bluuebunny/crossref_metadata_2025 huggingface dataset:
ALTERNATE: Neoadjuvant endocrine treatment (NET) approaches for clinical stage II or III estrogen receptor-positive HER2-negative breast cancer (ER+ HER2- BC) in postmenopausal (PM) women: Alliance A011106.
Authors: Ma Cynthia X. , Suman Vera J. , Leitch A. Marilyn , Sanati Souzan , Vij Kiran R. , Unzeitig Gary Walter , Hoog Jeremy , Watson Mark , Hahn Olwen Mary , Guenther J. Michael , Caudle Abigail Suzanne , Dockter Travis , Korde Larissa A. , Weiss Anna , Hunt Kelly , Hudis Clifford A. , Winer Eric P. , Partridge Ann H. , Carey Lisa A. , Ellis Matthew James ,   Alliance
Published: May 2020

504

Background: For PM patients (pts) with locally advanced ER+ HER2- BC, NET improves breast conservation surgery (BCS) rates, and modified preoperative endocrine prognostic index (mPEPI) 0, defined as pT1-2 pN0 Ki67< 2.7%, or pathologic complete response (pCR: no invasive disease in breast or lymph node) is associated with low risk of recurrence without adjuvant chemotherapy (CT). The ALTERNATE trial was initiated to assess if the endocrine-sensitive disease rate (ESDR: number of mPEPI 0 pts/number of eligible pts initiating NET) with fulvestrant (F) or F+anastrozole (A) is improved relative to A alone (reported here) and if the 5-year (yr) recurrence-free survival (RFS) rate for pts with mPEPI 0 on A alone without CT is ≥ 95% (awaits further follow-up). Methods: PM pts with clinical stage II/III ER+ HER2- BC were randomized 1:1:1 to 1 mg A po daily, 500 mg F IM every 4 week (wk)s after loading dose, or A+F for 6 months. Ki67 was tested centrally on biopsies acquired prior to NET, wk 4, wk 12 and at surgery. Pts with Ki67 >10% at wk 4 or 12 were recommended to go off protocol-directed ET and switch to CT. Pts with mPEPI 0 at surgery were recommended to continue assigned ET for 1.5 yrs followed by A for a total of 5 yrs ET (and not to receive CT). The primary endpoint of the neoadjuvant phase was ESDR. ESDR of each F arm was compared to that of the A alone arm. With 425 pts per arm, a one-tailed alpha = 0.025 chi-square test of two independent proportions has 84% power to detect an increase of ≥10% in ESDR for F or F+A compared to the A arm, assuming ESDR ≤30% in A. Results: 1362 pts (A 452; F 454; A+F 456) were enrolled Feb 2014 to Nov 2018. 63 pts were excluded (did not start NET). Of the remaining 1299 pts (A 434; F 431, A+F 434), 42% were cN1-3 and 73% were considered candidates for BCS. ESDR was 18.6% (95%CI: 15.1-22.7%) with A, 22.7% (95%CI: 18.9-27.0%) with F, and 20.5% (95%CI: 16.8-24.6%) with A+F. No significant difference in ESDR was found between A and F (p=0.15) or A and A+F (p=0.55). Among the 825 pts with wk 4 Ki67 < 10% who completed NET and surgery, ESDR and the BCS rate were 27.7% and 70.3% with A; 29.6% and 68.1% with F, and 26.8% and 69.9% with A+F, respectively. Conclusion: Neither F nor F+A significantly improved ESDR compared to A alone in PM pts with locally advanced ER+ HER2- BC. RFS data are awaited. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org ; NCI BIQSFP, BCRF, Genentech, AstraZeneca. Clinical trial information: NCT01953588 .
Study EV-103: Durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma.
Authors: Rosenberg Jonathan E. , Flaig Thomas W. , Friedlander Terence W. , Milowsky Matthew I. , Srinivas Sandy , Petrylak Daniel Peter , Merchan Jaime R. , Bilen Mehmet Asim , Carret Anne-Sophie , Yuan Nancy , Sasse Carolyn , Hoimes Christopher J.
Published: May 2020

5044

Background: Platinum chemotherapy is the standard for patients (pts) with metastatic urothelial carcinoma (mUC) in the first line (1L) setting. PD-1/PD-L1 inhibitors, such as pembrolizumab (P), have shown promising durability in this setting for PD-L1 high patients. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent MMAE to cells expressing Nectin-4, which is highly expressed in UC. EV recently received FDA accelerated approval based on tumor response rates for adults with locally advanced or mUC who have previously received a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy. EV is investigational in the 1L setting. Initial EV + P data were previously presented (Hoimes ESMO 2019); this provides durability data and an update on safety/ORR. Methods: This multicohort study (NCT03288545) evaluated the safety/activity of EV + P. We report a cohort of 1L cisplatin-ineligible patients treated with EV 1.25 mg/kg + P. In each 3-week cycle, EV was administered on Days 1 and 8 and P on Day 1. The primary endpoint was safety/tolerability; secondary objectives included determination of recommended EV dose, ORR, DCR, DOR/PFS per RECIST v1.1, and OS. Results: As of 8 Oct 2019, 45 1L or previously untreated mUC pts (median age 69 yr [51–90]) received a median of 9 (range 1-22) cycles of EV + P. The most common treatment-emergent adverse events (AE) were fatigue (58%, 11% ≥G3), alopecia (53%), and peripheral sensory neuropathy (53%, 4% ≥G3). One pt died due to an AE reported as related (multiple organ failure). With a median follow-up of 11.5 mo, confirmed investigator-assessed ORR was 73.3% (95% CI, 58.1, 85.4) including 15.6% CRs; DCR was 93.3%. The ORR in pts with liver metastasis was 53.3% (8/15). The ORR in pts with available PD-L1 status was 78.6% in PD-L1 high (11/14) and 63.2% in PD-L1 low (12/19). Of the 33 responders, 18 (55%) have ongoing responses including 11 responses beyond 10 months. The median DOR was not reached (range 1.2 to 12.9+ mo); the 12-month DOR rate was 53.7% (95% CI, 27.4, 74.1). The median PFS was 12.3 mo (95% CI, 7.98, -); the 12-month PFS rate was 50.1% (95% CI, 33.0, 65.0). The median OS was not reached (range 0.66 to 19.2+ mo); the 12-month OS rate was 81.6% (95% CI, 62.0, 91.8). Conclusions: In 1L cisplatin-ineligible pts with mUC, EV + P, a potential platinum free option, demonstrates promising activity and durability, with a manageable safety profile. Further evaluation of EV + P in mUC and muscle-invasive UC is ongoing. Clinical trial information: NCT03288545 .
Letrozole + ribociclib versus letrozole + placebo as neoadjuvant therapy for ER+ breast cancer (FELINE trial).
Authors: Khan Qamar J. , O'Dea Anne , Bardia Aditya , Kalinsky Kevin , Wisinski Kari Braun , O'Regan Ruth , Yuan Yuan , Ma Cynthia X. , Jahanzeb Mohammad , Trivedi Meghna S. , Spring Laura , Makhoul Issam , Wagner Jamie L. , Winblad Onalisa , Amin Amanda Leigh , Blau Sibel , Crane Gregory James , Elia Manana , Hard Mia , Sharma Priyanka
Published: May 2020

505

Background: Ribociclib (R) + letrozole (L) is superior to L in metastatic breast cancer (BC). Preoperative endocrine prognostic index (PEPI) score 0 after neoadjuvant endocrine therapy (NET) is associated with low risk of relapse without chemotherapy in ER+ BC. On-therapy change in Ki-67 predicts adjuvant recurrence. FELINE is a biomarker-based multicenter randomized trial comparing changes in Ki-67 and PEPI between L+ Placebo (P) & L+R. Methods: Postmenopausal women with >2 cm or node+ ER+ HER2- BC were randomized 1:1:1 between L+P, L+R 400 mg continuous dose (Rc) and L+R 600 mg, 3 weeks on/1 week off - intermittent dose (Ri). Treatment was continued for six 28-day cycles. Core biopsies, blood samples were obtained at baseline, Day 14 cycle 1 (D14C1), and surgery. Clinical measurement, mammogram and US were obtained at baseline, surgery; MRI at baseline, week 8. Primary endpoint was rate of PEPI score 0 between L+P and L+R (i+c combined). Other endpoints were change in centrally performed Ki-67, complete cell cycle arrest (CCCA): Ki-67 <2.7%, clinical/imaging response, and difference in response & toxicity between the two R (Rc and Ri) arms. Results: From 2/2016 to 8/2018, 120 women were enrolled at 9 US centers. Thirty-eight were randomized to L+P and 82 to L+R groups (41 in Ri and Rc). Treatment groups were balanced at baseline. PEPI score of 0 was equal (25%) in L+P & L+R groups. CCCA at D14C1 was observed in 52% vs. 92% in L+P, L+R respectively (p < 0.0001). CCCA at surgery was observed in 63.3% vs. 71.4% in L+P, L+R respectively (p = NS). A significant increase in Ki-67 was observed between D14C1 and surgery in 66% vs. 33% in L+R, L+P respectively (p = 0.006). There was no difference in clinical, mammographic, US or MRI response between L+P and L+R. CCCA at D14C1 and surgery was similar in Ri & Rc arms. Grade >3 AEs were observed in 4 (10%) patients in L+P, 23 (56%) in L+Ri, 19 (46%) in L+Rc arms. Conclusions: Addition of R to L as NET did not result in more women with a PEPI score of 0. At D14C1 twice as many women on L+R had CCCA compared to L+P (92% vs 52%). However, significantly more women on L+R had increased proliferation between D14C1 and surgery , resulting in similar CCCA at surgery. Correlative studies are being performed to determine mechanisms of on-therapy acquired resistance to ribociclib. Continuous and intermittent doses of R have similar efficacy, toxicity. Clinical trial information: NCT02712723 . [Table: see text]
Clinicogenomic predictors of extreme responses to anti-PD1/PDL1 checkpoint inhibitors (CPI) in metastatic urothelial cancer (mUC).
Authors: Teo Min Yuen , Whiting Karissa , Mota Jose Mauricio , Li Han , Regazzi Ashley Marie , Solit David B. , Aggen David Henry , Lee Chung-Han , Funt Samuel Aaron , Bajorin Dean F. , Ostrovnaya Irina , Iyer Gopa , Rosenberg Jonathan E.
Published: May 2020

5050

Background: Only a subset of mUC patients (pts) derives benefit from CPI. We sought to evaluate potential clinical and genomic predictors, with additional focus on extreme outcomes. Methods: CPI-treated mUC with tumor sequencing with MSK-IMPACT (up to 468 genes) were identified. Pre-CPI clinical variables (including hemoglobin [hgb], lymphocyte [lymph], neutrophil [neut] and eosinophil [eos] counts) were extracted. Endpoint was time on treatment (ToT). Poor responders were defined as ToT ≤9 weeks and overall survival ≤3 months; exceptional responders had ToT >20 months. A multivariate Cox model for ToT was performed with clinical variables chosen by stepwise selection minimizing Akaike information criterion. Genomic analyses were adjusted for multiple testing. Results: 166/171 identified mUC were evaluable. Median age was 68 years, 78% were male. 72% had bladder primary, while 17%, 35% and 28% had liver, lung and bone metastases (mets). 67% had prior platinum chemo. 24 pts (14%) were poor and exceptional responders, respectively. In univariate analysis, liver mets were associated with shorter ToT while DNA damage repair (DDR) gene alterations, higher body mass index (BMI), eos, hgb and tumor mutation burden (TMB) were associated with longer ToT. No specific genomic alterations achieved q<.05. In multivariate model, prior chemo (HR 1.6, p=.01), liver mets (HR 2.4, p<.01) and high neut were associated with shorter ToT while urethral primary (HR 0.1, p<.01), higher TMB (HR 0.9, p<.01) and higher eos (HR 0.1, p<.01) were independently associated with ToT. Univariate logistic regression to identify poor and exceptional responders are tabulated. Multivariate results will be reported. Conclusions: In addition to validation of various known mUC prognosticators, we observed potential non-linear influence of clinical and genomic factors on extreme outcomes. [Table: see text]
Model to predict brain metastasis (BM) in patients with metastatic germ-cell tumors (mGCT).
Authors: Ashkar Ryan , Althouse Sandra K. , Cary Clint , Masterson Timothy A. , Foster Richard , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: May 2020

5057

Background: BM is an independent adverse prognostic factor that can lead to treatment complications and failure in pts with mGCT. We aimed to establish an effective and practical model for prediction of BM in mGCT. Methods: 2,256 consecutive pts with mGCT treated at Indiana University between January 1990 and September 2017 were identified. Pts were divided into 2 categories: BM present (N = 144) and BM absent (N = 2112). Kaplan-Meier methods were used to analyze progression free survival (PFS) and overall survival (OS). Logistic regression was used to determine a predictive model for whether BM was present. The data was separated 50/50 into training and validation datasets with equal numbers of events in each. Results: Baseline characteristics for 2 groups are listed in Table. 2-yr PFS and OS for pts with vs without BM: 17% vs 66% (p < 0.001) and 62% vs 91% (p < 0.001) respectively. Among the 144 pts with BM, 64 (44%) had radiation only (whole-brain radiotherapy or gamma knife), 21 (15%) had BM-surgery only, 14 (10%) had both radiation and BM-surgery. 45 pts (31%) did not receive local therapy for BM. A stepwise selection was used to determine the best model with p < 0.15 as the entry and staying criteria. The model with the largest ROC AUC was used moving forward. The model was tested in the validation dataset. A model was generated including age at diagnosis≥40 (1 point), presence of pulmonary metastases (3 points), bone metastasis (1 point), pre-chemotherapy hCG≥5000 (1 point), and choriocarcinoma predominant histology (1 point). Patients with 0 points had a 0.4% probability of BM, 1 point: 1%, 2 points: 2.6%, 3 points: 7%, 4 points: 16%, 5 points: 32%, 6 points: 56%, and 7 points: 77%. Details regarding analysis in training and validation datasets will be presented. Conclusions: The prediction model developed in this study demonstrated discrimination capability of predicting BM occurrence and can be used by clinicians to identify high-risk pts. [Table: see text]
Olaparib as salvage treatment for advanced germ cell tumors after chemotherapy failure: Results of the open-label, single-arm, IGG-02 phase II trial.
Authors: De Giorgi Ugo , Schepisi Giuseppe , Gurioli Giorgia , Pisano Carmela , Basso Umberto , Lolli Cristian , Petracci Elisabetta , Casadei Chiara , Cecere Sabrina Chiara , Attademo Laura , Clemente Alberto , Zampiga Valentina , Galla Valentina , Cangini Ilaria , Di Napoli Marilena , Valmorri Linda , Pignata Sandro
Published: May 2020

5058

Background: Therapeutic options for patients with advanced germ cell tumors (GCTs) after multiple relapses or resistant disease are limited. Olaparib is an inhibitor of poly ADP ribose polymerase (PARP), an enzyme involved in DNA repair. We aimed to evaluate olaparib activity in patients with refractory GCT. Methods: In this proof-of principle open-label, single-arm, phase II trial of olaparib 300 mg twice daily in patients with relapsed/refractory metastatic germ cell cancer IGG-02 study (NCT02533765), patient eligibility included failure after high-dose chemotherapy or after at least 2 different cisplatin-based regimens. Measurements of serum tumor markers and computed tomography were carried out at baseline and every 6 weeks of olaparib treatment. The study primary endpoint was the overall response rate, the study planned to recruit initially 18 patients and not continue further recruitment until one or more responses were observed. Results: Between September 2015 and February 2019, 18 patients, median age 39 years (range, 22-61) were enrolled. The number of prior chemotherapy regimens was: 2 for 3 patients (16.7%), 3 for 5 patients (27.8%), >3 for 10 patients (55.6%). Sixteen cases (89.9%) received prior high-dose chemotherapy with support of hematopoietic progenitor cells. Grade 3-4 adverse events were observed in 5 patients (27.7%). There were no partial responses, 5 cases (27.8%) with stable disease (SD) lasting 3, 4, 4, 7 and 7+ months and 13 (72.2%) progressive disease. The 12-week progression-free survival probability was 27.8% [95% confidence interval (CI): 10.1%-48.9%]. The 12-month overall survival probability was 27.8% (95% CI: 10.1%-48.9%). A germline DNA repair profile panel showed only a BRCA1 mutated case associated with a SD lasted 4 months. Conclusions: Olaparib as a single agent has marginal activity in heavily pretreated GCT patients, however, an anecdotic 4-month SD in the only BRCA mutated patient has been reported. Plans for future studies with olaparib are suggested in combination or following salvage chemotherapy in less pretreated and more selected GCT patients. The Study has been conducted with AstraZeneca contribution. Clinical trial information: NCT02533765 .
MINDACT: Long-term results of the large prospective trial testing the 70-gene signature MammaPrint as guidance for adjuvant chemotherapy in breast cancer patients.
Authors: Cardoso Fatima , van 't Veer Laura , Poncet Coralie , Lopes Cardozo Josephine , Delaloge Suzette , Pierga Jean-Yves , Vuylsteke Peter , Brain Etienne , Viale Giuseppe , Kuemmel Sherko , Rubio Isabel T. , Zoppoli Gabriele , Thompson Alastair Mark , Matos Erika , Zaman Khalil , Hilbers Florentine , Dudek-Perić Aleksandra , Meulemans Bart , Piccart-Gebhart Martine J. , Rutgers Emiel J.
Published: May 2020

506

Background: The 70-gene signature MammaPrint has been shown to identify breast cancer patients for whom adjuvant chemotherapy (CT) could be safely omitted even in the presence of unfavorable standard clinical-pathological criteria. The MINDACT primary endpoint at 5 years median follow-up was met in 2016 (Cardoso et al, NEJM 2016) with a distant metastasis free survival (DMFS) rate at 5 years of 94.7% (95% CI: 92.5-96.2) in clinical high (C-High) / genomic low (G-Low) risk patients who received no CT. Longer follow-up is now available. Methods: 6693 patients were enrolled in the prospective phase III randomized MINDACT study (EORTC 10041/BIG3-04) between 2007-2011. We assessed the DMFS rate at 5 years in the primary test (PT) population of C-High / G-Low patients who were randomized to receive no CT (n = 644). As secondary analysis, we evaluated DMFS and overall survival (OS) in the intention to treat (ITT) population of the C-High / G-Low group randomized to CT vs no CT (n = 749 and 748 respectively). Comparisons between CT and no CT groups are low-powered. We used Kaplan-Meier estimates for time to event endpoints and hazard ratios (HR) with 95% CI from cox-regression models adjusted for stratification factors used for the randomization. Results: The median follow-up is 8.7 years, resulting in an updated 5-year DMFS rate for the PT population of C-High / G-Low patients with no CT of 95.1% (95% CI 93.1-96.6). The updated outcomes of the ITT population of C-High / G-Low patients are shown in the table. Further analyses will update the suggested age-dependent effect of CT omission for luminal breast cancer seen at 5 years in pre- versus post-menopausal women as in Tailor-X (Piccart et al, SABCS 2019). Conclusions: The primary DMFS endpoint at 5 years continues to be met in CT untreated C-High / G-Low risk women, confirming MINDACT as a positive de-escalation study. With longer follow-up and in line with the natural history of luminal breast cancer, more distant relapses do occur but the estimated gain of 2.6% for CT administration in C-High / G-Low patients remains small in light of CT harmful effects. The level IA evidence for the clinical utility of the 70-gene signature for adjuvant CT decision making is maintained. Clinical trial information: NCT00433589 . [Table: see text]
Association of neutrophil to lymphocyte ratio (NLR) with efficacy from JAVELIN Renal 101.
Authors: Bilen Mehmet Asim , Rini Brian I. , Motzer Robert J. , Larkin James M. G. , Haanen John B. A. G. , Albiges Laurence , Pagliaro Lance C. , Voog Eric , Lam Elaine Tat , Kislov Nikolai , McGregor Bradley Alexander , Huang Bo , di Pietro Alessandra , Krulewicz Stan , Choueiri Toni K.
Published: May 2020

5061

Background: The phase 3 JAVELIN Renal 101 trial (NCT02684006) in treatment-naive patients with advanced renal cell carcinoma (aRCC) demonstrated significantly improved progression-free survival (PFS; hazard ratio [HR], 0.69; 95% CI, 0.56, 0.84; P < 0.001) and higher objective response rate (ORR; 51.4% vs 25.7%) with avelumab + axitinib vs sunitinib (Motzer RJ, et al. N Engl J Med. 2019;380:1103-15). NLR has emerged as a potential prognostic biomarker in aRCC; elevated NLR is associated with poorer prognosis. Here, we describe the association of NLR with the efficacy of avelumab + axitinib from JAVELIN Renal 101. Methods: We examined baseline NLR and its association with efficacy outcomes. PFS, best overall response (per blinded independent central review using RECIST 1.1), and overall survival (OS) data from the avelumab + axitinib arm from the first interim analysis of JAVELIN Renal 101 were analyzed (data cutoff, June 20, 2018). Multivariate Cox regression analyses of PFS and OS were also conducted. Results: In the avelumab + axitinib arm, patients with < median NLR (N = 217) had longer observed PFS (stratified HR, 0.85; 95% CI, 0.634, 1.153) and longer observed OS (stratified HR, 0.51; 95% CI, 0.300, 0.871) than patients with ≥ median NLR (N = 217). The ORR was 57.1% in patients with < median NLR vs 47.5% in patients with ≥ median NLR, with complete response in 5.5% vs 1.4%. Multivariate analysis showed that low NLR was associated with longer PFS and OS by treating baseline NLR as either a continuous variable or a binary variable (dichotomized by median). Conclusions: Low NLR was associated with better observed treatment outcomes in patients with aRCC who received avelumab + axitinib. Clinical trial information: NCT02684006 .
A phase II multicenter study of stereotactic radiotherapy (SRT) for oligoprogression in metastatic renal cell cancer (mRCC) patients receiving tyrosine kinase inhibitor (TKI) therapy.
Authors: Cheung Patrick , Patel Samir , North Scott A. , Sahgal Arjun , Chu William , Soliman Hany , Ahmad Belal , Winquist Eric , Patenaude Francois , Niazi Tamim , Heng Daniel Yick Chin , Lim Gerald , Dubey Arbind , Czaykowski Piotr , Wong Rebecca , Swaminath Anand , Morgan Scott Carlyle , White Justin , Keshavarzi Sareh , Bjarnason Georg A.
Published: May 2020

5065

Background: SRT is increasingly considered to delay the need to change systemic therapy in metastatic cancer patients who develop oligoprogression. This prospective phase II study evaluated the use of SRT in the setting of mRCC patients who developed oligoprogression while on 1st or 2nd line TKI therapy. Methods: IMDC favourable or intermediate risk mRCC patients (pts) who had previous stability or response on ≥ 3 months of TKI therapy were eligible if they developed radiographic progression of ≤ 5 metastases. The oligoprogressive tumours were treated with SRT while other metastases which were stable or responding to TKI therapy were left alone. TKI therapy was temporarily stopped during SRT, and the same TKI drug then resumed. Endpoints included local control of the irradiated lesions, progression free survival (PFS), overall survival (OS), and cumulative incidence of changing systemic therapy after study entry. Results: 37 pts (median age 63, IMDC favourable 12, intermediate 25) with 57 oligoprogressive tumours were enrolled. 35 pts were on sunitinib and 2 on pazopanib. Median duration of TKI therapy prior to study entry was 18.6 months. 4 pts had IL-2 therapy prior to a 2nd line TKI. 21 pts had a solitary oligoprogressive tumour, while 17 pts had 2-3 oligoprogressive tumours treated with SRT. Median biological effective dose (BED10) was 72 Gy, corresponding to an SRT dose of 40 Gy in 5 fractions. Irradiated tumour sites were the following: 21 lung/pleural, 15 bone, 7 lymph node, 4 adrenal, 4 liver, 3 brain, 2 spleen, and 1 pancreas. At a median followup of 11.6 (1.8-53.5) months the median PFS from study entry was 9.6 months (95%CI 7.4-20.5) with the vast majority of progression occurring outside of the irradiated areas. The 2-year local control of the irradiated tumours was 96%. The 2-year OS from study entry was 77%. The cumulative incidence of changing systemic therapy was 47% at 1 year and 75% at 2 years, with a median time to a change in systemic therapy of 12.6 months. There were no grade 3-5 SRT related toxicities. Conclusions: To our knowledge, this is the first prospective evaluation of the use of SRT for oligoprogressive metastatic cancer. Local control of irradiated oligoprogressive mRCC tumours was high. After delivering SRT, mRCC patients did not need a change in their systemic therapy for a median of 1 year, effectively increasing the PFS of their TKI therapy. This novel approach should be studied in patients with oligoprogression on immunotherapy. Clinical trial information: NCT02019576 .
Outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first-line Immuno-oncology (IO) agents who do not meet eligibility criteria for clinical trials.
Authors: Gan Chun Loo , Dudani Shaan , Wells Connor , Bakouny Ziad , Dizman Nazli , Pal Sumanta K. , Szabados Bernadett , Wood Lori , Kollmannsberger Christian K. , Agarwal Neeraj , Donskov Frede , Basappa Naveen S. , Bjarnason Georg A. , Parnis Francis , Porta Camillo , Davis Ian D. , Vaishampayan Ulka N. , Kanesvaran Ravindran , Choueiri Toni K. , Heng Daniel Yick Chin
Published: May 2020

5070

Background: IO combination therapies [including IOIO and IO/vascular endothelial growth factor inhibitor (IOVE) combinations] in mRCC have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of trial ineligible patients who are treated with first-line IOIO or IOVE combinations are unknown. Methods: Metastatic RCC patients treated with first-line IOIO or IOVE were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria in IO trials) if they had a Karnofsky performance status (KPS) < 70%, no clear-cell component, brain metastases, hemoglobin (Hb) < 9 g/dL, eGFR < 40 mL/min, platelet count of < 100,000/mm3, and/or neutrophil count < 1500/mm3. Time to treatment failure (TTF) and overall survival (OS) were calculated from time of starting first-line IO therapy. Results: Overall, 26% (155/592) of patients in the International mRCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Baseline characteristics are listed in Table. The reasons for ineligibility were: no clear-cell component (34%, 53/155), Hb < 9g/dL (28%, 44/155), eGFR < 40 mL/min (19%, 30/155), brain metastases (19%, 29/155), KPS < 70% (14%, 21/155), platelet < 100,000/mm3 (3%, 4/155) and neutrophil count < 1500/mm3 (0%, 0/155). Between ineligible versus eligible patients, the response rate, median TTF and median OS of first-line IOIO or IOVE was 34% vs 46% (p = 0.02), 4.2 vs 9.7 months (p < 0.01), and 25.3 vs 44.4 months (p < 0.01), respectively. When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.50 (95% CI 1.05-2.14). Conclusions: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. These data may guide patient counselling and specific trials addressing the unmet needs of protocol ineligible patients are warranted. [Table: see text]
CT-based radiomic classifier of primary renal tumors to distinguish between metastatic and non-metastatic disease.
Authors: Kleeman Sam O , Grant Michael , Rallis Kathrine Sofia , Wozniak Anna , So Alfred , Tejpaul Resha , Heller Nicholas , Weight Christopher J. , Ordidge Katherine , Bex Axel , Sahdev Anju , Powles Thomas
Published: May 2020

5074

Background: Existing clinicopathological tools are unable to accurately identify renal cell carcinoma (RCC) patients who will develop metastases after surgery. As a result, it is unclear how long and how often to follow-up patients post-operatively. Tumor macropathology, as assayed by CT scanning, represents the sum product of tumor biology and microenvironment. We hypothesized that quantitative tumor features extracted from CT scans (termed radiomics) could discriminate between metastatic and non-metastatic RCCs. Methods: This retrospective study incorporated three cohorts of clear-cell RCC patients (n = 279, from TCGA, CPTAC and KiTS19 datasets) treated with nephrectomy. The study cohort was sub-divided into metastatic (n = 54, M1 at diagnosis or recurrence after surgery), high metastatic risk/HMR (n = 85, N1, T3-4, T2G3/4, T1G4) or low metastatic risk/LMR (n = 140, absence of these features) subsets. 3D primary tumor segmentation of arterial contrast CT scans was performed by trained investigators. Features were extracted using pyRadiomics 2.2.0 (n = 839) with gray value and voxel size normalization. For random forest (RF) model training, the cohort was randomly split into training (75%) and validation (25%) sets. Results: Multidimensional clustering of radiomic features by t-SNE analysis showed that metastatic and HMR tumors predominantly cluster together, while LMR tumors cluster separately. Consistent with this, there were no differentially regulated radiomic features (DR-features) between HMR and metastatic tumors. In contrast, we identified 26 DR-features (adjusted p-value < 0.05) between presumed-metastatic (n = 139, HMR and metastatic tumors) and LMR tumors, which were then used as input to a RF binary classifier. In the training set, the trained classifier discriminated between presumed-metastatic and LMR tumors with bootstrapped AUC = 0.81. In the validation set, the classifier discriminated subsets with AUC = 0.80. Conclusions: High-risk and metastatic tumors have similar radiomic properties, suggesting common biology driving metastasis in RCC. We propose a novel radiomic classifier that accurately distinguishes between presumed-metastatic and low-risk tumors. Further work will assess whether this tool can identify patients with micrometastatic disease at diagnosis, who may benefit from adjuvant therapy or closer, long-term surveillance.
Camrelizumab plus famitinib malate in patients with advanced renal cell cancer and unresectable urothelial carcinoma: A multicenter, open-label, single-arm, phase II trial.
Authors: Qu Yuan-Yuan , Guo Hongqian , Luo Hong , Zou Qing , Xing Ninazeng , Sun Zhongquan , Zhang Xuepei , Xia Shujie , He Chaohong , Zhang Hailiang , Cai Jinling , Zhang Xiao , Wang Quanren , Ye Dingwei
Published: May 2020

5085

Background: Camrelizumab (SHR-1210) is a humanised anti-PD-1 antibody. Famitinib malate is a tyrosine kinase inhibitor (TKI) against VEGFR-2, PDGFR, c-kit, and FGFR. This is an ongoing, open label, multi-center Phase II study to assess the preliminary efficacy and safety of camrelizumab in combination with famitinib malate in patients (pts) with genitourinary cancers and gynecologic cancers. Here we just report genitourinary cancers results. Methods: Eligible pts were aged 18 or older, who had advanced clear-cell renal-cell carcinoma with their primary tumour resected or unresectable urothelial carcinoma, had an ECOG performance status of 0-1and measurable disease. Previous system treatments were allowed (excluding prior PD-1/PD-L1 inhibitors or famitinib treatment). Famitinib 20 mg was administered orally once daily with SHR-1210 200 mg given intravenously every 3 weeks. We assessed antitumour activity and safety in all pts who received at least one dose treatment. The primary end point was objective response rate (ORR) per RECIST v1.1. Results: From 23 Jan 2019 to 24 Jun2019, 35 pts were enrolled (25 with RCC, 10 with UC). Median previous treatment line was 1 (range, 1-4), and 50.0% of pts had received ≥2 prior therapies in RCC, all pts received one or more-line therapies in UC. At the data cut-off date (Dec 31, 2019), after at least 6 months follow-up, 22 (63%) pts were still receiving study treatment. The most common reason for discontinuing treatments was disease progression (n = 10). 16 pts achieved a confirmed response, all were partial response, with 8 additional > 24 weeks stable disease. the ORR was 52.0% (13/25, 95% CI 31.3% to 72.2%) in RCC and 30.0% (3/10) in UC, the disease control rate was 84.0% (21/25) in RCC and 70.0% in UC. 13/16 confirmed PR pts were still on treatment, the median duration of response is not reached. The most common grade 3-4 treatment-related AEs (TRAEs) were hypertension (17.1%), proteinuria (11.4%), platelet count decreased (8.6%), hand-foot syndrome (8.6%) and anemia (5.7%). Immune-related adverse events were observed in 7 pts (20%) of 35 pts, 1 pt (2.9%) with grade 3 enteritis. Conclusions: The camrelizumab with famitinib combination appeared to show encouraging activity in pts with heavy-treated RCC and UC, and the safety profile of the combination seemed to be manageable and consistent with that of each drug alone. This combination represented a novel potential treatment option for these settings and warranted further investigation. Clinical trial information: NCT03827837 .
Tipifarnib, a farnesyltransferase inhibitor, for metastatic urothelial carcinoma harboring HRAS mutations.
Authors: Lee Jiyun , Kim Hana , Gualberto Antonio , Scholz Catherine Rose , Park Se Hoon
Published: May 2020

5086

Background: Tipifarnib is a farnesyltransferase inhibitor known to block RAS signaling and attenuate cancer cell proliferation. We tested the activity and safety of tipifarnib in patients with previously treated urothelial carcinoma (UC) carrying HRAS mutations. Methods: In a prospective phase II clinical trial, genetic screening was performed in 224 UC patients; those with missense HRAS mutations or STK11:rs2075606 received study treatment. Eligible patients received oral tipifarnib 900 mg twice daily on days 1–7 and 15–21 of 28-d treatment cycles. The primary endpoint was progression-free survival at 6 mo (PFS6). With two-stage design, at least 18 patients were required. Results: Among the 224 patients screened, we found 16 (7%) missense HRAS mutations (G13R, 7; Q61R, 4; G12S, 3; G12C, 2) and 104 (46%) STK11: rs2075606 carriers. In 21 patients enrolled, 14 and 7 patients had HRAS mutations and STK11:rs2075606, respectively. The most frequent adverse events included fatigue and hematologic toxicities. With a median follow-up of 28 months, 4 patients (19%) reached PFS6: 3 had missense HRAS mutations and one patient, enrolled as a STK11 carrier, had HRAS frameshift insertions at H27fs and H28fs rendering a nonsense HRAS mutation. Response rate was 24% (4 missense and one nonsense frameshift HRAS mutation); no response observed in UC patients with wild type HRAS tumors. Conclusions: Oral tipifarnib showed a manageable safety profile and encouraging anti-tumor efficacy against treatment-refractory UC containing HRAS mutations. Clinical trial information: NCT02535650 .
Comprehensive genomic profiling (CGP) of histologic subtypes of urethral carcinomas (UrthCa).
Authors: Grivas Petros , Jacob Joseph M , Shapiro Oleg , Necchi Andrea , Sokol Ethan , Killian Jonathan Keith , Lin Douglas I. , Ramkissoon Shakti H. , Severson Eric Allan , Huang Richard , Alexander Brian Michael , Venstrom Jeffrey , Reddy Venkataprasanth P. , McGregor Kimberly , Elvin Julia Andrea , Schrock Alexa Betzig , Danziger Natalie , Ross Jeffrey S. , Bratslavsky Gennady
Published: May 2020

5087

Background: UrthCa is an uncommon GU malignancy that can progress to advanced metastatic disease. Methods: 127 metastatic UrthCa underwent hybrid-capture based CGP to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: 49 (39%) urothelial (UrthUC), 31 (24%) squamous (UrthSCC), 34 (19%) adenocarcinomas (UrthAC) and 13 (9%) clear cell (UrthCC) were evaluated along with a control cohort of 2,130 bladderUC cases. UrthUC and UrthSCC were more common in men; UrthAC and UrthCC more common in women. Age was similar in all 4 groups. GA in PIK3CA were the most frequent potentially targetable GA; MTOR pathway GA in PTEN also identified. GA in other potentially targetable genes were also identified including ERBB2(6% in UrthUC, 3% in UrthSCC and 12% in UrthAC), FGFR1-3 (3% in UrthSCC), BRAF (3% in UrthAC), PTCH1 (8% in UrthCC) and MET (8% in UrthCC). Higher TMB was seen in UrthUC and UrthCC compared to UrthAC and UrthSCC, possibly reflecting their higher GA/tumor status and suggesting potential for immunotherapy benefit. MSI high status was absent throughout. The bladderUC cases had similar genomic pattern as UrthUC with significantly lower frequency of HPV16/18 positive cases. Conclusions: CGP reveals GA that may be predictive of both targeted and immunotherapy benefit in patients with advanced UrthCa and that could potentially be used in future adjuvant, neoadjuvant and metastatic disease trials. [Table: see text]
Immune phenotype and response to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC).
Authors: Yam Clinton , Alatrash Gheath , Yen Er-Yen , Garber Haven , Philips Anne V. , Huo Lei , Yang Fei , Bassett Roland L. , Sun Xiangjie , Parra Cuentas Edwin Roger , Symmans William Fraser , Seth Sahil , White Jason B , Rauch Gaiane M , Damodaran Senthil , Litton Jennifer Keating , Wargo Jennifer Ann , Hortobagyi Gabriel N. , Moulder Stacy L. , Mittendorf Elizabeth A.
Published: May 2020

509

Background: In TNBC patients (pts) receiving NAST, increasing tumor infiltrating lymphocytes (TILs) is associated with higher pathologic complete response (pCR) rates. However, since the presence of TIL do not consistently predict pCR, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. Methods: T cell receptor (TCR) sequencing, PD-L1 immunohistochemistry and multiplex immunofluorescence were performed on prospectively collected pre-NAST tumor samples from 98 pts with stage I-III TNBC enrolled in ARTEMIS (NCT: 02276443). TCR clonality was calculated using Shannon’s entropy. PD-L1+ was defined as ≥1% immune cell staining. Response to NAST was defined using the residual cancer burden (RCB) index. Associations between TCR clonality, immune phenotype, and response were examined with the Wilcoxon rank sum test, Spearman’s rank correlation and multivariable logistic regression using stepwise elimination (threshold p > 0.2), as appropriate. Results: The pCR rate was 39% (38/98). pCR was associated with higher TCR clonality (median = 0.2 [in pts with pCR] vs 0.1 [in pts with residual disease], p = 0.05). Notably, the association between pCR and higher TCR clonality was observed in pts with ≥5% TIL (n = 61; p = 0.05) but not in pts with < 5% TIL (n = 37; p = 0.87). Among pts with ≥5% TIL, TCR clonality emerged as the only independent predictor of response in a multivariable model of tumor immune characteristics (odds ratio/0.1 increase in TCR clonality: 3.0, p = 0.021). PD-L1+ status was associated with higher TCR clonality (median = 0.2 [in PD-L1+] vs 0.1 [in PD-L1-], p = 0.004). Higher TCR clonality was associated with higher CD3+ (rho = 0.32, p = 0.0018) and CD3+CD8+ (rho = 0.33, p = 0.0013) infiltration but lower expression of PD-1 on CD3+ (rho = -0.24, p = 0.021) and CD3+CD8+ cells (rho = -0.21, p = 0.037). Conclusions: In TNBC, a more clonal T cell population is associated with an immunologically active microenvironment (higher CD3+ and CD3/8+ T cell; lower PD-1+CD3+ and PD-1+CD3/8+ T cell; PD-L1+) and favorable response to NAST, especially in pts with ≥5% TIL, suggesting a role for deep immune phenotyping in further refining the predictive value of TILs.
De-escalated chemotherapy versus endocrine therapy plus pertuzumab+ trastuzumab for HR+/HER2+ early breast cancer (BC): First efficacy results from the neoadjuvant WSG-TP-II study.
Authors: Gluz Oleg , Nitz Ulrike , Christgen Matthias , Kuemmel Sherko , Holtschmidt Johannes , Priel Jan , Hartkopf Andreas , Potenberg Jochem , Luedtke-Heckenkamp Kerstin , Just Marianne , Wuelfing Pia , von Schumann Raquel , Graeser Monika , Wuerstlein Rachel , Kates Ronald E. , Kreipe Hans Heinrich , Harbeck Nadia
Published: May 2020

515

Background: HR+/HER2+ breast cancer (BC) is a distinct entity associated with better prognosis compared to HR-/HER2+ BC. However, combination of chemotherapy (CT) with (dual) anti-HER2 blockade is standard in HER2+ early BC (EBC), irrespective of HR-status. Despite of some promising data on combination of endocrine therapy (ET) with dual anti-HER2 blockade in EBC and metastatic HR+/HER2+ BC, no prospective comparison of neoadjuvant CT vs. ET + dual HER2-blockade has yet been performed. Methods: In the prospective WSG TP-II phase II-trial (NCT03272477; Sponsor: Palleos GmbH, Wiesbaden, Germany), 207 patients (pts) (257 screened; 40 centers) with centrally confirmed HR+/HER2+ EBC were randomized to 12 weeks of standard ET (n=100) vs. paclitaxel 80 mg/m2 weekly (n=107) +trastuzumab+pertuzumab q3w for all pts. Primary endpoint was pCR (ypT0/is/ypN0). Secondary endpoints include safety, disease-free and overall survival, translational research, and quality of life (QoL). Omission of further CT was allowed in all pts with pCR; dual HER2-blockade was administered in the adjuvant setting in all pts. Results: Baseline characteristics were well balanced between the arms. Median age was 53 years; 58% had cT2-4, 28% had cN+; 43% had G3 tumors. pCR data were available in 198 pts (ET: n=96; Pac: n=102). pCR was observed in 24% (95% CI: 16-34%) with ET+T+P vs. 57% (95% CI:47-67%) with Pac+T+P (OR 0.24, 95% CI: 0-0.46, p<0.001). In multivariable logistic regression analysis and corresponding sensitivity analysis (bootstrap/subsample inclusion frequencies and lasso regression) including study arm, BMI, menopausal, cT, and cN status, histological grade, HER2-status, Ki67, ER, PR as continuous variables, only study arm and HER2 3+ status were significantly associated with pCR. Neoadjuvant treatment was well tolerated in both study arms and completed per protocol in 93/92 (ET+P+T/Pac+P+T) patients. Only 9/13 SAEs (ET+P+T/Pac+P+T) were reported during neoadjuvant therapy. PAM50 and QoL analysis are ongoing. Conclusions: WSG TP-II is the first randomized prospective trial comparing two neoadjuvant de-escalation treatments in HR+/HER2+ EBC. The excellent pCR rate of 57% after only 12 weeks of Pac+P+T was clearly superior to the still promising 24% pCR rate in pts treated by ET+P+T. In both arms, treatment efficacy was most pronounced in HER2 3+ tumors. Survival results need to be awaited before definite recommendations for a de-escalated regimen in HR+/HER2+ EBC can be made. Clinical trial information: 2016-005157-21 .
Towards data-driven decision-making for breast cancer patients undergoing mastectomy and reconstruction: Prediction of individual patient-reported outcomes at two-year follow-up using machine learning.
Authors: Pfob André , Mehrara Babak , Nelson Jonas , Wilkins Edwin G. , Pusic Andrea , Sidey-Gibbons Chris
Published: May 2020

520

Background: Post-surgical satisfaction with breasts is a key outcome for women undergoing cancer-related mastectomy and reconstruction. Current decision making relies on group-level evidence, which may not offer optimal choice of treatment for individuals. We developed and validated machine learning algorithms to predict individual post-surgical breast-satisfaction. We aim to facilitate individualized data-driven decision making in breast cancer. Methods: We collected clinical, perioperative, and patient-reported data from 3058 women who underwent breast reconstruction due to breast cancer across 11 sites in North America. We trained and evaluated four algorithms (regularized regression, Support Vector Machine, Neural Network, Regression Tree) to predict significant changes in satisfaction with breasts at 2-year follow up using the validated BREAST-Q measure. Accuracy and area under the receiver operating characteristics curve (AUC) were used to determine algorithm performance in the test sample. Results: Machine learning algorithms were able to accurately predict changes in women’s satisfaction with breasts (see table). Baseline satisfaction with breasts was the most informative predictor of outcome, followed by radiation during or after reconstruction, nipple-sparing and mixed mastectomy, implant-based reconstruction, chemotherapy, unilateral mastectomy, lower psychological well-being, and obesity. Conclusions: We reveal the crucial role of patient-reported outcomes in determining post-operative outcomes and that Machine Learning algorithms are suitable to identify individuals who might benefit from alternative treatment decisions than suggested by group-level evidence. We provide a web-based tool for individuals considering mastectomy and reconstruction. importdemo.com . Clinical trial information: NCT01723423 . [Table: see text]
Early-stage breast cancer (BC) patients: Factors associated with aromatase inhibitor-induced musculoskeletal symptoms.
Authors: Elder Simran Arora , Sun Yamin , Jung Seungyoun , Mainor Candace Bavette , Murali Shruti , Rosenblatt Paula , Tkaczuk Katherine H. R.
Published: May 2020

525

Background: Hormone receptor positive (HR+) breast cancer comprises the largest subgroup of breast cancer. Aromatase Inhibitors (AI) are a key treatment for HR+ BC patients (pts) and reduce mortality. Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness, occur in up to 50% of pts leading to low adherence to and often discontinuation of therapy. Little is known of the mechanism of AIMSS or its predisposing risk factors. This study aims to identify risk factors associated with AIMSS development in BC patients on AI therapy. Methods: We conducted a medical record review of pts with non-metastatic HR+ BC on adjuvant AI therapy between January 2009 and June 2017 at the University of Maryland Comprehensive Cancer Center. This study included 194 ptswho were free of arthralgia prior to AI therapy. We analyzed pts’ demographics, lifestyle factors, reproductive history, tumor characteristics, medications, cancer treatment, co-morbidities, AI type, onset and severity of AIMSS. Severe AIMSS was defined as requiring change in AI therapy or discontinuation. Multivariable-adjusted logistic regression was used to identify risk factors for severe AIMSS. Results: The mean age of participants was 61. The mean BMI at diagnosis was 30 kg/m2. 41% of pts were White, 40% were Black, 7% other and 12% unknown. Most (79%) did not have a history of tamoxifen and 16% were on GnRH agonists. Most (71%) used letrozole as initial AI therapy; 18% anastrozole; and 11% exemestane. 56% experienced AIMSS while on AI therapy and 20% required change or hold of AI therapy. 4% permanently discontinued AI due to AIMSS severity. BMI at diagnosis was significantly positively associated with risk of AIMSS. Multivariate odds ratio (95% confidence intervals) comparing the highest to lowest tertile of body mass index (BMI) at diagnosis was 4.01 (1.07-10.90; Ptrend: 0.05). There were no significant associations with race, smoking, reproductive factors, type of AI therapy, tamoxifen use prior to AI therapy, medication use, experience of other cancer treatments, and tumor characteristics. Conclusions: 56% of BC pts on adjuvant AI therapy experienced AIMSS. 24% of these changed, held or discontinued AI regimen due to severe AIMSS. Higher BMI at diagnosis was associated with a higher risk of AIMSS. Our results confirm clinical significance of AIMSS among BC pts on AI therapy and suggest BMI as a modifiable factor for AIMSS. A larger study is warranted to replicate our findings and seek other possible risk factors for AIMSS.