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Is pegfilgrastim superior to filgrastim for the treatment of febrile neutropenia?

Biosimilars/Research | Posted 17/08/2012 1 Post your comment

A study to compare the cost-efficiency of three different recombinant granulocyte colony-stimulating factors (G-CSFs) for the treatment of chemotherapy-induced febrile neutropenia assumes that they are of comparable efficacy. But how solid is the evidence for this assumption? A study by Professor Matti Aapro and co-authors explores the available evidence regarding efficacy for the three G-CSFs, filgrastim (Neupogen, Amgen), pegfilgrastim (Neulasta, Amgen) and a filgrastim biosimilar (Zarzio, Sandoz/Novartis) and concludes that evidence behind previous claims of superiority for pegfilgrastim is ‘similar’ and ‘open to question’ [1]. Thus, originator and biosimilar filgrastim appear to be holding ground in the efficacy stakes.

Use of G-CSFs to treat febrile neutropenia
A life-threatening complication for patients undergoing chemotherapy is febrile neutropenia, which involves a loss of neutrophils (white blood cells) and fever. Patients are more susceptible to infection and can experience delays in further chemotherapy or surgery, as well as reduced well-being.

Granulocyte colony-stimulating factors are growth factors given to stimulate the production of neutrophils. For example, a meta-analysis of 3,493 patients in 17 randomised trials has shown G-CSFs to be clinically effective at reducing the incidence of febrile neutropenia by 46%, infection-related mortality by 45% and all-cause mortality during chemotherapy treatment by 40% [2].

The most commonly used G-CSFs are available in recombinant form as filgrastim and its pegylated form pegfilgrastim. Treatment regimens differ slightly: filgrastim is administered daily for up to a maximum of 14 days, either subcutaneously or intravenously, whereas pegfilgrastim treatment involves a single SC dose per chemotherapy cycle with no restrictions to every 14-day cycles only. EMA has approved a biosimilar to filgrastim–Zarzio, on the basis of its comparable quality, safety and efficacy to filgrastim. Given that pegfilgrastim is more convenient to administer as a single treatment per chemotherapy cycle, there is considerable interest in comparing pegfilgrastim with filgrastim for clinical efficacy and cost-effectiveness.

Is pegfilgrastim equivalent, or superior, in efficacy to filgrastim?
The main aim of the report by Professor Aapro and co-authors is to perform a cost-efficiency comparison for filgrastim, its biosimilar and pegfilgrastim, and for this the authors assume that the three products are equal in terms of treatment efficacy and safety. This assumption is based on two pivotal non-inferiority trials of filgrastim and pegfilgrastim, and the approval process for Zarzio with filgrastim as its reference product. However, as the authors highlight, there are also claims for superiority of pegfilgrastim over filgrastim, which has led to ‘considerable debate’ over the equivalence of filgrastim and pegfilgrastim.

Current clinical guidelines in both Europe and the US assume that filgrastim and pegfilgrastim are clinically equivalent [3, 4]. The two pivotal non-inferiority trials, upon which licensing depended; each concluded that filgrastim and pegfilgrastim are comparable in efficacy, safety and tolerance [5, 6]. However, as the Aapro report indicates, a pooled analysis of these two trials concluded that pegfilgrastim might have superior efficacy [7]. Likewise, a non-controlled observational study led to a similar conclusion that pegfilgrastim may be superior to filgrastim, although a direct comparison of the two products was not made [8]. This means, according to Professor Aapro and co-authors; that ‘claims of superiority of pegfilgrastim cannot be made’.

And although a separate placebo-controlled study demonstrated superiority of pegfilgrastim over placebo [9], such a result was ‘predictable’ and does not demonstrate superiority over filgrastim, according to Professor Aapro. Furthermore, two meta-analyses [2, 10] have indicated that pegfilgrastim is superior to filgrastim, but Professor Aapro argues that these are ‘methodologically compromised’ by the limited number of studies and the ‘inordinate weight’ of one study in favour of pegfilgrastim when others suggest equivalence between the two products. Professor Aapro and co-authors agree with the conclusion of one study which states that, ‘pegfilgrastim is definitely not inferior to classical filgrastim, but whether it might be more superior and more cost-effective cannot be derived from the presently available data, but it seems unlikely that major differences do exist’ [11].

The authors find ‘the evidence for any superiority of pegylated filgrastim is equivocal’ and ‘may be considered open to question’. They remain to be convinced that pegfilgrastim is clinically equivalent or superior to filgrastim. If pegfilgrastim turn out to be superior, then this would need to be taken into consideration when prescribing the biosimilar as a cheaper alternative.

Conflict of Interest
The study [1] was supported by an unrestricted grant from Sandoz Biopharmaceuticals (Sandoz International GmbH).

Editor’s comment
Readers interested to learn more of how biosimilars can save money in European healthcare systems are invited to visit www.gabi-journal.net to view the following peer reviewed article published in GaBI Journal:

Saving money in the European healthcare systems with biosimilars

If you are interested in contributing a research article in a similar topic to GaBI Journal, please send us your submission here.

The cost-effectiveness of biosimilars

References

1. Aapro M, Cornes P, Abraham I. Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia. J Oncol Pharm Pract. 2011.doi: 10.1177/1078155211407367.

2. Kuderer N, Dale D, Crawford J, Cosler L, Lyman G. Impact of primary prophylaxis with granulocyte colony-stimulating factor or febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007;25(21):3158-67.

3. Crawford J, Caserta F, Roila F, et al. Hematopoietic growth factors: ESMO clinical practice guidelines for the applications. Ann Oncol. 2010;21(Suppl 5):v252-6.

4. National Comprehensive Cancer Network. Myeloid growth factors. Practice guidelines in oncology v.1.2010 [monograph on the Internet]. c2012 [cited 2012 Aug 17]. Available from: www.nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf

5. Holmes FA, O’Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast Cancer. J Clin Oncol. 2002;20:727-31.

6. Green MD, Koebl H, Baselga J, et al. A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003;14:29-35.

7. Siena S, Piccart MJ, Holmes FA, et al. A combined analysis of two pivotal randomized trials of single dose pegfilgrastim per chemotherapy cycle and daily filgrastim in patients with stage II-IV breast cancer. Oncol Rep. 2003;10(3):715-24.

8. von Minckwitz G, Kummel S, du Bois A, et al. Pegfilgrastim +/-ciproflaxin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPATRIO study. Ann Oncol. 2008;19(2):292-8.

9. Vogel CL, Wojtukiewicz MZ, Carroll RR, et al. First and subsequent cycle use of pegfilgrastim prevents febrile neutropenia in patients with breast cancer: a multicenter, double-blind, placebo-controlled Phase III study. J Clin Oncol. 2005;23(6):1178-84.

10. Pinto L, Liu Z, Doan Q, et al. Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta-analysis of randomized controlled trials. Curr Med Res Opin. 2007;23(9):2283-95.

11. Klastersky J and Awad A. Prevention of febrile neutropenia in chemotherapy-treated cancer patients: pegylated versus standard myeloid colony stimulating factors. Do we have a choice? Crit Rev Oncol Hematol. 2011;78(1):17-23.

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Comments (1)

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Posted 14/11/2012 by C. D., USA

Comment on article: Is pegfilgrastim superior to filgrastim for the treatment of febrile neutropenia

With reference to the article entitled “Is pegfilgrastim superior to filgrastim for the treatment of febrile neutropenia?” there are several points that bear further attention for fair balance:

Overall, as observed in current practice, the use of daily G-CSF is often suboptimal, and as stated in the EORTC guidelines, “the use of pegfilgrastim may avoid this problem.”
 The study the afore-mentioned article referred to assumed no differences in efficacy between the three products (Neulasta®, Neupogen®, and Zarzio®), which is not supported by clinical data. There have been no head-to-head studies between Neulasta® and biosimilars. Pivotal studies only compared Neulasta® with a median of 11 days of Neupogen®, not more or less days. Hence for this publication to “assume that the three products are equal in terms of treatment efficacy and safety” is not correct.
 To provide perspective, the observational study cited in the article (von Minckwitz et al.) where pegfilgrastim superiority was claimed over filgrastim showed the use of pegfilgrastim compared to filgrastim that was used for a limited number of days (6 days), not similar to its use in registrational studies mentioned above. In studies looking at current practice usage of G-CSFs in Europe, daily filgrastim is often used in a suboptimal way.
 The 1) EORTC G-CSF guidelines (Aapro MS et al. Eur J Cancer 2011;47:8-32), 2) Hexafil study abstract and poster (Tesch H et al. Eur J Cancer; 47: Supplement 1 , September 2011: 208-81), and 3) Pettengell IMPACT NHL observational study publication (Pettengell R et al. Support Care Cancer 2012;20:647–652) state that in clinical practice, daily G-CSFs (including biosimilar filgrastims) are often used for a short duration of treatment, with delayed administration or with reactive use, and not according to the SmPCs. Hence, current clinical practice data and comparisons based on well conducted observational studies has strong relevance to investigate the clinical effectiveness of pegfilgrastim versus suboptimally dosed daily G-CSFs.
 The EORTC G-CSF guidelines also state that “Evidence from multiple low level studies derived from audit data and clinical practice suggests that some patients receive suboptimal daily G-CSFs; the use of pegfilgrastim may avoid this problem.”
 The current manuscript contains statements that contradict previously published statements by the same author. The Aapro et al. JOPP publication stated that “though meta-analyses have tried to argue the relative superiority of pegfilgrastim over filgrastim, they are methodologically compromised by the limited number of studies included.”
 In contrast, another publication by Aapro et al. in Support Care Cancer 2010 stated that: “a growing body of evidence suggests that pegfilgrastim—a PEGylated formulation of filgrastim with neutrophil-regulated pharmacokinetics that is given as a single dose once per cycle - is more effective than filgrastim.”
 Both Pinto et al. and Kuderer et al. meta-analyses criticized in this JOPP publication were also given as examples in the Support Care Cancer publication that “suggest pegfilgrastim was more effective than either lenograstim or filgrastim, although [in the Kuderer publication] pegfilgrastim data came from a single study. These findings might reflect the sustained stimulation of bone marrow by pegfilgrastim throughout the period of neutropenia.”
 A more recent meta-analysis by Cooper and colleagues (Cooper KL et al. BMC Cancer 2011;11:404 ) reinforced the superiority of pegfilgrastim based on several studies and by using appropriate methodology (heterogeneity assessed by the I2 statistics).
 The afore-mentioned article states that “pegfilgrastim treatment involves a single SC dose per 14-day chemotherapy cycle.” This is not correct. Pegfilgrastim is approved to be administered once per chemotherapy cycle – with no restriction to every 14 day cycles only.
 Lastly, this study is a cost-efficiency analysis that wrongly compared the price only of these drugs, which is not relevant for payers. A cost-effectiveness analysis takes into account all factors, such as cost of care over the span of the treatment/ condition, and is the most accepted tool for determining the economic value of a drug.