Managing the Toxicities of Novel Agents in Cancer Care

Grace K. Dy, MD

It was hoped that novel anticancer therapies, by directly targeting aberrant cancer cells, would avoid the toxicities of traditional cytotoxic agents. Instead, the range of expected toxicities has widened. Not only do classical chemotherapy-related toxicities such as alopecia, myelosuppression, mucositis, and neuropathy occur with various novel targeted therapies, but other toxicities—vascular, dermatologic, endocrine, and ocular—can occur frequently and can be associated with clinically significant sequelae.

At the recent 11th International Congress on Targeted Therapies in Cancer, held August 16-17, 2013, in Washington, DC, Grace K. Dy, MD, associate professor, Department of Medicine at Roswell Park Cancer Institute, in Buffalo, NY, addressed the pathogenesis of toxicities that are associated with targeted agents, and their management.The International Journal of Targeted Therapies in Cancerspoke with Dr. Dy about her presentation.

IJTT: With the use of novel agents, treatment discontinuation may be due to either “ontarget” or “off-target” effects. Could you provide an example of these types of toxic effects?

Dr. Dy:On-target effects refer to adverse events that arise when there is disruption of normal physiologic functions as the drug affects the target of interest, which is also found in normal cells/tissues (Table 1). Examples include hypertension and cardiovascular morbidity from anti-angiogenesis agents, and visual disorders from MEK inhibitors.

TABLE 1.

“On-Target” Effects

“Off-Target” Effects

• VEGF/VEGFR
  • Cardiovascular
  • Wound dehiscence/GI perforation

Hypertension

• MEK/ERK
  • Skin rash, diarrhea, neurotoxicity, ocular toxicity
• FGFR
  • Hyperphosphatemia, tissue calcification, ocular toxicity
• PI3K-Akt-mTOR
  • Hyperglycemia
• HSP90 inhibitors
  • Ocular toxicity
• CDK, PLK, AK inhibitors
  • Myelosuppression

• Fatigue
• Hand-foot skin reaction
• Pulmonary hypertension
• Hypothyroidism
• Hyperbilirubinemia
• Hyperlipasemia
• CK elevation
• Myelosuppression
• Secondary hyperparathyroidism
• Hypoglycemia
• Viral infections
  • VZV, JCV

Off-target effects refer to adverse events that arise when there is disruption of normal physiologic functions as the drug affects targets or cellular processes that are not pertinent to its primary mechanism of antitumor efficacy. In some cases, the mechanism of the off-target effect is known or biologically plausible— for instance, myelosuppression that is seen with sunitinib and is thought to be mediated by its effect on c-kit.

Various other off-target effects, such as fatigue and hand/foot skin reaction, are poorly understood and yet represent common reasons that patients quit taking a number of these agents even if they are effectively controlling their cancers.

The toxicities of kinase inhibitors, and separately, those of sorafenib and sunitinib, serve as examples of differing types and degrees of off-target effects. What would be the key clinical message in these instances?

Dr. Dy:The key message is that even among drugs with similar mechanisms of action and drugs that share similar profiles and key targets, there remain other drug-specific factors that can contribute to the variability in toxicities that we encounter in the clinic. These factors include the entire spectrum of drug targets that are affected, drug potency, drug administration route and/or schedule, drug chemical backbone, and other pharmacokinetic features.

What kinds of strategies can be employed to modulate drug toxicities in a general sense?

Dr. Dy:From the drug company point of view, strategies might include generating new agents with a narrower spectrum of targets (excluding those not directly relevant to antitumor efficacy).

Agents with different chemical structures would be advantageous in some instances. Agents having less hydrophobic molecules and less central nervous system (CNS) penetration would be favored if there are CNS toxicities. This could be a doubleedged sword, however, if this is an effective drug systemically otherwise. CNS relapse may be a common site for disease progression in breast and lung cancer, for instance.

From the clinical standpoint, apart from dose reduction, clinicians can evaluate a therapeutic regimen to ameliorate toxicities, including altering the schedule or route of administration when pharmacokinetically feasible. For example, subcutaneous administration of bortezomib results in lower incidence of neuropathy compared with intravenous administration.

Certain drug combinations can improve both antitumor efficacy and the safety profile with regard to certain toxicities. For instance, the combination of BRAF and MEK inhibitors can reduce the incidence of cutaneous squamous cell carcinoma (SCC) that is seen with BRAF inhibitor monotherapy.

The combination of bortezomib with the immunomodulatory drugs (IMiDs) thalidomide or lenalidomide for multiple myeloma is associated with lower rates of thrombosis compared with IMiD-based regimens.

Dermatologic side effects are either steroidresponsive or not steroid responsive. Nonsteroidresponsive side effects are exemplified by the BRAF inhibitors. What dermatologic toxicities are typical of this class of novel agents?

Dr. Dy:BRAF inhibitors are associated with increased photosensitivity as well as the unusual side effect of proliferative skin disorders such as hyperkeratosis and cutaneous SCC in the most serious category.

Does drug sequencing matter?

Dr. Dy:There have been anecdotal reports of a swift appearance of rash that can be severe in patients who started vemurafenib within one month of completing treatment with ipilimumab.1

Whether this will be replicated with dabrafenib has yet to be reported. Also, Dr. Antoni Ribas, in a personal communication, commented that in his experience, using vemurafenib concomitantly with ipilimumab didn’t seem to exacerbate the rash from vemurafenib. So, obviously, more data are awaited.

Another example of the relevance of drug sequencing applies in the timing of procedures such as radiation with antiangiogenesis agents. Since this class of drugs can affect wound healing, drug wash-out is recommended prior to proceeding with any pertinent interventions to minimize known potential complications. For example, radiation that is administered simultaneously with antiangiogenesis agents increases the risk of tracheoesophageal fistula formation in patients with lung cancer who were undergoing chemoradiation.

TABLE 2.

Modulating Toxicities of Drugs

• Drug schedule/route of administration
  • Neuropathy: Weekly/subcutaneous bortezomib
• • Fatigue/GI: Intermittent dovitinib
• • Diarrhea: Intermittent MEK+ PI3K
• Drug combination
  • Cutaneous SCC: BRAF+MEK inhibitor
• Dosage potency
• Timing of other procedures
  • Radiation + antiangiogenesis drugs

Drug interruption alone is not sufficient in instances of dermatologic toxicity with use of PI3 kinase inhibitor therapy?

Dr. Dy:We have seen several cases where a drug rash appears 1-2 weeks after the drug has been discontinued.

One of the rare but important side effects clinicians have to be attuned to is nodular regenerative hyperplasia. Can you comment on the hepatobiliary toxicity that is associated with trastuzumab emtansine therapy?

Dr. Dy:It is a rare side effect, occurring in less than 0.5% of patients, but because of its insidious onset and potentially fatal outcome, clinicians should be aware of it. In addition, many cases can arise in the absence of typical signs of hepatotoxicity. For instance, it may occur without elevation of transaminase levels.

What ophthalmic toxicities are commonly, or occasionally, associated with novel cancer therapies?

Dr. Dy:Visual disorders may be common but selflimited in some instances, such as with crizotinib administration. In other cases, visual disorders may be potentially serious and require drug discontinuation. Examples of the latter include central serous retinopathy or central retinal vein occlusion with MEK inhibitors, and retinal detachment with selective FGFR inhibitors. Understanding the pathophysiology helps us to be cognizant of and to anticipate the occurrence of certain toxicities. This and having close collaboration with an ophthalmologist are key steps in the management of this toxicity.

Finally, what range of drug toxicities has been seen with adoptive T-cell immunotherapy?

Dr. Dy:Some of these are expected, such as tumor lysis syndrome and cytokine release syndrome. Others are not previously known or are unexpected at the time of first occurrence—for example, cardiac and neurologic deaths with the engineered chimeric antigen receptor (CAR) T cells against certain MAGE proteins. This points to the importance of accurate and comprehensive preclinical models that can predict toxicities. Having a high index of suspicion and conducting relevant investigations to establish and understand the mechanisms of toxicities represent important features necessary to understand unanticipated toxicities retrospectively.

1. Harding JJ, Lacouture ME, Pulitzer M, et al. Hypersensitivity skin reactions in melanoma patients treated with vemurafenib after ipilimumab therapy.J Clin Oncol. 2012;30(suppl, abstr 8515).