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A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma

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Abstract

Checkpoint blockade has revolutionized the treatment of melanoma; however, it benefits only the minority of patients. Several agents have been combined with immunotherapy to improve T-cell activation and persistence including growth factor, chemotherapy, and radiation. Preclinical data suggest that temozolomide, which metabolizes to the same active compound as dacarbazine, selectively depletes regulatory T cells. This potential immunomodulatory effect of temozolomide provides rationale for combination with ipilimumab. We performed an open-label single-arm phase II study of ipilimumab plus temozolomide in the frontline setting for patients with metastatic melanoma and LDH ≤2× upper limit of normal. Ipilimumab was given at 10 mg/kg on day 1 and temozolomide 200 mg/m2 orally days 1–4 every 3 weeks for four doses followed by maintenance ipilimumab every 12 weeks plus temozolomide every 4 weeks. The primary objective of the study was 6-month PFS. A total of 64 patients were enrolled and the 6-month PFS was 45% with median OS of 24.5 months. There were 10 (15.6%) confirmed partial responses and 10 (15.6%) confirmed complete responses. Duration of response amongst responders is 35 months with 10 patients demonstrating an ongoing response at median follow-up of 20 months. There were no deaths or unexpected toxicities on study. The most common gastrointestinal side effects were nausea and constipation rather than diarrhea or colitis. These results suggest that the combination of induction ipilimumab plus temozolomide could potentially be an effective strategy to enhance antitumor activity with a manageable toxicity profile. These findings warrant further evaluation in a large prospective study.

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Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

CT:

Computed tomography

ECOG:

Eastern Cooperative Oncology Group

FDA:

Food and Drug Administration

IFN-γ:

Interferon-gamma

irRC:

Immune-related response criteria

PFS:

Progression-free survival

RANKL:

Receptor activator of nuclear factor-κB ligand

Teff :

Effector T cells

TNF-α:

Tumor necrosis factor alpha

Treg:

Regulatory T cells

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Author information

Author notes

  1. Dae Won Kim

    Present address: Moffitt Cancer Center, 12902 USF Magnolia Dr., Tampa, FL, 33612, USA

  2. Kevin B. Kim

    Present address: California Pacific Medical Center, 2323 Sacramento St. #2, San Francisco, CA, 94115, USA

  3. Jade Homsi

    Present address: The University of Texas Banner MD Anderson Cancer Center, 2946 E Banner Gateway Dr., Gilbert, AZ, 85234, USA

  4. Sapna P. Patel and Dae Won Kim contributed equally to this work.

Authors and Affiliations

  1. Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Sapna P. Patel, Dae Won Kim, Suzanne Cain, Edwina Washington, Wen-Jen Hwu, Kevin B. Kim, Nicholas E. Papadopoulos, Jade Homsi, Patrick Hwu & Agop Y. Bedikian

  2. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA

    Roland L. Bassett

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  1. Sapna P. Patel
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  2. Dae Won Kim
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Contributions

This manuscript was prepared by the two first co-authors, but all the authors contributed to patient enrollment, collection, and subsequent drafts of the manuscript.

Corresponding author

Correspondence to Sapna P. Patel.

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Funding

The clinical trial was funded by Bristol-Myers Squibb and the work supported by the MD Anderson Cancer Center Support Grant P30CA016672.

Conflict of interest

Dr. Patel reports clinical trial support from Bristol-Myers Squibb for conduct of the study; non-promotional speakers fees from Bristol-Myers Squibb Mexico, non-promotional speakers fees from Merck & Co, advisory board honoraria from Castle Biosciences, Amgen and Genentech, and clinical trial support from Novartis, Glaxo SmithKline, Reata, and Deciphera outside the submitted work. Dr. WJ Hwu reports clinical trial support from Bristol-Myers Squibb, Merck, Glaxo SmithKline, and Medimmune outside the submitted work. Dr. KB Kim reports clinical trial funding and speakers fees from Bristol-Myers Squibb outside the submitted work. Dr. P Hwu is an advisory board member for Lion Biotechnologies and Immatics. All the other authors declare that they have no conflict of interest.

Additional information

This work was published as a poster in its preliminary form at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting, Chicago, IL, USA June 1, 2012 and as a poster at the European Society of Medical Oncology (ESMO) 2012 Annual Meeting, Vienna, Austria, October 1, 2012.

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Patel, S.P., Kim, D.W., Bassett, R.L. et al. A phase II study of ipilimumab plus temozolomide in patients with metastatic melanoma. Cancer Immunol Immunother 66, 1359–1366 (2017). https://doi.org/10.1007/s00262-017-2030-y

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