Third-line Pazopanib Improves PFS For Advanced TKI-Refractory GIST

Third-line pazopanib may extend progression-free survival in advanced gastrointestinal stromal tumours

medwireNews: Phase II trial results suggest that adding the multitargeted receptor tyrosine kinase inhibitor (TKI) pazopanib to best supportive care improves progression-free survival (PFS) for patients with advanced gastrointestinal stromal tumours (GIST) resistant to imatinib and sunitinib therapy.

Median PFS was 3.4 months for the 40 patients assigned to receive pazopanib 800 mg/day alongside supportive care versus 2.3 months for the 41 patients given supportive care alone, giving a significant hazard ratio (HR) of 0.59. Patients treated with pazopanib were also significantly more likely to achieve 4-month PFS than controls (45.2 vs 17.6%, HR=0.59).

Furthermore, the majority (88%) of participants in the best supportive care only group later switched to pazopanib as a compassionate treatment and these patients achieved a median 3.5 months of PFS after pazopanib initiation, report Jean-Yves Blay, from Centre Léon Bérard in Lyon, France, and fellow PAZOGIST study group investigators.

“This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting for these patients”, they write in The Lancet Oncology.

Grade 3 or more severe adverse effects associated with pazopanib were reported by 72% of the 76 patients given the TKI in the two trial arms, including hypertension in 36–38%, and serious pazopanib-related events occurred in 17–35% of the patients, with eight patients developing pulmonary embolism. There were three pazopanib-related deaths (two cases of pulmonary embolism and one hepatic cytolysis).

“Tolerance of the treatment was consistent with the clinical experience gained in similar patient populations (with advanced sarcoma and advanced renal cell carcinoma)”, the authors observe.

Exploratory analysis indicated that PFS might be higher in patients who had not undergone gastrectomy. This and mutations in KIT and PDGFRA may account for the difference in outcome in a second recent trial of pazopanib for refractory GIST which was terminated early for poor PFS findings, Jean-Yves Blay et al hypothesise.

In an accompanying comment, Toshirou Nishida and Toshihiko Doi, from National Cancer Center Hospital East in Kashiwa, Japan, note it is unknown whether pazopanib has anti-tumour efficacy by inhibiting KIT and PDGFRα in GIST or by an antiangiogenesis effect through vascular endothelial growth factor inhibition.

“Because of the low proportion of patients achieving a response and limited efficacy despite the cost, it is important to ascertain pazopanib's mechanism of action and molecular markers to identify patients who will benefit from the drug”, they emphasize.

References

Mir O, Cropet C, Toulmonde M, et al. Pazopanib plus best supportive care versus best supportive care alone in advanced gastrointestinal stromal tumours resistant to imatinib and sunitinib (PAZOGIST): a randomised, multicentre, open-label phase 2 trial. Lancet Oncol 2016; Advance online publication 5 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00075-9

Nishida T, Doi T. Pazopanib for both GIST and soft-tissue sarcoma. Lancet Oncol 2016; Advance online publication 5 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00101-7

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