LUX-breast 2: Phase II, open-label study of oral afatinib in HER2-overexpressing metastatic breast cancer (MBC) patients (pts) who progressed on prior trastuzumab (T) and/or lapatinib (L)

This journal suppl. is the 2012 ASCO Meeting Abstracts Part 1Open Access JournalGeneral Poster Session: Breast Cancer - HER2/ER: abstract no. TPS651BACKGROUND: Management of HER2-overexpressing MBC has improved over the past decade. However, pts still develop resistance to currently available HER2-targeted therapies and novel effective treatments are increasingly required as dual targeted combinations are given in early treatment lines already. Current therapies focus on targeting HER2 and do not inhibit all relevant ErbB Family dimers. Afatinib is an oral, irreversible ErbB Family Blocker that inhibits signaling through activated EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptors and transphosphorylation of ErbB3. Preclinical studies have demonstrated efficacy in T-sensitive and T-resistant human BC xenograft models dependent on ErbB signaling. Efficacy of afatinib in a T-resistant SUM 190 xenograft model has been shown to be increased by addition of IV vinorelbine (V). Afatinib monotherapy has shown promising clinical benefit in 46% of HER2-overexpressing MBC pts who progressed on prior T, with 10% of pts achieving PR. METHODS: This open-label Phase II trial (NCT01271725) investigates efficacy and safety of afatinib alone (40 mg/d) followed by afatinib ‘beyond progression’ plus chemotherapy in 120 pts with HER2-overexpressing MBC, who progressed on prior neoadjuvant and/or adjuvant T and/or L. Pts who progress on afatinib monotherapy receive afatinib plus either weekly paclitaxel (P) 80 mg/m2 or V 25 mg/m2. Eligible pts have confirmed HER2-overexpressing BC, stage IV disease measurable by RECIST 1.1, progressed on T and/or L therapy in either neoadjuvant and/or adjuvant setting, are eligible for retreatment with P or V and should not have been pretreated with P (≤12 months) or V, respectively. Exclusion criteria: inadequate cardiac, renal, hepatic and hematological function, pre-existing gastrointestinal dysfunction, rapidly progressing visceral disease, ILD and active brain metastases. The primary endpoint is objective response (OR) and secondary endpoints include best overall response, duration of OR and PFS; safety will be assessed separately for afatinib mono- and combination therapy. Patient enrollment began in May 2011 in 35 sites and 5 countries.link_to_OA_fulltex

Abstract P1-10-01: A randomized, double-blind trial to compare the efficacy and safety of proposed biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim in patients with breast cancer (PROTECT1)

Abstract Background: An abbreviated pathway for biological products shown to be biosimilar to the reference product exists in Europe and the US. The randomized PROTECT1 trial compared the efficacy and safety of the proposed biosimilar pegfilgrastim with reference pegfilgrastim. Methods: In this multinational, prospective, double-blind trial, chemotherapy-naïve women aged ≥18 years with histologically proven breast cancer received up to 6 cycles of (neo)-adjuvant TAC chemotherapy (docetaxel 75 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2). Patients were randomized to a single 6 mg SC injection of the proposed biosimilar pegfilgrastim (LA-EP2006) or the reference (Neulasta®) on day 2 of each cycle. Primary endpoint was duration of severe neutropenia (DSN) during Cycle 1, defined as number of consecutive days with an absolute neutrophil count (ANC) &amp;lt;0.5 x 109/L. The study was powered at 90% and had a hierarchical testing procedure utilizing a ±1 day margin to test for equivalence (2-sided 95% confidence interval [CI]) and a subsequent −0.6 day non-inferiority margin (1-sided 97.5% CI) for DSN during Cycle 1. DSN was analyzed with an ANCOVA model adjusted for treatment, chemotherapy, region and baseline ANC. Secondary efficacy assessments were: time to ANC recovery, ANC nadir, incidence of febrile neutropenia, number of days of fever, frequency of infections and mortality due to infection. Safety was assessed at 4 weeks and 6 months after the last pegfilgrastim administration. Immunogenicity was assessed by testing for neutralizing anti-pegfilgrastim antibodies. Results: A total of 316 patients were randomized and included in the full analysis set (LA-EP2006: n=159; reference: n=157). Baseline demographics were similar in both groups (mean±SD age: LA-EP2006 49.9±9.53, reference 50.5±10.87 years; breast cancer stage II-III: LA-EP2006 n=155 [97.5%], reference n=151 [96.2%]). Mean±SD DSN in Cycle 1 was 0.75±0.88 days with LA-EP2006 and 0.83±0.90 days with reference, with a treatment difference of 0.07 days (95% CI: −0.12, 0.26); LA-EP2006 was both equivalent and non-inferior to the reference. There were no clinically meaningful differences between LA-EP2006 and reference in incidence of febrile neutropenia (3.8% vs 7.0% in Cycle 1, 5.7% vs 7.6% across all cycles), days with fever, depth of ANC nadir in Cycle 1, time to ANC recovery in Cycle 1, or frequency of infections in Cycle 1 and across all cycles. Treatment-emergent adverse events (TEAEs) were similar across groups and consistent with the known safety profile of pegfilgrastim. Most frequently reported TEAEs related to treatment were musculoskeletal and connective tissue disorders (LA-EP2006 4.4%, reference 5.7%). Serious TEAEs were reported in 10.1% of LA-EP2006 and 13.4% of reference patients. No neutralizing anti-pegfilgrastim antibodies were detected. Conclusions: Proposed biosimilar pegfilgrastim (LA-EP2006) met the primary endpoint demonstrating both equivalence and non-inferiority to the reference. LA-EP2006 and the reference are similar with no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving (neo)-adjuvant myelosuppressive chemotherapy. Citation Format: Harbeck N, Zbarskaya I, Lipatov O, Frolova M, Udovitsa D, Topuzov E, Ganea-Motan DE, Nakov R, Singh P, Rudy A, Blackwell K. A randomized, double-blind trial to compare the efficacy and safety of proposed biosimilar pegfilgrastim (LA-EP2006) with reference pegfilgrastim in patients with breast cancer (PROTECT1). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-10-01.</jats:p

Abstract OT1-1-17: LUX-Breast 2: Phase II, open-label study of oral afatinib in HER2-overexpressing metastatic breast cancer (MBC) patients (pts) who progressed on prior trastuzumab and/or lapatinib*

Abstract Background: Management of HER2-overexpressing MBC has improved over the past decade. However, pts still develop resistance to currently available HER2-targeted therapies and novel effective treatments are increasingly required as dual targeted combinations are given in early treatment lines already. Current therapies focus on targeting HER2 and do not inhibit all relevant ErbB Family dimers. Afatinib is an oral, irreversible ErbB Family Blocker that inhibits signaling through activated EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptors and transphosphorylation of ErbB3. Preclinical studies have demonstrated efficacy in trastuzumab-sensitive, and trastuzumab-resistant human BC xenograft models dependent on ErbB signaling. Efficacy of afatinib in a trastuzumab-resistant SUM190 xenograft model has been shown to be increased by addition of intravenous (i.v.) vinorelbine. Afatinib monotherapy has shown promising clinical benefit in 46% of HER2-overexpressing MBC pts who progressed on prior trastuzumab, with 10% of pts achieving a partial response.1 Methods: This open-label Phase II trial (NCT01271725) investigates efficacy and safety of afatinib alone (40 mg/day) followed by afatinib ‘beyond progression’ in combination with chemotherapy in 120 pts with HER2-overexpressing MBC, who progressed on prior neoadjuvant and/or adjuvant trastuzumab and/or lapatinib. Pts who progress on afatinib monotherapy receive afatinib + either weekly paclitaxel 80 mg/m2 or vinorelbine i.v. 25 mg/m2. Eligible pts have confirmed HER2-overexpressing BC, Stage IV disease measurable by RECIST 1.1, progressed on trastuzumab and/or lapatinib therapy in either neoadjuvant and/or adjuvant setting, are eligible for retreatment with paclitaxel (i.e. should not have been pretreated with paclitaxel within the past 12 months), or are eligible for treatment with vinorelbine (i.e. should not have been pretreated with vinorelbine). Exclusion criteria include inadequate cardiac, renal, hepatic and hematological function, pre-existing gastrointestinal dysfunction, rapidly progressing visceral MBC, interstitial lung disease, and active brain metastases. The primary endpoint is objective response (OR) and secondary endpoints include best overall response, duration of OR, progression-free survival (PFS) and safety. PFS and safety will be assessed separately for afatinib mono- and combination therapy. An early stopping rule was deployed to minimize the number of pts treated should afatinib be ineffective; once 20 evaluable pts (according to RECIST 1.1) completed at least two courses of afatinib (or progressed during the first course), a meeting was held to evaluate the objective tumor response rate and to decide whether to proceed with the trial or stop due to futility. If at least one unconfirmed OR had been witnessed from all available information at the time, then the trial was to continue to full accrual. This early stopping rule for futility has been passed and the trial will continue to full accrual. Pt enrollment began in May 2011 in ∼40 sites and five countries. 1. Lin NU, et al. Breast Cancer Res Treat 2012. DOI: 10.1007/s10549-012-2003-y. *Updated abstract from ASCO 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr OT1-1-17.</jats:p

Oxaliplatin and 5-FU/folinic acid (modified FOLFOX6) with or without aflibercept in first-line treatment of patients with metastatic colorectal cancer: the AFFIRM study.

BACKGROUND: The combination of aflibercept with FOLFIRI has been shown to significantly prolong overall survival in patients with metastatic colorectal cancer (mCRC) after progression on oxaliplatin-based therapy. This trial evaluated the addition of aflibercept to oxaliplatin-based first-line treatment of patients with mCRC. PATIENTS AND METHODS: Patients with mCRC were randomized to receive first-line therapy with mFOLFOX6 plus aflibercept (4 mg/kg) or mFOLFOX6 alone. The primary end point of this phase II study was the progression-free survival (PFS) rate at 12 months in each arm. The analysis of efficacy between the arms was a pre-planned secondary analysis. RESULTS: Of 236 randomized patients, 227 and 235 patients were evaluable for the primary efficacy analysis and safety, respectively. The probabilities of being progression-free at 12 months were 25.8% [95% confidence interval (CI) 17.2-34.4] for the aflibercept/mFOLFOX6 arm and 21.2% (95% CI 12.2-30.3) for the mFOLFOX6 arm. The median PFS was 8.48 months (95% CI 7.89-9.92) for the aflibercept/mFOLFOX6 arm and 8.77 months (95% CI 7.62-9.27) for the mFOLFOX6 arm; the hazard ratio of aflibercept/mFOLFOX6 versus mFOLFOX6 was 1.00 (95% CI 0.74-1.36). The response rates were 49.1% (95% CI 39.7-58.6) and 45.9% (95% CI 36.4-55.7) for patients treated with and without aflibercept, respectively. The most frequent treatment-emergent grade 3/4 adverse events (AEs) excluding laboratory abnormalities reported for aflibercept/mFOLFOX6 versus mFOLFOX6 were neuropathy (16.8% versus 17.2%) and diarrhea (13.4% versus 5.2%). Neutropenia grade 3/4 occurred in 36.1% versus 29.3%. The most common vascular endothelial growth factor inhibition class-effect grade 3/4 AEs for aflibercept/mFOLFOX6 versus mFOLFOX6 were hypertension (35.3% versus 1.7%), proteinuria (9.2% versus 0%), deep vein thrombosis (5.9% versus 0.9%) and pulmonary embolism (5.9% versus 5.2%). CONCLUSION: No difference in PFS rate was observed between treatment groups. Adding aflibercept to first-line mFOLFOX6 did not increase efficacy but was associated with higher toxicity. CLINICAL TRIAL NUMBER: NCT00851084, www.clinicaltrials.gov, EudraCT 2008-004178-41

РЕЗУЛЬТАТЫ МНОГОЦЕНТРОВОГО ДВОЙНОГО СЛЕПОГО РАНДОМИЗИРОВАННОГО КЛИНИЧЕСКОГО ИССЛЕДОВАНИЯ ПЕРВОЙ ФАЗЫ ПРЕПАРАТА BCD-022 ПО СРАВНЕНИЮ С ПРЕПАРАТОМ ГЕРЦЕПТИН®, ПРИМЕНЯЕМЫХ В СОЧЕТАНИИ С ПАКЛИТАКСЕЛОМ У БОЛЬНЫХ МЕТАСТАТИЧЕСКИМ РАКОМ МОЛОЧНОЙ ЖЕЛЕЗЫ

Within the framework of multicenter double-blind randomized clinical trial studied pharmacokinetics and safety of BCD-022 (trastuzumab, "Biocad" company, Russia), compared with the drug Herceptin (trastuzumab, F. Hoffmann-La Roche Ltd., Switzerland). Evaluation of the effectiveness was not the aim of the interim analysis, the results of which are shown. BCD-022 and Herceptin were used in combination with paclitaxel in patients with metastatic breast cancer with HER2 overexpressing (HER2 (+), mBC).Methods. The analysis included 46 patients with HER2 (+) metastatic breast cancer (mBC) at the age of 29 to 71 years (22 - in the group of studied drug BCD-022 and 24 - in the Herceptin group). All patients received one course of therapy of BCD-022 or Herceptin 8 mg/kg intravenously and paclitaxel 175 mg/m2 intravenously on day 1 of a three-week course of treatment and continue to receive treatment with the same scheme with the use of trastuzumab 6 mg/kg (mandatory in the study is to conduct 6 courses of therapy). Randomization was carried out in groups in a ratio of 1: 1. The primary endpoint of pharmacokinetics evaluation was the area under the curve "concentration-time» (AUC0-504) of trastuzumab after a single application, the secondary - Cmax, T1 / 2 and Tmax. Safety was assessed based on the incidence of adverse events after the first course of therapy.Results. Haematological toxicity, myalgia and arthralgia were the most frequent adverse events. Most reported adverse events had mild to moderate grade according to CTCA 4.03 and were caused  by effect of myelosuppressive chemotherapy. There were no statistically significant differences in adverse events frequency between the groups. There were 6 serious adverse events: 2 - in the BCD-022 group and 4 - in the Herceptin group. All pharmacokinetic parameters, including the primary endpoint (AUC 0-504) and secondary endpoints (Cmax, T1 / 2 and Tmax), of studied drug BCD-022 and Herceptin had no statistically significant difference.Conclusion. BCD-022 (trastuzumab, "Biocad" company, Russia) regarding to its safety profile and pharmacokinetic properties is fully consistent with the original drug trastuzumab Herceptin (F. Hoffmann-La Roche Ltd., Switzerland) and can be recommended for further clinical study.В рамках многоцентрового двойного слепого рандомизированного клинического исследования была изучена фармакокинетика и безопасность препарата BCD-022 (трастузумаб, ЗАО «БИОКАД», Россия) по сравнению с препаратом Герцептин® (трастузумаб, Ф. Хоффманн-Ля Рош Лтд, Швейцария). Оценка эффективности не входила в задачи промежуточного анализа, результаты которого представлены. BCD-022 и Герцептин® применялись в комбинации с паклитакселом у пациенток метастатическим раком молочной железы с гиперэкспрессией HER2 (HER2 (+) мРМЖ).Методы. В анализ включено 46 больных HER2 (+) мРМЖ в возрасте от 29 до 71 года (22 — в группу исследуемого препарата BCD-022, 24 — в группу Герцептин®). Все пациентки получили 1 курс терапии по схеме BCD-022 или Герцептин® 8 мг/кг внутривенно капельно и паклитаксел 175 мг/м2 внутривенно в 1 день трехнедельного курса и продолжают лечение по той же схеме с использованием трастузумаба в дозе 6 мг/кг (обязательным в исследовании является проведение 6 курсов терапии). Рандомизация в группы производилась в соотношении 1:1. Первичной конечной точкой для оценки фармакокинетики была площадь под кривой «концентрация-время» (AUC0–504) трастузумаба после однократного применения, вторичными — Cmax, T1/2 и Tmax. Безопасность оценивалась на основании частоты нежелательных явлений после первого курса терапии.Результаты. Среди нежелательных явлений наиболее часто встречалась гематологическая токсичность, миалгия, артралгия. Большинство зарегистрированных нежелательных явлений имели легкую и умеренную степень по СТСАЕ 4.03 и были обусловлены проведением миелосупрессивной химиотерапии. Статистически значимых различий между группами не было выявлено ни по одному из нежелательных явлений. Зарегистрировано 6 серьезных нежелательных явлений: 2 — в группе исследуемого препарата BCD-022 и 4 — в группе Герцептин®. Все фармакокинетические показатели, включая первичную конечную точку (AUC0–504) и вторичные конечные точки (Cmax, T1/2 и Tmax), исследуемого препарата BCD-022 и Герцептин® не имели статистически значимых отличий.Заключение. BCD-022 (трастузумаб, ЗАО «БИОКАД», Россия) по своему профилю безопасности и фармакокинетическим свойствам полностью соответствует оригинальному препарату трастузумаба Герцептин® (Ф. Хоффманн-Ля Рош Лтд, Швейцария) и может быть рекомендован для дальнейшего клинического изучения

Rituximab biosimilar RTXM83 versus reference rituximab in combination with CHOP as first-line treatment for diffuse large B-cell lymphoma: a randomized, double-blind study

This multicenter, double-blind, randomized study compared the efficacy, pharmacokinetics (PKs)/pharmacodynamics (PDs), safety and immunogenicity profile of RTXM83 vs. reference rituximab (R-rituximab), both with CHOP, as first-line treatment of diffuse large B-cell lymphoma (DLBCL). A total of 272 patients <65 years of age, with good prognosis (136 per arm) were randomized (1:1) to receive six cycles of either RTXM83 or R-rituximab. The primary efficacy endpoint was achieved (overall response rate of 83.6% for RTXM83 and 82.9% for R-rituximab) with a difference 0.7% between arms (95%CI: [-8.77% to 10.17%]) fulfilling the predefined non-inferiority margin (-13%). Similar number of patients reported at least one adverse event (AE) (131 per arm) or one serious AE (47 with RTXM83 and 45 with R-rituximab). Anti-drug antibody development was comparable between the arms. PK/PD secondary endpoint results support similarity between the compounds. RTXM83 exhibits non-inferior efficacy and similar safety/immunogenicity to R-rituximab, being an accessible alternative for the treatment of patients with previously untreated DLBCL

Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study

Background: Most patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma relapse after initial therapy. Bendamustine plus rituximab is often used in the relapsed or refractory setting. We assessed the efficacy and safety of adding ibrutinib, an oral covalent inhibitor of Bruton's tyrosine kinase (BTK), to bendamustine plus rituximab in patients with previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma. Methods: The HELIOS trial was an international, double-blind, placebo-controlled, phase 3 study in adult patients (>= 18 years of age) who had active chronic lymphocytic leukaemia or small lymphocytic lymphoma with measurable lymph node disease (>1.5 cm) by CT scan, and had relapsed or refractory disease following one or more previous lines of systemic therapy consisting of at least two cycles of a chemotherapy-containing regimen, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, and adequate bone marrow, liver, and kidney function. Patients with del(17p) were excluded because of known poor response to bendamustine plus rituximab. Patients who had received previous treatment with ibrutinib or other BTK inhibitors, refractory disease or relapse within 24 months with a previous bendamustine-containing regimen, or haemopoietic stem-cell transplant were also excluded. Patients were randomly assigned (1:1) by a web-based system to receive bendamustine plus rituximab given in cycles of 4 weeks' duration (bendamustine: 70 mg/m.intravenously on days 2-3 in cycle 1, and days 1-2 in cycles 2-6; rituximab: 375 mg/m.on day 1 of cycle 1, and 500 mg/m.on day 1 of cycles 2-6 for a maximum of six cycles) with either ibrutinib (420 mg daily orally) or placebo until disease progression or unacceptable toxicity. Patients were stratified according to whether they were refractory to purine analogues and by number of previous lines of therapy. The primary endpoint was independent review committee (IRC)-assessed progression-free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. Findings: Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13.7-20.7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13.3 months (11.3-13.9) in the placebo group (hazard ratio [HR] 0.203, 95% CI 0.150-0.276; p<0.0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0.203, 95% CI 0.150-0.276; p<0.0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. Interpretation: In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile

Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study

Background: In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. Methods: LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II–IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed. Findings: Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1–94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51–0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. Interpretations: Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. Funding: Janssen Research &amp; Development