Volovat, C., Bondarenko, I., Gladkov, O., Buchner, A., Lammerich, A., Muller, U., & Bias, P. (2016). Efficacy and safety of lipegfilgrastim compared with placebo in patients with non-small cell lung cancer receiving chemotherapy: Post hoc analysis of elderly versus younger patients. Supportive Care in Cancer, 24, 4913–4920. 

To study the potential benefits and risks of using lipegfilgrastim to reduce neutropenia in patients receiving myelosuppressive chemotherapy for advanced non-small cell lung cancer, and to compare the outcomes of older adults (defined as patients aged older than 65 years) and adults

After receiving first-line chemotherapy (cisplatin 80 mg/m² IV on day 1 and etoposide 120 mg/m² IV on days 1–3 every three weeks) for non-small cell lung cancer, participants were randomized 2:1 to receive a single subcutaneous injection of lipegfilgrastim 6 mg or placebo, administered approximately 24 hours after the last etoposide infusion. Patients received up to four cycles of cisplatin/etoposide, with the study medication given after each cycle. Monitoring for adverse events continued until three weeks after the last intervention. Blood was drawn (for complete blood count and chemistry testing) before each cycle and on day 15 of each cycle.

• N = 375 (intention to treat [ITT] analysis), with 250 completing the study
• MEAN AGE = 62.3 years
• MALES: 87%, FEMALES: 13%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: Stage IIIb–IV non-small cell lung cancer
• OTHER KEY SAMPLE CHARACTERISTICS: Individuals with high risk for febrile neutropenia (FN) were excluded because of ethical concerns

• SITE: Multi-site   
• SETTING TYPE: Not specified    
• LOCATION: Study participants came from 72 chemotherapy centers in eight European countries (Belarus, Bosnia-Herzegovina, Bulgaria, Poland, Romania, Russia, Serbia, and Ukraine).

PHASE OF CARE: Active antitumor treatment

This study was a post hoc analysis of subgroups of patients who had enrolled in a double-blinded, randomized, controlled trial.

To determine efficacy, the authors studied the incidence of FN following the first cycle of cisplatin/etoposide chemotherapy. FN was defined as an oral temperature greater than 38.5 degrees C on two or more consecutive measurements at least 60 minutes apart, with a concurrent absolute neutrophil count (ANC) less than 0.5 x 10⁹/L, or neutropenic sepsis or potentially life-threatening neutropenic infection. The authors also compared the incidence and duration of severe neutropenia (DSN), defined as grade 4 neutropenia with an ANC less than 0.5 x 10⁹/L; the time to ANC recovery, defined as the time from any post-chemotherapy day with an ANC less than  2 x 10⁹/L to the first day with an ANC of 2 x 10⁹/L or less; and the depth of ANC nadir. For study safety, patients were not assessed for adverse events (AEs) until three weeks after the last dose of study medication.

There was no significant difference in the incidence of FN following the first chemotherapy cycle between the lipegfilgrastim and placebo groups for patients aged 65 years or younger. None of the older patients who received lipegfilgrastim developed FN during the first chemotherapy cycle, compared to 13.3% in the placebo group. The difference in incidence of severe neutropenia between the placebo and lipegfilgrastim groups was more pronounced in younger patients (56.8% versus 27.6%) than in those older than 65 years (66.7% versus 49.1%). In both age groups, the mean DSN during cycle 1 was shorter (0.6 days versus 2.1 days for patients aged 65 years or younger; 1 day versus 3 days in patients aged older than 65 years) for patients who received lipegfilgrastim compared to those who received placebo. Mean time to ANC recovery during cycle 1 was less with lipegfilgrastim than with placebo and was comparable in both age groups (6.8 days versus 13.3 days for patients aged 65 years or younger; 6.5 days versus 12.2 days in patient aged older than 65 years). Similarly, mean depth of ANC nadir during cycle 1 was also higher with lipegfilgrastim than with placebo and was comparable in both age groups (1.6 x 10⁹/L versus 0.7 x 10⁹/L for patients aged 65 years or younger; 1.5 x 10⁹/L versus 0.5 x 10⁹/L for patients aged older than 65 years). Most AEs were likely attributable to the chemotherapy, and the incidence was similar between treatment groups. The exception was the incidence of hypokalemia (6.2% versus 2.1% in patients aged 65 years or younger; 15.1% versus 3.3% in patients aged older than 65 years) and hypophosphatemia (3.6% versus 1.1% in patients aged 65 years or younger; 9.4% versus 3.3% in patients aged older than 65 years), which were higher in the lipegfilgrastim group versus the placebo group. The older adults who received lipegfilgrastim also had a higher incidence of decreased appetite (17%) than the placebo group (6.7%).

In patients aged 65 years and younger, lipegfilgrastim did not decrease the incidence of FN but limited the severity, duration, and time to recovery of neutropenia. In older adults, who have a greater risk for myelosuppression, lipegfilgrastim significantly reduced the incidence of FN in addition to the benefits realized by younger patients.

• Risk of bias (no appropriate attentional control condition)
• Risk of bias (sample characteristics)
• Findings not generalizable
• Although the overall sample size is acceptable (n = 375), only 13% were female. It has been established that growth factors generally do not benefit patients aged younger than 65 years treated with cisplatin/etoposide; therefore, the National Comprhensive Cancer Network guidelines recommend the use of growth factors only for patients aged older than 65 years for this chemotherapy regimen. The appropriate study population is the group of patients aged older than 65 years and the sample sizes in the older adult subgroups were small (n = 25 in the placebo group and n = 46 in the intervention group). In addition, those at high risk for FN were excluded from the study, leading to an artificially low incidence of FN among the study population. Last, in patients aged older than 65 years, lipegfilgrastim should have been compared to the standard of care (pegfilgrastim/filgrastim) rather than placebo to demonstrate noninferiority.

The addition of lipegfilgrastim to a cisplatin/etoposide chemotherapy regimen for non-small cell lung cancer is beneficial in reducing the incidence, severity, and duration of FN in patients aged older than 65 years. Lipegfilgrastim was generally well tolerated in both the older adult and adult populations, but those aged older than 65 years may be at risk for hypokalemia, hypophosphatemia, and decreased appetite. The sample sizes in this study were too small to be of value.