Z. Jiang

Aim: To compare the efficacy, safety, and tolerability of abemaciclib plus endocrine therapy (ET) versus ET alone in postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC) from China, Brazil, India, and South Africa. Methods: This randomized, double-blind, phase III study was conducted between 9 December 2016 and 29 March 2019. Postmenopausal women with HR-positive, HER2-negative ABC with no prior systemic therapy in an advanced setting (cohort A) or progression on prior ET (cohort B) received abemaciclib (150 mg twice daily) or placebo plus: anastrozole (1 mg/day) or letrozole (2.5 mg/day) (cohort A) or fulvestrant (500 mg per label) (cohort B). The primary endpoint was progression-free survival (PFS) in cohort A, analyzed using the stratified log-rank test. Secondary endpoints were PFS in cohort B (key secondary endpoint), objective response rate (ORR), and safety. This interim analysis was planned after 119 PFS events in cohort A. Results: In cohort A, 207 patients were randomly assigned to the abemaciclib arm and 99 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: not reached versus 14.7 months; hazard ratio 0.499; 95% confidence intervals (CI) 0.346–0.719; p = 0.0001). ORR was 65.9% in the abemaciclib arm and 36.1% in the placebo arm ( p < 0.0001, measurable disease population). In cohort B, 104 patients were randomly assigned to the abemaciclib arm and 53 to the placebo arm. Abemaciclib significantly improved PFS versus placebo (median: 11.5 versus 5.6 months; hazard ratio 0.376; 95% CI 0.240–0.588; p < 0.0001). ORR was 50.0% in the abemaciclib arm and 10.5% in the placebo arm ( p < 0.0001, measurable disease population). The most frequent grade ⩾3 adverse events in the abemaciclib arms were neutropenia, leukopenia, and anemia (both cohorts), and lymphocytopenia (cohort B). Conclusion: The addition of abemaciclib to ET demonstrated significant and clinically meaningful improvement in PFS and ORR, without new safety signals observed in this population. Trial Registration: ClinicalTrials.gov identifier: NCT02763566.

Abstract Background: Neratinib (HKI-272), an irreversible pan-ErbB inhibitor of the tyrosine kinase receptors ErbB1, -2 and -4, has shown antitumor activity in patients with ErbB2+ disease, with or without prior trastuzumab exposure. In preclinical models, neratinib inhibits ErbB receptor complex downstream signaling via the phosphatidyl inositol-3-kinase (PI3K) pathway. PI3K signaling activity may mediate resistance to trastuzumab and endocrine therapy in breast cancer (BC). The objective of this ongoing phase 1/2 study is to evaluate the safety and efficacy of neratinib in combination with paclitaxel in patients with solid tumors and ErbB2+ metastatic BC.Material and Methods: This open-label, 2-part study enrolled patients with solid tumors (part 1; determine the maximum tolerated dose [MTD]) and ErbB2+ advanced/metastatic BC in the first- to fourth-line setting (part 2; objective response rate [ORR] at the MTD). In part 1, patients received ascending multiple daily oral dosages of neratinib (160 mg, 240 mg) plus IV paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle. In part 2, patients received neratinib plus paclitaxel at the MTD. Tumor response was assessed using modified RECIST criteria. Safety and pharmacokinetic (PK) parameters were also evaluated.Results: Full doses of both neratinib (240 mg) and paclitaxel (80 mg/m2) were well tolerated in part 1 and evaluated in patients with ErbB2+ BC in part 2. As of 1 May 2009, data were available for 102 patients in part 2 (median age [range], 50.5 [20.0-76.0] years; 100% were female). Treatment-emergent adverse events (TEAEs) reported in ≥10% of patients included diarrhea (89%), neutropenia (42%), rash (26%), nausea (26%), and vomiting (20%). Common grade ≥3 TEAEs included diarrhea (25%), leukopenia (20%), and neutropenia (17%). Diarrhea was generally observed early (median onset, 3 days after the first dose of neratinib; median duration, 17 days). One patient withdrew because of toxicity (renal failure, dehydration). Evaluation of preliminary PK parameters suggested no interaction between the 2 drugs; exposures were similar to those observed for each drug as monotherapy. The ORR in part 2 (complete plus partial responses) among 97 evaluable patients was 62.9% (80% confidence interval [CI], 55.9-69.4). Median progression-free survival is estimated at 40 weeks (76% of patients censored). Of 37 patients treated with prior Her2-directed therapy, 21 responded (ORR, 56.8% [80% CI, 44.9-68.0]), including 9 of 13 patients treated with prior lapatinib (ORR, 69.2% [80% CI, 47.7-85.8]). Responses were observed in 27 of 37 patients with prior endocrine therapy in any line (ORR, 73.0% [80% CI, 61.5-82.5]), and 43 of 60 patients with prior taxane treatment (ORR, 71.7% [80% CI, 62.9-79.3]).Discussion: The combination of neratinib 240 mg and paclitaxel 80 mg/m2 was tolerable, with a similar toxicity profile to each drug given as monotherapy. Although the sample size of the trial was limited, differential clinical activity was observed in ErbB2+ metastatic BC with respect to prior treatment, supporting further investigation of patient subsets in future trials. A phase 3 trial is planned to study this combination in the first-line setting compared with trastuzumab plus paclitaxel. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5081.

OBJECTIVE: To compare the efficacy and safety of daily administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF), and a single subcutaneous injection of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF), a sustained-duration rhG-CSF, in chemotherapy-induced neutropenia. METHODS: In the present randomized, open-label, match and cross-over study, enrolled 104 patients with previously untreated non-small cell lung cancer (NSCLC), breast cancer or non-Hodgkin's lymphoma and with normal bone marrow function from 13 centers were randomly divided into 2 matched groups, AB and BA group. Each patient received two cycles of chemotherapy of identical regimen. In the study cycle, the patients received a single subcutaneous injection of PEG-rhG-CSF 100 microg/kg on day 3; and in control cycle, daily subcutaneous infection of rhG-CSF 5 microg x kg(-1) x d(-1) began on day 3 and continued for 14 days or until the absolute neutrophil count (ANC) became > or = 5.0 x 10(9)/L twice after it decreased to the nadir. Efficacy and safety parameters were monitored. RESULTS: The incidence rates of ANC < 1.5 x 10(9)/L in the 103 evaluable study cycles and 100 evaluable control cycles were 30.00% and 20.00% with the duration of 2.39 days and 2.35 days respectively. The incidence rates of grade 3 neutropenia were 7.77% and 7.00%; and that of grade 4 neutropenia were 5.80% and 4.00% respectively in the trial and control cycles. However, all the difference mentioned above did not reached statistical significance. None of the patients experienced febrile neutropenia. The ANC nadir was (7.55 +/- 5.25) x 10(9)/L and (8.42 +/- 5.57) x 10(9)/L (P = 0.257) respectively after receiving PEG-rhG-CSF and rhG-CSF. Compared with that of rhG-CSF group, the ANC profile of PEG-rhG-CSF group exhibited limited "overshoot" of neutrophils after the nadir. Subgroup analysis according to disease type yielded similar results. The safety profiles of the PEG-rhG-CSF and rhG-CSF groups were similar. Musculoskeletal pain or arthralgia occurred in 16.5% of the study cycles and 26.00% of the control cycles (P = 0.963), mostly mild or moderate. Other adverse effects such as fever, fatigue, dizziness, gastrointestinal effects and injection-site pain, were transient and easily manageable. CONCLUSION: A single subcutaneous injection of PEG-rhG-CSF 100 microg/kg provides neutrophil support and a safety profile comparable to regimen of daily subcutaneous injection of rhG-CSF 5 microg x kg(-1) x d(-1) in Chinese patients receiving a variety of myelosuppressive chemotherapy regimens.