Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. METHODS: We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. RESULTS: Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. CONCLUSIONS: In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.)

Cost and Utilization Of Stored Autologous PBSC To Support Tandem ASCT In MM Patients In The Era Of Novel Agent Therapy

Introduction Historically, autologous stem cell transplantation (ASCT) for multiple myeloma (MM) improves overall survival (OS) compared to conventional chemotherapy alone. Before the introduction of novel agent therapy, tandem ASCT, defined as a second ASCT within 180 days of the first, was an important option for suboptimal responses after an initial ASCT and thus collecting adequate peripheral blood stem cells (PBSCs) for 2 transplants has been considered standard of care. However, the role of tandem transplants is being challenged by novel agent maintenance strategies. Considering this changing landscape of MM therapy, we sought to evaluate the current PBSC collection and storage practices that set the CD34+ cell dose goal to be sufficient for 2 transplants. Methods We obtained clinical, PBSC collection and storage data on MM patients who underwent ASCT from 1993 to 2011 from the Autologous Transplant and Cellular Therapy Laboratory databases at the Fred Hutchinson Cancer Research Center. We determined frequencies and trends of all second ASCTs, including tandem, costs involved in PBSC collection, storage, and utilization of the product that remained cryopreserved for a second ASCT. Cell dose target at our center is 5 x 106 CD34+ cells/kg/transplant. To analyze trends over time, we divided the sample into groups of 3 or 4 year periods. Collection and cryopreservation costs for second ASCT were calculated by first determining the number of days required to collect sufficient PBSC for one ASCT, then the number of additional days to complete the actual collection, and the cumulative costs of long-term storage in our facility. Cost was estimated per July 2012 charges: 1 day PBSC collection $3,016, 1 day processing for cryopreservation$5,955, 1 year storage fees $408 ($34/month). The cost of mobilization chemotherapy and growth factors were not included. Results From May 1993 to June 2011, 889 MM patients underwent PBSC collection and ASCT (111 of 1000 excluded due to incomplete records). Median total PBSC collection days was 2 (range 1 – 10) with median yield of 13.18 x 106/kg CD34+ cells. Median days to collect sufficient cells for one ASCT was 1 day (1 – 9) and 383 patients collected adequate cells for 2 ASCTs after 1 apheresis procedure. Of 889 patients, 135 underwent a second ASCT within a median 14 months (2.5 – 113) of the first. Number of second ASCTs per time period: 1993 to 1995 – 9 of 39 MM patients undergoing ASCT (23%), 1996 to 1999 – 18 of 100 (18%), 2000 to 2003 – 15 of 162 (9%), 2004 to 2007 – 62 of 251 (25%), 2008 to 2011 – 31 of 337 (9%). Fifty patients underwent tandem ASCTs and these accounted for 89%, 72%, 7%, 24%, and 42% of all second ASCTs during the respective periods; the other 85 occurred > 6 months after the first. Number of additional days and associated costs to collect and store PBSC for a second ASCT: 5 days ($44,855), n=1 patient; 4 days ($35,844), n=2; 3 days ($26,913), n=10; 2 days ($17,942), n=41; and 1 day ($8,971), n=211. 637 patients had unused PBSC that remained in storage for ≥ 1 year, with a rising trend over time: 1993 to 1995 – 7 (1From January 2009, some patients received plerixafor to achieve the collection goal for 1 ASCT. Its cost was not considered additional. Estimated average cost for PBSC collection, cryopreservation and storage was at least$20,065.96/person and at least $6718.11/person was spent to collect and store PBSC for a tandem ASCT that was never performed. Conclusions Approximately 70% of patients had PBSC products that remained unused and in prolonged cryopreservation after the first ASCT. Estimated cost for collection and storage of PBSC beyond that needed for a single ASCT accounted for roughly 1/3 of total costs. This conventional practice should be reconsidered in view of rising treatment costs, the evolving role of novel agents in maintenance therapy, and the deeper responses achievable with novel agents prior to first ASCT, thus reducing the need for tandem ASCT. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Impact Of Pre-Transplant Rituximab Sensitivity In Relapsed Follicular Lymphoma On Outcome After Autologous Transplant

Purpose Prior to the introduction of modern induction and maintenance regimens, autologous stem cell transplantation (ASCT) improved outcomes in chemotherapy-sensitive, relapsed follicular lymphoma (FL). We re-evaluated the impact of Rituximab (R) sensitivity on ASCT for relapsed FL in the current Rituximab era. Methods 194 consecutive patients with a confirmed diagnosis of relapsed, grade 1, 2 or 3A FL underwent ASCT at our center from April 1993 to October 2011. They were categorized as R-sensitive, R-refractory, or no R (NoR) if transplanted prior to use of Rituximab. Rituximab refractoriness was defined as failure (at any point in treatment) to achieve at least a PR or documented disease progression within 6 months of receiving the first dose of a full course of single-agent rituximab (³ 4 doses of 375mg/m 2 weekly), getting rituximab maintenance (R-maintenance) or completing 2 courses of Rituximab combined with chemotherapy (R-chemotherapy). The statistical significance of differences in event rates was evaluated with the proportional hazards regression model. Two-sided p-values less than 0.05 were considered statistically significant. Kaplan-Meier (K-M) curves were used to estimate the probabilities of overall survival (OS) and progression-free survival (PFS). Cumulative incidence of relapse was calculated in a competing risk data analysis considering non-relapse mortality as a competing event. Results There were 65 rituximab-refractory (RR), 35 rituximab-sensitive (RS) and 94 NoR patients. RS (11%) and RR (12%) patients received R-maintenance. High-risk FL international prognostic index (FLIPI) scores at the time of ASCT was imbalanced between the groups: RS 3%, RR 23% and NoR 26% (P = .009). Baseline characteristics were otherwise comparable between the 3 groups. Median follow-up from ASCT to time of last contact or death was 64 months (range 10-169), 42 months (range 1-157) and 91 months ( range 0.5-231) in the RS, RR and NoR groups, respectively. Univariate analyses showed significantly better OS ( P = .003) and PFS ( P = .0004) in RS patients with 3-year OS and PFS (Figure 3) of 97% and 85% compared with 63% and 35% in RR and 73.4% and 49% in NoR patients, respectively (Figures 1 & 2). Time to next treatment in relapsing patients was significantly shorter in the RR group compared to the RS and NoR groups. We performed multivariate adjustment for pre-ASCT factors that could affect outcomes i.e. age ≥ 50, FLIPI score ≥ 3, # prior chemotherapy regimens ≥ 3, chemo-resistance, elevated lactate dehydrogenase, prior radiation therapy, bone marrow stem cell source, and remission quotient ≥ 6 (defined as the months from diagnosis to ASCT divided by number of prior therapies). Multivariate adjustment showed OS to be significantly affected only by rituximab sensitivity, with a lower risk of death in RS patients (HR 0.24, P = .01). PFS was also significantly affected by pre-ASCT rituximab sensitivity (HR 0.35, P = .006). Cumulative incidence of relapse was increased in RR patients (HR 2.11, P = .01). The differences in post-ASCT OS, PFS, and relapse rates between the RS and RR patients were maintained independent of transplant conditioning regimen. There were no differences in OS, PFS or relapse whether RR patients were refractory to single-agent rituximab, R-maintenance, or R-chemotherapy. Conclusions Pre-transplant rituximab sensitivity in relapsed FL is a strong independent predictor of post-ASCT outcome. For RR FL patients with limited effective options, nearly half were alive and progression-free at 3 years after ASCT. Disclosures: Shustov: Seattle Genetics, Inc.: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau

Autologous transplant for relapsed follicular lymphoma: impact of pre-transplant rituximab sensitivity.

Patients with rituximab-refractory follicular lymphoma (FL) have limited options. Before the rituximab era, autologous stem cell transplant (ASCT) was shown to improve outcomes in chemotherapy-sensitive, relapsed FL, but the impact of rituximab-sensitivity on these results is unknown. We analyzed 194 consecutive relapsed patients with FL who underwent ASCT at out center and categorized them as rituximab-sensitive (RS, n = 35), rituximab-refractory (RR, n = 65) or no rituximab (NoR, n = 94) if transplanted before rituximab was used. Progression-free survival at 3 years was 85% in RS and 35% in RR patients (p = 0.0004). Only rituximab-sensitivity was significant on multivariate analysis with improved overall survival (OS) (hazard ratio [HR] 0.24, p = 0.01) and progression-free survival (PFS) (HR 0.35, p = 0.006) in RS patients and increased relapse in RR patients (HR 2.11, p = 0.01). Pre-transplant rituximab-sensitivity is a strong independent predictor of post-transplant outcomes in relapsed FL, although one-third of RR patients achieved a PFS of over 3 years with ASCT

Specific Features Identify Patients with Relapsed or Refractory Mantle Cell Lymphoma Benefitting from Autologous Hematopoietic Cell Transplantation

Outcomes with autologous hematopoietic cell transplantation (auto HCT) for relapsed and/or refractory mantle cell lymphoma (MCL) are typically poor. We hypothesized that certain factors could predict which patients experience a favorable outcome with this approach. We thus developed a predictive score from a cohort of 67 such patients using 3 factors independently associated with progression-free survival (PFS): (1) simplified Mantle Cell Lymphoma International Prognostic Index score before auto HCT (hazard ratio [HR], 2.9; P = .002); (2) B symptoms at diagnosis (HR, 2.7; P = .005); and (3) remission quotient, calculated by dividing the time, in months, from diagnosis to auto HCT by the number of prior treatments (HR, 1.4; P = .02). The estimated 5-year PFS for favorable-risk patients (n = 23) and unfavorable-risk patients (n = 44) were 58% (95% confidence interval [CI], 34% to 75%) and 15% (95% CI, 6% to 28%), respectively. These factors also independently predicted overall survival. In summary, we have defined 3 simple factors that can identify patients with relapsed/refractory MCL who derive a durable benefit from salvage auto HCT

Response to brentuximab vedotin versus physician's choice by CD30 expression and large cell transformation status in patients with mycosis fungoides: An ALCANZA sub-analysis

none31siIntroduction: Mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study. Methods: Baseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min &lt; 10% (≥1 biopsy with &lt;10% CD30 expression), or CD30min ≥ 10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS). Results: Clinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician's choice in patients: with CD30min &lt; 10% (40.9% versus 9.5%), with CD30min ≥ 10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician's choice in patients: with CD30min &lt; 10% (16.7 versus 2.3 months), with CD30min ≥ 10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups. Conclusion: These exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician's choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status. Clinical trial registration: Clinicaltrials.gov, NCT01578499.noneKim Y.H.; Prince H.M.; Whittaker S.; Horwitz S.M.; Duvic M.; Bechter O.; Sanches J.A.; Stadler R.; Scarisbrick J.; Quaglino P.; Zinzani P.L.; Wolter P.; Eradat H.; Pinter-Brown L.C.; Ortiz-Romero P.L.; Akilov O.E.; Trotman J.; Taylor K.; Weichenthal M.; Walewski J.; Fisher D.; McNeeley M.; Gru A.A.; Brown L.; Palanca-Wessels M.C.; Lisano J.; Onsum M.; Bunn V.; Little M.; Trepicchio W.L.; Dummer R.Kim Y.H.; Prince H.M.; Whittaker S.; Horwitz S.M.; Duvic M.; Bechter O.; Sanches J.A.; Stadler R.; Scarisbrick J.; Quaglino P.; Zinzani P.L.; Wolter P.; Eradat H.; Pinter-Brown L.C.; Ortiz-Romero P.L.; Akilov O.E.; Trotman J.; Taylor K.; Weichenthal M.; Walewski J.; Fisher D.; McNeeley M.; Gru A.A.; Brown L.; Palanca-Wessels M.C.; Lisano J.; Onsum M.; Bunn V.; Little M.; Trepicchio W.L.; Dummer R

Response to brentuximab vedotin versus physician's choice by CD30 expression and large cell transformation status in patients with mycosis fungoides: An ALCANZA sub-analysis.

IntroductionMycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma, can lead to disfiguring lesions, debilitating pruritus and frequent skin infections. This study assessed response to brentuximab vedotin in patients with MF in the phase III ALCANZA study.MethodsBaseline CD30 levels and large-cell transformation (LCT) status were centrally reviewed in patients with previously-treated CD30-positive MF using ≥2 skin biopsies obtained at screening; eligible patients required ≥1 biopsy with ≥10% CD30 expression. Patients were categorised as CD30min&nbsp;&lt;&nbsp;10% (≥1 biopsy with &lt;10% CD30 expression), or CD30min&nbsp;≥&nbsp;10% (all biopsies with ≥10% CD30 expression) and baseline LCT present or absent. Efficacy analyses were the proportion of patients with objective response lasting ≥4 months (ORR4) and progression-free survival (PFS).ResultsClinical activity with brentuximab vedotin was observed across all CD30 expression levels in patients with ≥1 biopsy showing ≥10% CD30 expression. Superior ORR4 was observed with brentuximab vedotin versus physician's choice in patients: with CD30min&nbsp;&lt;&nbsp;10% (40.9% versus 9.5%), with CD30min&nbsp;≥&nbsp;10% (57.1% versus 10.3%), with LCT (64.7% versus 17.6%) and without LCT (38.7% versus 6.5%). Brentuximab vedotin improved median PFS versus physician's choice in patients: with CD30min&nbsp;&lt;&nbsp;10% (16.7 versus 2.3 months), with CD30min&nbsp;≥&nbsp;10% (15.5 versus 3.9 months), with LCT (15.5 versus 2.8 months) and without LCT (16.1 versus 3.5 months). Safety profiles were generally comparable across subgroups.ConclusionThese exploratory analyses demonstrated that brentuximab vedotin improved rates of ORR4 and PFS versus physician's choice in patients with CD30-positive MF and ≥1 biopsy showing ≥10% CD30 expression, regardless of LCT status.Clinical trial registrationClinicaltrials.gov, NCT01578499