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 26th Annual Conference, which was held virtually during the pandemic, updates to the NCCN Guidelines were presented for several tumor types, which we briefly describe here. In addition, we’re including a section highlighting the field of immunotherapy for B-cell lymphoma.
Updates in HER2-Positive Breast Cancer
“With so many third-line options, how do you choose between trastuzumab deruxtecan and tucatinib? That’s the million-dollar question we are struggling with, and now we have margetuximab and neratinib in the mix.”
—Melinda L. Telli, MD
The recent approval of four agents for metastatic HER2-positive breast cancer has led to expanded recommendations in the NCCN Guidelines for this type of breast cancer, as described at the conference by Melinda L. Telli, MD, Professor of Medicine at Stanford University School of Medicine, Director of the Breast Cancer Program at the Stanford Cancer Institute, and Associate Director of the Stanford Women’s Cancer Center.
Melinda L. Telli, MD
Here is how the NCCN panel has incorporated these agents, along with updated guidance on other issues:
In advanced disease, a taxane plus trastuzumab and pertuzumab remains recommended in the first-line setting, and T-DM1 is recommended in the second line. For the third line and beyond, four new agents have been recently approved: (1) tucatinib plus capecitabine plus trastuzumab: indicated following at least one HER2-directed regimen for metastatic disease; efficacious in patients with brain metastases; (2) fam-trastuzumab deruxtecan-nxki (T-DXd): indicated following at least two HER2-directed regimens for metastatic disease; (3) margetuximab-cmkb plus chemotherapy: indicated following at least two HER2-directed regimens, at least one of which was for metastatic disease; (4) neratinib plus capecitabine: indicated following at least two HER2-directed regimens for metastatic disease.
Updates in Triple-Negative Breast Cancer
“The NCCN Guidelines give you a laundry list of options in metastatic disease, but there are new additions, including checkpoint inhibitors for PD-L1–positive patients, PARP inhibitors for BRCA1/2 mutations, and sacituzumab govitecan.”
—William J. Gradishar, MD, FACP, FASCO
William J. Gradishar, MD, FACP, FASCO, the Betsy Bramsen Professor of Breast Oncology and Chief of Hematology/Oncology at the Robert H Lurie Comprehensive Cancer
William J. Gradishar, MD, FACP, FASCO
Center of Northwestern University, Chicago, discussed updates for triple-negative breast cancer treatment. He provided data supporting the use of checkpoint inhibitors, both in the preoperative and metastatic settings; the antibody-drug conjugate sacituzumab govitecan-hziy for previously treated advanced disease; and inhibitors of poly (ADP-ribose) polymerase (PARP) for patients with BRCA1/2-mutated disease.
The guidelines have incorporated these drugs and others as follows:
Updates in Multiple Myeloma
“For previously treated patients, we now have a long list of drugs and combinations, and it speaks to the progress we have made in the field.”
—Shaji K. Kumar, MD
Shaji K. Kumar, MD
Shaji K. Kumar, MD, Professor of Medicine, Mayo Clinic Cancer Center, Rochester, Minnesota, described the expanded list of treatment options in newly diagnosed and recurrent multiple myeloma:
Gastric and Esophageal Cancers: Guidelines Updates
“In gastric, esophageal, and gastroesophageal junction cancers, I remember the time when we had one line of therapy. Now we are talking about multiple options in second and later lines, so we can tailor our regimens, not only to disease characteristics but to patient characteristics.”
—Crystal Denlinger, MD, FACP
In the treatment of gastric and esophageal cancers, recent studies have demonstrated robust findings for new drugs that, as a consequence, are being approved by the U.S. Food and Drug Administration and added to the NCCN Guidelines. These updates and their
Crystal Denlinger, MD, FACP
Mary F. Mulcahy, MD
supporting data were presented by Crystal Denlinger, MD, FACP, Chief of the Division of Gastrointestinal Medical Oncology and Co-Director of the Survivorship Program and Associate Professor in the Department of Hematology-Oncology at Fox Chase Cancer Center, Philadelphia, and Mary F. Mulcahy, MD, Professor of Hematology-Oncology at Northwestern University and Director of the Gastrointestinal Oncology Program at the Robert H. Lurie Comprehensive Cancer Center, Chicago. They reported:
Updates in Acute Myeloid Leukemia
“In the past years, NCCN Guidelines for AML have had changes due to new drug approvals. This year, the updates are more incremental than revolutionary, but there are some important ones.”
—Alexander E. Perl, MD
Alexander E. Perl, MD
The 2021 NCCN Guidelines for the management of acute myeloid leukemia (AML) emphasize physiologic rather than chronologic age as a criterion for choice of therapy; fit patients should be considered for intensive chemotherapy regardless of age, said -Alexander E. Perl, MD, of Abramson Cancer Center of the University of Pennsylvania, Philadelphia, where he is Associate Professor of Medicine. He described these new and emerging concepts and important updates to the guidelines:
Updates in Metastatic Castration-Resistant Prostate Cancer
“Metastatic castration-resistant prostate cancer represents the most advanced stage of prostate cancer, and patients may receive four or more lines of treatment at disease progression. The goal of treatment is to deliver effective, life-prolonging therapy to patients with metastatic castration-resistant prostate cancer, balancing longevity with quality of life.”
—Sandy Srinivas, MD
Sandy Srinivas, MD, Professor of Medicine, Stanford Cancer Institute, Palo Alto, California, described these developments in the field of metastatic castration-resistant prostate cancer.
Sandy Srinivas, MD
More sophisticated imaging methods are based on the use of prostate-specific membrane antigen (PSMA) and radionuclide ligands as part of positron-emission tomography (PET). PSMA PET overcomes the limitations of conventional computed tomography (CT) and bone scans and provides greater sensitivity and specificity. PSMA PET uses tracers to improve sensitivity, and some of these tracers are showing promise when used as part of treatment (eg, lutetium-177–labeled PSMA-617 [LuPSMA]).
In newly diagnosed patients, next-generation imaging can be considered under these circumstances: (1) when conventional imaging is equivocal or negative with continued high suspicion of metastatic disease; (2) for biochemically recurrent prostate cancer with prostate-specific antigen (PSA) ≥ 0.5 ng/mL; (3) for nonmetastatic castration-resistant prostate cancer in the setting of PSA doubling time up to 6 months when first-line metastatic therapy would be appropriate; and (4) for metastatic castration-resistant prostate cancer only if conventional scans are negative and there is a high suspicion of disease progression.
PARP inhibitors are considered for patients with genomic alterations in homologous recombinant repair (HRR) genes, including BRCA somatic and germline alterations. The NCCN Guidelines now incorporate both olaparib and rucaparib.
As a third-line option for patients previously treated with novel hormonal agents and/or docetaxel, cabazitaxel is a new option. The 2021 NCCN Guidelines incorporate the use of cabazitaxel or pembrolizumab in certain circumstances (ie, for patients with MSI-high tumors).
Updates in Non–Small Cell Lung Cancer
“A relatively new addition to the guidelines for NSCLC is dedicated to biomarker selection…. We believe that all newly diagnosed patients with NSCLC should be tested and that molecular testing should be considered for squamous cell lung cancer.”
—Dara L. Aisner, MD, PhD
Dara L. Aisner, MD, PhD
Gregory J. Riely, MD, PhD
Molecular testing has become an essential part of managing non–small cell lung cancer (NSCLC), as treatments are increasingly targeted. This issue is an important part of the updated NCCN Guidelines, as presented by Dara L. Aisner, MD, PhD, Associate Professor in the Department of Pathology at the University of Colorado School of Medicine, Aurora, and Gregory J. Riely, MD, PhD, Vice-Chair of Clinical Research in the Department of Medicine at Memorial Sloan Kettering Cancer Center and Associate Professor of Medicine, Weill Cornell Medical School. They reported the following updates:
Updates on CAR T-Cell Therapy for Relapsed or Refractory B-Cell Lymphomas
“Given the unprecedented bench-to-bedside clinical success, research and development aimed at refining our existing immunotherapies are proceeding at a rapid pace. It’s a very exciting time for oncologists.”
—Stephen J. Schuster, MD
Over the past 25 years, immunotherapy-based approaches to cancer treatment have become standards of care for a number of tumor types. In fact, immunotherapy is now considered the “fourth pillar” of clinical oncology.
Stephen J. Schuster, MD
Stephen J. Schuster, MD, Director of the Lymphoma Program and the Robert and Margarita Louis-Dreyfus Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research at the University of Pennsylvania, Philadelphia, described how one immunotherapy platform—CD19-directed chimeric antigen receptor (CAR) T-cell therapy—has entirely altered and improved the treatment of relapsed or refractory B-cell lymphomas.
Unlike the cells participating in a normal immune response, CAR T cells take a “direct approach.” They are engineered, he said, “to immediately engage targets, proliferate, and affect cytotoxicity.”
Prior to the advent of CAR T-cell therapy, first-line treatment of diffuse large B-cell lymphoma (DLBCL) was rituximab plus chemotherapy, which yielded a 5-year overall survival rate of 55%. Second-line treatment with high-dose chemotherapy plus autologous stem cell transplant would cure an additional 14% of patients. That left some 30% of patients with an unmet need, which was the impetus for the development of CAR T-cell technology, Dr. Schuster said.
Three different CD19-directed CAR T-cell products are approved for relapsed or refractory DLBCL: axicabtagene ciloleucel, approved in late 2017; tisagenlecleucel, -approved in early 2018; and lisocabtagene maraleucel, approved in 2021. All are indicated in the third-line setting, which means they are used for patients whose disease recurred after a second-line stem cell transplant and those who were unable to undergo transplant because of disease refractory to second-line therapy.
Key Data on Three Products: In the ZUMA-1 trial of axicabtagene ciloleucel,1 approximately 40% of patients were alive and progression-free at 24 months vs 4% of patients receiving third-line treatment in the pre–CAR T-cell era. Most failures occurred within the first 3 to 5 months, with very few events observed after 1 year.
In the global phase II JULIET trial of tisagenlecleucel, overall response rates and complete response rates were 54% and 40%,2 respectively, but as Dr. Schuster pointed out, response rates do not tell the whole story.
“What really matters is whether your patient is maintaining a response at 3, 6, and 12 months,” he said, reporting that one-third of tisagenlecleucel-treated patients were disease-free at 1 year. Patients in complete remission at 12 months have a 95% or better chance of long-term disease-free survival. “That’s how you should judge these products.”
In the Transcend NHL001 trial of lisocabtagene maraleucel, progression-free survival at 12 months was 44%; patients with a complete response (53%) had a 12-month progression-free survival of 65%.3 This study also demonstrated a similar pattern of early failures followed by a plateau beginning between 3 and 6 months; very few events were observed after 1 year.
Because the trials differed with respect to patient characteristics, Dr. Schuster emphasized that their outcomes cannot be compared. However, he noted that patients with high-grade B-cell lymphoma and DLBCL performed worse than those with primary mediastinal and transformed follicular lymphoma in the trials.
There are also some differences in toxicities between the CAR T-cell products. Cytokine-release syndrome is seen in all patients, but real-world data indicate that grade 3 cytokine-release syndrome occurs in the single digits, said Dr. Schuster, who noted that clinicians have “learned to mitigate this syndrome” by using tocilizumab earlier.
Although neurotoxicity is seen across the board in all three products, the products with 4-1BB co-stimulatory domains (tisagenlecleucel and lisocabtagene maraleucel) have considerably lower-grade neurotoxicity and cytokine-release syndrome than the CD28 product (axicabtagene ciloleucel).
“The takeaway message is we have three active products that are all capable of achieving long-term, disease-free survival in the third line of therapy for patients with DLBCL, transformed follicular lymphoma, or primary mediastinal large B-cell lymphoma,” he emphasized. “There are pros and cons in terms of logistics, but collectively, they represent the best option for patients in the third-line setting.”
Approaches for Improving Outcomes: Despite the success of CAR T-cell therapy, Dr. Schuster emphasized there is still a large unmet need for patients.
“We’re curing three times as many patients as we used to in the third-line setting, but only a third of patients with aggressive B-cell lymphomas are successfully treated,” he acknowledged. “Approximately half of the patients [for whom first-line chemotherapy fails] never make it to autologous transplant.”
For more from the 2021 NCCN Annual Conference, see interviews with Melinda L. Telli, MD; William J. Gradishar, MD, FACP, FASCO; Mary F. Mulcahy, MD; Alexander E. Perl, MD; Shaji K. Kumar, MD; Sandy Srinivas, MD, and others on The ASCO Post Newsreels at www.ascopost.com/videos.
The achievement of disease stability is important in terms of outcome. Apheresis and cell manufacturing are correlated with success or failure as well, as are the amount of prior therapy and the phenotype and quality of the pheresis product.
Finally, he added, bridging therapy is the “art of oncology.” Newer agents, including polatuzumab vedotin and ibrutinib, can help carry a patient to CAR T-cell treatment.
DISCLOSURE: Dr. Telli has served as a consultant or advisor to AbbVie, Aduro Biotech, Celgene, G1 Therapeutics, Daiichi Sankyo, Genentech/Roche, Immunomedics, Lilly, Merck, Natera, and Pfizer; has received institutional research funding from AbbVie, Bayer, Biothera, Calithera Biosciences, EMD Serono, Genentech, Medivation, Novartis, OncoSec, Pfizer, PharmaMar, Tesaro, and Vertex; has held other relationships with G1 Therapeutics; and has an immediate family member who has had other relationships with Pfizer. Dr. Gradishar has served as a consultant or advisor to AstraZeneca, Beyond Spring, Genentech/Roche, Merck, Pfizer, Puma, and Seattle Genetics. Dr. Kumar has served as a consultant or advisor to Cellectar, GeneCentrix, and Oncopeptides; has served as an institutional consultant or advisor to AbbVie, Amgen, Bluebird Bio, Celgene, Genentech/Roche, Janssen Oncology, Kite Pharma, Merck, Molecular Partners, and Takeda; and has received institutional research funding from AbbVie, CARsgen Therapeutics, Celgene, Janssen Oncology, Kite Pharma, MedImmune, Merck, Novartis, Roche/Genentech, Sanofi, Takeda, and TeneoBio. Dr. Denlinger has served as a consultant or advisor to Astellas Pharma, Bayer, BeiGene, Bristol Myers Squibb, Eli Lilly & Company, Exelixis, Merck, and Taiho Pharmaceutical; and has received institutional research funding from Agios, Amgen, Array BioPharma, AstraZeneca, BeiGene, Bristol Myers Squibb, Exelixis, Genmab, Lilly, MacroGenics, MedImmune, Sanofi, and Zymeworks. Dr. Mulcahy has received research funding from BTG. Dr. Perl has received honoraria from AbbVie, Actinium Pharmaceuticals, Astellas Pharma, BMS/Celgene, Daiichi Sankyo, Loxo, NewLink Genetics, and Syndax; has served as a consultant or advisor to AbbVie, Actinium Pharmaceuticals, Astellas Pharma, Daiichi Sankyo, FORMA Therapeutics, Onconova Therapeutics, and Sumitomo Dainippon; has received institutional research funding from AbbVie, Astellas Pharma, Bayer, Daiichi Sankyo, and Fujifilm; and has been reimbursed for travel, accommodations, or other expenses by AbbVie, Astellas Pharma, and Daiichi Sankyo. Dr. Srinivas has served as a consultant or advisor to AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Merck, and Seattle Genetics; has received institutional research funding from AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Genentech, Merck, and Seattle Genetics/Astellas; and has held other relationships with Pfizer. Dr. Aisner has received honoraria from Blueprint Medicines and Loxo, has received institutional research funding from Genentech/Roche, and holds intellectual property for “pneumatic cell collection device.” Dr. Riely has received institutional research funding from GlaxoSmithKline, Infinity Pharmaceuticals, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche/Genentech, and Takeda; holds institutional intellectual property in “pulsatile use of erlotinib to treat or prevent brain metastases”; has been reimbursed for travel, accommodations, or other expenses by Merck Sharp & Dohme; and has held other relationships with Pfizer, Roche/Genentech, and Takeda. Dr. Schuster has served as a consultant or advisory to AbbVie, Acerta Pharma/AstraZeneca, Allogene, BeiGene, Celgene, Genentech/Roche, Juno Therapeutics, Loxo Oncology, Nordic Nanovector, Novartis, and Tessa Therapeutics; has received institutional research funding from AbbVie, Adaptive Biotechnologies, Celgene, DTRM, Genentech/Roche, Incyte, Juno Therapeutics, Merck, Novartis, Pharmacyclics, and TG Therapeutics; and holds intellectual property in “combination therapies of CAR and PD-1 inhibitors” (via the University of Pennsylvania with royalties to Novartis).
1. Locke FL, Ghobadi A, Jacobson CA, et al: Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): A single-arm, multicentre, phase 1-2 trial. Lancet Oncol 20:31-42, 2019.
2. Schuster SJ, Bishop MR, Tam CS, et al: Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med 380:45-56, 2019.
3. Abramson JS, Palomba ML, Gordon LI, et al: Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): A multicentre seamless design study. Lancet 396:839-852, 2020.