BACKGROUND: Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum-based chemotherapy is often a first-line treatment. Pemetrexed has shown single-agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed-cisplatin for SCCHN. METHODS: In a double-blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m 2 ) plus cisplatin (75 mg/m 2 ; n ¼ 398) or placebo plus cisplatin (75 mg/m 2 ; n ¼ 397) to assess overall survival (OS) and secondary endpoints. RESULTS: Median OS was 7.3 months in the pemetrexed-cisplatin arm and 6.3 months in the placebocisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75-1.02; P ¼ .082). Median progression-free survival (PFS, months) was similar in both treatment arms (pemetrexed-cisplatin, 3.6; placebo-cisplatin, 2.8; HR, 0.88; 95% CI, 0.76-1.03; P ¼ .166). Among patients with performance status 0 or 1, pemetrexed-cisplatin (n ¼ 347) led to longer OS and PFS than placebo-cisplatin (n ¼ 343; 8.4 vs 6.7 months; HR, 0.83; P ¼ .026; 4.0 vs 3.0 months; HR, 0.84; P ¼ .044, respectively). Among patients with oropharyngeal cancers, pemetrexed-cisplatin (n ¼ 86) resulted in longer OS and PFS than placebo-cisplatin (n ¼ 106; 9.9 vs 6.1 months; HR, 0.59; P ¼ .002; 4.0 vs 3.4 months; HR, 0.73; P ¼ .047, respectively). Pemetrexed-cisplatin toxicity was consistent with studies in other tumors. CONCLUSIONS: Pemetrexed-cisplatin compared with placebo-cisplatin did not significantly improve survival for the intentto-treat population. However, in a prespecified subgroup analysis, pemetrexed-cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers. Cancer 2012;118:4694-705.
Eflapegrastim (Rolontis®) is a novel, long‐acting hematopoietic growth factor consisting of a recombinant human granulocyte‐colony stimulating factor (rhG‐CSF) analog conjugated to a human IgG4 Fc fragment via a short polyethylene glycol linker. We report results from a second pivotal, randomized, open‐label, Phase 3 study comparing the efficacy and safety of eflapegrastim to pegfilgrastim for reducing the risk of chemotherapy‐induced neutropenia. Patients with Stage I to IIIA early‐stage breast cancer (ESBC) were randomized 1:1 to fixed‐dose eflapegrastim 13.2 mg (3.6 mg G‐CSF) or pegfilgrastim (6 mg G‐CSF) administered one day after standard docetaxel/cyclophosphamide (TC) therapy for four cycles. The primary objective was to demonstrate noninferiority (NI) of eflapegrastim compared to pegfilgrastim in mean duration of severe neutropenia (DSN; Grade 4) in Cycle 1. A total of 237 eligible patients were randomized 1:1 to receive either eflapegrastim (n = 118) or pegfilgrastim (n = 119). Cycle 1 severe neutropenia was observed in 20.3% (n = 24) of patients receiving eflapegrastim and 23.5% (n = 28) receiving pegfilgrastim. The DSN of eflapegrastim in Cycle 1 was noninferior to pegfilgrastim with a mean difference of −0.074 days (NI P‐value < .0001). Noninferiority was maintained throughout the four treatment cycles (P < .0001 in all cycles). Other efficacy endpoints results were comparable between treatment arms, and adverse events, irrespective of causality and grade, were comparable between treatment arms. The results demonstrate noninferior efficacy and comparable safety for eflapegrastim, at a lower G‐CSF dose, vs pegfilgrastim. The potential for the increased potency of eflapegrastim to deliver improved clinical benefit warrants further clinical study.
This randomized, open‐label, active‐controlled study investigated the safety and efficacy of three doses of Rolontis (eflapegrastim), a novel, long‐acting myeloid growth factor, versus pegfilgrastim in breast cancer patients being treated with docetaxel and cyclophosphamide (TC). The primary efficacy endpoint was duration of severe neutropenia (DSN) during the first cycle of treatment. Patients who were candidates for adjuvant/neoadjuvant TC chemotherapy were eligible for participation. TC was administered on Day 1, followed by 45, 135, or 270 μg/kg Rolontis or 6 mg pegfilgrastim on Day 2. Complete blood counts were monitored daily when the absolute neutrophil count (ANC) fell to <1.5 × 109/L. Up to four cycles of TC were investigated. The difference in DSN (time from ANC <0.5 × 109/L to ANC recovery ≥2.0 × 109/L) between the Rolontis and pegfilgrastim groups was −0.28 days (confidence interval [CI]: −0.56, −0.06) at 270 μg/kg, 0.14 days (CI: −0.28, 0.64) at 135 μg/kg, and 0.72 days (CI: 0.19, 1.27) at 45 μg/kg. Noninferiority to pegfilgrastim was demonstrated at 135 μg/kg (P = 0.002) and 270 μg/kg (P < .001), with superiority demonstrated at 270 μg/kg (0.03 days; P = 0.023). The most common treatment‐related adverse events (AEs) were bone pain, myalgia, arthralgia, back pain, and elevated white blood cell counts, with similar incidences across groups. All doses of Rolontis were well tolerated, and no new or significant treatment‐related toxicities were observed. In Cycle 1, Rolontis demonstrated noninferiority at the 135 μg/kg dose and statistical superiority in DSN at the 270 μg/kg dose when compared to pegfilgrastim.
Background: SPI-2012 is a distinct biologic that uses the innovative proprietary long-acting protein/peptide discovery technology (LAPSCOVERY™) to enhance the activity of G-CSF. SPI-2012 consists of a novel, modified recombinant human G-CSF conjugated to the Fc fragment of IgG4 via a polyethylene glycol linker to produce a new, more potent, longer-acting G-CSF with a potentially unique distribution to areas rich in Fc receptors. To assess the effect of SPI-2012 in supporting patients with breast cancer receiving myelosuppressive chemotherapy with TC, we conducted a randomized Phase 2 study of 3 SPI-2012 doses versus pegfilgrastim. Methods: This was an open-label, global, multicenter, dose-ranging study designed to compare the safety and efficacy of SPI-2012 relative to a fixed, standard dose of pegfilgrastim as a concurrent active control. The study included 4 treatment arms: 3 dose levels of SPI-2012 (45 μg/kg, 135 μg/kg, and 270 μg/kg) vs pegfilgrastim (6 mg,). The primary objective of the study was the Duration of Severe Neutropenia (DSN) during Cycle 1 in patients with BC who received adjuvant or neoadjuvant TC chemotherapy. Results: A total of 147 evaluable patients were enrolled. Patient and tumor characteristics were comparable across all 4 treatment arms. Mean age was 58.2 years (range 32 to 77 years); most patients were <65 years (68%), female (98%) and white (95%). The study met its primary endpoint with DSN in patients treated in the 135 µg/kg and 270 µg/kg SPI-2012 treatment arms in Cycle 1 showing non-inferiority to the DSN in patients treated with pegfilgrastim (p=0.002 and p<0.001, respectively). In addition, superiority was demonstrated in patients treated with 270 µg/kg SPI-2012 compared to pegfilgrastim (p=0.023). Non-inferiority in DSN was also observed in Cycles 2 to 4 in both the 135 µg/kg and 270 µg/kg SPI-2012 treatment arms compared to pegfilgrastim. Duration of Severe Neutropenia in Cycle 1 of TC chemotherapy by Treatment Arm 45 μg/kg SPI-2012 (N=39) 135 μg/kg SPI-2012 (N=36) 270 μg/kg SPI-2012 (N=36)Pegfilgrastim (N=36)DSN Mean (SD)(days)1.03 (1.5)0.44 (1.3)0.03 (0.2)0.31 (0.8)Difference with pegfilgrastim0.720.14-0.28NANon-inferiority p-value0.2960.002<0.001NASuperiority p-value0.0060.5280.023NASD=Standard Deviation; NA=Not Applicable The common treatment-emergent adverse events observed in ≥20% of patients were similar across all 4 study arms with similar or lower incidence in the SPI-2012 treatment arms, and included fatigue, nausea, alopecia, diarrhea, and bone pain. Conclusions: All doses of SPI-2012 administered in this Phase 2 study were well tolerated, and no new or significant dose-related toxicities were observed. Most reported adverse events were mild and similar to those previously reported in clinical trials with filgrastim and pegfilgrastim in patients receiving myelosuppressive chemotherapy. In Cycle 1, the 135 µg/kg dose of SPI-2012 was non-inferior compared to pegfilgrastim, and the 270 µg/kg dose was superior in terms of DSN. Additional efficacy and safety data for SPI-2012 will be collected in planned Phase 3 clinical trials. Citation Format: Vacirca JL, Chan A, Mezei K, Adoo CS, Papai Z, McGregor K, Okera M, Horvath Z, Landherr L, Hanslik J, Hager SJ, Ibrahim EN, Ghazal H, Rostom M, Bhat G, Choi MR, Allen LF, Tedesco KL, Agajanian R, Lang I. Randomized phase 2, open-label, dose-ranging study of a novel, long-acting G-CSF (SPI-2012) or pegfilgrastim for the management of neutropenia in patients with breast cancer (BC) treated with (Neo) adjuvant chemotherapy with docetaxel + cyclophosphamide (TC). [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 P1-10-05.
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