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Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study

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Abstract

Purpose

Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent.

Methods

In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS.

Results

Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4–7.8) months, and median OS was 20.6 (11.5–23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3–4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively.

Conclusions

Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.

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Acknowledgments

We would like to thank Dr Krisztina Kovacs (University of Miami) for technical assistance on the biomarker studies. This work was supported by P2C contract N01-CM62205; Commonwealth Foundation (to CE), and CA 119545-02 (to JRM).

Conflict of interest

P.J.F. is on the speakers’ bureau for Genentech and Novartis. All other authors disclosed no conflicts.

Ethical standard

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

Informed consent

“Informed consent was obtained from all individual participants included in the study.”

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Authors and Affiliations

  1. Sylvester Comprehensive Cancer Center, University of Miami, 1475 NW. 12 Avenue. Suite 3400, Miami, FL, 33136, USA

    Jaime R. Merchan

  2. Mayo Clinic, Rochester, MN, USA

    Rui Qin, Henry Pitot, Briant F. Fruth & Charles Erlichman

  3. Washington University School of Medicine, St. Louis, MO, USA

    Joel Picus

  4. University of Wisconsin Carbone Cancer Center, Madison, WI, USA

    Glenn Liu

  5. Mayo Clinic Arizona, Scottsdale, AZ, USA

    Tom Fitch

  6. Mayo Clinic Jacksonville, Jacksonville, FL, USA

    William J. Maples

  7. Metro Minnesota CCOP, St. Louis Park, MN, USA

    Patrick J. Flynn

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  1. Jaime R. Merchan
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Correspondence to Jaime R. Merchan.

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Merchan, J.R., Qin, R., Pitot, H. et al. Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: a phase 2 consortium study. Cancer Chemother Pharmacol 75, 485–493 (2015). https://doi.org/10.1007/s00280-014-2668-5

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