Summary of Key Points
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Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), BRAF, C-ros oncogene 1 (ROS1), ret proto-oncogene (RET) tyrosine kinase inhibitors (TKIs), several antiangiogenesis agents, and antiprogram death 1 (anti-PD1) immunotherapy are effective targeted treatments for lung cancer patients. Each class of agents has class side effects. In addition, each drug may have its own unique side effects.
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Dermatologic and gastrointestinal side effects are frequently encountered side effects of targeted therapy. These side effects are manageable and preventable.
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Interstitial lung diseases are a unique side effect occasionally encountered in lung cancer patients treated with TKIs or anti-PD1 monoclonal antibodies. Although these pulmonary side effects are rare, they may become fatal if left unnoticed. Patients should be informed about the symptoms of these side effects and seek medical care immediately if in doubt. Early intervention including discontinuation of medication and steroid administration is important to reverse the interstitial lung disease process.
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Physicians should be aware of other infrequent but important side effects such as QTc prolongation associated with some TKIs; hypertension, thromboembolic, or hemorrhage side effects associated with antiangiogenesis agents; autoimmune colitis, hepatitis, thyroiditis, or adrenitis associated with anti-PD1 therapy; and skin tumor associated with treatment with B-raf inhibitors.
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Different incidence of side effects between Asian and non-Asian populations may be due to intrinsic genomic differences or extrinsic differences in clinical practice.
Several classes of targeted agents are effective for the treatment of nonsmall cell lung cancer (NSCLC). EGFR TKIs such as gefitinib, erlotinib, and afatinib are very effective for the treatment of NSCLC in patients with EGFR activating mutations. Novel EGFR TKIs such as osimertinib and rociletinib are efficacious in EGFR-mutant NSCLC patients with acquired EGFR T790M mutation. EGFR monoclonal antibodies such as necitumumab enhance chemotherapy drug activity in patients with NSCLC (squamous and nonsquamous). ALK inhibitors such as crizotinib, ceritinib (LDK378), alectinib (RO5424802 [CH5424802], AF802), and AP26113 are highly effective treatments for patients with ALK fusion oncoproteins. The most common of these proteins is echinoderm microtubule-associated protein-like 4-ALK, which is detected by ALK immunohistochemical staining or break-apart fluorescence in situ hybridization. V-raf murine sarcoma viral oncogene homolog B (BRAF) inhibitors, such as dabrafenib or vemurafenib, are being tested in patients with BRAF V600E mutation. ROS1 inhibitors such as crizotinib are highly active in patients with ROS1 rearrangements. Foretinib (XL880) may also effectively inhibit ROS1 in patients with NSCLC. These targeted therapies were designed to manage patients with tumors with specific driver mutations, and their side effects often can be predicted by the physiologic pathways that are inhibited. For example, the side effects of EGFR TKIs are diarrhea, skin toxicity, paronychia, hair changes, and mucositis. Rare side effects such as keratitis, nausea, and vomiting can also be linked to the physiologic function of the EGF–EGFR pathway. ALK, ROS1, and ret proto-oncogene (RET) inhibitors produce fewer but unpredictable side effects because less is known about the role of these genes in normal physiology.
Other classes of targeted agents inhibit general pathways that are involved in cancer development and growth. Antiangiogenic agents used in combination with chemotherapy have broad activity in various cancers, including lung cancer. Bevacizumab, a monoclonal antibody that targets vasculoendothelial growth factor (VEGF), improved response and survival in patients with lung adenocarcinoma treated with chemotherapy. Small molecule inhibitors such as vandetanib or nintedanib also have demonstrated anticancer activity in clinical trials. These agents usually cause side effects related to the vascular growth process, such as bleeding and thrombosis, and side effects related to disruption of VEGF pathways such as hypertension, proteinuria, and renal dysfunction.
Heat-shock proteins (HSPs) are chaperones that protect fragile proteins, especially oncoproteins, from disintegration. Inhibition of HSPs may lead to oncoprotein degradation and cancer cell death. HSP90 inhibitors are very effective in cancers such as NSCLC with ALK fusion proteins. Because HSP90 is universally needed in normal physiologic function the consequences of HSP90 inhibition are less clear.
Another class of targeted therapy that has already proven effective in controlling NSCLC is immunotherapy that disrupts the immune checkpoint program death 1 (PD1) on T lymphocytes and its ligands (PD-L1 and PD-L2) on tumor cells. Monoclonal antibodies that target any of these surface proteins can be highly effective in lung cancers harboring PD-L1. The blockage of this checkpoint is more specific on tumor cells than on normal cells. Therefore, these agents may produce fewer immunologic side effects than monoclonal antibodies that target upstream checkpoints such as ipilimumab, which blocks cytotoxic T lymphocyte antigen 4.
Hepatocyte growth factor (HGF) and cMET inhibitors may have a role in inhibiting the growth of NSCLC cells. cMET amplification was noted in up to 20% of individuals with EGFR mutations in whom resistance to EGFR TKIs developed. Monoclonal antibodies that target the ligand (HGF) or the receptor (cMET), as well as small molecule cMET kinase inhibitors, are under active development. The class side effects of HGF and cMET pathway inhibition are not very clear.
Insulin-like growth factor (IGF) and its receptor (IGFR) belong to the insulin receptor family. Overactivity of the insulin signaling pathway has been implicated in tumor progression in several tumor types. Use of the IGFR1 inhibitor figitumumab with chemotherapy has increased response rates in patients with NSCLC. Hyperglycemia and insulin resistance are typical side effects of IGF and IGFR pathway inhibitors.
Phosphatidylinositol 3-kinase, AKT, mitogen-activated and extracellular signal-regulated kinase (MEK), extracellular signal-regulated kinase (ERK), and mammalian target of rapamycin are the central control molecules for cellular proliferation and apoptosis. Inhibitors of these proteins may lead to tumor control in some people with cancer. Unfortunately, substantial side effects have been reported.
Some side effects from targeted therapy are related to the general molecular structures. For example, infusion reactions, such as chills, fever, hypotension, or even rare anaphylactic reactions, are found with many antibody biologic agents. These side effects often can be alleviated or prevented by pretreatment with a corticosteroid. A unique side effect of many small molecule TKIs is interstitial lung disease, also called interstitial lung fibrosis. Furthermore, similar to many other noncancer drugs or biologics, anticancer agents may have side effects that are not related to known pharmacologic or toxicologic properties. Therefore prescribing oncologists should be familiar with the side effect profiles of each targeted therapy.
Dermatologic Side Effects
EGFR TKIs and Monoclonal Antibodies
Dermatologic side effects develop in a considerable number of patients treated with EGFR TKIs or monoclonal antibodies that target EGFR. A papulopustular (acneiform) eruption is the most frequent side effect; xerosis, eczema, telangiectasia, hyperpigmentation, hair changes, and paronychia may also occur. Skin adverse events that result from treatment with EGFR TKIs may affect 45% to 100% of patients, and some of these side effects may be dose dependent. By studying the development of resistance to the reversible EGFR TKIs erlotinib and gefitinib, researchers have learned about the molecular mechanisms underlying the signaling pathways involving EGFR. Novel molecularly targeted therapies have been developed to overcome EGFR T790M resistance. Afatinib is an irreversible ErbB family blocker, and its side effect profile is similar to other EGFR inhibitors, with skin toxicity (and diarrhea) being the most frequently reported adverse events. Dacomitinib is another irreversible inhibitor of EGFR and human epidermal growth factor receptor-1 (HER1), HER2, and HER4. The monoclonal antibodies cetuximab and panitumumab also may produce skin toxicities because of their inhibition effect on EGFR.
The common adverse effects of treatment with EGFR inhibitors are papulopustular (acneiform) rash, pruritus, and dry skin; nail, hair, and mucosal changes occur less frequently ( Table 49.1 ). Papulopustular (acneiform) rash associated with anti-EGFR therapy occurs in 43% to 94% of patients, with an incidence of approximately 73% in a 2011 meta-analysis. The rash resembles acne vulgaris, but it is characterized by predominantly papular or pustular eruption, is not associated with comedones, and is pathologically and etiologically distinct from acne vulgaris ( Fig. 49.1 ). Commonly affected areas are the face (nose, cheeks, nasolabial folds, chin, and forehead), V-areas of the upper chest and back, and, less frequently, the scalp, arms, legs, abdomen, and buttocks ( Fig. 49.2 ). The palms, soles, and mucosa usually are spared. In general, the papulopustular rash manifests within 1 week to 3 weeks of starting an EGFR inhibitor, often commencing between days 7 and 14 and peaking by weeks 3 to 6. The reaction is reversible, usually with complete resolution within 4 weeks of withdrawal from treatment, but the rash may reappear or worsen once treatment is resumed. Spontaneous improvement with resolution or stabilization of the rash occurs with continued treatment.
| Adverse Effect | Description | Frequency (%) | Timing During Treatment |
|---|---|---|---|
| Papulopustular (acneiform) rash | Erythematous papular, follicular, or pustular lesions, which may be associated with mild pruritus Commonly affected areas: face (nose, cheeks, nasolabial folds, chin, forehead), V areas of the upper chest and back; less frequently, on the scalp, arms, legs, abdomen, and buttocks | 60–94 | Onset: between days 7 & 14 Peak: between weeks 3 & 5 |
| Pruritus | Generalized itching sensation | 16–60 | Onset: between weeks 2 & 4 Peak: between weeks 3 & 6 |
| Dry skin (xerosis) | Diffuse fine scaling on the whole body, especially the extensor areas | 4–38 | Onset: after appearance of rash |
| Paronychia | Painful periungual granulation lesions or friable pyogenic granuloma-like changes, associated with erythema, swelling, and fissuring of lateral nail folds or distal finger tufts | 6–12 | Onset: 2–4 months after start of treatment |
| Hair changes | Curlier, finer, and more brittle hair on scalp and extremities; extensive growth and curling of eyelashes and eyebrows | Unknown | Onset: as early as 7–10 weeks to many months after the start of treatment |
| Hypersensitivity reaction | Flushing, urticaria, and anaphylaxis | 2–3 | Onset: 1st day of initial dose |
| Mucositis | Mild to moderate mucositis, stomatitis, aphthous ulcers | 2–36 | Onset: during treatment, not related to dose or schedule |
The incidence of papulopustular (acneiform) rash was highest among patients with metastatic colorectal cancer treated with cetuximab and in patients with lung cancer treated with afatinib. The incidences of various cutaneous side effects of anti-EGFR treatments in various studies are hard to compare because the genetic background, clinical condition, treatment schedule, and patient characteristics differ in each trial ( Table 49.1 ). Patients with substantial cutaneous side effects are likely to benefit the most from treatment with EGFR inhibitors. Results from a 2013 systematic review and meta-analysis of 33 eligible trials showed that the presence of skin rash predicted the response to EGFR TKIs and the prognosis for patients with NSCLC.
Among patients taking EGFR TKIs or monoclonal antibodies, 4% to 69% have dry skin with diffuse fine scaling after the onset of papulopustular rash. Painful paronychial inflammation of the fingers and toes is seen in 6% to 47% of patients after 1 month to 4 months of anti-EGFR treatment. This inflammation is often described as a periungual granulation type of paronychia or pyogenic granuloma-like changes, presenting as erythema, tenderness, swelling, and fissuring of lateral nail folds or distal finger tufts ( Fig. 49.3 ).
In patients who take anti-EGFR medications for several months, hair abnormalities may develop, such as curlier, finer, and more brittle hair on the scalp and extremities or slowed growth of beard hair. Androgenetic alopecia-like frontal alopecia has been noted ( Fig. 49.4A ). Extensive growth of the eyelashes and eyebrows has also been seen in some patients after many months of anti-EGFR therapy ( Fig. 49.4B ). Patients who report symptoms of eye irritation should be seen by an ophthalmologist because of the risk of trichiasis.
Skin side effects related to EGFR inhibition are generally mild or moderate in severity. However, even mild events may increase the risk of secondary infections, and patients must cope with chronic discomfort, itching, and the disagreeable appearance of the rash. The rash predominantly affects visible areas of the body, which can cause distress, anxiety, negative self-image, and low self-esteem in some patients. Furthermore, high-grade (grade 3 or higher) skin reactions may lead to morbidity, treatment interruption, or dose modifications. Dermatologic side effects may also affect compliance with treatment. Survey results from 110 oncologists who administered EGFR inhibitor therapy indicated that 76% had interrupted therapy because of rash, whereas 32% had discontinued EGFR inhibitor therapy because of rash. Dermatologic reactions also affect a patient’s quality of life.
The mechanism underlying the skin toxicities associated with EGFR inhibition is not fully understood, but it is thought to be related to the disruption of physiologic EGFR-mediated signaling processes in the epidermis, especially the basal keratinocytes. Inhibition of EGFR-mediated signaling pathways affects keratinocytes in several ways, for example, inducing growth arrest and apoptosis, decreasing cell migration, increasing cell attachment and differentiation, and stimulating inflammation, which result in distinct cutaneous conditions. An EGFR-independent pathway, known as c-Jun NH2-terminal kinase activation, may also be related to keratinocyte damage induced by EGFR TKIs.
Several factors have been associated with an increased tendency for the development of rash. Among patients treated with erlotinib, rash is most likely to develop in nonsmokers, individuals with fair skin, and patients older than 70 years. Men younger than 70 years of age are at an increased risk for the development of a rash with cetuximab therapy. When exploring pharmacogenomic and clinical correlations, researchers found that variability in germline polymorphisms in EGFR was a determinant of cutaneous side effects in erlotinib-treated patients.
Symptomatic and preventive treatments are usually helpful for patients. Strategies include use of topical moisturizers or corticosteroids, administration of systemic steroidal medications or antihistamine drugs to palliate pruritus and inflammation, and dose delay or reduction in the case of severe reactions. Although several guidelines for managing cutaneous side effects have been published, they are based mainly on anecdotal evidence and clinical experience.
Patients initiating EGFR TKI or monoclonal antibody therapy should take precautions to protect their skin, such as using alcohol-free skin products and minimizing sun exposure by wearing protective clothing, a hat, and sunscreen with a sun protection factor greater than 30 and ultraviolet A and B protection. Some management strategies based on expert opinion have been proposed for the dermatologic side effects associated with anti-EGFR therapies ( Tables 49.2–49.5 ). For papulopustular (acneiform) rash, topical and oral corticosteroids or antibiotics can be used ( Fig. 49.5 and Table 49.2 ). Patients in whom pruritus develops may benefit from topical, oral, or systemic agents ( Table 49.3 ). Topical corticosteroids, ammonium lactate, and moisturizing creams are recommended for xerosis ( Table 49.4 ). For paronychia, topical antibiotics or antiseptics and silver nitrate applications can be beneficial ( Fig. 49.6 and Table 49.5 ). Patients with an intolerable grade 2 skin reaction and patients with a severe skin reaction (grade 3 or higher) should be referred to a dermatologist with experience managing patients taking EGFR inhibitors. These patients may also benefit from dose modification ( Fig. 49.7 ). Temporary interruption of EGFR inhibitors may relieve severe skin symptoms but should not last for more than 28 days. Anti-EGFR treatment should be permanently discontinued if dermatologic side effects remain at or above grade 3 despite dermatologic interventions and treatment interruption for 28 days. EGFR TKIs may be reintroduced at a lower dose for patients with a severe skin reaction (grade 3 or higher) that improves (grade 2 or lower) within 28 days of treatment interruption.
| Severity of Side Effect a | EGFR Inhibitor Dose | Treatment |
|---|---|---|
| Grade 1: macular or papular eruption or erythema without associated symptoms | Continue at current dose | Topical corticosteroid b OR tacrolimus ointment, twice daily OR topical antibiotic b twice daily |
| Grade 2: macular or papular eruption or erythema with pruritus or other associated symptoms; localized desquamation or other lesions covering <50% of the body surface area | Continue at current dose | Oral antibiotic c for 6 weeks Stop topical antibiotic, if being used Topical corticosteroids b OR tacrolimus ointment twice daily |
| Grade 3 or higher: Severe, generalized erythroderma or macular, papular, or vesicular eruption; desquamation covering ≥50% of the body surface area Generalized exfoliative, ulcerative, or bullous dermatitis | Interrupt treatment; resume at reduced dose when effect is rated grade 2 or lower | Oral antibiotic c for 6 weeks Refer to dermatologist If infection is suspected (yellow crusts, purulent discharge, or painful skin or nares): change to a broad-spectrum oral antibiotic with gram-negative coverage Consider skin swab for bacterial culture |
a Grade according to the National Cancer Institute-Common Terminology Criteria for Adverse Events.
b Topical corticosteroids may include (moderate or low strength) triamcinolone acetonide 0.025%, desonide 0.05%, alclometasone 0.05%, fluticasone propionate 0.05%, or hydrocortisone acetate 2.5%. Topical antibiotics include clindamycin 1-2%, erythromycin 1-2%, metronidazole 1%, or fusidic acid 2%.
c Oral antibiotics include doxycycline 100 mg twice daily, minocycline 100 mg twice daily, or oxytetracycline 500 mg twice daily.
| Severity of Side Effect a | EGFR Inhibitor Dose | Treatment |
|---|---|---|
| Grade 1: mild or localized | Continue at current dose | Moderate-strength topical corticosteroid twice daily OR topical antipruritic (pramoxine 1% or doxepin 5% cream) once daily |
| Grade 2: intense or widespread | Continue at current dose | Moderate-strength topical corticosteroid twice daily OR topical antipruritic (pramoxine 1% or doxepin 5% cream) once daily AND oral antihistamine b |
| Grade 3 or higher: intense or widespread and interfering with activities of daily living | Interrupt treatment; resume at reduced dose when effect is rated grade 2 or lower | Oral antihistamine b AND GABA agonist c OR aprepitant OR doxepin d Refer to dermatologist |
a Grade according to the National Cancer Institute-Common Terminology Criteria for Adverse Events.
b Oral antihistamines include levocetirizine 5 mg once daily, desloratadine 5 mg once daily, diphenhydramine 25 mg to 50 mg three times daily, or fexofenadine 60 mg two or three times daily.
c Gamma-aminobutyric acid (GABA) agonists include gabapentin 300 mg every 8 hours, or pregabalin 50 mg to 75 mg every 8 hours. The dose of either drug should be adjusted for patients with renal impairment.
d Aprepitant: 125 mg on day 1 and 80 mg on days 2 and 3; doxepin 25 mg to 50 mg every 8 hours.
| Severity of Side Effect a | EGFR Inhibitor Dose | Treatment |
|---|---|---|
| Grade 1–2: Asymptomatic Symptomatic, not interfering with activities of daily living | Continue at current dose | Over-the-counter moisturizing cream or ointment to face and body twice daily Over-the-counter moisturizing cream or ointment, ceramide-dominant cream, or corneotherapy to face and body twice daily |
| Grade 3: interfering with activities of daily living | Interrupt treatment; resume at reduced dose when effect is rated grade 2 or lower | Over-the-counter moisturizing cream or ointment, ceramide-dominant cream, or corneotherapy to face and body twice daily AND ammonium lactate 12% cream, urea 10% cream, OR salicylic acid 6% cream to body twice daily b AND topical steroid c to eczematous areas twice daily |
a Grade according to the National Cancer Institute-Common Terminology Criteria for Adverse Events.
b Avoid ammonium lactate, urea, or salicylic acid creams on erythematous, open skin areas, or fissure wounds.
c Topical corticosteroids may include (moderate or low strength) triamcinolone acetonide 0.025%, desonide 0.05%, alclometasone 0.05%, fluticasone propionate 0.05%, or hydrocortisone acetate 2.5%.
| Severity of Side Effect a | EGFR Inhibitor Dose | Treatment |
|---|---|---|
| Grade 1: nail fold edema or erythema; disruption of cuticle | Continue at current dose | Topical antibiotic b AND vinegar soaks c AND topical ultrapotent corticosteroid |
| Grade 2: nail fold edema or erythema with pain, associated with discharge or nail plate separation, limiting instrumental activities of daily living; localized intervention indicated; oral intervention indicated | Continue at current dose | Topical antibiotic b AND vinegar soaks c AND topical silver nitrate weekly AND topical ultrapotent corticosteroid d |
| Grade 3 or higher: limiting self-care activities of daily living; surgical intervention or intravenous antibiotics indicated | Interrupt treatment; resume at reduced dose when effect is rated grade 2 or lower | Topical antibiotic b AND vinegar soaks c AND topical silver nitrate weekly; consider nail avulsion AND systemic antibiotic e Refer to dermatologist |
a Grade according to the National Cancer Institute-Common Terminology Criteria for Adverse Events.
b Topical antibiotics include clindamycin 1%, erythromycin 1%, tetracycline 1%, or chloramphenicol 1%.
c Fingers or toes should be soaked for 15 minutes each day in a 1:1 solution of white vinegar and water.
d Topical ultrapotent corticosteroids include clobetasol propionate 0.05%, diflorasone diacetate 0.05%, or betamethasone dipropionate 0.25%.
e Systemic antibiotics include tetracycline, doxycycline, minocycline, or cephalexin.
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