tbuckley/cabot-search huggingface dataset:
Causes of death and patterns of metastatic disease at the end of life for patients with advanced melanoma in the immunotherapy era.
Authors: Daniel Lee, Alexander Yang, Madeline McNamara, Harriet M. Kluger, Thuy Tran, Kelly Olino, James Clune, Mario Sznol, Jeffrey Joseph Ishizuka
Journal: Journal of Clinical Oncology (2024)

e21522 Background: Despite the drastic improvement in survival of patients with metastatic melanoma from immune checkpoint inhibitors (ICIs), almost half of patients still die from their disease. Factors surrounding death including mechanisms of death, sites of disease, and settings of death remain poorly described. A better understanding of these factors is paramount to optimize management for these patients. Methods: A retrospective observational cohort study was performed for patients age &gt; 18 who died after treatment for advanced melanoma with anti-PD1 therapy or ipilimumab + nivolumab (Ipi/Nivo) at Yale Cancer Center (YCC) between 1/2009 and 6/2023. Primary outcome was cause of death. Statistical analyses were performed with Stata SE, version 15.0 (StataCorp, College Station, TX). This study was approved by the Yale Institutional Review Board (Protocol #2000034631). Results: Overall, 287 patients with melanoma who received ICIs were documented to be deceased; 183 met inclusion criteria. Median time from metastatic diagnosis to death was 16.1 mos (range 0.3 to 135.1 mos). Median age at death was 70 (range 22-101), 62.8% were male, and 90.2% were white. Most patients (52.5%) received Ipi/Nivo first line, and 79.8% of patients received both anti-PD1 and anti-CTLA4 treatment at some point. The median number of metastatic sites at death was 4 (range 0-13). The majority (90.1%) of patients with measurable disease had multi-system involvement of melanoma. Eleven patients had no evidence of disease at death and died due to non-melanoma causes. The most common sites of metastatic disease at death were distant lymph nodes (62.8%), lung (57.9%), liver (50.8%), brain (38.8%), and bone (37.7%). In total, 80.3% (147/183) experienced hospitalization within 3 months prior to death or hospice enrollment. Most died in the hospital (31.7%) or while enrolled in hospice (31.2% inpatient vs. 29.4% home). Overall, 10.9% of patients had survival &gt; 5 years after metastatic diagnosis; 76.2% of long-term survivors died due to melanoma. Of 174 patients with evaluable causes of death, 87.9% of deaths were due to melanoma (Table 1). Patients with pleural metastases were more likely to die of respiratory failure (p = 0.036, OR 2.41 95% CI 1.06-5.50). Conclusions: The majority of deaths were a consequence of metastatic melanoma, with the most common causes including FTT, respiratory failure, and infection. [Table: see text]
Fostering collaborative care in multiple myeloma: The impact of holistic education on decision-making with antibody and CAR-T platforms.
Authors: Carmine Deluca, Michael Beyer, Jennifer M. Ahlstrom, Robert Z. Orlowski, Beth Faiman, Irene M. Ghobrial, Abigail Brugger, Heather Drew
Journal: Journal of Clinical Oncology (2024)

e21008 Background: The management of multiple myeloma (MM) continues to be transformed by evidence supporting the use of CD38 antibodies and B-cell maturation antigen (BCMA) immunotherapy (chimeric antigen receptor (CAR-T) and bispecific antibodies) in newly diagnosed and relapsed/refractory MM (NDMM and RRMM), respectively. However, real-world evidence and survey data show that these approaches are under-utilized across lines of therapy and that educational outreach to patients on their use is inadequate (Puig N et al. ASH 2022. Abstract 1859; Pink S et al. ISPOR 2022. Abstract HSD44; Terpos E et al. Blood Cancer J. 2021;11:40; Adu Y et al. ASH 2023. Abstract 2418). Methods: To address these gaps, PeerView partnered with HealthTree Foundation for Multiple Myeloma to develop 4 live events and 5 online enduring activities from 06/2022 to 06/2023, to educate clinicians on the evidence and principles for integrating CD38 and BCMA antibody platforms into patient care. The activities’ core objectives focused on improving knowledge and skills for integrating CD38 antibodies and BCMA immunotherapy platforms into sequential MM treatment. Furthermore, through the partnership with HealthTree Foundation, the initiatives featured patient perspectives as well as tools and resources to foster clinician–patient communication on use of antibody and CAR-T therapy. Pre- and post-activity multiple choice questions measured changes in knowledge and skills. Responses from enduring activity learners were compared with those from a matched sample of nonparticipants. In a meta-analysis of outcomes from the 9 activities, learning objectives were grouped by key themes, with changes in knowledge and skills averaged across them. Results: Total learners: 12,248 (hematologist-oncologists/oncologists: 7,345; oncology nurses: 1,247) In all activities, learners’ knowledge and skills improved, with increases of: 35 percentage points (ppt) in knowledge of new evidence and changing practice guidelines supporting BCMA antibody platforms in RRMM (44% to 79%); 36 ppt in skills in treatment planning and evidence-based integration of CD38 and BCMA-targeting antibodies in the management of MM (52% to 88%); 46 ppt in ability to address safety considerations related to the use of antibody therapy and BCMA immunotherapy (39% to 85%); 58 ppt in patient interaction skills (eg, counseling, shared decision-making) when using antibody-based and CAR-T platforms (28% to 86%). Conclusions: Improvements in knowledge and skills, combined with a greater focus on patient-centricity, suggest that learners are poised to more effectively integrate CD38 antibodies and BCMA immunotherapy into guideline-recommended MM care that improves the overall well-being and outcomes of patients with MM.
Enhancing oncologist knowledge and skills through patient-centric medical education: A collaborative approach with LUNGevity.
Authors: Kadrin Wilfong, Michael Beyer, Upal Kunal Basu Roy, Nikki A. Martin, Stephen V. Liu, Dana Wills, Heather Drew
Journal: Journal of Clinical Oncology (2024)

e21007 Background: Patient centricity in healthcare delivery has evolved, driven by accumulating evidence of improved outcomes through patient empowerment. PeerView partnered with LUNGevity Foundation to develop multiple educational initiatives with a patient-centered approach to lung cancer care. Methods: 4 live events and 4 online enduring activities were developed to improve the knowledge and skills of oncologists and other healthcare professionals (HCPs) involved in the management of patients with small cell and non–small cell lung cancer. These initiatives followed a patient-centric approach, featuring: Learning objectives addressing incorporation of patient-centric approaches to provision of optimal and equitable lung cancer care in two of the activities; LUNGevity input on the co-creation and development of the activities, including curriculum planning, identifying faculty, highlighting advocacy resources, and incorporating the patient voice; Expert discussions framed with patient perspectives and illustrative case scenarios to highlight strategies for improving team-based collaboration, patient engagement, shared decision-making, and health equity in clinical care and research; Unique instructional elements, including patient focus group insights and video role play; and Tools designed to enhance clinician-patient communication, patient engagement in care, and shared decision-making Pre- and post-activity assessments included multiple choice questions to measure changes in knowledge and skills and Likert-style questions assessing intent to change practice. Responses from enduring activity participants were also compared with those from a matched sample of nonparticipants. Results: To date, 11,227 learners, including 8,112 oncologists, have participated in these activities. Substantial post-activity gains were consistent across all initiatives, with a 44-ppt average increase in knowledge and skills. Outcomes related to patient-centric care included increases of: 38 ppt in ability to implement team-based and patient-centric approaches to ensure timely and accurate diagnosis, appropriate biomarker testing, individualized treatment, and equitable care of all patients with NSCLC (43% to 81%); 44 ppt in ability to implement team-based and patient-centric approaches to ensure optimal and equitable use of immunotherapy in the care of all eligible patients with NSCLC (39% to 83%); and 15 ppt in intent to provide education, guidance, and resources to patients with lung cancer (68% to 83%). Conclusions: These initiatives demonstrated significant improvements in learner knowledge, skills, and confidence across all learning objectives. Furthermore, incorporation of patient-centric approaches represents an effective model for clinical education to increase HCPs’ compassion, empathy, and ability to provide effective and holistic patient care.
Phase 1b trial of IFx-Hu2.0, a novel in situ cancer vaccine, in checkpoint inhibitor-resistant Merkel cell carcinoma (MCC) and cutaneous squamous cell carcinoma (cSCC).
Authors: Andrew Scott Brohl, Ann W. Silk, Jacob Stephen Thomas, Zeynep Eroglu, Ahmad A. Tarhini, Deanryan B. De-Aquino, Edith Abraham, Nikhil I. Khushalani, Joseph Markowitz, Kenneth Yee Tsai
Journal: Journal of Clinical Oncology (2024)

9592 Background: MCC and cSCC have limited treatment options when refractory to immune checkpoint inhibitor (ICI) therapy. IFx-Hu2.0 (IFx) is a plasmid DNA encoding for an immunogenic bacterial protein, Emm55, formulated with a transfection agent for direct intra-tumoral (IT) injection. In this Phase 1b study, we evaluated the safety and efficacy of different schedules of IT IFx in patients (pts) with advanced MCC or cSCC. Methods: In the first trial stage (n=9), IT IFx was administered in up to 3 lesions on 3 schedules following a 3+3 exposure escalation schema; weekly x 1, 2, or 3. In the second trial expansion stage (n=11), IT IFx was administered weekly x 3. The primary objective of the study was to establish safety and feasibility of repeated IT administrations of the investigational agent. ≥80% completion of planned study therapy was predefined as a successful feasibility outcome. Given the proposed potential for immune priming effects of IFx, we performed an unplanned exploratory analysis of post-protocol treatment efficacy to evaluate response to ICI rechallenge. Results: We treated 22 pts (MCC, 13; cSCC, 9). All pts had received prior anti-PD(L)1 based treatment with disease progression being the reason for ICI discontinuation in all patients but one. Two pts did not complete planned study therapy due to rapid clinical progression and were replaced but included in the safety analysis. IT IFx was well tolerated at all dose schedules evaluated with 1 high-grade toxicity deemed possibly treatment related (G3 hepatitis in a patient recently treated with ICI). The study therefore met predefined study endpoints for safety and efficacy. After protocol specified IT therapy, 11 MCC pts and 6 cSCC pts were treated with anti-PD(L)1 based therapy as the immediate post-protocol treatment. Five of 9 (56%) evaluable MCC patients and 1 of 7 (14%) cSCC patients experienced an objective response to this ICI rechallenge, with duration of response ongoing in 4 patients (6+, 19+, 21+, 23+ months) and the two other responses lasting 23 and 33 months. The two remaining MCC patients were not evaluable for response from IO rechallenge due to radiation administered to the only measurable disease site(s), but both remain progression free at 11+ and 13+ months with previously progressive disease. Conclusions: IT IFx-Hu2.0 is safe and feasible to administer at weekly dosing repeated up to 3 weeks. An unplanned exploratory analysis revealed frequent (56%) and durable responses in advanced MCC to ICI re-challenge despite prior resistance to this class of drug, suggesting that IFx induced an immune priming effect. Preliminary biomarker analyses to investigate this phenomenon are ongoing and will be presented. Clinical trial information: NCT04160065 .
Tucidinostat plus toripalimab in patients with unresectable or metastatic melanoma: An open-label, single-arm phase II study.
Authors: Lili Mao, Jie Dai, Xue Bai, Yan Kong, Xinan Sheng, Zhihong Chi, Chuanliang Cui, Bin Lian, Bixia Tang, Xieqiao Yan, Xuan Wang, Siming Li, Li Zhou, Xiaoting Wei, Juan Li, Caili Li, Rong Duan, Huayan Xu, Jun Guo, Lu Si
Journal: Journal of Clinical Oncology (2024)

e21527 Background: Acral and mucosal melanoma respond poorly to anti–PD-1 monotherapy. Tucidinostat, a benzamide class of histone deacetylase (HDAC) inhibitor, potentially augments immunotherapy with PD-1 blockade. We therefore conducted a phase II study to investigate the safety and efficacy of tucidinostat plus toripalimab in unresectable or metastatic melanoma. Methods: This was a single center, single arm phase II clinical trial. Patients with pathologically confirmed locally advanced unresectable or metastatic melanoma were enrolled and received 30 mg tucidinostat orally twice a week and 240 mg toripalimab every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was the confirmed ORR per RECIST v1.1. Secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. Results: Between October 2022 and May 2023, a total of 21 patients(pts) were enrolled. All pts were included in the safety analysis set and 18 pts were included in the full analysis set (FAS) for efficacy analysis. In the FAS, the median age was 56.0 years (range: 49 to 60), 6 pts (33.3%) were acral melanoma, 9 (50.0%) mucosal melanoma, 1 (5.6%) cutaneous melanoma and 2 (11.1%) unknown primary melanoma. 15 pts were treated as first-line, and 3 pts were as second-line. By Dec 2023, the median follow-up was 8.8 mo (95% CI:7.6-10.4) , Confirmed ORR was 27.8% (95% CI:9.7-53.5%). The DCR was 61.1% (95% CI:35.7-82.7%). Median progression-free survival was 4.1 months (95%CI: 1.4-NR) ,OS was not reached. Subgroup analysis showed that, in acral and mucosal melanoma pts, the confirmed ORR was 50.0%(95%CI:11.8-88.2%) and 22.2%(95%CI: 2.8-60.0%), respectively. The incidence of treatment-related adverse events (TRAEs) was 90.5% (19/21). The most common ≥3 grade TRAEs were neutrophil reduction (28.6%), white blood cell count reduction (9.5%), alanine aminotransferase increase (9.5%), platelet count reduction (9.5%), aspartate aminotransferase increase (9.5%), and γ-glutamyl transferase increase (9.5%). No treatment-related deaths occurred. Conclusions: The combination of tucidinostat and toripalimab showed acceptable safety and encouraging efficacy in patients with unresectable or metastatic melanoma. Further research is warranted. Clinical trial information: NCT05478473 .
Germline pathogenic variants in a large convenience cohort of multiple melanoma subtypes.
Authors: Sarah E. Lochrin, Yelena Kemel, Jessica Stuart, James William Smithy, Diana Mandelker, Parisa Momtaz, Walid Khaled Chatila, Nikolaus Schultz, Michael A. Postow, Zsofia Kinga Stadler, Alexander Noor Shoushtari
Journal: Journal of Clinical Oncology (2024)

9595 Background: A heritable component accounts for approximately 10% of melanomas. These estimates derive from populations deemed high risk for a germline pathogenic variant (gPV). The prevalence and clinical features of a broader melanoma patient population are unknown. Methods: Using the MSKCC IMPACT dataset, we identified a convenience cohort of all pts with melanoma who had undergone targeted tumor-normal sequencing (NCT01775072) for gPV in 76-90 genes. gPV were categorized by association with cancer predisposition and penetrance. Results: 701 pts with melanoma and germline sequencing demonstrated 105 pathogenic variants in 29 genes (Table). 14% of pts (n=99) harbored a gPV in a cancer susceptibility gene (gPV+); 49% high/moderately pathogenic, 32% low/recessive, and 19% uncertain. 6% of gPV+ pts had 2 gPVs. 77% of gPVs were involved in DNA damage repair pathways. The genes known to be associated with melanoma risk accounted for 9% of gPVs, inclusive of CDKN2A (2%), CDK 4 (1%), MITF (4%), and BRCA2 (2%). A further 15% were in genes with suggested, as yet undefined, susceptibility for melanoma; BRCA1 (6%), ATM (5%), BAP1 (2%) and PALB2 (2%). gPV+ frequency varied by melanoma subtype: unknown primary (19%, n=18), cutaneous (15%, n=64), mucosal (13%, n=13), acral (7%, n=2) and uveal (4%, n=2) (p=0.039). No significant difference in age, sex, race, stage at diagnosis, personal history of other cancer, or family history (FHx) of melanoma was seen between gPV+ and gPV-, on univariate analysis. 47% of gPV+ pts had either &gt;1 primary melanoma, age&lt;45 years or a FHx of melanoma (n=47), of which 14 pts had &gt;1 risk factor. The presence of &gt;1 melanoma and FHx of melanoma was associated with gPV+ (p=0.016). There was no significant difference in somatic TMB and MAPK pathway alterations between gPV+ and gPV-. In this cohort selected for high-risk melanomas, melanoma was the first presenting cancer for 83% of patients with gPV+. Assessment of biallelic loss to clarify if gPVs may be driving melanoma carcinogenesis is ongoing. Conclusions: This represents the largest cohort of sequenced matched germline and somatic analysis in melanoma. There is a 14% overall gPV prevalence that varies by melanoma subtype. The association of &gt;1 primary melanoma, young age and a family history of melanoma with gPV+ is consistent with prior studies, however, would not capture 53% of gPV+ in this cohort. Melanoma represents the index cancer for the majority of gPVs, informing the need to expand germline testing in patients with melanoma. [Table: see text]
Behavioral analysis of social media and email usage among hematology-oncology fellowship applicants: A national survey.
Authors: Rahul Kumar Thakur, Charan Thej Reddy Vegivinti, Hasiya Yusuf, Rajvi Gor, Barun Ray, Monika Thakur, Shweta Deshpande, Abhishek Kumar
Journal: Journal of Clinical Oncology (2024)

e21003 Background: The advent of digital communication has transformed the landscape of fellowship programs, with social media(SoMe) emerging as pivotal platforms for information dissemination and engagement between applicants and programs. Despite its proven influence in surgical and urological specialty, the role of SoMe in Hematology-Oncology (HO) fellowships remains to be elucidated. This pioneering survey evaluates the utility and impact of SoMe alongside traditional email among Internal Medicine residents applying the fellowship application process in the era of virtual interviews. Methods: An anonymous, cross-sectional survey was administered via SurveyMonkey to residents applying to U.S. HO fellowships in the 2023-2024 cycle. Outreach methods included emails to all internal medicine program directors, SoMe, and online forums. The questionnaire probed the frequency of SoMe and email usage, types of content accessed, and the influence of these platforms on applicants' strategic choices and program preferences. Results: Analysis from 33 respondents revealed a demographic predominance of individuals aged 26-35 years, with an equal gender distribution and significant representation from the Middle Atlantic region. The majority were non-U.S. graduates (51.5%), predominantly identifying as Asian (54.5%). While 67% of respondents used Twitter/X, but only 13.6% used it for direct program contact, resulting in a minimal 4.5% receiving interview offers. Twitter/X was acknowledged as a useful information source by 55% of respondents, and 20% felt it influenced their program ranking decisions. Conversely, 70% and 45% used Instagram and LinkedIn respectively, but usage for fellowship applicants was minimal, with no respondents utilizing it for program outreach or reporting any increase in interview offers because of its use. Notably, 25% felt pressured to use SoMe to boost their application prospects. In contrast, 74% approached program directors through personalized emails, attributing a 34% increase in interview offers to this method. Conclusions: Our findings emphasize the enduring prominence of email in fellowship applications while illuminating the evolving but significant presence of SoMe. This divergence highlights a potential big change where SoMe particularly Twitter/X, begins to complement traditional methods. Such insights suggest that fellowship programs should strategically integrate digital tools into their application processes and actively improve their online engagement to align with applicant behaviors.
Dynamics of circulating cytokines and chemokines during and after tumor-infiltrating lymphocyte cell therapy with lifileucel in advanced melanoma patients.
Authors: Rongsu Qi, Amod Sarnaik, John M. Kirkwood, James Larkin, Jeffrey S. Weber, Michelle Blaskovich, Kranthi Kunkalla, Rana Fiaz, Giri Sulur, Jeffrey Chou, Hequn Yin
Journal: Journal of Clinical Oncology (2024)

9594 Background: Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, has demonstrated potentially clinically meaningful activity and durable responses in patients with advanced (unresectable or metastatic) melanoma. The regimen includes nonmyeloablative lymphodepletion (NMA-LD) prior to lifileucel infusion, and a short course of interleukin-2 (IL-2) post infusion. The safety profile of the regimen is consistent with the underlying disease and the known safety profiles of NMA-LD and IL-2. Cytokine release syndrome (CRS) is an acute and severe adverse event commonly associated with chimeric antigen receptor T-cell therapy. Here, we report circulating cytokine levels during and after the lifileucel treatment to monitor immune activation, and the dynamics of cytokines and chemokines to explore mechanism of action and potential predictive clinical biomarkers. Methods: The full analysis set of C-144-01 (NCT02360579) includes 153 patients with unresectable or metastatic melanoma who have progressed on checkpoint inhibitors and, if applicable, BRAF/MEK inhibitors. After tumor resection, patients received NMA-LD (cyclophosphamide on Days −7 to −6 and fludarabine on Days −5 to −1) followed by a single lifileucel infusion (Day 0) and up to 6 doses of IL-2 (Days 0-4). Peripheral blood samples were collected at baseline (pre-NMA-LD and pre-lifileucel infusion) and post-lifileucel infusion on Days 1, 4, 14, 42, and 84. Serum cytokine and chemokine levels were measured with BioPlex and included a multiplex panel for IL-6, IL-7, IL-9, IL-10, IL-12, CCL2, CXCL10, IFN-γ, and TNF-α. Plasma samples also were tested for IL-6, IL-15, and IL-7 levels by ELISA. Results: IL-15 levels following NMA-LD peaked at Day 1 and returned to baseline by Day 42. This is consistent with prior reports that NMA-LD increases circulating IL-15 levels, which may promote TIL expansion in the absence of competing endogenous lymphocytes. Similarly, IL-7 and CCL2 also peaked at Day 1. IL-6 did not increase during or after the lifileucel regimen, consistent with absence of severe systemic inflammation including higher grade CRS after lifileucel treatment. There was no difference in cytokine and chemokine levels between responders and nonresponders in the full analysis set. Conclusions: These data support the hypothesized mechanism of action of NMA-LD in the lifileucel regimen. Cytokine levels measured during treatment are consistent with lack of severe systemic inflammation observed in patients treated with lifileucel. Cytokine and chemokine dynamics did not predict for response to lifileucel. Clinical trial information: NCT02360579 .