1. Immunotherapy in Cancer: Insights for Nurses
Jointly provided by Postgraduate Institute for Medicine and Clinical Care Options, LLC
Immunotherapy in Cancer: Insights for Nurses
Michele S. Barber, MS, NP, AOCNP
Oncology Nurse Practitioner Department of Hematology/Oncology Lahey Hospital and Medical Center Peabody, Massachusetts
Supported by educational grants from Bristol-Myers Squibb, Genentech, and Merck.

2. About These Slides
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Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. Core Faculty
Cindi Bedell, RN, MSN, APRN-C Nurse Practitioner Texas Oncology Plano East Plano, Texas Grace Cherry, RN, MSN, NP Oncology Nurse Practitioner UCLA Melanoma Program Los Angeles, California
This slide lists the faculty who were involved in the production of these slides.

4. Disclosures
Michelle S. Barber, MS, NP, AOCNP, has no real or apparent conflicts of interest to report. Cindi Bedell, RN, MSN, APRN-C, has disclosed that she has received fees for non-CME/CE services from Amgen, Celgene, and Genentech. Grace Cherry, RN, MSN, NP, has disclosed that she has received consulting fees from Amgen and Merck and fees for non-CME/CE services from Genentech.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides and the content in the slidenotes.

5. Agenda Program Overview Principles of Cancer Immunotherapy
Current State of Checkpoint Inhibitor Therapy in Solid Tumors
Case-Based Application of Nursing Considerations and Adverse Events
Closing Remarks and Audience Question and Answer Session
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6. Please review the slidenotes for a discussion of each study by the expert faculty Michele S. Barber, MS, NP, AOCNP

7. Principles of Cancer Immunotherapy
For additional review of cancer immunotherapy, please review the ONS/inPractice Oncology Nursing chapter on immunotherapy:

8. History of Immunotherapy
2015: First oncolytic virus approved for melanoma
1997: First mAb for cancer approved, rituximab
2011: CTLA-4 inhibitor approved for melanoma
1976: BCG vaccine for bladder cancer
2008: First cancer vaccine approved for RCC
1992: IL-2 approved for RCC
1863: Connection between immunotherapy and cancer recognized
1796: First use of immunotherapy,
Jenner smallpox vaccine
: PD-1 inhibitors approved for melanoma, squamous NSCLC
BCG, Bacillus Calmette–Guérin; mAb, monoclonal antibody; RCC, renal cell carcinoma; CTLA-4, cytotoxic T-lymphocyte-associated antigen 4; PD-1, programmed death 1; cHL, classical Hodgkin’s lymphoma; UC, urothelial carcinoma.
Immunotherapy, as a treatment strategy, has existed for more than 200 years, with its first documented use likely being Jenner’s smallpox vaccine in Nearly 70 years later, the connection between immunotherapy and cancer was recognized, although the exact link was unknown. It took another 100 years for development of the Bacillus Calmette-Guérin vaccine for bladder cancer, which is still used today. Approximately 10 years later, interferon was approved and soon after that was interleukin-2, and then came the first of the monoclonal antibodies, rituximab. Starting in the 1990s, an onslaught of new immune mechanisms and targets emerged: a vaccine for renal cell carcinoma in 2008, sipuleucel-T for prostate cancer in Then, the first checkpoint immune inhibitor was launched in 2011, and it was an anti–CTLA-4 antibody, ipilimumab. PD-1 inhibitors came soon after in with the first PD-L1 inhibitor approved in 2016 and others on the horizon in the late phases of clinical development. CTLA-4 and PD-1/PD-L1 checkpoint inhibitors will be the focus of ensuing discussion.
1985: Interferon first approved for hairy cell leukemia
2010: Sipuleucel-T approved for prostate cancer
2016: PD-1 inhibitor approved for cHL
PD-L1 inhibitor approved for UC
Slide credit: clinicaloptions.com
Elert E. Nature. 2013;504:S2-S3.

9. Immune System Function and Immune Response
Identify and destroy foreign or abnormal cells in the body
Innate Immunity
Adaptive Immunity
Nonspecific
First line of defense
WBCs (natural killer cells, neutrophils)
Activation of adaptive response
Specific
Adapts specifically to diverse stimuli
B-cell antibody production
T-cell stimulation
Memory functions
Dendritic cell
Mast cell
Macrophage
B cell
λδ T cell
T cell
Natural killer cell
Basophil
Complement protein
Antibodies
Eosinophil
Natural killer T cell
CD4+ T cell
CD8+ T cell
Granulocytes
WBC, white blood cell.
To understand how checkpoint inhibition works, one must first understand the immune system, which is composed of 2 types of immunity. Innate immunity is nonspecific and fast acting, working within minutes to days of an injury or insult. A simple cut that turns red or produces pus, white blood cells rushing to the area, or developing a fever—these are instances of the innate immune system functioning well. By contrast, adaptive immunity is specific and occurs over time. T and B cells play critical roles here because they develop memory. Upon second exposure to a pathogen, these cells can eliminate a threat much more efficiently because they learned to recognize and respond to it during a previous, first encounter. The goal of immunotherapy for cancer, in terms of checkpoint inhibition, is to educate and then liberate the natural underlying cancer immune responses in the adaptive immune system.
Neutrophil
Immune surveillance:
Involves both innate and adaptive immune mechanisms
Tumor-associated antigens can be identified by the immune system and destroyed
Goal of immunotherapy for cancer: to “educate and liberate” underlying anticancer immune responses
Janeway CA Jr, et al. Immunobiology: the immune system in health and disease
Slide credit: clinicaloptions.com

10. T-Cell Response: Accelerate or Brake?
Activating Signals
Inhibitory Signals
CD28
OX40
CTLA-4
T cell
GITR
PD-1
CD137
TIM-3
CD27
BTLA
HVEM
VISTA
T cells receive and respond to both activating and inhibitory signals. Activating signals stimulate the immune system and accelerate its ability, for example, to fend off viruses or bacteria, whereas inhibitory signals “brake” the immune system and can dampen or inhibit T-cell responses. In general, without these inhibitory mechanisms, rampant autoimmune disease would emerge. Checkpoint inhibitors such as those against CTLA-4 and PD-1, however, are an advantageous example of circumventing these inhibitory signaling mechanisms.
LAG-3
T-Cell Stimulation
T-Cell Inhibition
Slide credit: clinicaloptions.com
Mellman I, et al. Nature. 2011;480:

11. Immune Checkpoint Pathway Blockade
Target cell-surface molecules known as immune checkpoint proteins
Receptor/ligand systems on immune cells
Modulate the immune response, preventing autoimmunity and minimizing damage to healthy tissue during an immune response
Interfering with these receptor/ligand systems restores antitumor immunity
Cytotoxic T lymphocyte-associated antigen (CTLA-4)
Programmed death-1/programmed death-ligand 1 (PD-1/PD-L1)
Immune checkpoint blockade targets the cell-surface molecules known as immune checkpoint proteins. A receptor/ligand system that modulates immune responses exists on immune cells. For example, after T cells have been stimulated and have responded to an infectious threat, receptor/ligand interactions communicate the need to shut down any subsequent responses, and this dampening occurs, in part, via immune checkpoint proteins. Unfortunately, certain types of cancer cells also express molecules that can activate immune checkpoint proteins and cause T cells to back down. Checkpoint inhibitors prevent this from happening and restore functional antitumor T-cell responses.
Slide credit: clinicaloptions.com

12. CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment
Priming phase (lymph node)
Effector phase (peripheral tissue)
T-cell migration
Dendritic cell
Cancer cell
T cell
T cell
Dendritic cell
T cell
MHC
TCR B7
CD28
CTLA-4
TCR
MHC
MHC, major histocompatibility complex; TCR, T-cell receptor.
Here, CTLA-4 (at left) and PD-1/PD-L1 (at right) checkpoint blockade is diagrammed.[1] The red monoclonal antibody binding to and blocking signaling through the CTLA-4 receptor, which is located on the surface of a T cell, is ipilimumab. By contrast, the PD-1/PD-L1 interaction is happening in the tumor microenvironment. At the tumor site, PD-1 on the T cell communicates with PD-L1 on the cancer cell, but checkpoint blockade can inhibit this interaction. It is important to understand that these are 2 separate locations and 2 separate processes because patients may receive 2 different drugs to address this.
Reference
1. Ribas A. Tumor immunotherapy directed at PD-1. N Engl J Med. 2012;366:
T cell
PD-1
Cancer cell
PD-L1
Slide credit: clinicaloptions.com
Ribas A. N Engl J Med. 2012;366:

13. Tumor Immunology: Overview3
Cytokines
Resting T cell
Activated T cell
TUMOR 2
LYMPH NODE
T-cell clonal expansion
Tumor antigen 1
During an immune response to cancer, a tumor produces antigens that are delivered to antigen-presenting cells, such as dendritic cells, which can then activate tumor-specific T cells. This crosstalk between dendritic and T cells typically occurs within the lymph nodes. Activated T cells traffic to the site of the originating tumor, recognize that tumor-specific antigen on the surface of cancer cells, produce cytokines that help to drive further T-cell expansion, and, ultimately, lyse or kill cancer cells in the tumor microenvironment.
This normal immune process can be circumvented when PD-L1, expressed by cancer cells in the tumor microenvironment, binds PD-1 on T cells, rendering them inert. Essentially, the immune system is rendered nonfunctional regarding this cancer. Immunotherapy (via checkpoint inhibition) works by turning it back on, by taking the foot off the brake.
Dendritic cell
Slide credit: clinicaloptions.com

14. Immune Checkpoint Inhibitor Therapies in Solid Tumors

15. Communicating With Pts
How do we explain this complicated process to pts and their caregivers?
Gas and brake pedal analogy
Pressing the gas pedal = restoring T-cell activity and starting immune response against tumor
Brake pedal = immune checkpoint
Lifting the foot off the brake = enabling T cell–mediated immune response to continue
“Removing muzzle off the dog” analogy
Patients may ask one to explain how immune checkpoint blockade works as well as its associated adverse events. Their treatment histories may include cytotoxic chemotherapy, EGFR inhibitors, or erlotinib. It is important to communicate that checkpoint inhibitors work differently than many other cancer therapeutics because they are not directly killing the tumor cells. For example, cisplatin causes a DNA change in the tumor cell itself that kills the cell. These drugs do not work that way. They do not directly affect the tumor cell; they affect the adaptive immune system, which then affects the tumor cell, and this takes time.
The first suggested analogy involves the gas and brake pedals of a car. One can explain to patients, “Well, your immune system has a gas pedal so that you can fight off infection, and it has a brake pedal so that it does not fight normal healthy cells.” Pressing the gas pedal is similar to the normal activation of T cells, which allows the car to move forward or the immune system to fight tumors. The brake pedal symbolizes immune checkpoints. Both of these stop something from happening: either a car from accelerating or an immune response from progressing, which is how tumor cells can evade the immune system. Treatment with a checkpoint inhibitor such as ipilimumab mirrors lifting one’s foot off of the brake or allowing the immune system (via tumor-specific T cells, in this case) to work again.
The second suggested analogy involves removing the muzzle from a dog. Here, the dog is one’s immune system. The muzzle represents various immune checkpoints. Removing the muzzle or treating by checkpoint blockade allows the dog (one’s immune system) to attack any incoming threats.
Slide credit: clinicaloptions.com
Ledezma B, et al. Cancer Manag Res. 2013;6:5-14.

16. Disease Can Get Worse Before It Gets Better With Checkpoint Blockade
Response to ipilimumab
Screening
Wk 8: “Progression”
Wk 12: Improvement
Wk 16: Continued Improvement
Wk 72: CR
Wk 108: Continued CR
In some patients, a “pseudoprogression” can be observed with peritumoral inflammation from lymphocyte infiltration.[1] In other words, the tumor appears to enlarge initially as a result of inflammation caused by the migration of T cells into the tumor, or a new lesion that was subclinical on baseline imaging becomes visible after immune checkpoint inhibitor therapy due to this same phenomenon. It is important to educate patients about this potential for disease worsening—or appearing to worsen—before improvement.
This series of photographs illustrates a patient’s trajectory through checkpoint blockade therapy with ipilimumab. The first picture occurs at screening or initial diagnosis. Eight weeks into therapy, the patient’s tumors appear larger, and new ones have appeared that were not visible originally. Reinforce that this is normal and advise patience. Explain that the brake is being taken off of the immune system, and the immune system is going to do its job, but one needs to give it a little more time. This is different from cisplatin or docetaxel. At 12 and 16 weeks, improvement is noticeable in this patient. At 72 weeks (or 1.5 years) from start of treatment, the patient is in CR with continued CR at 2 years.
Reference
1. Ribas A, Chmielowski B, Glaspy JA. Do we need a different set of response assessment criteria for tumor immunotherapy? Clin Cancer Res. 2009;15:
Slide credit: clinicaloptions.com
Images courtesy of Jedd Wolchok, MD

17. Nivolumab (10 mg/kg): Response of Metastatic NSCLC
NSCLC, non-small cell lung cancer.
Here is another example of pseudoprogression, highlighted through CT imaging,[1] of how checkpoint inhibitors work over time. This is a patient received nivolumab, a PD-1 inhibitor, for metastatic NSCLC. The arrows demonstrate initial “progression” in pulmonary lesions with subsequent regression, demonstrating an immune-related pattern of response. Here again, previously undetected lesions become apparent, likely due to lymphocyte infiltration.
Reference 1. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:
Initial progression in pulmonary lesions of a NSCLC pt with nonsquamous histology was followed by regression
Oxnard GR, et al. J Natl Cancer Inst. 2012;104: Topalian SL, et al. N Engl J Med. © 2012;366: Reprinted with permission from Massachusetts Medical Society.
Slide credit: clinicaloptions.com

18. CTLA-4 Inhibition

19. CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment
Priming phase (lymph node)
Effector phase (peripheral tissue)
T-cell migration
Dendritic cell
T cell
MHC
TCR B7
CD28
CTLA-4
Cancer cell
PD-1
PD-L1
Cancer cell
MHC, major histocompatibility complex; TCR, T-cell receptor.
Ipilimumab (diagrammed at right) is a CTLA-4 inhibitor, which targets a step during the priming phase of an immune response, when the dendritic cell is communicating with the T cell in the lymph node.
Slide credit: clinicaloptions.com
Ribas A. N Engl J Med. 2012;366:

20. Ipilimumab Approved Indications
Unresectable or metastatic melanoma
Dosing guideline: 3 mg/kg IV q3w x 4, infuse over 90 mins
Median OS of 10.1 mos vs 6.4 mos with gp100 led to approval[1]
Adjuvant treatment of melanoma
Dosing guideline: 10 mg/kg IV q3w x 4, infuse over 90 mins; followed by 10 mg/kg IV q12w x up to 3 yrs
Approval based on median RFS 26 mos vs 17 mos with placebo[2]
In combination with nivolumab for BRAF V600 wild type, unresectable or metastatic melanoma
Dosing guideline: nivolumab 1 mg/kg IV q3w x 4, infuse over 60 mins, followed by ipilimumab 3 mg/kg IV q3w x 4, infuse over 90 mins on same day
Approval based on 61% ORR with combination vs 11% with ipilimumab monotherapy[3]
RFS, relapse-free survival.
There are several approved indications for ipilimumab.[1] Patients with unresectable metastatic melanoma receive 3 mg/kg IV every 3 weeks for 4 cycles. In adjuvant treatment of melanoma, however, patients receive a much higher dose of 10 mg/kg. Finally, for BRAF V600 wild-type patients with unresectable or metastatic melanoma, it is recommended that ipilimumab be used in combination with nivolumab. This recommendation is based on an improved ORR of 61% with combination therapy over 11% with ipilimumab alone.[2]
For more information, please review the downloadable nursing resource, “At a Glance: Understanding Immune Checkpoint Inhibitors and Their Role in Cancer Care”:
References
1. Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb; October 2015.
2. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:
1. Hodi FS, et al. N Engl J Med. 2010;363: Eggermont AM, et al. Lancet Oncol. 2015;16: Postow MA, et al. N Engl J Med. 2015;372:
Slide credit: clinicaloptions.com

21. Kinetics of Appearance of irAEs With Ipilimumab
Rash, pruritus Liver toxicity Diarrhea, colitis Hypophysitis
Toxicity Grade
Wks 14 2 4 6 8 10 12
irAEs, immune-related adverse events.
As previously discussed, activation of the immune system following checkpoint inhibitor administration takes time. Similar to this delayed tumor response, adverse events also take time to show up because they are immune mediated. The kinetics of adverse event appearance were studied in a combined analysis of 325 patients receiving 10 mg/kg IV ipilimumab every 3 weeks for 4 cycles.[1] Typically, a rash was seen early on and then sometimes some diarrhea. Liver dysfunction occurred a bit later, and endocrinopathies happened very late—weeks to months after the completion of therapy.
Patients should undergo complete metabolic profiling with thyroid-stimulating hormone (TSH) and liver function tests (LFTs) at baseline and before every dose of ipilimumab. In addition to thyroid issues, adrenal insufficiency can emerge. If patients present as very tired and slightly nauseous with a mild headache, a full thyroid panel with adrenocorticotropic hormone (ACTH) should be obtained to better evaluate their pituitary function. Of note, patients sometimes get a little hyperthyroid before becoming hypothyroid.
Reference
1. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:
Combined analysis of 325 participants with 10 mg/kg IV q3w x 4
Slide credit: clinicaloptions.com
Weber JS, et al. J Clin Oncol. 2012;30:

22. Is Ipilimumab Just for Melanoma?
Ongoing clinical trials
In other malignancies:
Prostate/urothelial
RCC
NSCLC and SCLC
Pancreatic/liver/GIST
Breast/ovarian/cervix
Glioblastoma
Multiple hematologic malignancies (MDS)
In combination with:
Other immunotherapies
PD-1/PD-L1
Vaccines
Targeted agents
Radiation
Intralesional therapy
GIST, gastrointestinal stromal tumor; MDS, myelodysplastic syndrome; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; SCLC, small cell lung cancer.
Many clinical trials of ipilimumab are ongoing, alone or in combination with other therapeutic agents such as PD-1/PD-L1 checkpoint inhibitors.
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23. PD-1/PD-L1 Inhibition

24. CTLA-4 and PD-1/PD-L1 Checkpoint Blockade for Cancer Treatment
Priming phase (lymph node)
Effector phase (peripheral tissue)
T-cell migration
Dendritic cell
Cancer cell
T cell
T cell
Dendritic cell
T cell
MHC
TCR B7
CD28
CTLA-4
TCR
MHC
MHC, major histocompatibility complex; TCR, T-cell receptor.
PD-1 and PD-L1 checkpoint inhibition happens in the tumor microenvironment where T cells will interact directly with cancer cells.
T cell
PD-1
Cancer cell
PD-L1
Slide credit: clinicaloptions.com
Ribas A. N Engl J Med. 2012;366:

25. Clinical Development of PD-1/PD-L1 Immune Checkpoint Inhibitors
Target
Antibody
Molecule
Approval/Development Stage
PD-1
Nivolumab
Fully human IgG4
Phase I/II/III multiple tumors Approved: melanoma, NSCLC, RCC, cHL
Breakthrough Therapy: HNSCC
Pembrolizumab
Phase I/II/III multiple tumors
Approved: NSCLC/melanoma
Breakthrough Therapy: cHL/mCRC
Pidilizumab
(CT-011)
Humanized IgG1
Phase I/II multiple tumors
PD-L1
Durvalumab (MEDI-4736)
Engineered human IgG1
Breakthrough Therapy: UBC
Atezolizumab (MPDL-3280A)
Phase III Bladder, NSCLC
Approved: urothelial carcinoma
Avelumab
(MSB C)
Fully human IgG1
Phase I/II/III solid tumors
Breakthrough Therapy: mMCC
cHL, classical Hodgkin’s lymphoma; HL, Hodgkin’s lymphoma; HNSCC, head and neck squamous cell carcinoma; IgG, immunoglobulin G; mCRC, metastatic colorectal cancer; mMCC, metastatic Merkel cell carcinoma; NSCLC, non-small-cell lung cancer; RCC, renal cell carcinoma; UBC, urothelial bladder cancer; cHL, classical Hodgkin’s Lymphoma
Significant clinical development of PD-1/PD-L1 checkpoint inhibition is under way. Pembrolizumab and nivolumab are approved by the FDA and are currently in widespread use. Atezolizumab is the most recent, and first anti-PD-L1 agent to gain FDA approval. Several others have been given breakthrough therapy designation by the FDA.
Slide credit: clinicaloptions.com
ClinicalTrials.gov.

26. Pembrolizumab (Anti–PD-1) Approved Indications
Unresectable or metastatic melanoma (first line or beyond)
ORR vs ipilimumab: 34% vs 12%, in previously untreated pts[1]
Improved PFS and OS vs ipilimumab
Metastatic NSCLC (PD-L1+ with approved test) with disease progression on or after platinum chemotherapy and, if EGFR/ALK+, targeted therapy for these aberrations
KEYNOTE 001: cohort evaluating pembrolizumab as frontline therapy in pts with advanced PD-L1+ NSCLC[2]
ORR 45.2%; median PFS 6.3 mos; median OS not reached
Dosing guideline: 2 mg/kg IV q3w, infuse over 30 mins
NSCLC, non-small cell lung cancer.
Pembrolizumab is an anti–PD-1 checkpoint inhibitor approved for metastatic melanoma and non‑small-cell lung cancer (NSCLC). Patients with metastatic NSCLC receive this therapy only if PD-L1 positive with an approved test and after failure of platinum therapy or failure of a targeted therapy (eg, erlotinib, cetuximab, afatinib) if tumors are EGFR/ALK positive. Pembrolizumab demonstrated a 34% ORR vs 12% for ipilimumab in previously untreated patients.[1] Pembrolizumab is given 2 mg/kg IV every 3 weeks as opposed to nivolumab, which is given 3 mg/kg IV every 2 weeks.
For more information, please review the downloadable nursing resource, “At a Glance: Understanding Immune Checkpoint Inhibitors and Their Role in Cancer Care”:
Reference
1. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:
1. Robert C, et al. N Engl J Med. 2015;372: Garon EB, et al. N Engl J Med. 2015;372:
Slide credit: clinicaloptions.com

27. Nivolumab (Anti–PD-1) Approved Indications
Unresectable or metastatic melanoma
Frontline BRAF wild type ± ipilimumab (1-yr OS 73% vs 42% with dacarbazine; ORR 61% with nivolumab + ipilimumab)[1,2]
Following progression on ipilimumab and BRAF inhibitor for BRAF+ (ORR 32%)[3]
Dosing guideline: 3 mg/kg IV q2w, infuse over 60 mins; in combination with ipilimumab: 1 mg/kg followed by ipilimumab q3w X 4; then 3 mg/kg q2w
Metastatic NSCLC
PD on or after platinum chemotherapy and targeted therapy if EGFR/ALK+ (squamous: median OS 9.2 vs 6.0 mos with docetaxel; nonsquamous: 12.2 vs 9.4 mos)[4,5]
Advanced RCC
Following antiangiogenic therapy (median OS 25.0 vs 19.6 mos with everolimus)[6]
Classical Hodgkin’s Lymphoma
Following relapse or progression after ASCT and post- transplantation brentuximab vedotin (ORR 65%; PR 58%, CR 7%)[7]
Nivo, nivolumab; ipi, ipilimumab; PD, progressive disease; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; OS, overall survival; ORR, objective response rate; RCC, renal cell carcinoma; NSCLC, non-small cell lung cancer, ASCT, autologous stem cell transplantation; ORR, overall response rate; PR, partial response; CR, complete response.
Nivolumab is another anti–PD-1 checkpoint inhibitor. It is approved for unresectable or metastatic melanoma as a frontline treatment for BRAF wild-type patients with or without ipilimumab and following progression on ipilimumab and a BRAF inhibitor for BRAF-positive patients. Additional indications include metastatic NSCLC after platinum failure (and after targeted therapy if EGFR/ALK positive), advanced renal cell carcinoma after antiangiogenic therapy, and most recently classical Hodgkin’s Lymphoma following relapse or progression after ASCT and posttransplantation brentuximab vedotin. Improved OS for NSCLC and RCC has been demonstrated at approximately 3-5 months.[1-3]
For more information, please review the downloadable nursing resource, “At a Glance: Understanding Immune Checkpoint Inhibitors and Their Role in Cancer Care”:
References
1. Rounds A, Kolesar J. Nivolumab for second-line treatment of metastatic squamous non-small-cell lung cancer. Am J Health Syst Pharm. 2015;72:
2. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:
3. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:
1. Robert C, et al. N Engl J Med. 2015;372: Postow MA, et al. N Engl J Med. 2015;372: Weber JS, et al. Lancet Oncol. 2015;16: Rounds A, et al. Am J Health Syst Pharm. 2015;72: Borghaei H, et al. N Engl J Med. 2015;373: Motzer RJ, et al. N Engl J Med. 2015;373: US Food and Drug Administration. Nivolumab (Opdivo) for Hodgkin Lymphoma.
Slide credit: clinicaloptions.com

28. Atezolizumab (Anti–PD-L1) Approved Indication
Locally advanced or metastatic urothelial carcinoma with progression during or following platinum-containing chemotherapy or within 12 mos of neoadjuvant/adjuvant treatment with platinum-containing chemotherapy
ORR 14.8%
Patients with > 5% expression of PD-L1 in tumor-infiltrating immune cells: ORR 26.0%
Patients with ≤ 5% expression of PD-L1 in tumor-infiltrating immune cells: ORR 9.5%
Dosing guideline: 1200 mg IV q3w, infuse over 1 hr initial infusion; if tolerated, subsequent infusions may be given over 30 mins
PD-1, programmed death 1; ORR, objective response rate; PFS, progression-free survival; OS, overall survival; EGFR, epidermal growth factor receptor; ALK, anaplastic lymphoma kinase; NSCLC, non-small cell lung cancer.
Atezolizumab is the first anti-PD-L1 antibody to gain FDA approval and is currently indicated for the treatment of locally advanced or metastatic urothelial carcinoma. Of note, in clinical trials, a much higher response rate was observed in patients whose tumors had higher PD-L1 expression in tumor-infiltrating immune cells.
Slide credit: clinicaloptions.com
Atezolizumab [package insert]

29. Checkpoint Inhibitor Therapy: Select Phase III Combination Trials
Tumor
Phase III (Unless Otherwise Indicated)
Melanoma
Nivo/ipi + GM-CSF vs nivo/ipi (NCT )
Nivo + ipi followed by nivo (NCT )
Ipi/nivo before vs after dabrafenib/trametinib (NCT )
RCC
Nivo/ipi vs sunitinib (NCT )
Atezolizumab + bev vs sunitinib (NCT )
NSCLC
Ipi + pac/carbo vs pac/carbo (NCT )
Atezolizumab + CT (± bev) vs CT (+ bev) (NCT , NCT , NCT )
Nivo vs nivo + ipi vs nivo + CT vs CT (NCT )
SCLC
Nivo vs ipi + nivo vs placebo as maintenance post-CT (NCT )
HNSCC
Durvalumab + tremelimumab vs SOC (NCT )
GBM
Nivo/ipi vs nivo vs bev (NCT )
TNBC
Atezolizumab/nab-pac vs nab-pac (NCT )
bev, bevacizumab; carbo, carboplatin; CT, chemotherapy; GBM, glioblastoma; GM-CSF, granulocyte-macrophage colony-stimulating factor; HNSCC, head and neck squamous cell carcinoma; ipi, ipilimumab; nivo, nivolumab; NSCLC, non-small-cell lung cancer; pac, paclitaxel; pembro, pembrolizumab; RCC, renal cell carcinoma; TNBC, triple-negative breast cancer.
There are many ongoing phase III trials of PD-1/PD-L1 therapies in different tumor types. Patients with an active (or recent history of a) known or suspected autoimmune disease are excluded from these trials—in some cases, allow patients with type 1 diabetes, hypothyroidism on hormone replacement, or skin disorders not requiring systemic treatment.
Slide credit: clinicaloptions.com
ClinicalTrials.gov.

30. CheckMate 067: Treatment-Related AEs Associated With Nivo and Ipi
Select Grade 3/4 Treatment-Related AEs, %
Nivo + Ipi (n = 313)
Nivo (n = 313)
Ipi
(n = 311)
Any select AE 40 8 19
Skin
Pruritus
Rash
Maculopapular rash 6 2 3
< 1
Gastrointestinal
Diarrhea
Colitis 15 9 12
Hepatic
ALT increase
AST increase 1
Endocrine
Hypothyroidism 5
Pulmonary
Pneumonitis
AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; Ipi, ipilimumab; Nivo, nivolumab.
In the CheckMate 067 study, nivolumab and ipilimumab were combined in patients with previously untreated advanced melanoma.[1] Here, grade 3/4 treatment-related adverse events are summarized. Remember that adverse events take time to develop after initial administration of checkpoint inhibitors. Ipilimumab and nivolumab monotherapies yielded approximately 20% and approximately 10% total grade 3/4 treatment-related adverse events, respectively. When treatment was combined, the figure increased to 40%, indicating compounding toxicity with dual therapy. This should be considered during selection of treatment, in addition to a patient’s ability to sustain therapy. Skin, hepatic, and endocrine toxicities, highlighted in red, notably increase when the 2 checkpoint inhibitors are combined. By contrast, the gastrointestinal effects of combined therapy seem largely attributable to ipilimumab.
Reference
1. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34.
Slide credit: clinicaloptions.com
Larkin J, et al. N Engl J Med. 2015;373:23-34.

31. Management of Immune-Related AEs
AE, adverse event.

32. T-cell clonal expansion
Immune-Related AEs
Self-reactive T cells may proliferate when immune homeostasis or immune tolerance is disrupted
Self-reactive T cells may react with normal tissue
Dendritic cell
Tumor
Perforin granzyme
Cytokines (IL-2)
Activated T cell
T-cell clonal expansion
Resting T cell
Lymph node
TCR
CD28
MHC B7
Tumor antigen 1 2 3
AE, adverse event; IL, interleukin; MHC, major histocompatibility complex; TCR, T-cell receptor.
A major driver of immune-related adverse events is cytokines. Activated T cells flood these molecules into the system. Furthermore, self-reactive T cells may proliferate and react with normal tissues as checkpoint blockade disrupts immune homeostasis.[1]
Reference
1. Amos SM, Duong CP, Westwood JA, et al. Autoimmunity associated with immunotherapy of cancer. Blood. 2011;118:
Slide credit: clinicaloptions.com
Amos SM, et al. Blood. 2011;118:

33. Immune-Related AEs With Immunotherapy
Endocrine
Hypothyroidism
Hyperthyroidism
Adrenal insufficiency
Hypophysitis
Skin
Dermatitis exfoliative
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Vitiligo
Alopecia
Eye
Uveitis
Iritis
Pulmonary
Pneumonitis
Interstitial lung disease
Acute interstitial pneumonitis
Hepatic
Hepatitis, autoimmune
Renal
Nephritis, autoimmune
Renal failure
Gastrointestinal
Colitis
Enterocolitis
Necrotizing colitis
GI perforation
Neurologic
Autoimmune neuropathy
Demyelinating Polyneuropathy
Guillain-Barre
Myasthenia gravis–like syndrome
AE, adverse event.
Skin, gastrointestinal, and endocrine toxicities following checkpoint inhibitor treatment are common whereas autoimmune hepatitis is fairly rare. Note that endocrine-related adverse events can sometimes present subtly but still may require attention.
If not vigilant, may result in more serious immune-related AEs
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34. Immune-Mediated Colitis: Symptom Surveillance
Monitor for signs and symptoms
Median time to onset from first dose ~ 10 wks from first dose
Ask pts to report any bowel habit changes promptly
Rule out other causes of diarrhea
Clinical Pearl: colitis can occur without diarrhea; important to take all GI-related symptoms seriously and evaluate!
Symptom surveillance for immune‑mediated colitis is important, as is its proper documentation. Obtain a precise bowel history at baseline and regularly monitor for changes (every 2 or 3 weeks or as they come in). Ask specific questions (eg, how many bowel movements per day, if they are having abdominal pain). Signs and symptoms to monitor for include diarrhea, abdominal pain, nausea, inability to eat or drink, and mucus or blood in the stool. Ask patients to report any bowel habit changes promptly and to keep good records of the time of day, frequency, volume, and texture of stools. Other causes of diarrhea should be ruled out, including Clostridium difficile or other infectious diarrheas.
Diarrhea and/or colitis is a potentially serious complication of anti–CTLA-4 therapy but can also be seen with anti–PD-1 therapy. Bowel perforation, sepsis, and death have been reported. Close monitoring is required to prevent progression to more serious complications. Patients should be counseled on diet and managed with antidiarrheals (loperamide/lomotil), proton pump inhibitors, increased hydration, and avoidance of caffeine.
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Nivolumab [package insert]

35. Immune-Mediated Colitis: Symptom Management
Grade
Management
Mild/grade 1: ≤ 4 stools/day above baseline
Manage symptomatically (bland diet, PPI, antidiarrheal)
Consider delaying treatment until symptoms improve
Moderate/grade 2: increase of 4-6 stools/day above baseline (persistent)
Colonoscopy and steroids
Low-dose steroids may be sufficient
Hold treatment
Severe/grade ≥ 3: ≥ 7 stools/day above baseline
Initiate high-dose steroids
Discontinue treatment
Prevention
No known methods
PPI, proton pump inhibitor.
When immune-mediated colitis is mild (grade 1), it can be managed symptomatically. Progression to moderate (grade 2) colitis requires colonoscopy, low-dose steroids, and temporary suspension of treatment. Treatment is held because steroids suppress the immune system, which is in opposition and counteractive to the goal of checkpoint inhibitor treatment. Although recurrence of the disease is technically possible during this interval, the adaptive immune response (ie, T-cell memory) will hopefully be established enough to prevent this. For severe (grade ≥ 3) colitis, high‑dose steroids are recommended, as is stopping treatment. At this time, a preventive strategy for immune-mediated colitis is unknown.
Low-dose steroids may be sufficient (eg, 0.5 mg/kg/day of Solu-Medrol or equivalent). If there is no improvement within 24 hours, consider a higher dose (1 mg/kg of methylprednisolone or equivalent). Budesonide was tested as a way to prevent immune-related colitis in a randomized phase II trial, but no benefit was shown.[1]
Reference
1. Weber J, Thompson JA, Hamid O, et al. A randomized, double-blind, placebo-controlled, phase II study comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res. 2009;15:
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36. Immune-Mediated Hepatitis: Symptom Surveillance
Monitor LFTs at baseline and prior to each dose of treatment
Pts with abnormal LFTs should be monitored more frequently
Hepatotoxicity appears worse when ipilimumab combined other drugs[1-3]
LFT, liver function test.
For symptom surveillance of immune‑mediated hepatitis, check patient LFTs at baseline and before every dose of treatment. Hepatitis is less common than colitis, seen in 2% to 9% of patients, and at least 1 death has been reported on anti–CTLA-4 therapy alone.[1] With hepatotoxicity, the liver will become tender. Before outright jaundice, subtle changes such as nausea, appetite loss, minor discomfort, and bloating may alert one as well because these symptoms are not normal adverse events from immunotherapy or checkpoint inhibitors.
Hepatotoxicity appears worse when ipilimumab combined other drugs including dacarbazine,[2] vemurafenib,[3] and anti–PD-1 antibodies[4] and should be used cautiously.
References
1. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363:
2. Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:
3. Ribas A, Hodi FS, Callahan M, Konto C, Wolchok J. Hepatotoxicity with combination of vemurafenib and ipilimumab. N Engl J Med. 2013;368:
4. Wolchok JD, Weber JS, Maio M, et al. Four-year survival rates for patients with metastatic melanoma who received ipilimumab in phase II clinical trials. Ann Oncol. 2013;24:
1. Robert C, et al. N Engl J Med. 2011;364: Ribas A, et al. N Engl J Med. 2013;368: Wolchok JD, et al. Ann Oncol. 2013;24:
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37. Immune-Mediated Hepatitis: Symptom Management
Rule out other causes of LFT abnormalities
Increase LFT monitoring
Corticosteroid treatment with grade ≥ 2 LFTs (prolonged taper may be required)
Mycophenolate may be useful
LFT abnormalities appear to be dose dependent
LFT
Grade 1
Grade 2
Grade 3
Grade 4
Bilirubin
> ULN to 1.5 x ULN
> 1.5 to 3.0 x ULN
> 3.0 to 10.0 x ULN
> 10.0 x ULN
ALT/AST
> ULN to 2.5 x ULN
> 2.5 to 5.0 x ULN
> 5.0 to 20.0 x ULN
> 20.0 x ULN
Albumin
< LLN to 3 g/dL
< 3 to 2 g/dL
< 2 g/dL --
ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test; ULN, upper limit of normal; LLN, lower limit of normal.
Patients with immune-mediated hepatitis can be asymptomatic. Frequent monitoring is essential, and in some cases, grade 2 abnormalities correct without steroids. LFT increases should be monitored until improvement. Other causes of LFT abnormalities should be ruled out, and corticosteroids administered for grade ≥ 2 LFTs and a prolonged taper may be required. Note also that proton pump inhibitor administration for colitis can cause liver issues; H2 blockers may avoid this outcome if the patient is experiencing only minor indigestion. Mycophenolate may be useful in patients with persistent severe hepatotoxicity. Time-to-onset data are vague, but LFT abnormalities appear to be dose dependent.
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38. Immune-Mediated Dermatitis
Reported in up to 40% of pts with anti–CTLA-4 and anti– PD-1 agents
Occasionally severe rashes
Onset within a few wks of starting or several wks/mos into therapy
Severity driven by symptoms
Rule out other etiologies
Generally not infusion related
Immune-mediated dermatitis is commonly seen with anti–CTLA-4 and anti–PD-1 agents (up to 40%). The rash occurs weeks or even months after initial therapy (not during infusion) and responds well to corticosteroids. Low‑grade antihistamines are helpful, as is topical steroid cream. Occasionally, severe rashes can be seen, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, or full thickness dermal ulceration. The management of immune-mediated dermatitis is driven by the severity of symptoms. Other etiologies for rash should be ruled out, such as poison ivy, contact dermatitis, cellulitis, and so on. The rash is generally not considered an infusion-related event.
Hodi FS, et al. N Engl J Med. 2010;363: Image courtesy Matthew M. Burke, MBA, RN, MSN, APRN-BC.
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39. Immune-Mediated Dermatitis: Symptom Management
Severity
Management
Mild/moderate (rash/pruritus)
Topical nonsteroidal cream, antihistamine, oatmeal baths
Skin care, moisturize, sunscreen, avoid sun
Persistent (> 1 wk) or interferes with ADLs
Moderate-potency steroid creams or
Moderate-dose parenteral steroids
Severe
Discontinue treatment
High-dose steroids
Avoid rapid steroid taper
ADLs, activities of daily living.
Mild or moderate dermatitis (rash and pruritus) can be managed symptomatically with topical nonsteroidal anti-itch cream, antihistamines, and/or oatmeal baths. Encourage skin care with creams, use of sunscreen, and avoidance of sun exposure, especially with vitiligo. If rash persists for more than 1 week or interferes with activities of daily living, start moderate-potency steroid creams (triamcinolone 0.1%) or moderate-dose parenteral steroids at 0.5 mg/kg/day of prednisone or equivalent. Serious rashes require discontinuation of ipilimumab and management with high-dose steroids. Rapid tapering of steroids is not advised and may result in the recurrence or worsening of symptoms. Antibiotics are not helpful with immune- mediated dermatitis.
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40. Immune-Mediated Endocrinopathies
Can be serious or fatal if not managed correctly
Hypophysitis, thyroid disease, and primary adrenal insufficiency have all been reported
Mechanism of injury not fully understood
Monitor pt for pituitary, thyroid, or adrenal disease
Check TFTs at baseline and prior to each dose
Time to onset may be much later; median 11 wks
Hypothalamus
Thyroid gland
T T3
SULTs UGTs
liver 01
T4→T3
T3/TR
rT3,T2
inactive
T4/T3-sulfate
T4/T3-glucuronide inactive
Excretion
T4 >> T3
02.03
Pituitary gland
TFTs, thyroid function tests.
Immune‑mediated endocrinopathies can be serious or fatal if not managed correctly. Time to onset may be much later. The average onset in patients treated with ipilimumab was 9 weeks.[1] Low‑dose corticosteroids are recommended, levothyroxine can replace thyroid hormone, and treatment may have to be delayed. Hypophysitis, thyroid disease or abnormal thyroid function tests, and primary adrenal insufficiency have all been reported. The mechanism of injury is not fully understood. Hypophysitis can be permanent but can be managed with hormone replacement.
Patients should be monitored for signs and symptoms associated with pituitary, thyroid, or adrenal disease. Symptoms are often nonspecific but may include headache, fatigue, changes in mental status, abdominal pain, and hypotension. Thyroid function tests should be checked at baseline and prior to each dose. TSH is the most sensitive test, but if the patient is symptomatic, consider a full panel including T3, T4, cortisol, and ACTH.
Reference
1. Weber JS, Kähler KC, Hauschild A. Management of immune-related adverse events and kinetics of response with ipilimumab. J Clin Oncol. 2012;30:
Slide credit: clinicaloptions.com
Corsello SM, et al. J Clin Endocrinol Metab. 2013;98:

41. Immune-Mediated Endocrinopathies: Symptom Management
Hormone replacement, corticosteroids
Possibly delay treatment
Co-syntropin stimulation test
Many endocrinopathies can be controlled and treatment continued
Does a preexisting thyroid disorder put pts at higher risk of developing additional endocrinopathies?
Not as far as we know.
Treatment of endocrinopathies requires appropriate hormone replacement, corticosteroids and possibly delaying treatment. A co-syntropin stimulation test may be helpful prior to starting steroids. Many endocrinopathies can be controlled; if hormone levels are stable with < 7.5 mg of prednisone, treatment can be continued.
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42. Immune-Mediated Pneumonitis
Fairly uncommon, but potentially serious
Deaths have been reported
Need to carefully monitor pts
Pts at increased risk for pneumonitis
NSCLC in the setting of chronic lung inflammation
Heavily pretreated pts
Combination of CTLA-4 and PD-1 agents
Prior radiation to lung
History of COPD
COPD, chronic obstructive pulmonary disease; NSCLC, non-small cell lung cancer.
Although uncommon (approximately 3% of patients), pneumonitis can be a serious event with anti–CTLA-4 and anti–PD-1 treatment. Deaths have been reported. Patients with NSCLC may be at increased risk in the setting of chronic lung inflammation. Heavily pretreated patient may also be at increased risk. Careful monitoring for signs and symptoms of pneumonitis is important. The risk is increased with the combination of CTLA-4 and PD-1 agents and prior radiation to lung, or any preexisting pulmonary disease.
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43. Immune-Related Pneumonitis: Signs and Symptoms
Shortness of breath
Dry cough
New or increasing oxygen requirements
May be detected just on imaging
Decreasing O2 sat on room air
11/15/2013: Prepneumonitis
1/21/14: Pneumonitis
2/21/14: Improved with steroids; taper completed 3/7/14
O2 sat; oxygen saturation.
Immune-mediated pneumonitis is fairly uncommon. Patients can present gasping for breath and coughing upon movement, with decreased oxygen saturation. A chest x-ray should be ordered and examined for diagnosis. This progression of images details before, during, and after steroid treatment and resolution of pneumonitis.
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44. Other Immune-Related AEs
Immune-related AEs include
Ocular manifestations
Neurologic complications
Sarcoidosis
Systemic vasculitis, including renal disease
Autoimmune pancreatitis
Hematologic
AE, adverse event.
Other immune-related adverse events include ocular manifestations such as conjunctivitis, uveitis, and scleritis; neurologic complications such as Guillain-Barre syndrome, inflammatory myopathy, aseptic meningitis, temporal arteritis, and posterior reversible encephalopathy syndrome; sarcoidosis; systemic vasculitis, including renal disease; and autoimmune pancreatitis. Hematologic events have also been reported, including red cell aplasia, pancytopenia, autoimmune neutropenia, and acquired hemophilia A.
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45. Keys to Optimal Pt Management
Education of healthcare team, pts, and caregivers
Rapid and timely intervention
Corticosteroids for some intolerable grade 2 irAEs and any grade 3/4 irAEs
SLOW taper of glucocorticoids
Reinitiation of treatment may be possible
This goal is attainable through communication between all members of the healthcare team and pts
irAEs, immune-related adverse events.
Education is key to optimal patient management. All members of the healthcare team should be educated about potential adverse events. Rapid and timely diagnostic and therapeutic intervention is imperative for optimal control of immune-related adverse events. Persistent grade 2 and grade 3/4 immune-related adverse events are treated with corticosteroids, and it is important to taper the steroids slowly to avoid relapse of symptoms. Early discontinuation of glucocorticoids may predispose to relapse. It is also important to note that reinitiation of treatment may be possible with optimal management and effective communication between all members of the healthcare team and the patient.
The CCO immunotherapy nursing resource, “At a Glance: Understanding Immune Checkpoint Inhibitors and Their Role in Cancer Care,” is a patient education checklist that can be used with patients receiving cancer immunotherapy:
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46. Special Populations Pregnancy and lactation
Antibodies are known to cross placental barrier
Pregnancy category C; immune checkpoint inhibitors are not recommended
Advise pts to use highly effective contraception
Safety of breast-feeding has not been studied
Pregnant and breastfeeding women should not receive checkpoint inhibitors. Antibodies are known to cross the placental barrier and can affect the developing fetus. All checkpoint inhibitors approved to date are pregnancy category C. Patients should be advised to use highly effective contraception throughout treatment and then for up to 6 months after completing therapy. Antibodies can be transmitted via human breast milk and the safety of breast-feeding has not been studied.
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47. Infusion Reactions
Infusion reactions with checkpoint inhibitors are very rare
Reported in up to 10% of pts (often much fewer)
Usually mild: stop the infusion and restart at a lower rate
No steroids: premedications are not necessary
As with any infusion, monitor carefully and have emergency medications available
Infusion reactions with checkpoint inhibitors are very rare. Across various studies, infusionlike reactions are reported in up to 10% of patients. Many of these are mild and do not require any medical intervention other than stopping the infusion and then restarting at a lower rate. Premedications are not necessary (steroids should NOT be used as premedication). As with any infusion, monitor patients carefully during the infusion and have emergency medications available.
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48. Pt Education on Novel Therapies
Unique MOA and time to response
Toxicity profiles differ from standard chemotherapy
Early recognition of irAEs essential
irAEs infrequent, treatable, and respond well to steroids
Whom and when to call for AEs
These new therapies are helping many people
Reinforce teaching points at every point of contact
Notify healthcare team if the pt is admitted to another hospital
AEs, adverse events; irAEs, immune-related adverse events; MOA, mechanism of action.
Patient education on novel therapies is important. It is important to remember that the mechanism of action during checkpoint blockade is unique. The time to response after checkpoint blockade is unique. Patients need to be educated on this because panic can arise when tumors do not start shrinking immediately. Toxicity profiles are very different for checkpoint inhibitors compared with standard chemotherapy. Early recognition of immune-related adverse events is essential for effective management. Of importance, the healthcare team must be notified if the patient is admitted to another hospital.
Patient education should start before therapy onset and throughout therapy at every contact point the clinician has with the patient. Patients and their care partner(s) should be included to be active participants in the patient’s care especially if an adverse event develops. Emphasis should be placed on the importance of maintaining a treatment schedule to optimize the best outcomes and, conversely, to intervene when an adverse event develops and interferes with quality of life and potential for continuing treatment.
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49. Case-Based Application of Nursing Considerations and AE Management
AE, adverse event.

50. Case 1: J.G.
74-yr-old male with tibial metastasis of melanoma: 7 x 1 x cm lesion with bone destruction
Prescribed combination therapy with nivolumab and ipilimumab
After cycle 2, he is diagnosed with pneumonitis and successfully treated with high-dose prednisone taper
Now off steroids with no respiratory issues
A few days before scheduled visit for cycle 3, he calls complaining of watery stools, 1 per hr, blood in stool, abdominal discomfort, and severe weakness
He lives 200 miles from clinic
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51. Case 1: J.G.
Due to his very severe symptoms, the pt was advised to go to the emergency department
Emergency department staff was immediately made aware that this pt is receiving immunotherapy and likely has immune-related colitis and may be at risk for perforation
CT abdomen: moderate colitis and diverticulosis without diverticulitis; stool positive for occult blood
Colonoscopy: changes consistent with IBD; biopsy of colonic mucosa reveals moderate idiopathic colitis
IBD, inflammatory bowel disease.
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52. Case 1: J.G. J.G. is referred to a gastroenterologist
Stool evaluated for bacterial and viral gastroenteritis, parasitic and C difficile infection, all negative
Pt treated with oral steroids of prednisone 1 mg/kg with quick resolution of symptoms
Prednisone tapered after symptoms resolved
Pt calls again that his stools are again watery, approximately 15 times in half a day. What do you do?
C difficile, Clostridium difficile.
Note: You know that the patient had high-dose steroids but even if he was treated successfully, there is potential that this is colitis again.
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53. Case 1: J.G. Symptoms are reported to the oncologist
J.G. is admitted and given high-dose methylprednisolone 60 mg BID and 1 dose of infliximab at 5 mg/kg, followed by oral steroids
Pt was discharged when diarrhea/colitis resolved to grade 1 with 2 bowel movements/day and a prolonged prednisone taper over ≥ 4 wks
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54. Case 2: R.D.
72-yr-old female with T4 N1 melanoma diagnosed in November
Initial presentation: T4 lesion on left foot, resected along with 3 positive LNs
Declined adjuvant interferon
2009: recurrent inguinal disease; enrolled on clinical trial with oral BRAF inhibitor
Participated in 3 additional clinical trials before deciding to take a break from treatment
2015: bilateral pelvic masses, each > 4 cm, causing pain, plus 2 new liver lesions
February 2015: initiated treatment with ipilimumab
LN, lymph node; tx, treatment
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55. Case 2: R.D.
Tolerated first cycle of ipilimumab well: only complained of fatigue with some redness and itching of her skin
No visible rash but itching is uncomfortable for her
Presents for second dose
Labs normal except mild renal insufficiency and mild anemia of chronic illness; vital signs and weight are stable
As her nurse, do you have any concerns about starting the second cycle of ipilimumab?
What would you add to her home care regimen?
What AEs are more likely to develop during this second cycle of ipilimumab?
AE, adverse event.
The patient should proceed to treatment cycle 2. Advise her to drink more water. She may also benefit from palliative measures for her itching such as oatmeal baths, oral or topical antihistamines, and steroids. Oral second-generation antihistamines, such as loratadine, may also be of benefit. Of importance, monitor closely for the development of colitis, as this adverse event is more likely to develop between the second and third cycles of ipilimumab.
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56. Case 2: R.D.
On return for her third dose of ipilimumab, she is experiencing worsening rash
Papular rash over chest, back, and arms with itching keeping her up at night
Should she receive the third dose of ipilimumab?
At what point would you start steroids and/or hold ipilimumab?
It was determined she had a grade 2 skin rash and she was given a moderate-potency steroid cream to use. At this point, there were no bullous lesions or desquamation. The patient should receive her third course of ipilimumab. The rash is still relatively minor and can be treated without discontinuation of therapy. If the rash significantly progresses (eg, exhibits vesicles or bullous lesions, involves desquamation), high-potency steroids can be used, and treatment can be temporarily withheld. Upon improvement, ipilimumab could be resumed.
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57. Case 2: R.D.
She completed all 4 cycles of ipilimumab without worsening of her rash
The rash persisted for several wks after completion of the ipilimumab with itching and burning of the skin
Is this normal?
Rash can continue weeks to months after completion of ipilimumab and, at times, can reflare. If on steroids, tapering slowly helps. Continue with supportive care.
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58. Case 3: G.B.
59-yr-old male, nonsmoker with history of NSCLC, adenocarcinoma
Relapsed after cisplatin/pemetrexed and single-agent docetaxel
Histology: adenocarcinoma with EGFR, ALK, and KRAS wild type
ECOG PS: 1; continues to try to work
PD-L1 assay is performed and returns positive for PD-L1 expression
Initiated pembrolizumab and tolerated well except for fatigue
12-wk restaging scans: mixed response with some disease improvement and some areas of PD and possible new small pulmonary nodule
ECOG PS, Eastern Cooperative Oncology Group performance status; NSCLC, non-small cell lung cancer; PD, progressive disease.
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59. Case 3: G.B. G.B. continued on pembrolizumab
At 5 mos, developed mild dyspnea on exertion, most noticeably while climbing stairs with dry cough triggered by laughing and exercise
Chest x-ray: bilateral patchy airspace disease
What are you worried about?
What is in your differential?
What are the next steps?
Potential pneumonitis is a concern, although it is very hard to differentiate, by symptoms alone, between infection, disease progression, and drug toxicity.
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60. Case 3: G.B. Pembrolizumab is held and G.B. is sent to pulmonologist
Not able to perform PFTs due to coughing
Started on prednisone 100 mg/day with slow taper
At 12 wks, tapered off steroids to 2.5 mg/day
DLCO performed: 60% of predicted
PET reveals moderate improvement in inflammatory airway disease
What do you do now?
DLCO, carbon monoxide diffusing capacity of lungs; PFT, pulmonary function test.
Interstitial lung disease is rare but can be fatal. If he improves to the point of not needing steroids, he could possibly resume treatment cautiously with very close follow-up. If he requires continued steroids, ongoing treatment is questionable.
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61. Case 4: E.C. 55-yr-old female diagnosed with stage IIIC melanoma
She underwent successful resection and LN dissection with scans showing NED
Due to her high risk of recurrence, she is prescribed high-dose ipilimumab 10 mg/kg, which was recently approved by the FDA for adjuvant therapy
She returns to infusion room for fourth dose of ipilimumab and reports that her oncologist cleared her for infusion a few days prior
She is ambulatory but complaining of fatigue, stating she is “very, very tired,” with a headache and mild nausea but able to eat and drink; in bed all day yesterday and difficulty performing usual activities
LN, lymph node; NED, no evidence of disease
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62. Case 4: E.C.
No SOB or apparent distress; BP 111/70 mm Hg (lower than usual)
CBC and chemistries are all within normal limits
In addition, pt reports body aches
What would you do?
BP, blood pressure; CBC, complete blood count; SOB, shortness of breath.
Do not give the fourth dose and report signs and symptoms to the oncologist. The etiology of the symptoms is not known, but moderate or profound fatigue with immunotherapy to be is not expected to be normal. It is known that toxicities can happen anytime, even though this patient was seen a few days earlier. The severe headache is also not normal. In metastatic melanoma, patients are at high risk for brain metastases. Patients should be evaluated for possible causes such as infection, sepsis, brain metastases, and endocrine toxicity.
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63. Case 4: E.C. Endocrine labs are ordered
ACTH: < 2 pg/mL (range: 6-59)
Cortisol 0.4 μg/dL (range: morning 5-25 μg/dL, evening μg/dL)
TSH: 0.02 mIU/L ( mIU/L)
Pt is given hydrocortisone replacement 20 mg in am and 20 mg in afternoon and prescribed levothyroxine 75 μg/day
Brain MRI ordered to rule out metastasis or hypopituitarism
Enlargement of pituitary gland with thickening of the stalk
Referred to endocrinologist who was informed that pt has hypopituitarism related to immunotherapy
ACTH, adrenocorticotropic hormone; TSH, thyroid-stimulating hormone.
It is important to note that if patients have severe symptoms of hypotension, electrolyte imbalance (low sodium, high potassium), and dehydration, they may possibly be in adrenal crisis and should be hospitalized and treated with methylprednisolone 1-2 mg/kg IV followed by oral prednisone 1/2 mg/kg/day.
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64. Case 4: E.C.
Before
After
AP, anteroposterior.
The patient’s pituitary gland is slightly bigger with a thickened stalk and abuts the ventral surface of the optic chiasm in the right-hand image, as compared with the one on the left.  
The pituitary now abuts the undersurface of the optic chiasm. The pituitary infundibulum also appears slightly thickened in AP dimension
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65. Go Online for More CCO Coverage of Cancer Immunotherapy!
Downloadable Pocket Guide on immune checkpoint inhibitors developed by expert nursing faculty ONS/inPractice Oncology Nursing Chapter on Immunotherapy
clinicaloptions.com/oncology