Tyrosine Kinase Inhibitors, Antibody-Drug Conjugates, and Proteolysis-Targeting Chimeras: The Pharmacology of Cutting-Edge Lung Cancer Therapies

The number of therapeutic options available for patients with advanced non–small-cell lung cancer has been led by deeper understanding of molecular drivers, immune function, and fundamental biology. In this article, we describe the relevant clinical pharmacologic characteristics of three broad classes of existing and investigational treatments, with a focus on mechanisms of action, adverse event profiles, pharmacokinetic and pharmacodynamic properties, and known and predicted resistance pathways. Specifically, within the kinase inhibitor class, agents directed against the RET, MET, and KRAS pathways are reviewed. Additionally, the first antibody-drug conjugates that target HER2 and HER3 are in trials and will ideally be available for patients soon. Finally, proteolysis-targeting chimeras approach pathway inhibition through enzyme degradation rather than target inhibition and are a promising platform for new agents in non–small-cell lung cancer and across cancer types. Each of these classes requires knowledge of clinical pharmacologic principles in development and use to ensure patient care in clinics and trials is optimized and personalized, including dosing and scheduling strategies, potential drug interactions, use in special populations, and monitoring parameters. Ideally, oncologists will continue to have new agents available across the non–small-cell lung cancer treatment spectrum to offer to a patient group that, until relatively recently, had few options.

Disparities in Pediatric Oncology: The 21st Century Opportunity to Improve Outcomes for Children and Adolescents With Cancer

Adult cancer disparities have been documented for decades and continue to persist despite clinical advancements in cancer prevention, detection, and treatment. Pediatric cancer survival has improved significantly in the United States for the past 5 decades to over 80%; however, disparate outcomes among children and adolescents with cancer still affect many populations in the United States and globally, including racial and ethnic minorities, populations with low socioeconomic status, and residents of underserved areas. To achieve equitable outcomes for all children and adolescents with cancer, it is imperative that concerted multilevel approaches be carried out to understand and address health disparities and to ensure access to high-quality cancer care. Addressing social determinants of health, such as removing barriers to health care access and ensuring access to social supports, can reduce pediatric cancer disparities. Nevertheless, public health policy, health system interventions, and innovative delivery of evidence-based services are critically needed. Partnerships among patients, caregivers, and health care providers, and among health care, academic, and governmental institutions, have a pivotal role in reducing cancer disparities and improving outcomes in the 21st century.

Current Challenges in Access to Melanoma Care: A Multidisciplinary Perspective

A diagnosis of melanoma requires multidisciplinary specialized care across all stages of disease. Although many important advances have been made for the treatment of melanoma for local and advanced disease, barriers to optimal care remain for many patients who live in areas without ready access to the expertise of a specialized melanoma center. In this article, we review some of the recent advances in the treatment of melanoma and the persistent challenges around the world that prevent the delivery of the best standard of care to patients living in the community. With the therapeutic landscape continuing to evolve and newer more complex drug therapies soon to be approved, it is important to recognize the many challenges that patients face and attempt to identify tools and policies that will help to improve treatment outcomes for their melanoma.

Creating a Blueprint of Well-Being in Oncology: An Approach for Addressing Burnout From ASCO’s Clinician Well-Being Taskforce

Optimizing the well-being of the oncology clinician has never been more important. Well-being is a critical priority for the cancer organization because burnout adversely impacts the quality of care, patient satisfaction, the workforce, and overall practice success. To date, 45% of U.S. ASCO member medical oncologists report experiencing burnout symptoms of emotional exhaustion and depersonalization. As the COVID-19 pandemic remains widespread with periods of outbreaks, recovery, and response with substantial personal and professional consequences for the clinician, it is imperative that the oncologist, team, and organization gain direct access to resources addressing burnout. In response, the Clinician Well-Being Task Force was created to improve the quality, safety, and value of cancer care by enhancing oncology clinician well-being and practice sustainability. Well-being is an integrative concept that characterizes quality of life and encompasses an individual's work- and personal health–related environmental, organizational, and psychosocial factors. These resources can be useful for the cancer organization to develop a well-being blueprint: a detailed start plan with recognized strategies and interventions targeting all oncology stakeholders to support a culture of community in oncology.

Disparities in Breast Cancer Associated With African American Identity

Persistent disparities in the burden of breast cancer between African Americans and White Americans have been documented over many decades. Features characterizing breast cancer in the African American community include a 40% higher mortality rate, younger age distribution, greater advanced-stage distribution, increased risk of biologically aggressive disease such as the triple-negative phenotype, and increased incidence of male breast cancer. Public health experts, genetics researchers, clinical trialists, multidisciplinary oncology teams, and advocates must collaborate to comprehensively address the multifactorial etiology of and remedies for breast cancer disparities. Efforts to achieve breast health equity through improved access to affordable, high-quality care are especially imperative in the context of the COVID-19 pandemic and its disproportionately high economic toll on African Americans.

The Ethical Imperative of Equity in Oncology: Lessons Learned From 2020 and a Path Forward

The COVID-19 pandemic and the simultaneous increased focus on structural racism and racial/ethnic disparities across the United States have shed light on glaring inequities in U.S. health care, both in oncology and more generally. In this article, we describe how, through the lens of fundamental ethical principles, an ethical imperative exists for the oncology community to overcome these inequities in cancer care, research, and the oncology workforce. We first explain why this is an ethical imperative, centering the discussion on lessons learned during 2020. We continue by describing ongoing equity-focused efforts by ASCO and other related professional medical organizations. We end with a call to action—all members of the oncology community have an ethical responsibility to take steps to address inequities in their clinical and academic work—and with guidance to practicing oncologists looking to optimize equity in their research and clinical practice.

Breaking Barriers: Addressing Issues of Inequality in Trial Enrollment and Clinical Outcomes for Patients With Kidney and Bladder Cancer

Despite recent treatment advances, kidney and bladder cancer cases have continued to rise in both incidence and mortality over the last few decades. Not every demographic subgroup of patients diagnosed with these cancers has an equivalent outcome. Women diagnosed with bladder cancer have worse overall survival than men diagnosed with bladder cancer. Older adults with muscle-invasive bladder cancer have worse cancer-specific outcomes than do younger patients. Black patients diagnosed with kidney and bladder cancers appear to have worse overall survival than White patients diagnosed with these cancers. Although these differences in outcomes are likely multifactorial, in many cases they may be based on modifiable approaches to screening, diagnosing, and treating patients. We explore various causes of these differences in outcomes between patients and address patient engagement strategies and avenues to effect change. In 2021, equity in cancer and cancer care delivery has a more prominent place in the hierarchy of the continuum of medicine. Continued focus on this topic is critical, with clear accountabilities established and barriers to best care for patients eliminated.

Moving Beyond 3+3: The Future of Clinical Trial Design

Misgivings have been raised about the operating characteristics of the canonical 3+3 dose-escalation phase I clinical trial design. Yet, the traditional 3+3 design is still the most commonly used. Although it has been implied that adhering to this design is due to a stubborn reluctance to adopt change despite other designs performing better in hypothetical computer-generated simulation models, the continued adherence to 3+3 dose-escalation phase I strategies is more likely because these designs perform the best in the real world, pinpointing the correct dose and important side effects with an acceptable degree of precision. Beyond statistical simulations, there are little data to refute the supposed shortcomings ascribed to the 3+3 method. Even so, to address the unique nuances of gene- and immune-targeted compounds, a variety of inventive phase 1 trial designs have been suggested. Strategies for developing these therapies have launched first-in-human studies devised to acquire a breadth of patient data that far exceed the size of a typical phase I design and blur the distinction between dose selection and efficacy evaluation. Recent phase I trials of promising cancer therapies assessed objective tumor response and durability at various doses and schedules as well as incorporated multiple expansion cohorts spanning a variety of histology or biomarker-defined tumor subtypes, sometimes resulting in U.S. Food and Drug Administration approval after phase I. This article reviews recent innovations in phase I design from the perspective of multiple stakeholders and provides recommendations for future trials.

Beyond the Androgen Receptor: The Sequence, the Mutants, and New Avengers in the Treatment of Castrate-Resistant Metastatic Prostate Cancer

Targeting the androgen receptor by depriving testosterone with gonadotropin-releasing hormone agonists or antagonists, or surgical castration, has been the backbone of metastatic prostate cancer treatment. Although most prostate cancers initially respond to androgen deprivation, metastatic castration-resistant prostate cancer evolves into a heterogeneous disease with diverse drivers of progression and mechanisms of therapeutic resistance. Development of castrate resistance phenotype is associated with lethality despite the recent noteworthy strides gained via increase in therapeutic options. Identification of novel therapeutics to further improve survival and achieve durable responses in metastatic castration-resistant prostate cancer is a clinical necessity. In this review, we outline the existing avengers for treatment of metastatic castration-resistant prostate cancer by clinical presentation, placing into context the clinical state of the patient, such as burden of disease and symptoms. Doing so might aid in the ability to optimize the sequence of agents and allow for maximal exposure to life-prolonging therapeutics. Realizing the limitations of the androgen signaling inhibition, we explore the androgen-indifferent prostate cancer: the mutants. Classically, these subtypes have been associated with variant histology, but androgen-indifferent prostate cancer features are now frequently observed in association with heterogeneous morphologies, including double-negative prostate cancers, lacking both androgen receptor and neuroendocrine features, or clinicopathologic criteria, such as the aggressive variant prostate cancer criteria. The framework of new avengers against metastatic castration-resistant prostate cancer based on mechanism, including DNA repair, immune checkpoint inhibition, PTEN/PI3K/AKT pathway, prostate-specific membrane antigen targets, bispecific T-cell engagers, and radionuclide therapies, is summarized in this review.

Immune Checkpoint Inhibition in Advanced Bladder and Kidney Cancer: Responses and Further Management

Immune checkpoint inhibitors have an established role in the treatment of newly diagnosed metastatic kidney cancer. Treatment regimens combining nivolumab plus ipilimumab, pembrolizumab plus axitinib, nivolumab plus cabozantinib, and pembrolizumab plus lenvatinib have demonstrated superior overall survival compared with sunitinib in randomized studies. Response rates vary from 42% to 71.1% with these combinations. Atezolizumab and pembrolizumab have been approved for the treatment of cisplatin-ineligible patients with metastatic bladder cancer. These and other checkpoint inhibitors have been studied in metastatic bladder cancer and are routinely used after progression on platinum-based chemotherapy. Durable responses are observed in bladder and kidney cancer. Although some patients may experience immune-related adverse events requiring treatment discontinuation, a portion of these patients will continue to experience a response off-therapy. At the time of progression, patients with metastatic kidney cancer may be treated with antiangiogenesis agents, and there are data suggesting that they may also be treated with a rechallenge of immunotherapy. In patients with metastatic bladder cancer who have progression after immune checkpoint inhibition, there are considerable data supporting the use of enfortumab vedotin. Ongoing studies are evaluating novel combinations of immune checkpoint inhibitors with other agents; thus, the treatment landscape of metastatic bladder and kidney cancer is expected to continue to evolve rapidly.