bluuebunny/crossref_metadata_2025_split huggingface dataset:
A retrospective study of ipilimumab plus nivolumab in anti–PD-L1/PD-1-refractory merkel cell carcinoma.
Authors: Shalhout Sophia Z. , Emerick Kevin S. , Kaufman Howard E. , Miller David M. 
Published: June 2022

9521 Background: Merkel cell carcinoma (MCC) is a rare cutaneous neuroendocrine carcinoma with a high recurrence and mortality rate. Immune checkpoint inhibitors (ICIs) targeting the PD-L1/PD-1 axis have shown significant clinical benefit with durable responses in patients with advanced MCC leading to regulatory approvals by the U.S. Food and Drug Administration for two agents: avelumab (anti-PD-L1) and pembrolizumab (anti-PD-1). However, many patients (̃50%) with advanced MCC treated with ICI do not experience tumor regression. Studies regarding systemic therapy options following progression due to primary or acquired resistance to immunotherapy are limited and management remains a clinical challenge. In this retrospective study, we evaluated objective clinical response to combination ipilimumab and nivolumab (ipi-nivo) salvage therapy in advanced MCC refractory to anti-PD-L1/PD-1 treatment. Methods: We reviewed the electronic medical record at Mass General Brigham associated institutions to identify patients with advanced MCC that progressed on upfront immunotherapy (e.g., pembrolizumab, avelumab or nivolumab) and were re-challenged with combination ipi-nivo between 2016 to 2021. Patients treated with prior surgery, radiation, or cytotoxic chemotherapy after progressing on immunotherapy were not excluded. Responses to ipi-nivo were evaluated for every patient at each re-staging/interval assessment following baseline analysis utilizing Response Evaluation Criteria in Solid Tumors (RECISTv1.1) as well as immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) to ensure conventional RECIST did not underestimate the benefit of ipi-nivo. Results: Four patients (31%) experienced grade III/IV immune-related adverse events. No patients (0/13) in this case series achieved an objective response via RECISTv1.1/irRECIST. Stable disease was seen in 23% (3/13) and the median progression-free survival was 1.3 months (90% CI, 1.1-1.5). The median overall survival from the initiation of ipi-nivo was 4.7 months (95% CI, 3-17). Conclusions: This study suggests limited, if any, clinical benefit of ipi-nivo in patients with advanced anti-PD-L1/anti-PD-1-refractory MCC. New strategies for second-line treatment of MCC are needed and referral to innovative clinical trials should be a priority for patients with refractory metastatic MCC.
Fecal microbiota transplantation followed by anti–PD-1 treatment in patients with advanced melanoma.
Authors: Miller Wilson H. , Routy Bertrand , Jamal Rahima , Ernst D. Scott , Logan Diane , Esfahani Khashayar , Belanger Karl , Elkrief Arielle , Lapointe Rejean , Thebault Pamela , Ponce Mayra , Parvathy Seema Nair , Messaoudene Meriem , Silverman Micheal , Maleki Saman , Lenehan John Gordon 
Published: June 2022

9533 Background: The gut microbiome has been shown to be a biomarker of response in patients (pts) with melanoma. Strategies to modify the microbiome are currently being investigated. We report the effects of Fecal Microbiota Transplantation (FMT) on safety and anti-PD-1 response in pts with melanoma from a phase I trial (NCT03772899). Methods: 20 pts with advanced melanoma with RECIST-evaluable disease, without prior anti-PD-1 treatment for advanced disease, were recruited from 3 Canadian academic centers. Pts with ECOG > 2, autoimmune diseases, immunosuppression or unstable brain metastases were excluded. Pts received 80-100 g of healthy donor stool via oral capsules and were treated with anti-PD-1 one week later. The primary objective was safety of combining FMT with anti-PD-1 therapy. Objective response rate (ORR) by RECIST 1.1 and correlative studies were secondary objectives. Flow cytometry and multiplex ELISA were performed on pts blood samples. Avatar mice were transplanted with stool samples obtained from participants on the trial before and after FMT. Mice were subsequently implanted with B-16 or MCA-205 tumors and received anti-PD-1 antibodies. Results: Median age was 75.5 years, 12 (60%) were male, 18 (90%) had stage 4 disease, and 5 (25%) pts harbored a BRAF mutation. Median follow-up was 11.2 months. FMT-related adverse events included grade 2 diarrhea (2 pts) and hypophosphatemia (1 pt), and 13 pts (65%) experienced grade 1 gastrointestinal toxicities. Grade 3 immune-related adverse events (irAE) were one each of myocarditis, nephritis, and fatigue. Anti-PD-1 therapy was discontinued for toxicity in 2 (10%) pts. No unexpected irAE or death on treatment occurred. ORR was 65% (13/20), of which 3 were CR. Clinical benefit rate (includes SD lasting > 6 months) was 75% (15/20). Median PFS was not reached, and one pt died from their disease. Translational analyses demonstrated upregulation of IL-17 post-FMT in responders, which correlated with upregulation of the frequency of Th17 cells in peripheral blood. In parallel, murine experiments showed that feces from pts pre-FMT did not sensitize tumors to anti-PD-1. In both tumor models, only feces obtained post-FMT from responders restored anti-PD-1 efficacy in mice, providing strong support that FMT contributed to the anti-tumor response observed in pts. Conclusions: FMT followed by anti-PD-1 treatment in melanoma pts undergoing therapy is safe and may lead to improved anti-tumor responses that can be reproduced in tumor mouse models. The gut microbiome plays an important role in responses to anti-PD-1 in patients with advanced melanoma, paving the way for future microbiome-based interventions. Clinical trial information: NCT03772899.
Outcomes of combined ipilimumab/nivolumab in metastatic uveal melanoma: A prevalence meta-analysis.
Authors: Durer Ceren , Durer Seren , Hoilat Gilles Jad , Abu-Zaid Ahmed , Milhem Mohammed M. 
Published: June 2022

9534 Background: Uveal melanoma is the most common primary intraocular malignant tumor in adults and, approximately 40-50% of the patients eventually develop metastatic disease. Metastatic uveal melanoma has a dismal prognosis with an overall survival of < 50% at 1-year. Single-agent check point inhibitors revealed minimal benefit and novel approaches are underway to improve the outcomes with the recent approval of Tebentafusp in uveal melanoma. The purpose of this metanalysis was to assess the safety and efficacy of combined immunotherapy with ipilimumab (3 mg/kg x q3w for 4 cycles) and nivolumab (1 mg/kg x q3w for 4 cycles) in metastatic uveal melanoma. Methods: A comprehensive literature search on PubMed, Embase, Cochrane and Web of Science was conducted. Two independent reviewers screened the literature and extracted data. Our search strategy included MeSH terms and key words for metastatic uveal melanoma; ipilimumab and nivolumab. OpenMeta[Analyst] software was used for the analysis. The endpoints included the prevalence of overall response rate (ORR), complete response (CR), ≥grade-III diarrhea/colitis, and ≥grade-III hepatic toxicity. Additional endpoint included the median overall survival (OS) was reported as a range. Random-effects model (DerSimonian-Laird method) was applied. Results: Overall, eight studies (n = 379) were included for the analysis. Five studies were phase II, three studies were retrospective. 52% of the patients were male with good performance status. Median follow-up ranged from 9.2 mo-28 mo. 40% of the patients (n = 142) had elevated LDH at the time of treatment. GNAQ and GNA11 mutations were reported in three studies, BRAF mutation was reported in two studies. The pooled prevalence for ORR was 13.7% (95% CI: 9.2–18.2%, N = 6 studies, n = 33/226) with CR of 2.1% (95% CI: 0.3–3.9%, N = 6 studies, n = 8/226). The median OS ranged from 12.7 to 19.1 months (N = 7 studies). Majority of the patients experienced treatment-related adverse events. Most common side effects included diarrhea, colitis, hepatic toxicities, skin disorders, hypothyroidism. The pooled prevalence for ≥grade III hepatic toxicity was 26.2% (95% CI: 13.9–0.385%, N = 5 studies, n = 60/219). Conclusions: Combined checkpoint blockade with ipilimumab and nivolumab showed an ORR of 13.7% which appears to show better clinical activity than single-agent checkpoint inhibitor. Most common treatment side effect was hepatic toxicity.
Overall survival (OS) with first-line atezolizumab (A) or placebo (P) in combination with vemurafenib (V) and cobimetinib (C) in BRAFV600 mutation-positive advanced melanoma: Second interim OS analysis of the phase 3 IMspire150 study.
Authors: McArthur Grant A. , Gutzmer Ralf , Stroyakovskiy Daniil , Gogas Helen , Robert Caroline , Protsenko Svetlana , Pereira Rodrigo Perez , Eigentler Thomas , Rutkowski Piotr , Demidov Lev V. , Zhukova Natalia V. , Schachter Jacob , Yan Yibing , Caro Ivor , Hertig Christian , Xue Cloris , Kusters Lieke , Ascierto Paolo Antonio , Lewis Karl D. 
Published: June 2022

9547 Background: Primary analysis of the phase 3 IMspire150 study (NCT02908672) demonstrated improved investigator-assessed progression-free survival (PFS) with first-line A + V + C vs P + V + C in patients (pts) with BRAFV600 mutation–positive advanced melanoma (hazard ratio [HR] 0.78; 95% CI, 0.63-0.97; P= 0.025). With median follow-up of 18.9 months at primary analysis, OS data were immature; interim analysis of OS at the time of the primary analysis demonstrated a trend in favor of A + V + C over P + V + C (estimated 2-year OS rate, 60.4% vs 53.1%) (Gutzmer et al. Lancet 2020;395:1835-1844). Herein, we present results from the second interim OS analysis of the IMspire150 study. Methods: IMspire150 enrolled previously untreated pts with stage IV or unresectable stage IIIc BRAFV600 mutation-positive melanoma (n = 514). Pts were randomized 1:1 to receive 28-day cycles of A + V + C (n = 256) or P + V + C (n = 258). Pts received V + C in cycle 1; A or P was added on days 1 and 15 from cycle 2 onwards. The second interim OS analysis was planned after ̃270 OS events were recorded, and was projected to have a minimally detectable difference of HR of 0.74 with a P value boundary of 0.0140. OS was estimated using the Kaplan-Meier method. Results: At data cutoff (Sept 8, 2021), 273 OS events had occurred. Median follow-up was 29.1 months (range, 1-54) for A + V + C and 22.8 months (range, 0-54) for P + V + C. A continued trend toward OS benefit in favor of A + V + C over P + V + C was observed with median OS of 39.0 vs 25.8 months, but the difference did not reach statistical significance (HR, 0.84; 95% CI, 0.66-1.06; P= 0.1432). A delayed treatment effect was observed, with landmark OS rates for A + V + C vs P + V + C of 76.1% vs 76.5% at 12 months and 61.5% vs 53.3% at 24 months. With additional follow-up, A + V + C continued to show PFS benefit over P + V + C (HR, 0.79; 95% CI, 0.64-0.97; P= 0.0224); overall response rates (66.7% vs 65.0%) and median duration of response (21.0 vs 12.6 months) remained consistent with those reported at primary analysis. No new safety signals were observed with additional follow-up. Conclusions: With further follow-up, A + V + C demonstrated a consistent, but not statistically significant, improvement in OS and continued benefit in duration of response versus P + V + C in previously untreated pts with BRAFV600 mutation–positive advanced melanoma. Clinical trial information: NCT02908672.
Efficacy and safety of sequencing with vemurafenib (V) plus cobimetinib (C) followed by atezolizumab (Atezo) in patients (pts) with advanced BRAFV600-positive melanoma: Interim analysis of the ImmunoCobiVem study.
Authors: Schadendorf Dirk , Gogas Helen , Kandolf Sekulovic Lidija , Meier Friedegund Elke , Eigentler Thomas , Simon Jan-Christoph , Terheyden Patrick Andres Maximilian , Gesierich Anja Heike , Herbst Rudolf Alexander , Kähler Katharina C. , Ziogas Dimitrios C. , Mijuskovic Zeljko , Garzarolli Marlene , Garbe Claus , Roesch Alexander , Ugurel Selma , Gutzmer Ralf , Grob Jean-Jacques , Zimmer Lisa , Livingstone Elisabeth 
Published: June 2022

9548 Background: Immunotherapies (ICI) and targeted therapies (TT) have improved PFS and OS in BRAFV600-mutated advanced melanoma pts, but evidence regarding their optimal sequence is limited. The randomized phase 2 ImmunoCobiVem study evaluated efficacy and safety of an early switch to Atezo after initial treatment with V + C. Interim results are reported. Methods: Pts with previously untreated BRAFV600-mutated advanced melanoma received a 3-mo run-in with V (960 mg twice daily) + C (60 mg once daily for 21/28 days). Pts without PD/treatment interruption due to AEs during run-in were then randomized 1:1 to continue V + C (Arm A) or switch to Atezo (1200 mg every 3 wks; Arm B) until first documented PD (PD1), followed by crossover to the alternate treatment until second documented PD (PD2). End points were PFS1 (time from start of run-in until PD1 or death from any cause), PFS2 (time from start of run-in until PD2 or death from any cause), PFS3 (time from PD1 until PD2 or death from any cause), DCR, ORR, OS, and safety. Results: 185 pts were enrolled between Nov 2016 and Dec 2019 (63% male; median age 58 y); 135 pts completed run-in and were randomized to Arm A (n=69) or Arm B (n=66). At data cutoff, median follow-up for all pts was 19.0 mo. In Arm A, 36/69 pts (52%) discontinued V + C due to PD and 21/36 (58%) crossed over to Atezo; in Arm B, 49/66 pts (74%) discontinued Atezo due to PD and 35/49 (71%) crossed over to V + C. Median PFS1 was significantly longer in Arm A vs Arm B (HR 0.55; 95% CI 0.37–0.84; P=0.001), while median PFS3 was significantly shorter in Arm A vs Arm B (HR 2.24; 95% CI 1.17–4.30; P=0.013); median PFS2 was not significantly different between arms (HR 1.57; 95% CI 0.83–2.96; P=0.163) (Table). During the randomized phase, ORR and DCR were higher in Arm A before crossover and in Arm B after crossover (Table). OS was similar between arms (HR 1.22; 95% CI 0.69–2.16; P=0.389). Median (range) treatment duration across treatment phases was 11.2 mo (2.3–56.1) for Arm A and 10.7 mo (2.8–56.7) for Arm B. Grade 3/4 AEs occurred in 55% of pts in Arm A and 64% in Arm B; AEs led to discontinuation in 10% and 12%, respectively. Conclusions: Early switch from V + C to Atezo is feasible and safe, but tumor control achieved in run-in is maintained in only a subset of pts on subsequent ICI monotherapy. Crossover to ICI monotherapy at PD results in low response, while response to TT re-exposure is frequent. Clinical trial information: NCT02902029. [Table: see text]
Camrelizumab plus apatinib for patients with advanced mucosal melanoma: A prospective single-arm study.
Authors: Zou Zhengyun , Zhao Lianjun , Ren Yu , Sha Huizi , Liu Baorui 
Published: June 2022

9550 Background: Mucosal melanoma is a rare subtype in white populations, but the second most common subtype in Asian populations. This subtype is a more aggressive malignancy, with high risk of metastasis and death. Immune checkpoint inhibitor combined with anti-angiogenic agent has been investigated in many solid tumors, including some preliminary evidence (NCT03086174 and NCT04091217) in Chinese patients with advanced mucosal melanoma. This study investigated the efficacy and safety of camrelizumab plus apatinib in patients with advanced mucosal melanoma. Methods: In this prospective, single-arm study (ChiCTR1900023277), patients with inoperable stage III-IV or recurrent/metastatic mucosal melanoma and Eastern Cooperative Oncology Group performance status of 0-1 were enrolled. Patients received camrelizumab 200 mg once every 2 weeks and apatinib 500 mg once daily until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) according to the Response Evaluation Criteria In Solid Tumors, version 1.1. Results: Between April 2019 and January 2022, a total of 30 patients were enrolled (Table). As of January 2022, 21 patients had at least one efficacy assessment, and the median follow-up duration was 8.1 months. The ORR was 42.9%, including one (4.8%) patient with confirmed complete response, six (28.6%) with confirmed partial response (PR), and two (9.5%) with unconfirmed PR. The disease control rate (DCR) was 81.0%. The median progression-free survival was 7.2 months (95%CI, 5.8-not reached [NR]) in 21 patients, 7.7 months (95%CI, 5.8-NR) in 19 patients with first-line camrelizumab plus apatinib treatment, and 9.8 months (95%CI, 4.2-NR) in 11 patients without prior chemotherapy. The most common treatment-related adverse events in 27 patients with available safety data were fatigue (17 [63.0%]), hypertension (15 [55.6%]), and elevated transaminase (14 [51.9%]). No treatment-related deaths occurred. Exploratory analysis found a tendency that patients with high T cell receptor diversity had better prognosis. Higher frequencies of Vβ-Jβ (including Vβ5-8Jβ2-7, Vβ28J2-4 and Vβ12-5Jβ1-1) indicate better survival, and Vβ12-5Jβ1-1 is an independent factor after multivariate adjustment. Conclusions: Camrelizumab plus apatinib showed favorable ORR and DCR in patients with advanced mucosal melanoma, with an acceptable safety profile. Follow-up for survival outcomes is ongoing. Clinical trial information: ChiCTR1900023277. [Table: see text]
The relationship between circulating tumor DNA with Merkel cell carcinoma tumor burden and detection of recurrence.
Authors: Akaike Tomoko , So Naomi , Hippe Daniel S , Gunnell Lindsay , Doolittle-Amieva Coley , Lachance Kristina , Hall Evan Thomas , Bhatia Shailender , Rathore Richa , Rattigan Nicole Hook , Baker Kathryn Terese , Rodriguez Angel Augusto , Ecklund Andrew , Aleshin Alexey , Nghiem Paul , Zaba Lisa C. 
Published: June 2022

9566 Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of 40%. Early detection of recurrence can improve outcomes, and effective surveillance is crucial for management of patients with MCC. While Merkel cell polyomavirus (MCPyV) oncoprotein serology is useful in surveillance for MCPyV-positive MCC tumors, patients with MCPyV-negative tumors have no available blood biomarkers and require frequent imaging. This prospective, multicenter study assessed whether circulating tumor DNA (ctDNA) can assess disease burden and detect recurrence regardless of virus status. Methods: A total of 328 blood samples were collected from 125 patients at various time points with a median follow-up of 6 months (range: 0-21 months) between April 2020 to January 2022. Whole-exome sequencing was performed on tumor tissue and matched normal blood to identify a set of somatic, clonal single nucleotide variants, which were tracked in subsequent blood (plasma) samples using a personalized and multiplex PCR-NGS based ctDNA assay (Signatera). Clinically evident disease was defined as MCC noted either by physical exam or by imaging, and molecular evidence of disease was defined as a positive ctDNA test. Surveillance phase began once there was no clinically evident or molecular evidence of disease. Results: Among 125 patients, 47 (38%) had clinically evident MCC and all were found to be ctDNA-positive at the first time point (sensitivity: 100%; 95% CI: 91-100%). Of the 47, 24 were newly diagnosed with MCC and had a median primary tumor size of 2.2 cm (range 0.5-8.5 cm) and a median ctDNA value of 26 mean tumor molecules (MTM)/mL (range: 0.08-1470 MTM/mL). Primary tumor diameter and ctDNA value were strongly correlated (Spearman’s r = 0.81, p < 0.001). Of the 125 patients, 73 (58%) patients were assessed in the surveillance setting and had a total of 152 plasma samples available for longitudinal ctDNA testing. Over this period, 7 ctDNA tests were positive while 145 were negative. After a positive test, 5/7 developed a clinically evident recurrence (4 within 60 days). Of the remaining 2 without clinical recurrence, one had < 60 days of follow-up at time of data analysis. The estimated risk of recurrence, accounting for incomplete follow-up, was 57% within 60 days of a positive ctDNA test (n = 7 tests). In contrast, after a negative ctDNA test (n = 145 tests), the risk of recurrence was 0% within 60 days and 3% between 60-90 days. Conclusions: To our knowledge, this is the largest study to explore ctDNA testing in MCC patients. This study demonstrates that ctDNA testing can detect MCC recurrence early and is a promising clinical surveillance tool regardless of tumor viral status.
Neoadjuvant dabrafenib and trametinib (D+T) for stage III melanoma: Long-term results from the NeoCombi trial.
Authors: Menzies Alexander M. , Saw Robyn P.M. , Lo Serigne N. , Gonzalez Maria , Ch'ng Sydney , Nieweg Omgo E. , Shannon Kerwin Frank , Ferguson Peter M. , Lee Jenny HJ , Rizos Helen , Rawson Robert V , Stretch Jonathan , Thompson John F. , Emmett Louise , Kapoor Rony , Spillane Andrew John , Scolyer Richard A. , Long Georgina V. 
Published: June 2022

9580 Background: Neoadjuvant D+T has a high pathologic response rate and impressive short-term survival. The NeoCombi trial (NCT01972347) enrolled 35 patients with resectable stage III melanoma, with last patient commencing treatment April 19th 2017. We report 5-year outcomes from this trial. Methods: Pts received 12 wks neoadjuvant standard dose D+T, then 40 wks adjuvant D+T. Eligible pts were ≥ 18 yrs, ECOG PS ≤ 1 with clinical stage III BRAF V600E/K melanoma. CT and PET scans were performed at baseline and prior to surgery. Pathologic response was determined as per International Neoadjuvant Melanoma Consortium (INMC) criteria and defined as complete (pCR), near complete, partial (pPR) or no response (pNR). CT monitoring was continued 12 wkly thereafter to 2 yrs, then 6 monthly to 3 yrs, then as standard care. The primary endpoints were the complete pathological response (pCR) and RECIST response rate (rRR) at wk 12. Secondary endpoints included relapse free survival (RFS), OS, and toxicity. Results: 35 pts were enrolled, 6 with IIIB, 29 IIIC (7 ITM only) disease (clinical AJCCv7). At data cut August 17th 2021, median F/U was 60 mo (95% CI 56-72). No patients progressed in the neoadjuvant phase, and (49%) had a pCR, 1 near pCR, 6 pPR, 11 pNR. 5-year RFS, DMFS and OS data are shown in the Table. The majority of recurrences occurred within the first 2 years, with no recurrences beyond 3y. 21 patients recurred; 12 (57%) had first recurrence locoregional (6/12 subsequent distant recurrence) and 9 (43%) had first recurrence in distant sites (3/9 in brain). Locoregional recurrence was managed with surgery alone in 4/12, systemic therapy alone in 2/12, or both surgery and systemic therapy in 5/12 (4/5 had adjuvant systemic therapy), 1 pt was observed until distant recurrence. Subsequent systemic therapy in the 15 patients with a distant recurrence included PD-1 based immunotherapy (N=14) and BRAF targeted therapy (N=10). Conclusions: Neoadjuvant D+T in clinical stage III melanoma has impressive early activity, however patients remain at high risk of recurrence. Pathologic response can identify patients at the highest risk of recurrence, offering a chance of alternative adjuvant therapy in non-responders. Clinical trial information: NCT01972347. [Table: see text]