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Vistusertib fails to confer PFS benefit with fulvestrant for ER-positive breast cancer
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Fulvestrant in combination with everolimus extended PFS significantly longer than fulvestrant with vistusertib or fulvestrant alone among women with hormone receptor-positive metastatic breast cancer, according to results of the randomized phase 2 MANTA trial published in JAMA Oncology.
“Resistance to endocrine therapy remains a major clinical challenge in women with hormone receptor-positive advanced or metastatic breast cancer,” Peter Schmid, PhD, FRCP, medical oncologist at Barts Cancer Institute and lead of the Centre for Experimental Cancer Medicine at Queen Mary University in London, and colleagues wrote. “Preclinical investigation demonstrates that inhibition of [mammalian target of rapamycin (mTOR)] can overcome endocrine resistance. Clinical trials have demonstrated a substantial benefit of adding the mTOR inhibitor everolimus to endocrine agents, especially in endocrine-resistant breast cancer.”
Vistusertib (AZD2014, AstraZeneca), a dual inhibitor of mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2), has shown broad and superior activity to everolimus (Afinitor, Novartis), which targets only mTORC1, in preclinical breast cancer models.
Schmid and colleagues sought to determine whether the addition of vitusertib to fulvestrant (Faslodex, AstraZeneca) would improve PFS and other antitumor activity measures among 333 postmenopausal women (median age, 63 years; range, 56-70) with ER-positive metastatic breast cancer that progressed after aromatase inhibitor therapy. They also studied the efficacy of vistusertib vs. everolimus and whether intermittent dosing of vistusertib would enhance activity or tolerability compared with daily continuous treatment.
The researchers randomly assigned the women to receive fulvestrant (n = 67), fulvestrant plus vistusertib daily (n = 103), fulvestrant plus vistusertib intermittently (n = 98), or fulvestrant plus everolimus (n = 65). Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent.
PFS served as the study’s primary endpoint.
Median follow-up was 17.1 months (95% CI, 15.9-18.3).
Results showed median PFS of 5.4 months (95% CI, 3.5-9.2) with fulvestrant, 7.6 months (95% CI, 5.9-9.4) with fulvestrant plus daily vistusertib, 8 months (95% CI, 5.6-9.9) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7) with fulvestrant plus everolimus.
Researchers observed no significant differences in PFS between women receiving fulvestrant plus daily vistusertib (HR = 0.88; 95% CI, 0.63-1.24) or intermittent vistusertib (HR = 0.79; 95% CI, 0.55-1.12) compared with fulvestrant alone.
Overall, 255 progression events occurred, including 57 among patients assigned fulvestrant, 81 among those assigned fulvestrant plus vistusertib daily, 72 among those assigned fulvestrant plus vistusertib intermittently, and 45 among patients assigned fulvestrant plus everolimus.
The groups demonstrated similar treatment adherence.
Adverse events were more frequent and more severe among patients in combination treatment groups than among patients who took fulvestrant alone. The most common grade 3 to grade 4 adverse events among the combination groups included stomatitis, rash, asthenia, diarrhea, hyperglycemia, infection, dyspnea and nausea.
“High-dose intermittent pathway inhibition could not improve the antitumor activity in this randomized trial but was associated with an improved safety profile and might be further evaluated in the future with other agents,” Schmid and colleagues wrote. “The results presented here do not support further evaluation of vistusertib in ER-positive metastatic breast cancer, but also raise important questions around the future of this class of drugs.”
The results suggest that an mTORC1 inhibitor, not inhibited by TORC2-related toxic effects, might be a better solution to interrupting 4E-BP1 function and associated cancer cell protein translation, Nisha Unni, MD, assistant professor in the department of internal medicine at UT Southwestern Medical Center, and Carlos L. Arteaga, MD, director of Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, wrote in an accompanying editorial.
“Overall, the limitations for a more definitive interpretation of the results of the MANTA trial do not support the further clinical development of vistusertib,” Arteaga and Unni wrote. “It remains to be determined whether dual and potent therapeutic inhibition of mTORC1 and mTORC2 in cancer is clinically feasible and, if so, superior to mTORC1 inhibition alone.” – by John DeRosier
Disclosures: Schmid reports research grants and/or personal fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Celgene, Eisai, Genentech, Medivation, Merck, Novartis, Oncogenex and Puma Biotechnology. Please see the study for all other authors’ relevant financial disclosures. Arteaga reports research funding from Bayer, Eli Lilly, Pfizer, Puma Biotechnology, Radius and Takeda; advisory roles with AbbVie, Athenex, G1 Therapeutics, H3Biomedicine, Immunomedics, Merck, OrigiMed, Petra Pharma, Symphogen and Taiho Oncology; holding stock options in Provista and Y-TRAP; and a scientific advisory board role with Susan G. Komen Foundation. Unni reports an advisory/speakers bureau role with Eisai.
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