In 1996, the National Comprehensive Cancer Network (NCCN) published its first set of Clinical Practice Guidelines in Oncology®, covering eight tumor types. Guidelines are now published for more than 60 tumor types and topics. During the NCCN’s 25th Annual Conference, which was held virtually during the COVID-19 pandemic, key 2020 updates were presented for several tumor types, many of which are briefly presented here. We also want to emphasize the emerging recognition of cardio-oncology as an important aspect of cancer care and the changing landscape of acute myeloid leukemia. We’ve summarized those presentations as well.
Metastatic Breast Cancer
“The phase II Destiny-Breast01 trial results got everyone excited in San Antonio and led to the approval of fam-trastuzumab-deruxtecan by the U.S. Food and Drug Administration.”
—William J. Gradishar, MD
William J. Gradishar, MD
Updates in the systemic treatment of metastatic breast cancer were presented by William J. Gradishar, MD, the Betsy Bramsen Professor of Breast Oncology and Chief of Hematology/Oncology at the Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago. The updates were few, but they should significantly improve the care of patients:
Metastatic Colon Cancer
“The treatment paradigm for metastatic colorectal cancer has greatly changed in recent years. It’s no longer just FOLFOX and FOLFIRI.”
—Dustin A. Deming, MD
Dustin A. Deming, MD
Dustin A. Deming, MD, Associate Professor, Carbone Cancer Center at the University of Wisconsin, said the updates to the NCCN Guidelines reflect the importance of molecular alterations, for which all patients with metastatic disease should be tested, and the efficacy of their targeted treatments. Their importance is reflected in the following recommendations:
“In the NCCN Guidelines for rectal cancer, you see the active incorporation of the total neoadjuvant therapy strategy.”
—Christopher G. Willett, MD
Christopher G. Willett, MD
The updates to the NCCN Guidelines for rectal cancer are focused on the appropriate use of total neoadjuvant therapy, which has emerged as a standard of care, according to Christopher G. Willett, MD, Professor and Chair, Department of Radiation Oncology, Duke Cancer Institute.
“It is critically important to obtain molecular profiling (germline and somatic), as a real proportion of patients who have targetable alterations in their tumors/bloodline….”
—Eileen M. O’Reilly, MD
Eileen M. O’Reilly, MD
Eileen M. O’Reilly, MD, the Winthrop Rockefeller Endowed Chair in Medical Oncology at Memorial Sloan Kettering Cancer Center, New York, said the NCCN Guidelines emphasize the need for clinicians to undertake “agnostic” germline testing for all persons with pancreatic cancer. Dr. O’Reilly is also Head of Hepatopancreaticobiliary and Neuroendocrine Cancers and Medical Co-Director of the David M. Rubenstein Center for Pancreatic Cancer Research.
Pancreatic cancer is dominated by a series of mutations in key driver oncogenes, most notably KRAS, TP53, CDK/N2A, and SMAD4. The remainder of the genome is characterized by less frequent alterations, including DNA damage–repair gene alterations, for which there are treatment implications. With these points in mind:
“I’m excited that emerging therapies with PARP inhibitors and PSMA-targeted drugs are awaited and will hopefully improve outcomes in metastatic castration-resistant prostate cancer.”
—Sandy Srinivas, MD
Sandy Srinivas, MD
Level 1 evidence from three phase III trials—SPARTAN for apalutamide, PROSPER for enzalutamide, and ARAMIS for darolutamide—led to the current NCCN Guidelines for nonmetastatic castration-resistant prostate cancer. This is a category that has been questioned, though recent imaging with more sensitive technique, such as prostate-specific membrane antigen (PSMA), may now identify the presence of occult metastases not seen on traditional imaging, with hope that this disease state might be eliminated, said Sandy Srinivas, MD, a medical oncologist at Stanford Cancer Institute.
Dr. Srinivas described the studies in metastatic prostate cancer that have led to many changes in the NCCN Guidelines:
In addition to describing updates, Dr. Srinivas indicated there is discussion about the category of nonmetastatic castration-resistant prostate cancer, because patients with no evidence of disease on conventional computed tomography or bone scans will have “hot spots” on more sophisticated imaging, for example, with PSMA positron-emission tomography. This is a new area of interest, along with promising emerging approaches that include PARP inhibitors in selected patients with BRCA2 mutations and lutetium-177, a PSMA-directed therapy.
Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
“It’s important to incorporate this test [Combined Positive Score] into your routine practice for all patients with recurrent/metastatic head and neck cancer, just as we now incorporate human papillomavirus testing in the oropharyngeal sites.”
—Robert Haddad, MD
Robert Haddad, MD
Robert Haddad, MD, Leader of the Head and Neck Oncology Program at the Dana-Farber Cancer Institute in Boston, discussed updates in the management of recurrent or metastatic head and neck cancers. He noted the most substantial change to clinical practice for previously untreated patients is the use of pembrolizumab alone or with chemotherapy as a new standard of care, based on the KEYNOTE-048 trial, which led to the drug’s approval by the U.S. Food and Drug Administration (FDA) in this setting. In the NCCN Guidelines:
“In the treatment of low-grade gliomas, it’s increasingly important to recognize the need to more uniformly obtain molecular diagnostics, including IDH1 status and 1p/19q status.”
—Burt Nabors, MD
Burt Nabors, MD
Burt Nabors, MD, Program Leader for Neuro-Oncology at the O’Neal Comprehensive Cancer Center of the University of Alabama at Birmingham, discussed the following updates to the management of gliomas:
Non–Muscle Invasive Bladder Cancer
“It’s important to understand the FDA approved a rigorous definition of BCG-unresponsive, non–muscle invasive bladder cancer, and this was a pivotal point in the management of bladder cancer.”
—Philippe E. Spiess, MD, MS
Philippe E. Spiess, MD, MS, FACS
Philippe E. Spiess, MD, MS, FACS, a senior member urologic oncologist and Assistant Chief of Surgical Services at the Moffitt Cancer Center, discussed updates to the NCCN Guidelines in non–muscle invasive bladder cancer. He noted that one of the most significant advances is the emerging role of novel intravesical and systemic therapies for the management of select patients with recurrent or persistent high-grade non–muscle invasive bladder cancer highlighted by the recent addition of pembrolizumab to the guidelines. The FDA approved the use of pembrolizumab in this clinical context in January 2020.
Dr. Spiess also noted that new definitions of disease states have been important to clinical trial design and interpretation. These new definitions differentiate between BCG-unresponsive and BCG-relapsing disease among patients with high-risk tumors. These efforts to accurately and consistently define BCG-unresponsive disease, now adopted by the FDA and rapidly adapted in the design and reporting of clinical trials, have been pivotal in evaluating the efficacy of investigated treatment regimens compared to therapeutic benchmarks for bladder cancer.
Sequencing Therapy for Patients With Lung Cancer
“The exact way PD-L1 testing is done is a bit of a moving target right now, but I would emphasize it has to get done for all patients with NSCLC.”
—Gregory J. Riely, MD
Gregory J. Riely, MD
Gregory J. Riely, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, noted that outcomes in non–small cell lung cancer (NSCLC) are improving thanks to the integration of molecular analysis and PD-L1 testing into standard practice, which allow for more individualized treatment. Proper biomarker evaluation now includes testing of PD-L1 status and the most common oncogenic drivers: EGFR, ALK, ROS1, BRAF, MET Exon 14, RET, and NTRK. The optimal use of molecular profiling has led to some new recommendations:
The combination of ipilimumab and nivolumab was recently shown to improve overall survival compared with chemotherapy alone in patients with metastatic or recurrent NSCLC and no prior anticancer therapy, regardless of PD-L1 status. Thus, in May 2020, the FDA approved this combination as first-line treatment of advanced disease in patients with PD-L1 expression ≥ 1%.
Cancer Risk Assessment and Management of Hereditary Cancers
“It is reasonable to have patients with pathogenic and likely pathogenic variants in moderate-risk genes followed up every 1 to 3 years, to see if patient and family recommendations can be further clarified.”
—Jennifer M. Weiss, MD, MS
Jennifer M. Weiss, MD, MS
Jennifer M. Weiss, MD, MS, of the University of Wisconsin Carbone Cancer Center, spoke on the emerging role of moderate-penetrance genes as part of a panel focused on the management of hereditary cancers. She noted that moderate-penetrance genes play an increasingly important role in defining hereditary cancer risks. With these genes, organ-specific cancer risks are fairly well defined for at least one cancer site, but another cancer site might not be as well defined. Including these genes in multigene panels may identify cancer risks not apparent based on an individual’s family history alone and will likely facilitate the collection of data to better delineate cancer risks.
In recognition of the importance of identifying these cancer susceptibility genes, the NCCN recommends:
Cardio-oncology Now Recognized
“Common risk factors predispose people to both cardiovascular disease and cancer. This has major implications for patients about to undergo systemic cancer treatment and also for survivorship.”
—Javid J. Moslehi, MD
Javid J. Moslehi, MD
“Cardio-oncology is a new area of interest because of the increased need to recognize cardiovascular disease in patients with cancer. These two leading causes of mortality in the world—cardiovascular disease and cancer—intersect in several ways. Cancer itself can cause cardiovascular disease; however, it is the explosion of effective cancer therapies, many with a myriad of cardiovascular toxicities that have contributed to the explosion of the field of cardio-oncology,” explained Javid J. Moslehi, MD, an oncologist at Vanderbilt-Ingram Cancer Center.
It is well known that anthracyclines and radiation can have deleterious effects on the heart and blood vessels, and these effects can occur years after treatment. As new treatments have become available, there is a growing awareness of cardiotoxicity that can be associated with certain agents. They include HER2-targeted therapies, fluorouracil and related drugs, VEGF inhibitors, tyrosine kinase inhibitors, and androgen-deprivation therapy. More recently, immune checkpoint inhibitors have been associated with a rare but life-threatening cardiac condition called immune checkpoint inhibitor–associated myocarditis.
In recognition of the new-found links between cancer and cardiovascular disease, the NCCN Guidelines for survivorship now include recommendations for a full cardiovascular assessment and monitoring of patients with cancer and survivors. Dr. Moslehi advises history and physical exams and an echocardiogram for any patient who has completed anthracycline therapy and has at least one cardiovascular risk factor. “In that instance, one single echocardiogram could prevent heart failure,” he noted. “We increasingly recognize asymptomatic patients with structural heart disease on echocardiogram. It is important to pick this up before it becomes full-blown congestive heart failure.
Dr. Moslehi encouraged all oncologists to employ the “ABCDEs” of cardiovascular disease prevention in cancer survivors. This simple checklist can prevent the development of cardiovascular disease in cancer survivors:
Novel and Emerging Treatment Strategies for AML
“Due to the biologic diversity of AML, it is essential for newly diagnosed patients to undergo comprehensive genomic assessment that includes cytogenetics [to detect gene fusions] and molecular profiling [no gene fusions].”
—Eunice S. Wang, MD
Genetic testing is now part of the assessment of patients with acute myeloid leukemia (AML), and therapy can be safely delayed until these results are known, explained Eunice S. Wang, MD, Chief of the Leukemia Service, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Eunice S. Wang, MD
“Many of the novel drugs are specifically tailored for AML biology, and it makes sense to wait for genomic testing results,” Dr. Wang said. “Genomic testing is recommended as the disease progresses. Clinicians need to be aware of the best treatment at each stage of the disease.”
Based on the biology of AML, FLT3 inhibitors and IDH inhibitors are now used to treat patients with AML who have these respective mutations. Many FLT3 inhibitors are in development and many are being studied in combination with other drugs, including the “7+3” regimen, she said. IDH mutations occur less frequently in newly diagnosed patients than FLT3 mutations. IDH1 occurs in up to 10% and IDH2, in 15%–20%. Two IDH inhibitors are currently available: ivosidenib (IDH1 inhibitor) and enasidenib (IDH2 inhibitor).
Promising approaches for AML include venetoclax in combination with low-dose cytarabine and the 7+3 regimen, perhaps for use as a bridge to transplant. Small studies suggest that novel inhibitors of the apoptosis pathway for AML may be worthy of pursuit.
In general, studies of immune checkpoint inhibitors in AML have been disappointing. The rate of adverse events is high, and, at present, there is no clear role for checkpoint inhibitors in AML, according to Dr. Wang.
Small trials suggest a more promising approach may be to target specific antigens expressed on leukemic cells: CD33, CD70/CD27, and CD47, by the CD47-directed monoclonal antibody magrolimab. Antibody-drug conjugates and several bispecific antibodies are being explored in AML as well.
“After all of this work and all these new agents, surely we must have found a cure for AML. Unfortunately, despite groundbreaking, paradigm-changing therapies, the median overall survival remains 18 months,” she said. “The future of treating AML will rely on combinations of approved chemotherapy and targeted agents, novel mechanistic agents, and immunotherapy. I do think that over the next few years, we can do better.”
DISCLOSURE: Dr. Gradishar reported no conflicts of interest. Dr. Spiess serves as Vice Chair, NCCN Penile and Bladder Cancer Panel. Dr. Deming has served as a consultant or advisor to BMS, Array, Genentech, Taiho, Bayer, Ipsen, Novocure, Promega, and Pfizer and has received research funding from Merck, AbbVie, BMS, Lilly, and Revolution Medicine. Dr. Willett has received honorarium from Oakstone CME. Dr. O’Reilly has served as a consultant for Celgene, Ipsen, Targovax, Polaris, CytomX Therapeutics, Merck, AstraZeneca, Rafael, and Sobi and has received research or grant support from Celgene, Genentech-Roche, AstraZeneca, BMS, Silenseed, MabVax, and ActaBiologica. Dr. Srinivas has served as a consultant or advisor to and served on the speakers bureau for Genentech/Roche and has received institutional research funding from several companies. Dr Haddad has received research funding from BMS, Merck, Pfizer, Kur,a and Genentech; has served as a consultant for Merck, BMS, Eisai, Pfizer, AstraZeneca, Genentech, Loxo, Nanobiotix, GSK, Glenmark, and Immunomic. Dr. Nabors has served on the scientific advisory boards of BTG Pharmaceuticals, Karyopharm, KIYATEC, and Blue Earth Diagnostics and on the data safety and monitoring board for Ziopharm and the University of Pennsylvania. Dr. Riely has received institutional research funding from Novartis, Pfizer, Merck, Mirati, Roche, and Takeda. Dr. Weiss reported no conflicts of interest. Dr. Moslehi has served as a consultant or advisor to BMS, Deciphera, Ipsen, Myokardia, Novartis, Pfizer, Regeneron, and Takeda and has received research funding from BMS and Pfizer. Dr. Wang has served as a consultant or advisor to AbbVie, Agios, Amgen, Astellas Pharma, Celytad, Daiichi Sankyo, Jazz Pharmaceuticals, Kite/Gilead, Kura Oncology, Macrogenics, Pfizer, PTC Therapeutics, and Stemline Therapeutics and has served on the speakers bureaus of Jazz Pharmaceuticals and Stemline Therapeutics.