Unexpected toxicity of pazopanib/pemetrexed in NSCLC halts study

Dec 17 2013

By Afsaneh Gray, medwireNews Reporter

A phase II study comparing first-line combination pazopanib/pemetrexed chemotherapy with the standard cisplatin/pemetrexed treatment in non-small-cell lung cancer (NSCLC) was terminated early owing to an increased frequency of adverse events in the experimental arm.

“The combination of pazopanib/pemetrexed in first-line treatment of [NSCLC] showed some antitumor activity but had unacceptable levels of toxicity,” write lead researcher Giorgio Scagliotti (University of Turin, Italy) and colleagues.

It has previously been shown that pazopanib has activity in NSCLC, and the researchers hypothesized that the combination of pazopanib and pemetrexed would be effective and, based on each agent’s toxicity profile, have a safe overlapping toxicity profile.

However, despite intending to enroll 150 patients, the researchers had only randomly assigned 106 patients to treatment before a Safety Review Committee (SRC) recommended the study be discontinued. Three patients in the pazopanib/pemetrexed arm suffered fatal adverse events, including ileus, tumor embolism, and bronchopneumonia/sepsis.

Chemotherapy-naïve patients with histologically or cytologically proven NSCLC and, among other criteria, a predicted life expectancy of at least 12 weeks, were randomly assigned in a 2:1 ratio to receive combination therapy with daily oral pazopanib (800 mg) and intravenous (iv) pemetrexed (500 mg/m²) every 3 weeks, or iv cisplatin (75 mg/m²) and pemetrexed every 3 weeks. In both arms, patients had a maximum of six cycles and received standard pretreatment for pemetrexed.

After 62 patients were assigned to the pazopanib/pemetrexed arm, the SRC recommended a reduction in the starting dose of pazopanib to 600 mg, because an increased frequency of severe neutropenia and drug discontinuations had been noted in that group. Shortly after this, combination treatment was permanently discontinued, when an increase in mortality was detected compared with the control arm.

The primary endpoint of the study was progression-free survival (PFS), and there was no statistically significant difference between the groups on this measure (median PFS of 25.0 weeks for pazopanib/pemetrexed, 22.9 weeks for cisplatin/pemetrexed).

The authors note that, because enrolment in the experimental treatment group was discontinued, relatively more PFS data were censored from that arm than from the standard treatment group.

They write in the Journal of Thoracic Oncology: “With the limitation of the available data from this study, it cannot be excluded that the pazopanib/pemetrexed combination has activity with a [hazard ratio] for PFS of 0.75 (despite the proportion of censored data); however, the observed trade-off between activity and toxicity does not allow further clinical exploration for this combination.”

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