bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anti–PD-1 antibody spartalizumab in combination with dabrafenib and trametinib in advanced BRAF V600–mutant melanoma: Efficacy and safety findings from parts 1 and 2 of the Phase III COMBI-i trial.
Authors: Long Georgina V. , 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 , Pakhle Neha , Masood Aisha , Gasal Eduard , Dummer Reinhard 
Published: May 2020

10028 Background: Treatment (tx) with checkpoint inhibitors or targeted therapy improves outcomes in patients (pts) with BRAF V600–mutant advanced melanoma; however, many pts subsequently progress and die. Preliminary evidence suggests that targeted therapy may enhance the impact of checkpoint inhibitors and improve efficacy compared with either treatment alone. Methods: COMBI-i is investigating first-line spartalizumab 400 mg every 4 wk + dabrafenib 150 mg twice daily + trametinib 2 mg once daily in pts with unresectable or metastatic BRAF V600–mutant melanoma (NCT02967692). We report efficacy and safety data from parts 1 (run-in cohort) and 2 (biomarker cohort), with a median follow-up of 24.3 mo. Response was assessed per RECIST v1.1. The randomized part 3 is ongoing. Results: 36 pts were enrolled (part 1: n = 9; part 2: n = 27); 20 (56%) had stage IV M1c disease and 15 (42%) had elevated lactate dehydrogenase (LDH) levels (≥ upper limit of normal). At the data cutoff (August 19, 2019), tx was ongoing in 10 pts (28%). The confirmed investigator-assessed objective response rate (ORR) was 78% (n = 28), with 16 complete responses (CRs; 44%) and 12 partial responses (33%). Median duration of response (DOR; 10/28 responders with events) was not reached (NR); 24-mo DOR rate was 53.4% (95% CI, 29%-73%). Median progression-free survival (PFS) was 22.7 mo; 24-mo PFS rate was 41.4% (95% CI, 23%-59%). At the cutoff, median overall survival (OS) was NR, with a 24-mo OS rate of 74.1% (95% CI, 56%-86%). In pts with elevated LDH, ORR was 67%, with 4 CRs (27%); median PFS was 10.7 mo (95% CI, 4.6-19.1 mo), and median OS was NR. The estimated 24-mo PFS and OS rates in these pts were 26.7% and 52.5%, respectively. All pts had ≥ 1 tx-related adverse event (TRAEs); 26 (72%) had grade ≥ 3 TRAEs. The most common grade ≥ 3 TRAEs were pyrexia (17%), increased lipase (11%), neutropenia (11%), increased blood creatine phosphokinase (8%), and increased γ-glutamyltransferase (8%). AEs leading to discontinuation of all 3 study drugs occurred in 6 pts (17%). All-causality grade ≥ 3 AEs requiring immunosuppressive medication occurred in 19 pts (53%). One pt died of cardiac arrest that was not considered tx related. Conclusions: The combination of spartalizumab + dabrafenib + trametinib resulted in high ORR and CR rates, with a high frequency of durable responses, including in patients with poor prognostic factors. Clinical trial information: NCT02967692.
Response to immune checkpoint inhibitor (ICI) rechallenge after high-grade immune related adverse events (irAE) in patients (pts) with metastatic melanoma (MM).
Authors: Shah Payal , Boland Patrick , Pavlick Anna C. 
Published: May 2020

10045 Background: ICIs have transformed MM mortality. Pts receiving ICIs may experience high-grade irAEs that limit continuation of treatment per current guidelines. We aimed to evaluate the safety and response rate of ICI rechallenge. Methods: 551 MM pts treated with ICI were retrospectively reviewed from Jan 2014 to Jan 2020 after IRB approval. The incidence of a recurrent irAE in pts with ICI rechallenge within the same drug class after an initial high-grade (Grade III/IV) irAE was evaluated. Age, gender, irAEs, and outcomes were descriptively analyzed within the rechallenged cohort. Results: 32.7% of pts (180/551) experienced a high-grade irAE. 60.0% of these (108/180) pts were on combination therapy with at least one ICI. 50.6% (91/180) of pts were rechallenged with ICI within the same drug class. The rechallenged cohort had a median age of 63.8 [range: 28-86] years and 48.4% was female. The cohort’s initial irAE occurred at a median of 7.6 weeks from treatment onset with Grade 3/4 severity of 60.0% /40.0% (91). Toxicities included colitis 27.5% (25/91), hepatitis 23.1% (21/91), skin toxicity 22.0% (20/91), adrenal insufficiency 5.5% (5/91) hypophysitis 5.5% (5/91), neurological abnormality 4.4% (4/91), pancreatitis 3.3% (3/91), hematological abnormality 3.3% (3/91), arthralgia 3.3% (3/91), myalgia 3.3% (3/91), pneumonitis 2.2% (2/91), insulin dependent diabetes 1.1% (1/91), fatigue 1.1% (1/91), vasculitis 1.1% (1/91), and hyponatremia 1.1% (1/91). ICI rechallenge occurred at a median of 9.7 weeks from the first Grade 3/4 irAE. 51.8% (29/56) pts initially treated with combo were rechallenged with combo, while 48.2% (27/56) were rechallenged with single agent ICI. Of pts initially treated with single ICI, 60% (21/35) were rechallenged with single agent ICI and 40% (14/35) with combo. With a median follow-up of 21.1 months after rechallenge, irAEs occurred in 75.8% (69/91), with 44.9% of irAEs (31/69) presenting as a different type from the initial event and 31.9% (22/69) as high-grade events. There were no rechallenge irAE-related deaths. Within the rechallenge cohort, 39.6% (36/91) of pts had disease progression. Clinical benefit was achieved in 60.4% (55/91) of pts: 40.7% (37/91) complete response, 11.0% (10/91) partial response and 8.8% (8/91) stable disease. Conclusions: ICI rechallenge can be safely administered in pts with MM after recovery from an initial high-grade irAE. Rechallenge irAE’s did not always reflect initial irAE’s. Close monitoring for any type or grade of IRAE is recommended.
Discordant response comparing 18F-FDG PET/CT with response assessment by RECIST in patients with advanced melanoma treated with immune checkpoint blockade.
Authors: De Barros E Silva Milton Jos , Teixeira Marcos Rezende , Pandolfi Natasha Carvalho , Calsavara Vinicius Fernando , Oliveira Thiago Bueno , Rinck José Augusto , Tavares Monique Celeste , Garcia Daniel , Lima Joao Paulo SN , Duprat Joao 
Published: May 2020

10046 Background: Immune checkpoint blockade (ICB) has changed the natural history advanced melanoma (AM). Based on phase III trial, which used RECIST criteria, the complete response (CR) rate with anti-PD1 therapy is around 20%. In daily practice, PET/CT is a useful tool to evaluate response to treatment in melanoma patients. Little is known about the number of patients who achieve metabolic CR by PET/CT but with anatomic residual disease and their prognosis. Methods: We conducted a retrospective analysis of patients with AM treated with ICB who achieved metabolic CR by PET/CT but with residual disease on tomography and compared to patients with RECIST CR in a high-volume cancer center. Progression-free (PFS) and overall survival (OS) were obtained by Kaplan Meier method and log-rank test. Results: One hundred seventy pts with AM treated with anti-PD1 (79%) or anti-PD1 + anti- CTLA4 (21%) betweenSeptember 2013 and December 2019 were analyzed. At a median follow-up of 23.6 months, seventy-five (44%) pts achieved CR. RECIST criteria: 22 pts (29.3%) and metabolic CR: 53 pts (70.7%). All patients with metabolic CR had RECIST partial response. The median total time on treatment was 14.8m (95%CI:0.9-42.3). The median time to reach CR was 5.4m (95%CI: 3-39). The median time of treatment after CR was 6.8m (95%CI: 0-21.4). The rate of CR patients off treatment at the moment of this analysis was 69%. The median follow-up after discontinuing treatment was 5.2m. There was no difference in PFS (36 month-rate: 84.4% vs 74%, p:0.64) and OS (36 month-rate: 100% vs 86.3%, p:0.14) between pts with CR based on RECIST or PET-CT, respectively. Median time for PFS and OS have not been reached until the date cut-off. Nine pts have relapsed (12%). Seven of them had residual disease on tomography but with no metabolic active lesion(s) at the time of the end of treatment. Conclusions: Twice more patients achieve complete response considering only metabolic parameters on PET/CT compared to RECIST criteria and they seem to have comparable prognosis.
Clinical outcomes with early-elective discontinuation of PD-1 inhibitors (PDi) at one year in patients (pts) with metastatic melanoma (MM).
Authors: Pokorny Rebecca , McPherson Jordan P. , Grossmann Kenneth F. , Luckett Carolyn , Voorhies Benjamin Newell , Sageser Daniel S. , Wallentine Jocelyn , Tolman Zachary , Hu-Lieskovan Siwen , Swami Umang 
Published: May 2020

10048 Background: Randomized trials of PDi in MM permitted treatment for 2 years (pembrolizumab) or more (nivolumab). However, the optimal treatment duration is unknown, and shorter courses may be effective. We reviewed clinical outcomes of pts who electively discontinued PDi at 1 year at our institution. Methods: We performed a real-world, observational cohort study of pts with MM treated with single-agent PDi from 1/1/2015 to 12/31/2018 at Huntsman Cancer Institute. This was a continuous series of pts who made the joint decision with their provider to electively discontinue PDi at 1 year ( > 6 mos and < 18 mos) in the setting of ongoing treatment response or disease stability. Exclusion criteria: PDi with other systemic therapy, discontinuation due to disease progression or immune-related adverse event, and PDi in neoadjuvant, adjuvant, or clinical trial settings. Local therapies, as in real-world, were allowed. Best objective response (BOR) per RECIST 1.1 at PDi discontinuation, progression-free survival (PFS) and retreatment characteristics were analyzed. Results: Of 485 pts who received PDi, 52 met inclusion criteria. Median age was 60.5 years and 26.9% were female. Median duration of PDi from first to last dose was 11.1 mos (95% CI 10.5 - 11.4). BOR was complete response in 13 (25%), partial response in 28 (53.8%), and stable disease in 11 (21.2%) pts. After median follow-up of 20.5 mos (range 3 - 49.2) from treatment discontinuation, 39 (75%) pts remained without disease progression (median PFS not reached). Only 13 (25%) pts progressed. Median time to progression after treatment discontinuation was 3.9 mos (range 0.7-30.9). Of the 13 pts, 7 immediately underwent successful localized treatment to the solitary site of progression (3 SRS/SBRT, 4 resection; followed by PDi in 2), 5 were retreated with PDi and 1 received BRAF/MEK followed by PDi. Retreatment with PDi controlled disease in all 5 pts. All pts except 1 were alive at data cut-off. Conclusions: In the largest continuous series of pts with MM who electively discontinued PDi after 1 year of treatment, the majority remained without progression on follow-up. Risk of disease progression even in pts with residual disease on imaging was low, and retreatment was effective. Strengths of our study include real-world cohort and treatment pattern analysis. Limitations include single-institution, retrospective design. After prospective validation, elective PDi discontinuation at 1 year may reduce financial and PDi-related toxicity without sacrificing outcomes.
Activity and safety of third-line BRAF-targeted therapy (TT) following first-line TT and second-line immunotherapy (IT) in advanced melanoma.
Authors: Atkinson Victoria , Batty Kathleen , Long Georgina V. , Carlino Matteo S. , Peters Geoffrey David , Bhave Prachi , Moore Maggie A. , Xu Wen , Brown Lauren Julia , Arneil Melissa , Lyle Megan , Menzies Alexander M. 
Published: May 2020

10049 Background: Patients with advanced melanoma who progress on 1st line TT and 2nd line IT have limited treatment options. We explored the safety and efficacy of re-treatment with 3rd line TT. Methods: was pooled from 6 centers in Australia from 2009-2018. Eligible patients with BRAF V600 mutant melanoma had 1st line therapy with a BRAF/MEK inhibitor, 2nd line IO and were re-challenged with a BRAF/MEK inhibitor. Results: 90 patients were included; median age 61 years, 78% BRAF V600E, 89% ECOG 0-1 at baseline. 1st line TT was combination BRAF/MEK inhibitors in 80%, predominately dabrafenib/trametinib. Response to 1st line therapy was CR 20%, PR 41%, SD 17% and PD 13% and median duration of therapy was 7.2 months (0-33 months). 70% stopped for progressive disease, 9% toxicity and 16% had a planned switch to immunotherapy. For 2nd line IT, 49% had PD-1 alone, 33% had PD-1+CTLA-4, 14% had CTLA-4 alone. Only median duration on IT was 67 days (0-23 months), 81% ceased for PD, 14% for toxicity. Of patients who had a planned switch to IO before 1st line TT progression, one patient responded to second line IO with SD as BORR, there were no other responses to 2nd line IO in the planned switch group. At 3rd line TT re-challenge, 54% were AJCC stage IVd, 34% IVc, 51% had elevated LDH, 59% ECOG 0-1. 47% were re-challenged with dabrafenib/trametinib, 33% vemurafenib/cobimetinib, 11% encorafenib/binimetinib. BORR was 28%, with median duration on 3rd line TT 81 days. The OS was 1.7 years, with 34% alive at time of analysis. Conclusions: Despite progression on 1st line TT and 2nd line IT, patients may experience meaningful response and on re-challenge TT.
Checkpoint inhibitor treatment in patients with isolated in-transit melanoma metastases.
Authors: Storey Lucy , Abdul-Latif Mohammed , Kreft Sophia , Barrett Emma , Pickering Lisa M , Rohaan Maartje W. , Ahmed Sobia , Eigentler Thomas K. , Hassel Jessica Cecile , Haferkamp Sebastian , Meiss Frank , Steeb Theresa , Shaw Heather May , Blank Christian U. , Van Akkooi Alexander Christopher Jonathan , Larkin James M. G. , Schilling Bastian , Lorigan Paul , Nathan Paul D. 
Published: May 2020

10070 Background: In the context of multiple in-transit melanoma metastases without nodal involvement, a variety of treatment modalities have historically been employed including surgery, laser, isolated limb perfusion/infusion, intralesional interleukin-2, T-VEC and electrochemotherapy. Unfortunately, most patients treated with these modalities experience subsequent disease progression. While checkpoint inhibitors (CPI) are a standard of care for bulky unresectable stage III and for stage IV melanoma, patients with isolated in-transit metastases were rarely included in registration studies. There are anecdotal reports of lower response rates in these patients despite them having disease characteristics that would usually be associated with a good response. Methods: We report data from 11 retrospective patient cohorts treated at cancer centres across Europe who received CPI between 2016 and April 2019. All patients had multiple in-transit metastases without clinical or radiological evidence of nodal or distant disease. Disease response was assessed using CT, PET-CT or MRI depending on clinical indication. All patients had at least one prior resection of loco-regional relapsed disease and were deemed not curable by further surgery. Results: Sixty three patients meeting criteria were identified, 40 females and 23 males. Median age was 72 years and 54 (86%) patients had a normal lactate dehydrogenase (LDH). 19 (30%) patients had a BRAF mutation. At treatment initiation, the majority 55 (87.3%) received single agent PD-1 inhibitor, 7 (11.1%) combination ipilimumab + nivolumab and 1 (1.6%) received single agent anti-CTLA 4. The overall response rate was 62% for the full population. The response rate with anti-PD1 monotherapy was 59%. With a median FU of 23 months, the median PFS was 26 months, median OS not reached. OS estimates with 95% CI: 12 month - 93% (87-100%), 24 month - 88% (80-98%), 36 month - 80% (67-95%). Conclusions: The results show a high response rate to CPI in patients with in-transit metastases and support early treatment with CPI following identification of in-transit metastases not curable with surgery whilst disease characteristics remain favourable.
Exploring impact of mutations in non-BRCA DNA damage response (DDR) and non-DDR genes on efficacy in phase III EMBRACA study of talazoparib (TALA) in patients (pts) with germline BRCA1/2 mutated (gBRCAm) HER2-negative (HER2-) advanced breast cancer (ABC).
Authors: Litton Jennifer Keating , Laird Douglas , Rugo Hope S. , Ettl Johannes , Hurvitz Sara A. , Martin Miguel , Roche Henri , Im Young-Hyuck , Goodwin Annabel , Blum Joanne Lorraine , Eiermann Wolfgang , Chen Ying , Lanzalone Silvana , Chelliserry Jijumon , Czibere Akos , Albacker Lee A. , Frampton Garrett M. , Mina Lida A. 
Published: May 2020

1018 Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA showed an improvement in progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P < 0.001) vs physician's choice of chemotherapy (PCT) in g BRCAm HER2− ABC. Methods: Baseline tumor tissue from 308 pts (71%; intent-to-treat) was sequenced using the FoundationOne CDx panel. Mutations summarized below were known/likely pathogenic single-nucleotide variants, insertions, deletions, or rearrangements. Best tumor response (BOR) was using RECIST 1.1 by Investigator (confirmation of CR or PR not required). Results: 296/308 (96%) of evaluable pts exhibited ≥1 tumor BRCA mutation, with 7 of the remaining 12 exhibiting BRCA copy number alterations deemed pathogenic. Mutations in other genes implicated in DDR and/or potential sensitization to PARPi were rare, with mutations detected in BARD1, CDK12, FANCG, STAG2 (each 0.3%), ATR, BRD4, FANCC, PALB2, RAD51B (0.6%), ATM, BRIP1 (1.0%), NBN (1.3%), CHEK2, FANCA (1.6%), and ARID1A (2.3%). No association was observed between total number of DDR mutations, including BRCA1/2, and best tumor response (BOR) [odds ratio of 1 vs ≥2 DDR mutations (95% CI): TALA, 0.76 (0.31-1.87), P = 0.55; PCT, 0.98 (0.27-3.51), P = 0.97]. TP53 and PIK3CA were the most commonly mutated non- BRCA genes in BRCAm tumors (52.0 and 10.8%, respectively). TP53 mutations were more prevalent in BRCA1m vs BRCA2m tumors (85.2 vs 24.8%). PIK3CA mutations were more prevalent in BRCA2m vs BRCA1m tumors (15.9 vs 5.2%). With TALA, PFS was significantly shorter in pts with TP53 mutations than without [HR (95% CI) 1.693 (1.186-2.418), P = 0.0033]. A similar, non-significant, trend was evident with PCT [HR (95% CI) 1.439 (0.859-2.411), P = 0.1614]. PIK3CA mutational status had no impact on PFS in either arm. Conclusions: Selection based on g BRCA mutational status is appropriate to identify HER2─ ABC pts with potential for clinical benefit from TALA, with the total number of tumor mutations in BRCA1/2 and other DDR genes not impacting response (within the g BRCAm subset). TP53 mutations were associated with shorter PFS, likely reflecting the worse outcomes observed in g BRCA1m patients. Additional correlative analyses are ongoing. Clinical trial information: NCT01945775 .
Phase I dose escalation and expansion trial to assess the safety and efficacy of ADP-A2M4 SPEAR T cells in advanced solid tumors.
Authors: Hong David S. , Van Tine Brian A. , Olszanski Anthony J. , Johnson Melissa Lynne , Liebner David A. , Trivedi Trupti , Lin Quan , Elefant Erica , Dryer-Minnerly Rebecca , Navenot Jean-Marc , Williams Dennis , Ramachandran Indu R. , Fracasso Paula M. , Norry Elliot , Butler Marcus O. 
Published: May 2020

102 Background: MAGE-A4 is a cancer/testis antigen with expression in many solid tumors promoting cell growth by preventing cell cycle arrest and apoptosis. This study (NCT03132922) evaluated safety and efficacy of SPEAR T-cells directed against the MAGE-A4 peptide expressed in 9 tumor types. Methods: This Phase I dose-escalation, expansion trial evaluated patients (pt) who were HLA-A*02 positive with advanced cancers that expressed the MAGE-A4 protein. Autologous T-cells from eligible patients were isolated, transduced with a lentiviral vector containing the MAGE-A4c1032 TCR, and expanded. Prior to ADP-A2M4 infusion, pts received a lymphodepletion regimen of cyclophosphamide and fludarabine. Cohorts 1, 2, 3, and expansion were to receive transduced cell doses of up to: 0.12 × 109, 1.2 × 109, 6 × 109, and 10 x 109, respectively. Results: As of 23 October 2019, 9 pts were treated in dose escalation with no DLTs; 25 pts were treated in expansion. Median age was 56.5 yr (range: 31-78). All pts received prior chemotherapy. Most common ( > 30%) AEs ≥Grade 3 were lymphopenia, leukopenia, neutropenia, anemia, thrombocytopenia, and febrile neutropenia. Two pts had trial-related deaths (aplastic anemia and CVA) leading to modification of the lymphodepletion regimen and eligibility criteria. In Cohort 3/expansion (28 pts), Best Overall Response was PR (7), SD (11), PD (5), non-evaluable (5). All PRs, at the time of data cut-off, were in patients with synovial sarcoma. Transduced T-cells were detectable in all patients. Tumor infiltration of SPEAR T-cells was detectable in several cohort 3/expansion pts. Conclusions: The Phase I single agent ADP-A2M4 trial will complete enrollment shortly and updated data will be presented. ADP-A2M4 shows promising efficacy and a manageable safety profile at a dose range of 1.2 – 10 × 109. Clinical activity in various tumors has led to a separate on-going low dose radiation sub-study of this trial, a Phase II trial in sarcoma (SPEARHEAD-1, NCT04044768), and a Phase I trial (SURPASS, NCT04044859) with ADP-A2M4CD8, a next-generation SPEAR T-cell targeting MAGE-A4. Clinical trial information: NCT03132922.