Advocating for Action in HCC: Delivering Impartial and Personalized Care This transcript has been edited for style and clarity and includes all slides from the presentation.

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This educational activity is supported by a medical education grant from Exelixis, Inc., and is supported by an educational grant from Genentech, a member of the Roche Group. Advocating for Action in HCC: Delivering Impartial and Personalized Care Monica L. Baskin, PhD and Josep M. Llovet, MD, PhD

u Monica L. Baskin, PhD: Hello and welcome to this educational activity, Advocating for Action in HCC: Delivering Impartial and Personalized Care.

u I’m Dr. Monica Baskin. I’m delighted to present to you a little bit more about understanding health disparities and inequities in HCC. Dr. Llovet will then join us to discuss targeted therapies Monica L. Baskin, PhD and a new era in HCC management — combination Professor of Preventive Medicine therapies. Associate Director for Community Outreach and Engagement University of Alabama at Birmingham School of Medicine O’Neal Comprehensive Cancer Center Birmingham, Alabama

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 1 u Here is a disclaimer and disclosure indicating that we may be discussing off-label use DISCLAIMER of approved agents or agents Participants have an implied responsibility to use the newly acquired information to enhance patient that are in development. outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. DISCLOSURE OF UNLABELED USE This activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

u Here’s our financial disclosure information. Disclosure of Conflicts of Interest o Monica L. Baskin, PhD, has no real or apparent conflicts of interest to report. o Josep M. Llovet, MD, PhD, reported a financial interest/relationship or affiliation in the form of Consultant: Eli Lilly and Company; Bayer HealthCare, Inc; Bristol-Myers Squibb Co; Eisai Inc; Celsion Corp; Exelixis, Inc; Merck & Co, Inc; Ipsen Pharmaceuticals; Genentech, Inc; Roche; Glycotest Diagnostics; Fortress Biotech, Inc; Nucleix; Can-Fite BioPharma; Sirtex; MiNA Therapeutics; and AstraZeneca Pharmaceuticals. LP. Research grant: Bayer HealthCare, Inc; Eisai Inc; Bristol-Myers Squibb Co; Boehringer Ingelheim; and Ipsen Pharmaceuticals.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 2 u And these are the learning objectives for this activity. Learning Objectives

Upon completion of this activity, participants should be better able to: o Describe health disparities in o Identify patient populations at risk of hepatocellular carcinoma (HCC) developing HCC to eliminate that contribute to inequalities in disparities in HCC care for all health outcomes patients o Implement HCC screening and o Select appropriate treatment surveillance in racial and ethnic approaches for patients with HCC groups, disadvantaged populations, to help overcome disparities in care and in those at high risk for and promote health equity and development of HCC to improve improve quality of life early detection and prognosis

u To start, let’s make sure we understand what is meant by health and healthcare disparities.

Understanding Health Disparities and Inequities in HCC

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 3 u So when we’re talking about health and healthcare What Are Health and Healthcare Disparities? disparities, we’re referencing the difference in health or healthcare between groups o Health and healthcare disparities refer to differences in health and that are closely linked healthcare between groups that are with social, economic, and closely linked with social, environmental disadvantage. economic, and/or environmental So these can be examples disadvantage such as race and ethnicity, – Disparities occur across many dimensions, including race/ethnicity, socioeconomic status, their socioeconomic status, age, location, physical location, sex, disability sex, disability status, and sexual status, and sexual orientation. orientation

Artiga et al. 2020. https://www.kff.org/racial-equity-and-health-policy/issue-brief/disparities-in-health-and-health-care-five-key-questions-and-answers/.

u More specifically, the National Cancer Institute defines What Are Cancer Health Disparities? cancer health disparities as differences in cancer measures Cancer disparities (cancer health disparities) consist of differences in such as the number of new cancer measures such as: cases, all existing cases, deaths, cancer-related health – Incidence (new cases) – Survivorship, including quality of life complications, survivorship, after cancer treatment – Prevalence (all existing cases) financial burden, screening – Mortality (deaths) – Financial burden of cancer or rates, or stage at diagnosis. – Morbidity (cancer-related health related health conditions complications) – Screening rates – Stage at diagnosis

National Cancer Institute. 2020. https://www.cancer.gov/about-cancer/understanding/disparities

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 4 u One such example is depicted Cancer Death Rates* by Race and Ethnicity, here in this graph by the Centers for Disease Control US, 2013-2017 and Prevention. It’s looking at cancer death rates by race and ethnicity for the years 2013 to 2017. What you will see here is that the rates of cancer deaths do vary by race and ethnicity with non-Hispanic blacks, both male and female, having higher rates of cancer deaths during that period than any other racial and ethnic group. You might also notice the

*Per 100,000, age-adjusted to the 2000 US standard population. †Data based on Purchased/Referred Care Deliver Area counties. ‡Persons of Hispanic origin may be of any race. differences between males and Sources: National Center of Health Statistics, Centers for Disease Control and Prevention, 2019. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/incidence-and-mortality-rates-race-and-ethnicity-2012-2017.pdf females where overall, males were more likely to die from cancer than females across each of those groups.

u Why do these disparities exist? There are a number Why Do Health Disparities Exist? of reasons in the literature that suggest why we may o Social determinants of health see the differences in cancer health outcomes. There are o Unconscious/implicit bias social determinants of health Limited trust between patients and provider so things beyond biology o may be implicated in these o Limited trust between patients and the healthcare system disparities. We also know that unconscious or implicit bias o The payment system for medical professionals has a role, as well as limitations in trust both between patients and providers as well as patients and the healthcare system, in general, and there may be implications of the way in which health systems and providers are paid that may play a role. So we’ll briefly talk about each one of those now.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 5 Social Determinants of Health

Economic Neighborhood and Community and Health Care Stability Physical Environment Education Food Social Context System

Employment Housing Literacy Hunger Social Health Integration Coverage Income Transportation Language Access to Healthy Options Support Provider Expenses Safety Early Childhood Systems Availability Education Debt Parks Community Provide Vocational Medical Bills Playgrounds Engagement Linguistic and Training Cultural Support Walkability Discrimination Higher Education Competency Zip Code/ Stress Quality of Care Geography

Health Outcomes Mortality, Morbidity, Life Expectancy, Health Care Expenditures, Health Status, Functional Limitations

Artiga et al. 2020. https://www.kff.org/racial-equity-and-health-policy/issue-brief/disparities-in-health-and-health-care-five-key-questions-and-answers/. u First is social determinants code in determining your in the disparity. So whether of health. So we all probably health.’ So where you live, your you have appropriate social easily recognize that our housing and transportation, all supports to help you through biology and our genetics of that plays a role in terms of your cancer and other issues, play a role in our health and our health outcomes. whether you’re experiencing health outcomes. But what Education is another one of a significant amount of stress literature has shown is that those areas that’s considered or discrimination, and how there are these other things to be a social determinant well you’re integrated with that are not related directly of health. Not only your your neighbors and your to our physiology that have formal education, but also community are also implicated implications for our health related to issues of literacy— here. and outcomes. Those things your basic understanding of And finally, the healthcare include economic stability; ie, what’s happening specifically system has a role to play whether not an individual is around your health. Food in terms of determinants employed, their income, and is another one of the social of health. This could be other kinds of things related determinants—so whether something as broad as to economics play a major you have appropriate whether individuals have role. We also know that the or adequate food or are healthcare coverage but neighborhood and physical experiencing hunger, if also the issue of whether the environment or, basically, you have access to healthy providers are linguistically and where people live—you may options in your community. culturally competent in the have heard the phrase ‘your The community and social overall quality of care being zip code may be just as context that’s also been received. important as your genetic identified as an implication

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 6 u Implicit biases are also implicated in cancer health Implicit Bias disparities. These are our unconscious thoughts about o Racial bias can involve explicit or Higher implicit racial bias of individuals based on their negative thoughts and feelings about oncologists associated with: individuals of another race membership in a particular Shorter patient interactions o group. What the literature o Less patient-centered and supportive care Implicit racial bias is automatically o More patient difficulty remembering indicates specifically around activated and operates at a o contents of the interaction cancer is that higher implicit nonconscious level o Less patient confidence in recommended racial bias of oncologists treatments and greater perceived difficulty is associated with shorter o Non-black (i.e., white, Asian, and completing them Hispanic/Latino) health-care providers patient interactions between display substantial implicit racial bias that provider and the patient. toward blacks at levels comparable to the general public It’s also associated with less patient-centered and supportive care, more patient Penner et al. J Clin Oncol. 2016;34(24):2874-2880. difficulty remembering the contents of the interaction, and less patient confidence in being able to follow through with the recommendations of that provider.

u These are some data looking Indirect Effects Of Oncologist Implicit Bias at the direct quantifiable implications of those different On Patient Treatment Expectations biases on patient treatment outcomes.

Patients’ perceptions of Patients’ perceptions of Observers’ ratings of oncologist patient centeredness oncologist patient centeredness oncologist supportiveness and and confidence in treatment and expected difficulty in treatment patient confidence in treatment

Significant indirect effects of oncologist implicit racial bias on patients’ degree of confidence in recommended treatments and perceptions of difficulty in completing them

Penner et al. J Clin Oncol. 2016;34(24):2874-2880.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 7 u Another area that is implicated for cancer health disparities is Distrust in Medical Providers issues around trust. This recent poll looked at the distrust in medical providers. What they asked in the poll was ‘Do you think doctors not providing the same level of care to Black people is a reason why they have worse health outcomes, on average, than White people?’ And through these 3 different charts, you’ll see the responses by individuals who identified as being Black, Hispanic, and White. There’s a Fletcher. 2020. https://theundefeated.com/features/new-poll-shows-black-americans-see-a-racist-health-care-system-setting-the-stage-for-pandemics-impact/. © 2021 ESPN Internet Ventures. All rights reserved. notable difference in terms of those groups and considering whether this distrust is related to either a major reason for those worse health outcomes to not a reason at all.

u The poll similarly asked the question as it related to trust Distrust of the Healthcare System in the healthcare system. So it asked, ‘How often do you think our healthcare system treats people unfairly based on their race or ethnic background?’ And just as before, there are 3 charts here; they represent the responses by individuals identifying as Black, Hispanic, or White with the green color (at the bottom) being individuals that felt as though very often that was the case on up to the gray (at the top Fletcher. 2020. https://theundefeated.com/features/new-poll-shows-black-americans-see-a-racist-health-care-system-setting-the-stage-for-pandemics-impact/. © 2021 ESPN Internet Ventures. All rights reserved. of the pyramid) individuals either did not answer or just below that the response was never. So again, a considerable variability between those who believe that there is a role to play from our healthcare system in terms of the poor or unfair treatment that individuals from racial and ethnic backgrounds receive.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 8 What Is Needed to Make the Health System Better?

o Increased intercultural awareness

o Unconscious bias training and ongoing checks

o Improved relationship trust building between patients and provider

o Increased diversity in biomedical workforce

u So that’s a little bit about we can do something about of how people rate those what some of the challenges them, particularly in terms of relationships. So we need are. We’ve proposed a few making sure those biases don’t to improve that relationship things that we think are very negatively impact the patients between patients and much achievable. First, I think that we’re caring for. And providers, so that our patients there’s a need for increased oftentimes checking in. So it’s do have a sense of trust in intercultural awareness and not just you do the one-time the providers that they’re certainly being aware of the training, but we need to have, seeing. And lastly, is increasing different groups that come on an ongoing basis, some diversity in the biomedical for our care and what some way to check back in to make workforce. We’ve also seen of the unique needs may be. sure that those biases aren’t literature that suggests A second recommendation creeping back up. that many folks of color, is around unconscious bias A third recommendation particularly, prefer to have training and ongoing checks is trying to move toward providers that look like them for that. So being able to improved relationships or have a similar background. realize what may be some of and trust building between And therefore, that may be those biases that we bring patients and providers. We see one of the things that might into the healthcare system that there is a direct negative help to build up the trust in and how they may be having impact when patients and both providers and the medical a negative impact on patient providers don’t have that system. But we also know our outcomes and treatment. trusting relationship. We also biomedical workforce currently Being able to bring those into saw from the poll that there’s does not represent the overall the conscious minds, so that some variability in terms population.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 9 Case Example: Hepatocellular Cancer Treatment Planning

o Patient A (man) o Patient B (man) – Age 61 – Age 59 – Married – Not married – Some college – HS diploma – Private Insurance – Medicaid – Presence of hepatic – History of viral hepatitis, Child A encephalopathy, ascites cirrhosis, metabolic syndrome – Tumor size = 5.1 cm – Tumor size = 5.8 cm

What treatment: Liver transplant, resection, local ablation, systemic therapy, supportive care?

u Here’s an example of where with symptoms. So the treatment recommendations. It some of the biases and question here is what do you may also be about whether the challenges may show up think would be the treatment insurance that the person has in terms of HCC treatment of choice for each of these may be more equipped to pay and planning. There are 2 patients? So I’ll pause just a for some of the other more patients presented here, both second for you to think about invasive treatments. There are males. Patient A is age 61, that. a lot of things out there to be married, has gone to college, Now if you’ve got that in considered about this example. has private insurance, has mind what you’d recommend, What we see in the literature a few symptoms in terms one of the things that the is that typically, individuals of clinical presentation for literature suggests is that the who have government their cancer. Patient B is very patient on the right, patient B, insurance or no insurance similar in age. This person would be more likely to go in that may not have some of is, however, not married, did and have invasive treatment the social support are often not go onto college, and they versus the patient on the left. recommended for different have Medicaid or government And that may be attributed treatments than individuals insurance. And their clinical to particular biases around who seem to have a little bit presentation is a little bit whether this person may, more of those resources as in different but still presenting in fact, go on to follow the patient A.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 10 Medically Underserved Populations and COVID 19

u It goes without saying that of reaching those who are are highlighting the racially the COVID-19 pandemic most vulnerable from either a disproportionate number of has certainly impacted a racial and ethnic standpoint, individuals who are in those lot of what we do across socioeconomic standpoint, or clinical trials that are related the healthcare system. even a geographic standpoint to the vaccine, as well as the We also know that the and really highlighting some higher rates of deaths for medically underserved, in of the things that have been COVID-19. So we can’t discount addition to cancer, are also mentioned before. some of the challenges that those populations that are So Black individuals, for already exist that are outside significantly impacted by the example, asking why should of the treatment that we have pandemic. These are just a we trust you when it comes in cancer to think about how couple of the headlines that down to COVID-19 and may be they may, in fact, influence our have come out in the last year even more hesitant or skeptical patients as they’re coming in about the challenges in terms around vaccines. Other folks for their cancer treatment.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 11 u In thinking about the way Institute for Healthcare Improvement: forward, the Institute for Healthcare Improvement Health Equity identifies health equity in a sense of trying to make sure o Health equity: achieved when o Institutional (or institutionalized) racism: - Every person has the opportunity to differential access to the goods, services, that people have an equal attain their full health potential and opportunities of a society by race opportunity to attain their full - No one is disadvantaged from health potential. And then, you achieving this potential because of o Multiple determinants of health: know, on the flipside of that, social position or other socially range of personal, social, economic, and determined circumstances environmental factors that influence health inequity will be that there are status differences. Often those are o Health inequity: at a systemic level, but they differences in health outcomes that are are avoidable, and they are systematic, avoidable, and unjust certainly unjust. These issues can happen at the institutional level, particularly around Improving Health Equity: Assessment Tool for Health Care Organizations. Boston, Massachusetts: Institute for Healthcare Improvement; 2019. (Available at www.ihi.org) racism. We’re not speaking about individual people. As an individual, I have these racial views or biased views against another individual. Institutionally, we are talking about things that are baked into the system that really do make a difference for one group versus the other just by virtue of their identification with that group. And we’ve talked about these multiple determinants of health before referencing them as social determinants and how they also influence the health status.

u This graph highlights how to Institute for Healthcare Improvement Framework for improve that health equity. Healthcare Organizations to Improve Health Equity There are lots of ways to do Operationalizing a health equity that. Building infrastructure, strategy requires dedicated resources, Develop strategies to address including human resources and data Build multiple determinants of health: addressing those multiple resources, as well as an Infrastructure - Healthcare services organizational infrastructure to Support determinants or social - Organizational policies Health Equity - Organization’s physical determinants, eliminating Organizational leaders commit to environment improving health equity by Make Health Address the - Community’s socioeconomic racism and other forms of including equity in organization’s Equity a Multiple status strategy and goals Strategic Determinants - Encouraging healthy oppression particularly at Priority of Health Improve behaviors Equity is viewed as mission Health the systemic level. Partnering critical — mission, vision, and Equity business cannot thrive without a with communities and doing focus on equity community engagement, and Look at systems, practices, Partner with Eliminate and policies to assess where the then making health equity a Work in partnership with Racism and inequities are produced and Community to community members and Other Forms Improve where equity can be strategic priority—all of these community-based organizations of Oppression Health Equity proactively created that are highly engaged with strategies are what we can do, community members as a member of the healthcare Institute for Healthcare Improvement. 2019. http://www.ihi.org/_layouts/15/ihi/login/login.aspx?ReturnURL=%2fresources%2fPages%2fPublications%2fImproving-Health-Equity-Guidance- for-Health-Care-Organizations.aspx system, to advance health equity.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 12 Eliminating Healthcare Inequalities: IOM Assessment

o Differences in the kinds and quality of o IOM report findings: healthcare received by US ethnic – Disparities in healthcare exist and are minorities and non-minorities associated with worse health outcomes – Healthcare disparities occur in the context of broader inequality IOM concluded that a comprehensive, – There are many factors across health multilevel strategy is needed to systems, providers, patients, and managers eliminate these disparities that contribute to disparities – Bias, stereotyping, prejudice, and clinical uncertainty contribute to disparities – A small number of studies suggest that racial and ethnic minority patients are more likely to refuse treatment

IOM, Institute of Medicine. AMA. 2017. https://www.ama-assn.org/delivering-care/patient-support-advocacy/reducing-disparities-health-care. Institute of Medicine. 2003. https://doi.org/10.17226/12875. u More recently, the Institute of in the context of the broader that’s probably the case Medicine did this assessment inequality that we’ve been because of some of the other about eliminating healthcare talking about, so again, outside things that we talked about— inequities. What they found in those social determinants. the poll about distrust both in were differences in the kinds There are certainly multiple the provider and the medical and qualities of healthcare factors that are involved. And care system—may also play received by individuals in the biases, stereotypes, prejudice, into the smaller number of US, particularly minorities and and so forth also contribute to individuals refusing treatment. non-minorities, in this report. those disparities. This report They found that disparities also found that a small number exist, and they are associated of studies are suggesting that with worse health outcomes. racial and ethnic minority They also found that patients were more likely to healthcare disparities occur refuse treatment. However,

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 13 u So let’s move on to discussing how racial disparities and social determinants affect the care of our hepatocellular cancer (HCC) patient. How Racial Disparities and Social Determinants Affect HCC Care

u The literature presented Cumulative Incidence of Liver Transplant here present the cumulative incidence of liver transplant Waiting List Outcomes by Insurance Type waiting list outcomes by insurance type. As you look Liver Transplant Wait List Dropout at the graph, one of the take- aways points is that individuals who have public insurance are less likely to be moved up earlier on those transplant waiting lists. So those who have private insurance—in this dataset looking at the Kaiser Permanente versus other private—those individuals are

3/30/21 spending less and less time on Gutin et al. JAMA Netw Open 2019;2(8):e1910326. doi:10.1001/jamanetworkopen.2019.10326 the transplant list, and their likelihood of actually moving forward to transplant is not much higher.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 14 u Similarly, this study looked at Liver Transplant Waiting List Dropout Stratified the liver transplant dropout by Insurance Type and Reason for Dropout stratified by insurance type and reason. Again, looking at the same cohort of Kaiser Permanente insured individuals versus other private insurance versus public, you’ll see that there is some difference in terms of both the reason that individuals and the percentage of those who were on that wait list or dropped off of the waiting list.

3/30/21 Gutin et al. JAMA Netw Open 2019;2(8):e1910326. doi:10.1001/jamanetworkopen.2019.10326

u This slide looks across the Incidence for US by State: Liver & Bile Duct Cancers country at the incidence by White Black Hispanic state for liver and bile duct cancers. Again, you should draw your attention to the red in each of these maps indicate individuals who have the highest degree of incidence for the liver and bile duct cancers. American Indian/Alaskan Native Asian or Pacific Islander The blue represents individual states that have a lower incidence. And then a white or grayed out—that’s typically those states where we don’t have sufficient data, or the data were so small that it was https://statecancerprofiles.cancer.gov/map/map.noimage.php suppressed. What you might notice is that there are some geographic patterns in terms of who has the incidence of liver and bile cancer, and then there are also disparities as exists by race and ethnicity.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 15 u These graphs represent diagnosis and mortality. On the Diagnosis And Mortality left is late-stage liver and bile duct diagnoses between 2013 and 2017. Again, you can see Late-Stage Liver and Bile Duct Diagnosis, Liver and Bile Duct Mortality, some of the similar patterns 2013-2017 2013-2017 (both sexes, all ages) (both sexes, all ages) of racial and ethnic disparities. On the right, it’s looking at liver and bile duct mortality between 2013 and 2017. Again, racial and ethnic disparities are shown typically in both of these where you have a higher rate of Hispanic and Black individuals, both in terms of diagnosis and death. https://statecancerprofiles.cancer.gov/map/map.noimage.php

u Looking a little bit more in terms of what might be Contributing Conditions contributing conditions that also show up. We o Racial/ethnic minorities are know that racial and ethnic at higher risk of conditions minorities are at higher risk associated with poorer of other conditions that are outcomes for HCC associated with outcomes for HCC. So metabolic disorders, hepatitis, obesity, o Important to screen for these cirrhosis, and nonalcoholic and other risk factors steatohepatitis (NASH) are all of those combinations that may be contributing to the poorer outcomes that we see here. The point is being NASH, non-alcoholic steatohepatitis. able to screen for these other conditions that may have a negative impact on HCC treatment. So finding out whether they have a history as well as trying to identify and address issues around metabolic disorders and obesity in particular.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 16 u This slide describes a study Relationship Between Insurance Type looking at the relationship at Diagnosis and Survival between insurance type at diagnosis and survival. Similar Kaplan–Meier Survival Analysis of Patients with HCC, Stratified by Stage to the presentation before, we Localized Regional Distant see that there is a difference between those individuals who have private insurance versus those with public insurance (the middle line) and then those who are uninsured. So Uninsured individuals had the worst Uninsured individuals had the worst Survival disparities by insurance survival of those with localized disease survival in regional stage disease status were less apparent in distant uninsured individuals have (P < .001) (P < .001) stage disease as signified by the intersection of the survival curves the worse survival of all of

Privately insured patients those with localized disease. Medicaid-insured individuals Uninsured individuals We also see that uninsured individuals have the worse Adapted from Adler Jaffe et al. Cancer Epidemiol Biomarkers Prev. 2020;29:300-307. survival at the regional stage. And then, thinking of more distant survival disparities by insurance status were less apparent in that case. But certainly, localized and regional, we see a clear difference in terms of survival based on whether you have insurance and what type of insurance it is.

u We previously mentioned Patient Populations at Increased metabolic disorders—all of those things listed there—may Risk of Developing HCC increase the risk for HCC. We o Metabolic disorders associated with o Liver cirrhosis and hepatic also know that HCC incidence increased risk of HCC: dysfunction often complicate is expected to increase in – Obesity treatment of HCC older populations, and that – Diabetes – ~80% of patients diagnosed with HCC liver cirrhosis and hepatic have preexisting cirrhosis – NAFLD dysfunction often complicate – NASH – Can be caused by HBV, HCV, alcohol, and NAFLD treatment. o HCC incidence expected to increase in older populations due to Underlying chronic liver disease and cirrhosis underscores importance of health equity to rise in comorbid conditions ensure accurate and timely screening, – Hepatitis C, cirrhosis, obesity, diabetes, diagnosis, and treatment that is evidence- and NASH based and personalized for all HCC patients

HBV, hepatitis B virus, HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis. Benson et al. NCCN Guidelines 2020; Marrero et al. Hepatology 2018;68:723-750.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 17 u For screening and surveillance, we understand that HCC Screening and Surveillance populations likely to benefit from participation in the o Populations likely to benefit from o Screening and surveillance of these screening program include participation in an HCC screening program conditions that contribute to the include: development of HCC occur less often in those folks who are at higher – Patients with liver cirrhosis (from hepatitis B many Hispanic and Black populations risk. We should make sure that and C, alcoholic cirrhosis, and NAFLD or – Can delay diagnosis and leave them these individuals are prioritized NASH) ineligible for curative resection or – Hepatitis B carriers without cirrhosis due to transplantation due to advanced disease, for screening. We also know their high risk for development of HCC leading to worse prognosis that screening and surveillance – Over 60% of Hispanic HCC patients of these conditions often lead ineligible for liver transplantation to identifying many more

“Improved efforts at HCC screening and Hispanic and Black populations surveillance are needed among this group to who are at risk. That’s improve early detection” (Robinson et al, 2018) necessary so that we won’t delay their diagnosis and leave HCC, hepatocellular carcinoma; NAFLD, nonalcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis. Benson et al. NCCN Guidelines 2020; Robinson et al. World J Hepatol. 2018;10(12):956-965. them ineligible for some of the treatments that we know are much more likely to lead to longer-term survival.

u The screening recommendations are to HCC Screening Recommendations screen with ultrasound every 6 months and/or an alpha o Screening with ultrasound every 6 o Evidence suggest improved fetoprotein (AFP) for patients months and/or AFP for patients at outcomes for patients with HCC in at risk. And then, the other risk of HCC the setting of HBV or HCV cirrhosis recommendation is around – Cirrhosis caused by hepatitis B or C, when HBV/HCV is successfully looking at the evidence that alcohol, genetic hemochromatosis, treated suggests improved outcome NAFLD, stage 4 primary biliary – Referral to a hepatologist should be cholangitis, alpha-1 antitrypson considered for the management of for patients with HCC in the deficiency, and other causes these patients setting of hepatitis B virus – Without cirrhosis including hepatitis B, HBV carriers with a family history of or hepatitis C virus cirrhosis HCC, Asian men ³40 years old, Asian when either one of those is women ³50 years old, and Blacks with successfully treated. hepatitis B

AFP, alpha fetoprotein; HBV, hepatitis B virus, HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NAFLD, nonalcoholic fatty liver disease. Benson et al. NCCN Guidelines 2020; Marrero et al. Hepatology 2018;68:723-750.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 18 u So we’ll move on to strategies for advocating for action within your clinical practice.

Strategies for Advocating for Action Within Your Clinical Practice

How Can We Advocate for Action?

o Increase education, awareness, training – Self, Colleagues, Trainees, Healthcare Leaders, Policymakers o Support funding for early detection programs o Support efforts to increase access to cancer care o Promote programs for organ donation among racial/ethnic minorities o Partner with local/state advocates (eg, ASC Cancer Action Network)

u How can we advocate for mean the difference between but we’ve got to do our part action? There are several being able to get an effective to make sure that everyone things that are really important in and long-term survival. So who needs cancer care has for us, as members of making sure that we can come access. We can also promote the healthcare system, to in and detect cancers early, so programs for organ donation, advocate. So first, increase that we can have individuals particularly around Blacks, education, awareness, and with the most opportunities to Hispanics, and other racial/ training. That education and get the appropriate care. ethnic minorities who tend to training is for both ourselves, The third recommendation is have rates of organ donation our colleagues, our trainees, supporting efforts to increase that are much lower than healthcare leaders, and access to cancer care. We still those of other populations. policymakers. Making sure have a number of individuals And then, lastly, partnering that we’re all aware of these who don’t have easy access with local/state advocates like issues and that we can point to cancer care. So whether the American Cancer Society to solutions that we can lead it’s by geographic challenges Cancer Action Network, which in this area. The second is in terms of those who may is always advocating for more to support funding for early be in rural areas or not able resources for individuals who detection programs. We know to access oncologists or have cancer. that early detection often other types of cancer care,

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 19 How Can We Improve Communication and Promote Awareness Among Underserved Populations at Higher Risk of HCC?

o Training – Cultural competency, motivational interviewing, implicit bias o Actively work to reduce or eliminate bias o Invest in community engagement o Employ staff with training in social work, case management o Employ patient navigators o Employ community health workers

u We can also improve biases. We also want to invest to things like social work and communication and promote in community engagement. case management if those awareness among underserved So we often find that there’s barriers are particularly at the populations at higher risk. greater trust in the medical social determinants level. And And so, part of it is training system when the healthcare then lastly, you know, a number individuals, both those system and providers are of facilities have employed who already have cancer going as a community and community health workers. and their support systems helping to serve and recognize These are individuals who are and loved ones. We want what the community’s needs steeped in the community to make sure that we have are. We can also employ that are very aware of the culturally competent training staff with training and social cultural context. And they and information, that we are work and case management are interfacing and working utilizing patient modalities like in individuals who have a with the healthcare system, motivational interviewing in specialty to identify where in addition to working with which the provider is speaking the barriers and challenges individuals in the community, directly with the patient and are for individuals to get the and they have been shown to identifying that person’s values appropriate care. And then be quite effective in working and connecting that with care being able to have those with underserved populations. and treatment. And then we resources to address those Now I’d like to welcome Dr. also want to make sure that, challenges. Josep Llovet, who will highlight again, we’re aware of and We want to also utilize patient the latest emerging evidence checking implicit biases that navigators; they have been in HCC and how this impacts may pop up in the clinical found to be very effective current clinical practice. encounter. in one-on-one relationships We want to actively work to with patients to identify those reduce and eliminate those barriers and then link them

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 20 u Josep M. Llovet, MD, PhD: Hello, I am Dr. Josep Maria Llovet. I am professor of medicine and director of the liver cancer program at Mount Sinai, New York, and professor of medicine at the University Josep M. Llovet, MD, PhD of Barcelona. Thank you Dr. Baskin for your important Director, Liver Cancer Program Professor of Medicine, Division of Liver Diseases work in minority health, health Mount Sinai School of Medicine, New York University New York disparities, and cancer care. Professor of Research-ICREA You nicely defined for us how BCLC Group, Liver Unit IDIBAPS-Hospital Clinic racial disparities and social University of Barcelona Spain determinants affect HCC care.

u Now, I’m going to talk about molecular-targeted therapies in HCC.

Molecular Targeted Therapies in HCC

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 21 u And here, you have the outline Molecular Pathogenesis and Targeted of my presentation. We’ll talk about epidemiology, Therapies in HCC pathogenesis, targeted Epidemiology therapies, and combination o therapies. o Molecular pathogenesis and drivers o Targeted therapies • First and second line standard of care • Immunotherapy o Combination therapies: new era in HCC management • Atezolizumab + bevacizumab and beyond • Ongoing combinations and emerging treatments

HCC, hepatocellular carcinoma.

u HCC is the sixth most common cancer globally, the fourth Incidence and Mortality of HCC leading cause of cancer- related death with more than th o 6 most common cancer globally 850,000 new cases diagnosed th o 4 leading cause of cancer-related mortality every year—around 40,000 in the US. It’s the leading cause o >850,000 new cases of liver cancer (2018) – Eastern Asia: 570,000 of death in cirrhotic patients, – Europe: 68,000 and there is an increasing – United States: 37,000 incidence globally. And it’s o Leading cause of death in cirrhotic patients expected to reach 1,000,000

o Incidence increasing globally and will reach cases by 2025. 1M cases by 2025

HCC, hepatocellular carcinoma. IARC, https://gco.iarc.fr/today/home WHO, http://www.who.int/healthinfo/global_burden_disease/projections/en/ Villanueva A, NEJM 2019.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 22 u This slide summarizes the Epidemiology in the United States morality trends of patients with different malignancies Mortality trends of patients with different malignancies in the USA between 1990-2009 in the US between 1990 Cervical (uterus) Females Ovarian Males and 2009. As you can see, Breast Stomach for almost all solid tumors, Hodgkin lymphoma Prostate there has been a significant Colon and rectal Oral cavity and pharyngeal Lung and bronchus decrease in mortality with All malignant cancers Non-Hodgkin lymphoma two exceptions—melanoma in Myeloma Brain and other nervous system males and liver and bile duct Leukaemia Kidney and renal pelvis cancers both in males and Urinary bladder Pancreatic females, with an increasing Oesophageal Melanoma mortality ranging from 40% to Liver and bile duct -60 -40 -20 0 20 40 60 80 60%. Decrease in mortality (%) Increase in mortality (%)

Adapted from the American Association of Cancer Research © 2013. Sawyers et al. Clin Cancer Res. 2013;19:S4-S98. Llovet et al. Nat Rev Clin Oncol. 2015;12:408-424.

u What are the main risk factors Incidence and Risk Factors: HCC for the development of HCC? We know almost all of them. Incidence rates of HCC according to geographical area Hepatitis B virus infection represents at this point 54% of the attributable fraction

HBV of HCCs globally. Hepatitis C Alcohol virus infection still is the main cause of HCC in the West,

AB1 accounting for 31% of the cases. Then we have alcohol- NASH HCV related HCC, 20%. And NASH is associated with obesity and diabetes is a risk factor that is vastly increasing at this point in the West, particularly in the AB1, aflatoxin B1; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; NASH, non-alcoholic steatohepatitis. Adapted from Llovet et al. Nat Rev Dis Primers 2016;2:16018. US where 35% to 40% of the adult population is obese.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 23 u In terms of molecular Molecular Pathogenesis and Targeted pathogenesis, HCC is one of the tumors with around 40 Therapies in HCC to 60 mutations per tumor. Epidemiology But only a small proportion of o these mutations are known as o Molecular pathogenesis and drivers oncogenic drivers. o Targeted therapies • First and second line standard of care • Immunotherapy o Combination therapies: new era in HCC management • Atezolizumab + bevacizumab and beyond • Ongoing combinations and emerging treatments

HCC, hepatocellular carcinoma.

u As you can see, on the right- Landscape of Mutations in HCC hand side, we have TERT, beta-catenin, P53, ARID1A,

Genome Sequencing in HCC (n = 250) and others above 10%. And unfortunately, the most prevalent mutations in HCC are undruggable at this point.

Undruggable mutations

Vogelstein et al. Science 2013;339:1546-1558; Schulze et al. Nat Genet. 2015;47(5):505-511.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 24 u This is a meta-analysis we conducted in close to 1,000 cases of HCC for which whole exome sequencing was available. And, again, you have in red undruggable, unactionable mutations— TERT 55%, TP53 27%, beta- catenin 26%, and so on and so forth. And in green, you have actionable mutations. And you only have VEGF amplification, FGF19 amplification, and also mutations in JAK1, platelet- derived—all of those less than 10% in prevalence.

u Overall, 25% of HCCs have IMPAKT: Mutational Landscape 10,000 Patients actually at least one potential Actionable Drivers actionable target. And this falls in the low range of the potential actionable targets in oncology, as you can see in this slide where you have thyroid cancer or melanoma with 80% of the drivers that are potentially actionable. And on the other end of the spectrum, you have prostate, pancreatic cancer, and HCC with 20% or less of the drivers that are actionable. This is a study from Memorial Adapted from Zehir et al. Nat Med. 2017;23:703-713. Sloan Kettering Cancer Center. They sequenced 10,000 patients, and as a result of this analysis, they were able to treat, based on the mutations identified, 37% of the patients, providing that these patients have any drug available for these targets. And this goes up to 45% as you can see in biliary tract cancer. But, unfortunately, in HCC, only 5% of the patients were able to receive this type of personalized oncology.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 25 u Let’s talk about the therapies Molecular Pathogenesis and Targeted that are currently available for Therapies in HCC this disease.

o Epidemiology o Molecular pathogenesis and drivers o Targeted therapies • First and second line standard of care • Immunotherapy o Combination therapies: new era in HCC management • Atezolizumab + bevacizumab and beyond • Ongoing combinations and emerging treatments

HCC, hepatocellular carcinoma.

u This is just a summary of what we know about the Hepatocellular Carcinoma disease. The natural history

Stage 0 Stage A-C Stage D in blue at the early stages— ECOG 0, Child-Pugh A ECOG 3-4, Child-Pugh C ECOG 0, Child-Pugh A/B without treatment 36 months, Very early stage Early stage (A) Intermediate stage (B) Advanced stage (C) End stage (D) intermediate 16 months, (0) 1 HCC or 3 nodules Multinodular, Portal invasion, 1 HCC <2 cm ≤3 cm, ECOG 0 ECOG =0 N1, M1, ECOG 1/2 Carcinoma in situ advanced stage 8 months or median survival. While moving that to up to 60

Natural history (median survival) 8 mo month median survival with >36 mo 16 mo ~3 mo (5 mo in AFP>400) resection, transplantation,

1st: Atezolizumab+bevacizumab > 17 mo 1st/ 2nd Sorafenib: 14.6-10.7 mo/ Lenvatinib: 13.7 mo Best Resection, transplantation or Chemoembolization or local ablation at the early 3rd: Regorafenib: 10.6 mo supportive local ablation >60 mo 26-30 mo (14-45 mo) Cabozantinib: 10.2mo care Ramucirumab (AFP>400): 8.1 mo stages. Up to 26 to 30 months

Unmet needs A)1st line: combination therapies for chemoembolization Adjuvant therapy TACE vs TACE systemic therapy • TKI/mAb + immunotherapy Single agent or combinations TACE vs systemic therapy • Anti-PD1+anti-CTLA-4 B) Treatment of advanced HCC, Child-Pugh B at intermediate. And in

AFP, alfa fetoprotein; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; ECOG, Eastern Cooperative Oncology Group; mAb, monoclonal antibody. PD-1, programmed cell death protein 1; advanced, at this point, with TACE, trans-arterial chemoembolization; TKI, tyrosine kinase inhibitor; Llovet JM, Harrison 21st Edition, 2021 (in press) atezolizumab/bevacizumab in frontline, recently reported at ASCO GI, 19-month median survival. Then, we have sorafenib and lenvatinib with survivals around 13, 14 months. And in second line, regorafenib, cabozantinib, and ramucirumab with survivals around 10 months. Unmet needs are certainly adjuvant therapies after resection, local ablation, and combination therapies throughout all the stages of the disease.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 26 u What trials have been reported Molecular Therapies for Advanced HCC (2020) up to 2020? Well, we have

Positive Non-inferior Negative on the left-hand side the First-line Sorafenib +/- erlotinib positive trials. Sorafenib in Sorafenib vs placebo Sorafenib vs brivanib SHARP in the Asia-Pacific. (SHARP1, Asia-Pacific2) Sorafenib vs sunitinib Atezolizumab/bevacizumab— Sorafenib vs lenvatinib Sorafenib vs linifanib (REFLECT3,4) the IMbrave recently reported Sorafenib +/- doxorubicin Atezolizumab + bevacizumab in 2020 in frontline. (IMbrave1505) Sorafenib vs Y90 Sorafenib vs nivolumab In second-line, we have Second-line Ramucirumab vs placebo Brivanib vs placebo ramucirumab, the REACH-2; (AFP ≥ 400 ng/mL) Everolimus vs placebo (REACH-26) regorafenib, the RESOURCE; Tivantinib vs placebo Regorafenib vs placebo - and cabozantinib, CELESTIAL. (RESOURCE7) Pembrolizumab vs placebo These are the positive phase 3 Cabozantinib vs placebo trials. (CELESTIAL8) Then, you can see the 1. Llovet et al. N Engl J Med. 2008;359:378-390. 2. Cheng et al. Lancet Oncol. 2009;10:25-34. 3. Kudo et al. Lancet. 2018;391:1163-1173. 4. Alsina et al. J Clin Oncol. 2019;37:371-371. 5. Finn et al. N Engl J Med. 2020;382:1894-1905. 6. Zhu et al. J Clin Oncol. 2018;36:4003. 7. Bruix et al. Lancet. 2017;389:56-66. 8. About-Alfa et al. N Engl J Med. 2018;379:54-63. noninferior trials. The REFLECT trial, which compared lenvatinib versus sorafenib shows noninferiority. And in the second watch for superiority, it was not reached. Therefore, lenvatinib was identified as a drug with similar efficacy as compared to sorafenib. And then, on the right-hand side, you have all these drugs that have been discarded for the management of HCC— erlotinib, brivanib, sunitinib, linifanib, doxo, Y90 at least for advanced. And then, we’ll talk about nivolumab and brivanib, everolimus, tivantinib, and pembrolizumab.

u Here you have the NCCN NCCN Guidelines®: Systemic Therapy Guidelines, and the recently Version 5.2020 – August 4, 2020 updated recommendations for systemic treatment. And the

First-Line Therapy Subsequent-Line Therapy if Disease Progression preferred regimens in frontline, Preferred Regimens Regorafenib sorafenib, lenvatinib, and Sorafenib Cabozantinib atezolizumab plus bevacizumab. Lenvatinib Ramucirumab (AFP ≥400 ng/mL only) Whereas in subsequent lines of Atezolizumab + bevacizumab Lenvatinib Useful in Certain Circumstances Nivolumab therapy, you have the drugs that Nivolumab (ineligible for TKI or other anti-angiogenic agents) Nivolumab + ipilimumab have shown efficacy certainly FOLFOX Sorafenib – regorafenib, cabozantinib, Pembrolizumab ramucirumab, lenvatinib. And then you have nivolumab, nivolumab plus ipilimumab, and pembrolizumab. These drugs have been approved by FDA AFP, alpha fetoprotein; FOLFOX, fluorouracil, leucovorin, oxaliplatin; TKI, tyrosine kinase inhibitor. Benson et al. NCCN Guidelines Hepatobiliary Cancers. Version 5.2020. https://www.nccn.org/professionals/physician_gls/pdf/hepatobiliary.pdf based on phase 2 data, and therefore, are recommended by these guidelines based on accelerated program.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 27 u Let’s talk a bit about Immune Checkpoint Therapy immunotherapy. You’re very Timing of the Clinical Development of Checkpoint Therapy familiar with all types of anti–programmed cell death Responses to immunotherapy in oncology: 15%-50% ligand 1 (PD-L1), particularly atezolizumab, avelumab, and durvalumab; anti–programmed cell death protein (PD-1)— mostly pembrolizumab and nivolumab—in HCC; and anti-CTLA4—for instance, Checkpoint Blockade ipilimumab. These drugs are leading to 15% to 50% objective responses. In HCC, it’s between 15% and 20%.

Adapted from Rodriguez and Ribas. Cancer Cell 2017;31:848; Ribas and Wolchok. Science 2018;359:1350-1355.

u And here, you have an overview of the approvals Overview of Immunotherapy FDA Approvals in HCC by FDA. In frontline, we have atezolizumab plus Immunotherapy Trial FDA Approval bevacizumab that was First-Line approved in May 2020 1,2 Atezolizumab + IMbrave150 May 2020: patients with unresectable or metastatic for patients in frontline bevacizumab HCC who have not received prior systemic therapy Second-line advanced HCC. And then, as Nivolumab CheckMate-0403 Sept 2017 (accelerated approval): patients with HCC I mentioned before, you have who have been previously treated with sorafenib nivolumab, pembrolizumab, Pembrolizumab KEYNOTE-2244 Nov 2018 (accelerated approval): patients with HCC and nivolumab/ipilimumab who have been previously treated with sorafenib that were approved based Nivolumab + CheckMate-0405,6 March 2020 (accelerated approval): patients with HCC on phase 2 data between ipilimumab who have been previously treated with sorafenib September 2017 to March 2020. This is for nivolumab/

1. Cheng et al. Ann Oncol. 2019;30:ix186-ix187. 2. Finn et al. N Engl J Med. 2020;382:1894-1905. 3. El-Khoueiry et al. Lancet 2017;389:2492-2502. ipilimumab combination based 4. Zhu et al. Lancet Oncol. 2018;19:940-952. 5. Yau et al. J Clin Oncol. 2019; 37:4012-4012 6. He et al. J Clin Oncol. 2020;38:512. FDA, US Food & Drug Administration; HCC, hepatocellular carcinoma. on phase 2 data that got first breakthrough designation and then accelerated approval.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 28 u So, what do we know about Phase 2 CheckMate 040 Trial: these drugs? Here you Correlation ORR/OS With Nivolumab have the subgroup analysis PD-L1 Expression on Tumor Cells and Response according to type of response 1.0 Escalation phase Expansion phase (n=44)* (n=174)* for nivolumab. Patients who 0.9 PD-L1 ≥ 1%† 11 (25%) 34 (20%) 0.8 Complete or partial response (n = 22) Objective response 3/11 (27%; 6-61) 9/34 (26%; 13-44) were achieving complete or

0.7 Stable disease (n = 65) Complete response 1 (9%) 1 (3%) partial responses have an Progressive disease (n = 59) Partial response 2 (18%) 8 (24%) 0.6 outstanding outcome with Stable disease 0 16 (47%) 0.5 Median OS (95% CI), mo NR (NE-NE) Progressive disease 7 (64%) 9 (26%) overall survival beyond 36 0.4 Not determined 1(9%) 0 Median OS (95% CI), mo months. Whereas patients † 0.3 16 (13.8-20.2) PD-L1 ≤1 33 (75%) 140 (80%)

Probability of Survival (%) of Probability Objective response 4/33 (12%; 3-28) 26/140 (19%; 13-26) achieving stable disease 0.2 Median OS (95% CI), mo 8.9 (7.3-13.4) Complete response 2 (6%) 2 (1%) have a median survival of 16 0.1 n = 146 Partial response 2 (6%) 24 (17%) months. And patients with a 0 Stable disease 19 (58%) 62 (44%) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Progressive disease 8 (24%) 46 (33%) best response as progressive Months Not determined 2 (6%) 6 (4%) disease, median survival of Data are n (%); n/N (%; 95% CI). *Four patients in the dose-escalation phase and 40 patients in the dose-expansion phase did not have tumor PD-L1 expression data available. †PD-L1 membrane expression on tumor cells. around 9 months. ORR, objective response rate; OS, overall survival; PD-L1, programmed death-ligand1. Adapted from El-Khoueiry et al. Lancet 2017;389:2492-2502. And it seems that this is not associated with a status of PD- L1 immunostaining assessed by more than 1% of the cells in the histological analysis.

u This is the trial that was Phase 3 CheckMate 459 Trial: designed based on the Nivolumab vs Sorafenib First-line phase 2 results of nivolumab

Key eligibility criteria Stratification comparing nivolumab versus • Histologically confirmed factors Nivolumab Nivolumab Sorafenib advanced HCC not • Etiology 240 mg IV HR P sorafenib—CheckMate eligible for surgical and/or Vascular Q2W (n = 371) (n = 372) LRT; invasion n = 371 Median OS, mo 16.4 14.7 0.85 .0752 459. It was a head-to-head or progressive disease and/or EHS R after surgical and/or LRT • Geography 1:1 100 • Child-Pugh class A (Asia vs comparison. Nivolumab led • ECOG PS 0 or 1 Sorafenib non-Asia) N = 743 400 mg po 80 • Systemic therapy naive to 15% objective responses as BID n = 372 60 Objectives opposed to 7% in sorafenib. • Primary – OS • Secondary – ORR, PFS, efficacy PD-L1 status 40 But the nivolumab was • Exploratory – HRQoL using FACT-Hep Nivolumab Overall survival (%) 20 Sorafenib not able to hit the primary Nivolumab (n = 371) Sorafenib (n = 372) ORR,a n (%) 57 (15) 26 (7) 0 endpoint of overall survival Best overall response, n (%) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 CR 14 (4) 5 (1) No. at risk Months PR 43 (12) 21 (6) Nivolumab 371 326 271 235 211 187 165 146 129 104 63 39 17 0 significant differences despite Sorafenib 372 328 274 232 196 174 155 133 115 80 47 30 7 0 SD 130 (35) 180 (48) PD 136 (37) 105 (28) that median survival for a DCR,b n (%) 203 (55) 215 (58) Median time to response (range), mo 3.3 (1.6-19.4) 3.7 (1.5-11.1) Median duration of response (range), mo 23.3 (3.1 to 34.5+) 23.4 (1.9+ to 28.7+) patient receiving nivolumab as BID, twice daily; CR, complete response; ECOG PS, Eastern Cooperative Oncology Group performance status; DCR, disease control rate; HCC, hepatocellular carcinoma; HRQOL, health related quality of life; LRT, locoregional therapy; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; single agent in frontline was SD, stable disease. Adapted from Yau et al. Ann Oncol. 2019;30(suppl_5):v851-v934. 16.4 months—at that time, the best survival ever reported in frontline—compared to 14.7 months for patients receiving sorafenib. The hazard ratio was 0.85.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 29 u A similar issue happened Phase 3 KEYNOTE-240 Trial: Pembrolizumab vs Placebo Second-line with pembrolizumab versus Overall Survival Key eligibility criteria • Histo- or cytologically confirmed advanced HCC placebo. This is the KEYNOTE • BCLC Stage B or C, not amenable to locoregional therapy or refractory to locoregional therapy 240 study comparing • Child-Pugh A • Untreated HCV of >4 weeks of successful HCV treatment pembrolizumab versus • Has not had prior systemic therapy for HCC other than sorafenib placebo in second line. Again, R N=408 pembrolizumab was reported to induce 18% objective Pembrolizumab + BSC Placebo + BSC Search for biomarkers predicting response to checkpoint inhibitors response rate as opposed to in HCC is an UNMET medical need • Start Date: May 2016 4% in placebo. And in survival, • Primary endpoints: PFS, OS Objective Response Rate at Final Analysis • : ORR, DCR, TTP, DOR Other endpoints (RECIST 1.1, BICR) the hazard ratio was 0.78 with a substantial difference—13.9 months for second line as 1. https:..clinical traisl.gov/ct2/show/NCT02702401. Accessed May 18, 2017. 2. Adapted from Mellman I et al. Nature. 2011;480:480-489. aNominal one-sided P-value based on the Miettinen and Nurminen method stratified by randomization factors. opposed to 10.6 months for bFrom product-limit (Kaplan-Meier) method for censored data. c “+” indicates no PD by the time of last disease assessment. placebo. But the P value did Data cutoff: Jan 2, 2019. BSC, best supportive care; CR, complete response; DCR, disease control rate; DOR, duration of response; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ORR, objective response rate; OS, overall survival; PFS, not hit superiority because the progression-free survival; PR, partial response; SD, stable disease; TTP, time to progression. Adapted from Finn et al. J Clin Oncol. 2019;37:4004. prespecified P value was .017 and the achieved P value was .23.

u So, as you can see on this slide, the KEYNOTE-240 KEYNOTE-240: Updated Results trial, the median survival for pembrolizumab was 13.9 Pembrolizumab Placebo months versus 10.6 months (n=278) (n=135) for placebo. In terms of Median OS 13.9 months 10.6 months objective response, it was OS HR 0.77 24-month OS rate 28.8% 20.4% 18.3% for pembrolizumab 36-month OS rate 17.7% 11.7% and 4.4% for placebo, with a Median PFS 3.3 months 2.8 months PFS HR 0.70 median duration of response 24-month PFS rate 11.8% 4.8% of close to 14 months for 36-month PFS rate 9% 0% pembrolizumab and 15 months ORR 18.3% 4.4% Median TTR 2.7 months 2.9 months for placebo. The disease Median DOR 13.9 months 15.2 months control rate was close to 62% DCR 61.9% 53.3% in the pembrolizumab arm.

Median follow-up:39.6 months pembrolizumab, 39.8 months placebo. DCR, disease control rate; DOR, duration of response; ORR, objective response rate; TTP, time-to-progression. Merle et al. J Clin Oncol. 2021;39(suppl 3):268.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 30 u Certainly, this indicates that Phase 2 KEYNOTE-224 Trial: Pembrolizumab Second-line these drugs as single-agent have activity, probably very Key eligibility criteria • ≥18 y Pembrolizumab o Response assessed Q9W strong activity in a subgroup • Pathologically confirmed HCC 200 mg Q3W for 2y or o Primary endpoint: • Progression on or intolerance to until PD, intolerable Survival – OR (Recist v1.1, central review) of patients. And there is an sorafenib treatment follow-up Secondary endpoints: • Child Pugh class A toxicity, withdrawal of o unmet need to identify those • ECOG PS 0-1 consent or investigator – DOR, DCR, PFS, OS and safety • BCLC Stage C or B disease decision and tolerability patients. • Predicted life expectancy >3 mo And here, you have also with Maximum Percentage Changes From Baseline in Target Lesions pembrolizumab the phase 2 study and the breakdown of response according to etiology in a cohort of 104 patients, From Baseline From Percent Chang also supporting the fact that Study cohort (N = 104) Uninfected (n = 57) HCV infected (n = 26) HBV infected (n = 21) pembrolizumab is inducing

BCLC, Barcelona-Clinic Liver Cancer; DCR, disease control rate; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular objective response—either carcinoma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; Q3W, every 3 weeks; Q9W, every 9 weeks. Based on RESIST v1.1 by central radiology review in patients who had both pre- and post-treatment image measurements. Dotted line is threshold for response. Data cutoff date: Aug 24, 2017. complete or partial response— Adapted from Zhu et al. Lancet Oncol. 2018;19:940-952. in a proportion of patients that at the end will benefit in terms of overall survival.

u Well, which are these Biomarkers for Checkpoint Inhibitor Immunotherapy biomarkers for checkpoint Factors that predict response to immune checkpoint inhibitor therapy Factor Association with Validated in Predictive vs Cancer type Tissue type for Possible assay type for inhibitor immunotherapy to favorable clinical phase 3 prognostic biomarker assessment biomarker assessment outcome clinical trial? identify responders? Generally, Tumor mutation burden Positive Yes Predictive Multiple Blood or tumor tissue NGS WES or targeted gene panel sequencing tumor mutational burden PD-L1 expression Positive Yes Predictive Multiple Tumor tissue Immunohistochemistry Copy number variation Negative TBD Prognostic, Multiple Tumor tissue NGS WES or targeted gene panel predictive or both sequencing and PD-L1 expression are the HLA class I diversity Positive TBD Predictive Melanoma Blood NGS WES or PCR-based typing NSCLC two biomarkers accepted by LOH at HLA class I alleles Negative TBD Predictive Melanoma Tumor tissue TBD regulatory agencies in certain T cell repertoire clonality change Positive TBD Predictive Melanoma Tumor tissue or blood TBD T cell-inflamed microenvironment Positive TBD Prognostic, Multiple Tumor tissue NGS RNA-seq or immunostaining solid tumors. predictive or both SERPINB3 or SERPINB4 mutations Positive TBD Predictive Melanoma Tumor tissue NGS WES Gut microbial diversity Positive TBD Predictive Melanoma Oral or gut PCR or NGS Specific gut microbial species Positive or negative TBD Predictive Melanoma Oral or gut PCR or NGS TGFß expression Negative TBD Predictive Melanoma Tumor tissue or blood NGS, WES, targeted gene panel sequencing or RNA-seq Mutations in the ß-catenin pathway Negative TBD Predictive Melanoma Tumor tissue or blood NGS WES, targeted gene panel sequencing or RNA-seq JAK2 mutations (rare)c Negative TBD Predictive Melanoma Tumor tissue or blood NGS WES or targeted gene panel sequencing B2M mutations (rare) Negative TBD Predictive Melanoma Tumor tissue or blood NGS WES or targeted gene panel sequencing STK11 mutations (common) Negative TBD Predictive NSCLC Tumor tissue or blood NGS WES or targeted gene panel sequencing NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; PD-L1, programmed cell death protein ligand 1; TBD, to be determined. Adapted from Havel et al. Nat Rev Cancer 2019;19:133-150.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 31 u In HCC, we identified years ago Predictors of Response/Primary Resistance to ICIs what we called the immune class that involves 24% of HCCs. And these tumors are somehow inflamed tumors or hot tumors with enrichment of T cells, CD8s, TLS, cytotoxic, lytic activity, and signatures that predict response in other tumors such as melanoma. So, the actual classification suggests that there are the inflamed hot tumors and the noninflamed tumors. The inflamed tumors eventually

ICIs, immune checkpoint inhibitors. are those that may respond Sia et al. Gastroenterology 2017;153:812-826. to checkpoint inhibitors, and the noninflamed tumors are those that eventually will not respond to checkpoint inhibitors.

u And certainly, in experimental HCC Immune Subclass models, it seems that one of Molecular characterization of the immune subclass the mechanisms of exclusion, as it happens with melanoma, ß-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 is the presence of beta-catenin Therapy in HCC mutations. Experimental models in this nice study in Cancer Discovery—when animals with MYC and TP53 mutations were treated with PD-L1, they respond. Conversely, they were resistant if the tumor was driven by MYC and beta-catenin.

HCC, hepatocelular carcinoma; PD-1, programmed cell death protein 1; TIL, tumor-infiltrating lymphocytes. Pinyol et al. Clin Cancer Res. 2019;25:2021-2023. De Galarreta et al. Cancer Discov. 2019;9:1124-1141.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 32 u And in humans, we have very HCC Immune Subclass few data. Only this study Biomarkers predicting response to checkpoint inhibitors- WNT activation suggests that those patients that are resistant to checkpoint WNT activation in 27 HCC patients treated with checkpoint inhibitors inhibitors, certainly have an enrichment of mutations with beta catenin and AXIN1. And this is a concept that we need to follow.

HCC, hepatocelular carcinoma. Harding et al. Clin Cancer Res. 2019;25:2116-2126.

u Now, I’m moving to Molecular Pathogenesis and Targeted combination therapies that represent a breakthrough Therapies in HCC in the management of the Epidemiology disease after 12 years of o primacy of sorafenib and later o Molecular pathogenesis and drivers on lenvatinib as well as single o Targeted therapies agents. • First and second line standard of care Well, the concept of hot • Immunotherapy tumors is very clear—tumors Combination therapies: new era in HCC management that have an immune tumor o microenvironment enriched • Atezolizumab + bevacizumab and beyond with CD8ts and tumors that • Ongoing combinations and emerging treatments express PD-L1, CD4, and so on. And these are more prone to respond. Whereas cold HCC, hepatocellular carcinoma. tumors are those that have a nonimmunogenic tumor microenvironment and that need another drug to switch these nonimmunogenic to immunogenic transforming these cold tumors into hot tumors to achieve durable clinical benefit from checkpoint inhibitors.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 33 u And this certainly might Combining VEGF Inhibitors With Checkpoint Inhibitors be achieved with VEGF

HOT TUMORS COLD TUMORS inhibitors that have been

VEGF Inhibitors in HCC: widely studied: bevacizumab,

o Bevacizumab sorafenib, lenvatinib, ↓TAMs o Sorafenib ↓M2 phenotype regorafenib, cabozantinib, and o Lenvatinib ↓Treg ramucirumab. These drugs o Regorafenib o Cabozantinib might be able to decrease T o Ramucirumab reg cells; increase dendritic cells and maturation of

↓MDSC dendritic cells; decrease M2

↑ proliferation macrophages, TAMs, and ↑cytotoxic activity ↓exhaustion MDSCs; and certainly, favor ↑ DC ↑maturation the immune response to checkpoint inhibitors.

HCC, hepatocellular carcinoma; VEGF, vascular endothelial growth factor receptor. Sharma et al. Science 2015;348:56-61. Fukumura et al. Nat Rev Clin Oncol. 2018;15:325-340.

u Also, tyrosine kinase inhibitors Combining TKIs With Checkpoint Inhibitors (TKIs) are able to transform these cold tumors, that Oncogenic signalling pathways oncogenic signaling-mediated MAPK signaling • Increased production of immunosuppressive WNT-ß-catenin signaling CDK4-CDK6 signaling Pathways activated after PTEN loss cytokines IL-6 and IL-10 • Increased production of • Decreased sensitivity to dsRNA via T cell excluded, into hot • Negative regulation of antigen presentation immunosuppressive cytokines DNMT1 • Diminished type I interferon response to PAMPs • Suppression of differentiation antigens • Disruption of BATF3 dendritic cell • Decreased antigen presentation • Poor T cell recruitment via (melanoma) recruitment by CCL4 • Decreased interferon target gene tumors that have dendritic cell activation of autophagosome • Reduced sensitivity to antiproliferative effects • Treg cell development activation of IFNγ and TNF activation, T-cell infiltration, and increased tumor antigen presentation. These TKIs— at least the ones that have demonstrated to be able to switch—are those that are blocking MAP signaling, particularly BRAF, CDK4, and CDK6 signaling, and also WNT signaling. TKI, tyrosine kinase inhibitor. Adapted from Kalbasi et al. Nat Rev Immunol. 2020;20:25-39.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 34 u In terms of HCC, I’m going to Rationale for Combination Strategies in HCC talk about some combinations Combo #1 that have made an impact in the disease.

Adapted from Llovet et al. Nat Rev Clin Oncol. 2018;15:599-616.

Phase 3 IMbrave150 Trial: u And the most important one is atezolizumab plus Atezolizumab + Bevacizumab vs Sorafenib First-Line bevacizumab. This is the

Atezolizumab IMbrave150 trial where this 1200 mg IV q3w Stratification + combination was compared • Region (Asia, excluding bevacizumab Key eligibility Japana/rest of world) 2 to 1 to sorafenib as single 15 mg/kg q3w Until loss of • Locally advanced • ECOG PS (0/1) clinical agent and a standard of care or metastatic benefit or Survival and/or • Macrovascular invasion R N = 501b un- follow-up with a co-primary endpoint unresectable HCC (MVI) and/or extrahepatic 2:1 acceptable • No prior systemic spread (EHS) toxicity of overall survival (OS) and therapy (presence/absence) Sorafenib progression-free survival. • Baseline a-fetoprotein (AFP; 400 mg BID < 400/≥ 400 ng/mL) (open-label)

Co-primary endpoints Key secondary endpoints (in testing strategy) • OS • IRF-assessed ORR per RECIST 1.1 • IRF-assessed PFS per RECIST 1.1 • IRF-assessed ORR per HCC mRECIST a Japan is included in rest of world. b An additional 57 Chinese patients in the China extension cohort were not included in the global population/analysis. ECOG PS, Eastern Cooperative Oncology Group performance status; IRF, independent review facility; MAb, monoclonal antibody; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RCTs, randomized controlled trials. Finn et al. N Engl J Med. 2020;382:1894-1905.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 35 Phase 3 IMbrave150 Trial: u And as you can see here, the trial was stopped at the first Overall Survival (Co-primary endpoint) interim with a hazard ratio of 0.58. Median OS (95% CI), moa Atezolizumab + Bevacizumab NE mOS: NE Sorafenib 13.2 (10.4-NE) HR, 0.58 (95% CI: 0.42-0.79)b P = .0006b,c

mOS: 13.2 mo

NE, not estimable; mOS, median overall survival. a 96 patients (29%) in the Atezo + Bev arm vs 65 (39%) in the sorafenib arm had an event. b HR and P value were from Cox model and log- rank test and were stratified by geographic region (Asia vs rest of world, including Japan), AFP level (<400 vs ≥400 ng/mL) at baseline and MVI and/or EHS (yes vs no) per IxRS. c The 2-sided P value boundary based on 161 events is .0033. Data cutoff, 29 Aug 2019; median survival follow-up, 8.6 mo. Finn et al. N Engl J Med. 2020;382:1894-1905.

u And now, we have a follow-up of this study, which recently IMbrave150: Updated OS reported at ASCO GI with a hazard ratio of 0.66. Median OS longer with atezolizumab + bevacizumab vs sorafenib (P < .001) survival for atezolizumab/ bevacizumab now has been Atezolizumab + Sorafenib Bevacizumab (n=165) reported to be 19.2 months (n=336) Primary Analysis (8.6 months median follow-up) and for sorafenib 13.4 months. Median OS NE 13.2 months OS HR 0.58 84.8% 72.2% Estimated 6-month survival rate (95% CI 80.9-88.7) (95% CI 65.1-79.4) 67.2% 54.6% Estimated 12-month survival rate (95% CI 61.3-73.1) (95% CI 45.2-64.0) Updated Analysis (15.6 months median follow-up) Median OS 19.2 months 13.4 months OS HR 0.66

OS, overall survival; NE, could not be evaluated. Finn et al. N Engl J Med. 2020;382:1894-1905; Finn et al, 2021.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 36 Phase 3 IMbrave150 Trial: u This is a substantial difference achieved by Progression-free Survival (Co-primary endpoint) this combination therapy

Median PFS (95% CI), mob that also had an impact in Atezolizumab + Bevacizumab 6.8 (5.7-8.3) Sorafenib 4.3 (4.0-5.6) progression-free survival, with 6-mo PFS rate: 55% HR, 0.59 (95% CI: 0.47-0.76)c,d P < .0001d a strong difference of 6.8 for 6-mo PFS rate: 37% atezolizumab/bevacizumab compared to 4.3 for sorafenib.

mPFS: 4.3 mo mPFS: 6.8 mo

a Assessed by IRF per RECIST 1.1. b 197 patients (59%) in the Atezo + Bev arm vs 109 (66%) in the sorafenib arm had an event. c HR and P value were from Cox model and log-rank test and were stratified by geographic region (Asia vs rest of world, including Japan), AFP level (< 400 vs ≥ 400 ng/mL) at baseline and MVI and/or EHS (yes vs no) per IxRS. d The 2-sided P value boundary is .002. Data cutoff, 29 Aug 2019; median survival follow-up, 8.6 mo. mPFS, median progression-free survival. Finn et al. N Engl J Med. 2020;382:1894-1905.

u The updated information points to 6.9 months for IMbrave150: Updated PFS atezolizumab + bevacizumab versus 4.3 months for PFS longer with atezolizumab + bevacizumab vs sorafenib (P < .001) sorafenib with a hazard ratio of 0.65. Atezolizumab + Sorafenib Bevacizumab (n=165) (n=336) Primary Analysis (8.6 months median follow-up) Median PFS 6.8 months 4.3 months PFS HR 0.59 Updated Analysis (15.6 months median follow-up) Median PFS 6.9 months 4.3 months PFS HR 0.65

PFS, progression-free survival. Finn et al. N Engl J Med. 2020;382:1894-1905; Finn et al, 2021.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 37 u Also, differences in terms Phase 3 IMbrave150 Trial: of objective response Response Rate assessed by RECIST—27% for IRF RECIST 1.1 IRF HCC mRECIST atezolizumab/bevacizumab; Atezolizymab + Sorafenib Atezolizumab + Sorafenib Bevacizumab (n = 159) Bevacizumab (n = 158) 33% by modified RECIST. (n = 326) (n = 325)a Confirmed ORR, n (%) (95% CI) 89 (27) 19 (12) 108 (33) 21 (13)

CR 18 (6) 0 33 (10) 3 (2)

PR 71 (22) 19 (12) 75 (23) 18 (11)

Stratified P valueb <.0001 <.0001

SC, n (%) 151 (46) 69 (43) 127 (39) 66 (42)

PD, n (%) 64 (20) 39 (25) 66 (20) 40 (25)

DCR, n (%) 240 (74) 88 (55) 235 (72) 87 (55)

Ongoing response, n (%)c 77 (87) 13 (68) 84 (78) 13 (62)

Median DOR, mo (95% CI) NE 6.3 NE 6.3

Event-free rate at 6 months, n (%) 88 59 82 63 a IRF HCC mRECIST–evaluable population was based on patients who presented with measurable disease at baseline per HCC mRECIST criteria. b Stratification factors included geographic region (Asia vs rest of world, including Japan), AFP level (<400 vs ≥400 ng/mL) at baseline and MVI and/or EHS (yes vs no) per IxRS. c Denominator is patients with confirmed CR/PR. Data cutoff, 29 Aug 2019; median survival follow-up, 8.6 mo. CR, complete response; DCR, disease control rate; DOR, duration of response; ORR, objective response rate; PD, progressive disease; PR, partial response. Finn et al. N Engl J Med. 2020;382:1894-1905.

u And with a recent update at ASCO GI, we have for modified IMbrave150: Updated Secondary Efficacy Outcomes RECIST, it was 36%, and for RECIST, 30% for atezolizumab/ Atezolizumab + bevacizumab—significantly Sorafenib Bevacizumab (n=159) (n=326) different compared to Confirmed ORR 30% 11% sorafenib. CR, n (%) 25 (8) 1 (<1) PR, n (%) 72 (22) 17 (11) Also, in terms of disease SD, n (%) 144 (44) 69 (43) control rate overall, we’re Ongoing response, n (%) 54 (56) 5 (28) talking about 75% disease Atezolizumab + Sorafenib Bevacizumab (n=18) control rate with the (n=97) Median DOR 18.1 months 14.9 months combination compared to 55% for sorafenib.

CR, complete response; DOR, duration of response; NE, not estimable; ORR, objective response rate; PFS, progression free response; PR, partial response; SD, stable disease. Finn et al. N Engl J Med. 2020;382:1894-1905; Finn et al, 2021.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 38 u In terms of adverse events, Phase 3 IMbrave150 Trial: Safety overall, the grade 3/4 ≥10% frequency of adverse events in either arm and >5% difference between arms treatment-related adverse

Atezolizumab + Bevacizumab Sorafenib events accounted for 37% of Diarrhea the cases in atezolizumab/ PPE bevacizumab and 55% Decreased appetite for sorafenib. The most Hypertension remarkable grade 3/4 were Abdominal pain hypertension, certainly, for Alopecia atezolizumab/bevacizumab Asthenia and also ALT increase and Pyrexia proteinuria. And for sorafenib, ALT increased All-Grade AEs All-Grade AEs Proteinuria the well-known hypertension Infusion-related reaction Grade 3-4 AEs Grade 3-4 AEs and hand-foot skin reaction

60% 50% 40% 30% 20% 10% 0 10% 20% 30% 40% 50% 60% and also diarrhea were AEs, adverse events; ALT, alanine aminotransferase; PPE, palmar-plantar erythrodysesthesia. remarkable. a Safety-evaluable population. Finn et al. N Engl J Med. 2020;382:1894-1905.

u Finally, this trial also assessed Phase 3 IMbrave150 Trial: patient-reported outcomes. a Patient-reported Outcomes That is increasingly an endpoint that the FDA is very interested to assess. And certainly, time to deterioration of the quality of life was significantly longer for atezolizumab/ bevacizumab—11.2 months’ time to deterioration compared to 3.6 months for sorafenib with a substantial Atezolizumab + bevacizumab delayed the time to deterioration of patient- difference. reported quality of life compared with sorafenib

EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire for Cancer. a Pre-specified secondary endpoint that was not formally tested; EORTC QLQ-C30 administered every 3 weeks on treatment and every 3 months after treatment discontinuation or progression. Data cutoff, 29 Aug 2019; median survival follow-up, 8.6 mo. Finn et al. N Engl J Med. 2020;382:1894-1905.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 39 u So, on this slide, you have a the upper boundary of that despite it’s below the one summary of all of the trials— 1.08 defined as the limit for in terms of upper boundary the phase 3 investigations in noninferiority. did not reach statistical advanced HCC. Certainly, on And then, on the right- significance. And, therefore, the left-hand side, you have hand side, you have for single-agent checkpoint in frontline atezolizumab/ regorafenib, cabozantinib, inhibitors, we need biomarkers bevacizumab superior to and ramucirumab—all of them to guide the strategy of sorafenib. All these figures in green—where you have treatment. represent comparisons with superiority versus placebo. sorafenib. And on the left-hand side, you Lenvatinib, as you can see have nivolumab crossing the in orange, is noninferior. It’s one. And on the right-hand crossing the one, but below side, you have pembrolizumab

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 40 Treatment Strategy for Advanced HCC

Advanced stage (BCLC C: Portal invasion and/or extrahepatic spread) Intermediate stage (BCLC B: Multinodular) progressing upon loco-regional therapies

Atezolizumab + bevacizumab

OS HR=0.59 (vs Sorafenib)

Child-Pugh A - ECOG PS ≤1 Treatment of esophageal varices required

1st/ 2nd line

Sorafenib Lenvatinib

OS HR=0.69 (vs Placebo) OS HR=0.92 (vs Sorafenib) Child-Pugh A - ECOG PS ≤2 *Higher benefit in HCV Child-Pugh A - ECOG PS ≤1 infection and lack of EHS No invasion main portal vein

PD

Regorafenib Cabozantinib Ramucirumab Nivolumab/ 3rd OS HR=0.63 (vs Placebo) OS HR=0.76 (vs Placebo) OS HR=0.71 (vs Placebo) Pembrolizumab/ line Nivolumab + ipilimumab Child-Pugh A - ECOG PS ≤1 Child-Pugh A - ECOG PS ≤1 Child-Pugh A - ECOG PS ≤1 Tolerant to sorafenib (≈85%) AFP ≥ 400ng/ml

AFP, alfa fetoprotein; ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocelular carcinoma; OS, overall survival; BCLC, Barcelona-Clinic Liver Cancer; HCV, hepatits C virus; EHS, extrahepatic spread. Llovet et al. Harrison 21st edition (in press) u This is the strategy. Certainly, Do not have, for instance, frontline, they certainly might recently reported in several a GI endoscopy. An upper be used in second line followed papers. Atezolizumab/ GI endoscopy is required regorafenib, cabozantinib, and bevacizumab will be frontline. before starting atezolizumab/ ramucirumab. And then you And then sorafenib and bevacizumab to rule out have the three drugs involving lenvatinib might be also esophageal varices or at single agent checkpoint— frontline in patients that least if there these varices, nivolumab, pembrolizumab, or either do not tolerate the those varices need to be the combination of nivolumab/ drugs—either atezolizumab treated before starting this ipilimumab—that are also or bevacizumab—or have combination. approved by FDA in second any autoimmune disease or And then, if sorafenib and line. have any contraindication. lenvatinib are not used in

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 41 u This is another scheme that Management of HCC: 2020 was recently reported by the American Association for Hepatocellular carcinoma the Study of Liver Disease

Intermediate stage (B) Very early stage (0) Early stage (A) Advanced stage (C) Terminal stage (D) Multinodular Single nodule ≤2 cm Single or ≤3 nodules ≤3 cm Portal invasion, N1, M1 Child-Pugh C* in Hepatology about the Child-Pugh A-B, ECOG Child-Pugh A, ECOG 0 Child-Pugh A-B, ECOG 0 Child-Pugh A-B, ECOG 1-2 ECOG >2 0 recommendation of frontline

Solitary 2-3 nodules ≤3 cm and second-line and third-line

Yes No treatment therapies. Optimal surgical candidate**

1st line systemic therapy ‡ Atezolizumab+Bevacizumab Yes Transplant candidate 1st/2nd line systemic therapy‡ Sorafenib, Lenvatinib No 3rd line systemic therapy Regorafenib, Cabozantinib, Ramucirumab Transplantation Resectio (US: nivolumab & Ablation (DDLT/LDLT) Ablation Chemoembolization pembrolizumab) Best supportive care n

1st line: Median OS > 17mo Median OS: 10yr Transplantation ; > 6 yr for resection/ablation Median OS >26-30 mo 2nd line: 13-15 mo Median OS >3 mo 3rd line: 8-12 mo

ECOG, Eastern Cooperative Oncology Group; HCC, hepatocelular carcinoma; OS, overall survival. Llovet et al. Hepatology 2020 May 20. doi: 10.1002/hep.31327. Online ahead of print.

u Finally, very briefly, I’m going Molecular Pathogenesis and Targeted to talk about other common Therapies in HCC combinations.

o Epidemiology o Molecular pathogenesis and drivers o Targeted therapies • First and second line standard of care • Immunotherapy o Combination therapies: new era in HCC management • Atezolizumab + bevacizumab and beyond • Ongoing combinations and emerging treatments

HCC, hepatocellular carcinoma.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 42 u And one of those is certainly Rationale for Combination Strategies in HCC lenvatinib/pembrolizumab. But also, now, more increasingly, there are triplets in place in terms of trials with cabozantinib combined with Combo #1 Combo #2 nivolumab and ipilimumab.

Adapted from Llovet et al. Nat Rev Clin Oncol. 2018;15:599-616.

u So, this is the KEYNOTE-524 or Phase 1b KEYNOTE-524 Trial (Study 116): 116—lenvatinib/pembrolizumab Lenvatinib + Pembrolizumab as a single-arm, phase 2, 100 patients. Interestingly enough, Lenvatinib (8mg [bodyweight <60 kg] or 12 mg [bodyweight ≥60 kg] PO QD) + pembrolizumab (200mg or placebo IV Q3W) objective responses were Inclusion criteria: Expansion (part 1&2) • uHCC • N = 6+ 98 here at the level of 46% by • BCLC Stage B or C • No prior systemic therapy • Child-Pugh class A • Overall: 100 patients modified RECIST with disease- • ECOG PS 0-1 evaluable control rates that also are unprecedented up to 90%. In this phase 2 study or phase 1b/2 study, the median survival was 22 months, and the progression-free survival was 9.3 months with this combination.

CR, complete response; DCR, disease control rate; ECOG PS, Eastern Cooperative Oncology Group performance status; HCC, hepatocellular carcinoma; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease. Finn et al. J Clin Oncol. 2020;38:2960-2970. And now, we have the LEAP-002 as the phase 3 trial comparing lenvatinib/ pembrolizumab versus lenvatinib alone.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 43 u Another trial that has been Phase 1/2 CheckMate 040 Trial: reported in JAMA with Nivolumab + Ipilimumab nivolumab plus ipilimumab, Overall Population Survival Stratified By and certainly, one of the Survival by Treatment Arm Best Overall Response combinations was able to achieve median survival of 22.8 months in second line. And those patients achieving objective response—either complete or partial response— was around 30% of the patients. Had an outstanding outcome. The median was not reached, but certainly, it was beyond 33 months.

CR, complete response; HCC, hepatocellular carcinoma; mOS, median overall survival; ; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease. Yau et al. JAMA Oncol. 2020;6:e204564.

u Another study that was Phase 1/2 CheckMate 040 Trial: conducted was the combination of nivolumab/ Nivolumab + Ipilimumab +/- Cabozantinib ipilimumab with cabozantinib. CheckMate 040 is a Phase 1/2, open-label, non-comparative, dose escalation and expansion trial of nivolumab in adults (≥18 years) with histologically confirmed advanced HCC with or without hepatitis C or B (HCV or HBV) infection1

• Aged ≥ 18 years with advanced HCC Doublet arm Primary endpoints: • Sorafenib naive or Nivolumab 240 Q2W IV • Safety and tolerability progression after or + cabozantinib 40 QD PO • ORR by investigator intolerance to assessment 1:1 sorafenib • HBV, HCV, or non- Triplet arm Secondary endpoints: viral HCC Nivolumab 3 Q2W IV + • DCR, DOR, TTR, • Child-Pugh score A5 Ipilimumab 1 Q6W IV + TTP, PFS, OS or A6 cabozantinib 40 QD PO

DCR, disease control rate; DOR, duration of response; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 44 u As you can see, as a triplet, Phase 1/2 CheckMate 040 Trial: median overall survival was not achieved, but the median Nivolumab + Ipilimumab +/- Cabozantinib progression-free survival was remarkable at 6.8 months.

Doublet arm Triplet arm Doublet arm Triplet arm OS PFS n = 36 n = 35 n = 36 n = 35

21.5 (13.1-NR) NA (15.1-NR) Median PFS (95% CI), mo 5.4 (3.2-10.9) 6.8 (4.0-14.3) Median OS (95% CI), mo 30 (83) 22 (63) Patients with an event, n 16 (44) 14 (40) Patients with an event, n (%) 15-month OS rate, % (95% CI) 64 (45-78) 70 (51-83)

HCC, hepatocellular carcinoma; OS, overall survival; PFS, progression-free survival. Yau et al. J Clin Oncol. 2020;38:478.

u In terms of adverse events, Phase 1/2 CheckMate 040 Trial: certainly, the triplet doesn’t seem to have an Nivolumab + Ipilimumab +/- Cabozantinib unmanageable adverse event profile despite that certainly the grade 3/4 are slightly higher than with the doublet arm.

BICR, blinded independent central review; BOR, best overall response; CR, complete response; DCR, disease control rate; DOR, duration of response; HCC, hepatocellular carcinoma; PD, progressive disease; PR, partial response; SD, stable disease; TRAE, treatment-related adverse event; TTR, time to response. Yau et al. J Clin Oncol. 2020;38:478.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 45 New Targets and Agents in Phase 1/2 Trials u So, in terms of new agents, here you have a list of new Trial name/ Setting Treatment Primary endpoints Study type Planned identifier enrollment, n agents that are currently Phase 1/2 trials Ongoing trials of novel combinations of molecular therapies for HCC GO30140 Advanced HCC/first-line Bevacizumab + atezolizumab Safety, ORR, PFS Phase 1b 430 (across all NCT02715531 cohorts) tested in combination

NCT03006926 Advanced HCC/first-line Lenvatinib + pembrolizumab Dose escalation: Safety, DLTs Phase 1b (dose-escalation and 97 Dose expansion: ORR, DOR dose-expansion) with checkpoint inhibitors. NCT03418922 Advanced HCC/first-line Lenvatinib + nivolumab Part1: DLTs, safety Phase 1b (part 1 and part 2) 26 Part2: Safety And, of course, you have NCT03895970 Advanced hepatobiliary tumors/second-line Lenvatinib + pembrolizumab ORR, DCR, PFS Phase 1b 50

CheckMate 040 Advanced HCC/first- or second-line Cabozantinib + nivolumab +/- Safety, ORR Phase 1/2 (dose-escalation, dose- 620 (across all regorafenib here, and you have NCT01658878 ipilimumab expansion) cohorts)

COSMIC-021 Advanced solid tumors, HCC/first-line Cabozantinib + atezolizumab Dose escalation: MTD, Recommended dose Phase 1b (dose-escalation and 1000 (across all NCT03170960 Dose expansion: ORR dose-expansion) cohorts) galunisertib, also a TGF-beta

CaboNivo Locally advanced HCC/neoadjuvant Cabozantinib + nivolumab Safety, number of patients who complete preoperative Phase 1b 15 NCT03299946 treatment and proceed to surgery inhibitor that is currently in CAMILLA Advanced GI tumors, HCC/second-line Cabozantinib + durvalumab MTD Phase 1b 30 NCT03539822 place. NCT03347292 Advanced HCC/first-line Regorafenib + pembrolizumab Safety, DLTs Phase 1b (dose-escalation and 40 dose-expansion)

REGOMUNE Advanced GI tumors, HCC/second-line Regorafenib + avelumab Part 1: Recommended phase II dose of regorafenib Phase 1/2 (part 1 and part 2) 212 NCT03475953 Part 2: ORR I have to say that the

NCT02572687 Advanced solid tumors, HCC/second-line Ramucirumab + durvalumab DLTs Phase 1 114 and AFP ≥1.5x upper limit of normal combination therapies are now NCT02082210 Advanced solid tumors, HCC/second-line Ramucirumab + emibetuzumab Part A: DLTs Phase ½ 97 Part B: ORR the hot topic. And really, we’re NCT02423343 Advanced solid tumors, HCC/second-line Galunisertib + nivolumab Phase Ib: MTD Phase 1b/2 (dose escalation and 75 and AFP ≥200 ng/mL cohort expansion) now in a new era of treatment HOT Issue: Combination therapies! in HCC where we will probably

DCR, disease control rate; DLTs, dose-limiting toxicities; HCC, hepatocelular carcinoma; ORR, objective response rate; PFS, progression-free survival not see any more trials with Adapted from Faivre et al. J Hepatol. 2020;72:342-352. single agents. We know the first in class is certainly atezolizumab/bevacizumab, but we need to know if this is also the best in class or if other combinations may even have a better outcome when treating patients in frontline HCC.

u And here, you have a summary Phase 3 Trials Ongoing With of how these immunotherapies Immunotherapies in HCC now are currently being tested in the adjuvant settings.

Adjuvant Therapies in Early HCC (After Resection/Ablation)

CheckMate 9DX Nivolumab vs placebo

KEYNOTE-937 Pembrolizumab vs placebo

IMbrave 050 Atezolizumab + pembrolizumab vs placebo

EMERALD-2 Durvalumab + bevacizumab vs placebo

Intermediate HCC

EMERALD-1 TACE + bevacizumab + durvalumab vs TACE

LEAP 012 TACE + lenvatinib + pembrolizumab vs TACE

CheckMate 74W TACE + nivolumab + ipilimumab vs TACE

REGONIVO TACE vs regorafenib + nivolumab

TACE-3 TACE + nivolumab vs TACE

HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization.

Advocating for Action in HCC: Delivering Impartial and Personalized Care – 46 u In advance, again, we know Phase 3 Trials Ongoing in the first in class. Let’s see if this is the best therapy, Advanced HCC First Line or the new trials—LEAP- 002 testing lenvatinib/ Advanced HCC Global: TKI + Immunotherapy pembrolizumab, COSMIC-312 LEAP-002 Lenvatinib + pembrolizumab testing atezolizumab/ COSMIC-312 Atezolizumab + cabozantinib cabozantinib, CheckMate- Global: Immunotherapy + Immunotherapy 9DW testing nivolumab/ CheckMate-9DW Nivolumab + ipilimumab ipilimumab, the HIMALAYA HIMALAYA Durvalumab + tremelimumab (FDA Orphan Drug Designation) trial testing durvalumab plus China: TKI + Immunotherapy tremelimumab, or the RESCUE RESCUE Camrelizumab + apatinib trial of camrelizumab plus apatinib. Let’s see if they will have a different outcome or even an improved outcome.

HCC, hepatocellular carcinoma; TKI, tyrosine kinase inhibitor.

Conclusions

Epidemiology and Molecular Drivers Systemic Treatment o The incidence of liver cancer is growing globally o Atezolizumab + bevacizumab and will reach 1M cases/year by 2025 – Superior to sorafenib in OS/PFS (phase 3) o Only 25% of molecular drivers in HCC are – First-line therapy! actionable o Recommended therapies after progression first-line – Sorafenib and lenvatinib – Second line: Regorafenib, cabozantinib and This information has not yet impacted ramucirumab precision oncology in HCC – Nivolumab and pembrolizumab: FDA approved, phase 3 trials did not hit primary endpoints o Emerging therapies in combination are currently tested in phase 2/3 clinical trials – Adjuvant, intermediate and advanced HCC

HCC, hepatocellular carcinoma; OS, overall survival; PFS, progression-free survival. u So, in conclusion, in terms of Sorafenib and lenvatinib can nivolumab/ipilimumab are epidemiology and molecular be also still frontline in patients FDA approved based on phase drivers, the incidence of liver with any contraindications for 2 data and got accelerated cancer is growing globally and atezolizumab/bevacizumab approval. And the emerging will reach 1,000,000 cases or with esophageal varices. therapies now are mostly by 2025. And only 25% of Otherwise, it will be second all of them in combination. molecular drivers in HCC are line. And phase 2/phase 3 trials actionable. And, unfortunately, And then, those patients are currently conducted in these data have not yet who progress with these adjuvant, intermediate, and impacted precision oncology regimens may be treated with advanced HCC with certainly in HCC because most of the regorafenib. And particularly, most of the instances with most prevalent drivers are regorafenib in case a patient immune therapies in the set of undruggable. receives sorafenib as prior drugs that are currently tested. In terms of systemic therapy, or cabozantinib, Dr. Baskin and I thank you for treatment, now atezolizumab ramucirumab in patients with your attention. plus bevacizumab is AFP of more than 400. unquestionably the standard And finally, we have of care in frontline. It shows that nivolumab alone, superiority to sorafenib. pembrolizumab alone or even

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