Arnd Nusch

CEREBEL (EGF111438): A Phase III, Randomized, Open-Label Study of Lapatinib Plus Capecitabine Versus Trastuzumab Plus Capecitabine in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

PURPOSE CEREBEL compared the incidence of CNS metastases as first site of relapse in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer receiving lapatinib-capecitabine or trastuzumab-capecitabine. PATIENTS AND METHODS Patients without baseline CNS metastases were randomly assigned (1:1) to receive lapatinib-capecitabine (lapatinib 1,250 mg per day; capecitabine 2,000 mg/m(2) per day on days 1 to 14 every 21 days) or trastuzumab-capecitabine (trastuzumab loading dose of 8 mg/kg followed by an infusion of 6 mg/kg every 3 weeks; capecitabine 2,500 mg/m(2) per day on days 1 to 14 every 21 days). The primary end point was incidence of CNS metastases as first site of relapse. Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS The study was terminated early with 540 enrolled patients (271 received lapatinib-capecitabine, and 269 received trastuzumab-capecitabine). Incidence of CNS metastases as first site of relapse was 3% (eight of 251 patients) for lapatinib-capecitabine and 5% (12 of 250 patients) for trastuzumab-capecitabine (treatment differences, -1.6%; 95% CI, -2% to 5%; P = .360). PFS and OS were longer with trastuzumab-capecitabine versus lapatinib-capecitabine (hazard ratio [HR] for PFS, 1.30; 95% CI, 1.04 to 1.64; HR for OS, 1.34; 95% CI, 0.95 to 1.64). Serious adverse events were reported in 13% (34 of 269 patients) and 17% (45 of 267 patients) of patients in the lapatinib-capecitabine and trastuzumab-capecitabine arms, respectively. CONCLUSION CEREBEL is inconclusive for the primary end point, and no difference was detected between lapatinb-capecitabine and trastuzumab-capecitabine for the incidence of CNS metastases. A better outcome was observed with trastuzumab-capecitabine in the overall population. However, lapatinib-capecitabine efficacy may have been affected by previous exposure to a trastuzumab regimen and/or when treatment was given as first- or second-line therapy in the metastatic setting.

Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31

PURPOSE The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown. PATIENTS AND METHODS The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. RESULTS From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). CONCLUSION As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane.

A randomised phase II study of irinotecan in combination with 5-FU/FA compared with irinotecan alone as second-line treatment of patients with metastatic colorectal carcinoma.

We conducted a randomised phase II study to compare irinotecan monotherapy with irinotecan in combination with infusional 5-fluorouracil/folinic acid (5-FU/FA) regarding efficacy and safety of these regimens in second-line therapy after failed fluoropyrimidine therapy in patients with metastatic colorectal cancer (mCRC). Patients and Methods: 55 patients with mCRC after failure of a first-line therapy were randomised to receive either irinotecan 80 mg/m2 followed by FA 500 mg/m2 and 5-FU 2,000 mg/m2 24 h weekly for 6 weeks, with courses repeated on day 50 (arm A), or irinotecan 125 mg/m2 weekly for 4 weeks, with cycles repeated on day 43 (Arm B). Results: Both regimens yielded a partial response rate of 11% with identical progression-free survival (3.7 months for both regimens) and similar overall survival (9.5 months for the combination therapy vs. 10.7 months for the monotherapy). Both regimens were very well tolerated, and the combination of irinotecan with 5-FU/FA did not result in increased toxicity. Conclusion: Our study confirms that irinotecan alone or in combination with infusional 5-FU/FA is an effective and safe regimen for CRC patients who failed first-line therapies. However, the role of 5-FU in addition to irinotecan for fluoropyrimidine failures remains unclear. Due to the small sample size, a decision cannot be made which therapy should be preferred, and a significant contribution to the efficacy of single-agent irinotecan is not obvious from this small randomised phase II trial.

Survival of Patients With Advanced or Metastatic Renal Cell Carcinoma in Routine Practice Differs From That in Clinical Trials-Analyses From the German Clinical RCC Registry.

Micro‐Abstract A total of 732 prospectively recruited German patients with metastatic renal cell carcinoma were classified as either “trial‐eligible” or “trial‐ineligible” in accordance with the common exclusion criteria for clinical trials. The “trial‐ineligible” patients had shorter progression‐free and overall survival compared with the “trial‐eligible” patients, whose outcomes were comparable with those from clinical trials. Physicians should be aware of these differences when discussing the treatment options and outcome expectations with patients. Introduction: Because “real‐life” patients often do not meet the strict eligibility criteria of clinical trials, we assessed the trial eligibility of patients with advanced or metastatic renal cell carcinoma (mRCC) in routine practice and compared the survival of “trial‐ineligible” and potentially “trial‐eligible” patients. Patients and Methods: The present prospective, multicenter German cohort study is recruiting patients from 110 oncology/urology outpatient centers and hospitals at initiation of systemic first‐line treatment. The demographic, clinical, treatment, and survival data were collected. We defined patients as “trial‐ineligible” when ≥ 1 exclusion criterion (Karnofsky performance status < 80%, hemoglobin less than the lower limit of normal, non–clear cell carcinoma histology) was documented. Otherwise, the patients were considered “trial‐eligible”. Results: Of 732 patients included, 57% were classified as “trial‐ineligible”. Overall, the median first‐line progression‐free survival (PFS) was 7.9 months (95% confidence interval [CI], 6.9‐8.9 months). The median first‐line PFS of “trial‐eligible” and “trial‐ineligible” patients was 11.0 months (95% CI, 9.6‐13.1 months) and 5.3 months (95% CI, 4.6‐6.5 months), respectively. The median OS of the “trial‐eligible” and “trial‐ineligible” patients was 26.0 months (95% CI, 22.1‐29.7 months) and 12.6 months (95% CI, 10.6‐15.8 months), respectively. Conclusion: Our data suggest that patients in routine practice differ from patients treated in clinical trials and that almost 60% of mRCC patients in German routine practice would be ineligible for participation in clinical trials. While their first‐line PFS and OS were shorter than those of “trial‐eligible” patients, the PFS and OS of “trial‐eligible” patients were comparable with the results from clinical trials. Physicians should be aware of these differences when discussing treatment options and outcome expectations with patients.

Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced Breast Cancer: MONALEESA-3

Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%). Conclusion Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.

Treatment of Non-transplant patients with multiple myeloma: routine treatment by office-based haematologists in Germany--data from the prospective Tumour Registry Lymphatic Neoplasms (TLN).

SummaryBackground: Various treatment options exist for patients with multiple myeloma (MM). Clinical registries provide insight into routine treatment and identify changes in treatment over time. Patients and Methods: The Tumour Registry Lymphatic Neoplasms (TLN) prospectively collects data on the treatment of patients with lymphoid B cell neoplasms as administered by office-based haematologists in Germany. Data on patient and tumour characteristics, comorbidities, systemic treatments and outcome parameters are recorded. Results: 371 non-transplant patients with MM were recruited between 2009 and 2011. At the start of first-line (second-line) treatment, the median age was 73 (75) years; 67% (74%) of the patients had stage III MM (classification of Durie and Salmon) and 19% (28%) had renal insufficiency. In the first line, 40% of the patients received bortezomib + melphalan + prednisone (VMP), 25% received bortezomib ± dexamethasone (V±D) and 8% were treated with melphalan + prednisone + thalidomide (MPT). While use of bortezomib-based regimens increased from 67% (2009) to 85% (2011), use of melphalan-based regimens decreased from 68% to 48%. The overall objective response rate of treatment was 82%. In the second line, 34% of the patients received V±D and 16% lenalidomide + dexamethasone (LD). Conclusion: Bortezomib-based regimens dominate the first- and second-line treatment of MM. Future analyses will investigate outcome data, e.g. effectiveness of bortezomib retherapy compared to other second-line treatments.

Abstract CT045: Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): efficacy by baseline tumor markers

Background: Cyclin D-cyclin-dependent kinase (CDK) 4/6 complexes promote cell proliferation through phosphorylation of retinoblastoma protein (Rb). In breast cancer, cyclin D-CDK4/6 activity can be increased through cyclin D gene (CCND1) amplification or loss of the CDK4/6 negative regulator p16. Here we present efficacy data from the Phase III MONALEESA-2 study of ribociclib (CDK4/6 inhibitor) + letrozole vs. placebo + letrozole for first-line treatment of HR+, HER2- ABC, assessed in baseline tumors by protein levels of Rb, p16, the cell proliferation marker Ki67, and by gene expression levels of CDKN2A (p16) and CCND1. Methods: Postmenopausal women with HR+, HER2- ABC with no prior systemic therapy for advanced disease were randomized 1:1 to receive ribociclib or placebo (600 mg/day 3-weeks-on/1-week-off) + letrozole (2.5 mg/day continuous). The primary endpoint was investigator-assessed progression-free survival (PFS). Provision of a representative baseline tumor biopsy or archival tissue at screening was mandatory if available. Baseline tumor tissue was evaluated for protein biomarkers (immunohistochemistry) and gene expression (NanoString nCounter® Human Cancer Reference panel). Results: Of 668 patients randomized, 479 were evaluable for total Rb, and 416 (87%) displayed high levels (H-score ≥100). p16 protein levels were evaluable in 405 patients; 165 (41%) had low (H-score 14% of cells in 247 (53%) patients. The median messenger RNA expression level was used as the cut-off to define patients with low or high baseline CDKN2A and CCND1 gene expression. An improved PFS was observed by the addition of ribociclib to letrozole in all the above patient subgroups, with hazard ratios ranging from 0.40 (high p16 by H-score; 95% confidence interval [CI] 0.16-1.0; p=0.06) to 0.64 (≤14% Ki67-positive cells; 95% CI 0.39-1.0; p=0.07). Patients with less or greater than 14% Ki67-positive cells, lower or higher p16 levels, Rb levels, or CDKN2A or CCND1 gene expression benefitted from the addition of ribociclib to letrozole to a similar extent. Conclusions: A consistent benefit from ribociclib + letrozole vs. placebo + letrozole was observed irrespective of baseline Rb, p16, and Ki67 levels or CDKN2A and CCND1 gene expression levels. Hormone receptor positivity remains the only established biomarker of response to CDK4/6 inhibitors. Citation Format: Fabrice Andre, Salomon M. Stemmer, Mario Campone, Katarina Petrakova, Shani Paluch-Shimon, Yoon-Sim Yap, Norbert Marschner, Arlene Chan, Cristian Villanueva, Lowell L. Hart, Carlos L. Arteaga, Gabe S. Sonke, Eva-Maria Grischke, Emilio Alba, Arnd Nusch, Denise A. Yardley, Erik Jakobsen, Sibel Blau, Sara M. Tolaney, Faye Su, Wei He, Caroline Germa, Gabriel N. Hortobagyi. Ribociclib + letrozole for first-line treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): efficacy by baseline tumor markers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT045. doi:10.1158/1538-7445.AM2017-CT045

Abnormal Free Light Chain Ratios are Significantly Associated with Clinical Progression in Chronic Lymphocytic Leukemia

Serum Free Light Chains (FLC) have prognostic significance in diverse plasma cell dyscrasias. Although monoclonal protein secretion is a typical feature of these diseases, it can also be detected in other B cell malignancies including chronic lymphocytic leukemia. Recent data suggests a significant correlation between abnormal ratio of FLC and outcome. Therefore, we investigated the role of FLC in a large cohort of 135 patients and the correlation to immunofixation (IF) and flow cytometry. Abnormal FLC ratios were found in 78 patients (58%) whereas the IF was positive in only 32 cases (24%). In 55 cases the FLC ratio was positive while IF was negative and in only 9 cases IF was positive while the FLC ratio was normal. In 52 of 98 patients (53%) light chain restriction determined by flow cytometry was concordant with the monoclonal FLC whereas in 5 patients they did not agree. In 41 of 98 patients (42%) a normal ratio of FLC was observed while the immunophenotype was positive for lambda or kappa. Patients with an abnormal FLC ratio for lambda had a significantly shorter time to first therapy (TFT) than patients with an abnormal ratio for kappa FLC or with a normal FLC ratio (median TFT: 34 versus 76 versus 88 months, p for trend=0.039). Additionally, monoclonal FLC had a significantly shorter time to first treatment compared to polyclonal normal and abnormal FLC ratios (p for trend=0.0489). As expected, polyclonal sFLC correlated significantly with normal and abnormal serum-creatinine (p<0.0001). Future studies are warranted to elucidate the role of FLC as biomarkers of disease and as a prognostic factor for response.

Final Effectiveness and Safety Results of NABUCCO: Real-World Data From a Noninterventional, Prospective, Multicenter Study in 697 Patients With Metastatic Breast Cancer Treated With nab -Paclitaxel

Background: One of the most effective chemotherapies for metastatic breast cancer (MBC) is nab‐paclitaxel (nab‐P), which is approved for treatment of MBC after failure of first‐line therapy and when anthracyclines are not indicated. Randomized clinical trials have shown high efficacy and acceptable toxicity. Real‐world data of nab‐P in MBC, however, are still limited. Patients and Methods: The prospective multicenter noninterventional study NABUCCO collected data on the routine treatment of patients with MBC receiving nab‐P in 128 sites across Germany. The primary objective was time to progression. Secondary objectives were overall response rate, overall survival, safety, and quality of life. Results: Between April 2012 and April 2015, a total of 705 patients with MBC at 128 active sites had been enrolled. A total of 697 patients had evaluable data with a median follow‐up of 17.7 months. Median time to progression was 5.9 months (95% confidence interval, 5.6‐6.4), overall response rate was 37.2%, and median overall survival was 15.6 months (95% confidence interval, 14.2‐17.2). The results were similar in patients aged < 65 versus ≥ 65 years as well as in patients who received nab‐P on a weekly or a triweekly schedule. The most frequently reported grade 3/4 adverse events were leukopenia (55, 7.9%), peripheral sensory neuropathy (30, 4.3%), and infections (29, 4.2%). Patients reported no apparent treatment‐related impact on global quality of life. Conclusion: The results of the NABUCCO study confirm the clinical trial outcomes and the favorable safety profile of nab‐P in patients with metastatic breast cancer in a real‐world setting.