Understanding molecular pathways and the identification of subgroups of patients with specific biomarker predictors of drug response related to orphan drugs

Figures & data

Figure 1. Factors influencing successful orphan drug development.

Figure 2. Intrinsic breast cancer subtype DNA microarray.

Table 1. Examples of predictive biomarkers for drug response.

Biomarker	Cancer type	Drug therapy	Drug target
ER and PR protein expression	Breast	Tamoxifen	Estrogen receptor
HER2 gene amplification	Breast and advanced gastric	Trastuzumab	HER2
EGFR mutation	NSCLC	Erlotinib, gefitinib	EGFR
KRAS mutation	Metastatic CRC	Cetuximab, panitumumab	EGFR
BRAF V600E mutation	Melanoma	Vemurafenib	BRAF
ELM4-ALK fusion gene	NSCLC	Crizotinib	ALK

ALK: Anaplastic lymphoma kinase; CRC: Colorectal cancer; ELM4: Echinoderm microtubule-associated protein-like 4; ER: Estrogen receptor; HER2: Human epidermal growth factor receptor; NSCLC: Non-small cell lung cancer; PR: Progesterone receptor.

Table 2. Clinical trials studying crizotinib in ALK-positive advanced NSCLC.

Study name	Trial design	Objective	Treatment line	Study number	Efficacy
ALK inhibition in NSCLC	Phase I Open label Multicentre	Evaluate efficacy and safety		82	ORR 57% Estimated PFS at 6 months: 72%
PROFILE 1005	Phase II Multicentre	Evaluate response	Second line or greater	136	ORR 83% PR 54%
PROFILE 1007	Phase III Randomized	Determine whether crizotinib prolongs PFS vs standard of care chemotherapy (docetaxel/pemetrexed)	Second line	Estimated 318	PFS positive as per Pfizer press release, details awaited
PROFILE 1014	Phase III Randomized	Determine efficacy and safety of crizotinib vs standard of care chemotherapy (cisplatin/pemetrexed or carboplatin/pemetrexed)	First line	Results awaited	Results awaited

ALK: Anaplastic lymphoma kinase; NSCLC: Non-small cell lung cancer; ORR: Overall response rate; PFS: Progression-free survival; PR: Partial response.

Parker JS, Mullins M, Cheang MCU, Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol 2009;27(8):1160-7

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