibody, prolongs progression-free and overall survival in advanced NSCLC pts. Severe (≥grade 3) pulmonary hemorrhage (sPH) is a rare but serious event that has been associated with BV-based therapy in phase 3 trials (rate of 2–4%). Potential risk factors include squamous histology, prior history of hemoptysis, and presence of tumor cavitation. Rates of baseline (BL) cavitation in NSCLC pts and development of cavitation on BV therapy are unknown. Pts in ARIES, an OCS of approximately 2,000 pts with NSCLC, had BL scans assessed for tumor cavitation. A substudy of approximately 250 pts also had follow-up scans to analyze the likelihood of developing cavitation on BV therapy. For the entire ARIES population, any pt developing sPH is assessed for tumor cavitation. Methods: Pts at specified ARIES sites submitted on-treatment CT scans to an independent review facility (IRF), in addition to BL scans. Evaluable pts had measurable disease at BL and at least one-post-BL scan. Correlations between cavitation (pre-existing or developing on-study) and clinical, tumor and treatment characteristics are evaluated using a chi-squared test or t-test. Incidence of sPH based on cavitation status will be assessed using Fisher's exact test. Results: As of 9/15/08, 210 pts had a post-BL CT scan reviewed by the IRF. Of these pts, 171 had measurable tumors at BL. For the 171 pt cohort: median F/U is 9.2 m; 99% have ≥1 quarterly update. Key BL characteristics for the substudy and overall cohorts, respectively, include: 44% vs 51% ≥65 yrs; 67% vs 67% adenocarcinoma; 6% vs 5% therapeutic AC. BL radiographic features: 41% vs 39% presence of central tumor; 13% vs 15% presence of cavitation. In substudy pts, there is 1 sPH to date in a pt without baseline cavitation. Conclusions: sPH is a rare, potentially serious event in pts with NSCLC receiving BV. Whether cavitation (BL or developing on-treatment) is associated with an increased risk of sPH has not been defined. The final analysis of an ARIES Lung substudy assessing on-study development of cavitation and association with sPH will be presented at the meeting. [Table: see text]

Efficacy, safety and tolerability of dual monoclonal antibody therapy with pertuzumab + trastuzumab in HER2+ metastatic breast cancer patients previously treated with trastuzumab.

Abstract Abstract #3138 Pertuzumab (P), a humanized monoclonal antibody, is a first-in-class HER heterodimer inhibitor that binds to the HER2 dimerization domain, inhibiting the interaction of HER2 with other HER family members. Xenograft studies demonstrated a synergistic effect of P with trastuzumab (T) in combating HER2-amplified breast cancer, and two clinical P+T PhII studies were undertaken in HER2+ MBC.&amp;#x2028; The first Ph II study evaluated the efficacy and safety of P+T in HER2+ MBC patients (pts) who progressed during prior T therapy (Gelmon et al, ASCO 2008).&amp;#x2028; Pts received T at either 4mg/kg loading dose (LD) followed by 2mg/kg qw or 8mg/kg LD followed by 6mg/kg q3w and P 840mg LD followed by 420mg q3w; 21/66 pts remain on therapy. Of the 16/66 pts (24%) who responded to therapy, there were 5 CRs, 11 PRs, and an additional 17 pts with SD for ≥6mos, for a total of 33/66 (50%) receiving clinical benefit. Most frequent events include diarrhea (64%), fatigue (33%), nausea (27%) and rash (26%). Three pts experienced Gr3 AEs that resolved for therapy to continue, and no Gr4 AEs were noted. There were no symptomatic declines in left ventricular ejection fraction (LVEF). No pts withdrew for treatment or cardiac-related AEs.&amp;#x2028; The second Ph II study evaluated P+T in HER2+ MBC previously treated with T (Portera et al, Clin Can Res 2008). Pts in this study progressed on T-based regimens and had a baseline LVEF ≥55%. Pts received T 8mg/kg LD followed by 6mg/kg q3w and P 840mg LD followed by 420mg q3w. Of the 11 pts, 2 (18%) achieved PR and 3 pts had SD ≥18wks. Gr1-3 left ventricular systolic dysfunction (LVSD) was seen in 5/11 (45%) pts; 1 had symptomatic CHF. All 5 pts had previously received at least 240 mg/m2 doxorubicin, and LVSD resolved in 3/5 (60%) pts following therapy. Other AEs were mild- moderate and were not treatment limiting.&amp;#x2028; These studies have shown that the combination of P+T is well tolerated and active in HER2+ MBC pts who have progressed on T-based therapies. No dose limiting toxicities have been identified to date, and further data as well as biomarker analyses are ongoing.&amp;#x2028; This is a promising biologic combination therapy targeting HER2 disease that shows activity while avoiding typical chemotherapy side effects.&amp;#x2028; Additional studies examining this combination include the currently enrolling Ph III Cleopatra study (Clinical Evaluation of P and T), a 1st line HER2+ MBC trial that will randomize 800 pts to docetaxel (D) &amp; T +/- P. The primary endpoint compares progression-free survival (PFS) between pts based on tumor assessments by independent review facility (IRF). Pts will receive D 75mg/m2 q3w, T 8mg/kg LD followed by 6mg/kg q3w, and P 840mg LD followed by 420mg q3w or placebo. Extensive biomarker data will be collected to test markers that may correlate with treatment success. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3138.

Independent review of E2100 progression-free survival (PFS) with the addition of bevacizumab (B) to paclitaxel (P) as initial chemotherapy for metastatic breast cancer (MBC)

1036 Background: E2100 was an open-label, multi-center, randomized, Phase III trial comparing P to P+B as initial chemotherapy for MBC. The original analysis based on investigator-assessed progression found a significant improvement in PFS (HR 0.498, p <0.001) (K. Miller, PASCO '05). A retrospective independent review of blinded radiological and clinical data was conducted to confirm the results. Methods: Radiographic images and physical exam findings were provided to the independent review facility (IRF; RadPharm Inc.) who reviewed these data in a blinded fashion, in accordance with a prespecified IRF charter following the RECIST criteria. PFS was reanalyzed as an intent-to-treat analysis of all 722 randomized subjects, and included on-study deaths and progression events assessed by the IRF that occurred on or before Feb 9, 2005 (consistent with the data cut-off for the original interim analysis). PFS was also reanalyzed using investigator assessments but otherwise following the same analysis methods. Results: Images were submitted for review for 89.9% of patients. Missing data were balanced between the two treatment arms. Eight planned sensitivity analyses that tested the impact of non-protocol therapy, missing data, and informative censoring in the assessment of progression for individual patients were conducted; all retained statistical significance for the addition of bevacizumab. Conclusions: The PFS risk was reduced by more than half and the ORR more than doubled with the addition of bevacizumab to weekly paclitaxel in both analyses, confirming the substantial and robust bevacizumab treatment effect. The strong consistency of the IRF and Investigator based PFS and ORR results validate original data reported by ECOG in this open-label trial. IRF Assessed Investigator Assessed P N=354 P+B N=368 P N=354 P+B N=368 Progression-free survival (HR) 0.483 0.421 p value (log-rank) <0.0001 <0.0001 Median (months) 5.8 11.3 5.8 11.4 Objective response in patients with measurable disease at baseline (%) 22.2 49.8 23.4 48.0 p value <0.0001 <0.0001 HR=hazard ratio Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc., Roche Amgen, Genentech, Inc., Gilead Sciences Genentech, Inc. Genentech, Inc.

Randomized Phase III Trial of Capecitabine Compared With Bevacizumab Plus Capecitabine in Patients With Previously Treated Metastatic Breast Cancer

This randomized phase III trial compared the efficacy and safety of capecitabine with or without bevacizumab, a monoclonal antibody to vascular endothelial growth factor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. Patients were randomly assigned to receive capecitabine (2,500 mg/m2/d) twice daily on day 1 through 14 every 3 weeks, alone or in combination with bevacizumab (15 mg/kg) on day 1. The primary end point was progression-free survival (PFS), as determined by an independent review facility. From November 2000 to March 2002, 462 patients were enrolled. Treatment arms were balanced. No significant differences were found in the incidence of diarrhea, hand-foot syndrome, thromboembolic events, or serious bleeding episodes between treatment groups. Of other grade 3 or 4 adverse events, only hypertension requiring treatment (17.9% v 0.5%) was more frequent in patients receiving bevacizumab. Combination therapy significantly increased the response rates (19.8% v 9.1%; P = .001); however, this did not result in a longer PFS (4.86 v 4.17 months; hazard ratio = 0.98). Overall survival (15.1 v 14.5 months) and time to deterioration in quality of life as measured by the Functional Assessment Of Cancer Treatment--Breast were comparable in both treatment groups. Bevacizumab was well tolerated in this heavily pretreated patient population. Although the addition of bevacizumab to capecitabine produced a significant increase in response rates, this did not translate into improved PFS or overall survival.