Superior Effectiveness of Plinabulin (Plin) versus No-Treatment for Docetaxel (Doc)-Induced Neutropenia (N) and other Hematologic Complication in Breast Cancer (BC) Patients

Introduction: Minimizing hematologic complications (HC) in breast cancer patients (pt) increases pt safety and convenience, minimizes financial toxicity and may lower risk for COVID-19 infection. Plin is a novel small molecule which protects bone marrow progenitor stem cells and is non-inferior to Peg for the prevention of chemotherapy-induced neutropenia (CIN) after Doc (Blayney, JAMA Open 2021). In contrast to pegfilgrastim (Peg), Plin (as a single dose per cycle), is given on the same day of chemotherapy, has minimal bone pain and thrombopenia, has anti-cancer efficacy, and could minimize healthcare system touches (Blayney, JAMA Onc 2020;Han, ESMO 2021). Doc 75 mg/m2 in BC pts is typically used without G-CSF prophylaxis ('no treatment'). We evaluated Plin's HC preventive effects in comparison to no-treatment in BC patients receiving Doc from published studies. Method(s): The HC endpoints from the 27 early BC patients with at least one NCCN high FN risk factor (N=27) from the phase 3 CIN trial (PROTECTIVE-1, NCT03102606) were compared with NoTreatment (non-prophylactic Peg or G-CSF) in patients receiving 75 mg/m2 Doc. Plin was given by 30 minute (min) IV infusion as a single dose each cycle, 30 min after Doc, over 4 cycles. Cycle 1 hematology measurements in Plin-treated pts were taken pre-dose and days 1, 2, 6, 7, 8, 9, 10, 15 and 21 (10 ANC values in cycle 1);and in cycles 2-4 on days 1, 8, 21 and at end of study and were then analyzed by Covance Central Laboratory. No treatment neutropenia data was obtained from published cancer trials with monotherapy Doc 75 mg/m2 in two No-Treatment studies with at least weekly blood sampling (Harvey et al., JCO, 2006: ~3-4 draws in cycle 1), or twice-weekly (Dieras et al., Br J Ca, 1996: ~5-6 draws in cycle 1). The HC endpoints were all grade (Gr) N, Gr4N, Gr3/4N, Gr3/4 febrile N (FN), infections, anemia and thrombopenia. Other endpoints were adverse events (AEs) and Quality of Life (QoL with EORTC QLQ-C30). Result(s): Baseline demographics were generally comparable between the Plin and No-Treatment literature studies for age, ECOG, and number of prior lines. Gr4N frequency with Plin was 44%, 11%, 3% and 0% in cycles 1, 2, 3 and 4 respectively, thus no added Gr4N was observed after cycle 4. Plin had significantly less neutropenia, and numerically less anemia and thrombopenia vs NoTreatment. QoL with plinabulin remained unchanged over 4 cycles. Conclusion(s): Blood sampling in the No-Treatment studies (Harvey and Dieras) were infrequent, and likely underestimated the true Gr4N frequency. Despite a higher frequency of ANC sampling in cycle 1, Plin was superior vs No-Treatment for Doc-induced neutropenia and HC, while maintaining QoL and with minimal AE and bone pain burden. The same day dosing combined with the avoidance of AEs typically leading to healthcare touches, provides a distinct benefit with Plin for the prevention of Doc-induced neutropenia. (Table Presented).

A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis.

Background: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Methods: This prospective, randomized, open label trial conducted between March 2017 and March 2020 randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8 (clinicaltrials.gov NCT02776059). SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient's primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30,000/mm3 on Day 8. Primary outcome was survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Findings: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC > 30,000/mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval [CI]: 0.57-0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44-0.89]; p > 0.05; CI for difference: -0.18-0.38). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and there were no serious adverse events attributed to pegfilgrastim. Interpretation: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone. Funding: was provided by the United States National Institutes of Health and National Institute on Alcohol Abuse and Alcoholism U01-AA021886 and U01-AA021884.

Pegfilgrastim Biosimilars in US Supportive Oncology: A Narrative Review of Administration Options and Economic Considerations to Maximize Patient Benefit.

Granulocyte colony-stimulating factor (G-CSF) biologics, such as pegfilgrastim, are a standard of care in supportive cancer treatment that are administered once per chemotherapy cycle to reduce the incidence of febrile neutropenia. The high cost of these biologics in the United States can be a limiting factor to accessing care; however, lower-cost pegfilgrastim biosimilars have been available for several years for patients requiring prophylaxis of febrile neutropenia. Different options for pegfilgrastim administration are also now available to accommodate specific patient preferences. As patients may want to minimize the risk of both neutropenia and SARS-CoV-2 infection, same-day administration is a pertinent option during the present COVID-19 pandemic. Therefore, individualized, patient-centered approaches and risk-management strategies should be considered when selecting the treatment and administration method for prophylaxis of febrile neutropenia. Three methods of administration would minimize hospital or clinic visits while also providing the prophylactic effect of G-CSF: same-day administration after chemotherapy, use of the US Food and Drug Administration-approved on-body injector delivering pegfilgrastim approximately 27 h after chemotherapy, or self-administration by the patient or caregiver > 24 h after chemotherapy. Choice of the specific administration option should be based on the patient's specific needs, while also considering mitigating factors, such as the economic burden associated with biologic medications and the risk of COVID-19. Pegfilgrastim biosimilars can minimize the additional financial burden on patients and the health care system during this pandemic and beyond.

Efficacy and toxicity of carboplatin and gemcitabine dosed on day 1/day 8 versus day 1 alone for platinum-sensitive recurrent epithelial ovarian cancer

Background: Carboplatin, gemcitabine +/-bevacizumab is a preferred regimen for recurrent, platinumsensitive ovarian cancer (PSOC). A phase III trial established that the regimen of carboplatin on Day 1 (D1) and gemcitabine on D1 and Day 8 (D8) was associated with acceptable toxicity and improved progression free survival (PFS) compared to carboplatin alone. Treatment with gemcitabine on D8 incurs more exposure to cytotoxic therapy and increased burden on patients and the healthcare system, especially during the COVID-19 pandemic. However, it is unknown whether D1/D8 gemcitabine imparts an improvement in efficacy compared to D1 alone. Our objective was to compare efficacy and toxicity of carboplatin and gemcitabine D1/D8 (CG-D1/8) with a modified D1 regimen (CG-D1). Methods: A retrospective single-institution cohort study was performed in women with recurrent PSOC treated with carboplatin, gemcitabine +/-bevacizumab from 2009-2020. Data was analyzed by intention to treat comparing women who received CG-D1/8 vs CG-D1. Data was also analyzed by 3 groups: CG-D1/8 vs CG-D1/8 but dropped D8 vs CG-D1. The primary endpoint was response rate (RR), defined as complete or partial response at 6 cycles or maximum cycles if <6. Secondary outcomes included PFS, overall survival (OS), toxicity, Neulasta use and dose reduction. Results: Of 200 patients, 26% completed CGD1/ D8, 21.5% started CG-D1/D8 but dropped D8, and 52.5% received CG-D1. There were no significant differences in age, race, or ECOG between cohorts. Among CG-D1/D8, 45.3% dropped D8 primarily due to neutropenia (51.2%) or thrombocytopenia (30.2%). The RR at 6 cycles was 68.7% for CG-D1/8 completed, 70.7% for CG-D1/8 dropped D8, and 69.3% for CG-D1 (p=0.97). The median PFS was 13.1, 12.1 and 12.4 months for CG-D1/8 completed, CG-D1/8 dropped D8, and CG-D1, respectively (p=0.29). Similarly, median OS was 28.2, 33.5 and 34.3 months for the above groups respectively (p=0.42). While there was no difference in concurrent bevacizumab use for CG-D1/8 and CG-D1 (34.7% vs 29.5%, p=0.43), among the CG-D1/8 patients, a significantly higher proportion of patients who dropped D8 received bevacizumab (51.2% vs 21.2%, p=0.006). Table 1 lists secondary outcomes. Conclusions: There was no significant difference in RR, PFS or OS among women with PSOC receiving CG-D1/8 vs CG-D1, regardless of whether D8 was dropped. CG-D1/8 was associated with significantly greater hematologic toxicity. These findings suggest a modified D1 regimen may be a suitable alternative to standard CG-D1/8 treatment and warrant prospective validation.

A phase II, multicenter, open-label, randomized trial of pegfilgrastim for patients with alcohol-associated hepatitis

Background and aims: In trials conducted in India, recombinant granulocyte colony stimulating factor (GCSF) improved survival in alcohol-associated hepatitis (AH). The aim of this trial was to determine the safety and efficacy of pegfilgrastim, a long-acting recombinant GCSF, in patients with AH in the United States. Method: This prospective, open label trial randomized patients with a clinical diagnosis of AH and a Maddrey discriminant function score ≥32 to standard of care (SOC) or SOC+pegfilgrastim (0.6 mg subcutaneously) on Day 1 and Day 8. SOC was 28 days of either pentoxifylline or prednisolone, as determined by the patient’s primary physician. The second injection of pegfilgrastim was not administered if the white blood cell count exceeded 30, 000/mm3 on Day 8. Primary outcomewas survival at Day 90. Secondary outcomes included the incidence of acute kidney injury (AKI), hepatorenal syndrome (HRS), hepatic encephalopathy, or infections. Results: The study was terminated early due to COVID19 pandemic. Eighteen patients were randomized to SOC and 16 to SOC+pegfilgrastim. All patients received prednisolone as SOC. Nine patients failed to receive a second dose of pegfilgrastin due to WBC>30, 000/ mm3 on Day 8. Survival at 90 days was similar in both groups (SOC: 0.83 [95% confidence interval {CI}: 0.57–0.94] vs. pegfilgrastim: 0.73 [95% CI: 0.44–0.89];p > 0.05). The incidences of AKI, HRS, hepatic encephalopathy, and infections were similar in both treatment arms and therewere no serious adverse events attributed to pegfilgrastim. Conclusion: This phase II trial found no survival benefit at 90 days among subjects with AH who received pegfilgrastim+prednisolone compared with subjects receiving prednisolone alone.

Evaluation of a novel medical device for pegfilgrastim administration.

Pegfilgrastim, a pegylated form of granulocyte colony-stimulating factor, has reduced the risk of developing febrile neutropenia, which is associated with an increase in severe infection and prolonged hospitalization. However, pegfilgrastim administration requires that patients visit hospital following cancer chemotherapy, thus imposing a burden on patients and those around them. An on-body injector (OBI), which automatically administers pegfilgrastim about 27 hours after chemotherapy, was used in this study. The OBI, which consists of a main pump unit and infusion set, is a drug delivery device designed to be attached to the patient's body, with a timer-controlled dosing function. This study was conducted in breast cancer patients to evaluate the safety of pegfilgrastim administered subcutaneously via the OBI. The study period consisted of screening and treatment observation periods involving four cycles of neoadjuvant or adjuvant chemotherapy with docetaxel plus cyclophosphamide. One 3.6-mg pegfilgrastim dose was administered subcutaneously via OBI during each cycle of chemotherapy. The study enrolled 35 patients, and no serious adverse events or febrile neutropenia occurred. Administration of pegfilgrastim was successfully completed at all times when the OBI was attached to the patient, and no safety concerns associated with OBI function arose. For outpatients requiring pegfilgrastim following cancer chemotherapy, the use of an OBI was considered to be a safe option to reduce the need for outpatient visits that restrict their activities of daily living.