2020 Spring Oncology Conference
Raising the Bar for the Standard of Care: Advances in the Management of Advanced Renal Cell Carcinoma
Learning Objectives • Formulate treatment strategies for advanced renal cell carcinoma (RCC) based on current evidence and patient/disease factors • Identify potential immune-related adverse events (AEs) and their onset during and after therapy • Implement strategies to recognize and appropriately manage side effects associated with tyrosine kinase inhibitors (TKIs) for advanced RCC 3
Overview of RCC • More than 50% of patients with RCC have no symptoms ‒ Diagnosis is through incidental imaging of the abdomen or chest ordered for unrelated symptoms • Hematuria serves as a warning sign: necessitates further evaluation and imaging leading to a diagnosis and treatment plan • Solid tumors are managed by size ‒ 20% of tumors >3 cm discovered incidentally will be benign ‒ Tumors ≥ 4 cm have metastatic potential • Treatment options include active surveillance, ablation, nephron-sparing tumor excision, nephrectomy, and systemic treatment • Predictors of a poor prognosis include poor functional status and metastasis 4 Gray RE, Harris GT. Am Fam Physician. 2019;99:179-184.
RCC Statistics 8th most common cancer – more common in men than women – representing 4.2% of all new cancers in the US • • In 2019, there were ~73,820 new cases of kidney and renal pelvis cancer and ~14,770 deaths from this disease Percent of Cases by Stage 5-Year Relative Survival 100% 92.5% 3% Localized (Confined 16% 80% to Primary Site) Percent Surviving 69.6% Regional (Spread to 60% Regional Lymph 41.9% Nodes) 40% Distant (Cancer Has Metastasized) 17% 20% 12.0% Unknown (Unstaged) 65% 0% Stage Localized Regional Distant Unknown 5 National Cancer Institute Surveillance, Epidemiology, and End Results Program. seer.cancer.gov/statfacts/html/kidrp.html; Accessed Mar 26, 2020.
Risk Factors for RCC • Hereditary factors include familial syndromes, including: ‒ von Hippel-Lindau syndrome ‒ Hereditary type 1 papillary renal carcinoma ‒ Familial renal oncocytoma ‒ Birt-Hogg-Dube syndrome • Few risk factors for RCC have been established ‒ Nonhereditary risk factors that possibly contribute to RCC include: • Cigarette smoking (increases in a dose-dependent fashion) • Obesity, particularly in women (as weight increases, risk of RCC increases) • Older age (median age at diagnosis: 64 years) Chow WH, et al. Nat Rev Urol. 2010;7:245-257; Sachdeva K, et al. emedicine.medscape.com/article/281340-overview#showall. 6 Accessed Mar 26, 2020.
Histology of RCC • Clear-cell RCC is the most common variety: 70% to 90% • Non − clear-cell RCC includes: ‒ Papillary: 10% to 15% ‒ Chromophobe: 3% to 5% ‒ Collecting duct: 1% to 2% ‒ Unclassified: 4% to 6% • In one study of 254 patients with advanced RCC, 16.1% harbored pathogenic germline mutations ‒ More than 20% of patients with non − clear-cell RCC had germline mutations • Sarcomatoid or rhabdoid features can be associated with any histology ‒ Harbinger of a poor prognosis in the VEGF TKI era VEGF = vascular endothelial growth factor. Carlo MI, et al. JAMA Oncol. 2018;4:1228-1235; Muglia VF, Prando A. Radiol Bras. 2015;48:166-174; Warren AY, Harrison D. World J Urol. 7 2018;36:1913-1926.
Patient Factors to Consider When Selecting Therapy • Comorbidities, especially conditions that affect a patient’s immune status • Symptoms of disease • Sites of disease • ECOG PS • Histology • Risk stratification • Medication history, including use of steroids ECOG PS = Eastern Cooperative Oncology Group performance status. Heng DY, et al. J Clin Oncol. 2009;27:5794-5799; Heng DY, et al. Lancet Oncol. 2013;14:141-148; van der Zanden LF, et al. Urol Oncol. 8 2017;35:e9-e16.
Risk Stratification: Laboratory and Clinical IMDC Criteria Risk Factors Yes (1)/ Risk Group by Number of Risk Factors No (0) KPS <80% 1/0 Favorable 0 <12 months 1/0 Time from diagnosis Intermediate 1-2 Hemoglobin <LLN 1/0 Neutrophil count >ULN 1/0 Poor 3-6 Platelet count >ULN 1/0 Corrected serum calcium >ULN 1/0 • Current FDA indications restrict certain treatments based on these risk categories KPS = Karnofsky Performance Status; LLN = lower limit of normal; ULN = upper limit of normal. IMDC, International Metastatic RCC Database Consortium. 9 Heng DY, et al. J Clin Oncol. 2009;27:5794-5799; Heng DY, et al. Lancet Oncol. 2013;14:141-148.
Goals of Treatment • Goal of therapy is different for each patient ‒ May be curative vs improvement in length and/or quality of life, depending on staging • For active sites of disease ‒ Medical treatments aim to shrink and destroy the cancer ‒ Surgical treatment aims to remove the cancer ‒ Ablative treatments (eg, radiation or thermal) aim to destroy local disease • For patients with multiple sites of disease, the mainstay treatment has been medical/systemic therapy Choueiri TK, et al. J Urol. 2011;185:60-66; NCCN Guidelines. Kidney cancer. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. 10 Accessed Mar 26, 2020.
Changing Treatment Landscape for Metastatic RCC • In the last 15 years, the landscape of treatment for clear-cell mRCC has changed immensely Nivolumab + Sorafenib Temsirolimus Axitinib Ipilimumab Targeted Therapy Era Immunotherapy Combination Era 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Pembrolizumab Bevacizumab + IFN- ⍺ Nivolumab +Axitinib Sunitinib Everolimus Cabozantinib Avelumab Pazopanib Everolimus + Levatinib + Axitinib mRCC = metastatic renal cell carcinoma. Klaassen Z. www.urotoday.com/conference-highlights/asco-2019-annual-meeting/asco-2019-kidney-cancer/113076-asco-2019-evolving-front-line- 11 therapy-in-metastatic-renal-cell-carcinoma.html. Accessed Mar 26, 2020.
Immunotherapy Mechanism of Action • T-cell activation is required for effective antitumor response • PD-1 and CTLA-4 expressed on Activated T cell T cell T cells act as “off” switches to down - CTLA-4 regulate the immune response PD-1 • CD28 Tumor cells can masquerade as Anti-PD-1 TCR normal cells by expressing PD-L1 PD-L1 Anti- Tumor cell TCR CTLA-4 death MHC • Blockade of PD-1 and PD-L1 MHC B7 and CTLA-4 ultimately allow up-regulation of immune responses Antigen-presenting Renal cancer cell targeting the tumor cell CTLA-4 = cytotoxic T-lymphocyte antigen 4; PD-1 = programmed cell death protein; PD-L1 = programmed death-ligand 1. Buchbinder EI, Desai A. Am J Clin Oncol . 2016;39:98-106; Institute for Clinical Immuno-Oncology. www.accc-cancer.org/docs/immuno- 12 oncology/iclio-webinar-new-mechanisms-of-action-v3-final. Accessed Mar 26, 2020; Tarhini A, et al. Cancer Biother Radiopharm . 2010;25:601-613.
Targeted Therapy Plus Immunotherapy in Advanced RCC • Boosts the RCC armamentarium Anticancer Immunity • VEGF inhibitors infiltrate T cells into tumors and enhance antitumor CD4 CD3 immunity • Adding PD-1 inhibitors may augment Anti-VEGF Myeloid VEGF TKI CD3 DCs these effects • Standard of care has shifted to Anti-PD-1 VEGF/R immunotherapy-based combination CD3 Treg APC PD-1 regimens in the 1st-line setting MDSCs Anti-PD-L1 Macrophage Tumor PD-L1 (M2 phenotype) 13 Garje R, et al. Cancers (Basel). 2020;12:143.
Case Study 1: Oliver • 63-year-old African American man presented for evaluation of hematuria and urinary obstruction • Medical history notable for hypertension and ongoing smoking • CT scan showed a left renal mass: 13.3 x 12.3 x 10 cm • Imaging revealed multiple lung nodules measuring up to 1.5 cm, consistent with metastatic disease • Oliver underwent biopsy of a lung nodule ‒ Pathology revealed metastatic clear-cell RCC with no sarcomatoid features • Oliver has a good PS and no additional IMDC risk factors other than needing systemic therapy within a year of diagnosis 14 PS = performance status.
Guidelines for Recurrent or Advanced Clear-Cell RCC: First-line Therapy Risk Status First-line Therapy • Axitinib + pembrolizumab • Favorable risk Pazopanib • Sunitinib Preferred regimens • Poor/intermediate Axitinib + pembrolizumab • risk Ipilimumab + nivolumab • Cabozantinib • Ipilimumab + nivolumab • Favorable risk Cabozantinib • Other recommended regimens Axitinib + avelumab • Poor/intermediate Pazopanib • risk Sunitinib • Axitinib + avelumab 15 NCCN Guidelines. Kidney cancer. www.nccn.org/professionals/physician_gls/pdf/kidney.pdf. Accessed Mar 26, 2020.
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