Abstract Background. Triple negative breast cancer (TNBC) is the most aggressive molecular subtype. It is mostly observed in younger patients, however, substantial proportion of patients are above age of 60. Despite that, this group of patients was not studied and analyzed separately in previous studies. Objectives. To establish efficacy of neoadjuvant chemotherapy in elderly patients with stage II-III TNBC and patterns of progression for this group of patients. Methods. Since 2014 we treated 92 patients with histologically confirmed stage II-III TNBC. Neoadjuvant therapy included 6 cycles of Cisplatin 75mg/m2 day 1 and Paclitaxel 80mg/m2 days 1, 8, 15, every 4 weeks according to local protocol. After neoadjuvant chemotherapy patients proceeded to radical breast surgery with assessing pathological response. Then we analyzed clinical characteristics of patients and their survival according to the pathological response achieved. Results. In our analysis were included 92 patients, 22 of them were elderly patients (above 60). Pathological complete response was achieved in 57,6% of all patients. In the elderly group we observed significantly higher proportion of tumors with advanced stages (N3: 40,9% vs 20,0%, p<0.05, locally advanced: 77,3% vs 51,4%, p<0.05). Although not clinically significant, elderly patients less frequently achieved complete clinical response (28,6% vs 41,4%). Pathologic complete response was achieved in 52,6% of elderly patients and in 71,7% of younger patients (p<0.05). Higher proportion of patients above 60 experienced nephrotoxicity (54,5% vs 17,1%, p<0.05) and peripheral polyneuropathy (22,7% vs 17,1%, p=0.054). In this group of patients only 22,7% completed all 6 cycles as opposed to 65,7% of younger patients (p<0.05). Higher proportion of elderly patients had local recurrence: 45,5% vs 22,9% (p<0.05), visceral metastases: 36,4% vs 17,1% (p<0.05). We observed tendency for this group of patients to have liver and lungs as first sites of metastases (80%), as opposed to younger patients, for whom CNS was the most frequent first metastatic site (50%). To the date of cut-off (June 2019) 17 patients died, all of them due to the progression of the disease (31,8% in elderly group, 14,3% in younger group). Survival outcomes are presented in table below. Table 1. Survival outcomes.SurvivalBelow 60 y.o.Above 60 y.o.Recurrence-free survival<0.053 years73,7%61,9%5 years69,6%51,6%Survival without distant metastases<0.053 years78,9%68,6%5 years74,6%57,2%Overall survival0,0573 years81,8%72,4%5 years77%54,3% Conclusion. In our analysis elderly patients with early and locally advanced TNBC demonstrate decreased response, another safety profile and lower survival rates. Different efficacy could be explained with lower number of cycles of neoadjuvant chemotherapy administered and more advanced stages upon presentation. Different metastatic patterns which we observed in younger and elderly patients should be further studied. Citation Format: Olga Gordeeva, Irina Kolyadina, Lyudmila Zhukova, Inna Ganshina, Dmitry Komov, Andrey Meshcheryakov. Patterns of survival and efficacy of chemotherapy in elderly patients with triple-negative breast cancer treated in the neoadjuvant setting [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-16-34.

e12102 Background: Effect of neoadjuvant chemotherapy (NACT) is extremely important for patients with HER2-positive breast cancer stage II-III as it correlates with long-term outcomes. However, predictive factors for achieving complete pathologic response (pCR) remain unclear. Aim of the study: Assess an impact of clinical, morphological and genetic factors on pCR achievement in patients with HER2-positive breast cancer stage II-III treated by biosimilar of trastuzumab. Methods: We studied treatment results in 73 patients with HER2-positive breast cancer (BC) stage II-III (aged 29-71, median – 51 years), treated with NACT with anti-HER2 therapy and radical surgery in “N.N. Blokhin National Medical Research Center of Oncology” оf the Ministry of Health of the Russian Federation in 2015-2018. After radical surgery pathologic response was assessed. Initially operable tumors were observed in 45,2% patients, locally advanced - in 53,4%. Luminal HER2-positive BC was diagnosed in 41,1%, non-luminal HER2-positive in 58,9%. Ki67 was high (≥ 20%) in 91,5%. NACT included anthracycline and non-antracycline regimens with addition of biosimilar of trastuzumab ± pertuzumab. Radical mastectomy was performed in 78,8% patients, 21,2% had breast-conserving surgery. We studied biopsies obtained before the start of treatment in all women, HER2 amplification was detected by HER2 IQFISH pharmDx (DAKO) kit in accordance with ASCO/CAP 2018 guidelines. In 87,1% HER2+ status was defined as ASCO/CAP 2018 category 1; cluster amplification was detected in 30,1% patients. We analyzed the rate of bpCR и tpCR achievement depending on clinical, pathological data and amplification of HER2. Results: Pathologic complete response in primary tumor (bpCR) was achieved in 57,4%, both in primary tumor and lymph nodes (tpCR) – in 48,9% patients; bpCR achievement depended on age, NACT regimen, addition of pertuzumab and HER2 copy number ( < 0,05). The highest rate of bpCR was noted in women aged 50 and older (71,9%, p = 0,026); in patients received TCH±Р regimen (80,0%, p = 0,045); with addition of pertuzumab (88,9%, p = 0,049); and if cluster amplification was detected (81%, p = 0,013). Cluster amplification was the only one significant predictive factor for achieving tpCR: with cluster amplification - 68,8%, without - 38,7% (p = 0,049). Conclusions: Cluster amplification of HER2 is the most significant factor of especial sensitivity for NACT with biosimilar of trastuzumab in HER2-positive BC stage II-III.

BACKGROUND:In a phase 2 trial, lenvatinib, an inhibitor of VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor α, RET, and KIT, showed activity in hepatocellular carcinoma. We aimed to compare overall survival in patients treated with lenvatinib versus sorafenib as a first-line treatment for unresectable hepatocellular carcinoma. METHODS:This was an open-label, phase 3, multicentre, non-inferiority trial that recruited patients with unresectable hepatocellular carcinoma, who had not received treatment for advanced disease, at 154 sites in 20 countries throughout the Asia-Pacific, European, and North American regions. Patients were randomly assigned (1:1) via an interactive voice-web response system-with region; macroscopic portal vein invasion, extrahepatic spread, or both; Eastern Cooperative Oncology Group performance status; and bodyweight as stratification factors-to receive oral lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg) or sorafenib 400 mg twice-daily in 28-day cycles. The primary endpoint was overall survival, measured from the date of randomisation until the date of death from any cause. The efficacy analysis followed the intention-to-treat principle, and only patients who received treatment were included in the safety analysis. The non-inferiority margin was set at 1·08. The trial is registered with ClinicalTrials.gov, number NCT01761266. FINDINGS:Between March 1, 2013 and July 30, 2015, 1492 patients were recruited. 954 eligible patients were randomly assigned to lenvatinib (n=478) or sorafenib (n=476). Median survival time for lenvatinib of 13·6 months (95% CI 12·1-14·9) was non-inferior to sorafenib (12·3 months, 10·4-13·9; hazard ratio 0·92, 95% CI 0·79-1·06), meeting criteria for non-inferiority. The most common any-grade adverse events were hypertension (201 [42%]), diarrhoea (184 [39%]), decreased appetite (162 [34%]), and decreased weight (147 [31%]) for lenvatinib, and palmar-plantar erythrodysaesthesia (249 [52%]), diarrhoea (220 [46%]), hypertension (144 [30%]), and decreased appetite (127 [27%]) for sorafenib. INTERPRETATION:Lenvatinib was non-inferior to sorafenib in overall survival in untreated advanced hepatocellular carcinoma. The safety and tolerability profiles of lenvatinib were consistent with those previously observed. FUNDING:Eisai Inc.

e12651 Background: clinical and biological features and response to preoperative chemotherapy in genetic breast cancer (BC) stage T1-3N0-1 are poorly understood. Methods: Our study included 213 women (age 24-76, median - 47 years) with BC stage T1-3N0-1 treated in NCRC in 2004-2016. After neoadjuvant chemotherapy (anthracycline ± taxanes ± platinum regimes; in HER2+ BC with trastuzumab ± pertuzumab) patients had radical surgery. Tumor size distribution was: T1- 3,3%, T2- 63,4%, T3- 33,3; lymph node status was: N0 -25,8%, N1-74,2%. Biological subtype was luminal A (7,8%), luminal B HER2-negative (42,2%), luminal HER2+ (16,1%), triple negative (20,3%) and non-luminal HER2+ (13,5%). Genetic test of BRCA1/2 and CHEK-2 status was made in 82 women; clinically relevant genetic mutations (GM) were found in 16 cases, 19,5% (BRCA1- in 13,4%; CHEK2- in 3,7%; both BRCA1 and CHEK2- 2,4%). We studied the clinical and biological features and the rate of complete pathological response (pCR) in women with or without GM, analyze was made by SPSS 20,0. Results: We did not find any differences (p > 0,05) in histological type, grade, tumor size and lymph node status in group with or without GM. But median age of women with GM was significantly younger than without GM (33 vs 49 years, p < 0,01). Luminal A subtype was absent in group with GM in contrast to patients without GM (10,6%), but triple negative BC was in 50% women with GM and in 15% - without GM, р = 0,03. BRCA1 mutation associated with triple-negative BC (64%), but CHEK2 mutation - with HER2+ BC (60%), p < 0,01. The preoperative chemotherapy in group without GM included platinum regimes in 22% only, but in women with GM - in 62,5% cases. The rate of pCR was high (70,3% - in women with GM; 56,2% - in group without GM, р = 0,283). But the rate of pCR in non-genetic group did not depend from platinum incorporation in chemotherapy in contrast to women with GM who had the highest rate of pCR in platinum-containing chemotherapy (83%) and significantly lower rate of pCR (40%) in platinum-free regimes, p = 0,01. Conclusions: Genetic BC in Russian women was associated with young age and aggressive biology, but high response to preoperative platinum-containing chemotherapy

345 Background: LEN showed treatment effect on OS by statistical demonstration of noninferiority to SOR in a phase 3 study in pts with uHCC, with significant improvement ( P < 0.00001) in median PFS (7.4 vs 3.7 mos; HR: 0.66; 95% CI, 0.57−0.77), median TTP (8.9 vs 3.7 mos; HR: 0.63. 95% CI, 0.53−0.73), and ORR (24% vs 9%). Tumor assessments were by investigator review (IR) per modified RECIST (mRECIST). We present IIR results to assess concordance for IR vs IIR and mRECIST vs RECIST 1.1 by IIR. Methods: In this open-label study, pts with uHCC, ≥ 1 measurable target lesion, BCLC stage B or C, Child-Pugh class A, ECOG PS ≤ 1, and no prior systemic therapy were randomized 1:1 to LEN (body weight ≥60 kg: 12 mg/d; <60 kg: 8 mg/d) or SOR 400 mg twice daily. Primary endpoint was OS. Secondary efficacy endpoints were PFS, TTP, and ORR by mRECIST. IR tumor assessments were done every 8 wks. Post hoc exploratory blinded IIR studies were done using mRECIST and RECIST 1.1 (first timepoint at wk 8). Results: A total of 954 pts enrolled (LEN: 478; SOR: 476), of which 952 (99.8%) pts were IIR assessable (table). Adjudication rate (AR; percentage of cases adjudicated due to disagreement) for timepoint of PD was similar for mRECIST (47%) and RECIST 1.1 (45%); for responder (CR or PR)/nonresponder (SD, PD, or not evaluable [NE]), it was 32% for mRECIST and 17% for RECIST 1.1. PFS and TTP results were nearly the same per mRECIST by IIR as by IR and the same by IIR per mRECIST and RECIST 1.1. Very good concordance was seen between IIR and IR in best overall response (BOR) per mRECIST with the greatest discordance due to more pts being assessed as PR than SD for LEN. Conclusions: IIR supports IR results. ORR was higher in both arms by IIR vs IR but relative ORR was preserved in LEN vs SOR. Higher AR for IIR per mRECIST on response may be due to the greater number of responders or disease complexity. Median PFS and TTP were the same by IIR per mRECIST and RECIST 1.1, showing these data can be compared between methods. Clinical trial information: NCT01761266. [Table: see text]

4001 Background: SOR is the only approved agent in uHCC and new options are needed. LEN, an inhibitor of vascular endothelial growth factor receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet derived growth factor receptor α, RET, and KIT, showed activity in uHCC in a phase II trial. We report a phase III trial of LEN vs SOR as first-line therapy for uHCC. Methods: In this randomized, open-label, noninferiority (NI) study, pts had uHCC, ≥ 1 measurable target lesion, Barcelona Clinic Liver Cancer stage B or C, Child-Pugh class A, ECOG PS ≤ 1, and no prior systemic therapy. Pts were randomized 1:1 to LEN (body weight ≥ 60 kg: 12 mg/day; < 60 kg: 8 mg/day) or SOR 400 mg twice daily. The primary endpoint was overall survival (OS). The OS hazard ratio (HR) and its 95% CI were estimated with a stratified Cox proportional hazard model. The predefined NI margin was 1.08. Secondary efficacy endpoints were progression-free survival (PFS), time to progression (TTP) and objective response rate (ORR) by modified RECIST. Type I error rates for secondary efficacy endpoints were controlled with a fixed sequence procedure at 2-sided α = 0.05 after OS NI was claimed. Results: 954 Pts enrolled (LEN: 478; SOR: 476). Efficacy outcomes are shown in the table. A similar number of pts in both arms had treatment-emergent adverse events (TEAEs). Most common LEN TEAEs were hypertension (42%), diarrhea (39%), decreased appetite (34%), decreased weight (31%), and fatigue (30%). Median (range) treatment duration was 5.7 mos (0−35.0) for LEN and 3.7 mos (0.1−38.7) for SOR. 13% Of LEN-treated and 9% of SOR-treated pts discontinued due to adverse events. 33% Of LEN-treated and 39% of SOR-treated pts received second-line therapy. Conclusions: LEN is noninferior in OS, and achieves statistically significant and clinically meaningful improvements in PFS, TTP, and ORR, as first line therapy for uHCC. TEAEs were consistent with the known LEN safety profile. Clinical trial information: NCT01761266. [Table: see text]

Background CT-P6 is a proposed biosimilar to reference trastuzumab. In this study, we aimed to establish equivalence of CT-P6 to reference trastuzumab in neoadjuvant treatment of HER2-positive early-stage breast cancer.Methods In this randomised, double-blind, active-controlled, phase 3 equivalence trial, we recruited women aged 18 years or older with stage I-IIIa operable HER2-positive breast cancer from 112 centres in 23 countries. Inclusion criteria were an Eastern Cooperative Oncology Group performance status score of 0 or 1; a normal left ventricular ejection fraction of at least 55%; adequate bone marrow, hepatic, and renal function; at least one measureable lesion; and known oestrogen and progesterone receptor status. Exclusion criteria included bilateral breast cancer, previous breast cancer treatment, previous anthracycline treatment, and pregnancy or lactation. We randomly allocated patients 1:1 to receive neoadjuvant CT-P6 or reference trastuzumab intravenously (eight cycles, each lasting 3 weeks, for 24 weeks; 8 mg/kg on day 1 of cycle 1 and 6 mg/kg on day 1 of cycles 2-8) in conjunction with neoadjuvant docetaxel (75 mg/m(2) on day 1 of cycles 1-4) and FEC (fluorouracil [500 mg/m(2)], epirubicin [75 mg/m2], and cyclophosphamide [500 mg/m(2)]; day 1 of cycles 5-8) therapy. We stratified randomisation by clinical stage, receptor status, and country and used permuted blocks. We did surgery within 3-6 weeks of the final neoadjuvant study drug dose, followed by an adjuvant treatment period of up to 1 year. We monitored long-term safety and efficacy for 3 years after the last patient was enrolled. Participants and investigators were masked to treatment until study completion. The primary efficacy endpoint, analysed in the per-protocol population, was pathological complete response, assessed via specimens obtained during surgery, analysed by masked central review of local histopathology reports. The equivalence margin was -0.15 to 0.15. This trial is registered with ClinicalTrials.gov, number NCT02162667, and is ongoing, but no longer recruiting.Findings Between Aug 7, 2014, and May 6, 2016, we randomly allocated 549 patients (271 [49%] to CT-P6 vs 278 [51%] to reference trastuzumab). A similar proportion of patients achieved pathological complete response with CT-P6 (116 [46.8%; 95% CI 40.4-53.2] of 248 patients) and reference trastuzumab (129 [50.4%; 44.1-56.7] of 256 patients). The 95% CI of the estimated treatment outcome difference (-0.04% [95% CI -0.12 to 0.05]) was within the equivalence margin. 19 (7%) of 271 patients in the CT-P6 group reported serious treatment-emergent adverse events versus 22 (8%) of 278 in the reference trastuzumab group; frequent (occurring in more than one patient) serious adverse events were febrile neutropenia (four [1%] vs one [<1%]) and neutropenia (one [<1%] vs two [1%]). Grade 3 or worse treatment-related adverse events occurred in 17 (6%) of 271 patients in the CT-P6 group versus 23 (8%) of 278 in the reference trastuzumab group; the most frequently reported adverse event was neutropenia in ten (4%) versus 14 (5%).Interpretation CT-P6 showed equivalent efficacy to reference trastuzumab and adverse events were similar. Availability of trastuzumab biosimilars could increase access to this targeted therapy for HER2-positive early-stage cancer.

510 Background: CT-P6 (C) is a proposed biosimilar to trastuzumab. This trial (NCT02162667) evaluated the similarity of C and trastuzumab in efficacy and safety for HER2+ EBC. Methods: 549 patients with HER2+ EBC were randomized to receive C (n=271) or trastuzumab (n=278) in combination with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin, and cyclophosphamide (Cycles 5-8). C or trastuzumab was administered at 8 mg/kg (Cycle 1 only) followed by 6 mg/kg every 3 weeks. The primary endpoint was pathological complete response (pCR) rate at surgery. Secondary endpoints were overall response rate (ORR), PK, PD and safety. After surgery, patients received adjuvant C or trastuzumab to complete a total of 1-year treatment. Results: The pCR rate was 46.8% for C and 50.4% for trastuzumab. The 95% CIs for the risk ratio estimate were within the equivalence margin (0.74, 1.35) in PPS and ITT analyses. Other efficacy endpoints were similar between C and trastuzumab. The proportion of patients with at least 1 treatment-emergent SAE was 6.6% for C and 7.6% for trastuzumab. Only 1 patient in each group withdrew treatment due to significant LVEF decrease. Infusion-related reaction was reported for 8.5% of patients in C and 9.0% of patients in trastuzumab. Conclusions: This study demonstrated the similarity of efficacy in terms of pCR between CT-P6 and trastuzumab in EBC patients. Secondary efficacy endpoints also supported the similarity between CT-P6 and trastuzumab. CT-P6 was well tolerated with a similar safety profile to that of trastuzumab during the neoadjuvant period. Clinical trial information: NCT02162667. [Table: see text]

e11541 Background: the differences in treatment and recurrence-free (RFS) and cancer-specific (CSS) survival in Russian women with breast cancer stage I during last 25 years. Methods: In our study included 1341 women with breast cancer stage I treated in RCRC and RMAPE 1985-2012. We analyzed the clinical, morphological data, type of therapy in different time-period ( < 1995; 1996-1999; 2000-2004; 2005-2009; > 2010) and prognostic value these factors for RFS and CSS (median follow-up - 96 month). Results: Patients with breast cancer stage I treated < 2000 used adjuvant system therapy (endocrinotherapy, chemotherapy or both) only in 24% cases. In contrast to this, women treated > 2000 used adjuvant system therapy in 61% (2000-2004), in 85% (2005-2009) and in 91% ( > 2010), p < 0,0001. As result, 5- and 10-years RFS in women treated < 2000 was 71 and 61% only, and in patients treated > 2000 was 93 and 89%, p < 0,0001. The same data we saw in 5- and 10-years CSS: in women treated < 2000 was 87 and 75% only, in patients treated > 2000 was significant higher (98 and 95%), p < 0,0001. In multivariate analyze for prognostic value of different clinical and morphological factors for RFS and CSS only two factors were significant (p < 0,05): biological subtype and adjuvant system therapy. The most favorable was luminal A subtype (5- and 8-years RFS was 97 and 94%; 5- and 8-years CSS was 99 and 94%). In compare with luminal A subtype the risk of recurrences was significant higher in luminal B subtypes (HR 1,393), in triple negative cancer (HR 2,297) and ER-PR-HER2+ subtype (HR 6,001), p = 0,04. Adjuvant system therapy significantly reduced the risk of recurrence (HR = 0,276, p < 0,001). In compare with luminal A subtype the risk of death from cancer was significant higher in luminal B subtype (HR 1,466), triple-negative cancer (HR 4,269) and in ER-PR-HER2+ subtype (HR 7,477), p = 0,049. Adjuvant system therapy significantly reduced the risk of death from cancer too (HR 0,234, p = 0,023). Conclusions: Adjuvant system therapy according to tumor biology became the standard treatment in women with breast cancer stage I after 2000 and significantly improved RFS and CSS.

TPS8118^ Background: Hsp90 is a molecular chaperone recognized as a key facilitator of cancer cell growth and survival. Ganetespib is a resorcinolic Hsp90 inhibitor that has shown single-agent activity in patients with lung, breast, and other cancers after progression on standard treatments. Ganetespib in combination with docetaxel induces synergistic efficacy in human non-small-cell lung carcinoma (NSCLC) tumor xenografts. Ganetespib is well tolerated and has not shown severe liver or common ocular toxicities reported for other Hsp90 inhibitors. Transient diarrhea is the most common adverse event, and is manageable with appropriate supportive care. A large randomized Phase 2 study of ganetespib in combination with docetaxel in advanced NSCLC patients (GALAXY-1 Trial) indicated good tolerability of the combination, and improvement in efficacy, including OS. Methods: GALAXY-2 is a randomized (1:1), international, open-label Phase 3 study enrolling patients who received and progressed on 1 prior systemic platinum-based combination therapy for advanced NSCLC of adenocarcinoma histology, were diagnosed ≥6 months before study entry, and whose tumors are negative for both EGFR mutations and ALK translocation (Target Patient Population [TPP]). Patients (N=700 TPP) are prospectively stratified for ECOG PS, total screening LDH, and geographic region (North America and Western Europe vs Rest of World). The primary endpoint is OS in the TPP. Key secondary endpoints include PFS, ORR, DCR, and DOR in the TPP. OS will also be analyzed in 3 subpopulations of the TPP: mKRAS, elevated LDH, and elevated LDH5. Patients in the control arm are treated with docetaxel 75 mg/m2 on Day 1 of a 3-week cycle. In the combination arm, ganetespib 150 mg/m2 is given on Day 1 with 75 mg/m2 docetaxel, and ganetespib 150 mg/m2 alone is given on Day 15 of each 3-week cycle. Two interim analyses for OS will be performed. Tumor tissue and blood samples will be collected for planned translational studies. Clinical trial information: NCT01798485.

629 Background: CT-P6(C) is an anti-HER2 MoAb, a biosimilar to trastuzumab (T). This trial is a global phase III study to compare C with T, both in combination with paclitaxel (P) as first-line treatment in women with HER2+ MBC. Methods: 475 patients with centrally confirmed HER2+ MBC were randomized to receive either C+P (n=244) or T+P (n=231). Patients had to have a baseline LVEF ≥50% and no history of serious cardiac disease. Study medication was as follows: C or T 8 mg/kg i.v. (day 1), followed by 3-weekly C or T 6 mg/kg. P (175 mg/m23-weekly) was co-administered. The primary endpoint was overall response rate (ORR) as determined by independent review. Pooled analysis with data from phase I/IIb (NCT01084863) and III studies (NCT01084876) was predefined and endorsed by the EMA. Patient safety was monitored throughout the study by an independent data monitoring committee. Treatment was continued until disease progression, death or patient’s withdrawal. Results: In the pooled ITT population, ORR was 57% for C+P and 62% for T+P (difference: 5%; 95% CI: -0.14, 0.04) during the first 8 cycles of treatment. The limits of the 95% CIs for the difference in the proportions of responders were contained within the pre-defined range [-0.15, 0.15] required for equivalence. Median time to progression and median time to response were 11.07 vs. 12.52 months (P =0.10), and 1.38 vs. 1.38 months (P =0.37) for C+P and T+P, respectively. Frequency of treatment-related AEs is shown in the Table. Conclusions: Equivalence of C and T was observed for ORR in patients with HER2+ MBC in combination with P as first-line therapy. Secondary efficacy endpoints also supported the comparability between C and T. C was well tolerated with a safety profile comparable to that of T. Clinical trial information: NCT01084876. [Table: see text]

PURPOSE Brivanib is a dual inhibitor of vascular-endothelial growth factor and fibroblast growth factor receptors that are implicated in the pathogenesis of hepatocellular carcinoma (HCC). Our multinational, randomized, double-blind, phase III trial compared brivanib with sorafenib as first-line treatment for HCC. PATIENTS AND METHODS Advanced HCC patients who had no prior systemic therapy were randomly assigned (ratio, 1:1) to receive sorafenib 400 mg twice daily orally (n = 578) or brivanib 800 mg once daily orally (n = 577). Primary end point was overall survival (OS). Secondary end points included time to progression (TTP), objective response rate (ORR), disease control rate (DCR) based on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and safety. RESULTS The primary end point of OS noninferiority for brivanib versus sorafenib in the per-protocol population (n = 1,150) was not met (hazard ratio [HR], 1.06; 95.8% CI, 0.93 to 1.22), based on the prespecified margin (upper CI limit for HR ≤ 1.08). Median OS was 9.9 months for sorafenib and 9.5 months for brivanib. TTP, ORR, and DCR were similar between the study arms. Most frequent grade 3/4 adverse events for sorafenib and brivanib were hyponatremia (9% and 23%, respectively), AST elevation (17% and 14%), fatigue (7% and 15%), hand-foot-skin reaction (15% and 2%), and hypertension (5% and 13%). Discontinuation as a result of adverse events was 33% for sorafenib and 43% for brivanib; rates for dose reduction were 50% and 49%, respectively. CONCLUSION Our study did not meet its primary end point of OS noninferiority for brivanib versus sorafenib. However, both agents had similar antitumor activity, based on secondary efficacy end points. Brivanib had an acceptable safety profile, but was less well-tolerated than sorafenib.