The use of innovative treatments such as chimeric antigen receptor (CAR) T-cell therapy is rapidly expanding. The challenges of receiving and delivering this novel therapy were discussed at the NCCN 2019 Annual Conference’s keynote session. In a separate roundtable discussion, additional stakeholders discussed how payers and providers are grappling with the cost of incorporating CAR T-cell therapy into practices.
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Dwight H. Owen, Bhavana Konda, Jennifer Sipos, Tom Liu, Amy Webb, Matthew D. Ringel, Cynthia D. Timmers and Manisha H. Shah
BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine–refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V–activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.
ClinicalTrials.gov identifier: NCT01723202
Thomas Kaley and Louis B. Nabors
Meningiomas represent a full spectrum of tumors that are the most common type of brain tumor in adults. Although most are benign, recent research has shown that the recurrence rate is high, especially for WHO grades 2 and 3, and overall survival is poor for these grades. Treatment is evolving, and recently sunitinib and bevacizumab have shown promise compared with historical treatments. However, more research is needed to identify better treatments for meningiomas. Treatment of brain metastases is another evolving field. Studies suggest that stereotactic radiosurgery is preferable to whole-brain radiation therapy and that immune checkpoint inhibitors and therapies targeted to the T790M mutation and ALK can improve outcomes in patients with non–small cell lung cancer and brain metastases.
Judith A. Paice
Advances in cancer treatment have led to a growing number of survivors. At least 40% of those survivors live with chronic pain and need pain control medication. This coincides with an epidemic of opioid misuse and overdose deaths, resulting in restrictive practices that can impact patients who experience severe pain. Oncologists and other healthcare professionals who treat patients with cancer need to balance considerations of opioid misuse with effective pain control and become better educated about risk factors and management of opioids in cancer survivors.
Anthony J. Olszanski
According to Dr. Anthony J. Olszanski, the most significant updates to the treatment of cutaneous melanoma include the recently published results of MSLT-II, which demonstrated that ultrasound-guided follow-up can be performed rather than a complete lymph node dissection, improving morbidity in patients with sentinel node metastases while not adversely affecting survival. In the adjuvant setting, the PD-1 inhibitors nivolumab and pembrolizumab are now FDA-approved, in addition to dabrafenib and trametinib, for patients with BRAF mutations.
Featured Updates to the NCCN Guidelines
Patrick A. Brown, Matthew Wieduwilt, Aaron Logan, Daniel J. DeAngelo, Eunice S. Wang, Amir Fathi, Ryan D. Cassaday, Mark Litzow, Anjali Advani, Patricia Aoun, Bhavana Bhatnagar, Michael W. Boyer, Teresa Bryan, Patrick W. Burke, Peter F. Coccia, Steven E. Coutre, Nitin Jain, Suzanne Kirby, Arthur Liu, Stephanie Massaro, Ryan J. Mattison, Olalekan Oluwole, Nikolaos Papadantonakis, Jae Park, Jeffrey E. Rubnitz, Geoffrey L. Uy, Kristina M. Gregory, Ndiya Ogba and Bijal Shah
Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.
Melinda L. Telli, William J. Gradishar and John H. Ward
Advances in molecular testing have ushered in the new era of precision medicine. The 2018 publication of the TAILORx trial helped refine the use of genetic expression assays, specifically the 21-gene recurrence score, in assigning patients to endocrine therapy alone or with chemotherapy. The NCCN Guidelines for Breast Cancer explore the clinical applications of this study. The algorithm for managing the axilla in early breast cancer has been further refined, based on the presence or absence of clinical evidence of lymph node involvement. Ovarian suppression has been validated as the optimal approach in higher risk premenopausal women, based on updated analysis of the SOFT and TEXT pivotal trials. In the metastatic setting, the NCCN Guidelines further reinforce the benefit of the CDK4/6 inhibitors, extending the “preferred” recommendation to all the available agents in metastatic disease. Options in triple-negative breast cancer now include, for the first time, an immunotherapeutic agent.
Neil P. Shah
The NCCN Guidelines for Chronic Myeloid Leukemia (CML) criteria for discontinuation of tyrosine kinase inhibitor (TKI) therapy have not seen significant updates in the past year, but the current guidelines reinforce the safety of treatment discontinuation in appropriate and consenting patients with CML in the chronic phase who have achieved and maintained a deep molecular response. According to Dr. Neil Shah, who presented the current data, some clinicians are still unaware that treatment discontinuation is an option. Patients who wish to stop TKI therapy should consult with a CML specialty center to confirm that discontinuation is safe and appropriate; they also should be counseled on all potential benefits and risks of stopping therapy, including TKI withdrawal syndrome. In patients with CML who experience relapse after discontinuing TKI therapy, a second TKI discontinuation can be successful among those who regained a deep molecular response after TKI rechallenge, although experience to date with second discontinuation attempts is very limited. Second-generation TKIs have also demonstrated improvement in rates of deep molecular remission, making treatment discontinuation possible for a larger proportion of patients.
Wells A. Messersmith
In the last year, several impactful updates have been added to the NCCN Guidelines for Colorectal Cancer (CRC) for the management of metastatic disease, including additional options for BRAF-mutated advanced CRC and the inclusion of combination immunotherapy (PD-1 and CTLA-4) for deficient mismatch repair/microsatellite instability (MSI)–high advanced CRC. According to Dr. Wells A. Messersmith, targeted therapies (ie, VEGFR, EGFR, multitargeted tyrosine kinase inhibitors) play an important role in CRC management, but none of them have been successful in the adjuvant setting (although checkpoint inhibition is now being tested in MSI-high stage III CRC). Reliable predictive biomarkers for most agents are still greatly lacking, highlighting the importance of investing in CRC biomarker studies.