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Managing Adverse Effects with Multimodal Cancer Therapy: Pharmacists Perspectives

INTRODUCTION

Multimodal cancer therapy, a combination of 2 or more pharmaceutical agents targeting pathways that sustain cell growth or induce cancer, is the cornerstone of cancer treatment.1 Most commonly, cytotoxic chemotherapy, targeted therapy, hormonal therapy, biologic therapy, and immunotherapy are used. Although monotherapy is still common in the treatment of some forms of cancer, it is typically less effective than multimodal therapy. The multimodal approach is more effective because it combines different therapeutic targets, which allows for reducing drug resistance and cancer growth, as well as metastatic potential, by working synergistically or against different pathways. It also reduces toxicity because lower doses are needed in multimodal therapy than in monotherapy.

Combination therapy was first introduced in 1965 as a treatment for pediatric patients with acute lymphoblastic leukemia when several cytotoxic agents were combined (methotrexate, 6-mercaptopurine, vincristine, and prednisone) in a regimen known as POMP.1 This regimen reduced tumor burden and prolonged remission. Subsequently, this approach became the focus of ongoing cancer research throughout the years, with focus turning eventually to combining drugs that target different pathways and mechanisms of action to improve overall outcomes. The superiority of multimodal therapy results from the ability to minimize drug resistance because cancer cells are incapable of adapting to the simultaneous effects of 2 or more agents. The various pathways targeted in multimodal therapy also can target the heterogeneous nature of tumors, which can contribute to drug resistance and cancer recurrence years later.

Multimodal therapy combines cytotoxic chemotherapy, targeted therapies, and immunotherapies to treat many cancer types. The toxicity profiles of these agents vary, but some overlap occurs, as well. Despite the benefits of multimodal therapy, unwanted adverse effects do occur, and, at times, it is difficult to identify which anticancer agent is producing the adverse effect. This monograph is aimed at describing the emerging combination cancer therapies involving contemporary and conventional therapies, as well as the identification and management of adverse effects arising from the use of these novel combinations.

THE CHANGING LANDSCAPE OF CANCER CARE

Cytotoxic chemotherapy has been a mainstay of anticancer therapy since the 1940s when nitrogen mustard was used to treat lymphoma.2 With efforts to improve disease response rates and minimize toxicity, cancer research has focused on the development of novel agents with differing mechanisms of action. Targeted therapies revolutionized the treatment of many cancers, and the number of available agents has risen dramatically since imatinib was first introduced in 2001.3 Unlike cytotoxic chemotherapy, which targets inhibition of DNA and RNA replication and function, targeted agents block alterations in cancer cells that make them malignant. For example, targeted agents may block intracellular signaling pathways, which govern cell responses, movement, and division, eventually leading to apoptosis or stimulation of the immune system to destroy cancer cells. These drugs can either be small-molecular-weight drugs or monoclonal antibodies specifically designed to interact with extracellular receptors or interfere with intracellular signaling pathways and prevent subsequent downstream signaling, with the goal of decreasing cell proliferation and increasing cancer cell death.4 The first monoclonal targeted antibody, rituximab, was approved by the United States (U.S.) Food and Drug Administration (FDA) in 1997. Since then, more than 20 have been approved. Since 2001, more than 60 oral targeted agents have been approved by the FDA.

Recently, immunotherapy has again revolutionized cancer treatment.2 Although immunotherapy has been used in cancer treatments for many years, the introduction of checkpoint inhibitors, such as those targeting cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death-ligand 1 (PD-L1), has been practice changing. Immunotherapy provokes host immunity and induces a systemic response that produces higher and durable response rates with reduced toxicity.

In 2011, the CTLA-4 inhibitor ipilimumab became the first FDA-approved immune checkpoint inhibitor. It prevents T-cell inhibition and promotes activation and proliferation of effector T cells. It was initially approved for treating patients with advanced melanoma. Since then, PD-1 and PD-L1 inhibitors have been approved for use in both solid tumor and hematologic malignancy settings. PD-1 and PD-L1 inhibitors prevent the PD-1/PD-L1 interaction, which is responsible for immune tolerance, and, thus, facilitate a positive immune response.5

Once these therapies were shown to be as effective as monotherapy in many solid and hematologic tumors, combination regimens were developed to maximize efficacy. In fact, their use is growing. Targeted therapies have been combined with cytotoxic chemotherapy and immunotherapy, as well as other targeted therapies. Similarly, immunotherapy has been combined with cytotoxic therapy, targeted therapy, and other immunotherapies. See Table 1 for common combination therapies used in many cancer types.8-14

Table 1. Examples of Common Multimodal Cancer Therapies8-14
Cancer type Multimodal regimens
Acute myelogenous leukemia All-trans retinoic acid or arsenic oxide + gemtuzumab ozogamicin
Cytarabine + daunrobuicin + gemtuzumab ozogamicin
Cytarabine + daunorubicin + midostaurin
High-dose cytarabine + midostaurin or gemtuzumab ozogamicin
Glasdegib + low-dose cytarabine
Sorafenib + decitabine or azacitidine
Venetoclax + decitabine or azacitidine or cytarabine
Breast cancer Adjuvant chemotherapy ± hormonal therapy + trastuzumab ± pertuzumab
Atezolizumab + albumin-bound paclitaxel
Lapatinib + capecitabine
Lapatinib + trastuzumab
Colon cancer Chemotherapy* + bevacizumab or cetuximab or panitumumab
Nivolumab + ipilimumab
Dabrafenib + trametinib + cetuximab or panitumumab
Encorafenib + binimetinib + cetuximab or panitumumab
Irinotecan + cetuximab or panitumumab + vemurafenib
Kidney cancer Axitinib + avelumab
Axitinib + pembrolizumab
Bevacizumab + everolimus
Lenvatinib + everolimus
Nivolumab + ipilimumab
Melanoma Dabrafenib + trametinib
Encorafenib + binimetinib
Nivolumab + ipilimumab
Vemurafenib/cobimetinib
Non-small-cell lung cancer Atezolizumab + bevacizumab
Carboplatin or cisplatin + pemetrexed + pembrolizumab
Carboplatin + paclitaxel + bevacizumab + atezolizumab
Carboplatin + paclitaxel + pembrolizumab
Chemotherapy + bevacizumab
Dabrafenib + trametinib
Nivolumab + ipilimumab
Pembrolizumab + pemetrexed
Small-cell lung cancer Carboplatin + atezolizumab
Carboplatin + etoposide + durvalumab
Cisplatin + etoposide + durvalumab
Nivolumab + ipilimumab
*Chemotherapy such as FOLFOX (leucovorin, fluorouracil, oxaliplatin), CAPEOX (capecitabine, oxaliplatin), FOLFIRI (leucovorin, fluorouracil, irinotecan), FOLFOXFIRI (leucovorin, fluorouracil, irinotecan, oxaliplatin), fluorouracil/leucovorin, capecitabine, or irinotecan.

COMMON ADVERSE EFFECTS OF ANTICANCER THERAPIES

Adverse effects associated with anticancer therapy agents depend on the type of therapy, as well as patient-specific factors. Prevention and monitoring guidelines are available to mitigate adverse effects of therapy as much as possible, and ongoing assessment of patient response to therapy is recommended.

Cytotoxic chemotherapy

Cytotoxic chemotherapy targets rapidly dividing cells at one or more phases of the cell cycle, which causes destruction of both cancer and healthy cells.2 Typically, these agents have a very narrow therapeutic index and can have significant organ toxicity. Doses of cytotoxic agents are administered at a frequency that allows the patient to recover from the toxicity before the next dose (i.e., cyclic fashion, such as once every 3 weeks), and doses are often modified if significant toxicity occurs. Adverse effects usually manifest on the most rapidly proliferating cells of the body: bone marrow (myelosuppression), gastrointestinal tract (nausea, vomiting, mucositis, diarrhea), skin (hand-foot syndrome, nail changes, pigmentation changes), and hair follicles (alopecia).

Additional adverse effects may be related to the class of cytotoxic agents, which is typically based on mechanism of action. For example, anthracyclines like doxorubicin have the potential to cause cardiac toxicity, with a risk related to the cumulative dose. Microtubule agents, such as vinca alkaloids and taxanes, can cause neuropathy. Other toxicities can be related to accumulation of drug or toxic metabolites in organs or tissues, such as cisplatin-induced nephrotoxicity or ifosfamide-induced hemorrhagic cystitis or neurotoxicity.

Targeted therapy

Some oral targeted therapies are administered as continuous treatments and others are administered in a cyclic fashion like cytotoxic chemotherapy to allow recovery from toxicity (e.g., 3 weeks on, 1 week off). Targeted monoclonal antibodies are typically administered in a cyclic fashion due to the long half-life of these agents. Although adverse effects that are common with cytotoxic chemotherapy can occur with some targeted therapies (e.g., nausea, myelosuppression, mucositis), they are typically not dose-limiting, as they often are with cytotoxic chemotherapy.3 Instead, targeted therapies typically result in toxicities that are uncommon with cytotoxic chemotherapy and require different management practices. The common toxicities that occur with targeted agents are based on their pharmacologic mechanism, that is, which intracellular pathway they target.

Off-target effects, which is toxicity unrelated to the intracellular pathway but can be a result of modulation of other targets, can occur as well. For example, vascular endothelial growth factor (VEGF)-targeted agents (e.g., axitinib, bevacizumab, cabozantinib, lenvatinib, regorafenib, pazopanib, sunitinib) are all associated with hypertension due to the fact that VEGF is vital for maintenance of blood vessels and nitric oxide production, which is necessary for vasodilation and angiogenesis. When blocking this pathway, an increase in vascular resistance occurs, leading to decreased nitric oxide production, vasoconstriction, and, ultimately, hypertension. Another example includes the epidermal growth factor receptor (EGFR) pathway, which is involved in homeostasis of the epidermis through stimulation of keratinocyte proliferation and maturation. Inhibitors of the EGFR pathway, such as cetuximab, erlotinib, lapatinib, and osimertinib, all cause papulopustular eruption that occurs in a seborrheic distribution (i.e., scalp, face, upper chest, and back). Off-target effects of tyrosine kinase inhibitors include adverse effects such as anorexia, myelosuppression, reductions in laboratory values (e.g., phosphate, glucose), and edema. Some additional examples of on- and off-target toxicities of targeted therapies can be found in Table 2.15

Table 2. Examples of On-Target and Off-Target Toxicities of Targeted Cancer Therapies15
Drug class Drugs On-target adverse effects Off-target adverse effects
BRAF inhibitors Dabrafenib
Vemurafenib
Arthralgia
Cutaneous squamous cell carcinomas
Skin rash
Keratocanthomas
Hemolytic anemia in patients with G6PD deficiency
EGFR inhibitors Afatinib
Cetuximab
Erlotinib
Acneiform rash
Diarrhea
Mucositis/stomatitis
Anorexia
Hypophosphatemia
VEGF inhibitors Axitinib
Bevacizumab
Cabozantinib
Lenvatinib
Pazopanib
Sorafenib
Sunitinib
Arterial/vascular thrombosis
Gastrointestinal perforation
Hemorrhage
Hypertension
Poor wound healing
Hand-foot syndrome
Electrolyte disturbances
Hyperglycemia
Neutropenia
BRAF, proto-oncogene B-Raf and VRaf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; G6PD, glucose-6-phosphate dehydrogenase; VEGF, vascular endothelial growth factor.

Immunotherapy

Immunotherapies are typically better tolerated than cytotoxic chemotherapy.2,6 In contrast to cytotoxic chemotherapy, immune-related adverse events (irAEs) typically manifest as inflammation and autoimmune symptoms as a result of infiltration of hyperactivated CD4+ and CD8+ T cells into normal tissues and organs.6,7 irAEs can affect any organ but most commonly affect skin, the gastrointestinal tract, lungs, endocrine glands, and liver. Most are mild to moderate in nature, but they can become severe and life-threatening if not promptly identified and managed. The time to onset of irAEs varies according to the type of AE, type of immunotherapy, and whether the immunotherapy is combined with other agents. Rash, pneumonitis, and colitis are some typical early-onset irAE reactions. Delayed-onset irAEs involve organ-specific reactions, such as enterocolitis, hepatitis, and endocrinopathies.6,7

ASSESSMENT AND MANAGEMENT OF ADVERSE EFFECTS

For most adverse effects of cancer treatments, no approved mitigating or evidence-based treatment strategies exist.16 Development of such therapies are often limited by lack of mechanistic insight into adverse effects, difficulty in objectively measuring effects, and lack of good preclinical models and assays to test potential therapies for reducing or preventing adverse effects. Furthermore, funding for symptom and toxicity research is limited. Despite this, some evidence-based guidelines do exist (Table 3). 6,17-34 These guidelines tend to primarily focus on adverse effects most commonly associated with cytotoxic chemotherapy and immunotherapy, but, if applicable, may apply to targeted therapies. For example, some oral targeted therapies do cause significant nausea and vomiting and should be managed with prophylactic antiemetics. The National Comprehensive Cancer Network (NCCN) antiemesis guidelines provide guidance on which cancer therapies should have prophylactic antiemetics and the best types of antiemetics to use.29 In addition to guidelines, management strategies have been published and adopted by many practitioners. For example, dermatologic toxicities of EGFR inhibitors and metabolic disorders are treated with mammalian target of rapamycin (mTOR) inhibitors.35-38

Table 3. Evidence-Based Guidelines for Prevention and/or Treatment of Cancer Therapy Adverse Effects6,17-34

American Society of Clinical Oncology (ASCO) Guidelines

 Antiemetics

 Antimicrobial Prophylaxis for Adult Patients with Cancer-Related Immunosuppression

 Hepatitis B Virus Screening for Patients with Cancer Before Therapy: PCO Update

 Management of Cancer-Associated Anemia and Erythropoiesis-Stimulating Agents

 Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitors

 Medication-Related Osteonecrosis of the Jaw

 Outpatient Management of Fever and Neutropenia in Adults with Malignancy

 Platelet Transfusion for Patients with Cancer

 Recommendations for the Use of WBC Growth Factor Update

 Venous Thromboembolism Prophylaxis and Treatment

Multinational Association of Supportive Care in Cancer (MASCC) Guidelines

 Antiemesis

 Mucositis

 Medication-Related Osteonecrosis of the Jaw

National Comprehensive Cancer Network (NCCN) Clinical Guidelines

 Adolescent and Young Adult Oncology

 Antiemesis

 Cancer-Associated Venous Thromboembolic Disease

 Cancer-Related Fatigue

 Hematopoietic Growth Factors

 Management of Immunotherapy-Related Toxicities

 Prevention and Treatment of Cancer-Related Infections

 Survivorship

The approach to toxicity management in cancer care, however, is similar regardless of the type of cancer therapy. Awareness of potential adverse effects, close monitoring for those adverse effects, employment of prevention strategies if evidenced-based guidance is available, and prompt identification and management of adverse effects that occur are critical to patient care. In fact, overall outcomes are improved when adverse effects are mitigated and managed promptly and appropriately. To that end, it is important to know the potential adverse effects associated with the cancer therapy, as well as recommended monitoring parameters and frequency. This information can often be found in the package inserts of the drugs and in drug databases such as Lexicomp or Micromedex. Additionally, grading of the severity of the adverse event is important, since the management will be based on this severity. The grading system used in clinical trials and in patient care is the National Cancer Institute Common Terminology Criteria for Adverse Events, which grades adverse events from 1 to 5: grade 1, mild; grade 2, moderate; grade 3, severe; grade 4, life-threatening; and grade 5, death.39

The healthcare team should conduct regular assessments of cancer patients that include physical examination and assessment, patient interview, and laboratory monitoring that is specific to the therapy each patient is receiving. Prevention and treatment of adverse effects can be guided by evidence-based guidelines, if they exist (Table 3), existing clinical guidelines related to the condition (e.g., hypertension, hyperlipidemia), or with supportive care therapies that would be used for symptom control regardless of cause (e.g., correction of electrolyte abnormalities).40 See Table 4 for examples of assessment, prevention, and treatment strategies for targeted therapies.40,41 A review by Dy and colleagues also provides some guidance on managing toxicities of targeted therapies.40

Table 4. Examples of Assessment, Prevention, and Treatment of Adverse Effects Associated with Targeted Therapy40,41
Class Assessment Prevention Treatment*
EGFR inhibitors Cetuximab
· Magnesium, calcium, potassium weekly during and for at least 8 weeks following completion
· Vital signs during and for 1 hour after infusion
· Monitor regularly for pulmonary, dermatologic toxicity

Erlotinib
· Liver function tests periodically
· Renal function periodically
· Electrolytes periodically (in patients at risk of dehydration)
· Baseline ophthalmologic exam; reassess for toxicity at 4-8 weeks
· Monitor regularly for hydration status, pulmonary, dermatologic toxicity
For acneiform rash
· Oral minocycline or doxycycline
· Broad-spectrum sunscreen
· Avoid alcohol-containing skin products
· Emollients and mild topical steroids applied 2-3 times/day

For mucositis
· Avoid alcohol- or peroxide-based mouthwashes
For acneiform rash
· Topical antibiotics for eruptions
· 0.1% triamcinolone or 2.5% hydrocortisone for pruritus or tenderness
· Withhold treatment for grade 3 or 4 rash and start oral corticosteroids

For diarrhea
· Mild – antimotility agents
· Moderate-severe – withhold treatment and administer antimotility agents; consider octreotide

For mucositis
· Mild – anesthetic mouthwashes, topical corticosteroid mouth rinses
· Moderate – withhold treatment
· Severe – systemic corticosteroids (prednisone 1 mg/kg/day) if inadequate relief with topical treatments; pain control

Ocular toxicity
· Artificial tears
· Antibacterial ointment

Pulmonary toxicity
· Mild – f/u CT scan in 6-8 weeks
· Moderate – treatment interruption or dose reduction and corticosteroid (0.75-1 mg/kg/day)
· Severe – withhold treatment; consider hospitalization, high-dose corticosteroids (≥ 2 mg/kg/day)
Multikinase with VEGF inhibition Bevacizumab
· Urine protein at baseline and periodically
· Blood pressure every 2-3 weeks during therapy and after discontinuation
· Signs/symptoms of infusion reaction during therapy
· Sign/symptoms of GI perforation, fistula, bleeding, venous/arterial thrombotic events, wound healing, heart failure

Pazopanib
· Monitor liver function tests at baseline, weeks 3, 5, 7, and 9, at months 3 and 4, and periodically thereafter
· Serum electrolytes periodically
· Urine protein at baseline and periodically
· Thyroid function at baseline and every 6-8 weeks
· Blood pressure regularly
· ECG at baseline and periodically
· Signs/symptoms of GI perforation, venous/arterial thrombotic events, pneumonitis infection, heart failure, neurologic changes
For hand-foot skin reaction
· Callus removal
· Minimize friction and direct trauma to hands/feet (wear well-fitted shoes, gloves, thick socks, padded footwear, gel-pad inserts)
· Moisturize feet and hands 2-3 times/day with a product that contains salicylic acid, urea, or ammonium lactate

For hypertension
· Control before therapy

For mucositis
· Avoid alcohol- or peroxide-based mouthwashes

For QTc changes
· Maintain electrolyte balance
· Monitor concomitant medications that can increase QTc interval

For LVEF changes
· Careful evaluation of risk factors; baseline and periodic LVEF evaluation
For diarrhea
· Mild – antimotility agents
· Moderate-severe – withhold treatment and administer antimotility agents; consider octreotide

For hand-foot skin reaction
· Topical corticosteroids for painful blisters
· Interrupt therapy, if needed, or reduce dose

For hypertension
· Standard antihypertensive therapy (preferably with ACE inhibitor) targeted to < 140/90 mm Hg; dose reductions, if needed, and discontinuation if life-threatening symptoms despite antihypertensive treatment

For laboratory changes
· Replacement therapy if lower than normal limits (e.g., hypothyroidism, hypoglycemia)
· Treatment based on typical clinical care guidelines

For mucositis
· Mild – anesthetic mouthwashes, topical corticosteroid mouth rinses
· Moderate – withhold treatment
· Severe – systemic corticosteroids (prednisone 1 mg/kg/day) if inadequate relief with topical treatments; pain control

For LVEF changes
· Symptomatic and LVEF decline < 50% or ≥ 10% from baseline, withhold treatment and treat heart failure; may retreat if improvement
· Discontinue if grade 3 or higher heart failure, LVEF decline > 20% from baseline, or recurrence upon retreatment
*Dose reductions are recommended for toxicity – see individual drug package inserts for details.

ACE, angiotensin-converting enzyme; CT, computed tomography; ECG, electrocardiogram; EGFR, endothelial growth factor receptor; GI, gastrointestinal; LVEF, left ventricular ejection fraction; VEGF, vascular endothelial growth factor.

Assessment and management of irAEs

Generally, mild irAEs can be monitored closely and therapy can be continued. However, moderate to severe adverse effects can result in rapid declines in organ function and quality of life and even death. Therefore, prompt identification of these toxicities and proper management is needed. It is critical to understand that adverse effects can occur at any point during therapy, as well as after therapy has been completed.6,7 Management can include therapy discontinuation, systemic treatment with corticosteroids and, in some cases, infliximab and organ-specific therapies (e.g., thyroid replacement for hypothyroidism, oral antihistamines or gabapentin for pruritus). The goal for the management of these adverse events is to prevent, treat, and minimize their effects, thereby enabling patients to remain on treatment and improve their quality of life. Proactive management, along with ongoing patient education, can help to effectively manage symptoms, often without the need for dose modification or drug withdrawal. The American Society of Clinical Oncology (ASCO) and the NCCN have developed practice guidelines aimed at monitoring, evaluating, and managing adverse effects of checkpoint inhibitor immunotherapies.6

Steroids, specifically corticosteroids, are the main treatment for irAEs: prednisone doses of 0.5 to 1 mg/kg/day (or an equivalent dose), or up to 2 mg/kg/day according to severity, are usually prescribed.6 After resolution of irAEs, patients will require tapering of corticosteroid therapy or, in some cases, supportive prophylaxis treatments for long-term steroid use. In addition, utilization of other immunosuppressants may need to be considered on the basis of the severity of grade or lack of response to steroids.

Continued treatment with immunotherapy through grade 1 irAEs is typically recommended; however, in patients with grade 2 or greater irAEs, immunotherapy is often held until resolution of symptoms. In some cases, due to the type of side effect profiles, permanent discontinuation may indeed be warranted. Differences in the treatment and side effect profiles of irAEs are listed in Table 5.6 

Table 5. Management of Immune-Related Adverse Events6
Dermatologic Toxicities
Presentation Grade 1 Grade 2 Grade 3-4
Maculopapular rash
Grade 1
Covers < 10% BSA with or without symptoms

Grade 2
Covers 10%-30% BSA with or without symptoms; limits IADL

Grade 3-4
Covers > 30% BSA with or without symptoms; limits self-care ADL
· Continue IT
· Topical emollient
· PO antihistamine
· Moderate-potency topical steroids
· Consider holding IT
· Topical emollient
· PO antihistamine
· (High-potency topical steroids and/or prednisone 0.5-1 mg/kg/day)
· Hold IT
· High-potency topical steroids
· Prednisone 0.5-1 mg/kg/day (2 mg/kg/day if no response)
· Dermatology consult
· Consider inpatient admit
Pruritus
Grade 1
Mild or localized

Grade 2
Intense or widespread; intermittent; skin changes from scratching; limits IADL

Grade 3-4
Intense or widespread; constant; skin changes from scratching; limits ADL and sleep
· Continue IT
· PO antihistamines
· Moderate-potency topical steroids
· Continue IT
· PO antihistamines
· High-potency topical steroids
· Dermatology consult
· Hold IT
· PO antihistamines
· Prednisone 0.5-1 mg/kg/day
· Gabapentin or pregabalin
· Urgent dermatology consult
· Aprepitant or omalizumab (refractory cases)
Bullous dermatitis
Grade 1
Asymptomatic; blisters covering < 10% BSA

Grade 2
Blisters covering 10%-30% BSA; painful blisters limiting IADL
· Hold IT
· High-potency topical steroids
· Hold IT until < grade 1
· Prednisone 0.5-1 mg/kg/day
· See SJS/TEN (below)
SJS and TEN
Grade 3-4
Blisters covering > 30% BSA; fluid/electrolyte abnormalities
· Discontinue IT agent
· Prednisone 1-2 mg/kg/day
· Admit to inpatient care (assess for burn ICU admit)
· Urgent dermatology, ophthalmology, and urology consults
Gastrointestinal Toxicities
Intestinal presentation Grade 1 Grade 2 Grade 3-4
Diarrhea/colitis
Grade 1
Fewer than 4 BM/day above normal and no colitis suspicion

Grade 2
Between 4 and 6 BM/day above normal, colitis symptoms, not affecting ADL

Grade 3-4
More than 6 BM/day above normal, colitis symptoms, affecting ADL, other signs of serious toxicity
· Consider holding IT
· Loperamide or diphenyoxylate/ atropine
· Hydration
· Close monitoring
· Hold IT
· Stool evaluation to rule out infectious cause, consider abdominal/pelvic CT with contrast
· Consider GI consult
· Prednisone 1 mg/kg/day
· If no response in 2-3 days, increase prednisone to 2 mg/kg/day ± infliximab
· Discontinue IT (grade 3 – discontinue anti-CTLA-4 therapy; may resume anti-PD-L1 or anti-PD-1 therapy after resolution; grade 4 – permanently discontinue)
· Stool evaluation to rule out infectious cause, consider abdominal/pelvic CT with contrast
· Consider inpatient care
· IV methylprednisolone 2 mg/kg/day
· ± Infliximab (if no response with 2 days of IV steroids); vedolizumab if refractory to infliximab
Hepatic presentation Grade 1 Grade 2 Grade 3-4
Transaminitis
Grade 1
LFT < 3x ULN

Grade 2
LFT 3-5x ULN

Grade 3
LFT 5-20x ULN

Grade 4
LFT > 20x ULN
· Continue IT
· Increase monitoring of LFTs
· Hold IT
· LFTs every 3-5 days
· ± Prednisone 0.5-1 mg/kg/day
· Discontinue IT
· Prednisone 1-2 mg/kg/day
· Inpatient care (consider with grade 3; admit with grade 4)
· Monitor LFTs every 1-2 days (grade 3) or every day (grade 4)
· Hepatology consult
· Liver biopsy (grade 4)
· Mycophenolate 0.5-1 g BID (if no response after 3 days of steroids)
· Do NOT use infliximab
Transaminitis (any grade) with elevated bilirubin
(T-bili > 1.5x ULN)
· Rule out viral, disease-related, drug-induced causes
· Consider GI consult; hepatology consult
· Limit/discontinue hepatotoxic drugs
· Discontinue IT agent
· Prednisone 2 mg/kg/day
· Admit to inpatient care
· Monitor LFTs daily
· Mycophenolate 0.5-1 g BID (if no response after 3 days of steroids)
· Do NOT use infliximab
Pancreatic presentation Grade 1 Grade 2 Grade 3-4
Pancreatitis
Grade 1
Amylase ± lipase > 3x ULN or radiological or clinical findings

Grade 2
Amylase ± lipase > 3x ULN + radiological or clinical findings

Grade 3-4
Amylase ± lipase > 3x ULN + radiological ± severe abdominal pain, vomiting, or hemodynamically unstable
· Continue IT
· Consider GI consult
· Evaluate for pancreatitis and other causes
· Hold IT
· Prednisone 0.5-1 mg/kg/day
· Discontinue IT
· Prednisone 1-2 mg/kg/day
Other Common Toxicities
Renal presentation Grade 1 Grade 2 Grade 3-4
Acute kidney injury
Grade 1
SCr > 1.5-2x baseline or increase ≥ 0.3 mg/dL

Grade 2
SCr > 2-3x baseline

Grade 3-4
SCr > 3x baseline or > 4.0 mg/dL
· Consider holding IT
· Renal function tests every 3-7 days
· Hold IT
· Renal function tests every 3-7 days
· Nephrology consult
· Prednisone 0.5-1 mg/kg/day (beyond 1 week, increase to 1-2 mg/kg/day)
· Discontinue IT
· Inpatient admit
· Prednisone 1-2 mg/kg/day
· Nephrology consult
· Consider renal biopsy
· Consider adding azathioprine, cyclosporine, monthly cyclophosphamide, infliximab, or mycophenolate if remains grade 2 or higher after 1 week of steroids
Pulmonary presentation Grade 1 Grade 2 Grade 3-4
Pneumonitis
Grade 1
Asymptomatic, defined to 1 lung lobe or < 25% of lung parenchyma, clinical/diagnostic observation only

Grade 2
New or worsening SOB, cough, chest pain, fever, increased O2 requirements

Grade 3-4
Severe symptoms, both lobes or > 50% parenchymal involvement on CT, limiting ADLs, life-threatening O2 compromise
· Consider holding IT
· Reassess in 1-2 weeks (SaO2)
· Consider chest CT with contrast
· Hold IT
· Pulmonary consult
· Consider infection workup, bronchoscopy, CT chest with contrast
· Prednisone 1-2 mg/kg/day
· Empiric antibiotics until infection can be ruled out
· Monitor every 3-7 days
· Discontinue IT
· Admit to inpatient care
· Infection workup, bronchoscopy, PFTs
· Pulmonary and ID consults
· Methylprednisolone 1-2 mg/kg/day; assess response in 48 hours and taper over ≥ 6 weeks
· Consider adding infliximab 5 mg/kg IV (2nd dose 14 days later if needed), mycophenolate 1-1.5 mg PO BID (then taper) or IVIG if no improvement in 48 hours
Musculoskeletal presentation Grade 1 Grade 2 Grade 3-4
Inflammatory arthritis
Grade 1
Mild symptoms or only 1 joint involved

Grade 2
Multi-joint involvement, limits ADL

Grade 3-4
Limits ADL, joint erosion
· Continue IT
· NSAIDs or Prednisone 10-20 mg PO daily x 4 weeks
· Consider intra-articular steroids
· Consider holding IT
· Prednisone 0.5 mg/kg/day x 4-6 weeks
· If no improvement by week 4, rheumatology consult
· Discontinue IT
· Prednisone 1 mg/kg/day
· If no improvement by week 2, rheumatology consult and additional drug treatment (e.g., infliximab, methotrexate, tocilizumab, sulfasalazine, azathioprine, leflunomide, IVIG)
Myalgias/myositis
Grade 1
Mild pain

Grade 2-4
Moderate or severe pain
· Continue IT
· Pain management
· Monitor aldolase/CK
· Hold IT
· Muscle MRI and EMG
· Prednisone 1-2 mg/kg/day
· Consider muscle biopsy
· Monitor aldolase/CK until symptoms resolve or steroids discontinued
· Rheumatology or neurology consult
Endocrine Toxicities
Presentation Grade 1 Grade 2 Grade 3-4
Subclinical hypothyroidism
Grade 1
TSH 4-10 mU/L, normal free T4, asymptomatic

Grade 2
TSH > 10 mU/L, normal free T4

Grade 3-4
Normal/low TSH, low free T4
· Continue IT
· Monitor free T4 and TSH
· Continue IT
· Consider levothyroxine ~1.6 mcg/kg PO daily with goal to get TSH within range
· Consider holding IT until asymptomatic
· Treat as hypophysitis (see below)
Clinical hypothyroidism
Elevated TSH (> 10 mU/L), low free T4, clinical symptoms
· Continue IT
· Consider endocrine consult
· Levothyroxine ~1.6 mcg/kg PO daily with goal to get TSH within range
· Rule out concomitant adrenal insufficiency (morning cortisol level)
Thyrotoxicosis
TSH < 0.01 mU/L, any level free T4
· Continue IT
· Consider propranolol (10-20 mg PO every 4-6 hours PRN) or atenolol/metoprolol
· Monitor TSH and free T4 in 4-6 weeks; depending on results, treat accordingly
· Consider endocrine consult
Adrenal insufficiency
Morning cortisol < 5 mcg/dL, elevated ACTH
· Hold IT
· Hydrocortisone 20 mg PO in AM and 10 mg PO in PM (taper down to daily dose according to symptoms) or prednisone 7.5 or 10 mg PO (reducing to 5 mg) AND fludrocortisone 0.1 mg PO every other day (titrate up or down as needed)
· Endocrine consultation (no surgery or procedures until then)
· If hemodynamically unstable, admit to inpatient care and initiate high-dose (i.e., stress) steroids
· Educate patient about stress use of hydrocortisone, symptoms, and need for care
Hypophysitis
Low ACTH, low morning cortisol, low sodium and potassium, low testosterone, fatigue, weight loss, etc.
· Hold IT until acute symptoms resolve
· Prednisone 1-2 mg/kg/day if symptomatic
· Hormone replacement as indicated
· Endocrine consultation
· Educate patient about stress use of hydrocortisone, symptoms, and need for care
*Steroid therapy: long steroid tapers may be indicated in patients with recurrent or severe irAEs; prophylaxis for opportunistic infections is warranted when utilizing systemic corticosteroids for ≥ 4 weeks and ≥ 20 mg prednisone equivalents/day; steroid doses expressed in prednisone may be converted to equivalent doses of IV methylprednisolone.

ACTH, adrenocorticotropic hormone; ADL, activities of daily living; BSA, body surface area; BID, twice daily; BM, bowel movements; CK, creatine kinase; CT, computed tomography scan; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; EMG, electromyography; GI, gastrointestinal; IADL, instrumental activities of daily living; ICU, intensive care unit; ID, infectious diseases; irAE, immune-related adverse effects; IT, immunotherapy agent(s); IV, intravenous; IVIG, immune globulin; LFTs, liver function tests; MRI, magnetic resonance imaging; NSAID, non-steroidal anti-inflammatory drug; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PFTs, pulmonary function tests; PO, oral; PRN, as needed; SCr, serum creatinine; SJS, Stevens-Johnson syndrome; SOB, shortness of breath; T4, thyroxin; TEN, toxic epidermal necrolysis; T-bili, total bilirubin; TSH, thyroid stimulating hormone; ULN, upper limit of normal.

Adverse effects with combination therapy

Combined immunotherapies have demonstrated better anti-tumor activity than monotherapy but, not unexpectedly, have a higher incidence of irAEs. These irAEs also tend to be more severe than adverse events seen with monotherapy.7 Similar to monotherapy, the most common irAEs related to combined immunotherapy regimens include dermatologic-, gastrointestinal-, hepatic-, pulmonary-, and endocrine-related irAEs. For example, in the CheckMate 067 trial, in which advanced melanoma patients were randomly assigned to nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks for 4 doses followed by nivolumab (3 mg/kg) every 2 weeks, nivolumab monotherapy (3 mg/kg) every 2 weeks plus placebo, or ipilimumab monotherapy (3 mg/kg) plus placebo, 96% of patients in the combination group experienced irAEs compared to 86% of those receiving monotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 59% of patients receiving nivolumab plus ipilimumab, in 21% of the nivolumab group, and in 28% of the ipilimumab group. The most common adverse events of any grade within the combination group were diarrhea (45%), fatigue (38%), pruritus (35%), and rash (30%).42

When immunotherapy is combined with chemotherapy or targeted therapy, toxicities may overlap with irAEs but have different underlying causes and, thus, may need to be treated differently.7 Because of the complex nature of irAEs, however, it can sometimes be difficult to distinguish which symptoms are related to immunotherapy, which are caused by other drugs used in multimodal treatments, and which are caused by the disease itself.7 Adverse effects from cytotoxic chemotherapy tend to occur earlier in treatment than irAEs. With targeted therapies, the onset of adverse effects is variable. Knowledge of the timeline of presentation of adverse effects is an important factor in helping to distinguish irAEs in patients receiving combined therapies. For example, preliminary results of the JAVELIN Renal 100 trial of axitinib 5 mg by mouth twice daily plus avelumab 10 mg/kg intravenously every 2 weeks in patients with advanced renal cell carcinoma showed that the most common adverse events were diarrhea (58%), dysphonia (47%), hypertension (47%), and fatigue (46%).43 Diarrhea and fatigue are common with both of these drugs when used individually, and dysphonia and hypertension are more common with axitinib. Another example is with pembrolizumab and lenvatinib for endometrial cancer. Makker and colleagues44 evaluated lenvatinib 20 mg daily plus pembrolizumab 200 mg intravenously every 3 weeks in patients with advanced endometrial carcinoma. In this study, the most common any-grade treatment-related adverse effects were hypertension (58%), fatigue (55%), diarrhea (51%), and hypothyroidism (47%), and the most common grade 3 treatment-related adverse effects were hypertension (34%), diarrhea (8%), fatigue (6%), and palmar-plantar erythrodysesthesia syndrome (6%). Pre-specified irAEs occurred in 57% of patients, with 10% requiring high-dose steroid therapy as treatment. In this study, it was not unexpected that the hypertension and palmar-plantar erythrodysesthesia syndrome was related to lenvatinib, which is a multikinase inhibitor that inhibits VEGF. However, fatigue, diarrhea, and hypothyroidism could occur with either lenvatinib or pembrolizumab. Similar reports have occurred with other combinations. A prudent approach for the toxicities that are most common with the immunotherapy is to promptly identify the toxicity and then assess and accurately diagnose it to allow for appropriate intervention. If an immune-mediated toxicity is suspected, it is important to follow treatment guidance for irAEs because of the potentially life-threatening aspect of those adverse effects.

THE ROLE OF PHARMACISTS IN ADVERSE EVENT MANAGEMENT

Pharmacists should not only be aware of the unique adverse effects associated with cytotoxic, targeted, and immune-related therapies, but they should also know the strategies to prevent, treat, and minimize the effects, so that treatment is not stopped early in patients who may be benefiting.6 In fact, supportive care plays a key role in optimizing care for patients with advanced cancer. This is a crucial role of pharmacists, particularly for patients receiving immunotherapy in whom potentially life-threatening irAEs can occur. Prompt identification of irAEs and appropriate referral for accurate diagnosis and intervention can minimize irAE-related morbidity and prevent irAE-related mortality. Early recognition and treatment of irAEs may also allow the patient to continue immunotherapy treatment and, thus, achieve an improved duration of benefit. Additionally, pharmacists should screen patients for predisposing conditions that put them at high risk of irAEs (e.g., autoimmune diseases) and then, if present, monitor them more rigorously in close collaboration with an organ specialist. Early identification and prompt diagnosis and treatment are also important for preventable adverse effects such as nausea and vomiting with cytotoxic chemotherapy or targeted therapy or for those effects with known preventive measures that can mitigate the onset or severity of adverse effects, such as skin care for EGFR or VEGF inhibitors.

Patient education should include information about the adverse effects of the therapy, signs and symptoms of these adverse effects, and how and when to report these adverse effects to the healthcare team.6 It is important to provide patients with written information summarizing all of this information, as well as a wallet card that lists current therapy and contact details of the oncology team, as this can be a good tool for communicating with non-oncology healthcare professionals. Patient education should also be a continuous process in which these elements are reinforced several times throughout therapy. As an example, for patients receiving checkpoint inhibitors, patient education should describe irAEs and how they differ from traditional treatment toxicities. Specifically, patients should understand common signs and symptoms of irAEs (e.g., rash, itching, diarrhea, shortness of breath, extreme tiredness, hair loss, feeling cold), the fact that many symptoms can be related and that any new or changing symptoms could be related, and the timeline of development of irAEs (essentially, they can occur any time during or after therapy). The importance of paying attention to symptoms and reporting them immediately should also be emphasized. Finally, patients should be provided information about whom to call both during office hours and outside of office hours for immediate questions or concerns related to therapy.

Monitoring patients for signs and symptoms of adverse effects is also important for early diagnosis and effective management. Regular physical examination, review of pertinent laboratory values, and assessment of patient-reported outcomes will provide information about adverse effects. For immunotherapy, guidelines recommend routine monitoring in 4-to-6-week intervals, with frequency increasing with the onset of adverse effects.7 For cytotoxic chemotherapy or targeted therapy, monitoring is typically based on the cycle of the regimen and expected adverse effects. Package inserts and databases often provide this information. Symptom checklists can facilitate identification of adverse effects; some manufacturers provide these, but institutions can develop them, as well. Assessment of toxicity can also be done by phone between visits. By evaluating laboratory values and changes from baseline, as well as distinguishing adverse effects from different types of therapies within multimodal therapy, the pharmacist can assist with the prompt identification of adverse effects.

Pharmacists have the knowledge of pharmacology, pharmacokinetics, safety, and efficacy of anticancer therapies, but also understand supportive care, so they are ideally positioned to evaluate the risks and benefits of therapies and individualize adverse effect management, both preventive measures and treatment.6 With immunotherapy, pharmacists can provide recommendations on steroid tapers and the best immunosuppressive regimens for steroid-refractory irAE management. Medina and colleagues6 provide recommendations for steroid tapers. For patients receiving an orally administered steroid, they recommend tapering over 4 to 6 weeks by reducing the steroid dose by 10 mg every 3 to 7 days (as toxicity allows) until the dose is 10 mg per day. Once the 10-mg/day threshold is reached, the steroid should be tapered by 5 mg every 5 days and then stopped. During this period, patients should be monitored by telephone twice weekly to assess for the return of symptoms. If symptoms return, the dose should be increased again and tapered more slowly. For patients receiving intravenous steroids, the taper should occur over a minimum of 6 weeks. The 2-mg/kg/day dose should be administered for 5 days, switched to an oral steroid at 1 mg/kg/day for 3 days, and then reduced to 60 mg/day. Upon discharge from the hospital, a reduction in steroid dose of 10 mg every 7 days (as toxicity allows) is recommended until a 10-mg/day dose is achieved. Similar to the oral steroid taper, the dose is then reduced by 5 mg every 7 days and then stopped; again, monitoring the patient by telephone twice weekly during the taper is recommended.

When patients are refractory to steroids, alternative immunosuppressive regimens can be used. Refer to the NCCN/ASCO guidelines for recommendations and select the most appropriate therapy on the basis of individual patient characteristics (e.g., concomitant diseases and medications, organ function, adherence capability). Additionally, pharmacists can ensure care is optimized by following recommendations on monitoring and treatment initiation for endocrinopathies, which are typically not treated with steroids but rather thyroid-related medications. For example, thyroid adverse effects, such as hyperthyroidism or hypothyroidism, are common with checkpoint inhibitors. Pharmacists can optimize care by ensuring thyroid function tests are ordered and monitored, as well as initiating thyroid-regulating medications as needed.

CONCLUSION

Pharmacists are instrumental in the management of adverse effects with multimodal cancer therapy. Monitoring, identifying, and managing adverse effects are critical aspects of patient care, and outcomes can be optimized when adverse effects are mitigated or identified and treated promptly. Pharmacists are well positioned to participate in the management of patients receiving multimodal cancer therapy because of their knowledge, expertise, and skills related to drug therapy. They serve key roles in educating the patient, caregivers, and healthcare team about likely adverse effects, the need to identify and report effects promptly, and appropriate preventive and treatment options that are tailored to the individual patient. As more is learned about emerging multimodal therapies, pharmacists can assist the team by providing guidance about appropriate monitoring and treatment and their role is likely to evolve.

Update: September 25, 2020

  • On June 29, 2020, the Food and Drug Administration approved pembrolizumab for the first-line treatment of patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer
  • On June 30, 2020, the Food and Drug Administration approved avelumab for maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy
  • On July 7, 2020, the Food and Drug Administration approved an oral combination of decitabine and cedazuridine for adult patients with myelodysplastic syndromes.
  • On July 24, 2020 the Food and Drug Administration granted accelerated approval to brexucabtagene autoleucel, a CD19-directed genetically modified autologous T cell immunotherapy, for the treatment of adult patients with relapsed or refractory mantle cell lymphoma.
  • On July 30, 2020, the Food and Drug Administration approved atezolizumab in combination with cobimetinib and vemurafenib for patients with BRAF V600 mutation-positive unresectable or metastatic melanoma
  • On July 31, 2020 the Food and Drug Administration granted accelerated approval to tafasitamab-cxix, a CD19-directed cytolytic antibody, indicated in combination with lenalidomide for adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not otherwise specified, including DLBCL arising from low grade lymphoma, and who are not eligible for autologous stem cell transplant
  • On August 5, the Food and Drug Administration approved belantamab mafodotin-blmf for adult patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
  • On August 26, 2020, the Food and Drug Administration approved azacitidine tablets for continued treatment of patients with acute myeloid leukemia who achieved first complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and are not able to complete intensive curative therapy
  • On September 4, 2020 the Food and Drug Administration granted accelerated approval to pralsetinib for adult patients with metastatic RET fusion-positive non-small cell lung cancer as detected by an FDA approved test

New Black Box/Safety Warnings:

  • On September 8, 2020, the Food and Drug Administration alerted health care professionals and oncology clinical investigators about efficacy and potential safety concerns with atezolizumab in combination with paclitaxel for previously untreated inoperable locally advanced or metastatic triple negative breast cancer. The results of the Impassion131 study showed that this combination did not significantly reduce the risk of cancer progression and death compared with placebo and paclitaxel in patients who were PD-L1 positive and overall survival results favored paclitaxel + placebo in both PD-L1 positive and overall population. The FDA will review findings of study and provide further guidance on this combination.

Guideline Updates – many changes are made to each National Comprehensive Cancer Network (NCCN) guideline but the major changes are included below.

  • In the 2.2020 version of the NCCN Prevention and Treatment of Cancer-Related Infections guidelines, consideration of PJP and HSV prophylaxis is recommended for CD30 targeted monoclonal antibodies such as brentuximab

Update: June 29, 2020

On March 30, 2020, the Food and Drug Administration approved durvalumab in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer

On April 8, 2020, the Food and Drug Administration approved encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal cancer with a BRAF V600E mutation

On April 10, 2020, the Food and Drug Administration approved selumetinib for pediatric patients, 2 years of age and older, with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. 

On April 15, 2020, the Food and Drug Administration approved mitomycin for adult patients with low-grade upper tract urothelial cancer

On April 17, 2020, the Food and Drug Administration approved tucatinib in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received one or more prior anti-HER2-based regimens in the metastatic setting

On April 20, 2020, the Food and Drug Administration granted accelerated approval to pemigatinib for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.

On April 21, 2020, the Food and Drug Administration expanded the indication of ibrutinib to include its combination with rituximab for the initial treatment of adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

On April 22, 2020, the Food and Drug Administration granted accelerated approval to sacituzumab govitecan-hziy for adult patients with metastatic triple-negative breast cancer who received at least two prior therapies for metastatic disease.

On April 28, 2020, the Food and Drug Administration granted accelerated approval to a new dosing regimen of 400 mg every six weeks for pembrolizumab across all currently approved adult indications, in addition to the current 200 mg every three weeks dosing regimen.

On April 29, 2020, the Food and Drug Administration approved niraparib for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to first-line platinum-based chemotherapy.

On May 1, 2020, the Food and Drug Administration approved daratumumab and hyaluronidase-fihj for adult patients with newly diagnosed or relapsed/refractory multiple myeloma. 

On May 6, 2020, the Food and Drug Administration granted accelerated approval to capmatinib for adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to mesenchymal-epithelial transition (MET) exon 14 skipping as detected by an FDA-approved test.

On May 8, 2020, the Food and Drug Administration granted accelerated approval  to selpercatinib for

  • Adult patients with metastatic RET fusion-positive non-small cell lung cancer (NSCLC);
  • Adult and pediatric patients ≥12 years of age with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy;
  • Adult and pediatric patients ≥12 years of age with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate). 

On May 8, 2020, the Food and Drug Administration expanded the indication of olaparib to include its combination with bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency positive status defined by either a deleterious or suspected deleterious BRCA mutation, and/or genomic instability

On May 14, 2020, the Food and Drug Administration expanded the indication of pomalidomide to include treating adult patients with AIDS-related Kaposi sarcoma after failure of highly active antiretroviral therapy and Kaposi sarcoma in adult patients who are HIV-negative.

On May 15, 2020, the Food and Drug Administration approved the combination of nivolumab plus ipilimumab as first-line treatment for patients with metastatic non-small cell lung cancer whose tumors express PD-L1(≥1%), as determined by an FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.

On May 15, 2020, the Food and Drug Administration granted accelerated approval to rucaparib for patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. 

On May 15, 2020, the Food and Drug Administration approved ripretinib for adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.

On May 18, 2020, the Food and Drug Administration approved atezolizumab for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression (PD-L1 stained ≥ 50% of tumor cells [TC ≥ 50%] or PD-L1 stained tumor-infiltrating immune cells [IC] covering ≥ 10% of the tumor area [IC ≥ 10%]), with no EGFR or ALK genomic tumor aberrations.

On May 19, 2020, the Food and Drug Administration approved olaparib for adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC), who have progressed following prior treatment with enzalutamide or abiraterone.

On May 22, 2020, the Food and Drug Administration approved brigatinib for adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) as detected by an FDA-approved test. 

On May 26, 2020, the Food and Drug Administration approved nivolumab plus ipilimumab and 2 cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. 

On May 29, 2020, the Food and Drug Administration approved atezolizumab in combination with bevacizumab for patients with unresectable or metastatic hepatocellular carcinoma who have not received prior systemic therapy.

On May 29, 2020, the Food and Drug Administration approved ramucirumab in combination with erlotinib for first-line treatment of metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) mutations.

On June 10, 2020, the Food and Drug Administration approved nivolumab for patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

On June 15, 2020, the Food and Drug Administration granted accelerated approval for lurbinectedin for adult patients with small cell lung cancer with disease progression on or after platinum-based chemotherapy.

On June 16, 2020, the Food and Drug Administration extended the indication of gemtuzumab ozogamicin for newly diagnosed CD33-positive acute myeloid leukemia to include pediatric patients 1 month or older.

On June 18, 2020, the Food and Drug Administration approved burosumab-twza for treatment of patients 2 years and older with tumor-induced osteomalacia.

On June 18, 2020, the Food and Drug Administration granted accelerated approval for a new indication of tazemetostat for adult patients with relapsed/refractory follicular lymphoma with an EZH2 mutation detected by an FDA-approved test and who have had at least 2 previous systemic therapies and also for adult patients with relapsed/refractory follicular lymphoma with no alternative treatment options.

On June 18, 2020, the Food and Drug Administration granted accelerated approval for a new indication of pembrolizumab for treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) solid tumors, as determined by an FDA-approved test and have progressed following prior treatments and no satisfactory treatment options available.

On June 22, 2020, the Food and Drug Administration approved a new indication for selinexor for adults patients with relapsed or refractory diffuse large B-cell lymphoma arising from follicular lymphoma, after at least 2 lines of systemic therapy.

On June 24, 2020, the Food and Drug Administration approved a new indication for pembrolizumab for patients with recurrent or metastatic cutaneous squamous cell carcinoma that is not curable by radiation or surgery.

New Black Box/Safety Warnings:

  • On March 27, 2020, Food and Drug Administration-approved warnings were to the labeling of obinutuzumab related to embryo-fetal toxicity, infusion-related reactions and tumor lysis syndrome. Recommendations for contraception during and for 6 months after last dose in females of reproductive potential are included. Close monitoring for infusion-related reactions and to use prophylactic anti-hyperuricemics in those at risk for tumor lysis syndrome are recommended.
  • On April 10, 2020, Food and Drug Administration-approved warnings related to embryo-fetal toxicity, infertility and lactation were added to the labeling of oxaliplatin. Recommendations for contraception during and for 9 months after last dose in females of reproductive potential and males with female partners during and for 6 months after the last dose are included. Women lactating are recommended to not breastfeed during and for 3 months after last dose and that infertility can occur in men and women.
  • On May 4, 2020, the Food and Drug Administration approved an updated extensive labeling changes to oral methotrexate tablets since original approval was so long ago (1953). New black box warnings include embryo-fetal toxicity, hypersensitivity/anaphylaxis and close monitoring for adverse reactions of the bone marrow, gastrointestinal tract, liver, lungs, skin, and kidneys. More details on contraindications and warnings were also updated.
  • On May 19, 2020, a Food and Drug Administration-approved warning about venous thromboembolism (VTE) was added to the labeling of olaparib. Seven percent of patients with metastatic castrate-resistant prostate cancer developed VTE while on olaparib and androgen deprivation therapy. Monitor these patients closely.
  • On May 21, 2020, the Food and Drug Administration approved changes to the embryo-fetal toxicity warning of decitabine, clarifying contraception use in females of reproductive potential during and for 6 months after last dose and for males with female partners during and for 3 months after. Lactating women should avoid breastfeeding during and for 2 weeks after last dose
  • On May 22, 2020, the Food and Drug Administration approved labeling changes that provided recommendations for dose adjustments and discontinuation for toxicities related to brigatinib. See product labeling for more information.
  • On May 29, 2020, a Food and Drug Administration-approved warning regarding evaluation of varices within 6 months in patients with hepatocellular carcinoma was added to the bevacizumab labeling.
  • On June 6, 2020, the Food and Drug Administration approved labeling changes that provided recommendations for dose adjustments, discontinuation, and management for toxicities related to axitinib when used in combination with avelumab or pembrolizumab See product labeling for more information.
  • On June 16, 2020, the Food and Drug Administration approved labeling changes included recommendation for use of  effective contraception during  and for 6 months after last dose in females of reproductive potential and during and for 3 months after last dose in males with female partners of reproductive potential receiving gemtuzumab ozogamicin. Additionally breastfeeding should be avoid during and for 1 month after last dose.
  • On June 17, 2020, the Food and Drug Administration approved labeling changes that included recommendation for use of nonhormonal contraception during treatment and for 3 months after pegaspargase because the drug can render hormonal contraceptives ineffective.

Guideline Updates – many changes are made to each National Comprehensive Cancer Network (NCCN) guideline but the major changes are included below.

  • In the 2.2020 version of the NCCN Antiemetic guidelines, the previous recommendation to avoid corticosteroid antiemetics premedication with immune checkpoint inhibitors was removed but they still recommend to avoid corticosteroids 3-5 days before and 90 days after chimeric antigen receptor (CAR) T-cell therapies. Several new drugs were added to emetic risk tables.
  • In the 2.2020 version of the NCCN Prevention and Treatment of Cancer-Related Infections guidelines a new table was developed that describes infection concerns and recommendations for screening, monitoring and prevention of cancer-related infections for emerging immune-targeted treatments

FDA Approvals

  • On September 17, 2019, the Food and Drug Administration granted accelerated approval to the combination of pembrolizumab plus lenvatinib for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation.
  • On September 17, 2019, the Food and Drug Administration approved apalutamide for patients with metastatic castration-sensitive prostate cancer. It was initially approved in 2018 for patients with non-metastatic castration resistant prostate cancer.
  • On September 26, 2019, the Food and Drug Administration approved daratumumab for adult patients with multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
  • On October 23, 2019, the Food and Drug Administration approved niraparib for patients with advanced ovarian, fallopian tube, or primary peritoneal cancer treated with three or more prior chemotherapy regimens and whose cancer is associated with homologous recombination deficiency (HRD)-positive status
  • On November 14, 2019, the Food and Drug Administration granted accelerated approval to zanubrutinib for adult patients with mantle cell lymphoma who have received at least one prior therapy.
  • On November 21, 2019, the Food and Drug Administration approved acalabrutinib for adults with chronic lymphocytic leukemia or small lymphocytic lymphoma
  • On December 3, 2019, the Food and Drug Administration approved atezolizumab in combination with paclitaxel protein-bound and carboplatin for first line treatment of adult patients with metastatic non-squamous non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations
  • On December 16, 2019, the Food and Drug Administration approved enzalutamide for patients with metastatic castration-sensitive prostate cancer
  • On December 18, 2019, the Food and Drug Administration granted accelerated approval to enfortumab vedotin-ejfv for adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1 or PD-L1 inhibitor, and a platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced or metastatic setting
  • On December 20, 2019, the Food and Drug Administration granted accelerated approval to fam-trastuzumab deruxtecannxki for patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting
  • On December 27, 2019, the Food and Drug Administration approved olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated metastatic pancreatic adenocarcinoma, as detected by an FDA approved test, whose disease has not progressed on at least 16 weeks of a first-line platinum based chemotherapy regimen
  • On January 8, 2020, the Food and Drug Administration approved pembrolizumab for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high risk, non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy
  • On January 9, 2020, the Food and Drug Administration approved avapritinib for adults with unresectable or metastatic gastrointestinal stromal tumor harboring a platelet derived growth factor receptor alpha exon 18 mutation, including D842V mutations
  • On January 23, 2020, the Food and Drug Administration granted accelerated approval to tazemetostat for adults and pediatric patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma not eligible for complete resection
  • On February 25, 2020, the Food and Drug Administration approved neratinib in combination with capecitabine for adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting
  • On March 2, 2020, the Food and Drug Administration approved isatuximab-irfc in combination with pomalidomide and dexamethaonse for adult patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor
  • On March 10, 2020, the Food and Drug Administration granted accelerated approval to the combination of nivolumab and ipilimumab for patients with hepatocellular carcinoma who have been previously treated with sorafenib

New Black Box/Safety Warnings:

  • On September 13, 2019, the Food and Drug Administration warned that Abemaciclib, palbociclib, and ribociclib used to treat some patients with advanced breast cancers may cause rare but severe inflammation of the lungs. New warnings about this risk are now in the prescribing information and Patient Package Insert for the entire class of these CDK 4/6 inhibitor medications

Guideline Updates – many changes are made to each National Comprehensive Cancer Network (NCCN) guideline but the major changes are included below.

  • In the 1.2020 version of the NCCN Antiemetic guidelines, it was recommended that corticosteroid antiemetics premedication should be avoided with immune checkpoint inhibitors when administered without cytotoxic chemotherapy, a corticosteroid-sparing approach in combination regimens and to be avoided 3-5 days before and 90 days after chimeric antigen receptor (CAR) T-cell therapies
  • In the 2.2020 version of the NCCN Hematopoietic Growth Factors guidelines, an FDA-approved biosimilar is an appropriate substitute for epoetin-alfa, filgrastim, and pegfligrastim; several regimens were added as examples of high and intermediate-risk for febrile neutropenia; and use of granulocyte colony-stimulating factors (G-CSFs) are not recommended within 14 days after CAR T-cell therapies
  • In the 1.2020 version of the NCCN Management of Immune Checkpoint Inhibitor–Related Toxicities guidelines, the following were added
    • Consider GABA agonists such as gabapentin or pregabalin for Grade 2 pruritus
    • In no improvement after 3 days, consider adding rituximab for grade 2 bullous dermatitis
    • For grade 3 bullous dermatitis; if no improvement after 3 days consider rituximab or intravenous immune globulin (IVIG)
    • For Stevens Johnson syndrome or toxic epidermal necrolysis, consider IVIG
    • For grade 1 diarrhea or colitis, if persistent symptoms, check lactoferrin
    • For grade 2-4 diarrhea or colitis, vedolizumab can be consider if no response in 2-3 days
    • For grade 1 myalgias/myositis, treat pain as indicated (eg, NSAIDs)
    • For grades 2-4 myalgias/myositis, treat pain as indicated (eg, NSAIDs), consider IVIG, plasmapheresis, infliximab or mycophenolate if steroid refractory
    • For hypophysitis and grade 4 subclinical hypothyroidism, follow free T4 levels for determination of replacement therapy
  • In the 1.2020 version of the NCCN Prevention and Treatment of Cancer-Related Infections guidelines, recommendations for cancer-related infection prophylaxis, immunizations and drug-related reactions was included for emerging immune-targeted treatments.
  • In the 1.2020 version of the NCCN Survivorship guidelines, new sections were added for LGBTQ individuals with cancer and menopause and sexual health

REFERENCES

  1. Mokhtari RB, Homayouni TS, Baluch N, et al. Combination therapy in combating cancer. 2017;8(23):38022-43.
  2. Holle LM. Cancer Chemotherapy and Treatment. In: Chisolm-Burns MA, Schwinghammer TL, Malone PM, et al, eds. Pharmacotherapy Principles & Practice. 5th ed. New York: McGraw-Hill;2019:1313-44.
  3. Lohr LK. Toxicities of oral targeted chemotherapy. Ambulatory Care Self-Assessment Program 2017, Book 1. 2017;57-82.
  4. Shord SS, Cordes LM. Chapter 127: Cancer Treatment and Chemotherapy. In: DiPiro T, Matzke GR, Yee GC, et al, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th New York: McGraw-Hill;2017.
  5. Alsaab HO, Sau S, Alzhrani R, et al. PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: mechanism, combinations, and clinical outcomes. Front Pharmacol. 2017;8:561.
  6. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology in partnership with the American Society of Clinical Oncology (ASCO). Management of Immunotherapy-Related Toxicities. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/immunotherapy.pdf. Published April 8, 2019. Accessed December 3, 2019.
  7. Medina P, Jeffers KD, Trinh VA, Harvey RD. The role of pharmacists in managing adverse events related to immune checkpoint inhibitor therapy. J Pharm Pract. 2019.
  8. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Acute Myelogenous Leukemia. Version 2.2020. https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Published September 3, 2019. Accessed December 4, 2019.
  9. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Breast Cancer. Version 3.2019. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Published September 6, 2019. Accessed December 3, 2019.
  10. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Colon Cancer. Version 3.2019. https://www.nccn.org/professionals/physician_gls/pdf/colon.pdf. Published November 8, 2019. Accessed December 3, 2019.
  11. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Kidney Cancer. Version 2.2020. https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Published August 5, 2019. Accessed December 3, 2019.
  12. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Cutaneous Melanoma. Version 3.2019. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf. Published October 22, 2019. Accessed December 3, 2019.
  13. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Non-Small Cell Lung Cancer. Version 2.2020. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Published November 6, 2019. Accessed December 3, 2019.
  14. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/sclc.pdf. Published November 15, 2019. Accessed December 4, 2019.
  15. Vaidyanathan G. Toxicities of targeted therapies and their management. http://www.targetedonc.com/publications/targeted-therapies-cancer/2013/december-2013/toxicities-of- targeted-therapies-and-their-management. Accessed December 6, 2019.
  16. Cleeland CS, Allen JD, Roberts SA, et al. Reducing the toxicity of cancer therapy: recognizing needs, taking action. Nat Rev Clin Oncol. 2012;9(8):471-8.
  17. Key N, Khorna AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol.
  18. Yarom N, Shapiro CL, Peterson DE, et al. Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. J Clin Oncol. 2019;37(25):2270-90.
  19. Bohlius J, Bohlke K, Castelli R, et al. Management of cancer-associated anemia and erythropoiesis-stimulating agents. ASCO/ASH Clinical Practice Guidelines. J Clin Oncol. 2019;37(15):1336-51.
  20. Taplitz RA, Kennedy EB, Bow EJ, et al. Antimicrobial prophylaxis for adult patients with cancer-related immunosuppression: ASCO and IDSA Clinical Practice Guideline Update. J Clin Oncol. 2018;36(30):3043-54.
  21. Taplitz RA, Kennedy EB, Bow EJ, et al. Outpatient management of fever and neutropenia in adults with malignancy: American Society of Clinical Oncology and Infectious Diseases Society of American Clinical Practice Guideline Update. J Clin Oncol. 2018;36(14):1443-53.
  22. Schiffer CA, Bohlke K, Delaney M, et al. Platelet transfusion for patients with cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2017;36(3):283-99.
  23. Hesketh PJ, Kris MG, Basch E, et al. Antiemetics: American Society of Clinical Oncology Clinical Practices Guideline Update. J Clin Oncol. 2017;35:3240-61.
  24. Smith TJ, Bohlke K, Lyman GH, et al; American Society of Clinical Oncology. Recommendations for the use of WBC growth factor update: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2015;33(28):3199-212.
  25. Hwang JP, Somerfield MR, Alston-Johnson DE, et al. Hepatitis B virus screening for patients with cancer before therapy: American Society of Clinical Oncology Provisional Clinical Update. J Clin Oncol. 2015;33(19):2212-20.
  26. Roila F, Molassiotis A, Herrstedt J, et al; participants of the MASCC/ESMO Consensus Conference Copenhagen 2015. 2016MASCC and ESMO guideline update for the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting and of nausea and vomiting in advanced cancer patients. Ann Oncol. 2016;27(suppl 5):v119-33.
  27. Multinational Association of Supportive Care in Cancer. MASCC/ISOO Mucositis Clinical Practice Guidelines. https://www.mascc.org/mucositis-guidelines. Published July 2019. Accessed December 8, 2019.
  28. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Adolescent and Young Adult (AYA) Oncology. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/aya.pdf. Published July 11, 2019. Accessed December 8, 2019.
  29. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Antiemesis. Version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/antiemesis.pdf. Published February 28, 2019. Accessed December 8, 2019.
  30. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Cancer-Associated Venous Thromboembolic Disease. Version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/vte.pdf. Published February 28, 2019. Accessed December 8, 2019.
  31. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Cancer-Related Fatigue. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/fatigue.pdf. Published October 8, 2019. Accessed December 8, 2019.
  32. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Hematopoietic Growth Factors. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/growthfactors.pdf. Published November 15, 2019. Accessed December 8, 2019.
  33. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Prevention and Treatment of Cancer-Related Infections. Version 1.2019. https://www.nccn.org/professionals/physician_gls/pdf/infections.pdf. Published October 25, 2018. Accessed December 8, 2019.
  34. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Survivorship. Version 2.2019. https://www.nccn.org/professionals/physician_gls/pdf/survivorship.pdf. Published June 5, 2019. Accessed December 8, 2019.
  35. Burtness B, Anadkat M, Basti S, et al. NCCN Task Force Report: management of dermatologic and other toxicities associated with EGFR inhibition in patients with cancer. J Natl Comp Cancer Netw. 2009;7(suppl 1):S5-21.
  36. Lacouture ME, Anadkat MJ, Bensadoun R-J, et al; MASCC Skin Toxicity Study Group. Clinical practice guidelines for the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities. Support Care Cancer. 2011;19(8):1079-95.
  37. Hofheinz R-D, Deplanque G, Komatsu Y, et al. Recommendations for the prophylactic management of skin reactions induced by epidermal growth factor receptor inhibitors in patients with solid tumors. 2016;21(12):1483-91.
  38. Busaidy NL, Farooki A, Dowlati A, et al. Management of metabolic effects associated with anticancer agents targeting the pi3k-Akt-mTOR pathway. J Clin Oncol. 2012;30(23):2919-28.
  39. NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50. Accessed December 7, 2019.
  40. Dy GK, Adjei AA. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J Clin. 2013;63(4):249-79.
  41. Wolters Kluwer Clinical Drug Information, Inc. (Lexi-Drugs). Wolters Kluwer Clinical Drug Information, Inc. Accessed December 8, 2019.
  42. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med. 2017;377(14):1345-56.
  43. Chouieri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase Ib trial. Lancet Oncol. 2018;19(4):451-60.
  44. Makker V, Rasco D, Vogelzang NJ, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2019;20(5):711-8.

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