Dr Subbiah on the Combination of Sapanisertib and Ziv-Aflibercept in Solid Tumors

Vivek Subbiah, MD, chief, Early-Phase Drug Development, Sarah Cannon Research Institute, discusses the rationale for combining sapanisertib (CB-228) with ziv-aflibercept in patients with recurrent metastatic solid tumors, including kidney cancer, as evaluated in a phase 1 study (NCT03017833).

The rationale for combining sapanisertib with ziv-aflibercept in patients with recurrent metastatic solid tumors is rooted in the observed synergistic effects of mTOR pathway inhibition coupled with VEGFR inhibition, Subbiah begins. This synergy has been particularly notable in kidney cancer, as demonstrated in various preclinical models, he says. Multiple studies involving mTOR inhibitors combined with VEGF inhibitors have shown significant activity across different solid tumors, Subbiah explains.

Ziv-aflibercept is a recombinant fusion protein composed of VEGF receptor extracellular domains fused with the Fc portion of human IgG1, incorporating parts of extracellular domains from 2different VEGF receptors, he continues. This unique structure allows ziv-aflibercept to inhibit both VEGFR1 and VEGFR2 effectively, Subbiah shares. On the other hand, sapanisertib, an mTORC1/mTORC2 pathway inhibitor, disrupts several downstream pathways that contribute to antiangiogenic activity, he reports, adding that the combination of these inhibitors may reduce antiangiogenic activity more effectively than either agent alone. Therefore, clinical and preclinical evidence supports the rationale for combining ziv-aflibercept with a potent mTORC1/2 inhibitor, such as sapanisertib, Subbiah concludes.

Notably, the phase 1 study’s primary objective was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the combination among the 55 patients enrolled. Sapanisertib was administered orally at a dose of 4 mg for 3 days on and 4 days off in combination with 3 mg/kg of ziv-aflibercept given intravenously every 2 weeks on a 28-day cycle. This was defined as the MTD for this combination therapy.

Adverse effects (AEs) observed during the study were primarily grade 2 and included hypertension, fatigue, anorexia, and hypertriglyceridemia. Despite these AEs, the combination therapy was effective.