While targeted agents are generally well tolerated, clinical experience has uncovered a wide range of toxicities due to the physiologic and homeostatic functions mediated by the targets of drug action.
Department of Medicine,
Roswell Park Cancer Institute,
Department of Medicine,
Roswell Park Cancer Institute,
Targeted therapies have revolutionized approaches in the treatment of patients with cancer. While these targeted agents are generally well tolerated, clinical experience has uncovered a wide range of toxicities due to the physiologic and homeostatic functions mediated by the targets of drug action. Awareness and understanding of the pathophysiology behind these adverse effects facilitate prompt recognition and timely intervention to optimize drug therapy and minimize serious consequences. This article reviews the pathophysiology and management of selected dermatologic, ocular, constitutional, metabolic, and oncogenic toxicities of BRAF, MEK, and FGFR inhibitors, as well as immune checkpoint therapies that modulate T-cell activation.Better understanding of cancer biology has led to the development of a series of novel molecularly targeted therapies that disrupt the cellular processes that are critical for the development and maintenance of the malignant phenotype. Oncologists in the current era are faced with new patterns of toxicities beyond the typical myelosuppressive, neurotoxic, and gastrointestinal adverse events characteristic of conventional chemotherapy. Toxicities from targeted therapies may be broadly categorized as “on-target” or “off-target” (Table).
On-target adverse effects arise when the primary drug target/pathway in cancer cells/tissues also mediates physiologic functions in normal cells/tissues. On-target effects such as rash and hypertension may, in some cases, serve as biomarkers of drug efficacy. Off-target adverse effects arise from various mechanisms that are not directly related to a drug’s primary mechanism of antitumor efficacy. Either on- or off-target effects may prevent maintenance of the recommended dose and the schedule of drug administration, thus potentially compromising drug efficacy.
Various meta-analyses1-5have found that, notwithstanding clear improvements in efficacy, there is indubitable evidence that toxicities of targeted therapy may, in some cases, increase morbidity and treatment-related mortality. Treatment discontinuation rates due to toxicity, particularly when these new targeted agents are combined with cytotoxic chemotherapy, are often greater compared with control arm therapies.6Management of widely known toxicities of targeted agents against the EGFR, VEGF, ABL, and mTOR pathways are well-established in current clinical practice; therefore, this article provides a short summary of the current understanding and management of some of the more unique manifestations of selected toxicities that can arise from newer classes of targeted agents, either still in development or approved for clinical use within the past 2 years.Skin rashes and other dermatological side effects are common toxicities associated with many molecular therapeutics that affect the MAPK pathway. Selective BRAF inhibitors such as vemurafenib and dabrafenib have prominent cutaneous toxicities among their most frequent adverse effects. One notable cutaneous side effect seen with vemurafenib and dabrafenib treatment is the development of keratoacanthomas and cutaneous squamous cell carcinomas (SCCs).7The mean time to the diagnosis of the first cutaneous SCC or keratoacanthomas is 8 to 10 weeks.8,9
Poor wound healing
Poor wound healing
Retinal vein occlusion
Increased creatine kinase
squamous cell carcinomas
Hemolytic anemia in patients with
G6PD deficiency (dabrafenib has
Pulmonary arterial hypertension
The underlying pathophysiology is thought to be due to paradoxical activation of the RAS-RAF-MAPK pathway by these agents (Figure). This is thought to arise from the property of currently available selective BRAF inhibitors to promote dimer formation of other nonmutant RAF isoforms. These dimer complexes activate MAPK kinase (also known as MEK) and MAPK (also known as ERK) signaling downstream ofBRAFonly in the presence of upstream oncogenic signaling, such as RAS mutations or receptor tyrosine kinase activation.10-12This mechanism also explains why the development of SCC is suppressed by co-administration of MEK inhibitors such as trametinib.13,14Management of single skin lesions includes focal therapy such as cryotherapy, photodynamic therapy, or surgical excision. Use of systemic retinoids such as bexarotene has been employed for multiple lesions.15 Other common cutaneous manifestations of BRAF inhibitors involve hair follicle changes, including alopecia and keratosis pilaris-like eruptions (called “chicken skin bumps” in lay terms). The latter is typically managed with the use of topical medicated creams or lotions with exfoliating agents such as alpha-hydroxy acid, lactic acid, or urea. Rare cases of painful monomorphous erythema nodosum-like panniculitis with arthralgias have been reported with BRAF inhibitor treatment alone or in combination with a MEK inhibitor.16,17These latter phenomena can occur as early as 2 weeks, with a mean onset of 30 days into therapy. Management includes dose reduction or a treatment break and use of NSAIDs. Systemic steroids can successfully control cases that are not improved with the aforementioned approach.
The paradoxical activation of the MAPK pathway, particularly in the presence ofRASmutations, has raised the possibility of other drug-induced noncutaneous malignances, and recent reports provide some early support for this concern. A patient withRAS-mutant chronic myelomonocytic leukemia, for example, had worsening leukocytosis while on vemurafenib. Symptoms improved upon drug withdrawal, and upon vemurafenib retreatment at a lower dosage of 720 mg twice daily, symptoms worsened again with development of splenomegaly.18Another patient withBRAF-mutant melanoma, who had been receiving dabrafenibtrametinib combination therapy for melanoma, developed brain metastasis 12 weeks into treatment. TheBRAFwild-type brain metastasis that was resected had the sameKRASmutation detected in stage 2 colon cancer that was resected 3 years previously.19Further disease progression of the metastatic colon cancer was documented while continuing BRAF-MEK inhibitor therapy and was halted only upon withdrawal of dabrafenib.
Multiple colonic adenomas and gastric polyps have also been recently reported among those who received more than 2 years of vemurafenib therapy.20One patient who had negative endoscopy 5 months prior to starting vemurafenib developed gastrointestinal bleeding and was found to have developed several colonic adenomas, gastric polyps (≥2 cm), and a bleeding duodenal ulcer. Regrowth of resected gastric polyps within 6 months of retreatment with vemurafenib was seen. None of these patients had family history of colon cancer or polyposis.20These early clinical observations suggest that while more data and long-term follow-up are needed, some type of surveillance and screening should be strongly considered in patients who are anticipated to receive long-term BRAF inhibitor monotherapy, particularly those who are at risk of developing, or have a known concurrent or prior history of, aRAS-mutated cancer.A majority of patients taking crizotinib report transient and self-limited visual disturbances described as “trails of light” when adapting from dark to light conditions.21It is not clear that this effect is due to ALK inhibition; visual disturbances are rare with the newer-generation more selective ALK inhibitors, such as LDK378 and alectinib (CH5424802).22,23Blurred vision, delayed dark-to-light adaptation, and night blindness have also been reported with several HSP90 inhibitors. Preclinical pharmacokinetic (PK) modeling data suggest that the variability in the severity of symptoms reported with various HSP90 inhibitors may result from differential drug clearance. Drugs with slow clearance and high retinal/ plasma ratio, such as AUY922 and 17DMAG, induce photoreceptor apoptosis and cell death. By contrast, ganetespib, which is rapidly eliminated and has the lowest retinal/plasma ratio, does not cause this toxicity.24
A. When BRAF kinase is constitutively activated due to a mutation (eg,V600E), treatment with BRAF inhibitors results in blockade of downstream MAPK pathway. B. In cells with wild-type BRAF, treatment with BRAF inhibitors results in transactivation of CRAF and promotion of RAF dimerization, causing paradoxical activation of downstream MAPK pathway in the presence of upstream oncogenic changes, such asRASmutations.
FGFR and MAPK signaling pathways are critical in the maintenance and repair of the retinal pigment epithelium.25Ocular toxicity from MEK inhibitors dominates the literature at this time. Rare cases (<2%) of uveitis with blurred vision along with symptoms of pain, photophobia, and/or eye redness have been reported with vemurafenib, dabrafenib, and trametinib. Uveitis has also been seen with ipilimumab (anti-CTLA4), and other immune checkpoint inhibitors that activate T-cell immune responses, such as the anti- PD-1 monoclonal antibodies nivolumab and lambrolizumab. Uveitis can generally be treated successfully with topical corticosteroid drops.
Another unique ocular side effect seen with targeted therapies is retinal vein occlusion (RVO). Patients usually present with unilateral, painless acute visual impairment that may lead to permanent blindness. RVO has been reported with BRAF- or MEK-inhibitor monotherapy. The underlying pathophysiology is not well understood, although it is hypothesized that MEK inhibitor-induced RVO may arise as a result of increased oxidative stress, with inflammatory and prothrombotic effects leading to disruption of the blood-retinal barrier.26In response to ischemia caused by RVO, VEGF level becomes subsequently elevated, which results in increased vascular permeability and inflammation. Various interventions applied by ophthalmologists include grid laser photocoagulation and intravitreal VEGF inhibitor injections.25The lack of standard treatment options for RVO mandates close monitoring, rapid diagnosis, and collaboration with ophthalmologists when patients are started on these medications, with discontinuation of further treatment when RVO is suspected/diagnosed.
Bilateral, painless visual loss seen with MEK inhibitor therapy may herald the occurrence of central serous retinopathy (CSR). A potential mechanism involves disruption of the retinal pigment epithelium, because intact MEK signaling is required for photoreceptor proliferation and survival.27Another hypothesis is that this toxicity occurs upon increased vascular permeability mediated by treatment- induced alteration in levels of angiogenic factors.28Both RVO and CSR appear to be related to dose and duration of MEK inhibitor therapy. In contrast to RVO, retinal detachment due to CSR tends to be reversible with treatment interruption, but it can also recur even with dose reductions.29Asymptomatic CSR, detectable only through ophthalmologic examination, may spontaneously resolve, and thus treatment continuation with close monitoring may be considered.30Cases of retinal detachment have also been reported in a phase I study of the selective FGFR inhibitor AZD4547.31The mechanisms underlying fatigue and asthenia associated with targeted therapies are poorly understood. In some instances, these symptoms, which are multifactorial in nature and often difficult to distinguish from the effects of the underlying cancer itself, may be attributable to endocrinopathies that are the result of certain therapies. Management should include periodic measurement of hormone and electrolyte levels in patients receiving therapies outlined herein, with prompt institution of replacement or ablative therapies as indicated.
Hypothyroidism observed with various multikinase inhibitors (eg, imatinib, bosutinib, dasatinib, sorafenib, sunitinib), is not well understood. Case reports of thyrotoxicosis preceding development of hypothyroidism suggest thyroiditis may arise due to direct toxic effects on thyrocytes.32 Other mechanisms involve enhanced T3 and T4 metabolism (increased clearance) or attrition of normal thyroid follicular cells due to inhibition of angiogenesis.32
Fatigue and other symptoms of androgen deficiency, such as loss of libido, may be seen in patients taking crizotinib, sometimes with rapid onset of hypogonadism within 2 to 3 weeks of initiation of treatment.33Although a central mechanism is hypothesized due to accompanying low follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels, a more recent case series described elevated levels of FSH in association with low testosterone level suggesting primary testicular dysfunction.34More prospective evaluation is necessary to understand the mechanism involved.
Therapies that alter T-cell survival or function, such as alemtuzumab, ipilimumab, and other immune checkpoint inhibitors in development such as anti-PD-1/anti-PD-L1 antibodies (eg, nivolumab, lambrolizumab, MPDL3280A), may lead to autoimmune disorders that can affect the endocrine system. Fatigue and asthenia may herald the onset of hypothyroidism, adrenal insufficiency, and/or hypogonadism, either due to primary dysfunction arising or as a manifestation of hypophysitis caused by immunotherapies that activate T-cell function.35-39Of note, cases of hyperthyroidism have also been described.35Treatment interruption in conjunction with administration of high-dose corticosteroids (1-2 mg of prednisone or its equivalent) is recommended to manage symptoms indicative of severe endocrine disorder (eg, heart failure due to thyroid dysfunction) attributed to T-cell-modulating therapies.
Selective BRAF inhibitor monotherapy may result in paradoxical oncogenesis. This phenomenon arises from the property of these agents to transactivate other nonmutant RAF isoforms, thus forming RAF dimers that facilitate signaling, particularly in the presence of RAS mutations.
Worsening fatigue and muscle weakness may also be a symptom of hypophosphatemia, which is frequently seen with various multikinase inhibitors, mTOR inhibitors, and RAF inhibitors. The underlying mechanisms are varied, including induction of secondary hyperparathyroidism with or without vitamin D deficiency. In contrast, selective FGFR inhibitors cause dose-dependent hyperphosphatemia due to blockade of FGF23 signaling as an on-target adverse effect.40,41Prolonged, untreated hyperphosphatemia may potentially result in extraskeletal calcification.42Thus, this adverse effect should be promptly managed with the use of diuretics and phosphate binders.
Febrile drug reactions are reported in 20% to 30% of patients receiving agents that can potently inhibitRAF(eg, regorafenib, vemurafenib, dabrafenib). Most cases are manageable with antipyretic agents. Some cases may be accompanied by rigors and hypotension, and even renal failure, in the absence of infection or other identifiable causes. Recurrent fevers may necessitate the use of low-dose oral glucocorticoids. Combination with BRAF- and MEK-inhibitor therapy increases the risk for pyrexia, which was seen in approximately 70% of patients treated in a combination phase I study, with 5% to 9% of patients requiring hospitalization for evaluation and treatment of this adverse event.14The combination of a targeted therapy with either conventional chemotherapy or with another targeted agent to mitigate drug resistance and improve efficacy often results in increased toxicities. Examples of the latter include the higher frequencies of severe skin rash, mucositis, and transaminase elevation with the combination PI3K/AKT/mTOR pathway inhibitors and RAS/MAPK pathway inhibitors; myelosuppression, hypertension, proteinuria, and gastrointestinal events when VEGF inhibitors are combined with mTOR inhibitors; hepatotoxicity with the combination of a BRAF inhibitor and anti-CTLA-4 antibody; and higher rates of peripheral edema, decreased cardiac ejection fraction, febrile reaction, and ocular toxicity with the combination of BRAF and MEK inhibitors.14,43-45Increased toxicity arises due to the lack or insufficiency of compensatory mechanisms to overcome the effect of deprivation of physiologic and homeostatic signaling from either vertical or parallel pathway inhibition in normal cells and tissues. This contrasts the mechanismbased reduction in cutaneous malignancies as a toxicity when selective BRAF inhibitors are combined with MEK inhibitors due to differential dependence on signaling input betweenBRAF-mutant cancer cells and the specific drug effect on other wildtype isoforms (see discussion above on paradoxical MAPK pathway activation).
A large proportion of targeted therapies are administered in a continuous fashion, therefore, dose reduction poses a feasible approach in managing toxicities, particularly with drugs wherein optimal anticancer biologic effects can be achieved with dosages lower than the recommended dosage.46,47 Altering the schedule of drug administration is also commonly employed. Intermittent dosing of MEK and PI3K inhibitors appears to be effective in preclinical models, and this model is being evaluated in earlyphase studies.48The therapeutic successes seen with many of the novel targeted therapies are accompanied by the new challenge for oncologists of managing a wide variety of potential serious and, in some cases, unfamiliar toxicities that can negatively affect patient quality of life. In the absence of effective supportive care, attenuated doses or intermittent dosing are often necessary to enable patients to tolerate prolonged therapy. Thus, understanding the pathophysiology facilitates appropriate steps in toxicity management and surveillance. Astute observation and early recognition of relevant signs and symptoms enables prompt institution of supportive care to minimize the severity of these adverse effects.