Palbociclib with Letrozole in Postmenopausal Women with ER+/HER2- Advanced Breast Cancer: Hematologic Safety Analysis of the Randomized PALOMA-2 Trial.

BackgroundPALOMA-2 confirmed that first-line palbociclib + letrozole improved progression-free survival (hazard ratio, 0.58; 95% confidence interval, 0.46-0.72) in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This analysis evaluated palbociclib-associated hematologic adverse events (AEs) and provides insight on managing these AEs.Materials and methodsPostmenopausal women with ER+/HER2- ABC were randomly assigned 2:1 to letrozole (2.5 mg daily continuously) plus oral palbociclib (125 mg daily; 3 weeks on/1 week off) or placebo. Safety assessments were performed at baseline, days 1 and 15 (first two cycles) and day 1 of subsequent cycles, and included white blood cell, platelet, and absolute neutrophil count (ANC).ResultsPALOMA-2 randomized 666 women to palbociclib + letrozole (n = 444) or placebo + letrozole (n = 222). Neutropenia was the most common AE (95.3%) with palbociclib (grade 3, 55.6%; grade 4, 11.5%) and was managed by dose modifications; progression-free survival was similar between patients who experienced grade ≥ 3 neutropenia versus those who did not. Median (range) time to onset of neutropenia with palbociclib + letrozole was 15 (12-700) days (grade ≥ 3, 28.0 [12-854] days); median duration of each neutropenia episode grade ≥ 3 was 7.0 days. Asian ethnicity and low baseline ANC were associated with increased risk of grade 3/4 neutropenia with palbociclib (p < .001).ConclusionPalbociclib + letrozole was generally well tolerated. Neutropenia, the most frequently reported AE in women with ER+/HER2- ABC, was mostly transient and manageable by dose modifications in patients who experienced grade ≥ 3 neutropenia, without appearing to compromise efficacy. (Pfizer; NCT01740427) IMPLICATIONS FOR PRACTICE: Palbociclib demonstrated an acceptable safety profile in PALOMA-2 in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) receiving first-line palbociclib + letrozole. Although hematologic adverse events (AEs) are typically expected with anticancer therapies and are often clinically significant, palbociclib-related hematologic AEs, particularly neutropenia (most frequent AE), were transient/manageable by dose reduction, interruption, or cycle delay, which is in contrast to the more profound neutropenia associated with chemotherapy. Palbociclib dose adjustments decreased hematologic AE severity without appearing to compromise efficacy, supporting palbociclib + letrozole as a first-line treatment for ER+/HER2- ABC

Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.

PurposeIn the initial PALOMA-2 (NCT01740427) analysis with median follow-up of 23 months, palbociclib plus letrozole significantly prolonged progression-free survival (PFS) in women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) [hazard ratio (HR) 0.58; P < 0.001]. Herein, we report results overall and by subgroups with extended follow-up.MethodsIn this double-blind, phase 3 study, post-menopausal women with ER+/HER2- ABC who had not received prior systemic therapy for their advanced disease were randomized 2:1 to palbociclib-letrozole or placebo-letrozole. Endpoints include investigator-assessed PFS (primary), safety, and patient-reported outcomes (PROs).ResultsAfter a median follow-up of approximately 38 months, median PFS was 27.6 months for palbociclib-letrozole (n = 444) and 14.5 months for placebo-letrozole (n = 222) (HR 0.563; 1-sided P < 0.0001). All subgroups benefited from palbociclib treatment. The improvement of PFS with palbociclib-letrozole was maintained in the next 2 subsequent lines of therapy and delayed the use of chemotherapy (40.4 vs. 29.9 months for palbociclib-letrozole vs. placebo-letrozole). Safety data were consistent with the known profile. Patients' quality of life was maintained.ConclusionsWith approximately 15 months of additional follow-up, palbociclib plus letrozole continued to demonstrate improved PFS compared with placebo plus letrozole in the overall population and across all patient subgroups, while the safety profile remained favorable and quality of life was maintained. These data confirm that palbociclib-letrozole should be considered the standard of care for first-line therapy in patients with ER+/HER2- ABC, including those with low disease burden or long disease-free interval. Sponsored by Pfizer; ClinicalTrials.gov: NCT01740427

Understanding breast cancer patients' preference for two types of exercise training during chemotherapy in an unblinded randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Patient preference for group assignment may affect outcomes in unblinded trials but few studies have attempted to understand such preferences. The purpose of the present study was to examine factors associated with breast cancer patients' preference for two types of exercise training during chemotherapy.</p> <p>Methods</p> <p>Breast cancer patients (N = 242) completed a battery of tests including a questionnaire that assessed patient preference and the theory of planned behavior (TPB) prior to being randomized to usual care, resistance exercise training (RET), or aerobic exercise training (AET).</p> <p>Results</p> <p>99 (40.9%) participants preferred RET, 88 (36.4%) preferred AET, and 55 (22.7%) reported no preference. Past exercisers (p = 0.023), smokers (p = 0.004), and aerobically fitter participants (p = 0.005) were more likely to prefer RET. As hypothesized, participants that preferred AET had more favorable TPB beliefs about AET whereas participants that preferred RET had more favorable TPB beliefs about RET. In multivariate modeling, patient preference for RET versus AET was explained (R²= .46; p < 0.001) by the difference in motivation for RET versus AET (β = .56; p < 0.001), smoking status (β = .13; p = 0.007), and aerobic fitness (β = .12; p = 0.018). Motivational difference between RET versus AET, in turn, was explained (R²= .48; p < 0.001) by differences in instrumental attitude (β = .27; p < 0.001), affective attitude (β = .25; p < 0.001), and perceived behavioral control (β = .24; p < 0.001).</p> <p>Conclusion</p> <p>Breast cancer patients' preference for RET versus AET during chemotherapy was predicted largely by a difference in motivation for each type of exercise which, in turn, was based on differences in their beliefs about the anticipated benefits, enjoyment, and difficulty of performing each type of exercise during chemotherapy. These findings may help explain patient preference effects in unblinded behavioral trials.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov Identifier NCT00115713.</p

Experimental designs for phase I and phase I/II dose-finding studies

We review the rationale behind the statistical design of dose-finding studies as used in phase I and phase I/II clinical trials. We underline what the objectives of such dose-finding studies should be and why the widely used standard design fails to meet any of these objectives. The standard design is a ‘memoryless' design and we discuss how this impacts on practical behaviour. Designs introduced over the last two decades can be viewed as designs with memory and we discuss how these designs are superior to memoryless designs. By superior we mean that they require less patients overall, less patients to attain the maximum tolerated dose (MTD), and concentrate a higher percentage of patients at and near to the MTD. We reanalyse some recently published studies in order to provide support to our contention that markedly better results could have been achieved had a design with memory been used instead of a memoryless design

Randomised, phase II trial comparing oral capecitabine (Xeloda®) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines

Capecitabine, an oral fluoropyrimidine carbamate, was designed to generate 5-fluorouracil preferentially at the tumour site. This randomised, phase II trial evaluated the efficacy and safety of capecitabine or paclitaxel in patients with anthracycline-pretreated metastatic breast cancer. Outpatients with locally advanced and/or metastatic breast cancer whose disease was unresponsive or resistant to anthracycline therapy were randomised to 3-week cycles of intermittent oral capecitabine (1255 mg m−2 twice daily, days 1–14, (22 patients)) or a reference arm of i.v. paclitaxel (175 mg m−2, (20 patients)). Two additional patients were initially randomised to continuous capecitabine 666 mg m−2 twice daily, but this arm was closed following selection of the intermittent schedule for further development. Overall response rate was 36% (95% CI 17–59%) with capecitabine (including three complete responses) and 26% (95% CI 9–51%) with paclitaxel (no complete responses). Median time to disease progression was similar in the two treatment groups (3.0 months with capecitabine, 3.1 months with paclitaxel), as was overall survival (7.6 and 9.4 months, respectively). Paclitaxel was associated with more alopecia, peripheral neuropathy, myalgia and neutropenia, whereas typical capecitabine-related adverse events were diarrhoea, vomiting and hand–foot syndrome. Twenty-three per cent of capecitabine-treated patients and 16% of paclitaxel-treated patients achieved a ⩾10% improvement in Karnofsky Performance Status. Oral capecitabine is active in anthracycline-pretreated advanced/metastatic breast cancer and has a favourable safety profile. Furthermore, capecitabine provides a convenient, patient-orientated therapy