tbuckley/cabot-search huggingface dataset:
Screening for ocular toxicities of immunotherapy in a real-world population.
Authors: Logan C. Barr, Jacob Rullo, Tara D. Baetz
Journal: Journal of Clinical Oncology (2024)

e24125 Background: Nivolumab, Pembrolizumab, and Ipilimumab have revolutionized the treatment of melanoma. However, patients receiving these treatments risk immunotherapy-related adverse events (IRAEs). IRAEs can occur in any organ system, are treated with steroids or immunosuppressive medications, and may require treatment delay or discontinuation. Ocular IRAEs, which are caused by off-target reactions with ocular immune mechanisms, are often identified after significant damage to the eye. Ocular IRAEs are rare in the literature with an approximate prevalence of 3.3%. After observing intraocular inflammation (uveitis) with uveal depigmentation (pigment release) in some patients receiving immunotherapy, we hypothesized that the rate of such events in a real-world population may be higher than previously reported. We predict ophthalmic screening and early intervention may prevent severe and potentially permanent ocular IRAEs. Methods: Patients starting immunotherapy for melanoma were referred to an ocular screening clinic at the Cancer Centre of Southeastern Ontario (Queen’s University, Kingston, Canada) for baseline ocular assessments. Repeat assessments occurred every three months (single agent) or at every cycle (dual immunotherapy). Intake visits included examination by an attending ophthalmologist, including examination for uveitis and anterior chamber free pigment under high-powered field. Intraocular inflammation (IOI) was defined as the presence of endothelial deposits and/or anterior chamber cell and/or pigment that was not present at baseline. Ocular findings were monitored alongside other IRAEs during treatment. Results: 28 patients (17 male, 11 female) receiving adjuvant (46.4%) or palliative (53.6%) immunotherapy for melanoma were evaluated. 9 of these patients received dual immunotherapy (Ipilimumab/Nivolumab) and 19 received single agent immunotherapy. IOI was identified in 11 patients (39.2%), while only 4 presented with symptoms. None of the patients had overt signs of anterior segment inflammation such as erythema, conjunctival injection, and chemosis. IOI developed in 54.5% of dual immunotherapy-treated patients. Patients with ocular IRAEs were treated with topical/systemic steroids or other immunosuppressive medications. None required discontinuation of immunotherapy. The development of IOI was more common in metastatic patients whose cancer was responding to immunotherapy, and many of these patients sustained IRAEs in other organ systems. Conclusions: Our findings suggest IOI related to ocular IRAEs are quite common and develop in a third of patients receiving immunotherapy for melanoma. Ocular screening for IOI identified early, often asymptomatic toxicities that could progress to permanent visual disability. Further evaluation of dedicated ocular screening is indicated in patients receiving immunotherapy.
Mucosal melanoma treatment patterns and outcomes in real clinical practice: Single institution experience.
Authors: Igor Samoylenko, Anna Stroganova, Kristina V. Orlova, Angelina Kuzmenko, Margarita Martynova, Ekaterina Kogai, Valery V. Nazarova, Natalia N. Petenko, Lev V. Demidov
Journal: Journal of Clinical Oncology (2024)

e21571 Background: Mucosal melanoma (MM) is a challenging malignancy to diagnose and treat, even with the advent of modern drug therapies. There is a lack of established surgical, radiological, or pharmacological treatment approaches for locally advanced or metastatic mucosal melanoma. This study analyzes the treatment practices and clinical outcomes at a single institution over a five-year period to understand real-world clinical practices. Methods: A сomprehensive, continuous, retrospective study analyzed medical records of adults with histologically confirmed MM at the N.N. Blokhin Russian Cancer Research Center from January 2018 to December 2023. Data was digitized into an electronic questionnaire, with patient follow-up conducted via telephone. Results: A total of 87 patients were identified, comprising 72 females (82.8%) from 31 regions of Russia. The median age was 67.8 years (ranging from 29.5 to 90.1 years). The patient breakdown was as follows: 6 with head&amp;neck MM (6.9%), 41 with vulvovaginal MM (47.1%), 5 with penile MM (5.7%), 27 with anorectal MM (31.0%), and 8 with gastrointestinal MM (9.2%). A significant portion of the patients presented with locally advanced (22.9%) or metastatic disease (67.8%), while 9.2% of the patients had undergone surgery and were being considered for adjuvant treatment. The most common sites of metastasis were regional lymph nodes (23%), liver (14%), and lungs (11.5%), with one patient having CNS metastasis. Mutational status was determined for 48 of the 87 patients, revealing driver mutations in 12 patients (Table). The majority of patients were initially treated with immunotherapy. The most frequently used therapies included monotherapy with anti-PD-1 agents (nivolumab or pembrolizumab, accounting for 41.6%) and a combination of ipilimumab and nivolumab (33.3%). After a median follow-up of 17.7 months, the median overall survival (OS) for the entire cohort was 18.1 months (with a 95% confidence interval ranging from 6.8 to 23.2 months), showing no significant statistical differences in outcomes based on the location of the mucosal melanoma or the type of treatment received. Conclusions: Mucosal melanoma remains an under-researched malignancy. There is a critical need for prospective, randomized trials to explore more effective treatment options for patients with this condition. [Table: see text]
Neoadjuvant immunotherapy in clinical stage III melanoma: Real life experience in the community setting.
Authors: Fade Mahmoud, Mark Gimbel, Ryan Toledo, Jordan Abbott, Thomas D. Shellenberger, Chafeek Tomeh, Mark Andrew Healy, Vishangi Dave
Journal: Journal of Clinical Oncology (2024)

e21556 Background: There is a paradigm shift in the management of clinical stages IIIB-IIID melanoma. Results from phase II clinical trials revealed higher pathologic response rates in the neoadjuvant versus adjuvant setting. Methods: We conducted a retrospective study of patients with clinical stages IIIB-IIID melanoma who were deemed suitable for surgical resection and treated with neoadjuvant immunotherapy between January 2019 and December 2023. Patients must have had at least one cycle of neoadjuvant immunotherapy with ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). The primary objective was to assess pathologic and radiologic response rates and to determine the association of pathologic response with event free survival (EFS). Results: Thirty-one patients were enrolled with a median age of 60 (range: 31-84) years. 61% of patients received two cycles, 3 weeks apart, of intravenous (IV) ipilimumab 1mg/kg and nivolumab 3mg/kg, while 23% received one cycle of IV ipilimumab 1mg/kg and nivolumab 3mg/kg followed by two cycles, 2 weeks apart, of IV nivolumab 240 mg. Twenty-nine patients underwent therapeutic lymph node dissection; of those 66% had a pathologic complete response (pCR) and 79% had an overall pathologic response. Complete radiologic response using RECIST 1.1 was detected in 28% and radiologic partial response in 56%. Next gene sequencing revealed a total of 47 mutations with BRAF V600 mutation being the most frequently encountered (28%) followed by mutations in TERT promoter (21%) and CDKN2A loss (13%). Two patients died during follow up. One patient refused surgery after neoadjuvant immunotherapy and passed away 4 years later due to stage IV melanoma. The second patient died two years after his surgery due to brain metastases despite achieving a complete pathologic response to neoadjuvant immunotherapy. Any grade adverse events (AE) were detected in 76% of patients; 64% grades 1-2 and 12% grades 3-4. Colitis was the most encountered grade 3 and 4 AE. Three-year event-free survival among 23 evaluable patients who had at least 6 months of follow up after surgery was 95%. Conclusions: Neoadjuvant immunotherapy with ipilimumab and nivolumab resulted in a high pathologic response rate of 79%. A discrepancy was detected between pathologic and radiologic responses. Colitis was the most common grade 3 and 4 toxicity. Three-year event free survival was 95%. Two patients died due to development of stage IV melanoma.
Clinical significance of HER2 expression between primary tumors and metastatic lymph nodes in patients with extramammary Paget's disease.
Authors: Zhicheng Liu, Xingliang Tan, Yi Tang, Qianghua Zhou, Gangjun Yuan, Wensu Wei, Kai Yao
Journal: Journal of Clinical Oncology (2024)

e21568 Background: HER2 has been reported to be a potential oncogene and therapeutic target in extramammary Paget's disease (EMPD). However, the expression of HER2 in EMPD, especially in matched metastatic lymph nodes (LNs), is limited. Here, we investigated the heterogeneity of HER2 expression between primary tumors and positive nodes and its clinical significance in advanced EMPD patients and detected the efficacy of HER2-targeted antibody drug conjugates (ADCs) in EMPD. Methods: A total of 170 patients with pathologically confirmed EMPD of the scrotum and/or penis treated at SYSUCC from 2003 to 2023 were included. HER2 IHC staining (anti-HER2/neu (4B5), Ventana) and scoring were performed according to the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) 2023 guidelines. Outcome relationships were explored using Cohen's kappa coefficient, multivariate Cox regression and log-rank analysis. Results: A total of 102 primary tumor and 32 metastatic specimens were ultimately subjected to HER2 IHC staining. HER2 high-expression (IHC: 2/3+) was detected in 71.6% (0: 9.8%, 1+: 18.6%, 2+: 40.2% and 3+: 31.4%) and 68.8% (0: 21.9%, 1+: 9.4%, 2+: 28.1% and 3+: 40.6%) of the primary tumors and metastatic LNs, respectively. HER2-high EMPD patients experienced poorer outcomes, with a 5-year OS of 56.5%, than did HER2-low patients (P = 0.032). A multivariate Cox regression model showed that a positive lymph node (HR 15.39, 95% CI 3.79~62.43; P &lt; 0.001) and HER2 high-expression in primary tumors (HR 3.68, 95% CI 1.49~9.09; P = 0.005) were independent poor prognostic factors. Notably, in 31 paired samples, 35.5% (n = 11) of patients had inconsistent HER2 expression between primary tumors and corresponding lymph node metastases. Six (19.4%) patients exhibited a shift from high expression of HER2 in primary tumors to low expression of HER2 in the lymph nodes, and 5 (16.1%) patients exhibited the reverse change. Advanced EMPD patients with HER2 high-expression were treated with Disitamab Vedotin (RC48), for which the ORR was 80% and the DCR was 100% (n = 5). No adverse events (AEs) above grade 3-4 were observed. Conclusions: HER2 was highly expressed in both primary and metastatic LNs in EMPD patients. However, there was some heterogeneity in HER2 expression between paired primary and corresponding metastatic LNs. The expression status of HER2 should be evaluated in both primary tumors and corresponding lymph node metastases. A positive lymph node and HER2 high-expression are poor prognostic factors in patients with EMPD. RC48 demonstrated significant efficacy in treating patients with HER2-high advanced EMPD and has promising potential that requires further validation.
Immunotherapy toxicity prediction in patients with melanoma using machine learning algorithms.
Authors: Lakshya Sharma, Esha Mohan, Vaishnavi Balaji, Jonathan Wong, Adwait Joshi, Iosif Mporas, Jiaqi Shi, Yi Zhao, Amy C. Stoll-D'Astice, Vipula Tailor, Georgie Powell, Doraid Alrifai, Riyaz N.H. Shah, Justin S. Waters, Sola Michael Adeleke
Journal: Journal of Clinical Oncology (2024)

e21567 Background: Immune checkpoint inhibitor (ICI) related toxicity is common in melanoma patients, but identifying who will experience toxicity can be challenging. Precision medicine tools that accurately predict ICI toxicity could improve patient outcomes. This study aimed to use Machine Learning (ML) to predict ICI toxicity in patients with melanoma. Methods: 384 datasets were available for patients started on immunotherapy between 2014-2023 in a single, large regional cancer center in Kent, U.K. Raw data was preprocessed using a standard scaling function and one hot encoding, followed by SMOTE to balance the imbalanced classes. Six ML algorithms were developed using 80% of the training data, tested on 20% of validation data and used the Grid Search Cross-Validation technique for hyperparameter optimization. Shapley Additive Explanations (SHAP) explainable artificial intelligence was used to interpret the toxicity prediction model to improve the interpretation and transparency of the decision boundary. Results: Of the 384 patients, 112 patients (29%) had completely resected disease and then had adjuvant treatment while 272 (71%) were unresectable or had metastatic disease and had palliative treatment intent. In the metastatic setting, the commonest immunotherapy regimen was Pembrolizumab (155, 57%), followed by Ipilimumab/Nivolumab (85, 31%). The commonest regimen in the adjuvant setting was Pembrolizumab (86, 77%). 95 patients (25%) experienced ICI-related toxicity. The number of patients with Grades 1-4 toxicity was 2 ,4, 18 and 4 respectively, the remaining had unspecified toxicity grades. The commonest class of toxicity (CTCAE v5) was gastrointestinal (36, 38%), followed by endocrine (20, 21%) and skin (19, 20%). Linear Regression and Gaussian Naïve Bayes predicted toxicity with the most accuracy, 92% (Table 1). The model showed that increasing age, female gender and not receiving Nivolumab predicted toxicity. Regardless of the regimen or treatment intent, our ML model could also predict immunotherapy response with 90% accuracy. Conclusions: These ML algorithms used clinically available data to predict ICI toxicity accurately. Key predictors of toxicity included increasing age, female gender and not receiving Nivolumab in the setting of both adjuvant and palliative intent. Future work will aim to externally validate these models in other centers. We will also explore if models could be trained for use in patients treated with nivolumab in combination with new anti-LAG-3(relatlimab). [Table: see text]
Increase in blood pressure in patients with metastatic kidney cancer treated with combination checkpoint inhibitor and vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy.
Authors: Rick Y. Lin, Neil Jigish Patel, Jonathan Alexander Chatzkel, Tarik Benidir, Padraic O'Malley, Paul Crispen, Brian Hemendra Ramnaraign
Journal: Journal of Clinical Oncology (2024)

e24128 Background: The combination therapy of an immune checkpoint inhibitor (ICI) with a vascular endothelial growth factor receptor tyrosine kinase inhibitor (VEGFR-TKI) is considered a first line treatment option for patients with metastatic clear cell renal cell carcinoma (ccRCC). TKI-induced hypertension is a well-known potential side effect with VEGFR-TKIs however little is known about the real-world increase in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with and without underlying hypertension treated with this combination therapy. Methods: A retrospective study was performed that included patients with metastatic ccRCC who were treated at the University of Florida Health Cancer Center between June 2019 and September 2022 who received treatment with the combination of an ICI and VEGFR-TKI. The data collected included history of hypertension, patients use of anti-hypertensive therapy at baseline, SBP and DBP prior to initiation of therapy and at approximately one month after initiation of treatment. Results: We identified a total of 29 patients who met the inclusion criteria for our study. The median age was 68 years old (IQR 61-72) while 25 patients (86%) were male and 4 (14%) were females. There were 27 patients (93%) who were treated with axitinib with pembrolizumab, while 1 (3%) was treated with cabozantinib with nivolumab, and 1 (3%) was treated with lenvatinib with pembrolizumab. Out of the 29 patients, 11 (38%) did not have hypertension prior to therapy while 18 (62%) did have baseline hypertension and were receiving at least one anti-hypertensive treatment. In those patients without baseline hypertension, the median baseline SBP was 113 and the median SBP after one month of treatment was 144 (p = 0.01). Conversely, those patients with baseline hypertension, the median baseline SBP was 122 and median SBP after one month of treatment was 148 (p = 0.003). In those without hypertension at baseline, the mean SBP increase after one month was 27.3% while in those with baseline hypertension the mean increase in SBP of 17.0%. Conclusions: Our study demonstrates that in a real-world population of patients with metastatic ccRCC there is a statistically significant elevation of both SBP and DBP when treated with the combination of an ICI and VEGFR-TKI and that in those patients without baseline hypertension and not on anti-hypertensive therapy at baseline, there is a more pronounced increase in blood pressure. This data should reinforce the need to have close monitoring of SBP and DBP during therapy, regardless of whether the patient has underlying hypertension or not, and may help guide anti-hypertensive therapy during kidney cancer treatment.
Geospatial analysis of the distribution of uveal melanoma patients at a referral center in the United States.
Authors: Rino S. Seedor, Daniel T. Vader, Renee H. Moore, Alexandre J. Motta, Sara E. Lally, Carol L. Shields, Takami Sato, Marlana M. Orloff
Journal: Journal of Clinical Oncology (2024)

e21566 Background: Approximately 2500 new uveal melanoma (UM) cases (5.2 cases per million population) are diagnosed yearly in the United States. We previously identified three unique geospatial accumulations of UM in North Carolina, Alabama, and New York based on our clinical experience. Such unexpected findings prompted us to conduct a more systematic evaluation of geospatial accumulations of UM patients at our institution. Methods: Through the electronic medical record system, we identified patients seen at our institution with a diagnosis of UM. Identified living patients and family of deceased patients were either sent an e-mail or paper letter with an internet link to a survey. The survey asked for the patient’s name, date of birth, sex, date of primary UM diagnosis, address at time of UM diagnosis and number of years at that address, and all previous addresses and dates of residence prior to the UM diagnosis. Using these addresses, ArcGIS and R software was used to analyze the geospatial distribution of our UM patients. The data was supplemented with 2020 American Community Survey census estimates at the state, county, and census tract level to estimate population-based rates of UM. Results: We identified 2718 UM patients in our clinical database, and a total of 726 participants completed the survey with a total of 2939 US addresses. The majority of addresses were precise to the street address level (77.9%). At the time of UM diagnosis, patients had lived at their current address for a median of 16 years. Pennsylvania and the neighboring states expectedly made up the majority (63.6%) of our patients, but about 1/3 of our patients resided in other states at the time of their UM diagnosis (total of 42 different states). Several counties presented elevated rates of UM with ≥5 case per 100,000 persons. We observed a group of counties in central Pennsylvania, at the border of Pennsylvania and New York, and in upper New York by the Finger Lakes with notably elevated rates of UM, which was consistent with our clinical observations at our institution. Several neighboring counties in Kentucky and Virginia also presented elevated rates. Conclusions: Through this pilot project, we have demonstrated that it is possible to collect lifetime residency information from UM patients in order to map their geospatial distribution in the US. Furthermore, although institutional bias toward referring physicians should be considered, our geospatial analysis identified accumulations of UM in areas similar to our clinical concerns. The results of our study warrant further investigations into environmental influences on UM development. Our future goal is to extend our approach through national and international collaborations to increase the number of participants in the analysis and to minimize institutional bias.
Ulcer-related cutaneous squamous cell carcinoma: New kid on the block.
Authors: Mor Miodovnik, Inna Ospovat, Orit Gutfeld, Inbar Finkel, Yardenna Dolev, Yasmin Leshem
Journal: Journal of Clinical Oncology (2024)

e21559 Background: Cutaneous squamous cell carcinoma (cSCC) represents a favorable tumor microenvironment with high tumor mutational burden, and infiltration of immune cells that are highly responsive to immunotherapies. Yet, we encounter tumors arising on non-exposed skin, such as those developing from chronic ulcers in which the response to anti-PD1 is unknown. Methods: The authors reviewed the medical records of consecutive cSCC patients receiving Cemiplimab or Pembrolizumab at a single tertiary center. Results: Of the 84 eligible patients, 9 (11%) had ulcer-related cSCC. six out of the nine (67%) were located on the lower extremities. Only two out of these nine patients (22%) reached partial response (PR) and none reached complete response (CR). In contrast, of the 75 patients with non-ulcer-related cSCC, 40 had PR (53%), and 20 had CR (26%). The difference between the two subtypes was significant (P &lt; 0.001). Interestingly, two of the seven non-responders in the ulcer-related subtype received second-line chemo-immunotherapy and experienced a partial response that continued for 21 and 8 months. Patients with ulcer-related SCC had a significantly shorter median progression-free survival (PFS) (2.1 months vs. non-reached, p &lt; 0.001). Overall survival (OS) was also shorter, but didn't reach significance (17 vs. 30 months, p = 0.02). Multivariate analysis confirmed ulcer-related SCC as an independent risk factor for shorter PFS (hazard ratio [HR], 7.56; 95% confidence interval [CI], 1.26-40.74, p = 0.027). Conclusions: This study suggests immunotherapy is less beneficial in ulcer-related SCC. More work is needed to verify our findings and explore other treatment options including chemoimmunotherapy.