Immunotherapy is now the fourth pillar of cancer treatment, but the methodology used to determine who will benefit is still a work in progress. PD-L1 is commonly used as a predictive biomarker for immunotherapy, but others—such as immunogenic tumor biomarkers, host environment biomarkers and biomarkers of nonresponse—are being actively investigated. Additionally, research in combining biomarkers is currently being conducted, with new data emerging all the time.
Victoria T. Brown, Dana Drzayich Antol, Patrick N. Racsa, Melea A. Ward and Jarushka Naidoo
Background: Anti-PD1/PD-L1 therapy is standard-of-care for patients with a variety of advanced malignancies. Although clinical trials report a lower incidence of grade 3-4 toxicities than observed with cytotoxic agents, it is imperative that clinicians identify and manage the unique toxicities of these agents. We aimed to identify real-world incidence of immune-related toxicities and management for patients treated with anti-PD1/PD-L1 agents prior to publication of clinical practice guidelines. Methods: Patients enrolled in a Humana Medicare Advantage plan who initiated any anti-PD1/PD-L1 therapy September 1, 2014–February 28, 2018 were identified. NCCN Guidelines for immune-related toxicity were used to determine appropriate pharmacy and medical codes from administrative claims data for toxicity identification and management. ICD-10 codes were examined for patients requiring hospital or ED visits, and HCPCS and NDC codes were used for patients requiring toxicity treatment (eg, corticosteroids, anti-TNFα). Results: 6,005 patients were identified; 39.1% were female, median (IQR) age was 72 years (67–77). The majority (64.7%) had thoracic cancers; 16.3% genitourinary cancers; and 12.8% skin cancers. The median number of anti-PD1/PD-L1 doses received was 4 (2–8). Overall, 62.5% (n=3,751) of patients experienced >1 toxicity with half (n=1,913) requiring an inpatient stay or ED visit, and the other half (n=1,838) receiving outpatient toxicity medication. A similar proportion of patients developed >1 toxicity, regardless of age: <75 years, 62.4% (n=2,416); and 62.5% (n=1,335) >75 years. Systemic corticosteroids were used by 61.3% (n=2,300) of patients that experienced toxicity. The most frequently observed toxicity in this dataset by organ system was cardiovascular (18.5%, n=1,108), which was comprised largely of arrhythmias (13.7%; n=823), and endocrine toxicities (15.8%; n=950), mostly type 2 diabetes (11.9%; n=714). Conclusion: Real-world data from a large Medicare Advantage plan indicate that half of patients receiving anti-PD1/anti-PD-L1 may experience a toxicity resulting in an inpatient stay or ED visit with no difference by age. While attribution of toxicity may be challenging using claims data, the spectrum of immune-related toxicities in the real world may differ from those reported in clinical trials. Future research should evaluate incidence and management of toxicities post-guideline release and monitor changes in site of care for management.
Alexander S. Baras, Jarushka Naidoo, Christine L. Hann, Peter B. Illei, Charles W. Reninger III and Josh Lauring
Tumor DNA sequencing can identify rare driver genomic alterations that suggest targets for cancer therapy, even when these drivers cannot be suspected on clinical grounds. In some cases, genomic alterations identified in the tumor can lead to a change in diagnosis with implications for prognosis and therapy. This report describes a case in which evaluation of tumor sequencing results by a molecular tumor board (MTB) led to rediagnosis of a non–small cell lung cancer as highly aggressive NUT midline carcinoma, with implications for targeted therapy using an investigational bromodomain and extraterminal (BET) inhibitor. We discuss the molecular biology and diagnosis of this rare tumor, and suggest how improved annotation of tumor sequencing reports and multidisciplinary expertise of MTBs can facilitate timely diagnosis of rare tumors and application of potential targeted therapies.
Jarushka Naidoo, Jiajia Zhang, Evan J. Lipson, Patrick M. Forde, Karthik Suresh, Kendall F. Moseley, Seema Mehta, Shawn G. Kwatra, Alyssa M. Parian, Amy K. Kim, John C. Probasco, Rosanne Rouf, Jennifer E. Thorne, Satish Shanbhag, Joanne Riemer, Ami A. Shah, Drew M. Pardoll, Clifton O. Bingham III, Julie R. Brahmer and Laura C. Cappelli
Background: Immune checkpoint inhibitors (ICIs) may cause immune-related adverse events (irAEs). Methods to obtain real-time multidisciplinary input for irAEs that require subspecialist care are unknown. This study aimed to determine whether a virtual multidisciplinary immune-related toxicity (IR-tox) team of oncology and medicine subspecialists would be feasible to implement, be used by oncology providers, and identify patients for whom multidisciplinary input is sought. Patients and Methods: Patients treated with ICIs and referred to the IR-tox team in August 2017 through March 2018 were identified. Feasibility was defined as receipt of electronic referrals and provision of recommendations within 24 hours of referral. Use was defined as the proportion of referring providers who used the team’s recommendations, which was determined through a postpilot survey. Demographics and tumor, treatment, and referral data were collected. Patient features and irAE associations were analyzed. Results: The IR-tox team was found to be feasible and used: 117 referrals from 102 patients were received in 8 months, all providers received recommendations within 24 hours, 100% of surveyed providers used the recommendations, and 74% changed patient management based on IR-tox team recommendations. Referrals were for suspected irAEs (n=106; 91%) and suitability to treat with ICIs (n=11; 10%). In referred patients, median age was 64 years, 54% were men, 13% had prior autoimmunity, and 46% received ICI combinations versus monotherapy (54%). The most commonly referred toxicities were pneumonitis (23%), arthritis (16%), and dermatitis (15%); 15% of patients had multisystem toxicities. Multiple referrals were more common in those treated with combination ICIs (odds ratio [OR], 6.0; P=.035) or with multisystem toxicities (OR, 8.1; P=.005). The IR-tox team provided a new multidisciplinary forum to assist providers in diagnosing and managing complex irAEs. This model identifies educational and service needs, and patients with irAEs for whom multidisciplinary care is most sought. Conclusions: A virtual multidisciplinary toxicity team for irAEs was a feasible and used service, and facilitated toxicity identification and management.
John A. Thompson, Bryan J. Schneider, Julie Brahmer, Stephanie Andrews, Philippe Armand, Shailender Bhatia, Lihua E. Budde, Luciano Costa, Marianne Davies, David Dunnington, Marc S. Ernstoff, Matthew Frigault, Brianna Hoffner, Christopher J. Hoimes, Mario Lacouture, Frederick Locke, Matthew Lunning, Nisha A. Mohindra, Jarushka Naidoo, Anthony J. Olszanski, Olalekan Oluwole, Sandip P. Patel, Sunil Reddy, Mabel Ryder, Bianca Santomasso, Scott Shofer, Jeffrey A. Sosman, Momen Wahidi, Yinghong Wang, Alyse Johnson-Chilla and Jillian L. Scavone
The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions and ASCO, consisting of medical and hematologic oncologists with expertise in a wide array of disease sites, and experts from the fields of dermatology, gastroenterology, neuro-oncology, nephrology, emergency medicine, cardiology, oncology nursing, and patient advocacy. Several panel representatives are members of the Society for Immunotherapy of Cancer (SITC). The initial version of the NCCN Guidelines was designed in general alignment with recommendations published by ASCO and SITC. The content featured in this issue is an excerpt of the recommendations for managing toxicity related to immune checkpoint blockade and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to chimeric antigen receptor T-cell therapy, visit NCCN.org.
Featured Updates to the NCCN Guidelines
John A. Thompson, Bryan J. Schneider, Julie Brahmer, Stephanie Andrews, Philippe Armand, Shailender Bhatia, Lihua E. Budde, Luciano Costa, Marianne Davies, David Dunnington, Marc S. Ernstoff, Matthew Frigault, Benjamin H. Kaffenberger, Matthew Lunning, Suzanne McGettigan, Jordan McPherson, Nisha A. Mohindra, Jarushka Naidoo, Anthony J. Olszanski, Olalekan Oluwole, Sandip P. Patel, Nathan Pennell, Sunil Reddy, Mabel Ryder, Bianca Santomasso, Scott Shofer, Jeffrey A. Sosman, Yinghong Wang, Ryan M. Weight, Alyse Johnson-Chilla, Griselda Zuccarino-Catania and Anita Engh
The NCCN Guidelines for Management of Immunotherapy-Related Toxicities provide interdisciplinary guidance on the management of immune-related adverse events (irAEs) resulting from cancer immunotherapy. These NCCN Guidelines Insights describe symptoms that may be caused by an irAE and should trigger further investigation, and summarize the NCCN Management of Immunotherapy-Related Toxicities Panel discussions for the 2020 update to the guidelines regarding immune checkpoint inhibitor–related diarrhea/colitis and cardiovascular irAEs.