Summary
Background
Vandetanib is a once-daily oral inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor, and rearranged during transfection (RET) tyrosine kinases. In a randomised phase 2 study in patients with previously treated non-small-cell lung cancer (NSCLC), adding vandetanib 100 mg to docetaxel significantly improved progression-free survival (PFS) compared with docetaxel alone, including a longer PFS in women. These results supported investigation of the combination in this larger, definitive phase 3 trial (ZODIAC).
Methods
Between May, 2006, and April, 2008, patients with locally advanced or metastatic (stage IIIB–IV) NSCLC after progression following first-line chemotherapy were randomly assigned 1:1 through a third-party interactive voice system to receive vandetanib (100 mg/day) plus docetaxel (75 mg/m2 IV every 21 days; maximum six cycles) or placebo plus docetaxel. The primary objective was comparison of PFS between the two groups in the intention-to-treat population. Women were a coprimary analysis population. This study has been completed and is registered with ClinicalTrials.gov, number NCT00312377.
Findings
1391 patients received vandetanib plus docetaxel (n=694 [197 women]) or placebo plus docetaxel (n=697 [224 women]). Vandetanib plus docetaxel led to a significant improvement in PFS versus docetaxel alone (hazard ratio [HR] 0·79, 97·58% CI 0·70–0·90; p<0·0001); median PFS was 4·0 months in the vandetanib group versus 3·2 months in placebo group. A similar improvement in PFS with vandetanib plus docetaxel versus placebo plus docetaxel was seen in women (HR 0·79, 0·62–1·00, p=0·024); median PFS was 4·6 months in the vandetanib group versus 4·2 months in the placebo group. Among grade 3 or higher adverse events, rash (63/689 [9%] vs 7/690 [1%]), neutropenia (199/689 [29%] vs 164/690 [24%]), and febrile neutropenia (61/689 [9%] vs 48/690 [7%]) were more common with vandetanib plus docetaxel than with placebo plus docetaxel. The most common serious adverse event was febrile neutropenia (46/689 [7%] in the vandetanib group vs 38/690 [6%] in the placebo group).
Interpretation
The addition of vandetanib to docetaxel provides a significant improvement in PFS in patients with advanced NSCLC after progression following first-line therapy.
Funding
AstraZeneca.
Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.
Purpose: Pazopanib is an effective treatment for advanced renal cell carcinoma and soft-tissue sarcoma. Transaminase elevations have been commonly observed in pazopanib-treated patients. We conducted pharmacogenetic analyses to explore mechanistic insight into pazopanib-induced liver injury.Experimental Design: The discovery analysis tested association between four-digit HLA alleles and alanine aminotransferase (ALT) elevation in pazopanib-treated patients with cancer from eight clinical trials (N ¼ 1,188). We conducted confirmatory analysis using an independent dataset of pazopanib-treated patients from 23 additional trials (N ¼ 1,002). Genome-wide association study (GWAS) for transaminase elevations was also conducted.Results: The discovery study identified an association between HLA-B Ã 57:01 carriage and ALT elevation [P ¼ 5.0 Â 10 À5 for maximum on-treatment ALT (MaxALT); P ¼ 4.8 Â 10 À4 for time to ALT > 3Â upper limit of normal (ULN) event; P ¼ 4.1 Â 10 À5 for time to ALT > 5Â ULN event] that is significant after adjustment for number of HLA alleles tested. We confirmed these associations with time to ALT elevation event (P ¼ 8.1 Â 10 À4 for ALT > 3Â ULN, P ¼ 9.8 Â 10 À3 for ALT > 5Â ULN) in an independent dataset. In the combined data, HLA-B Ã 57:01 carriage was associated with ALT elevation (P ¼ 4.3 Â 10 À5 for MaxALT, P ¼ 5.1 Â 10 À6 for time to ALT > 3ÂULN event, P ¼ 5.8 Â 10 À6 for time to ALT > 5Â ULN event). In HLA-B Ã 57:01 carriers and noncarriers, frequency of ALT > 3Â ULN was 31% and 19%, respectively, and frequency of ALT > 5Â ULN was 18% and 10%, respectively. GWAS revealed a possible borderline association, which requires further evaluation.Conclusions: These data indicate that HLA-B Ã 57:01 carriage confers higher risk of ALT elevation in patients receiving pazopanib and provide novel insight implicating an immune-mediated mechanism for pazopanib-associated hepatotoxicity in some patients.
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