bluuebunny/crossref_metadata_2025 huggingface dataset:
Mefatinib as first-line treatment of patients with advanced non–small cell lung cancer harboring rare EGFR mutations.
Authors: Wang Pingli , Cao Liming , Tian Panwen , Ren Shengxiang , Miao Liyun , Zhou Chengzhi , Fan Yun , Li Yuping , Lv Dongqing , Zhao Xin , Yang Mei , Zhu Chaonan , Xu June , Song Yong , Wang Kai
Published: June 2022

9102

Background: Mefatinib is a novel, second-generation, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI). A Phase Ib/II study has showed promising efficacy in patients with advanced EGFR (19del/L858R) mutant non-small cell lung cancer (NSCLC). This study is aimed to assess the efficacy and safety of mefatinib as first-line therapy for advanced rare EGFR mutations (G719X/S768I/L861Q) NSCLC. Methods: In this phase II study, we enrolled patients with stage IIIB-IV lung adenocarcinoma with at least one mutation in G719X, L861Q, and S768I who hadn¡¯t received front-line anticancer therapy. Other concurrent EGFR mutations were allowed with the exception of Ex19del, L858R, and exon 20 insertions. Eligible patients were treated with mefatinib 80 mg orally once daily. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 criteria. Results: A total of 21 patients (median age 57.6, 47.62% male) have been enrolled, 80.95% with G719X, 33.3% S768I, and 19.05% L861Q. Six (28.57%) patients had concurrent mutations of G719X and S768I, and one (4.76%) patient had co-mutations of G719X and L861Q. As of data cut-off (Jan, 6, 2022), median follow-up was 25.1 months. Among the 21 efficacy evaluable patients, ORR was 85.71% (95% CI, 63.66-96.95) with a duration of response (DOR) of 22.2 months (95% CI, 8.4-NA). Disease control rate (DCR) was 100% (95% CI, 83.89-100.00). Median progression-free survival (mPFS) was 20.6 months (95% CI, 8.3-NA). Median overall survival (OS) was not reached.. The most common treatment-related adverse events (TRAEs) were rash (20, 95.24%), diarrhea (19, 90.48%), stomatitis (15, 71.43%), and pandactilitis (9, 42.86%). Grade 3 TRAEs were reported in 47.63% patients. Common Grade 3 TRAEs (¡Ý5%) included diarrhea (8, 38.10%) and rash (5, 23.81%). No ¡ÝGrade 4 TRAE or treatment-related SAE reported. 33.33% (n=7) of patients experienced dose reduction due to AEs (mainly diarrhea and rash). All TRAEs were reversible and remained stable or recovered without sequelae after dose reduction. None of the patients discontinued treatment or died due to TRAE. Conclusions: Mefatinib has shown promising anti-tumor activity and a favorable safety profile in patients with advanced NSCLC harboring rare EGFR mutations. Clinical trial information: CTR20190110. [Table: see text]
Improved survival from early combined radiotherapy: A phase II clinical study and underlying mechanisms of delaying EGFR-TKI acquired resistance in patients with advanced lung cancer.
Authors: Zhang Li , Peng Ping , Gong Juejun , Zhang Yujie , Chu Qian , Xia Shu , Meng Rui , Chen Yongshun , Han Guang , Zhang Peng , Zhang Lu , Chen Yuan
Published: June 2022

9114

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have a significant therapeutic effect in the treatment of advanced non-small-cell lung cancer (NSCLC). However, patients treated with EGFR-TKIs had a median progression-free survival (PFS) of only 8 to 18 months. The occurrence of acquired resistance greatly limits the survival benefit of TKI for NSCLC patients. Extensive efforts have been paid to find a well-tolerated drug or treatment that works before acquired resistance to EGFR-TKI with low toxicity. Focusing on clinical trials of targeted combination radiotherapy, we observed some encouraging results. Methods: Stage IV NSCLC patients with EGFR sensitive mutation (19DEL or 21L858R) have received first-line EGFR TKIs treatment and achieved stable disease or partial response have been enrolled in this prospective, multicenter, randomized controlled, phaseⅡstudy. Recruited from 4 hospitals in China, patients were divided into two groups: Stereotactic Body Radiation Therapy (SBRT) combined with TKIs group as the experimental and TKIs treatment group as an active comparator. The primary endpoint is PFS, and the secondary endpoint aims to overall survival (OS) and safety. To further confirmed these clinical observations in patients, xenograft experiments in nude mice were conducted. To examine the specific mechanism, transcriptome sequencing analysis was performed. Results: Between Mar 2015 and Mar 2018, A total of 61 patients who met the inclusion criteria were randomized to the TKI group and SBRT combined group. The median PFS of the TKI group and SBRT combined group were 9.0 vs 17.6 months (p = 0.016). Meanwhile, the median OS were 23.2 vs 33.6 months (p = 0.026). The total number of patients with T790m was 30(49.1%), and the incidence of T790M did not differ between the two groups. Toxicity data and subgroup analyses including different radiation sites will be presented at the conference. As for the xenograft experiments, data on tumor regression and time of drug resistance of early radiotherapy group was clearly superior to others. Transcriptome sequencing analysis found expression of c-Fos was the key point that led to the phenomena. Conclusions: The addition of SBRT significantly delayed the onset of EGFR TKIs acquired resistance and prolonged the PFS and OS of patients. Radiotherapy for the primary site alone might be superior to metastatic sites. Treatment-related adverse events were generally safe and controllable. The oncogenic role of c-Fos in the effect of radiotherapy on gefitinib resistance and promoting the proliferation of NSCLC cells is confirmed. Clinical trial information: NCT03595644.
Increased adherence to molecular profiling recommendations in non–small cell lung cancer through use of prior authorization and peer review.
Authors: Hamilton Stephen A. , Sagar Bhuvana , Christensen Kathryn , Bowers Anne , Dollear Tim
Published: June 2022

9129

Background: National oncology guidelines advocate for broad molecular profiling to detect potentially actionable driver mutations prior to initiation of first-line therapy for patients with advanced non-small cell lung cancer (NSCLC). Results of genomic tests can confirm the presence of specific cancer tumor mutations that are best treated with more targeted therapies. Recent studies have shown that up to 30% of lung cancer patients may not receive the most effective treatment due to a lack of guideline-concordant genomic testing. We analyzed data from our prior authorization medical oncology program to determine adherence to national guidelines recommendations, and then developed a program to improve adherence to broad molecular profiling utilizing our proprietary prior authorization algorithms and our proactive peer consultation model. Methods: eviCore healthcare uses the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) to support its proprietary program for medical oncology drug management, and requires attestation on the results of NCCN recommended genomic/molecular test results in advanced NSCLC during prior authorization of systemic therapy. In November 2019, we implemented a next-generation sequencing (NGS) testing results requirement for metastatic non-squamous NSCLC patients prior to first-line therapy approval. If testing had not been completed, a peer to peer consultation was performed to advocate for testing prior to initiation of chemoimmunotherapy regimens. The rate of appropriate tumor testing is defined by provider attestation of test results prior to initiation of therapy. We define the control period (pre- implementation) as October 2018 through September 2019 ( n = 667). The measurement period (post-implementation) is January 2020 through December 2020 ( n = 390). Results: From pre to post there was a 35% increase in testing adherence (p < 0.001). After the testing requirement was implemented, the appropriate tumor testing rate increased to 99% by the second half of 2020, compared to the control period (62%). Additionally, after the testing requirement began, pembrolizumab utilization for advanced stage NSCLC decreased by a net 4.2% per month. This decrease in pembrolizumab utilization likely reflected patients being matched to more appropriate targeted therapy based on genomic testing results. Conclusions: We demonstrate that by combining medical oncology prior authorization with focused peer consultation, adherence to national society recommendations for broad molecular profiling prior to initiating first line therapy in advanced NSCLC can be significantly improved. By improving testing adherence, the most effective and appropriate therapy can be matched to the patient.
Predictors of biomarker testing among patients (pts) with metastatic non–small cell lung cancer (mNSCLC).
Authors: Robert Nicholas J. , Chen Liwei , Espirito Janet L. , Karhade Mandar , Evangelist Makenzi Colleen , Neubauer Marcus A. , Bullock Susie A. , Walberg Jennifer M. , Coleman Robert L.
Published: June 2022

9130

Background: The MYLUNG (Molecularly Informed Lung Cancer Treatment in a Community Cancer Network) Consortium pragmatic study assessed real-world biomarker testing rates for mNSCLC within The US Oncology Network of over 1,000 providers. We previously reported that 90% of pts had at least one test performed for ALK, BRAF, EGFR, ROS1, or PD-L1, but only 46% had testing for all 5. We examined patient factors associated with rates of biomarker testing. Methods: Retrospective observational chart review study of pts with mNSCLC initiating first-line systemic therapy between 04/01/2018 and 03/31/2020. Patient characteristics including age, sex, race, geographic location, BMI, laboratory values, histology, performance status, stage at diagnosis, and comorbidities were obtained from iKnowMed electronic health records. Predictors of biomarker testing were identified using multivariable logistic regression. Results: Of the 3474 adults included in the study, median age was 69 years (range 23-90), 51% female, 65% White, 8% Black or African American, and 46% treated in the South US census region. Histology was adenocarcinoma in 74% and squamous cell carcinoma in 19%. Modeling for any biomarker testing resulted in histology and geographic region as significantly associated with increased likelihood of testing: adenocarcinoma vs squamous cell, odds ratio (OR) 1.76 (CI 1.33-3.23, p<0.0001) and Midwest vs South, OR 2.04 (CI 1.24-3.34, p=0.005). For comprehensive testing of all 5 biomarkers, increased albumin, adenocarcinoma or not otherwise specified histology, Midwest, Northeast or West geographic regions, and larger practice size were all significantly associated with increased likelihood of testing, while Black or African American race was associated with significantly decreased likelihood of testing (Table). Conclusions: Black or African American race, smaller practice size, Southern practice, and squamous cell histology were significantly associated with lower comprehensive biomarker testing rates. Understanding clinical and social determinants of health will be important when evaluating interventions to improve testing rates in the prospective phases of the MYLUNG study. [Table: see text]
The 10-year journey of non–small cell lung cancer: A real-world experience.
Authors: Jung Hyun Ae , Kim Kyunga , Chi Sang Ah , Yu Hyeyeon , Park Sehhoon , Sun Jong-Mu , Lee Se-Hoon , Ahn Jin Seok , Ahn Myung-Ju
Published: June 2022

9133

Background: Over the past 10 years, the treatment of non-small cell lung cancer (NSCLC) has been continuously revolutionized. This study evaluated how this revolution improved outcomes in the real-world. Methods: We collected clinical, pathological, and molecular data of patient with NSCLC using an in house real-time updated cohort (ROOT-HEALTH). The primary objective was the 3-year survival (OS3) rate by clinical stage, histology, and driver mutations including EGFR, ALK, ROS1, RET, MET exon 14 skipping, BRAF V600E, KRAS G12C, and NTRK between two time periods (Period I: 2010-2015 vs. Period II: 2016-2021). Results: We included data on 22,060 patients who received any anti-cancer treatment between January 2010 and December 2020. Adenocarcinoma (AD) was the predominant histology (70.2% in Period I vs. 74.2% in Period II) (Standardized mean difference [SMD] = 0.09, P < 0.001). In Period I, 36.8%, 10.4%, 15.9%, and 34.6% patients were in stage I, II, III, and IV respectively. In Period II, 44.8%, 9.6%, 15.1%, 29.9% were in each stage, respectively (SMD = 0.15, P < 0.001). Patients during Period II were more likely to perform molecular tests for EGFR, ALK, and/or others than those during Period I in both of AD (79.1% in Period I vs. 95.1% in Period II) and non-AD (53.5% in Period I and 85.0% in Period II). In patients with AD, 49.4% in Period I and 56.4% in Period II had any druggable mutations. Among non-AD patients, 4.9% and 6.2% of patients had any druggable mutations in Period I and II, respectively. In patients with AD, in Period I, the OS3 rates were 92.9 %, 72.6%, 56.6%, and 29.0% for each stage (I, II, III, and IV), respectively. In Period II, the OS3 rates of AD were 96.4 %, 86.8%, 70.2%, and 52.1% for each stage, respectively (P < 0.001). In stage IV AD with EGFR mutation, the OS3 rates were 42.5% and 65.4% in Period I and II, respectively (P < 0.001). In stage IV AD with ALK rearrangement, the OS3 rates were 53.2% and 73.6% in Period I and II, respectively (P < 0.001). In patients with non-AD, the OS3 rates were 71.6%, 60.2%, 38.8%, and 10.2% for each stage in Period I. In Period II, the OS3 rates of non-AD were 83.1%, 73.7%, 58.2%, and 29.6% for each stage (P < 0.001). In stage IV non-AD with any druggable mutations, the OS3 rates were 27.1% and 46.0% in Period I and II, respectively (P = 0.05). Conclusions: Our study is meaningful as a large-scale study that reflects changes of survival outcome in a timely manner.Through our real-world experience of over 10 years, the proportions of early stage and were found to be increased. The implementation of molecular testing has also been expanded. Of note, the survival outcomes were remarkably improved across all stages, especially in patients with stage III-IV. Further improvement of outcomes through effect of emerging driver mutations in the next five years is expected.
Nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) +/- ipilimumab (IPI) for kidney transplant recipients (KTR) with advanced cutaneous cancers.
Authors: Schenk Kara M. , Stein Julie E. , Chandra Sunandana , Davar Diwakar , Eroglu Zeynep , Khushalani Nikhil I. , Luke Jason J. , Ott Patrick Alexander , Sosman Jeffrey A. , Aggarwal Vikram , Schollenberger Megan Davis , Sharfman William Howard , Sharon Elad , Bagnasco Serena M. , Taube Janis M. , Topalian Suzanne Louise , Brennan Daniel C. , Lipson Evan J.
Published: June 2022

9507

Background: Cancer is a leading cause of death among KTR, but these patients (pts) have been excluded from trials of immune checkpoint inhibitors due to immunosuppression and risk of allograft loss. We report findings from the first prospective clinical trial of NIVO + TACRO + PRED +/- IPI in KTR with selected advanced cutaneous cancers. Methods: The primary composite endpoint was lack of tumor progression per RECIST v1.1 without allograft loss at 16 weeks (W) on NIVO. Adult KTR with advanced melanoma, basal, cutaneous squamous, or Merkel cell carcinoma (MEL, BCC, CSCC, MCC), for whom non-immune therapies were insufficient were eligible. Immunosuppression was standardized to low-dose TACRO (goal trough 2-5 ng/mL) + PRED 5mg daily; pts then received NIVO 480mg IV q4W. Pts with progressive disease (PD) could receive NIVO 3mg/kg + IPI 1mg/kg IV q3W x 4 followed by NIVO 480mg IV q4W. Donor-derived cell-free DNA (dd-cfDNA) levels were measured q2W as a potential predictor of allograft rejection. Results: From 11/2019 - 4/2021, of 12 pts enrolled, 8 pts with CSCC, MCC or MEL were evaluable for response (Table). All pts experienced PD on NIVO; treatment-related allograft loss (TRAL) occurred in 1 pt. 6 pts then received IPI + NIVO. Responses: 2 (33%) with marked tumor regression at 6W and eventual complete response (CR; 1 with TRAL), and 4 (67%) with PD (1 with TRAL). 7/8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. Only 2/5 on-NIVO biopsies demonstrated moderate immune infiltrates; both of these pts later developed a CR to IPI + NIVO. Rejecting allografts contained dense immune responses (plasma cells, CD4+ & CD8+ lymphocytes, PD-1+ lymphocytes, macrophages, PD-L1+ glomerular endothelium, and focal PD-1 & PD-L1 positivity in renal tubules). In 2/3 pts with TRAL, elevations in dd-cfDNA levels occurred 10 and 15 days earlier than increases in weekly serum creatinine levels. TRAL #3 occurred after discontinuation of study therapy (including TACRO) and dd-cfDNA monitoring. Conclusions: In KTR receiving low-dose TACRO + PRED, NIVO augments tumor immune cell infiltration in some pts but is insufficient to mediate tumor regression. Adding IPI can enhance anti-tumor immunity and mediate tumor regression. TACRO + PRED was insufficient to prevent allograft rejection after PD-1 +/- CTLA-4 blockade in 2/8 pts. In pts with TRAL, increased dd-cfDNA levels preceded increased serum creatinine. Based on these findings, we are modifying the trial therapy regimen to augment anti-tumor immunity and preserve allograft function. Clinical trial information: NCT03816332. [Table: see text]
AMBER parts 1c and 1e: A phase 1 study of cobolimab plus dostarlimab in patients (pts) with advanced/metastatic melanoma.
Authors: Ribas Antoni , Eroglu Zeynep , Trigo Perez Jose Manuel Manuel , Di Pace Brian , Wang Tianli , Ghosh Srimoyee , Dhar Arindam , Borgovan Theo , Waszak Angela , Davar Diwakar
Published: June 2022

9513

Background: TIM-3 and PD-1 are markers of T-cell suppression that are upregulated in melanoma. AMBER (NCT02817633) is evaluating cobolimab (TSR-022/GSK4069889), an anti-TIM-3 therapy, monotherapy or with PD-1 inhibitors, including dostarlimab, in pts with solid tumors. Methods: This multicenter, open-label study was conducted in 2 parts: dose escalation (Parts 1 A–D and F–H) and cohort expansion (Parts 2 A–D). Part 1C and exploratory cohort 1E (reported here) included pts with advanced/metastatic melanoma; prior therapies, except for immunotherapies, were permitted. Pts received cobolimab (100 [1C only], 300, or 900 mg IV) with dostarlimab (500 mg IV) Q3W. Part 1C primary endpoints were safety, tolerability, and recommended Phase 2 dose. Objective response rate (ORR; complete [CR] or partial [PR] response per RECIST v1.1) was a secondary endpoint in 1C and the primary endpoint in 1E (ad hoc efficacy analysis reported). An integrated safety analysis for all pts (Parts 1 and 2) receiving cobolimab with dostarlimab, regardless of tumor type or cobolimab dose, is reported here. Results: 28 pts were enrolled in 1C (n=10) and 1E (n=18). Most pts (n=23; 82.1%) had cutaneous disease of the skin. One pt had anorectal mucosal disease and 3 pts in the 900-mg cohort had uveal melanoma. Most pts (67.9%) had an ECOG PS=0. At data cut-off (May 19, 2021), treatment was ongoing in 5 pts. In the integrated safety analysis of pts who received cobolimab 100 mg (n=41), 300 mg (n=167), or 900 mg (n=69) with dostarlimab, treatment-related treatment-emergent AEs (TR-TEAEs) occurred in 53.7%, 57.5%, and 59.4%, respectively. The most common TR-TEAEs (any grade, ≥10% in 100 mg, 300 mg, or 900 mg groups, respectively) were fatigue (22.0%, 13.2%, 24.6%), rash (9.8%, 5.4%, 11.6%), diarrhea (4.9%, 6.0%, 10.1%), and dyspnea (2.4%, 0%, 10.1%). Grade ≥3 TR-TEAEs occurred in 12.2% (100 mg), 10.8% (300 mg), and 20.3% (900 mg); serious TR-TEAEs occurred in 7.3%, 7.8%, and 11.6%, respectively. No pts died due to TR-TEAEs; 2.4% (100 mg), 4.2% (300 mg), and 7.2% (900 mg) discontinued due to TR-TEAEs. ORR and disease control rate (DCR: stable disease [SD] ≥16 weeks, PR, or CR) are shown in the Table. Twelve pts achieved a PR and an immune-related (ir)PR (1 in 100 mg; 8 in 300 mg; 3 in 900 mg groups). Three pts achieved SD (2 in 300 mg; 1 in 900 mg groups); 8 pts had irSD (1 in 100 mg; 4 in 300 mg; 3 in 900 mg groups). Conclusions: Cobolimab with dostarlimab showed preliminary clinical responses in pts with advanced/metastatic melanoma and an acceptable safety profile across advanced cancers. Funding: GSK (213348). Clinical trial information: NCT02817633. [Table: see text]
Primary analysis of a phase 2, open-label, multicenter trial of talimogene laherparepvec (T-VEC) plus pembrolizumab (pembro) for the treatment (Tx) of patients (pts) with advanced melanoma (MEL) who progressed on prior anti–PD-1 therapy: MASTERKEY-115.
Authors: Gastman Brian , Robert Caroline , Gogas Helen , Rutkowski Piotr , Long Georgina V. , Chaney Marya F. , Joshi Harshada , Lin Yu-Lin , Snyder Wendy , Chesney Jason Alan
Published: June 2022

9518

Background: Despite advances in anti–PD-1–based Tx for MEL, an unmet need remains for immunotherapy failure in advanced metastatic or unresectable MEL. Also, there is a growing population of pts who received adjuvant anti–PD-1 and recurred; yet trials to address this population are lacking. Combination Tx with T-VEC, an oncolytic viral intratumoral Tx designed to produce GM-CSF, and pembro, an anti–PD-1 agent, may overcome immunotherapy failure. We report the MASTERKEY-115 primary analysis on the efficacy and safety of T-VEC + pembro in pts with advanced MEL who had progressive disease (PD) on prior anti–PD-1. Methods: This open-label, single-arm, multicenter, phase 2 study (NCT04068181) enrolled pts at 26 international sites (Jan 2020‒Feb 2021). Cohorts 1 and 2, primary and acquired resistance, respectively, received anti–PD-1 in a locally recurrent or metastatic setting and had PD within 12 wks of the last anti–PD-1 dose. Cohorts 3 and 4 included only pts who received adjuvant anti–PD-1 and were disease-free for < 6 mos (Cohort 3) or ≥ 6 mos (Cohort 4) before confirmed PD. Eligible pts had histologically confirmed unresectable or metastatic stage IIIB–IVM1d MEL, measurable and injectable disease, ECOG PS 0/1, and progressed on anti–PD-1 directly before enrollment. T-VEC at standard dosage and pembro 200 mg were given Q3W. The primary endpoint was objective response rate (ORR). Key secondary endpoints were complete response (CR) rate, progression-free survival (PFS), and safety. Tx decisions were per modified immune-related response criteria (irRECIST). Results: 72 pts (median age, 65 y) were enrolled. Of the 71 evaluable pts, 37 (52.1%) had stage IVM1b‒d disease, 30 (42.3%) had confirmed PD-L1–positive tumor (CPS ≥ 1%), 20 (28.2%) had a BRAFV600 mutation, and 21 (29.6%) had LDH > 1ULN. At data cutoff (Aug 2021), 47 (65.3%) pts remained on study. ORR was 0%, 6.7%, 40%, and 46.7% in cohorts 1–4, respectively (table). Any-grade Tx-related adverse events (TRAEs) were reported in 54 (76.1%) pts; the most common were pyrexia (29.6%), fatigue, and influenza-like illness (15.5% each). Grade ≥ 3 TRAEs occurred in 9 (12.7%) pts. Conclusions: T-VEC + pembro showed manageable safety in pts with advanced MEL after anti–PD-1 failure; the promising ORR observed in pts who progressed on prior adjuvant anti–PD-1 warrants further analysis. Clinical trial information: NCT04068181. [Table: see text]
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]