Allyson Perry

Bisphosphonates and denosumab are bone-modifying agents that prevent or delay cancer-induced bone disease (CIBD) and skeletal-related events (SREs) by inhibiting bone resorption.

Because these agents are administered as palliative care, avoiding toxicity is critically important.

Specifically, renal toxicity may pose a concern when treating with bisphosphonates, which are delivered at high doses intravenously (IV).

Bisphosphonates are a class of drugs that bind to bone material and induce osteoclast apoptosis, thus reducing hypercalcemia and the risk of fracture in cancer patients.

While 40% to 60% of bisphosphonate delivered IV binds to the bone, the remaining drug remains unmetabolized and is eliminated by the kidneys via glomerular filtration and active tubular excretion.

The mechanism of renal toxicity from bisphosphonates is not fully understood; however, it is thought to result from renal cell damage and apoptosis.

Treatment with zoledronic acid, the most commonly used bisphosphonate, has been reported to be associated with acute tubular necrosis, which can lead to kidney failure.

Treatment with pamidronate, another common bisphosphonate, was found to reduce the risk of renal impairment by half compared with zoledronic acid.

However, pamidronate treatment has been associated with nephritic syndrome and a range of glomerular lesions.

The reason for differences in renal toxicities among bisphosphonates is not well understood.

Because of these toxicity risks, it is recommended that patient renal function be evaluated before beginning treatment with bisphosphonates.

Because multiple myeloma (MM) can affect kidney function, patients with MM must be closely monitored and are at high risk for renal complications following bisphosphonate treatment.

The rate of creatinine clearance and estimated glomerular filtration rate may be useful for determining dosing and treatment frequency for patients with cancer.

A key topic of interest is whether drug holidays would be beneficial in patients with cancer who are receiving bisphosphonate therapy, as a means to prevent adverse effects from prolonged treatment, including renal toxicity. Clinical trials have shown both beneficial and detrimental effects from bisphosphonate drug holidays in cancer patients.

Further investigation is needed to determine whether adverse effects from bisphosphonate treatment are reduced with drug holidays and, if so, to determine optimal schedules for drug holidays in different patient populations.

Denosumab is a monoclonal antibody against receptor activated nuclear factor-&kappa;B ligand (RANKL) that prevents osteoclast formation, function, and survival by preventing activation by RANK.

Denosumab was approved by the US Food and Drug Administration (FDA) in 2011 for the treatment of bone loss in patients with breast or prostate cancer who are receiving hormone ablation therapy.

In 3 identical phase III clinical trials of patients with prostate cancer, breast cancer, and advanced cancers (excluding breast and prostate) or MM, denosumab was compared with zoledronic acid for the prevention of SREs and renal toxicity.

Denosumab reduced risk of a first SRE by 17% in  patients with cancer compared with zoledronic acid.

Unlike zoledronic acid, dosing of denosumab did not require monitoring or modification based on renal status, although hypocalcemia was more common in patients treated with denosumab.

Allan Lipton, MD, professor of medicine and oncology at the M.S. Hershey Medical Center of the Pennsylvania State University said, &ldquo;These efficacy gains coupled with the convenience of a subcutaneous injection and no need for renal monitoring make denosumab an attractive option for these patients.&rdquo;

Renal toxicity is a concern when treating with bisphosphonates, which are delivered at high doses intravenously for cancer treatment.

Although the mechanism of renal toxicity from bisphosphonates is not fully understood, it is thought to result from renal cell damage and apoptosis.

It is recommended that patient renal function be evaluated before beginning treatment with bisphosphonates.

Additional investigation is needed to determine whether adverse effects from bisphosphonate treatment are reduced with drug holidays.

Dosing of denosumab does not require monitoring or modification based on renal status.

Denosumab was approved and granted Orphan Drug Designation by the FDA on December 8, 2014, for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Overall, treatment with bisphosphonates or denosumab is well-tolerated in patients with unimpaired renal function at the start of treatment. These agents have been instrumental in reducing SREs in  patients with cancer and in improving quality of life.

&ldquo;Before we had bisphosphonates, if a breast cancer patient had bone metastases for 2 years, she had a 64% chance of developing a SRE: fracture or pain,&rdquo; said Theresa A. Guise, MD, professor of oncology at Indiana University School of Medicine.

&ldquo;With the advent of bisphosphonates, this was reduced to 43% with the less potent bisphosphonates, then 34% with the more potent zoledronic acid. Denosumab shows further improvement with a 27% incidence rate,&rdquo;

Rizzoli R, Body J-J, Brandi M-L, et al. Cancer-associated bone disease. Osteoporos Int. 2013;24(12):2929-2953.

Diel IJ, Bergner R, Gr&ouml;tz KA. Adverse effects of bisphosphonates: current issues. J Support Oncol. 2007;5(10):475-482.

American Cancer Society. Systemic treatments for bone metastases. American Cancer Society Web site. Available at: http://www.cancer.org/treatment/understandingyourdiagnosis/bonemetastasis/bone-metastasis-systemic-treatments. Updated February 17, 2014. Accessed December 7, 2014.

Body J-J, Pfister T, Bauss F. Preclinical perspectives on bisphosphonate renal safety. Oncologist. 2005;10(suppl 1):3-7.

Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int. 2008;74(11):1385-1393.

Tandon VR, Sharma S, Mahajan A. Bisphosphonate drug holidays: Can we recommend currently? J Midlife Health. 2014;5(3):111-114.

Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48(16):3082-3092.

Killingsworth P. Amgen sites new studies, claiming experimental drug denosumab superior to Zometa. Living with Multiple Myeloma Web site. Available at: http://multiplemyelomablog.com/2010/10/amgen-sites-new-studies-claiming- experimental-drug-denosumab-superior-to-zometa.html. Published October 12, 2010. Accessed December 8, 2014.

FDA Approves Denosumab for Treatment of HCM. Available at: http://www.prnewswire.com/news-releases/fda-approves-amgens-xgeva-denosumab-for-the-treatment-of-hypercalcemia-of-malignancy-refractory-to-bisphosphonate-therapy-300005931.html. Accessed December 9, 2014.

Harris J. Denosumab reduced breast cancer skeletal-related events further than zoledronic acid. Healio: Endocrine Today Web site. Available at: http://www.healio.com/endocrinology/news/online/%7Bde7674b4-b530-4594-aa04- a47c3f83f300%7D/denosumab-reduced-breast-cancer-skeletal-related-events-further- than-zoledronic-acid. Published December 11, 2009. Accessed December 8, 2014.

Articles

Bisphosphonates and denosumab are bone-modifying agents that prevent or delay cancer-induced bone disease and skeletal-related events by inhibiting bone resorption.

Renal Complications Need Consideration in CIBD

Checkpoint inhibition has demonstrated efficacy for the treatment of melanoma in several clinical trials.

However, biomarkers to predict safety and efficacy of immunotherapies in individual melanoma patients are lacking.

There is an urgent need for prognostic biomarkers to predict patient responses to specific therapies for melanoma in order to provide safe and effective treatment options. Concurrent treatment of patients with the programmed cell death-1 (PD-1) inhibitor nivolumab and ipilimumab, an antibody against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), has resulted in significant side effects while combination treatment with ipilimumab and the oncolytic virus talimogene laherparepvec (T-VEC) has shown better tolerability.

The identification of biomarkers for response to checkpoint inhibition in melanoma is in the early stages of development. Several checkpoint inhibitors have been targeted by companies using antibodies. In addition to nivolumab and ipilimumab, the anti-PD-1 antibody pembrolizumab and antibodies targeting programmed death ligand 1 (PD-L1), MEDI4736 and MPDL3280A, have generated excitement for their antitumor responses in melanoma.

However, the use of these checkpoint inhibitors as prognostic biomarkers for treatment response remains in question.

There are several challenges to consider when systematically evaluating potential biomarkers. Some of these include protocols for processing tissue samples, standardization of biomarker testing, and timing cutoffs for data interpretation.

Choosing the proper tissue samples and processing protocol is critical for identifying biomarkers for any disease. First, the source of the tumor sample, primary or metastatic disease, must be determined.

Tumor heterogeneity and the possibility of the presence of multiple tumors are added levels of complexity when acquiring tissue samples.9 Another consideration includes the method of biopsy for tissue collecting: excisional, core, or fine needle aspiration.

Finally, the tissue sample must either be frozen or formalin-fixed, paraffin embedded for biomarker measurement. Different assays may require different tissue processing.

In order to conduct a high-powered study to determine the clinical implications of candidate biomarkers for melanoma, common assays must be adopted, including standardized antibody and tissue staining conditions for immunohistochemistry.

Measuring assay output manually or in an automated fashion must also be determined.

Part of the reason that the use of PD-L1 as a prognostic biomarker remains unknown is the lack of standardization of PD-L1 testing by various organizations. Mario Sznol, MD, of Yale Cancer Center in New Haven, Connecticut stated, &ldquo;Multiple assays are in development for PD-L1 by drug companies. It is confusing to know which assay to use.&rdquo;

Defining standardized cutoffs between biopsy and treatment for evaluating positive results is critical for determining the prognostic value of a biomarker.

Biomarker expression may be time or therapy dependent, and measurements need to be taken at optimal times in order to determine the relevance of a potential biomarker&rsquo;s expression to treatment response.

Additionally, the effects of other previous or concomitant treatments must be taken into account when evaluating the utility of a potential biomarker.

Researchers must take care to consider patient histories when selecting samples for biomarker testing, because particular treatments or variation among patient histories may confound testing results.

Finally, details of immunohistochemical staining may be indicative of patient response to treatment. Staining of immune cells versus tumor cells, extracellular versus intracellular staining, and the presence of T cells near the staining may all provide clues about a therapy&rsquo;s method-of-action as well as how tumors confer resistance to therapies, which may uncover novel targets for treatment.

While there are many challenges associated with biomarker identification among checkpoint proteins, Louis M. Weiner, MD, director of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington DC, believes that targeting checkpoint proteins will be instrumental in future therapeutics.

&ldquo;That which makes the cancer survive is also by definition the Achilles heel of the cancer. If you can disable that dominant mechanism, you ought to be able to have a meaningful effect, and I personally think what the whole PD-1/PD-L1 story is about is essentially there are some cancers where this checkpoint is the critical checkpoint,&rdquo; said Weiner. &ldquo;I am pretty confident that there are going to be other checkpoints that can be interrogated and used as targets in other diseases.&rdquo;

Looking toward the future of melanoma therapy, biomarkers will play instrumental roles in leading decision making for practicing oncologists and their patients, and biomarker identification, validation, and standardization will contribute to improved survival in this cancer patient population.

Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.

Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.

Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.

Hodi FS, O&rsquo;Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.

Hamid O, Dreicer R, Herbst RS, Socinski MA, Weiner LM. Future Role of Checkpoint Inhibitors in Melanoma. OncLive website. http://www.onclive.com/peer-exchange/immunotherapy/Future-Role-of-Checkpoint-Inhibitors-in-Melanoma. Published August 4, 2014. Accessed November 16, 2014.

Cancer Immunotherapy: Melanoma. Cancer Research Institute website. 2014. http://www.cancerresearch.org/cancer-immunotherapy/impacting-all-cancers/melanoma. Updated August 2014. Accessed November 16, 2014.

Sznol M. The Promise of PD-1/PD-L1 Antagonists in Treating Metastatic Melanoma. Cancer Therapy Advisor website. http://www.cancertherapyadvisor.com/the-promise-of-pd-1pd-l1-antagonists-in-treating-metastatic-melanoma/article/344658/.2014. Published May 1, 2014. Accessed November 16, 2014.

Incollingo BF. Herbst Tackles Key Questions in Emerging PD-1/PD-L1 Immunotherapy in NSCLC. OncLive website. http://www.onclive.com/conference-coverage/ilcc-2014/Herbst-Tackles-Key-Questions-in-Emerging-PD-1-PD-L1-Immunotherapy-for-NSCLC. Published August 2, 2014. Accessed November 16, 2014.

Herbst R. Talk presented at: 14th Annual Targeted Therapies of the Treatment of Lung Cancer Meeting; February 19-22, 2014.

Prilutskaya M, Pustilnik J, Balukova O, Dyakova N, Fenik L. Quality Bio-Specimens for Novel Biomarker Discovery.

Goodman A. Expert Point of View: Mario Sznol, MD. ASCO Post. May 1, 2014. http://www.ascopost.com/issues/may-1,-2014/expert-point-of-view-mario-sznol,-md.aspx. Accessed November 16, 2014.

Chau CH, Rixe O, McLeod H, Figg WD. Validation of analytic methods for biomarkers used in drug development. Clinical cancer researchâ€¯: an official journal of the American Association for Cancer Research 2008;14(19):5967-5976.

Weiner LM, Hamid O, Dreicer R, Herbst RS, Socinski MA. Future Role of Immunotherapy in Cancer. OncLive website. http://www.onclive.com/peer-exchange/immunotherapy/Future-Role-of-Immunotherapy-in-Cancer. Published September 8, 2014. Accessed November 19, 2014.

Checkpoint inhibition has demonstrated efficacy for the treatment of melanoma in several clinical trials. However, biomarkers to predict safety and efficacy of immunotherapies in individual melanoma patients are lacking.

Allyson Perry | Authors

Articles

Renal Complications Need Consideration in CIBD

Challenges Abound With Immunotherapy Biomarkers