Toxicities of Targeted Therapies and Their Management

Gayatri Vaidyanathan, MD

Clinical Fellow

Department of Medicine,

Roswell Park Cancer Institute,

Buffalo, NY

Grace K. Dy, MD

Associate Professor

Department of Medicine,

Roswell Park Cancer Institute,

Buffalo, NY

Abstract

Introduction

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.

Dermatologic Toxicities

Various meta-analyses^1-5have 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

TABLE. Examples of On-Target and Off-Target Adverse Effects

Drug Example

Main Target

On-Target Effects

Off-Target Effects

Erlotinib

Afatinib

Cetuximab

EGFR

Skin rash

Diarrhea

Stomatitis/mucositis

Anorexia

Bevacizumab

Aflibercept

VEGF

Hypertension

Poor wound healing

GI perforation

Cardiac toxicity

Sunitinib

Axitinib

Sorafenib

Pazopanib

Cabozantinib

VEGFR-2

Hypertension

Poor wound healing

GI perforation

Cardiac toxicity

Hypophosphatemia

Neutropenia

Hand-foot syndrome

Hypoglycemia

Everolimus

Temsirolimus

mTOR

Hyperglycemia

Pneumonitis

Stomatitis/mucositis

Hypertriglyceridemia

Trametinib

MEK

Retinal detachment

Retinal vein occlusion

Skin rash

Decreased LVEF

Increased creatine kinase

Vemurafenib

Dabrafenib

BRAF

Skin rash

Arthralgia

Keratoacanthomas, cutaneous

squamous cell carcinomas

Hemolytic anemia in patients with

G6PD deficiency (dabrafenib has

sulfonamide moiety)

Dasatinib

BCR-ABL

BCR-ABL

Edema/effusions

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.

Drug-Induced Malignancies

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.

Ocular Toxicities

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

FIGURE. A model of paradoxical MAPK pathway activation caused by selective BRAF inhibitors

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.

Constitutional/Metabolic Toxicities

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.

Clinical Pearls

• Aside from keratoacanthomas and cutaneous squamous cell carcinomas, BRAF inhibitor-induced paradoxical oncogenesis may result in progression of other noncutaneous neoplasms such as colonic adenomas, gastric polyps, andRAS-mutant colon cancer.
• New-onset or worsening fatigue and asthenia may herald endocrine and metabolic abnormalities, such as symptomatic androgen deficiency with crizotinib.
• Retinopathies can occur in patients receiving MEK inhibitors (eg, trametinib). Cases of retinal detachment have been reported with the selective FGFR inhibitor AZD4547 in development.
• Hyperphosphatemia is an on-target side effect of selective FGFR inhibitors.

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.

Toxicities From Drug Combinations

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).

Conclusion

References

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.

1. Nalluri SR, Chu D, Keresztes R, Zhu X, Wu S. Risk of venous thromboembolism with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis.JAMA. 2008;300(19):2277-2285.
2. Ranpura V, Hapani S, Wu S. Treatment-related mortality with bevacizumab in cancer patients: a meta-analysis.JAMA. 2011;305(5): 487-494.
3. Iacovelli R, Palazzo A, Mezi S, Morano F, Naso G, Cortesi E. Incidence and risk of pulmonary toxicity in patients treated with mTOR inhibitors for malignancy. A meta-analysis of published trials.Acta Oncologica. 2012;51(7):873-879.
4. Iacovelli R, Palazzo A, Procopio G, et al. Incidence and relative risk of hepatic toxicity in patients treated with antiangiogenic tyrosine kinase inhibitors for malignancy.Brit J Clin Pharmacol. 2013.doi:10.1111/ bcp.12231.
5. Systems biology. Proceedings of Nobel Symposium 146; June 22-27, 2009; Sanga-Saby, Sweden.FEBS Lett. 2009;583(24):3881-4029.
6. Niraula S, Seruga B, Ocana A, et al. The price we pay for progress: a meta-analysis of harms of newly approved anticancer drugs.J Clin Oncol. 2012;30(24):3012-3019.
7. Anforth R, Fernandez-Penas P, Long GV. Cutaneous toxicities of RAF inhibitors.Lancet Oncol. 2013;14(1):e11-e18.
8. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma.N Engl J Med. 2010;363(9):809-819.
9. Sosman JA, Kim KB, Schuchter L, et al. Survival in BRAF V600- mutant advanced melanoma treated with vemurafenib.N Engl J Med. 2012;366(8):707-714.
10. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors trasactivate RAF dimers and ERK signaling in cells with wild-type BRAF.Nature. 2010;464: 427-430.
11. Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth.Nature2010;464:431-435 .
12. Heidorn SJ, Milagre C, Whittaker S, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.Cell. 2010;140:209-221.
13. Su F, Viros A, Milagre C, et al. RAS mutations in cutaneous squamouscell carcinomas in patients treated with BRAF inhibitors.N Engl J Med. 2012;366(3):207-215.
14. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations.N Engl J Med. 2012;367(18):1694-1703.
15. Marquez CB, Smithberger EE, Bair SM, et al. Multiple keratoacanthomas arising in the setting of sorafenib therapy: novel chemoprophylaxis with bexarotene. Cancer Control : Journal of the Moffitt Cancer Center. 2009;16(1):66-69.
16. Zimmer L, Livingstone E, Hillen U, Domkes S, Becker A, Schadendorf D. Panniculitis with arthralgia in patients with melanoma treated with selective BRAF inhibitors and its management.Arch Dermatol. 2012;148(3):357-361.
17. Sinha R, Edmonds K, Newton-Bishop J, Gore M, Larkin J, Fearfield L. Erythema nodosum-like panniculitis in patients with melanoma treated with vemurafenib.J Clin Oncol. 2013;31(19):e320-e321.
18. Callahan MK, Rampal R, Harding JJ, et al. Progression of RASmutant leukemia during RAF inhibitor treatment.The N Engl J Med. 2012;367(24):2316-2321.
19. Andrews M. Colorectal cancer promoted in a melanoma patient receiving dabrafenib (GSK2118436) in combination with MEK1/2 inhibitor trametinib (GSK1120212).Pigment Cell Melanoma Res. 2012;25:842.
20. Chapman P, Metz D, Sepulveda A, et al. Development of colonic adenomas and gastric polyps in BRAF mutant melanoma patients treated with vemurafenib.Pigment Cell Melanoma Res. 2012;25:847.
21. Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.Lancet Oncol. 2012;13(10):1011-1019.
22. Mehra R, Camidge DR, Sharma S, et al. First-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors.J Clin Oncol. 2012;30(15_suppl),abstr 3007.
23. Nakagawa K, Kiura K, Nishio M, et al. A phase I/II study with a highly selective ALK inhibitor CH5424802 in ALK-positive non-small cell lung cancer (NSCLC) patients: updated safety and efficacy results from AF-001JP.J Clin Oncol. 2013;31(15_suppl),abst8033.
24. Zhou D, Liu Y, Ye J, et al. A rat retinal damage model predicts for potential clinical visual disturbances induced by Hsp90 inhibitors. Toxicol and Applied Pharmacol.J Clin Oncol. 2013;273(2):401-409.
25. van der Noll R, Leijen S, Neuteboom GH, Beijnen JH, Schellens JH. Effect of inhibition of the FGFR—MAPK signaling pathway on the development of ocular toxicities.Cancer Treat Rev. 2013.
26. Huang W, Yang AH, Matsumoto D, et al. PD0325901, a mitogen-activated protein kinase kinase inhibitor, produces ocular toxicity in a rabbit animal model of retinal vein occlusion.J Ocul Pharmacol Ther. 2009;25(6): 519-530
27. Kinkl N, Sahel J, Hicks D. Alternate FGF2-ERK1/2 signaling pathways in retinal photoreceptor and glial cells in vitro.J Biol Chem. 2001;276: 4387-4388
28. Kim KB, Chesney J, Robinson D, et al. Phase I/II and pharmacodynamics study of dovitinib (TKI258), an inhibitor of fibroblast growth factor receptors and VEGF receptors, in patients with advanced melanoma.Clin Cancer Res. 2011;7:6451-6461.
29. Schoenberger SD, Kim SJ. Bilateral multifocal central serous-like chorioretinopathy due to MEK inhibition for metastatic cutaneous melanoma.Case Rep Ophthalmol Med. 2013;2013:673796
30. Renouf DJ, Velazquez-Martin JP, Simpson R, Siu LL, Bedard PL. Ocular toxicity of targeted therapies.J Clin Oncol. 2012;30(26):3277-3286.
31. Andre F, Ranson M, Dean E, et al. Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors. 2013.Presented at: 2013 American Association for Cancer Research Annual Meeting; April 6-9, 2013; Washington, DC.
32. Hamnvik OP, Larsen PR, Marqusee E. Thyroid dysfunction from antineoplastic agents.J Natl Cancer Inst. 2011;103(21):1572-1587.
33. Weickhardt AJ, Rothman MS, Salian-Mehta S, et al. Rapid-onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer.Cancer. 2012;118(21):5302-5309.
34. Sargis RM, Salgia R. Multiple endocrine disruption by the MET/ALK inhibitor crizotinib in patients with non-small cell lung cancer [published online ahead of print August 7, 2013].Am J Clin Oncol. 2013.
35. Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti—PD-1) in melanoma.N Engl J Med. 2013;369: 134-144.
36. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012;366:2443- 2454
37. Brahmer JR, Tykodi SS, Chow LQJ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N Engl J Med. 2012;366:2455- 2465.
38. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma.N Engl J Med. 2013;369:122-133.
39. Costelloe L, Jones J, Coles A. Secondary autoimmune diseases following alemtuzumab therapy for multiple sclerosis. Expert Review of Neurotherapeutics. 2012;12(3):335-341.
40. Wolf J, LoRusso P, Camidge R, et al. A phase I dose escalation study of NVP-BGJ398, a selective pan FGFR inhibitor in genetically preselected advanced solid tumors.Cancer Res. 2012;72: LB-122.
41. Andre F, Ranson M, Dean E, et al. Results of a phase I study of AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), in patients with advanced solid tumors. 2013
42. Martin A, David V, Quarles LD. Regulation and function of the FGF23/ klotho endocrine pathways.Physiological Reviews. 2012;92(1):131-155.
43. Shimizu T, Tolcher AW, Papadopoulos KP, et al. The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ ERK pathways in patients with advanced cancer.Clin Cancer Res. 2012;18(8):2316-2325.
44. Molina AM, Feldman DR, Voss MH, et al. Phase 1 trial of everolimus plus sunitinib in patients with metastatic renal cell carcinoma.Cancer. 2012;118(7):1868-1876.
45. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab.N Engl J Med. 2013;368(14):1365-1366.
46. Lind JS, Postmus PE, Heideman DA, Thunnissen EB, Bekers O, Smit EF. Dramatic response to low-dose erlotinib of epidermal growth factor receptor mutation-positive recurrent non-small cell lung cancer after severe cutaneous toxicity.J Thorac Oncol. 2009;4(12):1585-1586.
47. Satoh H, Iinoue A, Kolbayashi K, et al. Low-dose gefitinib treatment for patients with advanced non-small cell lung cancer harboring sensitive epidermal growth factor receptor mutations.J Thorac Oncol. 2011; 6(8):1413-1417.
48. LoRusso P, Shapiro G, Pandya SS, et al. A first-in-human phase Ib study to evaluate the MEK inhibitor GDC-0973, combined with the pan-PI3K inhibitor GDC-941, in patients with advanced tumors.J Clin Oncol. 2012;(suppl; abstr 2566).