In 1996, the National Comprehensive Cancer Network® published its first set of Clinical Practice Guidelines in Oncology (NCCN Guidelines®) covering eight tumor types. Guidelines are now published for more than 60 tumor types, subtypes, and topics. During the NCCN’s 28th Annual Conference, updates to the NCCN Guidelines were presented for several tumor types. We briefly describe here the latest key recommendations.
Colon Cancer
“We tried to more clearly differentiate the algorithms for mismatch repair–deficient (dMMR/MSI-H) and mismatch repair–proficient tumors.”
—Aparna R. Parikh, MD
For the treatment of colon cancer, Breakthrough Therapy designations and approvals have recently been granted for KRAS G12C inhibitors, BRAF V600E inhibitors, and the tucatinib and trastuzumab combination for HER2-amplified metastatic disease. These developments indicate a promising future for an expanded arsenal of treatment options in colon cancer, according to the panelists who discussed this malignancy at the conference:
Aparna R. Parikh, MD
Midhun Malla, MD, MS
Katrina S. Pedersen, MD, MS
Aparna R. Parikh, MD, Assistant Professor of Medicine, Harvard Medical School, and Director, Massachusetts General Hospital Cancer Center’s Global Cancer Care Program; Midhun Malla, MD, MS, Assistant Professor of Medicine, West Virginia University Cancer Institute; and Katrina S. Pedersen, MD, MS, Associate Professor of Medicine, Siteman Cancer Center, Barnes-Jewish Hospital and Washington University School of Medicine.
The NCCN Guidelines have largely been restructured to reflect the different approaches for patients whose tumors are mismatch repair–deficient (dMMR or microsatellite unstable [MSI-H]) vs those with microsatellite-stable (MSS) tumors. This applies not only to the metastatic disease setting but now to the neoadjuvant setting as well.
In the treatment of the primary tumor, patients with dMMR/MSI-H clinical T4b tumors can be considered for neoadjuvant therapy with a checkpoint inhibitor (preferred); this list now includes single-agent dostarlimab-gxly in addition to single-agent pembrolizumab and nivolumab with or without ipilimumab, with FOLOX (fluorouracil, leucovorin, oxaliplatin) and CAPEOX (capecitabine/oxaliplatin) remaining the alternative options. Neoadjuvant therapy for patients with MMR-proficient/MSS tumors is with FOLFOX or CAPEOX.
This same neoadjuvant approach can also be taken for resectable oligometastatic disease. Dostarlimab was added as a category 2A recommendation for the neoadjuvant treatment of dMMR/MSI-H resectable synchronous liver-alone and/or lung-alone colorectal cancer metastases. As primary treatment for dMMR/MSI-H resectable metachronous colorectal cancer metastases in patients with no previous immunotherapy, dostarlimab, pembrolizumab, and nivolumab with or without ipilimumab were added as category 2A options.
Other updates include the following additions:
- For patients with HER2-amplified, RAS/BRAF wild-type MMR-proficient tumors who have experienced disease progression on oxaliplatin- or irinotecan-based regimens, trastuzumab plus tucatinib and trastuzumab plus fam-trastuzumab deruxtecan-nxki
- For refractory metastatic disease, the combination of trifluridine/tipiracil plus bevacizumab
- For the small percentage of patients with metastatic tumors harboring rare genetic alterations, selpercatinib for RET fusions and larotrectinib and entrectinib for NTRK fusions.
Bladder Cancer
“We are getting closer to [optimizing a] targeted, personalized therapy for our patients with bladder cancer.”
—Arlene O. Siefker-Radtke, MD
Targeted agents have revolutionized the treatment of metastatic urothelial cancer. The NCCN Guidelines still recommend platinum-based chemotherapy as the front-line standard, but these older regimens may potentially be replaced by targeted immunotherapeutic agents, according to Arlene O. Siefker-Radtke, MD, Professor of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center.
Arlene O. Siefker-Radtke, MD
The NCCN Guidelines state that single-agent pembrolizumab is an option for patients who cannot tolerate platinum-based front-line therapy. The NCCN Guidelines have been updated to include atezolizumab as another alternative. Moreover, for patients achieving a response or stable disease after front-line platinum-based chemotherapy, maintenance treatment with avelumab can now be considered. This recent category 1 recommendation provides clinicians with more options to improve long-term outcomes in the setting of metastatic urothelial cancer, Dr. Siefker-Radtke said.
Newer targeted options entered the NCCN Guidelines for metastatic urothelial cancer more than 1 year ago, “but they may still be new in the minds of many,” she said. They include the following agents:
- Erdafitinib, the first biomarker-directed therapy to be approved in this setting
- Enfortumab vedotin, the first antibody-drug conjugate to be approved, which was recently granted accelerated approval in combination with pembrolizumab
- The highly specific antibody-drug conjugate sacituzumab govitecan-hziy.
The NCCN Guidelines should soon reflect the approval of enfortumab vedotin plus pembrolizumab, a combination with the potential to change the front-line standard for cisplatin-ineligible patients with bladder cancer. “Maybe we now have a strategy that can beat platinum in general and result in less toxic therapy for our patients,” she said.
Kidney Cancer
“At this point in time, we have no studies with a background of individuals who have experienced disease progression on a contemporary doublet.... We want that to change.”
—Eric Jonasch, MD
The key updates to the NCCN Guidelines in kidney cancer were centered on subsequent therapies, according to Eric Jonasch, MD, Professor, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center. “We now have treatments separated out for individuals who received prior immunotherapy and for those who are immunotherapy-naive,” he said.
Eric Jonasch, MD
For patients with advanced clear cell renal cell carcinoma who experience disease progression on front-line agents, the NCCN Guidelines do not offer a list of “preferred” regimens. For immunotherapy-naive patients, treatment with an immunotherapy/immunotherapy doublet or immunotherapy/tyrosine kinase inhibitor doublet after a front-line tyrosine kinase inhibitor is reasonable, based on anecdotal evidence and smaller studies, he said.
For patients who have received prior immunotherapy, the treatment choice becomes more challenging, and includes both single agents and doublets. “It’s still evolving, but I think the main point is to look at the comorbidities of patients and their previous treatments and choose a regimen based on those factors,” he said. “Most of the time, you are going to see some kind of benefit from one of these regimens in the subsequent-line setting.”
Additions to the NCCN Guidelines in advanced kidney cancer follow:
- For tumors with clear cell histology, belzutifan was added as “useful in certain circumstances” (category 2B).
- For tumors with clear cell histology, tivozanib was added as an “other recommended” regimen for patients with prior immunotherapy and was considered “useful in certain circumstances” in the immunotherapy-naive population (both category 2A).
- For tumors with non–clear cell histology, nivolumab plus cabozantinib was added as an “other recommended” regimen (category 2A), and nivolumab plus ipilimumab was added as “useful in certain circumstances” (category 2B).
Malignant Glioma
“Using the [re]classification of gliomas by the World Health Organization criteria, we can resolve a lot of cases that otherwise were a bit of a coin toss.”
—Craig M. Horbinski, MD, PhD
An update in the treatment of malignant glioma were presented by L. Burt Nabors, MD, Vice-Chair for Research of Neurology and Neurosurgery, Professor and Director of Neuro-Oncology, University of Alabama at Birmingham O’Neal Comprehensive Cancer Center, and Craig M. Horbinski, MD, PhD, Professor of Pathology and Neurological Surgery and Director of Neuropathology, Northwestern University and Northwestern Memorial Hospital, Chicago.
L. Burt Nabors, MD
Craig M. Horbinski, MD, PhD
The fifth edition of the World Health Organization (WHO) classification of central nervous system tumors, which was published in 2021, regrouped diffuse gliomas into two primary categories: adult-type and pediatric-type. The former, which was the focus of the presentation at the NCCN Annual Conference, comprises IDH-mutant astrocytomas, IDH-mutant oligodendrogliomas with 1p/19q codeletion, and IDH–wild-type glioblastomas. The new classifications have been incorporated into the NCCN Guidelines, Dr. Horbinski said.
Dr. Nabors described additional updates related to the NCCN recommendation for the separate treatment of grade 2 and 3 astrocytomas, which he noted are based on the results of two phase III trials that demonstrated survival benefits: RTOG 9802 and CATNON. Based on these findings, the NCCN Guidelines for IDH-mutated astrocytoma and Karnofsky Performance Status ≥ 60 now recommend the following:
- For patients with high-risk WHO grade 2 IDH-mutated astrocytomas, standard radiotherapy followed by adjuvant chemotherapy with procarbazine plus lomustine and vincristine (carmustine may be substituted for lomustine)
- For patients with WHO grade 3 IDH-mutated astrocytomas, standard radiotherapy followed by adjuvant temozolomide for 12 months.
- For patients with WHO grade 4 IDH-mutated astrocytomas, standard radiotherapy plus concurrent and adjuvant temozolomide with or without alternating electric field therapy.
Esophageal or Gastroesophageal Junction Cancer
“Until immunotherapy came along, we had been stuck for a while with cytotoxic chemotherapy. But now, we have immune checkpoint inhibitors, which when added to cytotoxic drugs will increase the survival of patients with recurrent metastatic squamous cell carcinoma of the esophagus.”
—Michael K. Gibson, MD, PhD
The key update to the NCCN Guidelines for treating esophageal cancer is the addition of immunotherapy to chemotherapy in the first-line setting for recurrent or metastatic squamous cell carcinoma, according to Michael K. Gibson, MD, PhD, Director of Translational Research for Esophago-Gastric Cancer and Associate Professor of Medicine, Vanderbilt-Ingram Cancer Center, Nashville.
Michael K. Gibson, MD, PhD
Three large randomized clinical trials—KEYNOTE-590 for pembrolizumab, CheckMate 648 for nivolumab, and ESCORT-1st for camrelizumab—have shown that a survival benefit can be achieved by adding immunotherapy to a chemotherapy backbone. This has led to the NCCN panel’s consensus on the efficacy of these regimens and the recommendation of pembrolizumab and nivolumab in the NCCN Guidelines for advanced esophageal squamous cell carcinoma, Dr. Gibson said.
Also of note, the section on next-generation sequencing has been updated to better guide the selection of targeted agents. At present, these agents include trastuzumab, selpercatinib, pembrolizumab/nivolumab, entrectinib/larotrectinib, and dabrafenib/trametinib.
The panel also revisited the NCCN Guidelines for surveillance after successful local therapy for esophageal and gastroesophageal junction cancers. The optimal surveillance strategy for these patients has remained controversial, with no high-level evidence to guide the development of algorithms that balance benefits and risks (including cost) within this cohort, Dr. Gibson said.
The NCCN has now provided guidance for individualized stage-specific surveillance, with recommendations that vary according to the depth of tumor invasion and treatment modality. For patients with stage II or III tumors, those treated with bimodality therapy (ie, definitive chemoradiation) should undergo surveillance with esophagoduodenoscopy for at least 24 months, whereas those receiving trimodality therapy may forgo esophagoduodenoscopy but should be monitored for at least 36 months, the panel recommended.
Listed here are other updates for esophageal cancer:
- The recommendation for preoperative chemotherapy for locally advanced, resectable disease was removed.
- The section, Principles of Systemic Therapy for Unresectable Locally Advanced, Recurrent or Metastatic Disease, has been revised to better distinguish between adenocarcinoma and squamous cell carcinoma, with some changes in the NCCN Category of Preference designations.
Non–Small Cell Lung Cancer
“The guidelines now recommend the use of immune checkpoint inhibitors in addition to the use of induction or adjuvantchemotherapy for some patients with early-stage non–small cell lung cancer.”
—Gregory J. Riely, MD, PhD
In non–small cell lung cancer (NSCLC), tumor histology and the status of PD-L1 drive treatment selection. The NCCN Guidelines now include, for patients with stage II or III disease, the option of adjuvant pembrolizumab or atezolizumab to follow chemotherapy, said Gregory J. Riely, MD, PhD, Attending Physician and Vice-Chair of Clinical Research, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York.
Gregory J. Riely, MD, PhD
New to the NCCN Guidelines as well is the addition of neoadjuvant chemotherapy plus immunotherapy as a recommended treatment approach in a subset of patients. The NCCN Guidelines state: “All patients should be evaluated for preoperative therapy, with strong consideration for nivolumab plus chemotherapy in those patients with tumors ≥ 4 cm or node-positive and no contraindications to immune checkpoint inhibitors.”
Multiple molecular targets have been identified in NSCLC, with agents now approved in the first-line setting for patients with alterations in EGFR, ALK, ROS1, RET,MET exon 14, and BRAF. “In addition, new therapies are addressing targets we’ve not been able to target before, and we now have data for them in the second-line setting,” Dr. Riely said.
These new agents and their corresponding targets include fam-trastuzumab deruxtecan-nxki for HER2-mutant tumors, amivantamab and mobocertinib for tumors with EGFR exon 20 insertions, and sotorasib and adagrasib for KRAS G12C–mutant tumors. The NCCN Guidelines now recommend these agents as second-line options in the appropriate patients.
Multiple Myeloma
“Immunotherapy is where myeloma is going in the next few years, in a big way.”
—Natalie S. Callander, MD
In multiple myeloma, rapid changes in the treatment landscape have resulted in the “downgrading” of alkylators, anthracyclines, and thalidomide, given that multiple alternatives are much more effective, said Natalie S. Callander, MD, Professor of Medicine, University of Wisconsin School of Medicine and Public Health, and Director, Myeloma Clinical Program, Carbone Cancer Center.
Although quadruplet induction regimens in newly diagnosed patients became part of the NCCN’s recommendations more than a year ago, “there is now increased enthusiasm” about this approach, Dr. Callander said. These regimens, which typically include daratumumab, are backed by a strong body of phase II data, early phase III data, “and the expectation that we will have a large phase III trial sustaining the use of quadruplet
therapy,” she said.
Natalie S. Callander, MD
“However, immunotherapy is where myeloma is going in the next few years, in a big way,” she added. This includes chimeric antigen receptor (CAR) T-cell therapy, a growing number of antibody-drug conjugates and bispecific T-cell engagers, and naked antibodies, many of which target the myeloma-specific B-cell maturation antigen (BCMA). “Therapeutics with new targets are also in development.”
To this end, the NCCN Guidelines have been updated to recommend the BCMA-targeting bispecific antibody teclistimab, which has proved effective in patients who are refractory to three or more classes of drugs. The NCCN Guidelines also recognize that BCMA-targeted, CAR T-cell products have a useful role in patients who can afford a 4- to 6-week delay during their manufacturing. Two commercially available CAR T-cell products—idecabtagene vicleucel and ciltacabtagene autoleucel—have been added to the treatment options. Newer CAR T-cell products with shorter manufacturing times are in development.
“We just don’t know the optimal sequence of these treatments yet. At our center, we tend to move first to the bispecific T-cell engagers because they are more available. For fitter patients, we can start discussing and planning for CAR-T,” Dr. Callandar said.
The NCCN panel recently agreed to endorse the Second Revised International Stage System for multiple myeloma, meaning this should soon appear in the NCCN Guidelines. This more nuanced staging system evaluates cytogenetic risk in greater detail, resulting in three levels of risk rather than two.
Metastatic Breast Cancer
“The introduction of newer therapies and combination treatments has allowed for a more nuanced approach to treating breast cancer, leading to improved patient outcomes.”
—William J. Gradishar, MD
In metastatic breast cancer, the latest update to the NCCN Guidelines reflects the growing importance of combination therapies and personalized medicine in managing estrogen receptor–positive, HER2-positive, and triple-negative subtypes of breast cancer, according to William J. Gradishar, MD, the Betsy Branson Professor of Breast Oncology, Professor of Medicine, and Chief, Division of Hematology and Medical Oncology, Feinberg School of Medicine, Northwestern University, Chicago.
William J. Gradishar, MD
“Although the traditional endocrine therapies, such as aromatase inhibitors, tamoxifen, and fulvestrant, have shown benefits in treating estrogen receptor–positive breast cancer, they also present limitations, including the development of ESR1 [resistance] mutations and various toxicity issues,” said Dr. Gradishar.
Thus, options for treatment after disease progression in recurrent or metastatic disease have expanded to include the selective estrogen degrader elacestrant, PI3K inhibitors, and other targeted agents, which are reflected by the following additions to the NCCN Guidelines in patients with corresponding biomarkers:
- ESR1 mutation (hormone receptor–positive, HER2-negative): Elacestrant as “other recommended regimen” (category 2A)
- PIK3CA-activating mutation (hormone receptor–positive, HER2-negative): Alpelisib plus fulvestrant as the preferred second-line or subsequent-line therapy (category 1)
- NTRK fusion (any subtype): Larotrectinib or entrectinib as “useful in certain circumstances” (category 2A)
- MSI-H/dMMR (any subtype): Pembrolizumab or dostarlimab as “useful in certain circumstances” (category 2A)
- RET fusion (any subtype): Selpercatinib as “useful in certain circumstances” (category 2A)
- High tumor mutational burden (≥ 10 mut/mb; any subtype): Pembrolizumab as “useful in certain circumstances” (category 2A).
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
“There has been a shift toward using second-generation BTK inhibitors because of their comparable efficacy and reduced toxicity.”
—Deborah M. Stephens, DO
The NCCN Guidelines underscore the need for an individualized approach to treating chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). For front-line therapy, treatment selection considers a patient’s IGHV status, del (17p)/TP53 mutation status, age, and comorbidities. In choosing subsequent therapy, factors to consider include prior therapy, comorbidities, and resistance mutations, said Deborah M. Stephens, DO, Director of Chronic Lymphocytic Leukemia and Lymphoma Program, Associate Professor of Hematology and Hematology Malignancies, Huntsman Cancer Institute, University of Utah.
Deborah M. Stephens, DO
Updated recommendations for treatment have separated patients according to the presence or absence of del(17p)/TP53 mutations. Key updates based on this stratification include the following:
- Removal of ibrutinib as a “preferred” regimen across the board, based on toxicity; it is now listed as “other.”
- For patients with del(17p)/TP53 mutations:, ibrutinib plus venetoclax was added as an “other” regimen (category 2B); in the second line and beyond, ofatumumab was removed.
- For patients without del(17p)/TP53 mutations, in the first-line setting, venetoclax plus obinutuzumab as well as zanubrutinib have received category 1 recommendations. Ibrutinib plus venetoclax was added (category 2B).
- For patients without del(17b)/TP53 mutations, treatments were reorganized as second- and third-line treatments vs treatment for relapsed or refractory disease after prior Bruton’s tyrosine kinase (BTK) inhibitors or venetoclax.
- For patients without del(17p)/TP53 mutations, several regimens were removed, including in the first line chlorambucil, rituximab and fludarabine/rituximab, and in the second or third lines, chlorambucil/rituximab, alemtuzumab/rituximab, bendamustine/rituximab/ibrutinib, and dose-dense rituximab.
Recurrent or Metastatic Cervical Cancer
“KEYNOTE-826 moved the combination of pembrolizumab, platinum, and paclitaxel, plus or minus bevacizumab, into the first-line choice for patients with recurrent/advanced disease—in sites where the regimen is available.”
—Nadeem R. Abu-Rustum, MD
With immune checkpoint inhibitors having proved beneficial in cervical cancer, the NCCN Guidelines recommend that all patients with recurrent or progressive cervical cancer be tested for PD-L1 expression. In addition,
Nadeem R. Abu-Rustum, MD
where possible, testing for DNA mismatch repair status (deficient vs proficient) and tumor mutational burden (TMB) is also recommended. Although they are rare, NTRK gene fusions are seen in patients with cervical sarcoma, as are RET fusions in patients with advanced disease; with targeted agents available for these tumors, testing for these alterations can be beneficial, said Nadeem R. Abu-Rustum, MD, Chief, Gynecology Service, and the Avon Chair in Gynecologic Oncology Research, Memorial Sloan Kettering Cancer Center, New York.
The key update to the NCCN Guidelines for cervical cancer is the incorporation of pembrolizumab. Here is how the NCCN Guidelines have incorporated this checkpoint inhibitor:
- Pembrolizumab with cisplatin or carboplatin and paclitaxel plus or minus bevacizumab as a “preferred” first-line therapy for patients with PD-L1–positive recurrent tumors (category 1)
- Pembrolizumab as a “preferred” regimen in the second or subsequent line for patients with PD-L1–positive, dMMR/MSI-H or TMB-high tumors. Tisotumab vedotin-tftv has also become a “preferred agent” in this setting.
As Dr. Abu-Rustum pointed out, although pembrolizumab-based regimens are effective, their use requires specific pathologic testing, and the drugs are expensive; thus, this NCCN-recommended approach may not be feasible in countries with limited resources, where most cervical cancer occurs. Second-line options may include cisplatin/paclitaxel with bevacizumab or carboplatin/paclitaxel and bevacizumab. In rare cases of tumors with PD-L1 positivity, RET gene fusions, and NTRK gene fusions, approved drugs such as nivolumab, selpercatinib, and larotrectinib or entrectinib, respectively, are listed in the NCCN Guidelines as “useful in certain circumstances.”
For small cell neuroendocrine carcinoma of the cervix, the following drugs were added as “other” recommended regimens in the first-line setting: cisplatin/etoposide plus atezolizumab or durvalumab; carboplatin/etoposide plus atezolizumab or durvalumab; topotecan/paclitaxel/bevacizumab; and cisplatin or carboplatin plus paclitaxel. Several single agents were added for treating this tumor in the second or subsequent line.
Hepatobiliary Cancer
“Biliary tract cancer is the most targetable and actionable gastrointestinal tract cancer….Genomic profiling is the standard of care in the management of these cancers.”
—Mitesh J. Borad, MD
Updates in hepatobiliary cancers were presented at the conference by Mitesh J. Borad, MD, Director of the Cancer Cell, Gene, and Virus Therapy Lab, Director of the Liver and Biliary Cancer Research Program, and Director of Precision Cancer Therapeutics, Center for Individualized Medicine, Mayo Clinic Comprehensive Cancer Center, Scottsdale, Arizona.
Mitesh J. Borad, MD
Of most importance, the NCCN Guidelines for hepatobiliary cancers have been reorganized into separate Guidelines for hepatocellular carcinoma and biliary tract cancers. The text was also revised to have more “patient-centered” language.
Most of the changes in hepatobiliary cancer, as with other malignancies, pertained to the incorporation of checkpoint inhibitors, mainly durvalumab. The TOPAZ-1 trial evaluated the addition of durvalumab to gemcitabine/cisplatin; it found improvements in overall survival, progression-free survival, and response, without a meaningful increase in toxicity over chemotherapy alone. “The combination of gemcitabine and cisplatin plus durvalumab represents a new standard of care,” Dr. Borad said.
Highlights of the updated NCCN Guidelines for liver cancer follow:
- As first-line systemic therapy for inoperable or metastatic disease, durvalumab became a category 1 “other” recommended regimen. Additions considered “useful in certain circumstances” included atezolizumab plus bevacizumab for Child-Pugh class B tumors (category 2A) and nivolumab plus ipilimumab (category 2B) for TMB-high tumors.
- As subsequent-line systemic therapy, nivolumab plus ipilimumab was added for TMB-high tumors (category 2B). Some categories of recommendation for other treatments changed.
- The NCCN Guidelines have added a new section, Principles of Molecular Testing.
- The NCCN Guidelines for biliary tract cancer reflect the following changes, drawing on the value of durvalumab and the genomic landscape of this cancer:
- As neoadjuvant therapy, several regimens have been removed: fluorouracil/oxaliplatin (replaced with FOLFOX), gemcitabine/oxaliplatin, and single agents fluorouracil, capecitabine and gemcitabine.
- As neoadjuvant therapy, durvalumab plus gemcitabine/cisplatin has been added. This regimen already was the preferred systemic adjuvant treatment (category 1).
- As systemic adjuvant therapy, fluorouracil/cisplatin and capecitabine/cisplatin have been removed.
- Nivolumab plus ipilimumab was added for TMB-high tumors in the primary treatment setting (category 2B) and as subsequent treatment (category 2A).
- Newer targeted agents have been added as “useful in certain circumstances.” In the primary treatment setting, they include entrectinib and larotrectinib for NTRK fusion–positive patients; pralsetinib and selpercatinib for RET fusion–positive cholangiocarcinoma; pembrolizumab for dMMR/MSI-H tumors; and nivolumab/ipilimumab for TMB-high tumors.
- The previously listed agents are also recommended as subsequent-line therapy, joining dostarlimab for dMMR/MSI-H tumors, futibatinib and pemigatinib for cholangiocarcinomas with FGFR2 fusions or rearrangements (infigratinib was removed), and ivosidenib for cholangiocarcinomas with IDH1 mutations.
Metastatic Prostate Cancer
“Although androgen-deprivation therapy is still the backbone of therapy for metastatic hormone-sensitive prostate cancer, the treatment landscape has progressed to include doublet and triplet therapies.”
—Archana Ajmera, MSN, ANP-BC, AOCNP
Treatment decisions for metastatic prostate cancer are often dictated by tumor location, biology, and health status of the patient, despite androgen-deprivation therapy being a well-established standard of care in this disease setting. At the conference, the nuances of and updates to the treatment of this malignancy were discussed by Rana R. McKay, MD, Associate Professor of Medicine and Urology; nurse practitioner Archana Ajmera, MSN, ANP-BC, AOCNP, both of the University of San Diego Moores Cancer Center; and Kelly L. Stratton, MD, Associate Professor of Urologic Oncology, University of Oklahoma Health Stephenson Cancer Center.
Rana R. McKay, MD
Archana Ajmera, MSN, ANP-BC, AOCNP
Kelly L. Stratton, MD
The NCCN Guidelines offer category 1 evidence from phase III studies to support the efficacy of doublet therapy upon a backbone of androgen-deprivation therapy plus abiraterone, apalutamide, or enzalutamide. Category 1 evidence also supports triplet therapy with androgen-deprivation therapy plus docetaxel and either abiraterone or darolutamide.
This evidence is reflected in the updated NCCN Guidelines for the treatment of metastatic prostate cancer:
- The term “castration-naive” has been changed to “castration-sensitive.”
- For patients with high-volume metastatic castration-sensitive prostate cancer, androgen-deprivation therapy plus docetaxel has been removed as a “preferred” option, and androgen-deprivation therapy plus docetaxel with either abiraterone or darolutamide has been added as “preferred.”
- Pembrolizumab has been removed as a treatment option for MSI-H, dMMR, or TMB ≥ 10 mut/Mb cases in patients with prior novel hormone therapy/no prior docetaxel and prior docetaxel/no prior novel hormonal therapy; it is now listed as “useful in certain circumstances” in patients with prior docetaxel and prior novel hormonal therapy.
- A new section has been added: Principles of Quality-of-Life and Shared Decision-Making.
Ovarian Cancer
“The results of the studies are impressive. They suggest we may be changing the natural history of ovarian cancer by giving PARP inhibitors to women with BRCA-mutated ovarian cancer.”
—Joyce F. Liu, MD, MPH
Joyce F. Liu, MD, MPH
Although established as effective targeted agents for ovarian cancer, PARP inhibitors have recently been associated with some mixed results in some settings in the treatment of ovarian cancer. “The PARP inhibitor space has gotten to be more complex,” according to Joyce F. Liu, MD, MPH, Associate Chief and Director of Clinical Research, Division of Gynecologic Oncology, Dana-Farber Cancer Institute.
The NCCN Guidelines have addressed these recent developments in the following updates:
- Rucaparib was added as an option for first-line maintenance therapy after response to platinum-based chemotherapy.
- As a result of altered indications by the U.S. Food and Drug Administration (FDA) for PARP inhibitors, the NCCN Guidelines now include the following recommendations:
- For maintenance, restriction of niraparib to patients with deleterious or suspected deleterious germline BRCA mutations alone
- For maintenance, restriction of rucaparib to patients with deleterious or suspected BRCA-mutated tumors
- For recurrence, change in level of recommendation of all three PARP inhibitors (olaparib, niraparib, and rucaparib) to category 3, based upon the SOLO3 and ARIEL4 data, and withdrawal of FDA indications for PARP inhibitors as therapy for recurrent ovarian cancer.
- A statement was added that caution should be exercised when using maintenance PARP inhibition beyond 24 months, based upon retrospective data suggesting there may be risks for myelodysplastic syndrome or acute myeloid leukemia with longer exposure.
In another important update, the NCCN panel added the antibody-drug conjugate mirvetuximab soravtansine-gynx, which targets folate receptor alfa (FRα), as a “preferred” treatment for recurrent platinum-resistant ovarian cancer in patients with high FRα expression. Clinicians should be aware of the black box warning for ocular toxicities and should carefully follow instructions for monitoring and supportive care, she emphasized.
DISCLOSURE: Dr. Parikh has served as a consultant or scientific advisor to AbbVie, Bayer, Checkmate Pharmaceuticals, CVS Health Corporation, Delcath Systems, Eli Lilly, Foundation Medicine, Inivata, Karkinos Healthcare Private Limited, Pfizer, SAGA Diagnostics AB, Scare Therapeutics, SeaGen, Taiho Pharmaceuticals, and Value Analytics Labs; disclosed equity interest/stock options in or royalties from C2i Genomics, Parithera Ltd, UpToDate, and XGenomes; and has received grant or research support from Bristol Myers Squibb, Daiichi Sankyo, Erasca, Genentech, Mirati, Novartis, PMV Pharmaceuticals, PureTech Health, and Takeda. Dr. Malla has served as a consultant to AstraZeneca and Natera. Dr. Pedersen has served as a scientific advisor or consultant to AstraZeneca, GlaxoSmithKline, Novartis, and Pfizer; and has received grants or research support from Arcus Biosciences, BioLineRx, Boston Biomedical, Bristol Myers Squibb, Daiichi Sankyo, Genentech, HCW Biologics, Ipsen, Incyte Corporation, MedImmune, Merck, Natera, Nouscom, Novartis, Pfizer, Pierre-Fabre, Rafael Pharmaceuticals, and Roche. Dr. Siefker-Radtke has received consulting fees or honoraria from Janssen, Merck, and Taiho Pharmaceuticals and grant support from Bristol Myers Squibb, Janssen, Merck, Millennium Pharmaceuticals, and Nektar Therapeutics. Dr. Jonasch has served as a consultant, advisor, or expert witness for Aravive, AVEO Pharmaceuticals, Eisai, Exelixis, Ipsen, Merck, NiKang, Novartis, Pfizer, and Takeda and has received clinical research support from or has served on the data safety monitoring boards of Aravive, Arrowhead, Merck, NiKang, and Novartis. Dr. Horbinski reported no conflicts of interest. Dr. Nabors has served as a scientific advisor to Chimerix. Dr. Gibson has served as a scientific advisor to or received honoraria from AbbVie, Coherus BioSciences, and Daiichi Sankyo and has received grants or research support from Bristol Myers Squibb, Merck, PapiVax Biotech, and Soligenix. Dr. Riely has received grant/research support from Merck, Mirati Therapeutics, Novartis, Pfizer, Roche Laboratories, and Takeda Pharmaceuticals North America. Dr. Callander reported no conflicts of interest. Dr. Gradishar has served as a scientific advisor to or received honoraria from AstraZeneca, Biotheranostics, Daiichi Sankyo, Eli Lilly, ImmunoGen, MacroGenics, Puma Biotechnology, and Seattle Genetics. Dr.Stephens has served as a consultant to AstraZeneca, BeiGene, Bristol Myers Squibb, Celgene, Eli Lilly, and Genentech. Dr. Abu-Rustum has received grants or research support from GRAIL, Inc. Dr. Borad reported no conflicts of interest. Ms. Ajmera has received honoraria from Astellas, Bayer, Eisai, and Pfizer. Dr. McKay has served as a consultant to AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera Biosciences, Caris Life Sciences, Dendreon Corporation, Exelixis, Janssen, Merck, Myovant Sciences GmbH, Novartis, Pfizer, sanofi-aventis, SeaGen, Sorrento, Telix, and Tempus and has received grant/research support from Bayer HealthCare. Dr. Stratton reported financial relationships with Bayer, Carden Jennings Publishing, and Merck and has received grant/research support from Alliance Foundation Trials, AstraZeneca, Cold Genesys, EMD Serono, Istari Oncology, Myriad Genetic Laboratories, PAREXEL International Corporation, Pfizer, Propella Therapeutics, Sarah Cannon, Steba Biotech, TD2 Master CDA, Theradex Oncology, and UroGen Pharma. Dr. Liu has served as a consultant or advisor to AstraZeneca, Bristol Myers Squibb, Clovis Oncology, Genentech/Roche, GlaxoSmithKline, and Regeneron; and has received research funding from 2X Oncology, Acetylon Pharmaceuticals, Agenus, Aravive, Arch Oncology, AstraZeneca, Boston Biomedical, Bristol Myers Squibb, Clovis Oncology, CytomX Therapeutics, Genentech/Roche, Impact Therapeutics, Regeneron, Surface Oncology, Vigeo Therapeutics, and Zentalis.
