579P - Methodological considerations for clinical equivalence of bevacizumab biosimilars

Abstract

Background

Clinical studies between the biosimilar and reference medicinal product should be conducted to demonstrate comparable clinical efficacy, in adequately powered, randomized, parallel group comparative clinical trial(s). Equivalence margins need to be selected based on statistical and medical reasoning using reference product data, such that potential loss in long-term efficacy is mitigated. This analysis aimed to identify equivalence margins for assessing bevacizumab (bev) biosimilar candidates.

Methods

We applied meta-analyses and regression models to randomized bev clinical trial-level data, to assess equivalence margins for bev biosimilar candidates. The indications assessed were ovarian cancer (OC), advanced non-small cell lung cancer (NSCLC), metastatic colorectal cancer (mCRC), metastatic renal cell cancer (mRCC), and metastatic breast cancer (mBC).

Results

Selection of the non-inferiority margin for ORR (i.e. lower margin in an equivalence trial) is provided by the lower bound of the 95% CI of the meta-analysis. Equivalence margins for ORR of 10% (required sample sizes around 900 patients) are associated with large predicted maximum loss (PML) in long-term efficacy, with exception of NSCLC where the predicted loss in PFS may be clinically acceptable (Table). For mCRC, mBC and advanced OC, the predicted loss at an equivalence margin for ORR of 7% is clinically not acceptable, suggesting that for those indications, the margin would need to be lower than 7%, corresponding to a sample size of 1500+.rn

Table: 579P Meta-analytic regression of ORR on long-term efficacy endpoint PFS

rnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrnrn

rn	mCRC		mBC		mRCC		mNSCLC		OC
Equivalence margins	PML	N	PML	N	PML	N	PML	N	PML	N
5%	35.1%	3684	27.9%	3650	18.9%	2950	9.5%	3572	68.5%	3690
7%	45.1%	1878	33.2%	1860	23.7%	1508	14.3%	1822	75%	1880
10%	62.4%	958	41.8%	910	32.0%	738	22.3%	890	85.6%	920
15%	98.5%	406	58.9%	402	51.2%	328	38.6%	394	105.4%	408

rn

Conclusions

The analyses conducted suggest that the magnitude of ORR benefit is heterogeneous across indications and do not provide a large effect size in all indications. For NSCLC, ORR may be considered with an equivalence margin of 10%. When using ORR in mBC, mRCC, equivalence margins would be 

Clinical trial indentification

Not applicable

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd, Basel, Switzerland

Funding

N/A

Disclosure

D. Heinzmann: Employee of F. Hoffmann-La Roche Ltd