bluuebunny/crossref_metadata_2025 huggingface dataset:
Overall survival and biomarker analysis of a phase Ib combination study of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) with axitinib in patients with metastatic mucosal melanoma.
Authors: Sheng Xinan , Yan Xieqiao , Chi Zhihong , Si Lu , Cui Chuanliang , Tang Bixia , Li Siming , Mao Lili , LIAN BIN , Wang Xuan , Bai Xue , Zhou Li , Kong Yan , Dai Jie , Flaherty Keith , Guo Jun ,   Shanghai Junshi Biosciences
Published: May 2020

10007

Background: Metastatic mucosal melanoma responds poorly to PD-1 blockade therapy in comparison with cutaneous melanoma. Vascular endothelial growth factor (VEGF) is indicated to play an important immunosuppressive role in mucosal melanoma. Combination of VEGF inhibition with PD-1 blockade might provide therapeutic opportunities. Toripalimab was approved as a second-line treatment for metastasis melanoma in Dec 2018. This study is to evaluate the safety and clinical efficacy of toripalimab combined with axitinib for the treatment of metastatic mucosal melanoma. (Clinical trial ID: NCT03086174). Methods: Patients with metastatic melanoma receive 1 or 3 mg/kg toripalimab Q2W in combination with 5 mg axitinib BID until disease progression, unacceptable toxicity, or voluntary withdrawal. Clinical response is assessed every 8 weeks according to RECISTv1.1. Tumor PD-L1 expression, tumor mutational burden (TMB), and gene expression profile (GEP) will be evaluated for correlation with clinical response. Results: From April 2017 to April 2018, 33 patients were enrolled in the study. No DLT or treatment related death was observed. 97% patients experienced treatment related AE (TRAE) and 39.4% patients experienced Grade 3-4 TRAEs. Most common TRAEs include diarrhea, proteinuria, hand and foot syndrome and hypothyroidism. Only one patient discontinued treatment due to TRAE. Among 29 treatment naïve mucosal melanoma patients, 14 PR and 11 SD were observed for an ORR of 48.3% and a DCR of 86.2%. The median DOR was 13.7 months. The median PFS was 7.5 months and the median OS was 20.7 months. PD-L1 expression or TMB had no significant differences in responders versus non-responders. In contrast, GEP scores of eight selected immune-related and four angiogenesis-related genes showed strong correlation with clinical response, whereas previous published immune related signature or angiogenesis signature alone had no correlation. Conclusions: Toripalimab combined with axitinib is a promising treatment option for metastatic mucosal melanoma. GEP scores of selected immune-related and angiogenesis-related genes might predict the response to the combination. A randomized 3-arm Phase 2 trial has been initiated to compare toripalimab plus axitinib with toripalimab or axitinib alone. Clinical trial information: NCT03086174.
Results of a phase II randomized trial of cisplatin +/- veliparib in metastatic triple-negative breast cancer (TNBC) and/or germline BRCA-associated breast cancer (SWOG S1416).
Authors: Sharma Priyanka , Rodler Eve , Barlow William E. , Gralow Julie , Huggins-Puhalla Shannon Leigh , Anders Carey K. , Goldstein Lori J. , Brown-Glaberman Ursa Abigail , Huynh Thu-Tam , Szyarto Christopher Scott , Godwin Andrew K. , Pathak Harsh B , Swisher Elizabeth M. , Radke Marc R , Timms Kirsten M , Lew Danika L. , Miao Jieling , Pusztai Lajos , Hayes Daniel F. , Hortobagyi Gabriel N.
Published: May 2020

1001

Background: PARP inhibitors(i) are effective in BRCA-mutation -associated metastatic breast cancer(MBC). However, there are no studies evaluating PARPi + platin chemotherapy in BRCA wild-type(wt) TNBC. Approximately 1/2 of BRCAwt TNBC demonstrate homologous recombination deficiency (HRD) resulting in a BRCA-like phenotype which might render them sensitive to PARPi. S1416 compared the efficacy of cisplatin plus PARPi veliparib (Vel) or placebo (P) in 3 groups of MBC: gBRCA+; BRCA-like; and non-BRCA-like. Methods: Patients (pts) with metastatic TNBC or g BRCA1/2-associated MBC, who had received < 1 line of prior therapy were treated with cisplatin (75mg/m2) plus Vel or P (300 mg po BID days 1-14), every 3 weeks. All pts underwent central gBRCA testing. A priori established multipronged biomarker panel was used to classify BRCAwt pts into BRCA-like and non-BRCA-like groups, and included myChoice HRD score, somatic BRCA1/2 mutations, BRCA1 methylation and non- BRCA1/2 HR germline mutations. Primary end-point was progression-free survival (PFS) in the three pre-defined groups; secondary end-points included objective response rate (ORR), overall survival (OS), toxicity. Results: 323/335 randomized pts were eligible for efficacy evaluation; 31% had received 1 prior chemotherapy for MBC. 248 pts were classified into the three groups: (1) 37 gBRCA+ (2) 101 BRCA-like; (3) 110 non- BRCA-like. Remaining 75 could not be classified due to missing biomarker information. In the gBRCA+ group (which reached 62% of its projected accrual), numerically better PFS was noted with Vel compared to P (HR=0.64; p=0.26) though this difference was not statistically significant. In BRCA-like group improved PFS was noted with Vel vs P (median PFS 5.7 vs 4.3 months HR=0.58; p=0.023, 1 years PFS 20% vs 7%). Numerically better OS (median OS 13.7 vs 12.1 months, HR=0.66; p=0.14) and ORR (45% vs 35%, p=0.38) were noted with Vel vs P in BRCA-like group. Non-BRCA-like group did not show benefit of veliparib for PFS (HR=0.85; p=0.43) neither did the unclassified group (HR=0.97). Grade 3/4 neutropenia (46% vs 19%) and anemia (23% vs 7%) occurred at higher frequency in Vel arm compared to P. Conclusions: Addition of Vel to cisplatin significantly improved PFS and showed a trend towards improved OS for BRCA-like advanced TNBC. Integral biomarkers used in this study identified a subgroup of BRCAwt TNBC who benefited from addition of PARPi to cisplatin; platinum plus PARPi combination should be explored further in BRCA-like TNBC. Clinical trial information: NCT02595905 .
Long-term survival from pembrolizumab (pembro) completion and pembro retreatment: Phase III KEYNOTE-006 in advanced melanoma.
Authors: Long Georgina V. , Schachter Jacob , Arance Ana , Grob Jean-Jacques , Mortier Laurent , Daud Adil , Carlino Matteo S. , Ribas Antoni , McNeil Catriona M. , Lotem Michal , Larkin James M. G. , Lorigan Paul , Neyns Bart , Blank Christian U. , Petrella Teresa M. , Hamid Omid , Jensen Erin , Krepler Clemens , Diede Scott J. , Robert Caroline
Published: May 2020

10013

Background: 5-year follow-up of the phase 3 KEYNOTE-006 study (NCT01866319) showed pembro improved OS vs ipilimumab (ipi) in patients (pts) with advanced melanoma. 3-y OS rate from pembro completion for pts who completed 2 y of pembro was 93.8%. Results with 8 mo of additional follow-up are presented to inform clinical care. Methods: Eligible pts with ipi-naive advanced melanoma, ≤1 prior therapy for BRAF-mutant disease, and ECOG PS 0 or 1 were randomized to pembro 10 mg/kg Q2W or Q3W for ≤2 y or ipi 3 mg/kg Q3W for 4 doses. Pts discontinuing pembro with CR, PR, or SD after ≥94 weeks were considered pts with 2-y pembro. Pts who stopped pembro with SD, PR or CR could receive ≤12 mo of additional pembro (2nd course) upon disease progression if still eligible. ORR was assessed per immune-related response criteria by investigator review. OS was estimated using the Kaplan-Meier method. Pembro arm data were pooled. Post hoc ITT efficacy analyses are shown. Results: Median follow-up from randomization to data cutoff (Jul 31, 2019) was 66.7 mo in the pembro and 66.9 mo in the ipi arms. OS outcomes are shown in Table. For the 103 pts with 2-y pembro (30 CR, 63 PR, 10 SD), median follow-up from completion was 42.9 mo (95% CI, 39.9-46.3).Median DOR was not reached. 36-mo OS from pembro completion was 100% (95% CI, 100.0-100.0) for pts with CR, 94.8% (95% CI, 84.7-98.3) for pts with PR, and 66.7% (95% CI, 28.2-87.8) for pts with SD. 15 pts received 2nd-course pembro; BOR in 1st course was 6 CR, 6 PR, and 3 SD. Median time from end of 1st course to start of 2ndcourse was 24.5 mo (range, 4.9-41.4). Median follow-up in pts who received 2nd-course pembro was 25.3 mo (range, 3.5-39.4). Median duration of 2nd-course pembro was 8.3 mo (range, 1.4-12.6). BOR on 2ndcourse was 3 CR, 5 PR (ongoing responses, 7 pts), 3 SD (ongoing, 2 pts), and 2 PD (1 death); 2 pts pending. Conclusions: Pembro improves the long-term survival vs ipi in pts with advanced melanoma, with all pts who completed therapy in CR still alive at 5 years. Retreatment with pembro at progression in pts who stopped at SD or better can provide additional clinical benefit in a majority of pts. Clinical trial information: NCT01866319. [Table: see text]
TBCRC 048: A phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded).
Authors: Tung Nadine M. , Robson Mark E. , Ventz Steffen , Santa-Maria Cesar Augusto , Marcom Paul Kelly , Nanda Rita , Shah Payal D , Ballinger Tarah Jean , Yang Eddy Shih-Hsin , Melisko Michelle E. , Brufsky Adam , Vinayak Shaveta , Demeo Michelle , Jenkins Colby , Domchek Susan M. , Wulf Gerburg M. , Krop Ian E. , Wolff Antonio C. , Winer Eric P. , Garber Judy Ellen ,   Translational Breast Cancer Research Consortium
Published: May 2020

1002

Background: Olaparib, a PARP inhibitor, is approved for HER2-negative MBC in g BRCA1/2 mutation carriers. Olaparib Expanded, an investigator-initiated study, assessed the response to olaparib in MBC patients with sBRCA1/2 mutations or g/s mutations in DDR-pathway genes other than BRCA1/2. Methods: Eligibility included: MBC with measurable disease; progression on < 2 metastatic chemotherapy regimens. Prior PARP inhibitor or progression on platinum was not allowed. Cohort 1 included patients with germline mutations in non- BRCA1/2 DDR-pathway genes. In Cohort 2 were those with somatic mutations in these genes or BRCA1/2; germline testing was required only to exclude a gBRCA mutation if a s BRCA mutation was present. Patients received olaparib 300 mg bid until progression or unacceptable toxicity. For each cohort, a single-arm Simon two-stage design was used with 13 then 14 patients in the 1st and 2nd stages, respectively. The null hypothesis within each cohort [≤ 5% objective response rate (ORR)] would be rejected if > 4 responses were seen at the end of stage 2. Secondary endpoints include clinical benefit rate, progression-free survival, and duration of response. Results: 54 patients enrolled from March 2018 to Jan 2020; 1 ineligible s BRCA2 was excluded. Median age was 59 yrs (range: 30-87). 40 patients had ER+ HER2-, 3 HER2+, and 10 TNBC. 87% had a mutation in PALB2, s BRCA1/2, ATM or CHEK2. ORR was 29.6% (8/27, 90%-CI: 15.6%-47.1%) in Cohort 1 and 38.5% (10/26, 90%-CI: 22.5%-56.4%) in Cohort 2. Responses were gene specific (Table): g PALB2 and s BRCA mutations predicted response; no responses were seen with only a CHEK2 or ATM mutation. To date, responses as long as 16.4 months have been observed. Responses were seen in all subtypes: 5/10 TNBC, 1/3 HER2+, 12/40 ER+ HER2-. 11 responses occurred after prior CDK4/6 inhibitor. In June 2020, final data for confirmed ORR and secondary endpoints will be reported. Conclusion: In this proof-of-principle study, single-agent olaparib successfully met its primary endpoint in both cohorts. Activity was seen largely in patients with MBC and s BRCA1/2 or g PALB2 mutations but not with ATM or CHEK2 mutations. Clinical trial information: NCT03344965 . [Table: see text]
Pyrotinib or lapatinib plus capecitabine for HER2+ metastatic breast cancer (PHOEBE): A randomized phase III trial.
Authors: Xu Binghe , Yan Min , Ma Fei , Hu Xi-Chun , Feng Ji Feng , Ouyang Quchang , Tong Zhongsheng , Li Huiping , Zhang Qingyuan , Sun Tao , Wang Xian , Yin Yongmei , Cheng Ying , Li Wei , Zhu Xiaoyu , Chen Chunxia , Zou Jianjun ,   The PHOEBE Group
Published: May 2020

1003

Background: Pyrotinib (an irreversible pan-ErbB inhibitor) plus capecitabine showed clinically meaningful benefits and acceptable tolerability in patients (pts) with HER2+ metastatic breast cancer (MBC) in phase 1 and 2 studies. Methods: This open-label, multicenter, randomized phase 3 study enrolled HER2+ MBC pts after trastuzumab and taxanes, and/or anthracyclines. Up to two prior lines of chemotherapy (chemo) for metastatic disease were allowed. Pts were randomly assigned (1:1) to receive pyrotinib 400 mg or lapatinib 1250 mg qd continuously plus capecitabine 1000 mg/m2 bid on days 1–14 of 21-day cycles. The primary endpoint was progression-free survival (PFS) per blinded independent central review. Results: From Jul 2017 to Oct 2018, 267 pts were randomized to the pyrotinib (n=134) or lapatinib (n=133) arm. One pt in the lapatinib arm did not receive study treatment and was excluded from analyses. 42.5% and 34.8% of pts in the pyrotinib and lapatinib arm had no prior chemo for metastatic disease, 41.8% and 49.2% had one prior line, and 15.7% and 15.9% had two lines. At the planned interim analysis, the median PFS was 12.5 months (95% CI 9.7–not reached) with pyrotinib plus capecitabine vs 6.8 months (95% CI 5.4–8.1) with lapatinib plus capecitabine (HR 0.39 [95% CI 0.27–0.56]; P<0.0001), which met the criterion for statistical significance (≤0.0066). Among trastuzumab-resistant pts, prolonged PFS with pyrotinib plus capecitabine was also observed (12.5 months [95% CI 6.9 to not reached] vs 6.9 months [95% CI 5.4 to not reached]; HR 0.60 [95% CI 0.29 to 1.21]). Benefits in objective response rate, clinical benefit rate, and duration of response with pyrotinib plus capecitabine were also indicated (Table). The most common grade ≥3 adverse events were diarrhea (30.6% vs 8.3% in the pyrotinib vs lapatinib arm) and hand-foot syndrome (16.4% vs 15.2%). Conclusions: In pts with HER2+ MBC after trastuzumab and chemo, pyrotinib plus capecitabine achieved a significant better PFS than lapatinib plus capecitabine, with manageable toxicity, verifying the phase 2 findings. Clinical trial information: NCT03080805 . [Table: see text]
Surgery for unresectable stage IIIC and IV melanoma in the era of new systemic therapy.
Authors: Blankenstein Stephanie , Aarts Maureen J.B. , van den Berkmortel Franchette , Boers-Sonderen Marye , van den Eertwegh Alfonsus Johannes Maria , Franken Margreet G. , de Groot Jan Willem , Haanen John B. A. G. , Hospers Geke , Kapiteijn Ellen , Piersma Djura , Van Rijn Rozemarijn , Suijkerbuijk Karijn , ten Tije Albert J. , Van Der Veldt Astrid Aplonia Maria , Vreugdenhil Gerard , Wouters Michel W.J.M. , Van Akkooi Alexander Christopher Jonathan
Published: May 2020

10032

Background: Over the past decade opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapies. However, selecting patients who will benefit from surgery after systemic therapy is still difficult. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage III and IV melanoma, who have previously been treated with immune checkpoint inhibitors (ICI) or targeted therapy, to provide insight in which patients may benefit from surgery. Methods: Data was extracted from the prospectively collected, nationwide, Dutch Melanoma Treatment Registry (DMTR) onunresectable stage IIIC or advanced/metastatic stage IV melanomapatients who obtained disease control with systemic therapy and underwent subsequent surgery. Disease control was defined as a complete response (CR), partial response (PR) or stable disease (SD). After disease control was achieved with systemic therapy, progressive disease (PD) was allowed as a most recent status of disease prior to surgery, to avoid excluding patients with oligoprogression. Major exclusion criteria were non-cutaneous melanoma and brain metastases. Results: Of 3959 patients in the DMTR database, 154 patients met our inclusion criteria. Of these patients, 79 (51%) were treated with ICI, 61 (40%) with targeted therapy and 9.1% with study or other treatments before surgery. The best response to systemic therapy was a CR in 5.2%, PR in 46.1% and SD in 44.2% of patients. At a median follow-up of 10.0 months (IQR 4-22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression free survival (PFS) was 9.0 months (95% CI 6.3-11.7). A multivariate cox regression analysis showed that when surgery led to CR or PR, the PFS and OS were better than if surgery led to SD or PD (p < 001). Also, ICI seemed to be more favorable than targeted therapy in both PFS (median of 15 versus 7 months) and OS (median not reached versus 32 months) (p = 0.026 and p = 0.003). Conclusions: We conclude that selected unresectable stage IIIC or stage IV melanoma patients might benefit from surgery after achieving disease control with systemic therapy. Expected residual tumor after surgery could be an important selection criterion. Especially patients undergoing surgery after initial tumor response on ICI have a chance of long-term survival.
A phase II study of ERK inhibition by ulixertinib (BVD-523) in metastatic uveal melanoma.
Authors: Buchbinder Elizabeth Iannotti , Cohen Justine Vanessa , Haq Rizwan , Hodi F. Stephen , Lawrence Donald P. , Giobbie-Hurder Anita , Knoerzer Deb , Sullivan Ryan J.
Published: May 2020

10036

Background: Uveal melanoma is a rare and aggressive subset of melanoma that is minimally responsive to traditional therapies. Greater than 80% of uveal melanomas have a mutation in GNAQ or GNA11 which lead to downstream signaling through the MAPK pathway. This has led to efforts to treat uveal melanoma with MEK inhibition with mixed results. Ulixertinib (BVD-523) is a potent and reversible small molecule ATP-competitive inhibitor of both ERK1 and ERK2 protein kinases which has undergone phase I testing. Methods: We performed a phase II study to determine the efficacy and safety of BVD-523 in patients with metastatic uveal melanoma. This was conducted as a Simon two-stage design with a total sample size of 25 patients (pts) and an initial evaluation of efficacy after 13 pts. Two responses were required to continue to the second stage. Results: From April 2018 to April 2019 thirteen pts were enrolled. Pts were predominantly female (69%) with a median age of 64 yrs. (34 -76). Sites of metastasis included liver (84.6%) and lung (30.8%). Grade 3 and 4 toxicities associated with therapy were consistent with BVD-523 and other ERK inhibitors and included LFT elevation, hyponatremia, pruritis, amylase elevation, anemia and rash. The best response, per RECIST 1.1, was stable disease (SD) in 4 pts, and disease progression (PD) in 7 patients. Two patients were unevaluable for response due to withdrawing themselves from the study. Median time to progression was 2.0 months (90% CI: 1.8 – 3.6 mos.). There were eight deaths due to disease progression with a median survival time of 6.9 months (90%CI: 3.2 to 8.3 mos.). Analysis of correlative data from pre- and on-treatment biopsies exploring the change in expression of key signaling proteins relating to treatment is underway. Conclusions: ERK inhibition with ulixertinib (BVD-523) did not demonstrate activity in patients with metastatic uveal melanoma. The toxicities observed on study were consistent with what would be expected with MAPK pathway inhibition. Clinical trial information: NCT03417739.
Vismodegib (V) for organ preservation for locally advanced (LA) orbital/periocular basal cell carcinoma (BCC).
Authors: Worden Francis P. , Unsworth Shelby A , Andrews Chris A , Chan May , Bresler Scott , Bichakjian Christopher Keram , Durham Alison Bates , Demirci Hakan , Elner Victor , Nelson Christine , Kim Denise , Joseph Shannon , Swiecicki Paul , Kahana Alon
Published: May 2020

10069

Background: LA BCC of the eye/lacrimal drainage system most often requires disfiguring radical surgery, possibly including exenteration. As an alternative to radical surgery, we evaluated ophthalmologic outcomes following treatment with V using a novel Visual Assessment Weighted Score (VAWS) in patients (pts) with locally advanced periocular BCC. Methods: In this open label, non-randomized trial, pts with globe- and lacrimal-threatening orbital/periocular BCC were scored with VAWS prior to treatment with 150 mg of V daily. Pts were evaluated by ophthalmic exam (OE) every 3 mo & with MRI/CT at 5-9 mo. Pts with progressive disease (PD) were offered salvage surgery. Tumor response was assessed by RECIST v1.1. Responders (CR, PR, SD) continued V if tolerating therapy. Pts with intolerable side effects stopped V & were offered surgery of their residual tumor. Post-surgical specimens were assessed for histologic presence of BCC by a dermatopathologist. The primary endpoint, maintenance of visual function, was evaluated by VAWS at final post treatment assessment (FPTA), 1 yr after the start of V or 2 mo post-surgery. A VAWS of 21/50 was considered successful, representing preservation of a functional eye. Results: 50 pts were planned for enrollment, but the study was stopped early for benefit. From 06/25/2015 to 05/16/2019, 35 pts signed consent; 1 was a screen failure; 34 (97%) received V & 35 were evaluable for analysis by ITT; 1 died from aspiration pneumonia. The median time on study was 261 days. Average treatment with V was 223 days. 32 (91%) underwent OE & 27 (77%) had an MRI/CT. 27 (77%) underwent surgery & 33 (94%) attained organ preservation. Overall response rate (ORR) on OE was 84% (0%-PD,6%-SD,29%-PR,54%-CR, 11% not assessed(NA)). ORR by MRI/CT was 72% (0%-PD,6%-SD, 26%-PR,46%-CR,22% NA). 31 (89%) were scored with VAWS at 3 mo & 30 (86%) at FPTA. The mean VAWS at baseline was 44/50, 46/50 at 3 mo, & 47/50 at FPTA. Of the 35 pts scored at baseline by VAWS, 1 (3%) had a major decline during follow up, 5 (14%) a minor decline, 27 (77%) stable/improved, & 2 (6%) NA. No pts experienced grade 3-5 events. Of the 27 post-surgical pathologic specimens evaluated for histological response, 67% had NED, 22% had clear margins, & 11% had BCC to the margin. Two pts have recurred & underwent Mohs surgery. Conclusions: Treatment with V led to organ preservation for pts with LA periocular BCC, with preservation of visual function. Vismodegib is practice changing as neoadjuvant therapy for LA BCC of the eye/lacrimal drainage system in which surgery would result in unacceptable morbidity. Clinical trial information: NCT02436408.
Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy.
Authors: Khan Shaheer , Lutzky Jose , Shoushtari Alexander Noor , Jeter Joanne M. , Chiuzan Cody , Sender Naomi , Blumberg Lauren Esther , Nesson Alexandra , Singh-Kandah Shahnaz V. , Hernandez Susana , Ambrosini Grazia , Surriga Oliver , Schwartz Gary K. , Carvajal Richard D.
Published: May 2020

10075

Background: Uveal melanomas (UM) measuring at least 12mm in base diameter with a class 2 signature as defined by gene expression profiling (DecisionDx-UM) are characterized by high metastatic risk, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk. The growth factor receptor Met is highly expressed in UM. We have previously shown that crizotinib, an inhibitor of Met, is an effective adjuvant therapy in preclinical models (Surriga et al, Mol Cancer Ther 2013). We therefore conducted a phase II study of adjuvant crizotinib in high-risk UM. Methods: Eligibility included: primary lesion ≥12mm in base diameter; class 2 by DecisionDx-UM testing; definitive therapy within 120 days before starting crizotinib; and, no evidence of metastatic disease. Patients (pts) received 12 four-week cycles of crizotinib (250 mg twice daily). Surveillance imaging (chest CT and MRI abdomen/pelvis) were performed q3 months. The primary endpoint was distant relapse-free survival (RFS). Secondary endpoints were overall survival (OS) and toxicity. We hypothesized that the addition of crizotinib would increase the 32 month RFS from 50% to 75% (α = 0.05; β = 0.11). Results: As of 1/31/2020, 34 pts had enrolled and received at least one dose of study drug with median age of 60 (range, 26-86); 41% female; and median ECOG PS 0 (range, 0-1). 2 pts could not be evaluated for the primary endpoint due to early withdrawal and loss to follow-up. The median time from primary treatment to crizotinib initiation was 60 days (range, 0-106). All pts experienced a treatment-related adverse event (AE) of any grade. 11/34 (32%) experienced a grade 3 or 4 AE, the most common being transaminase elevation (n = 8/11). 9 pts (28%) did not complete the full 48-week treatment course due to disease recurrence (n = 5) or toxicity (n = 4). An additional 5 pts required dose reduction due to hepatic toxicity or diarrhea. 15/32 evaluable pts developed distant disease relapse, with 14 developing relapse within 32 months. With a median duration of follow up of 28.7 months, the median RFS was 30.6 months (95% CI: 27.8-58.5%). The median OS was not reached. Conclusions: The use of adjuvant crizotinib in patients with high-risk UM did not reduce rates of relapse in this multicenter, single arm trial. 9/32 (28%) pts required dose modification or discontinuation due to AE which may have limited efficacy. Further investigations of adjuvant treatment options are warranted. Clinical trial information: NCT02223819.
Randomized trial of a collaborative palliative and oncology care intervention to improve communication about end-of-life care in patients with metastatic breast cancer.
Authors: Temel Jennifer S. , Moy Beverly , El-Jawahri Areej , Jackson Vicki A. , Kamdar Mihir , Jacobsen Juliet , Lindvall Charlotta , Shin Jennifer Adrienne , Rinaldi Simone , Carlson Heather , Sousa Angela , Gallagher Emily J. , Moran Samantha , Ruddy Margaret , Anand Maya , Carp Julia , Greer Joseph A.
Published: May 2020

1008

Background: Studies have demonstrated the benefits of early, integrated palliative care in improving quality of life (QOL) and end-of-life (EOL) care for patients with poor prognosis cancers. However, the optimal timing and outcomes of delivering palliative care for those with advanced cancers that have longer disease trajectories, such as metastatic breast cancer (MBC), remains unknown. We tested the effect of a collaborative palliative and oncology care model on communication about EOL care in patients with MBC. Methods: Patients with MBC and clinical indicators of poor prognosis (N=120) were randomized to receive collaborative palliative and oncology care or usual care between 05/02/2016 and 12/26/2018. The intervention entailed five structured palliative care visits, including a joint visit with oncology when possible, which focused on symptom management, coping, prognostic awareness, decision-making, and planning for EOL. The primary outcome was documentation of EOL care discussions in the electronic health record. Patients also completed questionnaires at baseline and 6, 12, 18, and 24 weeks regarding communication with clinicians about EOL care, QOL, and mood symptoms. Results: The sample included only women (100.0%) who mostly identified as white (87.5%), with a mean age of 56.91 years (SD=11.24). The rate of EOL care discussions documented in the health record was higher among intervention patients versus those receiving usual care (67.2% vs 40.7%, p=0.006), including a higher completion rate of a Medical Orders for Life Sustaining Treatment form (39.3% vs 13.6%, p=0.002). Intervention patients were also more likely to report discussing their EOL care wishes with their doctor compared to usual care patients (OR=3.10, 95% CI: 1.21, 7.94, p=0.019). Study groups did not differ in reported QOL or mood symptoms. Conclusions: This novel collaborative palliative care intervention significantly improved communication and documentation regarding EOL care for women with MBC. Further work is needed to examine the effect of this care model on healthcare utilization at the end of life.
Prognostic impact of ESR1 mutations in ER+ HER2- MBC patients prior treated with first line AI and palbociclib: An exploratory analysis of the PADA-1 trial.
Authors: Bidard Francois Clement , Callens Celine , Dalenc Florence , Pistilli Barbara , De La Motte Rouge Thibault , Clatot Florian , D'hondt Veronique , Teixeira Luis , Vegas Helene , Everhard Sibille , Lemonnier Jerome , Bieche Ivan , Pradines Anne , Paitel Jean FranCois , Spaeth Dominique , Moullet Isabelle , Pierga Jean-Yves , Berger Frederique , Hardy-Bessard Anne-Claire , Bachelot Thomas
Published: May 2020

1010

Background: The question of which is the best endocrine partner to CDK4/6 inhibitors in first line for ER+ HER2- metastatic breast cancer (MBC) remains open. ESR1 mutations might be of paramount importance, as they confer resistance to AI but not to SERD. In pts treated with first line palbociclib-AI combination (PADA-1 trial, NCT03079011), we investigated ESR1mut detection rate at inclusion, prior to any therapy, and their prognostic impact. Methods: The PADA-1 phase 3 trial (NCT03079011, UCBG-GINECO) evaluates the utility of monitoring the onset of ESR1mut in cell-free DNA (with a ddPCR assay [Jeannot et al, Oncogene 2020]) of pts receiving AI-palbociclib in first line. Included pts had no prior therapy for MBC and no overt resistance to AI. Results: N = 1017 ER+ HER2- MBC pts were included in 22 months from 04/2017 and had their cfDNA tested for ESR1mut at inclusion and during therapy. N = 33/1017 pts had a detectable circulating ESR1mut at inclusion (3.2%, 95%CI [2.2;4.5]), ESR1mut positivity being associated with a prior exposure to AI in the adjuvant setting (p < 0.01). N = 1 pt died after 1 month on treatment. In N = 25/32 evaluable pts (78%), ESR1mut became undetectable in cfDNA (AF < 0.1%) within the first 5 months on treatment, with a median time to ESR1mut ‘clearance’ of 34 days. Among these 25 pts, 14 pts (56%) had ESR1mut detected again during therapy; 2 pts (8%) experienced a progression with no ESR1mut detected; the remaining 9 patients (36%) were still both ESR1mut -free and progression-free at time of analysis. With a median FU time of 12.4 months (range: 0-25.3m) under AI-palbociclib, the 33 ESR1mut-positive pts had a shorter PFS (median: 17.5mo, 95%CI[10.5-NR]) than the 984 ESR1mut-negative pts (median not reached), with an estimated HR = 2.8 [1.6;5.0]. Updated data will be presented at the meeting. Conclusions: ESR1mut are rarely detected in the cfDNA of ER+ HER2- MBC patients with no overt resistance to AI. The quick ‘clearance’ of ESR1mut under treatment and the observed 17.5 months-long median PFS both suggest that the AI-palbociclib combination retain a clinical activity in this population. ESR1mut-positivity prior was however associated with a significantly shorter PFS, suggesting that ESR1mut positivity at baseline could accelerate the onset of resistance to AI-palbociclib. These findings may put into perspective the incoming results of the PARSIFAL trial. Clinical trial information: NCT03079011 .
Results of ENCORE 602 (TRIO025), a phase II, randomized, placebo-controlled, double-blinded, multicenter study of atezolizumab with or without entinostat in patients with advanced triple-negative breast cancer (aTNBC).
Authors: O'Shaughnessy Joyce , Moroose Rebecca L. , Babu Sunil , Baramidze Kakhaber , Chan David , Leitner Stuart P. , Nemsadze Gia , Ordentlich Peter , Quaranto Christine , Meyers Michael L. , González Graf Valeria , Smith Taunya J. , Bee-Munteanu Valerie , Fresco Rodrigo , Slamon Dennis J.
Published: May 2020

1014

Background: Chemotherapy remains as the only standard treatment option for aTNBC in second and subsequent lines. Entinostat (ENT) is an oral, class I-selective histone deacetylase inhibitor, that has shown antitumor activity in preclinical models of TNBC when combined with immune checkpoint blockade. ENCORE 602 evaluated the efficacy and safety of atezolizumab (ATEZO) + ENT vs ATEZO + placebo (P) in patients (pts.) with pretreated aTNBC. Methods: Pts. with previously treated aTNBC (PD-1/PD-L1 inhibitors naïve) were randomized 1:1 to receive ATEZO (1200 mg IV Q3W) + ENT (5 mg PO QW) or ATEZO+P. Treatment continued until unequivocal progressive disease or unacceptable toxicity. The primary endpoint was PFS as determined by the investigators using RECIST 1.1. The hypothesis was that the combination would improve median PFS by 3 months (hazard ratio = 0.57). Sixty events (from 70 pts.) would provide 80% power with 1-sided significance level of 0.1. Secondary endpoints were PFS per immune-related RECIST (irRECIST), ORR, clinical benefit rate (CBR), Overall Survival (OS), and safety. Results: 81 pts. were enrolled, median age 56 years (range 29-87), 69% received 1 prior line of therapy and 31% > 1 line. No significant difference in PFS per RECIST 1.1 was observed between ATEZO+ENT and ATEZO+P (median PFS 1.68 and 1.51 months, respectively [p = 0.64; HR 0.89, 95% CI: 0.53-1.48]), nor in any of the secondary efficacy endpoints (median PFS per irRECIST 1.68 vs 1.54 months; ORR 10.0% vs 2.4%; CBR 37.5% vs 31.7%; median OS 9.8 vs 12.4 months, respectively). Frequency of treatment-emergent adverse events (TEAEs), SAEs, discontinuations due to TEAE and TEAE with outcome death were higher in the ENT+ATEZO arm. Conclusions: In pts. with previously treated aTNBC, median PFS was not prolonged when ENT was added to ATEZO compared to ATEZO and placebo, and the combination resulted in greater toxicity. Clinical trial information: NCT02708680 .
International retrospective cohort study of locoregional and systemic therapy in oligometastatic breast cancer (OLIGO-BC1).
Authors: Ueno Takayuki , Bi XiWen , Liu Guangyu , Sim Sung Hoon , Im Seock-Ah , Takao Shintaro , Wang Kun , Im Young-Hyuck , Futamura Manabu , Ahn Sung Gwe , Lee Jeong Eon , Park Yeon Hee , Toi Masakazu , Fujiwara Yasuhiro , Saito-Oba Mari , Kitagawa Yuko , Nishiyama Masahiko , Imoto Shigeru
Published: May 2020

1025

Background: Systemic therapy is the standard care in metastatic breast cancer (BC). However, retrospective studies demonstrated survival benefits of locoregional and systemic (combination) therapy in oligometastatic BC. To clarify it, the Federation of Asian Clinical Oncology conducted an international retrospective cohort study (OLIGO-BC1) (UMIN No.000030047). Methods: Oligometastatic BC patients diagnosed from 2007 to 2012 were registered. “Oligometastases” is defined as low volume metastatic disease with limited number and size of metastatic lesions up to five and not necessarily in the same organ by the ABC guidelines. Overall survival (OS) from the diagnosis of oligometastases was the primary endpoint and compared between combination and systemic therapy using a log-rank test. Assuming the 5-year OS of 50% and 40%, respectively, 698 patients were required to achieve 80% power to detect the superiority of combination therapy, at a two-sided significance level. A multivariable Cox regression model with stratification by country was performed to estimate hazard ratio (HR) for therapy and other risk factors. Results: While 1,262 cases had been registered from February 2018 to May 2019, 1,200 remained for analysis after exclusion of unavailable cases. Among them, 573, 529 and 98 cases were registered from China, Japan and Korea, respectively. Luminal BC was recorded in 526 cases (44%), luminal-HER2 BC in 189 (16%), HER2 BC in 154 (13%), triple-negative BC in 166 (14%) and others in 165 (13%). One oligometastatic BC was found in 578 cases, 2 in 289, 3 in 154, 4 in 102 and 5 in 77. Bone metastases were recorded in 301 cases, visceral metastases in 387, locoregional recurrence in 25, local recurrence in 83 and multiple metastatic sites in 404. Combination therapy was performed in 595 cases and systemic therapy in 404. At median follow-up of 4.9 years, 5-year OS was 59.6% and 41.9%, respectively (p < 0.01). An adjusted HR was 0.61 (95% CI: 0.51, 0.74). Type of systemic therapy, younger age, ECOG performance status 0, stage I BC, non-triple negative subtype, fewer metastatic sites, local recurrence and longer disease-free interval were significantly favorable prognostic factors. Discussions: Oligometastatic BC under some conditions seems to be curable. Taken together with recent molecular targeted therapy, locoregional therapy will be advantageous to conquer it. Conclusions: Combination therapy is a promising strategy for patients with oligometastatic BC.
Circulating tumor DNA (ctDNA) to evaluate stage III and stage IV metastatic breast cancer (MBC), describe tumor heterogeneity, and outcome.
Authors: Zhang Qiang , Cai Zheng , Gerratana Lorenzo , Davis Andrew A. , Jacob Saya , D’Amico Paolo , Vagia Elena , Zhang Youbin , Qiang Wenan , Wehbe Firas , Kerby Katy Lucretia , Flaum Lisa E. , Shah Ami N. , Behdad Amir , Gradishar William John , Platanias Leonidas C. , Cristofanilli Massimo
Published: May 2020

1028

Background: MBC is a challenging clinical condition treated with palliative intent due to tumor heterogeneity. We reported in 2019 ASCO that the correlation of HER2 and ESR1 mutations of ctDNA with CTCs results in worse prognosis in MBC. Here we reported that ctDNA mutations is a key point which is different between Stage III and Stage IV, and it would be helpful to evaluate the MBC metastasis and outcome. Methods: This study included 33 Stage III and 204 Stage IV MBC patients who received systemic treatments at NMH (2016-2019). Plasma ctDNA before treatment was isolated from patients and then was analyzed by Guardant 360 Health NGS-based assay for a 73 genes panel for genomic alterations including single nucleotide variants, insertions/deletions, gene fusions/rearrangements and copy number variations. Causal Inference with Ensembel Learning was used for statistical analyses. Results: Among stage III patients, 40% are luminal, 44% are HER2+ and 16% are TNBC, while in stage IV 50% patients are luminal, 20% are HER2+ and 30% are TNBC. The major differences in ctDNA between two stages lie in several genes including PIK3CA, ERBB2 and KRAS. On the top of the list is PIK3CA, which is detected in 2 out of 33 stage III patients (1 luminal, 1 HER2+) (6.06%) in baseline, each of them carries 1 mutation on PIK3CA (E542K, E545G). In 43 out of 204 stage IV patients (21.57%) who carry this gene, 15 show 1 amplification, 34 have 1 mutation (mainly H1047R, E542K, E545K and H1047L), 11 have 2 mutations (E542K/E726K, D454N/D1029N, E545K/D1017H, E545K/L287L, H1047R/E453K, H1047R/N426S and P539R/H1047R), and 1 has 3 mutations (E542Q/D454N/D1029N and E545K/E726K/R93Q). On treatment effects, PIK3CA is found to be very detrimental on prognosis and on its effects on the treatment outcome. Patients without any mutation in PIK3CA live 2.65 times longer than those with more than one mutations on PIK3CA ( p-value = 4.47e-06, CI = [1.731, 3.926]). PIK3CA, ESR1, TP53 and ARID1A are found to significantly affect liver metastasis when RET, FBXW7, ERBB2, CCND2, BRAF and MET are found to be associated with lung metastasis for both stages. EGFR, KIT and ARID1A are associated with CNS metastasis. Conclusions: We elucidated that ctDNA mutations on PIK3CA and other genes dramatically increased in Stage IV patients compared to Stage III patients which provides a new insight on the Stage III and Stage IV MBC determination. New set of genes especially PIK3CA are identified to correlate with metastasis and affect the outcome which may also be reliably used to monitor the response to therapy.
Detection of actionable gene mutations in breast cancer by amplicon-based next-generation sequencing liquid biopsy.
Authors: Lim Jing Shan , Choudhury Yukti , Phyo Wai Min , Gupta Chaitanya , Ho Yiliang , Tay Carina , Sim Yuki , Ng Wei Shuen , Tan Min-Han , Tsang Janice , See Hui Ti
Published: May 2020

1035

Background: The PI3K-inhibitor, alpelisib, was approved for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancers with PIK3CA mutations based on findings from the SOLAR-1 trial. PIK3CA-positivity in tumor tissue was 29% (341/1172), but was only 15% (177/1172) in plasma cell-free DNA (cfDNA). The lower mutation detection rate observed in cfDNA may limit the clinical application of liquid biopsy in breast cancer. Amplicon-based next-generation sequencing (NGS) approach may confer improved sensitivity, allowing more effective profiling. We conducted a study to evaluate the use of this technology. Methods: Plasma cfDNA from 113 breast cancer patients (82.3% metastatic) underwent real-world testing in a CAP and ISO15189 accredited central laboratory. We analysed genetic alterations in cfDNA using an amplicon-based NGS technology. The presence of PIK3CA and other mutations relevant to breast cancer were correlated to molecular subtypes and treatment histories. Results: At least one mutation was detected in 70.8% of cases. Mutations were more frequent in metastatic cases (77.4%) compared to non-metastatic cases (27.3%). Across all patients, mutations in PIK3CA (33.6%), TP53 (32.7%), ESR1 (22.1%), GATA3 (7.1%) and ERBB2 (7.1%) were most frequently detected, in accordance with tumor tissue genotyping studies. PIK3CA mutations were more common in HR+ HER2- patients (44.4% vs 28.6% of other patients). Among PIK3CA-mutant cases, multiple PIK3CA mutations were present in 18.4% of cases, and hotspot mutations H1047R (34.2%), E542K (26.3%) and E545K (15.8%) were most frequent. An association was seen between PIK3CA mutation and prior treatment with CDK4/6 inhibitors (palbociclib, ribociclib) or mTOR inhibitor (everolimus), with 58% of PIK3CA-mutant cases having received these treatment previously compared to only 20% of PIK3CA-wild type (wt) cases. In addition, 75% of previously treated ESR1-mutant cases had specifically received hormonal treatment, compared to 60 % of ESR1-wt cases that received any treatment. Conclusions: We report similar PIK3CA mutation frequencies (~30%) with amplicon-based NGS on cfDNA compared to tumor tissue testing in breast cancer. Importantly, other driver mutations were also observed at similar frequencies as external tissue studies, implying high sensitivity as the primary reason for performance. This supports the clinical utility of an amplicon-based NGS-based approach to liquid biopsy for the sensitive detection of actionable mutations in breast cancer.
A phase Ib study of pembrolizumab (pembro) plus trastuzumab emtansine (T-DM1) for metastatic HER2+ breast cancer (MBC).
Authors: Waks Adrienne Gropper , Keenan Tanya , Li Tianyu , Tayob Nabihah , Wulf Gerburg M. , Richardson Edward T. , Mittendorf Elizabeth A. , Overmoyer Beth , Krop Ian E. , Winer Eric P. , Van Allen Eliezer Mendel , Agudo Judith , Tolaney Sara M.
Published: May 2020

1046

Background: Preclinical evidence suggests treatment (tx) with T-DM1 plus an anti-PD1 antibody triggers antitumor immunity. We conducted a phase 1 trial to determine the safety and explore the efficacy of T-DM1 plus pembro. Methods: Eligible patients (pts) had MBC previously treated with trastuzumab (H) and taxane (T), were T-DM1-naïve, and received >1 prior line of tx for MBC or developed recurrence within 6 months (mo) of adjuvant tx. A dose de-escalation (esc) design was used with 6 pts in the dose-finding cohort, followed by an expansion (exp) cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies (bx). The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR), progression-free survival (PFS), and clinical benefit rate (CBR: complete response + partial response + stable disease >24 weeks). Associations between immune biomarkers and tx response were explored. Results: 20 pts started protocol tx (6 in dose de-esc cohort; 14 in exp cohort). Median follow-up was 23.5 mo. Pts had median age 54 yrs and median 1 line of prior MBC tx (range 0-2); 100% had received prior T, H, and pertuzumab. There were no dose-limiting toxicities in the dose de-esc cohort; thus full doses of T-DM1 (3.6 mg/kg q21 days) and pembro (200 mg q21 days) were the RP2D. 85% of pts experienced tx-related adverse events (AEs) > grade (gr) 1; 20% of pts experienced gr3 AEs. There were no gr>4 AEs. Gr3 AEs were fatigue; AST increase; ALT increase; pneumonia; pneumonitis; oral mucositis; and vomiting, each in 1 pt. 17 pts had baseline bx; 6 pts had repeat bx after 1 tx cycle. Efficacy results, overall and by PD-L1 Combined Positive Score (CPS; 22C3 staining) and tumor-infiltrating lymphocyte (TIL) status, are shown in the table. Tumors’ antigen presentation will be explored through HLA/dendritic cell marker staining and immune signatures by RNA sequencing. Conclusions: T-DM1 plus pembro was safe and tolerable. The regimen demonstrated clinical activity. Further exploration of immune-related predictive biomarkers is warranted. Clinical trial information: NCT03032107 . [Table: see text]
Utility of circulating cell-free DNA (cfDNA) analysis in patients with carcinoma of unknown primary (CUP) in identifying alterations with strong evidence for response or resistance to targeted therapy.
Authors: Weipert Caroline , Kato Shumei , Saam Jennifer , Kurzrock Razelle
Published: May 2020

105

Background: CUP is a rare, heterogeneous group of cancers with an overall poor prognosis; the standard treatment remains chemotherapy. The OncoKB database is a curated list of somatic molecular alterations. Alterations with the highest classification must be an FDA-recognized biomarker associated with response to an FDA-approved drug (Level 1), be recommended by major guidelines or expert panels as predictive of response to an FDA-approved drug (Level 2) or be predictive of resistance to an FDA-approved drug (R1). We explored the landscape of alterations classified as Level 1, 2 or R1 based on the OncoKB scale in a large cohort of CUP patients tested via a well-validated cfDNA assay. Methods: We queried consecutive samples from advanced cancer patients with a listed diagnosis of CUP who underwent testing via a commercially available liquid biopsy assay (Guardant360) between November 2016 and November 2019. The cfDNA assay included targeted next-generation sequencing of 73- to 74-genes specifically curated to include genes with potential targeted therapy options. Alterations were classified based on their ranking in the OncoKB database as of January 2020. Results: In total we identified 2,022 samples with a diagnosis of CUP, and 90.0% of these samples had >1 cfDNA alteration detected. The median age of patients was 68 years and 51% were female. Overall, 20.7% of patients had a Level 1 alteration, 9.5% had a Level 2 alteration, and 23.9% had an R1 alteration (select alterations outlined in Table). Conclusions: cfDNA analysis of patients with advanced CUP identified a significant number of patients with alterations associated with strong evidence for either response or resistance to treatment based on the OncoKB classification schema. While many of these alterations are associated with approvals in specific cancer types, the identification of these alterations suggests many CUP patients may have targeted therapy options. We will present case examples illustrating patient outcomes from CUP patients who received targeting therapy based on cfDNA results. [Table: see text]