bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrative tumor and immune cell multi-omic analyses to predict melanoma response to immune checkpoint blockade.
Authors: Anagnostou Valsamo , Bruhm Daniel C. , Niknafs Noushin , White James R , Sidhom John-William , Stein Julie E. , Tsai Hua-Ling , Wang Hao , Belcaid Zineb , Murray Joseph Christopher , Ross-Macdonald Petra B. , Wind-Rotolo Megan , Baras Alexander S , Taube Janis M. , Scharpf Robert B. , Grasso Catherine , Ribas Antoni , Pardoll Drew M. , Topalian Suzanne Louise , Velculescu Victor E.
Published: May 2020

10009

Background: The complex crosstalk between tumor and immune cells during immune checkpoint blockade mandates the development of integrated models to interpret the antitumor immune response and predict clinical outcome. Methods: We performed comprehensive genomic, transcriptomic and T cell repertoire analyses on tumor biopsies from 64 patients with advanced melanoma receiving nivolumab +/- ipilimumab on CheckMate-038 (NCT01621490). Tumor biopsies were obtained at baseline and 2-4 weeks on therapy. Machine learning and Cox proportional hazards regression analyses were employed to integrate multi-omics features in predictive models of response, defined by RECISTv1.1 as complete and partial response, and survival (PFS and OS). Results: Responding patients had a higher tumor mutation burden (TMB) than non-responders. Expressed TMB more accurately predicted overall survival than genomic TMB (log rank p = 0.028 vs 0.078). High tumor aneuploidy was associated with worse prognosis especially for the patients in the nivolumab + ipilimumab group (log rank p = 0.01). TCR sequencing of paired tumors before and on-treatment revealed that responders had a significantly higher number of unique TCR clones at baseline and more clonotypic shifts on-treatment (p = 0.0018). Gene rearrangement analyses using transcriptome data identified a higher number of rearrangements involving immunoglobulin (Ig) genes in baseline tumors from responders. Deconvolution of transcriptomic data confirmed an enrichment in tumor associated B cells in baseline tumors of responders, suggesting that pre-existing B cell infiltration is a predictor of clinical outcome. Random forests were utilized to integrate Ig rearrangements, expressed TMB and tumor aneuploidy, into a predictive model of response that was superior to TMB (AUC = 0.89 and 0.65 respectively). Multivariate Cox proportional hazards analysis incorporating the same features was utilized to generate a risk score for each patient; those with high risk scores had a significantly shorter PFS compared to low risk patients (median PFS 1.45 months vs 29.01 months, log rank p = 3.4e-06, HR = 9.18, 95% CI: 3.14-26.85). Conclusions: Our findings highlight the multi-faceted interactions between the tumor and the immune system and the importance of pre-existing T and B cell immunity in driving clinical response and PFS after immune checkpoint blockade, laying the groundwork for integration of genomic and immune features into predictive models that may ultimately optimize therapeutic decisions.
Update on overall survival in COLUMBUS: A randomized phase III trial of encorafenib (ENCO) plus binimetinib (BINI) versus vemurafenib (VEM) or ENCO in patients with BRAF V600-mutant melanoma.
Authors: Gogas Helen , Ascierto Paolo Antonio , Flaherty Keith , Arance Ana , Mandalà Mario , Liszkay Gabriella , Garbe Claus , Schadendorf Dirk , Krajsova Ivana , Gutzmer Ralf , de Groot Jan Willem , Dutriaux Caroline , Loquai Carmen , Gollerkeri Ashwin , Pickard Michael D , Robert Caroline , Dummer Reinhard
Published: May 2020

10012

Background: Treatment of patients with BRAF V600–mutant melanoma includes BRAF/MEK-inhibitor combinations based on demonstrated benefits on progression-free survival (PFS) and overall survival (OS). To better understand the proportion of patients who derive long-lived benefit and their characteristics, we performed an updated analysis of OS and other endpoints from the COLUMBUS trial. Methods: In Part 1 of COLUMBUS, 577 patients with advanced/metastatic BRAF V600‒mutant melanoma, untreated or progressed after first-line immunotherapy, were randomized 1:1:1 to ENCO 450 mg QD + BINI 45 mg BID (COMBO450) vs VEM 960 mg BID (VEM) or ENCO 300 mg QD (ENCO300). An updated analysis including PFS, OS, objective response rate (ORR), and safety was conducted after an additional 24 months’ follow-up from the initial analysis. The study is ongoing. Results: At data cutoff (November 2019, as-is data), events had occurred in 65%, 59%, and 75% of patients in the COMBO450, ENCO300, and VEM treatment arms, respectively. Across arms, median follow-up for OS was 60.6 months (mo), with median OS of 33.6 mo (95% CI, 24.4–39.2) for COMBO450, 23.5 mo (95% CI, 19.6–33.6) for ENCO300, and 16.9 mo (95% CI, 14.0–24.5) for VEM. Compared to VEM, COMBO450 decreased the risk of death by 38% (HR, 0.62 [95% CI, 0.49–0.79]). Updated median PFS was COMBO450, 14.9 mo (95% CI, 11.0–20.2), ENCO300, 9.6 mo (95% CI, 7.4–14.8), and VEM, 7.3 mo (95% CI, 5.6–7.9). PFS was longer for COMBO450 vs VEM (HR, 0.52 [95% CI, 0.40–0.67]). A landmark analysis showed a higher rate of OS for COMBO450 at each year analyzed, with OS rates at 4 years of 39%, 37%, and 26% COMBO450, ENCO300, and VEM, respectively. Updated safety analysis confirmed the beneficial long-term tolerability of COMBO450. Conclusions: In the COLUMBUS trial, results for updated PFS and OS with COMBO450 continue to demonstrate long-term benefits in patients with BRAF V600‒mutated melanoma. Clinical trial information: NCT01909453.
Melanoma recurrence after adjuvant targeted therapy: A multicenter analysis.
Authors: Bhave Prachi , Pallan Lalit , Atkinson Victoria , Cohen Justine Vanessa , Chiarion-Sileni Vanna , Nyakas Marta , Kaehler Katharina C. , Plummer Elizabeth , Ascierto Paolo Antonio , Zimmer Lisa , Lebbe Celeste , Maurichi Andrea , Robert Caroline , Lesimple Thierry , Patel Sapna Pradyuman , Versluis Judith M. , Khattak Muhammad Adnan , Van Der Westhuizen Andre , Carlino Matteo S. , Haydon Andrew Mark
Published: May 2020

10016

Background: Adjuvant targeted therapy (TT) improves relapse free survival (RFS) in patients (pts) with BRAF mutant stage 3 melanoma. The outcomes and optimal management of pts who relapse after adjuvant TT is unknown. Methods: Pts from 21 centres with recurrent melanoma after adjuvant TT were included. Disease characteristics, adjuvant therapy, recurrence, treatment at relapse and outcomes were examined. Results: 87 pts developed recurrent melanoma; 21 (24%) during and 66 (76%) after cessation of adjuvant TT. Median time to 1st recurrence was 16.3 months with median follow up after 1st recurrence of 31 months. 30 (34%) pts recurred locoregionally, 51 (59%) pts developed distant recurrence and 6 (7%) pts had both. Of those who recurred locoregionally, 23/30 (77%) pts underwent surgery to no evidence of disease, only 3 (13%) of which received adjuvant anti-PD1 therapy, and 15/30 (50%) subsequently developed distant disease. 29 (33.3%) pts have died. 75 (86%) pts received systemic therapy at either 1st or subsequent recurrence. 40 (46%) pts received 1st line anti-PD1 based therapy (single agent anti-PD1, anti-PD1 with ipilimumab or anti-PD1 with investigational agent), 12 (14%) pts received ipilimumab monotherapy, 18 (21%) pts received retreatment with combination BRAF/MEK inhibitors and 5 (6%) pts received other agents (chemotherapy, TVEC). 57 (66%) pts had disease that was assessable for response rate (RR). RR after relapse was 69.7% (23/33) to 1st line anti-PD-1 based therapy, 46% (6/13) to TT and 9% (1/11) to ipilimumab monotherapy (Table). Median overall survival (OS) from date of 1st recurrence for all pts was not reached. OS varied by drug class received as 1st line systemic therapy after relapse. 3 year OS was 79% for anti-PD-1 based therapy, 55% for TT and 25% for ipilimumab. Conclusions: This study demonstrates that pts who relapse after adjuvant TT may respond to subsequent immunotherapy at similar rates to the treatment naïve setting. [Table: see text]
Phase II study of cemiplimab in patients (pts) with advanced cutaneous squamous cell carcinoma (CSCC): Longer follow-up.
Authors: Rischin Danny , Khushalani Nikhil I. , Schmults Chrysalyne D. , Guminski Alexander David , Chang Anne Lynn S. , Lewis Karl D. , Lim Annette May Ling , Hernandez-Aya Leonel Fernando , Hughes Brett Gordon Maxwell , Schadendorf Dirk , Hauschild Axel , Stankevich Elizabeth , Booth Jocelyn , Li Siyu , Chen Zhen , Okoye Emmanuel , Lowy Israel , Fury Matthew G. , Migden Michael Robert
Published: May 2020

10018

Background: Cemiplimab monotherapy achieves clinically meaningful activity in pts with advanced CSCC (metastatic [mCSCC] or locally advanced [laCSCC] not amenable to curative surgery or curative radiation) and has a safety profile consistent with other anti–PD-1 agents. Based on initial data (median follow-up of 9.4 months in the pivotal study, NCT02760498), cemiplimab (cemiplimab-rwlc in the US) was approved for the treatment of pts with advanced CSCC. Historical data shows median overall survival (OS) of approximately 15 months with conventional chemotherapy or EGFR inhibitors (ASCO 2019, e21033). We present ~1-year additional follow-up from the largest prospective data set in advanced CSCC. Methods: Pts received cemiplimab 3 mg/kg Q2W (Group [Gp] 1; mCSCC; Gp 2, laCSCC) or cemiplimab 350 mg Q3W (Gp 3, mCSCC). The primary endpoint was objective response rate (ORR; complete response + partial response) per independent central review (ICR). Data presented here are per investigator review (INV); ICR data will be available at the meeting. Results: 193 pts were enrolled (Gp 1, n = 59; Gp 2, n = 78; Gp 3, n = 56). 128 pts had received no prior anti-cancer systemic therapy, 65 pts were previously treated. As of Oct 11, 2019 (data cut-off), median duration of follow-up was 15.7 months (range: 0.6–36.1) among all pts; 18.5 months (range: 1.1–36.1) for Gp 1, 15.5 months (range: 0.8–35.0) for Gp 2, and 17.3 months (range: 0.6–26.3) for Gp 3. ORR per INV was 54.4% (95% CI: 47.1–61.6) for all pts; 50.8% (95% CI: 37.5–64.1) for Gp 1, 56.4% (95% CI: 44.7–67.6) for Gp 2, and 55.4% (95% CI: 41.5–68.7) for Gp 3. ORR per INV was 57.8% (95% CI: 48.8–66.5) among treatment-naïve pts and 47.7% (95% CI: 35.1–60.5) among previously treated pts. Median duration of response (DOR) has not been reached (observed DOR range: 1.8–34.2 months). In responding pts, estimated proportion of pts with ongoing response at 24 months was 76.0% (95% CI: 64.1–84.4). Median OS has not been reached. Estimated OS at 24 months was 73.3% (95% CI: 66.1–79.2). The most common treatment-emergent adverse events (TEAEs) by any grade were fatigue (34.7%), diarrhea (27.5%), and nausea (23.8%). The most common grade ≥3 TEAEs were hypertension (4.7%) and anemia and cellulitis (each 4.1%). Conclusions: For pts with advanced CSCC, cemiplimab achieves ORRs, DOR and survival superior to what has been reported with other agents. Clinical trial information: NCT02760498.
A phase II, multicenter study of encorafenib/binimetinib followed by a rational triple-combination after progression in patients with advanced BRAF V600-mutated melanoma (LOGIC2).
Authors: Dummer Reinhard , Sandhu Shahneen Kaur , Miller Wilson H. , Butler Marcus O. , Blank Christian U. , Muñoz-Couselo Eva , Burris III Howard A. , Postow Michael A. , Chmielowski Bartosz , Middleton Mark R. , Berking Carola , Hassel Jessica Cecile , Gesierich Anja , Mauch Cornelia , Kleha Joseph , Gollerkeri Ashwin , Harney Allison , Pickard Michael D , Ascierto Paolo Antonio
Published: May 2020

10022

Background: LOGIC2 evaluates the benefit of a 3rd agent added to encorafenib (enco)/binimetinib (bini), selected at progression based on the genetic tumor evolution. Methods: In part I/run-In, pts were treated with enco/bini until disease progression (as defined per RECIST v1.1). Foundation One NGS was applied on a baseline sample and on a PD sample. Based on the genetic evolution between the biopsy at inclusion (bxI) and at progression (bxPD) and clinical considerations, pts entered part II and received one of four 3rd agent additions to enco/bini combinations: A. LEE011 (CDK4/6 inhibitor), B. BKM120 (PI3K inhibitor), C. INC280 (c-Met inhibitor), or D. BGJ398 (FGFR inhibitor). An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with overdose control (EWOC) principle was used to make dose escalation decisions. Assessments include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and safety. Data cutoff for this analysis was May 12, 2019. Data is as is. Part 1 of study is ongoing. Part 2 of study is closed to enrollment. Results: 58 pts enrolled into part II (group A=38; B=6; C=13; D=1). 29 pts were assigned to treatment based on bxPD results (Table). In groups A, B, and C, the confirmed ORR was 5.3%, 0%, and 0%, and the DCR was 26.3%, 16.7%, and 15.4%, with median PFS of 2.1, 1.6, and 2.2 months, respectively. Safety was consistent with known profiles of the individual agents. Conclusions: Triple therapy is feasible when a 3rd agent is added to enco/bini at progression based on genetic alterations, although activity observed was low. Further exploration to identify patterns of resistance susceptible to the addition of a 3rd agent is needed. Gene alterations for enrollment into part 2. Clinical trial information: NCT02159066. [Table: see text]
Time to central nervous system (CNS) metastases (mets) with atezolizumab (A) or placebo (P) combined with cobimetinib (C) + vemurafenib (V) in the phase III IMspire150 study.
Authors: Ascierto Paolo Antonio , Robert Caroline , Lewis Karl D. , Munhoz Rodrigo , Liszkay Gabriella , de la Cruz Merino Luis , Olah Judit , Queirolo Paola , Mackiewicz Jacek , Li Haocheng , Zhu Qian , McNally V. , Mckenna Edward Francis , Gutzmer Ralf , McArthur Grant A.
Published: May 2020

10023

Background: The phase 3 IMspire150 study (NCT02908672) demonstrated improved progression-free survival with first-line combination treatment with A+C+V vs P+C+V in patients (pts) with previously untreated BRAFV600 mutation–positive advanced melanoma. Here we report incidence and time to development of CNS mets with A+C+V vs P+C+V in the IMspire150 study. Methods: Eligible pts were randomized 1:1 to receive A+C+V or P+C+V. A or P were given on day 1 and 15 of each 28-day cycle after an initial cycle of C+V. Incidence and time to development of CNS mets were evaluated in pts with no history of CNS mets at baseline confirmed by magnetic resonance imaging/computed tomography (MRI/CT). On study MRI/CT assessments were performed as clinically indicated. Time-to-event outcomes were estimated using the Kaplan-Meier method and competing risks analysis. Sensitivity analyses were conducted using landmark analysis at time of initiation of A or P. Results: 514 pts were randomized to receive A+C+V (n = 256) or P+C+V (n = 258); 244 and 247 pts, respectively, had no history of CNS mets at baseline. After a median follow-up of 18.9 months, CNS mets had developed in 52/244 pts (21%) in the A+C+V arm and 62/247 pts (25%) in the P+C+V arm. In both arms, pts with CNS mets were more likely to have other known unfavorable prognostic factors: elevated LDH, presence of liver mets, and/or higher tumor burden. Cumulative incidence of CNS mets as first site of progressive disease with A+C+V vs P+C+V was 8% vs 9%, 16% vs 19%, 20% vs 24%, and 23% vs 26% at 6, 12, 18, and 24 months, respectively (hazard ratio [HR] 0.87; 95% CI 0.60-1.26). Estimated CNS mets-free survival rates for A+C+V vs P+C+V were 91% vs 90%, 81% vs 75%, 74% vs 66%, and 69% vs 62% at 6, 12, 18, and 24 months, respectively, with a trend for improved CNS mets-free survival with A+C+V (HR 0.79; 95% CI 0.55-1.14). Results of landmark analyses for CNS mets-free survival and cumulative incidence of CNS mets were similar to those in the overall analysis. Conclusions: The addition of anti–programmed death-ligand 1 to C+V is associated with numerically lower rates of interval development of CNS mets, consistent with the overall benefit observed for A+C+V in the study. This finding requires further follow-up to fully assess the magnitude of benefit of A+C+V on CNS mets-free survival. Clinical trial information: NCT02908672.
Combination anti-PD-1 and ipilimumab (ipi) therapy in patients with advanced melanoma and pre-existing autoimmune disorders (AD).
Authors: Brown Lauren Julia , Weppler Alison , Bhave Prachi , Allayous Clara , Patrinely James Randall , Ott Patrick Alexander , Sandhu Shahneen Kaur , Haydon Andrew Mark , Lebbe Celeste , Johnson Douglas Buckner , Long Georgina V. , Menzies Alexander M. , Carlino Matteo S.
Published: May 2020

10026

Background: Clinical trials of immunotherapy exclude patients (pts) with pre-existing AD. While retrospective data exist regarding the efficacy and safety of single agent ipi and anti-PD1 antibodies (PD1) in pts with AD, no data are available regarding the safety and efficacy of combination therapy in pts with AD, which has a higher toxicity risk. Methods: Pts with melanoma and pre-existing AD treated with combination ipi/PD1 were retrospectively identified from 10 international centres. Data regarding AD, treatment, toxicity and outcomes were examined. Results: Fifty-five pts were included, 46 were treated with ipi/nivolumab and 9 with ipi/pembrolizumab. 40 had an ipi dose of 3mg/kg while 15 had a lower dose regimen. 9 pts received prior PD1 therapy; 3 suffered moderate immune-related adverse events (irAE) with no flares of AD on single agent PD1. Pre-existing AD included inflammatory bowel disease (IBD), thyroiditis, rheumatoid arthritis (RA), multiple sclerosis and psoriasis. 10 pts had active symptoms of AD and 13 were immunosuppressed at commencement of ipi/PD1. Eighteen pts (33%) experienced a flare of their AD including 4/7 with RA, 3/6 with psoriasis, 5/9 with IBD, 3/18 with thyroiditis, 1/1 with Sjogren’s syndrome, 1/1 with polymyalgia, 1/1 with Behcet’s syndrome. Median time to flare was 19 days (range 4 – 167). 13 pts were managed with steroids, 5 required additional immunosuppressants. 7 pts were hospitalised for management of flare (5 with IBD, 2 with RA). 2 pts required intensive care and vasopressors for severe IBD flare, quiescent prior to ipi/PD1. One for diarrhoea and shock and one for duodenal perforation. 8 pts ceased treatment due to flare (3 with IBD, 2 with RA, 1 with Behcet’s, 1 with Sjogren’s). Thirty-seven pts (67%), experienced an irAE unrelated to their AD, 38% G3 or G4. The most frequent irAEs were colitis (n = 16), hepatitis (n = 12), endocrinopathies (n = 12), with 13 pts experiencing an irAE in ≥ 2 organs. 9 pts experienced both AD flare and an irAE. 20 pts (36%) ceased immunotherapy due to irAEs. ORR was 55% (54% in PD1 naive pts), at a median follow up of 14 months, 77% of responses ongoing. ORR in pts who had a flare of their AD was 44% and in pts on immunosuppression was 46%. Median PFS was shorter in pts who had a flare of AD compared with those who did not (2.6 vs 9 months; P-value 0.047). Conclusions: Combination ipi/PD1 shows efficacy comparable to clinical trial populations in pts with pre-existing AD and advanced melanoma. Whilst there was a substantial risk of flare of AD, no increased frequency of irAE’s was observed.
Effect of first-line spartalizumab + dabrafenib + trametinib on immunosuppressive features detected in peripheral blood and clinical outcome in patients (pts) with advanced BRAF V600–mutant melanoma.
Authors: Dummer Reinhard , Biette Kelly , Gusenleitner Daniel , Ramesh Radha , Lebbe Celeste , Atkinson Victoria , Mandalà Mario , Nathan Paul D. , Arance Ana , Richtig Erika , Yamazaki Naoya , Robert Caroline , Schadendorf Dirk , Tawbi Hussein Abdul-Hassan , Ascierto Paolo Antonio , Ribas Antoni , Flaherty Keith , Gasal Eduard , Brase Jan C. , Long Georgina V.
Published: May 2020

10034

Background: Spartalizumab + dabrafenib + trametinib has previously shown a high response rate of 78% (28 of 36 pts), with a complete response (CR) rate of 42%. A correlative analysis of gene expression signatures (GES)/pathways using whole-transcriptome RNA-seq data from tissue showed that pts with a CR had significantly lower expression levels of immunosuppressive factors in the tumor microenvironment (TME) at baseline (BL). Here we analyze BL peripheral blood markers in the same cohort of pts to assess whether liquid markers can also predict response and clinical outcome to spartalizumab + dabrafenib + trametinib. Methods: The Phase III COMBI-i study (NCT02967692) is evaluating spartalizumab + dabrafenib + trametinib in pts with previously untreated BRAF V600–mutant unresectable or metastatic melanoma. In parts 1 (safety run-in; n = 9) and 2 (biomarker cohort; n = 27), blood and tissue samples were collected at BL, on treatment after 2-3 wk and 8-12 wk, and at disease progression. Lactate dehydrogenase (LDH) and other blood-based markers (including cytokine profiling [n = 45] and blood RNA-seq [114 signatures]) were assessed in all 36 pts. Pts were divided into 2 groups of 24 and 12 pts based on progression-free survival (PFS) of > 1 or < 1 y. Results: In addition to LDH, previously described blood markers such as neutrophil to lymphocyte ratio (NLR) and plasma IL-8 were identified among other neutrophil and immunosuppressive features as top candidates associated with PFS > 1 y. Low plasma IL-8 levels were also associated with CR, and multivariate models suggested that IL-8 may add independent predictive value to LDH and NLR for PFS > 1 y and CR. Pts with high IL-8 levels in the circulation were characterized by high neutrophil chemokine signaling (ρ = 0.553) and high neutrophil markers (ρ = 0.466) in the tumor as measured by RNA-seq GES levels. We observed a decrease in plasma IL-8 levels from BL upon treatment with spartalizumab + dabrafenib + trametinib. Conclusions: Our peripheral blood marker analysis confirmed recent findings from tissue samples that intratumoral immunosuppressive features may preclude a CR and are associated with poor outcomes. High BL plasma IL-8 levels may be associated with an immunosuppressive TME. Further validation is warranted; the randomized placebo-controlled part 3 of COMBI-i is ongoing. Clinical trial information: NCT02967692.
A phase II study of vorolanib (CM082) in combination with toripalimab (JS001) in patients with advanced mucosal melanoma.
Authors: Si Lu , Sheng Xinan , Mao Lili , Li Caili , Wang Xuan , Bai Xue , Qi Zhong Hui , Chi Zhihong , Cui Chuanliang , LIAN BIN , Tang Bixia , Yan Xieqiao , Zhou Li , Li Siming , Duan Rong , Xu Huayan , Mao Li , Ding Lieming , Guo Jun
Published: May 2020

10040

Background: Vorolanib (CM082) is a multi-target tyrosine kinase inhibitor including VEGF, PDGF, c-kit, and Flt-3. Toripalimab (JS001) is a humanized IgG4 mAb against programmed death-1 (PD-1) with clinical activity in metastasis melanoma but not in its mucosal subtype. In this phase II study (NCT03602547), we investigated the safety and efficacy of CM082 in combination with JS001 in patients (pts) with advanced mucosal melanoma. Methods: The study enrolled pts from 18 to 75 years-old with histologically confirmed metastatic mucosal melanoma, ECOG PS 0-1, no prior systemic anti-cancer treatment. Eligible pts were treated with CM082 tablet (150 or 200 mg once daily) combined with JS001 (240mg every 2 weeks, IV, Q2W) until confirmed disease progression or unacceptable toxicity. Clinical response was evaluated every 8 week. The primary endpoint was overall response rate (ORR) using RECIST v1.1. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), duration of remission (DOR), and time to first remission (TTR) according to RECIST v1.1 and iRECIST. The safety was also assessed. Results: Between July 2018 and April 12, 2019, 40 pts (19 pts in 150mg group; 21 pts in 200mg group) were enrolled and 38 pts were evaluable for tumor response (150mg n = 18, 200mg n = 20), with 4 (22.2%) confirmed partial response (PR), 6 (33.3%) stable disease (SD) and 8 (44.4%) progression disease (PD) in the 150mg CM082 group; 3 (15%) PRs (including 2 unconfirmed), 10 (50%) SD, and 7 (35%) PD were reported in the 200mg CM082 group. Tumors shrank in 10 pts (56%) in the 150mg group and 10 pts (50%) in the 200mg group. At data cut-off (November 28, 2019), 29 pts had PFS events (150mg n = 12; 200mg n = 17). The median PFS was 5.7 (95% CI 2.0, NE) months and 5.6 (1.9, 7.7) months in the two groups, respectively. The most common treatment-related adverse events (AEs) were grade 1 or 2, including leukopenia, elevated LDH, increased ALT, neutropenia, increased AST, and elevated GGT. Common grade 3 or higher adverse events ( > 10%) were increased ALT (12 pts, 30%), increased AST (11 pts, 27.5%), neutropenia (6 pts, 15%) and elevated GGT (6 pts, 15%). Eight pts had 9 serious AEs (SAEs). The study is still ongoing and more data will be presented in the future. Conclusions: PFS benefit was observed in both 150mg and 200mg subgroups. This study demonstrated potentially improved efficacy with predictable toxicities of CM082 in combination with JS001 therapy, which may be an effective treatment option for pts with advanced mucosal melanoma. Clinical trial information: NCT03602547.
CA209-9JC: A phase II study of first-line nivolumab (NIVO) in patients (pts) with locally advanced or metastatic cutaneous squamous cell carcinoma.
Authors: Munhoz Rodrigo Ramella , Camargo Veridiana Pires De , Marta Guilherme N , Martins Jade Cury , Nardo Mirella , Barbosa Caroline Chaul , de Souza Carina Echer , Barbosa Ingrid , Ricci Herminia , de Mattos Marcela Rodrigues , Menezes Thiago , Machado Guilherme Urano , Bertolli Eduardo , Barros Milton Jose , Franke Fabio A. , Feher Olavo , Castro Gilberto
Published: May 2020

10044

Background: Cutaneous squamous cell carcinoma (cSCC) is among the most frequent malignancies worldwide, and an increasing incidence has been documented over the past decades. For those not amenable to treatment with curative intent, immune checkpoint blockade (ICP) with anti-PD-1 monoclonal antibodies emerged as a novel therapeutic option, supported by evidences of high mutational burden and expression of PD-L1. In this single-arm study, we sought in investigate the activity of NIVO in pts with advanced cSCC (AcSCC). Methods: We conducted a Simon two-stage, open-label, phase II study to evaluate the safety/efficacy of NIVO for up to 24 systemic-treatment-naïve pts with metastatic and/or locaally advanced cSCC. NIVO at 3mg/kg was administered intravenously every 2 weeks (w) until disease progression, unacceptable toxicity or 12 months of treatment. The primary endpoint was the best objective response rate (bORR) at 24w as per RECIST criteria. Tumor measurements were performed every 12w. Secondary endpoints included safety/tolerability, progression-free survival (PFS) and overall survival (OS). Results: Between October 2018 and October 2019, 24 pts with AcSCC were enrolled, with a median age of 74 years (range 48-93) and a male/female ratio of 1.4:1. Most frequent primary sites were head/neck (42%), trunk (29%) and extremities (25%); identified risk factors included chronic sun exposure or burn scars in 66 % and 12.5 %, respectively. Upon enrolment, the proportions of patients with locally advanced, locoregional (regional lymph node involvement) and metastatic disease were 16.6%, 66.6% and 16.6%, respectively. At data cut off (median number of doses of NIVO: 15), 15 pts (62.5%) remain on treatment and 6 pts have progressed and/or died. Three pts completed 12 months of treatment and entered surveillance. Among 22 pts evaluable for response (n = 2 have not reached 12w of treatment), the bORR was 54.5% (12/22), and disease control (stable disease or objective response) was achieved in 77% (17/22). Median duration of response, PFS and OS have not been reached. Grade ≥3 treatment-related adverse events occurred in 21% of the pts, and 1 patient discontinued NIVO due to toxicities. Conclusions: NIVO resulted in robust antitumor activity and good tolerability in systemic treatment-naïve pts with AcSCC. There were no new safety signals, despite the inclusion of individuals at advanced ages. These data provide further evidence to support the use of ICP as the standard treatment option for pts with AcSCC. Clinical trial information: NCT03834233.
A first-in-human phase I/II study of HL-085, a MEK Inhibitor, in Chinese patients with NRASm advanced melanoma.
Authors: Wang Xuan , Si Lu , Mao Lili , Cui Chuanliang , Chi Zhihong , Sheng Xinan , Bai Xue , Zhou Li , LIAN BIN , Tang Bixia , Yan Xieqiao , Li Siming , Kong Yan , Guo Jun
Published: May 2020

10047

Background: MEK inhibitors have confirmed effects on malignant tumors, especially for those induced by RAS/RAF dysfunction. There is no effective drug in clinic for NRASm advanced melanoma. HL-085 is a selective MEK inhibitor, showing good safety and efficacy in preclinical studies. This study is a phase I/II study to evaluate the safety, tolerability, pharmacokinetic and preliminary anti-cancer activity of HL-085 in patients(pts) with NRASm advanced Melanoma. Methods: The phase I/II study is conducted using a “3+3” regimen for dose escalation. The pts are treated with HL-085 at a starting dose of 0.5mg BID to 18mg BID. Adverse events (AEs) are reported per NCI CTCAE version 5.0. Preliminary anti-cancer activity is evaluated by ORR, DCR, PFS and DoR. Results: Total 33 pts were enrolled in the study. The histologic types were acral (51.4%), mucosal (27.2%) and other (21.2%). The NRAS mutation types were Q61 (72.7%), G12 (18.2%) with half for G12D, and G13 (9.1% ). Most AEs were G1 or G2, and the most common drug-related AEs were rash, increased creatine phosphokinase, peripheral edema, increased alanine aminotransferase and aspartate aminotransferase. No dose-limited toxicity was observed. PK analysis was shown linear PK profile with no obvious accumulation. Among 12 evaluable pts over 9 mg, 4 pts were at the stage of M1c with 1 liver metastasis. Average targeted tumor size was 74.6mm with the largest 184 mm. 10 pts achieved tumor shrinkage [ 60% with Q61, 20% with G12D, 10% each with G12S and G13R]. 4 pts ( 2 acral, 1 mucosal and 1 other, each pt has mutaiton type of Q61R,Q61L, Q61K and G12S respectively ) had confirmed partial response(PR) [median treatment duration 26.6 weeks (wks) with longest 47.6 wks]). 6 pts achieved stable disease (SD) (median treatment duration 15.72 wks with longest 24 wks), and 66.7% were over 14 wks . The median PFS was 17.4 wks, and confirmed best ORR was 33.3% with DCR 83.3% . Conclusions: Our data demonstrated that HL-085 is well tolerated, with manageable side-effects and promising anti-cancer activity in pts with NRASm advanced melanoma. Clinical trial information: NCT 03973151.
Preclinical and clinical studies of a class I/IV HDAC inhibitor, mocetinostat, in melanoma.
Authors: Weber Jeffrey S. , Laino Andressa S , Vassallo Melinda , Pavlick Anna , Malatyali Saundra , Krishnarajapet Swathi , DeLeon Gabriel , Chen Isan , Hallin Max , Woods David
Published: May 2020

10052

Background: Mocetinostat is a class I/IV HDAC inhibitor with HDAC1/2/3/11 activity. Preclinical murine data suggest that HDAC inhibition has immune activity and may augment the clinical benefit of checkpoint inhibition. Several trials are assessing the effects of adding HDAC inhibition to PD-1 blockade. Methods: Patients with therapy-naive metastatic melanoma were treated in a pilot phase Ib trial with nivolumab at 3 mg/kg/ipilimumab at 1 mg/kg every three weeks four times and a starting dose of mocetinostat at 70 mg orally three times a week in a 12-week induction cycle followed by 12-week maintenance cycles of nivolumab 240 mg every 2 weeks and mocetinostat at the same dose and schedule as induction. Endpoints were toxicity, definition of a recommended phase 2 dose and preliminary assessment of response as well as correlative marker determination. Peripheral blood mononuclear blood cells from patients were tested in vitro at varying concentrations of mocetinostat, and its impact on T, regulatory T and myeloid-derived suppressor cell phenotypes were assessed by flow cytometry, as well as cytokine production by Luminex. Results: In the mocetinostat, nivolumab and ipilimumab phase I trial, 10 patients were treated, including 5 males and 5 females with a median age of 59. There were 2 complete and 5 partial responses confirmed; 6 of 7 are maintained at a median of 16 months of follow up. Three patients had progressive disease. Seven patients had grade 3-4 immune related adverse events; in 3 they were multiple. No patients died. In vitro, mocetinostat at doses from 125 to 500 nM increased relative percentage of CD4/CD8 central memory T cells, and decreased IL-6 levels while increasing interferon-gamma production (p = 0.005). Percentages of regulatory T and monocytic myeloid-derived suppressor cells were decreased by mocetinostat (p = 0.005), which also down-modulated regulatory T cell function by reducing FOXP3, HELIOS and GARP (p = 0.001). Conclusions: In vitro, mocetinostat promoted accumulation of central memory CD8 and CD4 T cells from melanoma patients, and decreased percentages and suppressive activity of T regulatory cells and myeloid-derived suppressor cells. In a pilot clinical trial, mocetinostat combined with nivolumab and ipilimumab in treatment-naïve metastatic melanoma patients exhibited a response rate of 70% with long duration of response but all ten patients treated had at least one grade 3 or 4 immune-related toxicity. De-escalation of the mocetinostat dose to 50 mg three times a week was felt to be indicated due to the toxicity of the triple regimen. Clinical trial information: NCT03565406.
Risk of disease progression (PD) following discontinuation of BRAF±MEK targeted therapies for reasons other than PD in patients (pts) with metastatic or unresectable melanoma.
Authors: Corti Francesca , Randon Giovanni , Bini Marta , Raimondi Alessandra , Manglaviti Sara , Zattarin Emma , Bisogno Ilaria , Vetrano Irene , Cimminiello Carolina , De Braud Filippo G. , Del Vecchio Michele , Di Guardo Lorenza
Published: May 2020

10053

Background: In pts with metastatic melanoma bearing BRAF V600E/K mutations BRAF V600±MEK inhibitors are administered until PD/unacceptable toxicity. In patients achieving durable responses, outcomes following discontinuation for reasons other than PD are largely unknown. Methods: We identified all patients who interrupted BRAF±MEK inhibitors for reasons other than PD after complete (CR) or partial response (PR) from a clinical dataset of patients with BRAF mutated metastatic/unresectable melanoma treated with targeted therapy at a single Institution. Results: We included 24 pts. Fifteen (62.5%) and 9 (37.5%) pts were treated respectively with BRAF inhibitor monotherapy and BRAF+MEK inhibitor combination. All pts had normal baseline LDH and ECOG PS0, 2 (8%) pts had brain metastases and 15 (62.5%) had multi-organ metastatic involvement. Dose reduction was required for 12 (50%) pts. Median treatment duration was 59 (12-88) months. Causes of discontinuation were unacceptable toxicity (19 pts-79%) and consent withdrawal (5 pts-21%). At the time of discontinuation, 17 (71%) and 7 (29%) pts had achieved respectively CR and PR. At a median follow up of 31 (8-59) months after treatment discontinuation, 9 (37.5%) pts had experienced PD. Median time to PD after treatment discontinuation was 9 (3-16) months. At time of PD, 2 (22%) pts displayed involvement of new organ sites. Risk of PD following discontinuation was respectively 31% and 45% at 12 and 24 months. Neither baseline characteristics nor treatment duration and time to best response influenced risk of PD; we found a non-significant trend towards higher risk of relapse for patients interrupting treatment with residual disease compared to those who interrupted treatment after achieving CR [HR 3.3; 95%CI (0.8–14.1); log-rank p = 0.081]. After PD, 6 pts received BRAF+MEK inhibitors with a response rate of 100% and 3/6 pts achieving CR. Conclusions: In a subset of patients with favorable prognostic characteristics and retained sensitivity to BRAF±MEK inhibitors, treatment discontinuation was associated with relevant risk of relapse with about one third of pts experiencing PD within one year. Biomarker studies are needed to identify pts who might safely discontinue therapy due to sustained toxicity, especially after achieving CR.
Landmark analysis of immunotherapy duration and disease free survival in advanced melanoma patients with a complete response.
Authors: Selig Grayce N. , Huang Alexander Chan Chi , Karakousis Giorgos C. , Xu Wei , Zheng Cathy , Carberry Mary , Giles Lydia , Kreider Kristin , McGettigan Suzanne , Lukens John Nicholas , Schuchter Lynn Mara , Amaravadi Ravi K. , Mitchell Tara C.
Published: May 2020

10054

Background: Checkpoint blockade improves survival in patients with melanoma, with durable complete responses (CR) after stopping therapy. Based on data from KEYNOTE-001, immunotherapy is often continued for 24 months in patients with confirmed CR. Outcomes with treatment of less than 24 months hav not been adequately evaluated and reported. If equally efficacious, shorter courses would potentially reduce health care costs and toxicity. Methods: 45 patients with locally advanced stage III and IV melanoma who received immunotherapy (pembrolizumab, nivolumab or ipilimumab/nivolumab) as 1st line or subsequent therapy, achieved a CR, and stopped therapy were identified under an IRB approved protocol at Penn. Disease Free Survival (DFS) was defined as time from declaration of CR until recurrence or date of analysis (1/15/20). Landmark DFS from time of CR was analyzed based on duration of therapy (less than or greater than 7 months, based on early trial requirements to treat patients with confirmed CR for at least 6 months). Rationale for stopping (toxicity or CR) was also analyzed. Results: Of 45 patients with CR, 27 (60%) were treated less then 7 months (median 4.8, range 1 day to 6.7 months) and 18 (40%) were treated for greater than 7 months (median 12.4, range 7.5 to 24.2 months). Patients who were treated for less than 7 months had a median DFS from time of CR of 30.4 months (95% CI 23.7 to 37.2, range 2.9 to 65.7 months). Patients treated for greater than 7 months had a median DFS of 28.0 months (95% CI 18.9 to 37, range 8.5 to 73.7 months). Patients who stopped due to toxicity (N = 17, 40%) had a median treatment duration of 3.7 months. Their median DFS from time of CR was 30.4 months (95% CI 20.7 to 40.1, range of 2.9 to 65.7 months). Patients who stopped due to CR (N = 28, 60%) had a median treatment duration of 8.5 months. Their median DFS was 27.6 months (95% CI 21.2 to 34 range 7.2 to 73.7 months). Two of 27 (7.4%) patients treated for less then 7 months and 3 out of 18 (16%) patients treated greater than 7 months recurred after stopping. One out of 17 (5.8%) recurred after stopping for toxicity vs. 4/28 (14.3%) who stopped after CR. Conclusions: Patients who stop therapy at less than 7 months have CRs that are equally durable as those treated longer than 7 months, without reduction in landmark DFS. Patients who stopped therapy due to toxicity and then achieved a CR had no difference in DFS compared to patients treated until CR. There was no significant difference in recurrence after achieving a complete response in patients treated for a longer vs shorter treatment course.
Long-term immune-related adverse events under PD-1 inhibitors: a multicenter prospective cohort study (MELBASE).
Authors: Nardin Charlee , Dalle Stéphane , Leccia Marie Thérèse , Mortier Laurent , Dalac-Rat Sophie , Dutriaux Caroline , Legoupil Delphine , Montaudie Henri , Dereure Olivier , De Quatrebarbes Julie , Granel-Brocard Florence , Le-Bouar Myrtille , Charles Julie , Brunet-Possenti Florence , Dreno Brigitte , Lefevre Wendy , Allayous Clara , Lebbe Celeste , Aubin Francois
Published: May 2020

10057

Background: PD-1 inhibitors (anti-PD1) are frequently associated with immune-related adverse events (IRAE). Since melanoma patients included in clinical trials were frequently treated during two years, data on IRAE occurring after 2 years of treatment are lacking. This study aimed to describe IRAE in melanoma patients treated with anti-PD1 for longer than 2 years in a real-life setting. Methods: Patients were screened from MelBase, a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. All patients who received anti-PD1 for at least 2 years between January 2013 and November 2019 were included. Among them, patients who experienced IRAE and long-term IRAE defined as IRAE occurring after 2 years of anti-PD1 were identified. Results: Among 1849 patients with advanced melanoma included in Melbase, 119 patients received anti-PD1 monotherapy during at least 2 years, from January 2013 to November 2019, with a median follow-up of 41.7 months (25.2-57.5). Patients characteristics at treatment initiation were: male gender (61%), mean age of 63 years old, past history of autoimmune disease (11%), BRAF WT (72%), AJCC stage IV (84%), brain metastases (22%), ECOG 0-1 (88%) and normal LDH (56%). Patients were treated with Nivolumab (n = 53) or Pembrolizumab (n = 66). IRAE occurred in 99 patients (83%) with a median time of 13.3 months (0-53.9), including severe IRAE (grade 3 or 4) in 30 patients (30%). Long-term IRAE, mostly grades 1-2, occurred in 52 patients (43%). Long-term IRAE led to 5 hospitalizations (4%) of which 4 were grades 3-4. Among patients with long-term IRAE, 45 patients (87%) previously experienced IRAE within the first 2 years of anti-PD1 and 29 patients (56%) experienced multiple IRAE. Conclusions: Our data demonstrate that long-term IRAE are frequent especially in patients who already experienced IRAE within the first two years of treatment. These data should be taken into account to establish formal recommendations on the duration of anti-PD1 therapy.
Clinical outcomes in patients with BRAFV600 mutant melanoma and undetectable circulating tumor DNA treated with dabrafenib and trametinib.
Authors: Algazi Alain Patrick , Othus Megan , Voorhies Benjamin Newell , Kendra Kari Lynn , Dakhil Shaker R. , Harker-Murray Amy K. , Lao Christopher D. , Chmielowski Bartosz , Lo Roger , Grossmann Kenneth F. , Ribas Antoni
Published: May 2020

10059

Background: Circulating tumor DNA (ctDNA) analysis has been promoted as a less-invasive surrogate assay for tumor-tissue based tumor oncogene analysis. Here, we associate detection of BRAF mutant ctDNA with PFS and OS in patients with tissue-confirmed BRAFV600 mutant melanoma enrolled in S1320, a randomized phase 2 clinical trial of continuous versus intermittent dosing of dabrafenib and trametinib. Methods: Patients with BRAFV600 melanoma received continuous therapy with dabrafenib and trametinib for 8 weeks after which patients were randomized 1:1 to proceed with intermittent treatment on a 3-week-off, 5-week-on schedule or to continue with continuous therapy. Pre-treatment blood samples were interrogated using the Guardant 360 ctDNA assay for all exons of 30 known oncogenes including BRAF and for all exons with known oncogenic mutations in the COSMIC database in 40 additional oncogenes. Clinical responses were assessed at 8-week intervals by RECIST v1.1 and PFS and OS estimates were compared using log-rank test in patients with detectable versus undetectable BRAFV600 mutant ctDNA,. Results: Somatic BRAFV600E or BRAFV600K ctDNA was detected in 34 of 50 patients with baseline (before lead-in cycle 1) blood samples available for analysis including 16 of 23 (70%) patients randomized to continuous dosing, 15 of 21 (71%) randomized to intermittent dosing, and 3 of 6 (50%) who were not randomized due to disease progression at 8 weeks or other factors. Four additional patients had other detectable somatic mutations but no detectable BRAFV600 ctDNA at baseline, and 12 patients had no detectable somatic ctDNA mutations at baseline. Detection of BRAFV600 ctDNA was associated with baseline disease stage (p = 0.008). There was no difference in the overall response rate based on baseline ctDNA detection. Detection of ctDNA at baseline was associated with worse PFS (median BRAFV600 ctDNA positive = 5.8; 95% CI: 4.2-9.6 months, BRAFV600 ctDNA negative = 21.4 mos; 95% CI 10.4-NA; measured from registration to lead-in cycle 1, p = 0.001) and OS (BRAFV600 ctDNA positive = 17.8 mos; 95% CI 9.76-NA, BRAFV600 ctDNA negative = not reached; 95% CI NA-NA, p = 0.0021). Conclusions: The absence of detectable BRAFV600 ctDNA at baseline is associated with improved PFS and OS in patients receiving treatment with dabrafenib and trametinib. Clinical trial information: NCT02196181.
Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results.
Authors: Rugo Hope S. , Lerebours Florence , Ciruelos Eva , Drullinsky Pamela , Ruiz Borrego Manuel , Neven Patrick , Park Yeon Hee , Prat Aleix , Bachelot Thomas , Juric Dejan , Turner Nicholas C. , Sophos Nickolas , Zarate Juan Pablo , Arce Christina , Shen Yu-Ming , Chia Stephen K. L.
Published: May 2020

1006

Background: PIK3CA mutations (mut) occur in ~40% of pts with HR+, HER2– ABC and are associated with poor prognosis and resistance to treatment (tx). ALP, a PI3Kα inhibitor, plus FUL demonstrated efficacy in the phase 3 SOLAR-1 trial of HR+, HER2– PIK3CA-mut ABC. Little clinical data and few prospective studies are available to inform tx decisions for pts with HR+, HER2– PIK3CA-mut ABC in the post-CDKi setting. BYLieve is the first trial evaluating ALP + endocrine therapy (ET; FUL or letrozole) in pts with HR+, HER2– PIK3CA-mut ABC who progressed on/after prior therapy, including CDKi. In this ongoing phase 2, open-label, noncomparative study, 112 pts with centrally confirmed PIK3CA mut in tumor tissue are enrolled in each cohort per immediate prior tx of CDKi + AI, CDKi + FUL, or systemic chemo or ET. Enrollment is complete in prior CDKi + AI and CDKi + FUL cohorts and ongoing in prior systemic chemo or ET cohort. We report on the cohort of pts with CDKi + AI as immediate prior tx. Methods: Pts received ALP 300 mg/day + FUL 500 mg Q28D + C1D15. Primary endpoint was proportion of pts alive without disease progression at 6 mo per local assessment; 2-sided 95% confidence intervals (CI) were calculated using Clopper and Pearson (1934) exact method. Evidence of clinically meaningful tx effect was defined as the lower bound of the 95% CI > 30%. Safety was assessed in all patients; AEs presented by preferred term. Results: 127 pts whose immediate prior tx was CDKi + AI were enrolled, of whom 121 had centrally confirmed PIK3CA mut; median follow-up was 11.7 mo. Primary endpoint was met: proportion of pts without disease progression at 6 mo was 50.4% (95% CI, 41.2-59.6). Most frequent all-grade AEs were diarrhea (60%), hyperglycemia (58%), nausea (46%), fatigue (29%), decreased appetite (28%), and rash (28%). Most frequent grade ≥3 AEs included hyperglycemia (28%), rash (9%), and rash maculopapular (9%). Incidence of AEs leading to discontinuation was low; most frequent AEs leading to discontinuation were rash (5 pts, 3.9%), colitis, hyperglycemia, urticaria, and vomiting (2 pts, 1.6% each). Conclusions: With follow-up still ongoing, BYLieve shows in a large number of pts that ALP + FUL demonstrates clinically meaningful efficacy and manageable toxicity post CDKi tx. Building on findings from SOLAR-1, BYLieve further supports use of ALP + FUL for HR+, HER2– PIK3CA-mut ABC. Clinical trial information: NCT03056755 .