Peerview.Com/FDM900 Rethinking Patient Care in Endometrial And

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CNE Rethinking Patient Care in Endometrial and Cervical Cancer: How Nurses Can Lead the Targeted and Immunotherapeutic Revolution

Chair Kimberly Halla, MSN, FNP-C Arizona Oncology Associates PC Scottsdale, Arizona

What’s Inside 3 Recent Updates in Endometrial Cancer

8 Recent Updates in Cervical Cancer

12 The Nurse’s Role in Gynecological Cancer Care

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Media: Enduring Material Disclosure of Unlabeled Use Accredited Activity Release Date: August 5, 2020 This educational activity may contain discussions of published and/or Accredited Activity Expiration Date: August 4, 2021 investigational uses of agents that are not indicated by the FDA. The planners Time to Complete Activity: 60 minutes of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of Activity Description the faculty and do not necessarily represent the views of the planners. Please In this CNE activity, a family nurse practitioner brings the nurse’s perspective refer to the official prescribing information for each product for discussion of to patient care in endometrial and cervical cancer. Kimberly Halla, MSN, FNP-C, approved indications, contraindications, and warnings. discusses modern management techniques for patient’s receiving targeted therapy and immunotherapy, as well as combination therapies, and gives her Disclaimer take on how to approach the unique safety profiles associated with these Participants have an implied responsibility to use the newly acquired treatment options. information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve Target Audience as a guideline for patient management. Any procedures, medications, or other This activity has been designed to meet the educational needs of oncology courses of diagnosis or treatment discussed or suggested in this activity should nurses and other clinicians involved in the management of patients with not be used by clinicians without evaluation of their patient's conditions and cervical and endometrial cancers. possible contraindications and/or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations Educational Objectives of other authorities. Upon completion of this activity, participants will be able to: • Summarize the current treatment and regulatory landscape in the Method of Participation management of gynecologic cancers, including the role of novel targeted, There are no fees for participating in or receiving credit for this accredited immunotherapeutic, and combination approaches in cervical and activity. For information on applicability and acceptance of continuing endometrial cancers education credit for this activity, please consult your professional licensing • Describe safety and efficacy evidence surrounding targeted, immune board. checkpoint inhibitor, and combination strategies for the management of gynecologic cancers A statement of credit will be issued only upon receipt of a completed activity • Educate patients about therapeutic and safety considerations associated evaluation form and will be emailed to you upon completion. You will receive with recently approved and emerging options for endometrial and cervical your certificate from [email protected]. If you have questions cancers regarding the receipt of your emailed certificate, please contact via email at • Manage the unique spectrum of adverse events associated with targeted [email protected]. and immunotherapy used to treat endometrial and cervical cancers In order to receive credit, participants must view the activity and complete the Providership, Credit, and Support post-test and evaluation form. A score of 70% or higher is needed to obtain This CNE activity is jointly provided by Medical Learning Institute, Inc. and PVI, CNE credit. There are no prerequisites and there is no fee to participate in PeerView Institute for Medical Education. this activity or to receive CNE credit. Statements of Credit are awarded upon successful completion of the post-test and evaluation form. This activity is supported by educational grants from GlaxoSmithKline, Merck & Co., Inc., and Seattle Genetics. About This CNE Activity PVI, PeerView Institute for Medical Education, and Medical Learning Institute, Continuing Nursing Education Inc. are responsible for the selection of this activity’s topics, the preparation Medical Learning Institute, Inc. is accredited as a provider of continuing of editorial content, and the distribution of this activity. Our activities may nursing education by the American Nurses Credentialing Center's contain references to unapproved products or uses of these products in Commission on Accreditation. certain jurisdictions. The preparation of PeerView activities is supported by Successful completion of this continuing nursing education activity will be educational grants subject to written agreements that clearly stipulate and awarded 1.0 contact hour. enforce the editorial independence of PVI and Medical Learning Institute, Inc.

Faculty Disclosures The materials presented here are used with the permission of the authors Chair and/or other sources. These materials do not necessarily reflect the views of Kimberly Halla, MSN, FNP-C PeerView or any of its partners, providers, and/or supporters. Family Nurse Practitioner Arizona Oncology Associates PC Scottsdale, Arizona

Kimberly Halla, MSN, FNP-C, has a financial interest/relationship or affiliation in the form of: Speakers Bureau participant with GlaxoSmithKline and Merck & Co., Inc.

Planning Committee Disclosures Tracy L. Greene, MSN, RN, FNP-C, Lead Nurse Planner, MLI, has nothing to disclose.

The planners from Medical Learning Institute, Inc., the accredited provider, and PeerView Institute for Medical Education, the joint provider, do not have any financial relationships with an ACCME-defined commercial interest related to the content of this accredited activity during the past 12 months unless listed below.

Content/Peer Reviewer Disclosures The following Content/Peer Reviewer has nothing to disclose:

Pamela Ash, RN, MSN, CBCN

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Recent Updates in Uterine Cancer: Age-Adjusted New Cases and Deaths— SEER, 1975-2017 (All Races)1 Endometrial Cancer 40

25 Kimberly Halla: Hello, my name is Kimberly Halla, and I’m a nurse 20 practitioner currently working at Arizona Oncology Associates 15 10

here in Scottsdale, Arizona, specializing in gynecologic oncology. Rate Per 100,000 Persons 0 Welcome to this educational activity titled, “Rethinking Patient 1975 1980 1985 1990 1995 2000 2005 2010 2017 Care in Endometrial and Cervical Cancer: How Nurses Can Lead Year the Targeted and Immunotherapeutic Revolution.” This program is Rate of New Cases Death Rate designed to improve the management of patients with advanced 1. https://seer.cancer.gov/statfacts/html/corp.html. endometrial or cervical cancers. As we move on to the next slide looking at the age-adjusted cases and deaths, in 1975, we saw a decent drop in endometrial cancer Endometrial Cancer Snapshot: SEER Data1 diagnoses, along with stabilization of the death rate. How Common Is This Cancer? Percent of New Cases by Age Group: Uterine Cancer 3.6% Median Age at

40 35 33.9% Diagnosis Uterine cancer represents 3.6% of all 30 28.8% new cancer cases in the U.S. 1 25 Endometrial Cancer Stage and Survival 20 15.2% 15 11.8% 10 63 4.9% 3.9% 5 1.5% NEW SLIDE FROM 6076 Percent of New Cases Please Trendschange in ‘Percent Age-Adjusted Uterine Cancer Incidence Rates, Trends in Age-Adjusted Uterine Cancer Death Rates, 0 <20 20-34 35-44 45-54 55-64 65-74 75-84 >84 Surviving 5by Years’ Racial/Ethnic to ‘5- Group—United States, 1999-2015 by Racial/Ethnic Group—United States, 1999-2016 Percent of Cases by Stage Age Year Relative Survival’ Overall (AAPC = 1.1) 30 10 Black (AAPC = 1.5) 3% 9% 5-Year Relative Survival 5-Year Relative White (AAPC = 1.0) Hispanic (AAPC = 1.7) Localized (67%) 9

AI/AN (AAPC = 1.4 [NS]) API (AAPC = 2.5) Confined to primary site 100 95% Survival 25

90 Regional (21%) 80 7 69% 20 Spread to regional lymph nodes 70 21% 6 Distant (9%) 60 52.9% Cancer has metastasized 50 15 5 81.2% Unknown (3%) 40 4 Unstaged 30 10 Women 100,000 67% Percent Surviving 3 20 16.8% Black (AAPC = 2.4) Overall (AAPC = 0.7) per per Women 100,000 per 2 10 Rate of Uterine Cancer 5 White (AAPC = 0.5) Hispanic (AAPC = 1.8) 0 AI/AN (AAPC = 2.7) API (AAPC = 2.0) 1 Localized Regional Distant Unknown Rate of Uterine CancerDeaths 0 0 Stage 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 1. https://seer.cancer.gov/statfacts/html/corp.html. Time of Diagnosis, y Time of Death, y

Incidence increased 12% Death rates increased 21% First, let’s take a look at endometrial cancer as a whole. According to the SEER data, endometrial cancer makes up about 3.6% of 1. Henley SJ et al. MMWR Morb Mortal Wkly Rep. 2018;67:1333-1338. newly diagnosed cancers in the United States, with the average age of approximately 63 years old. And if we look at the 5-year However, looking forward into the future now, looking at ages survival rate, as well as the cases identified by staging, they are and ethnic groups, the incident rate of endometrial cancer is rising closely entwined, meaning that those patients who are diagnosed approximately 12%, with associated death rates increasing by 21%. with a localized endometrial cancer, 5-year survival rate is approximately 95%. And if we look at this closely, we think to ourselves, why is this occurring? Where cancer rates are typically dropping, why is And that 5-year survival rate continues to drop as cancer spreads. endometrial cancer on the rise? It is strongly related to that So those patients diagnosed with a regional and distant disease unopposed estrogen that we have in menopause. As women are have less likelihood of a cure and more likelihood of death. heavier and have higher rates of obesity, we have unopposed estrogen, which can increase the risk of endometrial cancers.

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NCCN Guidelines: As we shift our paradigms and we look closely at the molecular Recurrent, Metastatic or High-Risk Disease1 I updatedclassification graphs and for our female patients, looking at GOG 129, looking NCCN Guidelines Version 1.2020 Endometrial Carcinoma refs from similar slide in NCCN Evidence BlocksTM 6076 –at standard of care chemotherapy, the overall response rate is less Systemic Therapy for Recurrent, Metastatic, or High-Risk Disease

Chemotherapy Regimens Adjuvant Treatment When Used for Uterine- than 15% for those patients with metastatic disease. Preferred Regimens Confined-Disease Preferred Regimens • Carboplatin/paclitaxel (category 1 for carcinosarcoma) • Carboplatin/paclitaxel • Carboplatin paclitaxel/trastuzumab (for stage III/IV or recurrent HER2+ uterine serous carcinoma) GOG 209 established Other Recommended Regimens Hormone Therapy Preferred Regimens 2 paclitaxel carboplatin as SOC • Carboplatin/docetaxel • Bevacizumab • Medroxyprogesterone acetate/tamoxifen And as we look into the GOG 229, there is also a low response with • Cisplatin/doxorubicin • Temsirolimus (alternating) OS vs Trastuzumab, All Evaluable Subjects • Cisplatin/doxorubicin/paclitaxel • Docetaxel • Megestrol acetate/tamoxifen (alternating) With Number of Subjects at Risk 1 • Cisplatin/paclitaxel/bevacizumab (category 2B) • Progestational agents targeted agents. However, as we look into improved checkpoint 0.8 HR: 0.581; • Cisplatin • Lenvatinib/pembrolizumab – Medroxyprogesterone acetate 90% CI: 0.339-0.994; • Carboplatin • Ifosfamide – Megestrol acetate 0.6 P = .0462 • Doxorubicin (for carcinosarcoma) – Levonorgestrel IUD (for select fertility- inhibitors, looking at combination therapies, such as KEYNOTE-028 0.4 • Liposomal doxorubicin • Ifosfamide/paclitaxel sparing cases) Proportion AliveProportion

0.2 • Paclitaxel (for carcinosarcoma) • Aromatase inhibitors • Albumin-bound paclitaxel • Cisplatin/ifosfamide • Tamoxifen 0 and KEYNOTE-158, for those patients with PD-L1 positivity in their 0 12 24 36 48 60 72 84 • Topotecan (for carcinosarcoma) • Fulvestrant Time From On-Treatment Date, mo No 28 23 15 6 5 5 4 1 Useful in Certain Circumstances Other Recommended Regimens Yes 30 28 21 10 7 4 0 Trastuzumab No Yes • Pembrolizumab (for MSI-H/dMMR tumors) • Everolimus letrozole (for endometrioid • Larotrectinib or entrectinib for NTRK gene histology) tumors, there’s shown to be a 13% overall response rate, and again, Addition of trastuzumab based fusion-positive tumors (category 2B) 3 on OS data for UPSC improved overall response rate in KEYNOTE-158 in patients who 1. https://www.nccn.org/professionals/physician_gls/pdf/uterine_blocks.pdf. 2. Miller DS et al. Society of Gynecologic Oncology 2012 Annual Meeting (SGO 2012). Abstract LBA1. 3. Fader AN et al. SGO 2020. Abstract 12. have MSI-high tumors.

The NCCN guidelines have shown us that standard of care with A Quick Guide to How Immunotherapy Works… GOG 209, those patients with metastatic and high-risk disease respond somewhat well to carboplatin and paclitaxel. Those patients who are HER2-positive can add trastuzumab, and those patients show benefit as well. Normally, cancer cells can avoid detection by the Treatment Options body’s immune system (T cells)

T Cell Cancer Cell

Immune checkpoint inhibitors

Combinations So let’s dive in to see exactly how immune therapy works in the (chemotherapy, VEGF inhibition) advanced cancer setting. Now as you look at this slide, you can see a description of what a cancer cell looks like and what we call a T cell. A T cell is part of the body’s immune system that kind of regulates the cells in the body. So if a virus comes in or bacteria comes in, the T cell can quickly identify that those cells as foreign But what happens with those patients who have metastatic and not “self.” disease and who do not respond well to standard chemotherapy? What can we do next? And as we look at the future, immune T cells are programmed to look at those cells and kill cells that are checkpoint inhibitors and combination therapies, such as abnormal to us. And then the immune system can recognize those chemotherapy, immune therapy, and VEGF inhibition, are next on abnormal cells in future situations. When the body is presented the horizon. with these abnormal cells, the immune system recognizes them, and quickly takes care of them keeping our body from becoming Shifting the Paradigm: Changing the Focus to ill. Molecular Classification • Low responses with chemotherapy (GOG 129 series) Now cancer cells are a little trickier. Cancer cells are able to get by – ORR <15% with most chemotherapy agents1 these T cells. They’re able to get by the immune system, kind of like • Low responses with targeted agents (GOG 229 series) in a cloaking pattern. So cancer cells are kind of hidden and the T – Only bevacizumab, aflibercept, brivanib, and cediranib cells look at them and say, “Well, they’re not quite right. However, 2 met the bar for further study they don’t look like they’re a threat to me.” So they allow the • Improved responses with checkpoint inhibitors (anti–PD-1) cancer cells to continue to multiply unchecked and unbalanced, – KEYNOTE-028: ORR 13%; 24 PD-L1–positive tumors3 causing cancer to spread. – KEYNOTE-158: ORR 57%; 49 MSI-H tumors4

1. Lincoln S et al. Gynecol Oncol. 2003;88:277-281. 2. Arend RC et al. Gynecol Oncol. 2018;150:569-580. 3. Ott PA et al. J Clin Oncol. 2017;35:2535-2541. 4. Marabelle A et al. J Clin Oncol. 2019;38:1-10.

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…As an Anti-Cancer Strategy PD-1 and PD-L1 Inhibition

Tumor cell T cell TCR + A new class of drugs, Activated immune checkpoint inhibitors, “takes the brakes off” the body’s immune system, and allows T cells to attack + and destroy cancer cells Activated Immunotherapy enhances the ability of T cells to attack cancer cells PD-L1 PD-1

Now, a new class of medication, immune and checkpoint If we activate that system, utilizing anti–PD-1 medication, we can inhibitors, really takes the cloak off of that cancer cell. It ramps up then activate the T cells to recognize those cancer cells as foreign, or takes the brakes off the immune system, and allows those T cells causing apoptosis and cell death. to recognize the cancer cells as foreign and attack those cancer cells. So in other words, we’re using our own immune system to Anti–PD-1 Agents in the Second-Line Setting attack cancer cells. • Single agent As we continue to use our immune system and we look at the – Pembrolizumab1 pathway between PD-1 and PD-L1 inhibition, if we activate those  Keynote-028 trial was performed in multiple tumor types 2 T cells, decloaking or taking the brakes off of our immune system – Dostarlimab  GARNET trial and ramping up our immune system, the line between the PD-L1 • Dual agent and PD-1 can be activated, allowing for our T cells to destroy the – Pembrolizumab + lenvatinib3 tumor cells.  FDA-approved combination

PD-1 and PD-L1 Inhibition 1. Ott PA et al. J Clin Oncol. 2017;35:2535-2541. 2. Oaknin A et al. 2019 Society of Gynecologic Oncology Annual Meeting (SGO 2019). Abstract 33. 3. Makker V et al. Lancet Oncol. 2019;20:711-718.

Tumor cell T cell TCR As we look at the current situation, in second-line, advanced + Activated cancers, we look at single-agent pembrolizumab. Noted in the KEYNOTE-028 clinical trial, pembrolizumab was used in all sorts of multiple tumor types, as well as, dostarlimab in the GARNET trial.

+ Inactivated Now looking at dual agents such as pembrolizumab and - lenvatinib, there has been an FDA approval for both of those PD-L1 PD-1 medications in combination for advanced endometrial cancer.

See updates in red – I deleted some info – please re-size as KEYNOTE-028: Endometrial Cancer Highlights1 needed with extra space We can take advantage of this by looking at PD-1 and the PD- 100 • Study design L1 inhibition. Currently, T cells, as we described, are not able to 80

– N = 24 locally advanced/metastatic recognize all tumor cells as cancer. EC (all subtypes) that progressed % 60 Take Home after standard treatment PFS, 40 • Treatment: Pembrolizumab 10 mg/kg 20 every 2 weeks for up to 24 months or until progression/unacceptable toxicity 0 0 4 8 12 16 20 • Primary endpoint: ORR by RECIST No. at Risk Time, mo Pembrolizumab is • Secondary endpoints: safety/ 23 5 4 3 3 0 100 effective in patients tolerability; DOR, PFS, OS • Results: 80 with advanced EC

– Primary endpoint (ORR):13.0% % 60

– Secondary endpoints (PFS and OS) OS, 40 FDA approved 20 FDA indication 0 0 4 8 12 16 20 24

No. at Risk Time, mo 23 15 13 9 5 2 0 1. Ott PA et al. J Clin Oncol. 2017;35:2535-2541.

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Specifically looking at KEYNOTE-028 endometrial cancer highlights Rationale for Combinations1,2 and looking at pembrolizumab, there was FDA approval for those Promoting the presentation of tumor antigens patients showing great response to single-agent pembrolizumab Advantages of combination immunotherapy in endometrial cancer. Increasing the infiltration of T cells and the activity of CTLs Enhancing the immunogenicity of tumor cells Limitations of PD-1/L1 blockade Eliminating or reducing the efficacy of immunosuppressive molecules Phase 1/2 GARNET Trial: Dostarlimab in Recurrent or Advanced MSI-H/MSS EC1 NEW SLIDE Relapse and recurrence of tumor Part 1 Part 2A Part 2B Lack of accurate prediction indicators Dose finding Fixed-dose safety run-in Expansion cohorts

irAEs Combination approaches A1a: MSI-H/MSS Combination with chemotherapy Different response rates in patients with homologous tumors Combination with radiotherapy Combination with targeted therapy MSI Status Combination with other immunotherapy MSI-H MSS Total Hyperprogression following checkpoint blockade treatment Best Overall Response unknown (n = 41) (n = 79) (N = 125) (n = 5) 1. Wang D et al. J Hematol Oncol. 2019;12:42. 2. Makker V et al. American Society of Clinical Oncology 2019 Annual Meeting (ASCO 2019). Abstract TPS5607. Overall response rate, n (%) 20 (48.8) 16 (20.3) 1 (20.0) 37 (29.6) [95% CI] [32.9-64.9] [12.0-30.8] [0.5-71.6] [21.8-38.4] Complete response, n (%) 2 (4.9) 4 (5.1) 0 (0) 6 (4.8) Partial response, n (%) 18 (43.9) 12 (15.2) 1 (20.0) 31 (24.8) Looking at the rationale for combination therapy, there are several Disease control rate, % [95% CI] 63.4 [46.9-77.9] 46.8 [35.5-58.4] 60.0 [14.7-94.7] 52.8 [43.7-61.8] Response ongoing, % 85.0 81.3 100 83.8 advantages for the combination of immune therapy, such as

The treatment was tolerable and the infusion schedule was favorable promoting the presentation of tumor antigens and increasing the a By NGS/PCR. 1. Oaknin A et al. SGO 2019. Abstract 33. infiltration of T cells. Combination approaches with chemotherapy, radiation, targeted cell therapy, and other immune therapies have As we look at the GARNET trial and looking at dostarlimab, they advantages as well. break down individually the MSI-high, MSI-stable, MSI-unknown status. The overall response rate was 48.8% in patients in the MSI- KEYNOTE-146: Phase 2 Trial of Lenvatinib Plus high settings, and those patients who were MSI-stable had an ORR Pembrolizumab in Patients With EC1-3 of 20%. These are patients who had very few options when it came Eligibility Criteria to the recurrent setting, and using medications like dostarlimab, • Age ≥18 years • Metastatic EC (unselected for which was very tolerable, improved patient life. MSI or PD-L1) Until disease progression, • ECOG PS 0-1 Lenvatinib 20 mg/day orally development of • ≤2 previous systemic + pembrolizumab 200 mg IV unacceptable toxic therapies every 3 weeks effects, or withdrawal Let’s update the text in the blue circle 1 • Measurable disease of consent GARNET: Updated Efficacy Results to includeaccording the prior slideto irRECIST data also: • Life expectancy of ≥12 weeks Dostarlimab is effective in recurrent or advanced MSI-H, MSIN =- S,357 and dMMR • Patients with progression after prior platinum doublet regimen EC progression after platinum doublet • Interim analysis, N = 70 regimen Take Home a • ORR at 11.2 months: n = 30 (42%; 95% CI, 31-55) • Primary endpoint: ORR at week 24 NOTE dMRR is incorrect in blue circle 130 Best overall response • Secondary endpoints: Overall ORR, DOR, PFS, OS, DCR, CBR, DSDR, no. of patients with

currently – needs to be dMMR 110 by RECIST v1.1 Dostarlimab is TEAEs and treatment-emergent SAEs, AUC of lenvatinib, and apparent clearance of lenvatinib CR

90 effective in recurrent PR Please1. https://www.clinicaltrials.gov/ct2/show/NCT02501096. increase font size on key/plot 2. Makker V et al. Lancet Oncol. 2019;20:711-718. % 70 SD 3. Makker V et al. J Clin Oncol. 2020 Mar 13 [Epub ahead of print]. PD or advanced MSI-H, as able 50 NE

Size, MSS, and dMMR Ongoing 30 EC progression after ORR 43% needs to be 42% 10 Lesion -10 platinum doublet regimen -30 Looking at KEYNOTE-146, this is a phase 2 trial of lenvatinib plus

Target -50 -70 Best Change in From Baseline -90 Investigational pembrolizumab. This allowed for both oral lenvatinib and IV -110 Patients pembrolizumab to be used in patients who were not MSI-high or The ongoing phase 3 RUBY trial is directly comparing carboplatin + paclitaxel with placebo or dostarlimab in patients with recurrent or primary advanced EC (NCT03981796)2 patients who did not have a PD-1 expression. This infusion went on 1. Oaknin A et al. SGO 2020. Abstract 9. 2. https://clinicaltrials.gov/ct2/show/NCT02715284. until progression or the development of unexpected toxicities.

See red text updates Looking at GARNET, there are updated efficacy results, but it is 1 KEYNOTE-146: Final Efficacy Results Please move ‘a’ footnote to the y axis currently investigational. The overall response rate is 11.2 months. label on the plot.

• Patients with progression after previous systemic treatment (N = 108)

• ORR at week 24 = 41 (38.0%; 95% CI 28.8-47.8)a Again, these patients had very limited chemotherapy options in Take Home Also need another footnote: Histology Subtypes ‘Investigator Assessment; irRECIST’ for 100 Endometrioid adenocarcinoma Clear cell adenocarcinoma

the recurrent setting. b Serous adenocarcinoma Other the ORR bullet

80 Maximum tumor shrinkage PD-1/PD-L1 Status: + Positive o Not Available 60 >0% = 72/84 (85.7%) ≥50% = 26/84 (31.0%) Re-alphabatize footnotes as needed 40 + ≥75% = 13/84 (15.5%) + Pembrolizumab + 20 + + ++ + Also ongoing is the phase 3 RUBY trial comparing carboplatin/ 0 + + + + + + + + ++ + + o o ++ + + + + + + + ++ o o o ++ + ++ ++ + ++ o + lenvatinib is effective -20 in patients with 30% paclitaxel with placebo or dostarlimab. -40 advanced EC 50% Lesions from % from Lesions Baseline, -60

Change in Sum of Diameters of -80 75% Target LesionsFrom Baseline, % Change in Sum of Diameters of Target -100 FDA approved • In September 2019, the FDA approved lenvatinib + pembrolizumab for the treatment of patients with advanced EC that is not MSI-H or dMMR who have disease progression FDA indication following prior systemic therapy2 • A randomized phase 3 trial of lenvatinib + pembrolizumab (study 309/KEYNOTE-775 [NCT03517449]) for patients who have received ≤1 prior therapies is currently enrolling3

a Investigator Assessment; irRECIST. b Per independent imaging review; RECIST v1.1. 1. Makker V et al SGO 2020. Abstract 10. 2. https://www.accessdata.fda.gov/scripts/cder/daf. 3. https://clinicaltrials.gov/ct2/show/NCT03517449.

In September of 2019, the FDA approved the indication allowing for pembrolizumab and lenvatinib, because it showed effectiveness, in treatment of advanced endometrial cancer.

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These patients had very limited choices until medications such as pembrolizumab and lenvatinib were shown to be effective, and chemotherapy was limited in its effectiveness.

Summary of New Developments for Endometrial Cancer Care • Traditionally, these patients have limited treatment options, representing a high unmet need • Checkpoint inhibitor monotherapy is promising – Pembrolizumab is approved for second-line therapy in MSI-H/dMMR tumors – Dostarlimab treatment resulted in a robust ORR in patients with recurrent or advanced EC (MSI-H, MSS, dMMR) that had progressed on prior therapy, with durable responses • Pembrolizumab + lenvatinib combination has accelerated FDA approval for second-line therapy in MSS tumors

As we summarize endometrial cancer, again, these patients have limited treatment options and there is representation of a high unmet need. Understanding these tumors will allow us better potential therapeutic responses. Medications such as checkpoint inhibitors in monotherapy are extremely promising. Pembrolizumab alone is shown to work in those patients who have an MSI-high tumor.

Dostarlimab resulted in a robust overall response rate for patients as well. Pembrolizumab with the combination of lenvatinib received an FDA accelerated approval in those patients in second- line therapy and MSI-stable tumors. And there are lots of other chemotherapy studies ongoing.

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Chemoradiation induces tumor cell death, activates IC, and promotes tumor cell phagocytosis HPV triggers ↑ PD-L1 1 PD-L1 Tumor cell antigen Phase 1 NCT01711515 : SOC CRT followed by 1,2 SOC ↑ IFN Cervical Cancer Snapshot: SEER Data ↑ HMGB1 ipilimumab Fallopian ↑ ATP tube Uterus ↑ CRT SOC IC Percent of New Cases by Age Group: Cervical Cancer How Common Is This Cancer? Ovary MHC I or II Tolerable safety Cervical cancer is most frequently Endometrium 12-month OS: 90% diagnosed among women Cervical tumor Tumor cells Vagina PFS: 81% 40 aged 35-44 35 Cervical cancer represents 0.8% of Chemoradiation all new cancer cases in the U.S. 30 Median Age 25 22.8% 22.5% 20 19.7% at Diagnosis 15 13.8% Ongoing 12.0% + 10 PD-1 CD8 PD-1 6.4% T cell 5 2.7% Durvalumab T-cell 2

Percent of New Cases 0.1% 50 + Phase 3 CALLA : 0.8% 0 receptor CD8 IC <20 20-34 35-44 45-54 55-64 65-74 75-84 >84 PD-L1 T-cell receptor T cell Age SOC CCRT vs Percent of Cases by Stage MHC I or II 5-Year Relative Survival Tumor cell antigen durvalumab + SOC CCRT 4% Localized (44%) 100 followed by durvalumab Confined to primary site 91.8% 16% 90 5-Year Relative Tumor cell death monotherapy Regional (36%) 80 Survival + Spread to regional lymph nodes 70 PD-L1 blockade disinhibits IC activates CD8 T cell 44% 60 57.6% chemoradiation immunogenicity Distant (16%) 49.7% 50 1. Mayadev JS et al. JAMA Oncol. 2020;6:92-99. 2. Mayadev J et al. Int J Gynecol Cancer. 2020 May 23 [Epub ahead of print]. Cancer has metastasized 40 30 66.1% Unknown (4%) Unstaged 20 16.8% Percent surviving 10 2010-2016 36% 0 Localized Regional Distant Unknown Stage 1. https://seer.cancer.gov/statfacts/html/cervix.html. 2. https://gis.cdc.gov/Cancer/USCS/DataViz.html. As we continue to look at standard of care chemotherapy for those patients with cervical cancer, we also look at if immune As we now look into cervical cancer, cervical cancer as an overall therapy will assist in these patients as well. Now traditionally, we snapshot according to SEER data only represents about 0.8% of use medications such as cisplatin with radiation. Now, what if we new cancer diagnoses in the United States, with the average age looked at different clinical research trials such as the CALLA trial. of approximately 50 years old. Most women are diagnosed around The phase 3 trial with a cohort looking at patients using standard age 35 to 44 years. Similar to endometrial cancer, if cervical cancer of care chemotherapy, cisplatin, with durvalumab, followed by is found to be localized, there’s a 5-year survival rate of almost durvalumab monotherapy. Will this assist and aid our patients as 92%. well?

However, as cervical cancer is found at more regional and distant A Randomized Phase 2 Study of Chemoradiation and Pembrolizumab 1,2 disease sites, the 5-year survival rate declines rapidly. The 5-year for Locally Advanced Cervical Cancer: Design survival rate overall is 66.1%. ARM 1: Pembrolizumab After CRT Eligibility criteria • Cisplatin 40 mg/m2 weekly for 5-6 weeks • Squamous, • CCRT: EBRT plus brachytherapy 1 adenosquamous, • 3 cycles of consolidative pembrolizumab: 200 mg every 21 days Chemoradiation for Early Stage/Locally Advanced Disease adenocarcinoma beginning week 9 for 3 cycles of the cervix 1:1 • Stages IB2-IVA or R IB1 with positive nodes (FIGO ARM 2: Pembrolizumab During CRT Chemoradiation 2009) • Cisplatin 40 mg/m2 weekly for 5-6 weeks • ECOG PS of 0-2 • 3 cycles of concurrent pembrolizumab: 200 mg every 21 days Preferred Regimens beginning day 1 for 3 cycles • CCRT: EBRT plus brachytherapy • Cisplatin • Primary endpoint: Safety • Carboplatin if patient is cisplatin intolerant • Secondary endpoint: CR, PFS, OS

1. Duska LR et al. SGO 2020. Abstract 17. 2. https://clinicaltrials.gov/ct2/show/NCT04221945. Other Recommended Regimens • Cisplatin + fluorouracil These patients also have the ability to look at clinical trials utilizing standard of care chemotherapy with pembrolizumab. Now looking 1. NCCN Clinical Practice Guidelines in Oncology: Cervical Cancer. Version 1.2020. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. at a new clinical trial, does pembrolizumab work better prior to chemotherapy and during, or after chemotherapy? We know So looking at standard of care of chemotherapy for cervical that cisplatin works well, but by adding pembrolizumab, will our cancers, usually we can have alteration of disease with surgery. patients have a better outcome? However, those patients with cervical cancer who have locally advanced disease will need chemotherapy and usually radiation. These treatments consist of cisplatin or, if the patient is cisplatin intolerable, carboplatin with the use of radiation, as well as cisplatin and fluorouracil.

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A Randomized Phase 2 Study of Chemoradiation and Pembrolizumab for to another treatment, and if they are positive for PD-L1 or have an Locally Advanced Cervical Cancer: Safety1,2 MSI-high tumor or an MMR deficiency, we are able to use immune therapy.

AE to any treatment: 3 dose-limiting Diarrhea (n = 35) No pulmonary AEs toxicity events in • ≥1 grade 4 AE Checkpoint Inhibitors in Cervical Cancer • Grade 1 (n = 27) 2 patients: (n = 11) • Grade 2 (n = 6) Rash • Grade 3 diarrhea • ≥1 grade 3 AE 1 • Grade 3 (n = 2) (n = 3, all grade 1) • Grade 3 nausea • Pembrolizumab (n = 12) • Grade 3 vomiting – Keynote-028 trial was performed in multiple tumor types – FDA approved in recurrent or metastatic disease – Investigational in locally advanced disease • Nivolumab + ipilimumab2 – CheckMate -358 trial 1. Duska LR et al. SGO 2020. Abstract 17. 2. https://clinicaltrials.gov/ct2/show/NCT04221945. • Ongoing investigations3

With the utilization of immune therapy, as nurses and nurse practitioners, we are now challenged with identifying side effects. Typical side effects for immune therapy consist of GI discomfort 1. Ott PA et al. J Clin Oncol. 2017;35:2535-2541. 2. Oaknin A et al. SGO 2019. Abstract 33. 3. https://clinicaltrials.gov. and distress, nausea, and vomiting, and it’s up to us to educate our nurses and our patients on how these side effects are going to Now, checkpoint inhibitors in cervical cancer currently consists of interfere with their lives. pembrolizumab, and we’ve talked about that in the KEYNOTE-028 trial performed in multiple tumor types, allowing for the FDA- And looking at this study of chemotherapy with pembrolizumab, approved indication for this metastatic disease. But we also want it shows us that diarrhea can occur in approximately 35 patients to look at medications such as nivolumab and ipilimumab in the in this clinical trial. However, grade 1 and grade 2 were more likely CheckMate -358 trial. Also, there are further ongoing investigations compared with grade 3. And looking at those, we can intervene that we will talk about in just a moment. often and actually make those side effects much more tolerable for our patients. KEYNOTE-158: Phase 2 Trial of Pembrolizumab in Previously Treated Advanced Cervical Cancer1,2 NCCN Guidelines: Eligibility Criteria • Histologically/cytologically 1,2 Recurrent or Metastatic Cervical Cancer documented advanced cervical SCC Systemic Therapy Regimens for Recurrent or Metastatic Cervical Cancer • ECOG PS 0-1 For 2 years or until • Progression on/ disease progression, Pembrolizumab 200 mg First-line Combination Therapy: intolerance to prior intolerable toxicity, or 1 every 3 weeks Preferred Regimens therapies physician or patient

• Cisplatin + paclitaxel + bevacizumab (category 1) 0.8 • Radiologically measurable decision • Carboplatin + paclitaxel + bevacizumab disease 0.6 Tumor imaging was performed every P = .04 • Life expectancy of 9 weeks for the first 12 months and Possible First-Line Single-Agent Therapy: 0.4 ≥3 months N = 98 every 12 weeks thereafter Preferred Regimens 0.2 • Cisplatin Proportion Surviving ORR assessed 0 Primary endpoint: 0 12 24 36 48 60 2018: FDA granted accelerated approval of pembrolizumab for by RECIST v1.1 a Second-Line Therapy: Months on Study patients with advanced PD-L1+ cervical cancer who Secondary endpoint: Safety Preferred Regimens experienced progression during or after chemotherapy • Pembrolizumab for PD-L1+ Consider MMR/MSI, or PD-L1, and/or NRTK gene a PD-L1 (CPS ≥1) as determined by an FDA-approved test. or MSI-H/dMMR tumors fusion testing for patients with recurrent, 1. Chung HC et al. J Clin Oncol. 2019;37:1470 1478. 2. https://clinicaltrials.gov/ct2/show/NCT02628067.

progressive, or metastatic disease ‐

1. https://www.nccn.org/professionals/physician_gls/pdf/cervical.pdf. 2. Tewari KS et al. Lancet. 2017;390:1654-1663. Currently, the KEYNOTE-158 trial utilizing pembrolizumab in those patients with previously treated cervical cancer, we know that Currently, NCCN guidelines show that in first-line combination pembrolizumab works. therapy for those patients with metastatic cervical cancer, category 1 allows us to give cisplatin, paclitaxel, and bevacizumab, KEYNOTE-158: Efficacy Results1,a or substitute the cisplatin for carboplatin, paclitaxel, and • Patients with previously treated advanced cervical cancer bevacizumab. These are in the recurrent setting. • N = 98, single-arm study • ORR at 10.2 months: n = 12 (12.2%; 95% CI, 6.5%-20.4%)b Take Home

100 However, if you test your patients and they are showing PD-L1 or PD-L1 positive 80 PD-L1 negative MSI-high, we have the ability to use pembrolizumab, which brings 60 PD-L1 unknown Pembrolizumab is 40 effective in patients up a great question: when are you testing your patients? Are you 20 +20% with PD-L1–positive

Target Target Lesion Size, % 0 advanced cervical tested when they have their initial pathology? Are you tested after -20 Best Change Best Change From in Baseline cancer 30% their first line of chemotherapy? -40 Target Lesion Size, % Target -60 FDA approved

Best Change From Baseline in -80

-100 FDA indication When I test, my patients want to know “Why test, if I am not able a Assessed by RECIST v1.1 per independent central review. b 3 CR and 9 PR; all were in patients with PD-L1–positive disease. to use this medication?” I tell them, “I use this as an ace up our 1. Chung HC et al. J Clin Oncol. 2019;37:1470 1478. ‐ sleeve.” And if we do have to return to chemotherapy or return

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The take-home from this is that we know in those patients with Emerging Therapies: Antibody-Drug Conjugates PD-L1 positivity on their cervical cancer pathology pembrolizumab Phase 1/2 innovaTV 201 works. The FDA approved pembrolizumab with accelerated (NCT02001623)1 • ORR: 22% approval in 2018. • Median DOR: 6.0 months • 6-month PFS: 40%

1 Binds to antigen Phase 2 innovaTV 204 Microtubule Phase 1/2 CheckMate -358: Nivolumab + Ipilimumab in Complex is internalized 4 2 2 disruption and traffics to lysosome (NCT03438396) Metastatic Cervical Cancer1-3 • ORR: 24% 3 Payload is released Cell cycle arrest • Median DOR: 8.3 months and apoptosis Eligibility criteria Nivolumab 3 mg/kg every Phase 1/2 innovaTV 205 (NCT03786081)3 • Age ≥18 years 2 weeks + ipilimumab 1 mg/kg every 6 weeks • In combination with • Histopathologic confirmation of pembrolizumab cervical SCC Tisotumab vedotin targets tissue factor, a protein often highly 1:1 • ≤2 prior systemic treatments for R expressed in cervical cancer and associated with poor prognosis advanced disease 1. Hong DS et al. Clin Cancer Res. 2020;26:1220-1228. 2. https://www.firstwordpharma.com/node/1736552?tsid=17. 3. https://clinicaltrials.gov/ct2/show/NCT03786081. • ECOG PS 0-1 Nivolumab 1 mg/kg + ipilimumab • Measurable disease by CT or MRI 3 mg/kg every 3 weeks for 4 N = 91 doses followed by nivolumab 240 mg every 2 weeks Emerging therapies, such as antibody–drug conjugates, utilizing

Primary endpoints: incidence of TRAEs and treatment-related SAEs, ORR, rate of surgery delay the medication tisotumab vedotin, or as I like to call it TV, looks at a Secondary endpoints: PFS, OS, DOR different way to attack cervical cancer cells. Now, TV targets tissue 1. Naumann RW et al. J Clin Oncol. 2019;37:2825-2834. 2. https://clinicaltrials.gov/ct2/show/NCT02488759. 3. Naumann RW et al. Ann Oncol. 2019;30(suppl 5):v898-v899. factor, which is a protein that’s highly expressed in cervical cancer. You can see in this slide the disruption of microtubules, allowing The CheckMate -358 trial of nivolumab and ipilimumab in for cell cycle arrest, and leading to apoptosis. This is an ongoing metastatic cervical cancer looks at two arms in this clinical trial. clinical trial; however, early data show us an overall response rate Nivolumab is given at 3 mg/kg every 2 weeks, and ipilimumab is of approximately 22% in the phase 1/2 trials. given at 1 mg/kg every 6 weeks compared with alternating doses of nivolumab at 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks Emerging Therapies: Adoptive Cell Therapy1,2 for 4 doses. Change in vivo to ex vivo and Italicize

LN-145 Remove patient population/advanced Phase 2: innovaTIL-04 disease row (above N) in table N 27 1 Adoptive cell transfer with CheckMate -358: Combination Therapy Efficacy Results autologous infiltrating lymphocytes ORR, n (%) 12 (44.4) (LN-145) CR, n (%) 3 (11.1)

• Patients with recurrent/metastatic cervical cancer PR, n (%) 9 (33.3) • N = 91; randomized 1:1 Surgical Fragment Lymphodepletion SD, n (%) 11 (40.7) Take Home Expand TILs resection of tumor and and infusion of ex vivo tumor isolate TILs TILS and IL-2 DCR, % 85.2 Nivolumab (3 mg/kg) + Nivolumab (1 mg/kg) + Ipilimumab (1 mg/kg) Ipilimumab (3 mg/kg) Median DOR,a mo NR Combination therapy No Prior Prior No Prior Prior with nivolumab and Median PFS, mo NR Treatment Treatment Treatment Treatment ipilimumab was effective Primary endpoint: ORR assessed by RECIST v1.1 ORR at 31.6 23.1 45.8 36.4 in patients with Secondary endpoints: DOR, DCR, and safety 12 mo, % advanced cervical cancer Median 13.8 3.6 8.5 5.8 a Median follow-up: 7.4 months. PFS, mo 1. Jazaeri AA et al. J Clin Oncol. 2019;37:2538. 2. https://clinicaltrials.gov/ct2/show/NCT03108495. Investigational

Other emerging therapies, such as adoptive cell therapy—looking 1. Naumann RW et al. Ann Oncol. 2019;30(suppl 5):v898-v899. at the body’s own TILs, or tumor-infiltrating lymphocytes—what occurs here is that there’s a surgical resection of the tumor. We are Currently, this medication is investigational. Looking at early data able then to isolate the TILs. We expand them in a laboratory and shows us that the overall response rate in those patients without they’re able to be grown. And then after bone marrow-depleting prior treatment is 31.6%. The median progression-free survival chemotherapy, these TILs are reinjected, allowing for the body to time in those patients ranged from 5.8 to 13.8 months. Sometimes identify those cancer cells as foreign. I ask myself 5.8 months is not a long time; however, given the prior information that these patients had limited opportunities for There are only about 27 patients currently on this clinical trial. chemotherapy, 5.8 months allows for treatment to continue and However, there has been 3 complete responses and 9 partial life to continue as well. responses.

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Summary of New Developments Select Ongoing Phase 3 Trials With Immunotherapy1 for Cervical Cancer Care NEW SLIDE

Immunotherapy Combinations in Advanced Endometrial Cancer Immunotherapy in Advanced Cervical Cancer Treatment Primary Treatment Primary • Single-agent immunotherapy is approved for advanced cervical Trial Name Setting NCT Number Trial Name Setting NCT Number Arms Endpoint(s) Arms Endpoint(s) cancer care in the second-line setting Dostarlimab + carboplatin- Persistent, Pembrolizumab + KEYNOTE-826 RUBY 1L paclitaxel vs placebo + PFS NCT03981796 recurrent, or chemotherapy vs placebo PFS, OS NCT03635567 (MK-3475-826) • Immunotherapy combination approaches are showing promise carboplatin-paclitaxel metastatic + chemotherapy

Atezolizumab + AtTEnd/ EMPOWER- Cemiplimab vs 1L carboplatin-paclitaxel vs Recurrent or • Additional emerging therapies are on the horizon ENGOT-en7 PFS, OS NCT03603184 Cervical 1 investigator’s OS NCT03257267 placebo + carboplatin- metastatic (GOG 3016) choice chemotherapy – Antibody-drug conjugates paclitaxel Durvalumab + carboplatin- Locally Durvalumab + SOC CCRT DUO-E/ CALLA PFS NCT03830866 paclitaxel, followed by advanced vs placebo + SOC CCRT GOG-3041/ 1L PFS NCT04269200 – Adoptive cell transfer durvalumab (± olaparib) ENGOT-EN10 maintenance Locally Pembrolizumab + CRT vs KEYNOTE-A18 PFS, OS NCT04221945 – Vaccines advanced placebo + CRT ENGOT-en9/ Lenvatinib + MK-7902-001/ 1L pembrolizumab PFS, OS NCT03884101 Cisplatin/paclitaxel + LEAP-001 vs carboplatin-paclitaxel BEAT Metastatic bevacizumab ± OS NCT03556839 atezolizumab

Lenvatinib + Recurrent or KEYNOTE-775 2L pembrolizumab vs PFS, OS NCT03517449 STARa Niraparib + dostarlimab ORR NCT04068753 physician's choice chemo progressive a Phase 2. 1. https://clinicaltrials.gov.

As we summarize cervical cancer, much like endometrial cancer, Currently, ongoing phase 3 clinical trials are going on for cervical we look its role in advanced cancers. Single-agent immune therapy cancers in multiple settings, such as persistent and recurrent is approved for cervical cancer in the second-line setting. Immune settings, metastatic settings, and locally advanced disease, therapy and combinations are showing promise in ongoing clinical utilizing chemotherapy, immune therapy, and checkpoint research. inhibitors.

In addition, emerging therapies, things that we think are outside of the box, such as vaccines, cell transfer with TILs, and antibody– drug conjugates, which are all just part of the cervical cancer research protocols that we are utilizing.

Are Clinical Trials Right for Your Patients?

• Patients with many types of Many patient organizations provide resources for gynecological cancers, including those fielding questions on clinical trial enrollment, 3,4 with newly diagnosed, advanced, or from the basics to more complex issues resectable disease, can benefit from clinical trial enrollment1,2 Sample Q&A

• Cultivate an institutional culture to offer Potential re-order – can the clinical trials to all patients1 Q. Is a clinical trial right for me? clinical trials slides go after the cervical summary? See notes in • Share resources that can help Delete clearity foundation website – script 2 A clinical trial can be a very good option for that is ovarian with patient education A. treatment if you have cancer. Can add: from PAs https://www.foundationforwomenscancer.org/ The most obvious reason for considering a clinical trial https://www.sgo.org/patient-resources/cervical-cancer/ is to find a treatment that will be best for you. https://www.sgo.org/patient-resources/uterine-cancer/ Many patients join a trial hoping that the treatment http://cervivor.org/ they can get on a trial is better than the current standard of care.

1. Greenwade MM et al. Gynecol Oncol. 2017;146:465-469. 2. Mathews C et al. Gynecol Oncol. 2009;112:161-165. 3. https://www.foundationforwomenscancer.org. 4. https://www.clearityfoundation.org.

Now, in my current practice setting, we have a large clinical research trial program, and many patients come just because of our clinical research trial program. And their question to me is, “Is this clinical trial right for me? Am I going to be getting a sugar pill?” There are lots of questions regarding clinical trials, so our role as nurse practitioners, nurses, and those people seeing patients is to give patients the proper information.

Let patients know that standard of care treatment is given, plus or minus additional medications, give them the tools to look up information online, and give them the resources that can help with specific patient questions.

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The Nurse’s Role in Gynecological The Spectrum of AEs With TKI Therapy Cancer Care

GI events (diarrhea)

Watch for “classic” events The Oncology Nurse’s Role in Gynecological Cancer Care associated with TKI therapy … and remind your patients what to expect Fatigue HFSR

Understanding of the MOA of newer agents Hypertension What nurses Support for patients receiving can bring to TKIs or immunotherapy the table Vigilance and education on TKI- and immune-related AEs Traditional chemotherapy, we’re all used to. We know the side effects of that. Chemotherapy has been around for years. But immune therapy is different. There are the “itises” in immune therapy. We have GI events, gastritis, diverticulitis. Other events can happen, things like fatigue. But we need to do our best and What can we do as nurses and nurse practitioners, and how can look at what is causing these events. we continue to help our patients? Our role as nurses and nurse practitioners is to better understand the mechanism of action Is it the oral therapy that’s causing the GI toxicity? Is it anemia for these new agents. We need to be able to support patients causing fatigue? This skin reaction, is it because the patient is receiving these targeted immune therapies, and we need to be just fair-skinned and they have lighter skin? Are they having a vigilant on education in those patients as well as in our staff. rash? What are these side effects and how can we best help our patients?

Patient and Professional Communication1 Differences to Note Between • Educate patients and family caregivers ONS Immunotherapy Wallet Card Example Checkpoint Inhibitors and TKIs – Share timely and up-to-date information about • Unlike TKIs, checkpoint inhibitors are intravenously administered immunotherapies, their MOA, and possible irAEs prior to initiating therapy and throughout treatment and using an every 2- to 4-week schedule survivorship – Use of calendars can be helpful to convey a complex • Emphasize schedule – Immunotherapy works differently than traditional • Checkpoint inhibitors are associated with a unique spectrum of chemotherapy AEs that are likely related to immune stimulation – Immunotherapy is associated with unique responses and irAEs • Consistently assess and document each encounter with your patient

1. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768.

Education is the backbone of nursing. That will never leave us. And how we continue to educate our patients will determine how long These therapies aren’t given traditionally like chemotherapy, as they can sometimes stay on these medications. Educating not only we well discussed. Using a calendar is very, very beneficial for the patients, but also the family and the caregivers. I also would these patients because sometimes they’re receiving two or more like to extend this to educating your nursing staff, or those people therapies. What happens when you have a therapy that lands who answer the phone or who are triaging patients. They can every 2 weeks and one that lands every 3 weeks? And oh, by really utilize step therapy in looking at things. the way, you have to have laboratory tests in between. Use of a calendar can greatly impact how compliant your patient is. Some How is this rash presenting, making sure that they have patients continue to want paper calendars, great. Some people information, knowing what your patients are on because side want you to help them set it up on their phone. And you will get effects are different. Patients will come in and they will ask you, questions such as, “When do I show up for chemotherapy? When “I would like the immune therapy. I want immune therapy. I don’t do I get labs? How come I need labs so often? I didn’t need labs so want traditional chemotherapy.” However, immune therapy has often during chemotherapy? What are all these labs?” its own set of side effects. It works differently than traditional chemotherapy. We also need to do our best to educate our patients on that and give them the tools that they need so they can continue on therapy.

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The Spectrum of Immune-Related AEs1,2 person answering the phone is, which is coming first? Is the rash coming from the immune therapy or is the rash coming from the 1. “Taking the brakes off” of the immune system can help the body fight cancer, but it can also VEGF therapy? lead to toxicity from a supercharged immune system 2. Any organ system can be affected Encephalitis, aseptic meningitis Hypophysitis The easiest thing to do in my clinical practice that I’ve utilized is to More commonly occurring irAEs are Thyroiditis, hypothyroidism, Uveitis • Dermatologic (rash, pruritus, blisters, hyperthyroidism Dry mouth, mucositis stop the oral medication. If we stop the oral medication and the ulcers, and vitiligo) Pneumonitis • GI (diarrhea, enterocolitis, Rash, vitiligo transaminitis, hepatitis, and Thrombocytopenia, toxicity goes away, we know it was the oral medication that caused anemia pancreatitis) Myocarditis • Endocrine (thyroiditis, hypophysitis, Hepatitis it. If we stop the oral medication and we continue to have the side Adrenal insufficiency diabetes, and adrenal insufficiency) Pancreatitis, • Pulmonary (pneumonitis) Nephritis autoimmune diabetes effects, then we know that our immune system therapy is what’s Vasculitis Colitis Arthralgia, causing the issue. myositis Enteritis Neuropathy

1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. Immunotherapy Side Effect Management Toolbox

As we talked about taking the brakes off of the immune system, Anti-diarrhea Anti-nausea • Here’s an idea: it sounds like we are kind of slowing it down. However, when we medications and medications probiotics – Patient is on a combo or monotherapy take the brakes off of the immune system, it allows our immune – If combo, patient describes AE that could be due to either agent Grading of side Permission to call system to activate. Looking at different things, as our immune effects sheet – Thinking of Venn diagram overlap… system is under checks and balances, when we release those – Should you discontinue one agent or the other? Reduce dose? checks and balances, our immune system gets very hyper-aware. – Address corticosteroid use/duration of use? We want it hyper-aware; we want it to fight cancer. Immunotherapy Toolbox But it can also lead to toxicities. As we supercharge our immune system, again, I call this the “itises.” Anything developing with an “itis” involves inflammation. Our immune system is overactive. Is that cough that our patient calls in about, is it pneumonitis or So as we utilize medications such as immune therapy and targeted is it a cough? Is it thrombocytopenia? Is it colitis? Is it uveitis? Is it therapies, I sit down with my patients. In general, I sit down with mucositis? All of these “itises” are what can be caused by and are a them for approximately an hour and we talk about realistic side result of immune therapy. effects, and I give them a toolbox so that they can be successful at home. And part of their toolbox is a side effects grading sheet. Because when I have a patient call me and they say, “Kimberly, I Immunotherapy + TKI Combination Toxicities am having such bad GI discomfort. I was able to eat my breakfast; Be aware of overlapping toxicities that can occur with however, then I went to lunch and I had great spicy tacos. And ! immunotherapy + TKI combination therapy then I came home and I went to go take my oral medication, my

Immunotherapy VEGF TKI oral targeted medication, and I had a lot of GI distress. I had an Pruritus Rash Hypertension episode of diarrhea. I didn’t like it, and you told me to call you Pneumonitis Diarrhea Taste changes Myocarditis Hepatitis Stomatitis anytime I had diarrhea.” Adrenal crisis Hypothyroid Dyspepsia AMS Cytopenias HFSR Encephalitis PRES Compared with the patient that says, “Hey, Kimberly, you know, I haven’t been able to get out of bed. I have such bad diarrhea that Stop the VEGF TKI every time that I leave my bedroom, I feel uncomfortable. I have accidents. I’m no longer able to have bowel control.”

So when our patients are asking for immune therapy, we also need Now both of these patients have extreme diarrhea that is causing to be realistic and let them know that it comes with its own set of them discomfort and affecting their daily life. However, looking side effects. But if we intervene early and we intervene often, this back at our first patient, I’m going to ask her, “You know, Mrs. will allow us to continue and have patients on therapy for long Smith, did you get your grading sheet out? What can we do periods of time. different? It looks like currently you have grade 1 diarrhea; what can we do to fix that? Can we alter your oral intake? Can we talk As we look at immune therapy and VEGF TKIs, they have very about maybe not having quite as spicy of a lunch?” similar side-effect profiles; however, very similar but also very different. If you look at immune therapy, we call it the “itises”, right, Compared with that patient who probably has grade 3 or grade 4 myocarditis, pruritus. Different things like hypertension can occur diarrhea, where she’s probably going to need hospital admission with VEGF therapy, as well as stomatitis. However, those are very at this point because I’m worried about electrolyte imbalance. individualized, but if you combine these, you can also have rash in So giving my patients that grading sheet is a great tool and it both, as well as diarrhea and hepatitis. And your question as the empowers them to be able to be part of their care.

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I also give tools to the nursing staff who answers the phone, Managing Fatigue Related to TKIs1-4 because when my patients call in, I want my nursing staff to first of all to know that a patient is on immune therapy. So my nursing Recommend that patients: staff has a list of who’s on immune therapy. And is this rash part of 1. Stay as active as possible, which can help regulate sleep Counsel your patients on a new detergent? Is this rash that they’re calling about, is it grade 2. Maintain a normal work and these key principles for 1, is it grade 3, and we’re having an issue and we’re going to need social schedule combating fatigue some topical steroids or maybe even some IV steroids for this 3. Take breaks as needed 4. Tell the medical team if activity patient as well? So giving my patients realistic expectations of their is intolerable or fatigue worsens immune therapy side effects allows them to be empowered. 5. Medical management: Consider methylphenidate I also send them home with anti-diarrhea medications. I also 1. Lacouture ME et al. Oncologist. 2008;13:1001-1011. 2. McLellan B et al. Ann Oncol. 2015;26:2017-2026. 3. Brose MS et al. Semin Oncol. 2014;41(suppl 2):s1-s16. send them home with medications like probiotics, medications 4. Walko CM et al. Semin Oncol. 2014;41(suppl 2):s17-s28. that are going to allow them to continue to have appropriate bowel care. Medications work for some with nausea and different Fatigue related to targeted therapies is a very real thing for medications work with others. By this time, your patient knows patients. However, if we can, encourage them to stay as active as what medications work for them when it comes to anti-nausea. possible, to maintain some sort of normalcy between work and Give them those medications and allow them to be part of their a social schedule, and allowing them to take breaks as needed care and allow them to empower themselves to do these things. and justify those breaks. Talk to your patients about good sleep hygiene, making sure that they’re getting adequate rest. And Now in the recurrent or advanced stages, these patients letting your medical team know how things are working. sometimes are hesitant to call. Give your patients and your families permission to call so you can talk about these side effects. Because Is fatigue related to anemia? Is fatigue related to medications? if we look at these medications and we intervene quickly and we There are different reasons for fatigue, and being an investigator intervene often, this will allow our patients to be able to stay on will greatly improve your patients’ lives. Sometimes you have to medication and allow them better outcomes for their cervical and consider different medications, such as methylphenidate. That endometrial cancers. might help and allow your patients to continue on treatment.

Managing Diarrhea Related to TKIs1-4 Managing Hypertension1-2

1. Monitor bowel habits and report any Recommendations increase in activity above normal 1. Obtain a BP cuff and track BP Remind your patients to 2. Avoid spicy or fatty foods; plain, at the same time every day or have Educate patients on notify the medical team of simple foods are best; avoid BP monitored in clinic or local hypertension warning diarrhea or abdominal fruit and caffeine pharmacy signs and monitoring distress 3. Maintain adequate fluid intake 2. Call if BP is >150/90 mmHg to avoid dehydration 3. May require changes to current 4. Monitor/manage electrolytes anti-hypertension regimen 5. Medical management: Loperamide 4. May require delayed initiation of TKI is usually effective; if ineffective, therapy (until hypertension is well consider diphenoxylate/atropine controlled) 5. Keep a log of morning and evening BP 1. Lacouture ME et al. Oncologist. 2008;13:1001-1011. 2. McLellan B et al. Ann Oncol. 2015;26:2017-2026. 3. Brose MS et al. Semin Oncol. 2014;41(suppl 2):1-16. 4. Walko CM et al. Semin Oncol. 2014;41(suppl 2):17-28. 1. Agarwal M et al. Curr Oncol Rep. 2018;20:65. 2. Maitland ML et al. J Natl Cancer Inst. 2010;102:596-604.

Now if we look at the medical management for diarrhea, 1 or 2 Hypertension—as we look closer into medications, specifically episodes of diarrhea can usually be resolved, and as we rule out looking at blood pressure, it can be increased with these VEGF infection, by over-the-counter medications and if need be, can medications. I encourage my patients to obtain a blood pressure step up with medications that can be prescribed. cuff; sometimes they can do that through their insurance company as well. I also encourage them to bring their blood pressure cuff in with them when they have their chemotherapy education session, so we can calibrate their blood pressure medications to the ones currently in clinic.

Give your patients parameters. If your patient has very low blood pressure, maybe a parameter of 150/90 mmHg is too high for them; maybe more often 125, maybe 130/70 to 80 mmHg is a better parameter for those patients. Individualize that parameter for the patient.

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Educate your patients on what hypertension is. And honestly, a lot of symptoms. It’s a small but significant change from baseline. let them know that they may require delayed medication or In general, these patients can continue to have treatment. We they may have to go on hypertension medication. Even if their want them to call and tell us these things. We want them to call hypertension is currently controlled, it may need to be altered. I and say, “Hey, you know, I’m having 3 episodes of diarrhea a day.” have my patients keep a log of their blood pressure. First thing in And we need to ask them, “What are you doing for those? Looking the morning, they take their blood pressure, they write it down in at your sheets, are you eating small meals? Are you taking your their log. The last thing they do before they go to bed that evening anti-nausea medications? Are you taking your anti-diarrheal is take their blood pressure. I also have them bring that log in with medications?” Grade 1, again, are usually mild, minimal symptoms, them so I can analyze and look at that with the patient to see how but we can continue to treat. their blood pressure is being controlled when they’re not in the office. irAE Management: Grade 2

Managing Hand–Foot Skin Reactions1 • Hold checkpoint inhibitor therapy for most grade 2 toxicities1,2 • Consider resuming immunotherapy Grade 2 RAAR Hot water, direct sunlight, constrictive footwear, when symptoms and/or laboratory (Mild to moderate Common symptoms excessive friction, vigorous Calluses and values revert to grade ≤1 symptoms) activity, and contact with • Erythema with hyperkeratotic cleaning products with regions Remove Avoid • Corticosteroids (initial dose or without blisters strong chemicals of 0.5-1 mg/kg/d of prednisone or • Hyperkeratotic lesions equivalent) may be administered on palms and soles

• Commonly accompanied Moisturizer (daily), Apply Report Signs and by dysesthesia (burning, cold packs (indirectly) symptoms for 20 min/d; wear thick immediately pain, and tingling) cotton gloves and socks, gently pat hands/feet dry after washing

1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. Various preventive (eg, urea cream) and treatment strategies (such as clobetasol 0.05% ointment or dose interruption) can be used depending on severity 1. Walko CM et al. Semin Oncol. 2014;41(suppl 2):s17-s28. As we look into management of grade 2 side effects, these are more than mild. They can be moderate symptoms. However, Skin reactions are common with immune medications. Now, looking at immune therapy, you might want to consider holding these can range from simple dermatitis, to having blisters, or medication at this time. We want to look back and make sure that things on your hands and feet known as hyperkeratotic lesions. these side effects go to approximately a grade 1 or lower before Those things can be commonly accompanied by burning, pain, we restart. and tingling. And how do we look at those? Making sure that when those patients call in because they developed a rash, the At this time, you may want to consider initiation of corticosteroids. person answering the phone and triaging is trained with proper Doses typically range between 0.5 to 1 mg/kg/day. Again, assessment skills to be able to determine the severity. advising these patients that use of corticosteroids can cause insomnia, making sure that they’re educated with some realistic When patients are on immune therapy, this isn’t a simple rash. This expectations. But again, you might want to utilize holding that could be something very life-threatening for these patients, and if checkpoint inhibitor at this time until we can get those side effects we intervene with medications such as urea cream, moisturizers, back to a grade 1 or lower. or corticosteroids, or we can interrupt the dose as well, we can actually continue patients on treatment. irAE Management: Grade 3/4

irAE Management: Grade 1 Grade 3 toxicities1,2 • Hold checkpoint inhibitor therapy Grade 3/4 • Initiate high-dose corticosteroids (prednisone (Severe or 1-2 mg/kg/d or methylprednisolone IV 1-2 mg/kg/d) life-threatening • In general, checkpoint inhibitor therapy • If no improvement with in 48-72 hours of high-dose symptoms) Grade 1 should be continued with close monitoring, corticosteroid, infliximab may be offered for some toxicities ( (Minimal or no with the exception of some neurologic, 1,2 • Taper corticosteroids over at least 4-6 weeks symptoms; diagnostic hematologic, and cardiac toxicities changes only) • When symptoms and/or laboratory values revert Grade 4 toxicities1,2 to grade ≤1, rechallenging with immunotherapy may • In general, permanent be offered; however, caution is advised, especially discontinuation of checkpoint in those with early onset irAEs; dose adjustments are inhibitor therapy is warranteda Common Terminology Criteria for AEs not recommended Grade 1: Mild; asymptomatic or mild symptoms Grade 2: Moderate; minimal, local, or noninvasive intervention indicated a With the exception of endocrinopathies that have been controlled by hormone replacement. Grade 3: Severe or medically significant, but not immediately life-threatening 1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. Grade 4: Life-threatening consequences; urgent intervention indicated Grade 5: Death related to an AE

1. Postow MA et al. N Engl J Med. 2018;378:158-168. 2. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. Serious side effects, such as grade 3 and 4 toxicities, we need to hold those checkpoint inhibitors. Looking specifically into management of all grading of side effects. Grade 1, as we identify it, there are very minimal, not really

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These patients will more than likely require hospitalization, Nursing Take-Homes utilizing high-dose corticosteroids, about 1 to 2 mg/kg/day. These Caring for Patients on TKIs and Immunotherapy • TKIs patients can have severe life-debilitating treatment side effects. • Pay attention to oral administration issues – Pay attention to oral administration issues TKIs • Be prepared to address the classic spectrum of AEs (eg, fatigue, They can have pneumonitis, they can have gastritis, diverticulitis. hypertension, diarrhea, HFSR) – Be prepared to address the classic spectrum of AEs (eg, fatigue, hypertension, diarrhea, These are severe and life-threatening systems. HFSR) • Immunotherapy • IV administration – IV administration Immunotherapy • A unique spectrum of irAEs requiring vigilance and education of patients – A unique spectrum of irAEs requiring vigilance and education of patients Sometimes if we have the ability to restart their checkpoint • Dual checkpoint inhibitor and immunotherapy-TKI regimens are available inhibitors, we need to really follow them closely and cautiously. – Dual checkpoint inhibitor and immunotherapy-TKI regimens are available • Clinical trials Especially with those patients who had early onset symptoms, we • Always an option for patients with cancer – Always an option for patients with cancer Clinical Trials • Cancer patient support groups can be an excellent resource for patients might need strict and early dose adjustments. who may be clinical trial candidates – Cancer patient support groups can be an excellent resource for patients who may be clinical trial candidates

Dose adjustments are not recommended. However, early intervention is what we need and desire in this setting. Generally, with grade 4, we’re not able to restart those medications and these As we look further into different options for chemotherapy, such patients are usually on corticosteroids for a long period of time. as immune therapy and targeted therapy for those patients And warning your patients that it takes a long time to come off not only in cervical cancer but endometrial cancer, we need to corticosteroid use, and this is a slow, tapering process. pay attention strictly to oral medications, making sure patients understand them and are compliant. They need to understand that there are different spectrums of AEs. There are different ways irAEs: Useful Tools for Patients1 that these medications can work. And different side effects that ONS Immunotherapy Wallet Card Example IMMUNOTHERAPY WALLET CARD2 these medications have. NAME: ______Wallet cards detailing symptoms to CANCER DX: ______IO AGENTS RECEIVED:  Single-Agent Checkpoint Inhibitor  Multiple Checkpoint watch for and how to notify their Inhibitors  Tyrosine Kinase Inhibitors healthcare provider are effective DRUG NAME(S): ______Looking at immune therapy, yes, it is given IV. However, these tools in empowering patients and IMMUNOTHERAPY TX START DATE: ______OTHER CANCER MEDICATIONS: ______patients are in your infusion centers less often, for a shorter period their caregivers to recognize and Note: Immunotherapy agents are not chemotherapy, and adverse events must be managed differently manage irAEs ONS Immunotherapy Wallet Card Example of time. Make sure that they understand immune therapies have

IMMUNE-MEDIATED SIDE EFFECTS*, COMMON WITH CHECKPOINT INHIBITORS VARY IN SEVERITY AND MAY REQUIRE REFERRAL AND STEROIDS. PATIENTS May be useful to other healthcare HAVE A LIFETIME RISK OF IMMUNE-RELATED SIDE EFFECTS. their own set of side effects. *May present as rash, diarrhea, abdominal pain, cough, fatigue, headaches, vision changes, etc. Confer with your WALLET CARD providers (eg, emergency oncology team before changing an IO regimen or starting treatment for an adverse event. department staff) caring for patients ONCOLOGY PROVIDER: ______ONCOLOGY PROVIDER #: ______with a history of immunotherapy EMERGENCY CONTACT: ______

IMMUNOTHERAPY IMMUNOTHERAPY CONTACT PHONE #: ______Clinical trials are always an option for your cancer patients. Clinical trials allow for supportive therapy. Clinical trials allow for patients 1. Brahmer JR et al. J Clin Oncol. 2018;36:1714-1768. 2. Adapted from the ONS wallet card for immunotherapy: https://www.ons.org/sites/default/files/2019-01/IO%20Card%201-sided_Vertical.pdf. to be exposed to medications that they might not have been on or have the opportunity to get. Looking up different clinical trials More useful tools for your patients. I love the ONS immune therapy not only in your current clinical setting, but also around the United wallet card that is shown on the slide. Some of my patients will States will allow patients to have access to all clinical trials. say, “I know what medications I’m on. I know how to use them.” However, when I tell them, “You know what, you’re going to feel And as I talk to my cancer patients and I want to understand them so good on these medications that you’re going to want to travel. better, I’ve utilized cancer support groups. Many cancer patients You’re going to want to get out of the area that you currently live don’t like to tell their significant other, or they don’t like to tell in. their family members, truly what they’re experiencing, and no one knows exactly what they’re experiencing better than someone And let’s say you developed a fever. And let’s say you have to end who’s walked in their shoes. up in an emergency room. When you’re in the emergency room, not many people are thinking straight. And these wallet cards will Educate your patients. Give them realistic expectations. Give them allow any emergency room physician, anybody treating you that’s good clinical trial information, and allow them to have support not your typical oncologist, to have the name of your oncologist, groups within your clinic or at outside clinics so that you can best what your diagnosis is, and what exactly your medications are. support them and be there for your patients.

Because if you go into an emergency room and you tell them you I hope that you have found today’s presentation to be extremely have diarrhea, but don’t tell them that you’re on a checkpoint helpful. We covered a lot of information and new concepts inhibitor or on immune therapy, they might not know what to look regarding clinical management of patients with advanced for, things like gastritis. This allows them the tools to better serve endometrial cancer and cervical cancers, and I hope this will be their patients and allows them better contact information.” Tell useful in your practice. Thank you for your time, and thank you for your patients to slip it in their wallet, slip it in their purse, and if your attention. they’re able to go out of town and they do get ill, they have this to be able to help and aid their treatment.

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Narrator: This activity has been jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

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This CNE activity is jointly provided by Medical Learning Institute, Inc. and PVI, PeerView Institute for Medical Education.

This activity is supported by educational grants from GlaxoSmithKline and Merck & Co., Inc.

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