Immune Checkpoint Inhibitors in Lung Cancer and Melanoma

ARTICLE IN PRESS Seminars in Oncology Nursing 000 (2019) 150932

Contents lists available at ScienceDirect

Seminars in Oncology Nursing journal homepage: https://www.journals.elsevier.com/seminars-in-oncology-nursing

Immune Checkpoint Inhibitors in Lung Cancer and Melanoma Kathleen Madden, FNP, AOCNP, APHNa,*, Mary Kate Kasler, MSN, ACNP-BC, DNP(c)b a b

NYU Langone Perlmutter Cancer Center, New York, NY Memorial Sloan Kettering Cancer Center, New York, NY

A R T I C L E

I N F O

Key Words: Melanoma NSCLC SCLC Immune checkpoint inhibitor PDL-1 durable response irAEs

A B S T R A C T

Objective: To provide a synopsis of immune checkpoint inhibition in solid tumors with a focus on lung cancer and melanoma for the oncology nurse. Data Sources: A literature search was conducted from 2012 to the present using key search terms including: ipilimumab, pembrolizumab, nivolumab, durvalumab, atezolizumab, immune checkpoint inhibitor, NSCLC or SCLC, melanoma, incidence, toxicity, and immune-related adverse events (irAEs). Conclusion: Immune checkpoint inhibition has caused a pivotal shift in the treatment of melanoma and lung cancer. Additionally, it has supported the use of immunotherapy as a modality and pillar of cancer treatment. The interdisciplinary team plays an integral role in facilitating patients’ understanding of their treatment modality, symptom management, and guidance through their cancer journey. As more research continues in various tumor types to understand how immune-modulated agents can impact tumor burden, disease control, and quality of life, it is hoped that more patients will have access to these therapies. Implications for Nursing Practice: Patient safety is paramount and nurses are aligned to educate, assess, and guide patients during immune checkpoint inhibitor therapy. Developing a rapport and relationship that is based on trust and open communication are vital for helping patients adhere to therapy and safely navigate symptom reporting at the onset of symptoms. © 2019 Elsevier Inc. All rights reserved.

Introduction Monoclonal antibodies that focus on immune checkpoints have prompted a change in the oncology treatment paradigm and have become a significant revelation in cancer therapeutics. Among the immune checkpoint inhibitors (ICIs), programmed death-1 (PD-1) programmed death ligand-1 (PDL-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors show promising therapeutic outcomes. Some ICI’s have been approved by the US Food and Drug Administration (FDA) for the treatment of a variety of cancers. Clinical trials are paving the way for new ICI therapy agents and expanding the current use of approved therapies. ICIs eradicate inhibitory signaling of T-cell activation, which fosters the ability of the T cell to mount an effect an immune-mediated response against tumor cells.1 T cells with regulatory properties function to maintain immune responses to avert autoimmunity. Ipilimumab, which affects CTLA-4, was the first FDA-approved ICI for the treatment of patients with advanced melanoma.1,2 CTLA-4 precludes T-cell inhibition and stimulates the activation and growth of effector T cells. The approval of ipilimumab stimulated the research of other ICIs, such as PD-1 and PDL-1. * Address reprint requests to: Kathleen Madden, NYU Langone Perlmutter Cancer Center, 160 East 34th St, New York, NY 10016 E-mail address: [email protected] (K. Madden). https://doi.org/10.1016/j.soncn.2019.08.011 0749-2081/© 2019 Elsevier Inc. All rights reserved.

The role of PD-1 as a checkpoint is to diminish T-cell activation, typically in later phases of T-cell activity with the purpose of preventing central and peripheral resistance and T cell auto-reactivity. PD-1 receptors encounter with PDL-1/ PDL-2 ligands typically are inhibitory and weaken T cell activation by shutting down the active T cell. Pembrolizumab and nivolumab are PD-1 inhibitor ICI's, atezolizumab and darvulumab are PDL-1 inhibitors. These inhibitors bind to either T cell surface or tumor surface and block tumor cell receptors from turning off activated T cells thereby allowing anti-tumor activity to continue. These FDA approved therapies have shown promising results in patients with melanoma and non-small cell lung cancer (NSCLC).2 5

Lung Cancer Lung cancer is the leading cause of cancer death irrespective of sex or ethnicity.6 An estimated 228,000 people in the United States will be diagnosed with lung cancer in 2019.6 Lung cancer is credited with 13% of all new cancer diagnoses and 24% of all cancer deaths.6 An estimated 19% of people diagnosed with lung cancer will have a survival rate of 5 years or more; however, if detected early, the rate of survivorship increases. Patients are often diagnosed in the later stages of disease. While standard therapy, such as cytotoxic therapy and radiation, have played a role in the treatment of lung cancer, clinical benefit has been achieved with targeted therapy. As a result of

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these findings with targeted therapy, research has expanded to include immuno-oncology, specifically ICIs, in an effort to achieve durable responses in the treatment of the lung cancer. Histology Histology and molecular profiling are the two different tactics used to delineate the type of lung cancer a person is diagnosed with. Histology is defined as the anatomy of cells when examined on a cellular level and molecular profiling is described as the genomic alterations expressed on tissue. Lung cancer is histologically divided into several types, including NSCLC, small cell lung cancer (SCLC), lung carcinoid tumors, and mesothelioma. NSCLC accounts for 80% to 85% of lung cancer diagnoses, and SCLC comprises an additional 15% to 20% of incidences, together accounting for approximately 95% of all bronchogenic carcinoma. Lung carcinoid tumors and mesothelioma encompass <5% of lung cancer diagnoses.6 9 For the purposes of this review we will focus on NSCLC and SCLC. The three most common histologies of NSCLC include adenocarcinoma, squamous cell carcinoma (SCC), and large cell carcinoma. Adenocarcinoma accounts for approximately 40% of NSCLC diagnosis among men and women in the United States. Adenocarcinoma begins in cells that secrete a medium such as mucus. Lung adenocarcinomas are well known for their clinical, radiologic, pathologic, and molecular heterogeneity. Adenocarcinoma originates in the distal airways. SCC accounts for 30% of lung cancer diagnoses and originate in the proximal airways. These cancers start in the early versions of squamous cells and coat the inside of the airways in the lungs. SCC often have a contributory link to smoking or history of smoking and tend to be found in the central portion of the lungs, near a main airway (bronchus).6 10 Staging Staging of NSCLC is defined by identification of the (T) primary tumor size and location, (N) the presence of lymph nodes impacted, and (M) distant metastasis. NSCLC is staged from 0 to IVb based on the TNM staging established using the American Joint Committee on Cancer (AJCC) staging.6,9,10 SCLC is a form of neuroendrocrine carcinoma with small, flat cells as compared with other cancer cell presentations. SCLC is most often diagnosed in patients with a history of smoking. SCLC is staged as limited disease, in which disease remains confined to one side of the chest, or extensive disease, in which the cancer has metastasized to distant regions of the body from the primary site.6,10 Staging is an essential tool in devising a treatment plan for the patient with lung cancer. Cytotoxic and radiation therapy have played a role in the treatment of lung cancer. Additionally, the evolution of targeted therapy has further derived significant benefit with the identification of driver mutations such as EGFR, ALK, BRAF, ROS1, and MET. Targetable mutations can yield rapid responses; however, they often have limited periods of efficacy because of developing resistance to the pathway inhibition that may lead to reactivation and progression. ICI as a treatment modality continues to be explored because they can create tumor recognition and suppression leading to long-term durable responses.4,6,10 12 Mutational burden PDL-1 is a known biomarker that can be expressed on some tumor cells. PDL-1 status is obtained by testing fresh or archival tissue through immunohistochemistry assays that result in percentages (the higher the percent the more likely a benefit will be seen from ICI therapy). The prognostic impact of PDL-1 expression has demonstrated some variability based on the assays and platforms used. PDL-

1 offers guidance in the absence of non-driver mutational lung cancer. However, PDL-1 is not the sole source of biomarker guidance.13 Tumor mutational burden (TMB) is described as the number of mutations per DNA megabases. TMB was initially measured as a biomarker for ICI based on the observation of successful immune checkpoint inhibition in solid tumors with high TMB, such as NSCLC, melanoma, head and neck, or bladder cancer.12 Treatment Approach for Patients With Advanced Lung Cancer Once a patient’s cancer is differentiated between NSCLC and SCLC, further evaluation as previously discussed is conducted, including staging, molecular profiling, and the patient’s overall performance status. Those diagnosed with stage I through III lung cancer are often treated with one or a combination of conventional modalities such as surgery, radiation, and chemotherapy.9,10,12 For those patients that are deemed unresectable, demonstrated recurrence after definitive therapy, or for which the patient has distant metastasis, systemic therapy must be chosen. The goal of treatment is to optimize survival and maintain quality of life. Initial therapy can be directed by key factors such as histology, molecular profile, and determining the presence of a driver mutation, TMB including PDL-1 status, extent of disease, and patients’ performance status. Driver mutations indicate the presence of molecular alterations that may match to targeted therapy to control the cancer pathway regulating cancer cell proliferation.9,12,13 Patients who experience PDL-1 expression on at least 50% of tumor cells are generally offered pembrolizumab monotherapy. In KEYNOTE-024, a phase III trial was conducted with 305 advanced treatment-naïve NSCLC patients who had 50% PDL-1 expression on tumor cells in the absence of a driver mutation.4 Patients were randomly assigned to platinum-based therapy versus pembrolizumab.4 Patients had the ability to cross over to pembrolizumab upon disease progression on platinum therapy. Median progression-free survival was 10.3 months in the pembrolizumab cohort compared with 6.0 months in the chemotherapy group (hazard ratio [HR]for disease progression or death, 0.50; 95% confidence interval [CI], 0.37 to 0.68; P <.001).4 As a result, pembrolizumab was accelerated for FDA approval and has become first-line therapy for patients with high PDL-1 expression. Non-small cell lung cancer (NSCLC) Patients with adenocarcinoma of the lung with PDL-1 status <50% are recommended to receive doublet platinum therapy in combination with pembrolizumab. The KEYNOTE-021 trial randomized 123 patients to chemotherapy with or without pembrolizumab.14,15 The objective response rate improved with the addition of pembrolizumab compared with the chemotherapy-alone cohort (55% v 29%; 95% CI, 8 42).14 This study supported FDA approval of the combination therapy of carboplatin, pemetrexed, and pembrolizumab in treatment-naïve advanced non-squamous NSCLC.14 Atezolizumab is a PDL-1 inhibitor that stimulates immunemediated recognition of cancer cells. Additionally, atezolizumab has been approved as second-line therapy in non-squamous NSCLC. According to the phase 3 OAK study, atezolizumab exhibited overall survival (OS) compared with docetaxel (HR = 0.75, 95% CI, 0.64 0.89; P = .0006. OS was prolonged with atezolizumab despite histology (median OS, 15.6 v 11.2 months in non-squamous NSCLC; HR, 0.73; 95% CI, 0.60 0.89; median OS, 8.9 v 7.1 months in squamous NSCLC; HR, 0.73, 95% CI, 0.54 0.98).16 Treatment for advanced non-squamous NSCLC remains an ongoing area of study. In SCC histology when there are no targetable mutations, the only option for treatment is chemotherapy. The only option for treatment is chemotherapy. However, the addition of pembrolizumab to

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chemotherapy in this cohort resulted in an extended OS (15.9 months v 11.3 months) and median progression-free survival of 1.6 months. Furthermore, no single-agent therapy has resulted in better survival than that seen with docetaxel. In phase 1 and 2 trials, nivolumab was associated with response rates of 15% and approximately 17%, with a median OS of 8.2 to 9.2 months and survival rates of 41% at 1 year and 19% at 3 years, among previously treated patients with advanced squamous-cell NSCLC.3,4,15 Brahmer et al reported the results of a randomized, open-label, international, phase 3 study that compared nivolumab monotherapy with docetaxel monotherapy in patients with advanced squamous-cell NSCLC in whom the disease progressed during or after one prior platinum-containing chemotherapy regimen.3,4,11,14,15 Additional data from the PACIFIC trial which studied patient with stage III unresectable disease treated with platinum- based chemoradiotherapy, compared placebo versus darvulumab which demonstrated and appreciable impact on survival. Compared with placebo, durvalumab demonstrated an appreciable impact on survival. Durvalumab was approved by the FDA as an every-2-week infusion after study results showed an OS rate of 66.3% at 24 months. Progression-free survival was 17.2 months versus 5.6 months in the placebo arm.17 Small cell lung cancer (SCLC) SCLC is an aggressive malignancy that, although initially sensitive to chemotherapy and radiation therapy, inevitably relapses resulting in poor survival. Increasing evidence suggests that immune responses against SCLC cells make immunotherapy a viable therapeutic approach. Several ICIs have been approved to treat patients with metastatic or extensive-stage SCLC. Additional research continues in this patient population to address unmet treatment needs.9,10,18 The phase 3 IMpower 133 study conducted a randomized doubleblind study of 202 patients with extensive-stage SCLC.18 Patients were randomized to receive four 21-day cycles of carboplatin and etoposide with either the addition of atezolizumab or placebo. Patients were then transitioned to a maintenance phase in which they continued either atezolizumab or placebo. Median OS was 2.0 months higher in the atezolizumab group (HR for death, 0.70; 95% CI, 0.54 0.91; P = .007). Additionally, median progression-free survival was 5.2 months in the atezolizumab cohort compared with 4.3 months in the placebo group (HR for disease progression or death, 0.77; 95% CI, 0.62 0.96; P = .02).18 The IMpower 133 study was pivitol in validating the utility of immunotherapy as a therapeutic approach in the first-line treatment of SCLC. Pembrolizumab was examined in extensive staged SCLC in KEYNOTE 028. Pembrolizumab showed an objective response rate of 19%, with a median duration of response of 19.4 months and 1-year survival of 37.7% in previously treated PD-L1 positive (1% staining) extensive staged SCLC patients. The vast majority (87.5%) of patients were previously treated with two or more lines of therapy.19 Additional data have supported ICI as second-line therapy in SCC of the lung. In CheckMate 017, 272 patients with advanced SCC of the lung were randomized to be treated with either nivolumab or docetaxel after progression on platinum doublet therapy. The nivolumab cohort demonstrated improved OS of 3.2 months median OS, 9.2 v 6.0 months). PDL1 tumor expression of at least 1% was demonstrated in almost all patients, but this did not appear to influence survival outcomes.19,20 Melanoma Newly diagnosed melanoma cases in the US are estimated at 96,480 for 2019. It is the fifth leading cancer diagnosed among men and the sixth among women. Although melanoma comprises 5.5% of all new cancer cases, it holds the highest mortality rate among all skin cancers at 7,230 (4,740 men, 2,490 women) annually. It is estimated that one person dies every hour from melanoma.21 Incidences

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of melanoma are on the rise, but this rise is largely comprised of earlier stage tumors, diagnosed earlier because of increased awareness and engagement of both patients and providers.22 A primary melanoma tumor can develop in any area of the body where melanocytes (pigment-producing cells) are located. The most heavily melanocyte populated area of the body is the skin. There are four main types of cutaneous melanoma divided by the following histology: superficial spreading, nodular, lentigo maligna, and acral lentiginous.21 23 Superficial spreading melanoma constitutes approximately 70 % of all cutaneous melanomas. These lesions are typically flat, irregularly shaped, variably pigmented brown to black, red, or variation of flesh tones and may evolve over time into raised erosive lesions. Nodular melanoma represents 15% to 30% of tumors. These may be blue to black or amelanotic; they tend to be a more firm, raised tumor with a faster vertical growth pattern above and below the skin surface. Lentigo maligna melanomas account for 4% to 10% of cutaneous melanomas, typically with a larger radius of approximately 3 cm, flat and tan in color. These tumors often start as small freckle-like lesions and expand over time. They are most commonly found in chronic sun-exposed areas.21 23 Acral lentiginous incidence varies in people with lighter and darker pigmented skin. An incidence of 2% to 8% is reported in whites; whereas a 35% to 60% incidence is reported in darker-skinned persons diagnosed with melanoma. The primary locations of diagnosis are in lighter pigmented regions, such as the palms on the hands or soles of the feet (which can appear as a stain of tan, brown, or black in this tissue). A subungal (below the nail beds) presentation appears more commonly as a non-healing trauma or streak, which can eventually become ulcerated and split or erode through the nail.21,22 There are two other variants of melanoma, which are non-cutaneous and comprise 1% of primary melanomas. These variants can arise from mucosal tissue (sinus, nose, rectum, vagina) and the eyes.24 According to 2019 SEER data for localized melanoma, 5-year relative survival rates for melanoma stage 0, I, and II are 98.4%, 63.6% for stage III, and 22.5% for stage IV. With proper surgical interventions, early stage melanomas have better long-term outcomes. However, stage III disease that has spread to the lymph nodes and stage IV (indicating organ involvement) disease have significant reductions in 5-year survival rates. It is this data that compels continued attention to the development of more effective treatment strategies for advanced stages of melanoma.23,25 Melanoma biomarker testing Melanoma tumors are among the most highly immunogenic of cancers. They carry varying degrees of mutational activity based on the primary tissue from which the tumor arose. Somatic mutations in cutaneous melanomas carry an approximate 50% to 60% incidence of BRAF mutation, 15% to 20% incidence of NRAS, 6% of MEK1, and 2% to 3% of CTNNB1; mucosal or sun-damaged areas maybe associated with a higher incidence of a KIT mutation (2.6%) and ocular melanoma GNAQ (1%) or GNA11 (2%) mutations.26,27 Small-molecule tyrosine kinase inhibitors have been created to block V600E, K-mutated melanomas (BRAF inhibitors), and its optimal use is in combination with an MEK inhibitor. Blockade of somatic driver mutations along the mitogen activated protein kinase (MAPK) pathway can inhibit tumor activity, rapidly leading to brisk regression in tumor burden. Unfortunately, the development of resistance can be high; 50% developed resistance after 6 months of BRAF monotherapy. Therefore, adding an MEK inhibitor as an additional concurrent blockade to BRAF has helped to enhance responses and contribute to longer durations of therapy, impacting OS.26,28 The role of PD-L1 testing in melanoma is not a requirement for treatment as with other tumor types such as lung and renal cell cancers, where high PD-L1 expression correlates with response rates.

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Melanoma patients in two phase III trials evaluating PD-1 inhibitors nivolumab and pembrolizumab demonstrated high responses rates in those patients with high PD-L1expression. However, a smaller sub-set of patients who had low to no PD-L1 expression still yield responses. These responses are unclear and this area is still evolving in scientific research and advancement. Because of these results, it is not a requirement that melanoma patients have PD-L1 testing before treatment with a PD-1 inhibitor.5,23,29,30 PD-L1 testing may serve as a guide when a question arises whether to start a patient on PD-1 inhibitory monotherapy versus combination CTLA-4 inhibitor plus PD-1 inhibitor therapy. If a patient has a low or no PD-L1 expression, the decision to start with combination therapy may be preferred over monotherapy as an initial treatment to boost the immune system by priming and amplifying naïve T cells.31 38

Immunotherapy in melanoma There have been unexpected successes with immunotherapies in the treatment of melanoma using and exploiting the immune system’s innate ability to seek out and eradicate cancerous cells and tumors. Immune-modulating therapy is not a new concept in respect to melanoma; therapies such as biotherapy interferon alpha, adoptive T-cell therapy, bio-chemotherapy, viral intra-tumoral vaccine, and interleukin- 2 have all played a role in the treatment of melanoma in recent years. However, ICIs, specifically CTLA-4 and PD-1 inhibitors, have led the most rapid and progressive advancements in melanoma therapeutics to date. As a result of the responses in melanoma, ICI use expanded rapidly across the cancer spectrum demonstrating efficacy in numerous tumor types.5,23,31,33,37 Ipilimumab led groundbreaking research and paved the wave for further development of ICI treatment modalities. In the phase 3 trial comparing ipilimumab alone, gp100 monotherapy, or a combination of ipilimumab and gp100, it was noted that ipilimumab with or without gp100 improved OS in patients with metastatic melanoma. Median OS with ipilimumab alone was 10.1 months (HR for death in comparison with gp100 alone, 0.66; P = .003) Median OS was 10.0 months among patients receiving ipilimumab plus gp100, as compared with 6.4 months among patients receiving gp100 alone (HR for death, 0.68; P < .001).37 As a result, this prompted further research in immune checkpoint inhibition. Three years later, pembrolizumab was approved by the FDA as the first anti-PD-1 checkpoint inhibitor in the treatment of advanced melanoma patients who have progressed on ipilimumab and were BRAF V600E mutant. The KEYNOTE-001 trial demonstrated an objective response rate of 24% (95% CI, 15% 34%) to pembrolizumab 2 mg/kg.35 Based on CheckMate-037 data, nivolumab, another PD-1 inhibitor, was approved under the same pretense a few months later. The overall response of the nivolumab 3 mg/kg cohort was found to be 32% redundant statement in patients with unresectable or metastatic

melanoma who previously received ipilimumab therapy and, if relevant, a BRAF inhibitor (95% CI, 23% 41%).29 As a result of the success of these agents in monotherapy, further research was done on the clinical benefit of anti-CTLA-4 inhibitor agents such as ipilimumab in combination with anti-PD1 agents like nivolumab. The CheckMate-067 randomized control trial revealed patients with metastatic or advanced melanoma exhibited longer OS with combination therapy compared with the monotherapy cohorts. The OS rate was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, compared with 34% in the ipilimumab group.23,29,34 Immune checkpoints: mechanism of action Immune checkpoints serve as “on” and “off” regulators for immune cells, specifically T lymphocytes. Through these switches or checkpoints, T cells are able to detect infection and inflammation, and mark abnormal and cancer cells for elimination. Additionally, these checkpoints interact with other immune cells and serve as a communication method to help manage self-recognition and peripheral tolerance so that immune cells do no attack other immune cells or healthy tissue.2,31,32 The approved ICIs for both melanoma and lung cancer exploit the inhibitory or “break” system for immune checkpoints. These agents influence the immune response to block or remove the natural break mechanism that exist to prevent heightened or autoimmune attack of normal tissue. By binding ipilimumab with CTLA-4, it allows ongoing T-cell replication thereby increasing the number of circulating T cells to enhance the surveillance, recognition, and destruction of cancer cells.2,31,32,37 PD-1 is a negative regulator of T-cell function that typically plays a role later in the immune response, presenting in exhausted T cells to prevent peripheral resistance. PD-1 presentation is also associated with non-naïve T cells, such as memory T cells.2,5,31 33 The PD-1 inhibitor works directly within the microtumor environment, binding and blocking the tumor surface ligands from shutting down T cells, therefore allowing them to sense and mount responses against tumors. The synergy and combination of early phase and late phase inhibition upregulating the immune system at two critical time points enhances tumor surveillance and detection, and enhances tumor destruction.2,5,31–34 Approval and sequencing of ICIs Melanoma and NSCLC are recognized as highly immunogenic cancers that have contributed dramatic impact in response and survival rates because of advances in ICI therapies. ICI use in the treatment of melanoma spans from the adjuvant, to advanced unresectable, to metastatic settings. Updates to the adjuvant setting therapies suggest that interferon alpha 2b is no longer recommended and biochemotherapy has been removed from adjuvant treatment recommendations because

Table 1 PD-L1 testing requirements for checkpoint inhibitors used to treat advanced NSCLC. Checkpoint Inhibitor

Line of Therapy

Monotherapy/Combination Therapy

Testing Guidelines

Pembrolizumab

First line Second line First line Second line First line Second line Consolidation

Monotherapy Monotherapy Combination therapy Monotherapy Combination therapy Monotherapy Monotherapy following concurrent chemo-RT regimen

PD-L1 >50% TPS PD-L1 >1% TPS None required None required None required None required None required

Nivolumab Atezolizumab Durvalumab

NOTE: Small cell lung cancer currently does not require PD-L1 testing. Abbreviations: PD-L1, programmed cell death ligand 1; TPS, tumor proportion score; RT, radiation therapy. Data from Davies.38

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Table 2 Summary of immunotherapy trials for melanoma, non small cell lung carcinoma, and small cell lung carcinoma. Tumor type, ICI, and Line

Study

Regimen

Survival Outcome

Melanoma Ipilimumab (CTLA4 inhibitor) First line Second line Pembrolizumab (PD-1 inhibitor) First line

Robert et al, 201139 Hodi et al, 201040

Ipilimumab (3 mg/kg) + dacarbazine v dacarbazine Ipilimumab v gp100 antigen vaccine

mOS: 11.2 v 9.1 mo mOS: 10 v 6.4 mo

Robert et al, 201541 (Keynote-006 trial) Ribas et al, 201542 (Keynote-002 trial)

Pembrolizumab (10 mg/kg every 2 or 3 weeks) v ipilimumab Pembrolizumab (10 mg/kg or 2 mg/kg) v chemotherapy

mOS: 74% v 58%

Robert et al, 201543 (CheckMate-066 trial)

Nivolumab (3 mg/kg) v dacarbazine

Larkin et al, 201544 Hodi et al, 201833 (CheckMate-067 trial)

3-Arm randomization: A: Nivolumab (1 mg/kg) + ipilimumab (3 mg/kg) every 3 weeks B: Nivolumab (3 mg/kg) C: Ipilimumab (3 mg/kg)

OS: 1 yr: 72.9% v 42.1% 2 yr: 5.5% v 26.7% mPFS: 11.5 v 6.9 v 2.9 mo 2018 update: NR v NR v 20 mo

Brahmer et al, 20153 (CheckMate-017 trial)

Nivolumab (3 mg/kg) v docetaxel

mOS: 9.2 v 6 mo

Atezolizumab + carboplatin+ etoposide v Placebo

mOS: 12.3 v 10.3 mo

Nivolumab (3 mg/kg) v Docetaxel

mOS: 12.2. v 9.4 mo

Pembrolizumab (200 mg) v platinum-based chemotherapy

mOS 2019: 30 v 14.2 mo

Pembrolizumab A) 2 mg/kg or B) 10 mg/kg C) Docetaxel Pembrolizumab + pemetrexed + carboplatin v chemotherapy Pembrolizumab (or placebo) + carboplatin and either paclitaxel or nab-paclitaxel

mOS: A) 10.4 mo B) 12.7 mo C) 8.5 mo Objective response: 56% v 30%

Second line Nivolumab (PD-1 inhibitor) First line

First line: combination

Small Cell Lung Cancer Nivolumab (PD-1 inhibitor) Second line

Atezolizumab (PD-L1 inhibitor) First line: for advanced disease Horn et al, 201845 (IMpower133 clinical trial; PD-L1 staining not required) Non small Cell Lung Cancer Nivolumab (PD-1 inhibitor) Second line Borghaei et al, 201511 (CheckMate -057 clinical trial) Pembrolizumab First line Reck et al, 201646 Reck et al, 201947 (Keynote-024 clinical trial) PD-L150% TPS Second line Herbst et al, 201648 (Keynote-010 clinical trial) Excluded PD-L1 <1% First line: combination First line: combination

Atezolizumab (PD-L1 inhibitor) Second line First line: combination

Borghaei et al, 201949 (Keynote-021 clinical trial) Paz-Ares et al, 201850 (Keynote-407)

Rittmeyer et al, 201751 Atezolizumab 1,200 mg v docetaxel every 3 weeks (OAK clinical trial) 52 Reck et al, 2019 (IMpower150) Negative: EGFR or ALK tumor aberrations A) Atezolizumab + carboplatin + paclitaxel B) Atezolizumab + bevacizumab, paclitaxel, and carboplatin C) Bevacizumab + paclitaxel + carboplatin (control arm)

mOS: 14 v 13.4 v 11 mo

ORR: Pembrolizumab arm: 58% mOS: 15.9 mo Placebo arm: 36% mOS: 13.6 mo mOS: 13.8 v 9.6 mo mOS: A) B) C)

NE (not estimable) according to the data 19.2 mo 14.7 mo

Abbreviations: mOS, median overall survival, mo, month; OS, overall survival; mPFS, median progression-free survival, NR, not reached; TPS: tumor proportion score, RT= radiation therapy; NE, not estimable. Data from Nixon et al30 and Davies.38

of the lower toxicity profile and higher efficacy of ICIs.23 FDA approvals for ICI use in the treatment of lung cancer has evolved and expanded over the past 6 years, offering more options from monotherapy to complex combination therapies with chemotherapy (Table 1).5,35,36,38 Clinical trials have also demonstrated the efficacy and utility of montherapy and combination therapy approaches in the treatment of melanoma. (Table 2).3,14,30,34,39 52 irAEs Accurate assessment and grading of irAEs is imperative to guide management. There are nuances to managing each toxicity; however,

by using established common terminology criteria for adverse events (CTCAE), not every toxicity is managed the same but general management strategies translate across tumor types.2,5,23,34,37,53 56 The America Society of Clinical Oncology and National Comprehensive Cancer Network guidelines on the management of ICI-related irAEs offer practical and clinical guidance in managing ICI-related toxicities.53,54,56 The highest incidence of irAEs tend to be grades 1 and 2 at onset. However, combination therapies can enhance the potential for more rapid onset and intensity of toxicities, but the combination can be impactful, yielding higher response rates. In the CheckMate -067 trial, which evaluated combination therapy of nivolumab plus ipilimumab

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versus nivolumab or ipilimumab alone, combination therapy demonstrated durable response rates of 65%. The onset of symptoms is typically 6 to 12 weeks after the initiation of immune checkpoint blockade. Additionally, one or more organs may be impacted by an inflammatory pattern related to stimulation of the immune system. 5,37,38,53 56

Implications for Nursing Practice Patient safety is paramount, and nurses are aligned to educate, assess, and guide patients during ICI therapy. Developing a rapport and relationship that is based on trust and open communication are vital in helping patients adhere to therapy, navigate symptom reporting at the onset of symptoms and safely managing irAE’s. 5,36,37,55,56

Brain metastases Conclusion Melanoma and NSCLC are the two malignancies that, in advanced disease, have a 50% and 40% to 50%, respectively, incidence of developing metastases to the brain. Brain metastases can pose a significant challenge to functionality and quality of life. In a recent phase II study, CheckMate 204 has demonstrated the effective use of combination nivolumab plus ipilimumab and limited stereotactic radiation therapy (SRS) had better response rates of 56% intracranial responses in the management of melanoma of intracranial metastases. Prior therapies did not yield response rates as high as combination therapy, and with modalities that involved multi-site SRS or whole-brain radiation, patients developed higher incidences of radionecrosis.57 59 For both tumor types, targeted therapy (especially BRAF) mutated lesions may respond well with the combination of targeted oral therapy and SRS.60 Gamma knife SRS is often a first choice of radiation approaches to metastatic melanoma or lung cancer tumors because it maximizes multifocal targeting of tumor and healthy tissue preservation. This is an area of ongoing discussion and development of better treatment modalities for both disease and long term side effects of SRS. Response criteria to checkpoint inhibition An evaluation of effectiveness relies on the understanding of potential patterns of response that, for ICIs, can be very different from targeted and chemotherapy response patterns. Patients may have a transient inflammatory response where there may be new lesions that evolve and existing disease worsens clinically and/or radiologically before tumor regression. This is a commonly observed pattern with ICI therapy so patients should be cautioned to not stop or change treatment at this juncture. In other words, if disease appears worse and the patient is not having significant toxicity issues but also feels very ill, consideration for symptomatic progression should be taken seriously and evaluated with a short-term follow-up. However, a patient who has radiologically appearing advancing disease but who feels well or better than before the start of therapy, this patient should be continued on therapy or expectantly observed. Late responses were observed during early clinical trials in melanoma where patients experienced regression of disease after a “pseudo-progression” period and continued to have sustained tumor suppression even off therapy. It is this phenomenon that posits a different evaluation criteria specific for immune-related activity. Dr Wolchok developed an evaluation criteria specific to immune responses. While not widely used at this time, these criteria can be helpful to delineate progression from pseudo-progression and to help in decision-making to ensure not abandoning treatment with an ICI therapy too early. Long-term responses can be observed in many cases, even if an initial response is delayed.55,61 Duration of therapy There is no terminating point for immunotherapy. While induction with combination ipilimumab and nivolumab are administered for 4 infusions, it is typically followed by maintenance nivolumab and there is no appropriate duration of treatment. Treatment duration is typically based on toxicity and response.62 There is some discussion that if a tumor has stabilized and remains unchanged, it may have reached maximal immune response. This is a topic of ongoing discussion.

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