tbuckley/cabot-search huggingface dataset:
Detection of molecular residual disease in stage II and III melanoma utilizing circulating tumor DNA.
Authors: Emily Chen, Elise Kornreich Brunsgaard, Timothy Kuzel, Alan Tan
Journal: Journal of Clinical Oncology (2024)

e21564 Background: Overall survival for patients with melanoma has significantly improved with advancements in immunotherapy, especially with immune checkpoint inhibitors and BRAF/MEK inhibitors becoming standard of care for advanced melanoma. However, the decision to proceed with adjuvant therapy should be considered against the risk of adverse side effects, particularly in early-stage melanoma patients. Accurate biomarkers are needed to risk stratify patients, determine who will most likely benefit from adjuvant therapy, and identify when the ideal time is to initiate treatment. This study evaluates the prognostic value of personalized, tumor-informed circulating tumor DNA (ctDNA) testing in patients with stage II and III melanoma. Methods: In this real-world study, plasma samples (n =429) were analyzed from 90 stage IIA-IIID cutaneous melanoma patients treated at Rush University Medical Center between 03/30/2021 and 01/30/2024. A clinically-validated, personalized, tumor-informed 16-plex PCR assay (SignateraTM, Natera, Inc.) was used for detection and quantification of ctDNA in plasma samples. Results: Personalized, tumor-informed ctDNA assays were created using tissue samples from either initial biopsy or surgical excision specimen. Assay design was successful for 100% (90/90) of patients with sufficient tissue; test requests for 4 patients could not proceed due to insufficient tissue. ctDNA was detectable in 28% (25/90) of patients at one or more time points. There was a higher ctDNA-positivity rate in stage III patients (20/50, 40%) compared to stage II patients (5/40, 13%). Of the 25 patients with identifiable ctDNA during surveillance, 13 tested positive on the initial test (2 stage II and 11 stage III). Eighteen of the 25 ctDNA-positive patients received immunotherapy; eight patients achieved sustained ctDNA clearance, 2 had transient clearance, 2 have remained positive on ctDNA testing, and 6 continue to receive adjuvant IO and follow-up ctDNA testing. Clinical or radiographic recurrence occurred in 11/90 patients, 10 of whom tested positive for ctDNA. Conclusions: Personalized, tumor-informed ctDNA offers an adjunct to conventional monitoring for melanoma patients to detect molecular residual disease and was found to be prognostic in our patient cohort. Prospective studies are needed to evaluate the role of ctDNA in clinical decision making for surveillance imaging intervals and appropriate initiation, intensification, or discontinuation of adjuvant therapy.
Dendritic cell vaccine as a strategy to prevent melanoma recurrence after local resection: A systematic review and meta-analysis.
Authors: Raquel Oliveira de Sousa Silva, João Luís Reis Freitas, Ocílio de Deus da Rocha Ribeiro Gonçalves, Bárbara Melão, Edgar Paulo da Silva Neto, Camila Mariana de Paiva De Paiva Reis, Gabriele Eckerdt Lech, Patricia Viana, Rafael Morriello
Journal: Journal of Clinical Oncology (2024)

e21561 Background: Melanoma has a high risk of recurrence and death even following complete surgical excision, specially in stages III and IV. Immunotherapy with checkpoint inhibitors, among other treatments, has been employed as adjuvant therapy in an effort to improve overall survival (OS) and disease free survival (DFS) in these patients. Cancer vaccines, particularly those based on dendritic cells loaded with tumor lysate particles (TLPLDC), have been investigated as new adjuvant therapy, these vaccines utilize autologous tumor lysate from an individual tumor, captured by dendritic cells to generate a personalized vaccine that stimulates an active cellular immune response. We conducted a meta-analysis to assess the effectiveness of these vaccines in patients with melanoma following complete resection. Methods: We searched in Pubmed, Cochrane and Embase in December 2023 for articles evaluating the effectiveness of TLPLDC vaccines on the recurrence and survival of patients with locoregional melanoma completely resected. The outcomes of interest included DFS for 3 years and OS for 2 and 3 years, comparing TLPLDC against the control. Additionally, we performed a subgroup analysis comparing an alternative TLPLDC technique named TLPLDC+G against the control. Random-effects models were employed to pool hazard ratios from studies using R software version 4.3.1. Results: We included 4 randomized controlled trials comprising 564 patients. The OS at the 3-year follow-up favored TLPLDC against control (logHR = -1.718[-2.697,-0.740], p = 0.0006,I² = 0%). In the 2-year comparison, treatment was also favored (logHR = -1.511,CI[-2.743,-0.279],p = 0.0162,I² = 36%). However, TLPLDC+G did not exhibit a statistically significant difference from the control in the 3-year long comparison (logHR = 0.043[-0.504,0.590],p = 0.8780,I² = 0%). Regarding the DFS in 36-month comparison, TLPLDC was favored with a 95% CI (logHR = -0.419,[-0.831,-0.006],p = 0.0468,I² = 48%). For TLPLDC+G, there was no statistical difference (0.269[-0.07,0.609],p = 0.1201,I² = 0%). Conclusions: Our results suggests that TLPLDC had a significant impact on OS at 2 and 3-year follow-up with a relatively low heterogeneity between the studies. Regarding the DFS, the TLPLDC group showed a significant difference favoring the vaccine; however, it presented higher heterogeneity. The TLPLDC+G subgroup did not exhibit a significant difference from control in both OS and DFS. Despite the favorable outcomes associated with the TLPLDC vaccine it is important to consider the potential effects of curve reconstruction, the limited number of studies, individual variations in patients immune responses, and differences in vaccine protocols between institutions as limitations of our analysis.
Efficacy and safety of first-line (1L) nivolumab plus relatlimab (NIVO + RELA) versus NIVO plus ipilimumab (NIVO + IPI) in advanced melanoma: An updated indirect treatment comparison (ITC).
Authors: Dirk Schadendorf, Hussein A. Tawbi, Evan J. Lipson, F. Stephen Hodi, Paolo Antonio Ascierto, James Larkin, Christopher D. Lao, Jean-Jacques Grob, Flavia Ejzykowicz, Jennell Palaia, Viviana Garcia Horton, Zheng-Yi Zhou, Dana Christensen, Lisa Rosenblatt, Laura McDonald, Barbara Ratto, Anthony Salvatore, Divya Patel, Leon A. Sakkal, Georgina V. Long
Journal: Journal of Clinical Oncology (2024)

9557 Background: An ITC comparing NIVO + RELA and NIVO + IPI, approved dual immunotherapy treatment options for patients with advanced melanoma, was previously conducted using pt-level data from the pivotal RELATIVITY-047 (RELA-047; NIVO + RELA vs NIVO) and CheckMate 067 (CM-067; NIVO + IPI or NIVO vs IPI) trials (Schadendorf 2023). Here we present results using updated, 3-year follow-up data from RELA-047. Methods: Inverse probability of treatment weighting was used to adjust for cross-trial imbalances in baseline characteristics. Database locks were selected to best align follow-up length in RELA-047 (median 34 mo) and CM-067 (median 38 mo). Progression-free survival (PFS) per investigator, confirmed objective response rates (ORRs) per investigator, overall survival (OS), melanoma-specific survival (MSS), treatment-related adverse events (TRAEs), and TRAEs leading to discontinuation (DC) were analyzed. PFS, OS, and ORR were evaluated across key subgroups. PFS, OS, and MSS were compared using Kaplan–Meier curves and hazard ratios (HRs); ORRs were compared using odds ratios (ORs). The weighted NIVO arm from each trial was compared for internal validation. Results: After weighting, key baseline characteristics were balanced for NIVO + RELA (n=339) and NIVO + IPI (n=297). Efficacy outcomes after weighting were similar between NIVO + RELA and NIVO + IPI and between NIVO arms (table). Similar outcomes between the NIVO arms validate the ITC methodology. Across subgroups, efficacy appeared similar between treatments, although trends favoring NIVO + IPI were observed for ORR among pts with BRAF MT disease or lactate dehydrogenase &gt; 2x the upper limit of normal. TRAEs were less common with NIVO + RELA (23%) compared to NIVO + IPI (61%); any-grade TRAEs leading to DC occurred in 17% and 41% of pts, respectively. Conclusions: Consistent with previous results, this updated ITC suggests that 1L treatment with NIVO + RELA may have comparable efficacy to, and lower toxicity than, NIVO + IPI in pts with advanced melanoma. Results should be interpreted with caution given differences in study designs and changes in treatment landscape. Research is ongoing to determine which pts respond best with each combination. [Table: see text]
Real-world outcomes of combined lenvatinib and anti-PD-1 in advanced melanoma: Lenvamel, a multicenter retrospective study of the French Group of Skin Cancers.
Authors: Perrine Rousset, Charlée Nardin, Eve Maubec, Valentine Heidelberger, Alexandra Picard, Emilie Gérard, Nora Kramkimel, Maud Steff, Gaëlle Quéreux, Caroline Gaudy-Marqueste, Candice Lesage, Claire Mignard, Geraldine Jeudy, Thomas Jouary, Mélanie Saint-Jean, Barouyr Baroudjian, Elodie Archier, Laurent Mortier, Celeste Lebbe, Henri Montaudie
Journal: Journal of Clinical Oncology (2024)

9546 Background: Treatment options for patients (pts) with advanced melanoma who experience resistance to immunotherapy (ICI) +- targeted therapy are lacking. Studies suggest the anti-tumour activity of combined pembrolizumab and lenvatinib in pts progressing on ICI. We report the clinical outcomes of combined lenvatinib and anti-PD-1 in this population. Methods: This French multicenter real-world study was conducted from 09/2020 to 07/2023. The primary endpoint was objective response rate (ORR) according to the RECIST criteria (v.1.1). Secondary endpoints were treatment-related adverse events (TRAEs), progression-free survival (PFS), overall survival (OS) and duration of response (DOR). Results: Of the 67 pts included (median age, 69 years; median follow-up, 5.0 months), 85% had stage IV M1c or M1d disease. Baseline characteristics are presented (Table). Overall ORR was 28.4% (95%CI, 18–41%), including 3 complete (4.5%) and 16 partial (23.9%) responses. ORR was 71.4% (95%CI, 29–96%) for mucosal melanoma, 32,8% (95%CI, 21–46%) for pts pre-treated with anti-PD-1 + anti-CTLA-4, and 31,5% (95%CI, 20–46%) for BRAF wild-type melanoma. Median DOR was 3.1 (IQR, 1.3–4.3) months. Median PFS and OS were 3.1 (95% CI, 2.5–3.7) and 9.8 (95% CI, 5.6–13.9) months respectively. Grade 3–4 TRAEs occurred in 16 pts (24%, no grade 5); common TRAEs were fatigue (43.3%), nausea/vomiting (26.8%), diarrhea (20.9%), and hypertension (20.9%). Conclusions: Our study demonstrates an interesting response rate and acceptable safety profile of this combination, with manageable toxicities, in an immuno-refractory population with poor prognostic factors. Pts pre-treated with anti-PD-1+ anti-CTLA-4, and those with BRAF wild-type melanoma seemed to benefit more from this strategy. Our study also provides promising data (considering the small sample) for pts with mucosal melanoma. Our data support this treatment option for refractory melanoma, though not yet approved by the health authorities, and highlight the need for new strategies. [Table: see text]
When to stop immunotherapy for advanced melanoma: Emulation of target trials.
Authors: Mathilde Amiot, Laurent Mortier, Stéphane Dalle, Olivier Dereure, Sophie Dalac, Caroline Dutriaux, Marie Thérèse Leccia, Eve Maubec, Jean-Philippe Arnault, Florence Brunet-Possenti, Julie De Quatrebarbes, Florence Granel Brocard, Caroline Gaudy-Marqueste, Cécile Pagès, Pierre-Emmanuel Stoebner, Delphine Legoupil, Henri Montaudie, Bastien Oriano, Celeste Lebbe, Raphaël Porcher
Journal: Journal of Clinical Oncology (2024)

9521 Background: Immune checkpoint inhibitors (ICI) have demonstrated their effectiveness with a 7.5-year overall survival (OS) close to 50% for advanced stages. The design of clinical trials allowed treatment until progression or toxicity, or for a maximum duration of two years. Prolonged follow-up of responders after cessation shows sustained response and a low risk of relapse in the months following cessation. As of yet, the optimal duration of anti-PD-1 therapy for metastatic melanoma remains unestablished. The objective of this work was to evaluate the optimal duration of ICI. Methods: We conducted emulated trials using the cloning, weighting and censoring approach. Each emulated trial aimed at comparing the causal effect of stopping versus continuing ICI at a specific timepoint, in patients still under treatment and with disease control at that time. Results: The study comprised 1017 participants to the MELBASE cohort. Results of the 6-month discontinuation emulated trial showed a significantly lower OS if treatment was discontinued, compared to continuing treatment for at least three months. The 48-month survival difference was 37.8% (95% confidence interval [CI] 19.8 to 60.5), and the corresponding restricted mean survival time difference 8.3 months (95% CI: 4.1 to 12.7). The 12-month and 18-month discontinuation emulated trials both showed no evidence of benefit of either discontinuing or continuing ICI at any of those timepoints. The 24-month discontinuation emulated trial results were more in favor of stopping compared to continuing treatment at that decision point, with an absolute 48-month survival 10.5% higher (95% CI 4.4 to 18.1). Conclusions: These results suggest that a one-year course of immunotherapy is both necessary and sufficient for patients with advanced melanoma. Prolonged treatment beyond 2 years does not appear to be beneficial in terms of survival and could even be detrimental.[Table: see text]
Pembrolizumab (pembro) for locally advanced (LA) or recurrent/metastatic (R/M) cutaneous squamous cell carcinoma (cSCC): Long-term results of the phase 2 KEYNOTE-629 study.
Authors: Eva Muñoz Couselo, Brett Gordon Maxwell Hughes, Laurent Mortier, Jean-Jacques Grob, Ralf Gutzmer, Osama Roshdy, Rene Lazaro Gonzalez Mendoza, Jacob Schachter, Ana Maria Arance, Florent Grange, Nicolas Meyer, Abhishek Jagdish Joshi, Salem Billan, Sven Erik Ojavee, Jianda Yuan, Burak Gumuscu, Åse Bratland
Journal: Journal of Clinical Oncology (2024)

9554 Background: Pembro monotherapy is approved in certain countries, including the US, for treatment of LA or R/M cSCC based on results from the open-label phase 2 KEYNOTE-629 trial (NCT03284424). Promising antitumor activity was demonstrated with pembro in both the LA and R/M cohorts. ORR (95% CI) was 50.0% (36.1-63.9; 16.7% CRs) in the LA cohort and 35.2% (26.2-45.2; 10.5% CRs) in the R/M cohort. We present data from KEYNOTE-629 with an additional follow-up of 38 mo for LA and R/M cohorts. Methods: Adults with histologically confirmed LA or R/M cSCC, measurable disease per RECIST v1.1 by blinded independent central review (BICR), and ECOG PS 0 or 1 received pembro 200 mg IV every 3 weeks for up to 35 cycles (~2 years). The primary end point was ORR per RECIST v1.1 by BICR. Secondary end points were DOR, DCR (CR + PR + SD ≥12 wks), and PFS per RECIST v1.1 by BICR; OS; and safety. End points were analyzed in pts who received ≥1 dose of pembro. Results: A total of 159 pts were treated with pembro (LA, n = 54; R/M, n = 105). As of September 13, 2023, 33 pts (20.8%) completed treatment and 126 pts (79.2%) discontinued treatment. Median (range) follow-up was 52.4 mo (47.6-56.9) for the LA cohort, 64.7 mo (62.1-69.5) for the R/M cohort, and 63.1 mo (47.6-69.5) in the total population. ORR and DCR are shown in the table. Median DOR (range) was 47.2 mo (1.0+ to 49.9+) in the LA cohort, not reached (NR; 2.7 to 64.2+ mo) in the R/M cohort, and 52.5 mo (1.0+ to 64.2+) in the total population; the proportion of responders with responses ≥12 mo by Kaplan-Meier estimate were 84.8%, 77.8%, and 80.7%, respectively. Median (95% CI) PFS was 14.4 mo (5.5-43.6) in the LA cohort, 5.7 mo (3.1-8.5) in the R/M cohort, and 8.0 mo (5.3-14.4) in the total population; 12-mo rates were 56.7%, 37.3%, and 43.7%, respectively. Median (95% CI) OS was NR (33.3-NR) in the LA cohort, 23.8 mo (13.4-30.9) in the R/M cohort, and 29.8 mo (20.0-42.8) in the total population; 36-mo rates were 62.0%, 39.5%, and 47.0%, respectively. Grade 3-5 treatment-related AEs occurred in 11.3% of pts, and grade 3-5 immune-mediated AEs and infusion reactions occurred in 8.8% of pts. Two pts (1.3%) died due to a treatment-related AE (colitis, cranial nerve disorder). Conclusions: With a median follow-up of more than 5 years, pembro continued to show durable responses in pts with LA or R/M cSCC. No new safety signals were observed. Results from this study continue to support the use of pembro in this pt population. Clinical trial information: NCT03284424 . [Table: see text]
Efficacy and safety of RP1 combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial.
Authors: Michael K.K. Wong, Joseph J Sacco, Caroline Robert, Judith Michels, Tawnya Lynn Bowles, Gino Kim In, Katy K. Tsai, Celeste Lebbe, Caroline Gaudy-Marqueste, Eva Muñoz Couselo, Mark R. Middleton, Adel Samson, Dirk Schadendorf, Georgia Beasley, Jiaxin Niu, Bartosz Chmielowski, Trisha M. Wise-Draper, Junhong Zhu, Marcus Viana, Mohammed M. Milhem
Journal: Journal of Clinical Oncology (2024)

9517 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from pts with anti–PD-1–failed melanoma, including the initial cohort and updated data from a registration-directed (R-D) cohort, from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts had locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) while on therapy and received anti–PD-1 ± anti–CTLA-4 therapy for ≥8 consecutive weeks, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy had confirmed PD while on adjuvant therapy. RP1 was initially given intratumorally at 1×10 6 plaque-forming units (PFU)/mL and then every 2 weeks (Q2W) at 1×10 7 PFU/mL for up to 8 total cycles (≤10 mL/cycle) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then received nivo alone (240 mg Q2W or 480 mg Q4W IV) for up to 2 years, with the option to receive additional courses of RP1 if specified criteria were met. Results: Overall, 156 pts were enrolled (initial melanoma cohort, n = 16; R-D cohort, n = 140); 46.2% of pts had been treated with prior anti–PD-1 combined with anti–CTLA-4, and 51.3% of patients had stage IVM1b-d disease. The overall objective response rate (ORR) was 31.4%, and 12.2% of pts achieved complete response (CR; Table). Responses were observed irrespective of prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions and in bulky and visceral disease. The ORR for pts with primary anti–PD-1 resistance was 34.1%. In pts who failed prior ipilimumab + nivo, the ORR was 26.4% (Table). The median duration of response (time from baseline to end of response for responders) was &gt; 24 months, with 100% of responses lasting &gt; 6 months from baseline; 78% of responses were ongoing. Treatment-related adverse events (TRAEs) associated with RP1 + nivo were predominantly grade 1–2; there was 1 grade 5 TRAE (immune-mediated myocarditis attributed to nivo). Conclusions: The updated data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated. Clinical trial information: NCT03767348 . [Table: see text]
A phase 2 study of de-escalation in resectable, locally advanced cutaneous squamous cell carcinoma (cSCC) with the use of neoadjuvant pembrolizumab: De-Squamate.
Authors: Rahul Ladwa, Jenny HJ Lee, Sandro V Porceddu, Margaret Louise McGrath, Caroline Cooper, Howard Liu, Ruta Gupta, Claire Cuscaden, Michelle K. Nottage, Jonathan Clark, Dieu Le, Marketa Pauley, Jazmina Gonzalez-Cruz, Ian Frazer, Brett Gordon Maxwell Hughes, Benedict J Panizza
Journal: Journal of Clinical Oncology (2024)

9514 Background: Neoadjuvant anti-Programmed Death therapy has shown a 64% complete or major pathological response rate in patients (pts) with resected stage II-IV(M0) cSCC. The De-Squamate study (NCT05025813) evaluated the feasibility of a risk adapted surgical de-escalation approach guided by clinical, radiological and pathological response in resectable cSCC pts of all sites receiving neoadjuvant pembrolizumab. Methods: This multi-centre, open-labelled, non-randomised, single-arm phase 2 study evaluated the response of neoadjuvant Pembrolizumab for 4 cycles administered IV 200mg Q3W in immunocompetent pts with Stage II-IV (M0) resectable cSCC. Pts underwent CT/MRI and 18F-FDG-PET imaging at baseline and following completion of neoadjuvant pembrolizumab. In those with a complete metabolic response, mapping biopsies of target site(s) were performed and if negative for residual SCC (clinical complete response [CCR]), surgery and post operative radiation therapy (PORT) were omitted. Patients with clinical or radiological residual disease/ positive mapping biopsy underwent surgical resection. PORT was de-escalated if there was a pathological complete response (PCR - no residual tumour cells) or major pathological response (MPR - less than or equal to 10% viable tumour cells). Pts proceeded to 13 cycles of maintenance Pembrolizumab. The primary endpoint was the combined rate of PCR, MPR and CCR following neoadjuvant Pembrolizumab and secondary endpoint includes treatment de-escalation and safety. Results: All 27 patients were enrolled and received a minimum of 2 cycles of neoadjuvant Pembrolizumab. The primary endpoint was observed in 17 patients (63%, 95% CI: 42-80), comprised of PCR (15%), MPR (0%) and CCR (48%). De-escalation of both surgery and PORT was achieved in 48% and a further 15% avoided PORT alone. With a minimum follow up of 6 months, no pts with PCR/MPR/CCR recurred. Investigator assessed treatment-related adverse events ≥ grade 3 was seen in 2 patients (7%). Conclusions: Pembrolizumab led to a high rate of PCR and CCR in resectable cSCC. The de-squamate study design effectively selected pts for surgical and PORT de-escalation and demonstrated a sustained response in this cohort. Clinical trial information: NCT05025813 .