Longer PFS Research Articles

1417P - Preliminary results of PRINCiPe (predictors of resistance to immunotherapy with nivolumab [NIV]) study in advanced pretreated non-small cell lung cancer (APNSCLC), investigating the role of an immune genomic signature (IGS) including JAK2, JAK3, PIAS4, PTPN2, STAT3, IFNAR2 alterations

Background: Although immunotherapy impressively improved the outcome of APNSCLC, many patients (pts) rapidly progress. The mechanism of resistance may be influenced by genomic abnormalities in immune-escape/editing genes. Methods: FFPE-tumor blocks of APNSCLC pts undergone NIV were retrospectively sequenced for Somatic Mutations/Copy Number Variations (SM/CNV) (Ampliseq 17-genes customized panel: APLNR, B2M, IFNAR1, IFNAR2, IFNGR1, IFNGR2, IRF9, JAK1, JAK2, JAK3, PIAS4, PTPN2, SOCS1, STAT1, STAT2, STAT3, TYK2). End-points of PRINCiPe study: overall-, progression-free-survival (OS/PFS) and objective response rate (ORR). Results: 24 APNSCLC pts were gathered (median age 69.5 yrs, median number of previous lines 3 [2-5], 2nd line NIV [70.8%], male/female 79.2/20.8%, squamous/non- squamous 41.7/58.3%, EGFR mutant 5 [20.8%], median follow-up 6.8 months [range 1-23], deaths 14 [58.3%]). JAK3/JAK2 (6/3 pts, 25/12.5%) CNV, and IFNAR2/STAT3 SM (2 pts, 8.3%) were the most frequent abnormalities. Pts (12) with JAK3, PIAS4, PTPN2, STAT3, IFNAR2 SM and/or JAK2/3 CNV (IGS+) had a significantly lower OS/PFS than those without (IGS-). At multivariate analysis, IGS+ was independently associated with shorter OS (HR 4.90, 95% CI 1.40-16.5, p = 0.01) and PFS (HR 6.10, 95% CI 2.0-18.7, p = 0.001); the (previous) surgery was significantly associated with longer PFS (HR 4.20, 95% CI 1.1-11.4, p = 0.03). IGS+ pts were significantly more associated with the presence of liver metastases (p = 0.04). A trend towards lower activity of NIV in EGFR+ pts was found.Table: 1417PIGS+IGS-p-valueORR (%, 95% CI)-16.6% (2-31)0.09Median OS (months, 95% CI)4 (1-8)13 (n.e.)0.046Median PFS (months, 95% CI)3 (2-3.5)6 (5-9)0.002 Open table in a new tab Conclusions: The derived IGS appears to identify APNSCLC pts with a lower chance to benefit from NIV, supporting intrinsic resistance. Given the small sample, a prospective larger and external validation is ongoing. Legal entity responsible for the study: Emilio Bria. Funding: University of Verona. Disclosure: All authors have declared no conflicts of interest.

P2.01-112 Prognostic Value of Changes in Neutrophil-To-Lymphocyte Ratio in Patients with Lung Cancer Treated with Nivolumab

Nivolumab, an anti-programmed cell death 1(PD-1) antibody, is a standard regimen for the second-line treatment of non-small cell lung cancer (NSCLC). However, compared with molecular-targeted drugs, the response rate to nivolumab is low, and biomarkers of efficacy are currently lacking. It has been recently reported that the neutrophil-to-lymphocyte ratio (NLR) can be a biomarker of efficacy. Here, we examined the possibility for NLR to predict efficacy of nivolumab. We retrospectively examined all patients with NSCLC who were treated with nivolumab at our institution. We compared 35 patients with NLR of ≥3 and 44 with NLR of <3, all of whom were treated with nivolumab. There was no difference in response rates between the two groups. The median (m) PFS and mOS were 130 and 583 days in the NLR≥3 group, whereas those were 169 days and not reached (NR) in the NLR<3 group. Longer PFS and OS were observed in the NLR<3 group than in the NLR≥3 group. Next, we analyzed the relationship between treatment efficacy and relative change of NLR (ΔNLR), the ratio of the value at 4 weeks after the administration of nivolumab to the value at baseline. In 42 patients with ΔNLR of ≥1, mPFS and mOS were 122 and 564 days, respectively. In 31 patients with ΔNLR of <1, mPFS and mOS were 280 days and NR, respectively. PFS and OS were significantly better in the group with ΔNLR of <1. With respect to adverse events, grade 1-2 rashes were observed in 29% of patients in the group with ΔNLR of <1 and in 9.5% of patients in the group with ΔNLR of ≥1. Relative ratio of NLR at 4 weeks/at baseline is a predictive biomarker in patients with NSCLC who are treated with nivolumab.

P3.01-62 A New Method for Non-Invasive Prediction of Radiotherapy: SDH5 Depletion Enhances Radiosensitivity by Regulating P53

Radiotherapy is an important and effective treatment for lung cancer. Some molecules can predict the effect of radiotherapy, but it is an invasive test that will cause trauma to patient. So the development of reliable non-invasive methods for predication of radiotherapy has become essential to guide therapy. We initiated an analytical, observational, open, and retrospective study (ChiCTR1800014878) of 53 patients with stage III lung adenocarcinoma who were ready for radiotherapy. The performance status (PS) scores of the patients are all over 2. Blood and tumor tissue before treatment were collected to detect SDH5 concentration. We then evaluated the prognostic role of SDH5 expression in these patients. To further verify the effect of SDH5 on radiosensitivity, two mice models (orthotopic mice bearing lung cancer and SDH5 gene knock-out mice) were established and the internal mechanism between SDH5 and radiotherapy was explored. The patients whose tumor shrink significantly one month after radiotherapy had lower expression of SDH5 in tumor, and loss of SDH5 expression correlated with down regulation of DNA-PKcsThr2609 and ku86. More importantly, SDH5 can be directly detected in blood by qRT-PCR, and the result is consistent with that in tissue. And more exciting, patients with deficiency of SDH5 had longer PFS and OS after radiotherapy, and the results in blood and in tumor are consistent. To further verify the effect of SDH5 on radiosensitivity, in vivo experiments were carried out. In the orthotopic model, SDH5 knock down tumors showed higher radiation sensitivity with smaller volume. In SDH5 knock-out mice, lung epithelial cells exhibited elevated DNA damage after radiation. Moreover, our data indicated that SDH5 depletion causes P53 translocated from cytoplasm to nucleus, which enhances radiosensitivity of non-small cell lung cancer. Furthermore, consistent with in vivo data, the tumor growth was partially reversed when p53 was co-depleted with SDH5. In this experiment we found that SDH5 regulated radiosensitivity by P53 and it can be detected in tumor tissue. It is a suitable marker for predicting radiosensitivity. More than this, the expression of SDH5 can be directly measured by qRT-PCR in the blood, and it is consistent with that in the tumor tissue. This provides a novel non-invasive method for predicting the radiosensitivity of the patients unable to tolerant the biopsy.

Abstract 4209: First-line doublet chemotherapy for mTNBC: circulating tumor cell analysis of the tnAcity trial

Abstract Introduction Circulating tumor cells (CTCs) have been shown to be prognostic in patients (pts) with metastatic breast cancer (MBC) (Pukazhendhi, Gluck, J Carcinog. 2014). The tnAcity trial evaluated the efficacy/safety of 3 chemotherapy combination regimens (nab-P/carboplatin [C], nab-P/gemcitabine [G], or G/C) as first-line treatment for pts with mTNBC. nab-P/C resulted in a significantly longer PFS &amp; numerically higher ORR vs nab-P/G or G/C (Yardley. SABCS 2016; manuscript in process). CTC levels were assessed at baseline (BL) &amp; during treatment to determine correlation with clinical benefit. Methods Pts with pathologically confirmed mTNBC &amp; no prior cytotoxic chemotherapy for MBC received (1:1:1) nab-P 125 mg/m2 with C area under the curve (AUC) 2, nab-P 125 mg/m2 with G 1000 mg/m2, or G 1000 mg/m2 with C AUC 2, all given d1 &amp; 8 q3w. Primary endpoint: investigator-assessed PFS. Secondary endpoints included ORR &amp; OS; CTC enumeration was a prespecified exploratory objective. CTC levels, assessed (CELLSEARCH®) at BL &amp; start of cycles 3 &amp; 5 (post-BL), were grouped as follows: 0 CTCs/7.5 mL blood at BL (−−), ≥ 1 CTCs/7.5 mL blood at BL &amp; post-BL (++), &amp; ≥ 1 CTCs/7.5 mL blood at BL &amp; clearance of CTCs in ≥ 1 post-BL measurement (+−). Results In total, 126 pts were included: 48, 24, &amp; 54 in the −−, ++, &amp; +− groups, respectively. Mean BL CTC levels for the ++ &amp; +− groups were 55 &amp; 66 CTCs/7.5 mL blood. Pts with BL CTCs of ≥ 1 vs 0 had numerically similar median PFS (7.0 vs 5.9 mo; HR 1.45 [95% CI 0.93 - 2.25]) &amp; OS (15.0 vs 16.0 mo; HR 0.90 [95% CI 0.57 - 1.42]) &amp; higher ORR (64% vs 44%). Mean cycle 3 &amp; 5 CTC levels in the ++ group were 17 &amp; 111 CTCs/7.5 mL blood. Pts in the −− &amp; +− groups had longer PFS vs the ++ group (median 5.9, 8.5, &amp; 4.7 months). Similar improvements in OS &amp; ORR were noted (Table). Conclusions Absence of CTCs at BL &amp; during treatment &amp; clearance of CTCs from BL at least once during treatment were generally associated with improved efficacy outcomes in pts with mTNBC treated with combination chemotherapy. Table. Outcomes by Change in CTC Level from BaselineGroupOutcome−− n = 48+− n = 54++ n = 24PFS, median, mo HR (95% CI)5.9 0.60 (0.34-1.06)a8.5 0.30 (0.17-0.54)a4.7OS, median, mo HR (95% CI)16.0 0.40 (0.22-0.73)a17.8 0.35 (0.20-0.62)a9.8ORR, %43.879.629.2CR6.316.74.2PR37.563.025.0SD35.420.454.2PD16.7—16.7NE4.2——CR, complete response; HR, hazard ratio; NE, not evaluable; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. a vs ++ group. Citation Format: Minetta C. Liu, Wolfgang Janni, Vassilis Georgoulias, Denise A. Yardley, Nadia Harbeck, Xin Wei, Desmond McGovern, Robert Beck. First-line doublet chemotherapy for mTNBC: circulating tumor cell analysis of the tnAcity trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4209.

Abstract 2631: Cancer associated macrophage-like (CAMLs) cells in blood predict progression and survival for all stages of solid tumors

Abstract Background: We previously demonstrated that cancer associated macrophage-like cells (CAMLs) are cancer specific giant polyploid cells circulating in the blood of patients with solid tumors. Building on our initial discovery, others have shown that these hyperploidy cells are an innate immune response that is associated with decreased survival. However to date, no studies have been done to elucidate their clinical significance as in relation to the various stages of malignant disease. We established a 4 year prospective study of 315 patients from a variety of solid tumors (breast, prostate, lung, renal cell, pancreas, and esophageal) comparing the morphological properties of CAMLs in both early and late stage disease as they relate to progression free and overall survival (PFS/OS). These data suggest that CAML size appears have a strong negative correlation with progression and survival of cancer patients, irregardless of stage of disease, indicating their possible use as a non-invasive blood based biomarker in solid tumors. Methods: A prospective multi-institutional study used anonymized peripheral blood from 315 cancer patients [stage I (n=62), stage II (n=72), stage III (n=69) &amp; stage IV (n=106)] from subjects with breast (n=59), esophageal (n=27), lung (n=59), renal cell carcinoma (n=37), prostate (n=74), pancreas cancers (n=59). CAMLs were isolated by the CellSieve™ microfiltration technique at 5 institutions and stained for cytokeratin 8, 18, &amp; 19, CD14 and CD45. After imaging, a size based threshold ≥50µm was used to separate the patient cohorts, based on previously published assessments. Results: At least one CAML was found in 92% of cancer patients (n=289/315), with the lowest sensitivity in stage 1 (86%), followed by stage 2 (90%), stage 3 (97%) and stage 4 (95%). The property of CAML size was then evaluated. Overall, CAMLs of &amp;lt;50µm in size had superior PFS (HR: 3.8; 95% CI 2.8-5.3; p&amp;lt;0.001) and OS (HR=3.8; 95% CI 2.6-5.7;p&amp;lt;0.001) than those with ≥50 µm CAMLs. By each stage individually, stage 1 (PFS HR=7.5; 95% CI 3.2-17.7; p&amp;lt;0.001), stage II (PFS; HR=4.1; 95% CI 1.9-8.8; p&amp;lt;0.001), stage III (PFS HR=3.1; 95% CI 1.7-5.7; p=0.007), and stage IV (PFS HR=2.7; 95% CI 1.6-4.4; p&amp;lt;0.001). Conclusions: In this first large scale prospective study of the clinical utility of CAMLs, it appears that they are present in every stages of invasive solid tumor malignancies, with prevalence increasing with stage. Interestingly decreased CAML size was found to be associated with improved outcome and longer PFS. These data suggest that CAML detection and size assessment constitute a new real time predictor of progression, and survival in both early and late stage disease indicating the need for additional validation studies. Citation Format: Daniel L. Adams, Steven H. Lin, R. Katherine Alpaugh, Thai Ho, Jeffrey R. Marks, Stuart S. Martin, Susan Tsai, Saranya Chumsri, Cha-Mei Tang, Massimo Cristofanilli, Raymond Bergan. Cancer associated macrophage-like (CAMLs) cells in blood predict progression and survival for all stages of solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2631.

Autologous stem cell transplantation in first remission is associated with better progression-free survival in multiple myeloma.

Majority of patients obtained CR/VGPR post-ASCT. Longer PFS was seen with patients who were transplanted in first remission.

Updated survival data and biomarker assessment of the CBCSG006 trial: A randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.

1093Background: It was previously reported in CBCSG006 trial that patients with metastatic TNBC were more likely to have higher response rate and longer PFS to cisplatin plus gemcitabine (GP) than ...

Serial minimal residual disease (MRD) monitoring during first-line FCR treatment for CLL may direct individualized therapeutic strategies

Achieving undetectable MRD (U-MRD) status after chemoimmunotherapy predicts longer progression-free and overall survival. The predictive factors and timing of relapse in patients with U-MRD and value of interim MRD analysis are ill-defined. This was a prospective study of 289 patients with CLL treated first-line with FCR. MRD analysis was performed after course 3 (C3) and at end-of-therapy (EOT) in bone marrow using 4-color flow cytometry (sensitivity 10−4). Eighteen percent of patients had U-MRD after C3 and 48% at EOT. U-MRD status at EOT was associated with longer PFS (median NR vs 38mo, p<0.001). MRD level (≤1% vs. >1%) after C3 predicted greater likelihood of U-MRD status at EOT (64% vs. 9%, p<0.001). PFS was significantly longer for patients with MRD ≤1% vs. >1% after C3 (median 73mo vs 41mo, p<0.001), but similar for <0.01% vs. 0.01–1%. Interim MRD status may therefore be used for risk stratification and to individualize therapy. Eighty-five patients with U-MRD status at EOT had yearly blood MRD monitoring; MRD re-emerged in 38/85, a median of 48mo after EOT and preceded clinical progression by a median of 24 months, which may allow development of early intervention strategies.

Number of Resected Lymph Nodes and Survival of Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Preoperative Chemoradiotherapy.

The association of extended lymph node (LN) dissection with improved outcomes in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who received preoperative chemoradiotherapy (CRT) followed by surgery is debatable. We reviewed data from patients with esophageal cancer enrolled in three phase II clinical trials of preoperative paclitaxel and cisplatin-based CRT during 2000-2012. Patients with ESCC who underwent planned esophagectomy were enrolled. The number of resected LNs and other clinicopathological factors were analyzed regarding their impact on progression-free (PFS) and overall (OS) survival using Cox proportional hazards model. In total, 139 patients were included. The median PFS and OS were 24.4 and 31.8 months, respectively. The median number of resected and positive LNs were 19 (range=2-96) and 0 (range=0-9), respectively. The mean number of positive LNs did not differ significantly among quartile groups of total resected LNs (quartile 1: 2-12, 2: 13-19, 3: 20-29, and 4: 30-96). The resected LN number analyzed as dichotomies divided by the median or as continuous variables was not associated with PFS or OS. However, in an exploratory analysis, patients of quartiles 2 and 3 had longer PFS and OS than those with quartiles of 1 and 4 in multivariate analysis (p=0.019 and 0.005, respectively). Although extensive LN dissection was not associated with improved survival, resection of 13-29 LNs was associated with improved survival in patients with locally advanced ESCC receiving preoperative paclitaxel and cisplatin-based CRT.

Prediction of outcome in bone metastatic, castration-resistant prostate-cancer-patients under enzalutamide by combining biomarkers.

334 Background: Under early Enzalutamide (Enza) treatment of bone mCRPC (bmCRPC), prostate-specific antigen (PSA) might be misleading, since a PSA-flare may occur. Bouncing of alkaline phosphatase (APB) was shown as a promising surrogate for survival outcome. Low lactate dehydrogenase (LDH) usually predicts better outcome. The purpose of this study was to evaluate the prognostic ability of APB, LDH, PSA and information of the pooled markers after initiation of Enza. Methods: 89 bmCRPC-patients were analyzed. PSA, LDH and AP were monitored at 2, 4, 8, 12 and 20 weeks. APB was defined as an increase of AP after initiation of Enza with a subsequent, significant decline below baseline during the first 8 weeks of therapy. APB vs. no Bounce as well as LDH and PSA increase vs. decline were analyzed using Kaplan-Meier analyses (KMA) and uni- and multivariate (UV/MV) cox-regression models. Results: In KMA declining PSA and LDH as well as APB were associated with longer median PFS with 7 (95% confidence interval: 4.2-9.8) vs. 3 months (2.3-3.7) for PSA, 6 (4.1-8) vs. 2 (1.2-2.8) for LDH and 8 (0-16.3) vs. 3 (1.9-4.1) for APB. Analysis of OS showed similar results with 17 (11.7-22.3) vs. 12 months (7.0-17.1) for PSA, 17 (13.2-20.8) vs. 7 (5,8-8.2) for LDH and 19 (7.9-30.1) vs. 12 (7.7-16.3) for APB. In UV APB (Hazard Ratio (HR): 0.52 (0.3-1.0); p = 0.02), PSA-decline ≥50% (HR: 0.49 (0.3-0.7); p &lt; 0.01) and LDH-normalization (LDHnorm) (HR: 0.39 (0.2-0.6); p &lt; 0.01) were significantly associated with longer PFS. Considering OS LDHnorm was a significant prognosticator for longer survival (HR: 0.39 (0.2-0.6); p &lt; 0.01). In MV only LDHnorm showed a trend towards better OS (HR: 0.49 (0.2.-1.1); p = 0.09). Combining those markers and separating a group with APB, LDHnorm and PSA-decline and a group with PSA-decline alone KMA showed better PFS (11 (0.2-21.8) vs. 4 (0-8.6)) and OS (20 (17.7-22.3) vs. 8 (0.3-15.7)) in favor of the group with 3 beneficial markers. In UV the presence of all 3 markers was significantly associated with longer PFS (HR: 0.23 (0.1-0.7); p &lt; 0.01) and OS (HR: 0.26 (0.1-0.8); p = 0.02). Conclusions: APB and LDHnorm may add to identifying bmCRPC-patients with favorable prognosis during early Enza-therapy.

Prognostic and predictive role of fumarate hydratase in metastatic clear cell renal cell carcinoma.

617 Background: Metabolic disruption is frequent in renal cell carcinoma (RCC). Loss of the mitochondrial fumarate hydratase (FH) enzyme is associated with enhanced glycolytic metabolism, angiogenesis and clinical aggressiveness in type 2 papillary RCC. However, FH expression has never been evaluated in clear cell RCC (ccRCC). In this study, we investigated the impact of FH expression on the outcomes of patients (pts) with metastatic ccRCC (mccRCC). Methods: We included pts with mccRCC, for whom formalin-fixed, paraffin embedded (FFPE) tissue from the primary tumor had been obtained before initiation of systemic treatment. FH levels were evaluated by immunohistochemistry (IHC), and were defined as “normal” if FH expression in most cancer cells was comparable to the adjacent normal tubular cells and “low” in the opposite case. We evaluated the association between FH levels and clinico-pathological characteristics through the chi-squared or Fisher’s exact test. The log-rank test was used to compare survival between patient subgroups. Results: We evaluated 49 mccRCC pts, of whom 36 (73.5%) had synchronous metastases. FH levels were normal in 29 (59.2%) pts and low in 20 (40.8%) pts. FH expression was not associated with patient age (p = 0.5), sex (p = 0.34), tumor grade (p = 0.66), T stage (p = 0.38), N stage (p = 0.88), metastatic disease at the time of diagnosis (p = 0.4), number of metastatic sites (p = 1) or sarcomatoid morphology (p = 0.36). 44 pts received first-line therapy with tyrosine kinase inhibitors (TKIs). In pts with low as compared to normal FH levels, median progression free survival (mPFS) during any first-line treatment was 34 and 10.1 months, respectively (HR 0.39, 95% CI 0.18-0.85; p = 0.014), while mPFS during first-line TKI therapy was 34 and 8.42 months, respectively (HR 0.4, 95% CI 0.17-0.94; p = 0.03). Median overall survival (OS) was not reached in pts with FH-low tumors, while it was 22.9 months in normally expressing ones (HR 0.14, 95% CI 0.032-0.63; p = 0.028). Conclusions: In mccRCC pts, low FH expression in primary tumors is associated with longer PFS during any first-line or TKI treatment, and also with better OS. This is the first study to reveal a prognostic and predictive role of FH levels in mccRCC.

Abstract PD6-13: Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer

Abstract Background: Eribulin mesylate (ERI), a nontaxane microtubule inhibitor with effects on tumor biology (increased vascular perfusion, reversal of epithelial to mesenchymal transition), is approved as a monotherapy for the treatment of patients (pts) with metastatic breast cancer who received ≥2 prior chemotherapeutic regimens for metastatic disease. In a pooled analysis, ERI significantly prolonged OS compared with capecitabine or treatment of physician's choice in pts with metastatic triple-negative breast cancer (mTNBC; 12.9 vs 8.2 mo, n=428). Pembrolizumab (PEM) is a human programmed death (PD) receptor-1–blocking antibody approved for the treatment of several advanced cancers. In a phase (Ph) 2 study in mTNBC, PEM monotherapy as first-line therapy demonstrated ORR, 23%; median PFS, 2.1 mo [95% CI 2.0-3.9], and in pts pretreated with ≥1 prior chemotherapy demonstrated ORR, 5%; median OS, 8.9 mo [95% CI 7.2-11.2]). Methods:This open-label Ph 1b/2 trial enrolled pts (aged ≥18 yrs; ECOG PS ≤1) with mTNBC treated with ≤2 prior lines of chemotherapy for metastatic disease. Ph 1b included a safety cohort of ≥6 pts who received intravenous (IV) ERI 1.4 mg/m2 on day (d) 1 and d8 and IV PEM 200 mg on d1 of a 21-d cycle. In Ph 2, pts were enrolled based on prior chemotherapy in the metastatic setting [0 vs 1–2 lines]. Primary endpoints: safety, tolerability (Ph 1b), and ORR (Ph 2); secondary endpoints: PFS, OS, and efficacy in PD-L1+ pts. Results: We report data from 82 of 104 enrolled pts (data cut-off Nov 1, 2016).The RP2D was ERI 1.4 mg/m2 on d1 and d8 and PEM 200 mg on d1 of a 21-d cycle. Most common treatment-emergent adverse events (TEAEs) were fatigue (73.2%), nausea (51.2%), peripheral sensory neuropathy (46.3%), alopecia (43.9%), and pyrexia (36.6%). Most common Grade (G) 3 or 4 TEAEs related to ERI: neutropenia (29.3%), peripheral neuropathy (8.5%), and asthenia/fatigue (7.3%). G3/4 immune-related TEAEs related to PEM: 19.5% of pts. TEAEs that led to drug withdrawal/dose reduction: 18.3%/28.0% of pts. G5 events: 3 pts (respiratory failure, pleural effusion, and multiple organ failure; none related to study drug). Response was irrespective of PD-L1 status (Table1). Results of the final analysis will be available for presentation. Overall (n=82)No prior chemotherapy in metastatic setting (n=48)1-2 Prior lines of chemotherapy in metastatic setting (n=34)PD-L1+ (n=35)PD-L1- (n=36)ORR, n (%) [95% CIa]21 (25.6) [16.8, 35.4]12 (25.0) [14.0, 37.8]9 (26.5) [13.3, 41.8]9 (25.7) [12.9, 40.8]9 (25.0) [12.5, 39.8]CBRb, n (%)25 (30.5)13 (27.1)12 (35.3)10 (28.6)12 (33.3)DCRc, n (%)46 (56.1)28 (58.3)18 (52.9)19 (54.3)21 (58.3)Median PFS, mo [95% CI]4.1 [2.3-4.8]4.1 [2.2-4.9]3.9 [2.1-6.3]4.1 [2.1-4.8]4.1 [2.3-6.3]Median OS, mo [95% CI]NE [17.7-NE]17.7 [13.7-NE]NE [13.1-NE]----a Credible interval from Bayesian analysis; b clinical benefit rate = CR+PR+SD; c disease control rate = CR+PR+SD ≥24 weeks. NE, not estimable. Conclusions: ERI+PEM was well tolerated and demonstrated activity in pts with mTNBC. The combination resulted in improved ORR, with longer PFS, OS, and comparable TEAEs to those observed with either treatment as monotherapy. Further exploration of this combination is warranted. Citation Format: Tolaney SM, Kalinsky K, Kaklamani V, Savulsky C, Olivo M, Aktan G, Kaufman PA, Xing D, Almonte A, Misir S, Karantza V, Diab S. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD6-13.

Abstract P5-04-01: The TRANSERI project: Effect of eribulin (E) in patients with metastatic breast cancer (mBC) on circulating TGFβ and TNFα. Relationship with outcome

Abstract Background: E is approved for the treatment of mBC patients (pts) after failure of at least 2 previous chemotherapy (CT) regimens containing antracyclines and taxanes. Its mechanism of action interferes with microtubule leading to cell cycle arrest in G2/M phase and cell apoptosis. An in vitro study in triple negative BC cell lines shows that exposure to E reverses epithelial mesenchimal transition (EMT) phenotype toward an epithelial morphology and induces changes of gene profiling and protein expression. Accordingly in mice E reduces metastatization and can reverse EMT. TGFβ is an immunosuppressive cytokine and a growth factor for cancer-associated fibroblasts (CAFs). In addition it drives EMT. TNFα synergizes with TGFβ to promote EMT. While CAFs pave the way for metastatization, EMT permits cancer cells trafficking through the blood flow following CAFs and finally developing metastases. The purpose of the study is to investigate whether E interferes with TGFβ and TNFα levels and if the changes correlate with the outcome and the metastatic spread. Methods: Pts with mBC, after failure of at least 2 previous CT lines were treated with E delivered at 1.23 mg/m2, d 1–8 every 21 d. Blood levels of TGFβ and TNFα were determined at baseline, before cycle 3, 5 and at disease progression. The changes observed were correlated with the outcome and the metastatic spread. Results: The study is ongoing. Here we report preliminary data on 16 pts who completed 3 cycles of E. No change of TNFα level was observed during treatment. On the contrary, TGFβ levels changed during treatment. Basal levels of TGFβ were divided in upper or lower the median (m) value. We did not observe any difference in m PFS between high or low values (137 d vs 141). However the m TGFβ value in pts was much higher than that observed in 3 healthy volunteers (m concentrations: 205 pg/ml [C.I. 115-920] vs 108 pg/ml [C.I. 85-120] respectively). In 5 pts, TGFβ increased between cycle 1 and cycle 3, while diminished in 11 pts. We observed a numerical difference in PFS between the pts with decreased and increased values (150 d vs 85, p=NS). We then divided the population in 3 groups: pts with TGFβ increased more than 25% of their basal levels (increased), pts with changes between +25% and -25% compared to their basal levels (stable) and pts with decreased values more than 25% of their basal levels (decreased). Comparing “increased” vs “stable” + “decreased” we observed a trend toward longer PFS favouring the latter group (77 d vs 144 p=0.12). We collected the third determination in 14 pts. We did not analyse these data yet. However we observed that in 6 pts, TGFβ continues to decline. None of these pts progressed. In these pts the m value of TGFβ approaches healthy controls value (m concentrations: 180 pg/ml [C.I. 200-100] vs 108 pg/ml [C.I. 85-120]). Conclusions: TNFα does not change during E treatment. On the contrary, TGFβ changes compared to basal levels. In pts with increased TGFβ between cycle 1 and 3 the PFS is lower than that observed in pts with stable or decreased levels (p=0.12). Pts with continue decline of TGFβ at cycle 5, approach the values of the healthy volunteers. None of them progressed. Updated results will be presented. Citation Format: Garrone O, Tonissi F, Lingua D, Vandone AM, Vivenza D, Denaro N, Lo Nigro C, Merlano MC. The TRANSERI project: Effect of eribulin (E) in patients with metastatic breast cancer (mBC) on circulating TGFβ and TNFα. Relationship with outcome [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-04-01.

Identification of biomarkers for TAS-102 efficacy in metastatic colorectal cancer patients based on preclinical analysis and clinical validation.

669 Background: Trifluridine (FTD) incorporation into DNA is the main anti-tumor mechanism of action of TAS-102. We performed preclinical analysis and translational validation study to identify the candidate cytokines for TAS-102 efficacy in metastatic colorectal cancer (mCRC) patients (pts). Methods: As a first preclinical process, we selected candidate cytokines according to our transcriptomic and cell biological analysis. We then validated predictive value of the cytokines in mCRC pts receiving TAS-102 (discovery) and regorafenib (control). Blood samples were obtained at baseline (BL), before second cycle (2nd) and progressive disease (PD), and cytokine levels were measured using ELISA. The change patterns were defined as ‘increased’ or ‘decreased’ from BL. Results: 93 pts were included in this study: 67 received TAS-102 and 26 received regorafenib. Preclinical cDNA microarray analysis with colon cancer cell lines demonstrated marked changes in the RNA expression of interleukin-8, VEGF-A and epiregulin (EREG) after FTD treatment. Particularly, in preclinical model, EREG secretion was highly measured after FTD treatment in FTD-sensitive cells, while not in FTD-resistant cells. In the discovery cohort, increased EREG levels at 2nd showed trend toward longer PFS and OS than decreased changes (2.6 vs 2.3 mos, P= 0.096; 10.8 vs 6.2 mos, P= 0.091). Meanwhile, decreased EREG levels at PD were marginally associated with longer PFS and significantly with longer OS than increased (4.0 vs 2.3 mos, P= 0.130; 9.8 vs. 6.2 mos, P= 0.016). Combined analysis of EREG changes showed that pts with either increased at 2nd or decreased at PD had significantly longer PFS and OS compared to those with both decreased at 2nd and increased at PD (3.0 vs 2.0 mos, HR: 0.47, 95%CI: 0.24-0.93, P= 0.031; 10.8 vs 5.3 mos, HR: 0.30, 95%CI: 0.14-0.61, P= 0.001). The findings were confirmed in the multivariate analysis for OS (HR: 0.311, 95%CI: 0.15-0.66, P= 0.002), and no significant differences were observed in the control cohort. Conclusions: Our preclinical data-based translational validation study suggests that serum EREG levels may predict clinical outcome in mCRC pts receiving TAS-102.

Lymphocyte-to-monocyte ratio (LMR) compared to sidedness of primary tumor to predict outcome of anti-EGFR monotherapy in metastatic colorectal cancer.

809 Background: In RAS-wild type metastatic colorectal cancer (mCRC) treatment with cetuximab or panitumumab is the standard of care. Previously, the association between overall survival (OS) and inflamatory biomarkers were reported in several studies in mCRC (NLR, LMR). According to recent observations, primary site location can predict the superior outcome of anti-EGFR agents in first line of treatment. Here we test the relationship between inflamatory biomarkers and sidedness on outcomes of anti-EGFR therapy. Methods: Total 186 consecutive patients treated with panitumumab (n = 106) or cetuximab (n = 80) in monotherapy in third or following lines of palliative treatment were identified via electronic survey of medical records of Maria Sklodowska-Curie Memorial Cancer Center, Poland. All identified patients were treated within the state reimbursment programme with pre-specified inclusion criteria (including ECOG 0-2 mCRC, failure of previous irinotecan, oxaliplatin and fluoropiridine, all RAS-wt tumors) and treatment was administered until RECIST progression. The pretreatment inflamatory biomarkers (NLR, dNLR, LMR, PLR) were obtained for all patients. Results: Median overall survival of the cohort was 31.5 months when calculated from the start of treatment, with no difference for left- and right-sided tumors (31.8 m. vs 29.5 m.; p = 0.58). In third line treatment no difference in PFS between left- and right-sided tumors were observed (p = 0.22; PFSleft 4.82 m. vs PFSright 3.44 m.). No prognostic effect of either biomarker was noted on OS or time to failure of first two lines of treatment. Only a high lymphocyte-to-monocyte ratio (LMR &gt; 2.6) and low derived neutrocyte-to-lymphocyte ratio (dNLR &lt; 3.0) were associated with longer PFS on anti-EGFR treatment (5.5 m. in LMR &gt; 2.6; 2.5 m. in LMR &lt; 2.6; HR 0.53; p = 0.008). Notable, the patients with LMR &gt; 2.6 were more likely to be diagnosed with left sided tumor (p &lt; 0.001; 54% and 15% of left- and right-sided tumors respectively). Conclusions: High limfocyte-to-monocyte ratio may indicate the potential subpopulation of patients which can benefit mostly from anti-EGFR treatment in monotherapy in the refractory setting.

Circulating angiogenesis-related markers as predictors of benefit from regorafenib in metastatic colorectal cancer (mCRC) patients (pts).

675 Background: Regorafenib is a treatment option for refractory mCRC pts. Considering its limited clinical benefit and the palliative setting, patients’ selection is essential to optimize the cost-effectiveness ratio. We aimed to describe the modulation of selected circulating angiogenic factors by regorafenib and to investigate their correlation with clinical outcome. Methods: IL-8, Ang-2, PDGF, bFGF, Tie-2, sVEGFR2, sVEGFR3, PlGF, VEGF-A, VEGF-B were assessed by ELISA on plasma samples collected at baseline (d1), after 15 days of treatment (d15), at the best RECIST response, at disease progression (PD) in mCRC pts treated with regorafenib, as per indication. Comparisons among concentrations of each marker at different timepoints were performed by Wilcoxon test. Markers showing significant changes were analyzed for correlation with outcome. Results: 105 pts were included. Median PFS and OS were 2.1 and 7.0 months (mos), respectively. As compared to d1, IL-8 and Ang-2 levels increased at PD. An early decrease at d15 was observed for PDGF, Tie-2, sVEGFR2 and sVEGFR3 levels, followed by an increase at PD. Conversely, PlGF levels increased at d15 and then decreased at PD. Baseline levels of Ang-2 and Tie-2 below the median value were associated with longer PFS (HR:0.61 [0.37-0.83] p = 0.006; HR:0.69 [0.43-0.95] p = 0.04, respectively) and OS (HR:0.45 [0.26-0.60] p &lt; 0.0001; HR:0.68 [0.44-0.98] p = 0.04, respectively). With regard to Ang-2, 40 (45%) out of 89 pts with available plasma samples at d15 showed increased levels at d15 as compared to d1. Among them, 21 (53%) achieved disease control, as compared to 14 out of 49 (29%) pts with Ang-2 decreased levels (p = 0.03). Median PFS of pts with increased and decreased Ang-2 levels were 3.1 and 1.8 mos, respectively (HR:0.57 [0.33-0.78] p = 0.004). Conclusions: A dynamic modulation of plasma angiogenic factors occurs during the treatment with regorafenib. Low baseline Ang-2 and Tie-2 levels seem to be associated with good prognosis. The early modulation of Ang-2 levels may predict benefit from regorafenib. These results need validation in independent series.

Nano-liposomal irinotecan and 5-FU/LV (N+F) for the treatment of advanced PDAC: Memorial Sloan Kettering (MSK) Single Cancer Center Evaluation.

471 Background: Therapy options for advanced pancreatic adenocarcinoma (PDAC) are finite. NAPOLI-1, a phase III randomized trial, demonstrated the efficacy of N+F following progression on gemcitabine (G) based therapy (mPFS 3.1 mo, mOS 6.1 mo). There are limited additional data on the safety and efficacy of N+F following FDA approval in October 2015. We examined the post approval safety, tolerability and effectiveness of N+F in advanced PDAC patients at MSK. Methods: A retrospective chart review was conducted of all patients treated with N+F from Feb 2016 and ending in Aug 2017. Using the EMR and institutional database, information was extracted pertaining to demographics, performance status (ECOG), prior therapies, dose, duration of N+F, adverse events, PFS, OS and treatment response per RECIST. Results:N = 56 identified. Demographics: M/F 29/27, age 68 (range 42-88), prior lines of palliative chemotherapy (0/1/2/3/ &gt; 3, 4/20/21/11). Median PFS was 2.9 months and median OS was 5.3 months. There was a significant difference in PFS, OS and prior lines of therapy between patients who previously progressed on irinotecan (N = 27) versus not (N = 29); PFS = 2.4 v 4.8 mo, p = 0.0154; OS = 3.9 v 8.4 mo, p = 0.0021; 2 v 1 line. ECOG score was not predictive of PFS or OS. There were 19 dose reductions (DR), most frequent reasons: fatigue (42%) and diarrhea (37%). Regarding RECIST: PR = 2 (4%), SD = 19 (34%). 10/43 (23%) experienced &gt; 50% CA 19-9 reduction. Dose reductions were not associated with worse outcomes, in fact, patients with 1 or more DR experienced significantly longer PFS v none (DR 2, not reached; DR 1, 5.2 mo; DR 0, 2.5 mo, p = 0.0185). For the subset who received sequential therapy with G+nab-paclitaxel (P) followed by N+F (N = 25) mOS of 25.4 mo. Conclusions: These data support the safety and efficacy of N+F, re-inforcing results of NAPOLI-1. Patients whose disease previously progressed on irinotecan fared significantly worse than patients who did not, when treated with N+F. N+F appears active even in patients requiring DR. Sequential therapy with G+P followed by N+F demonstrates encouraging mOS. Collectively these findings underscore the utility of N+F in the therapy of advanced PDAC.

Clinical features and prognosis of 93 elderly patients with multiple myeloma

目的探索老年多发性骨髓瘤（MM）患者的临床特征以及转归。方法回顾性分析2011年8月至2016年8月第二军医大学长征医院收治的93例70岁以上的初发MM患者的临床特征，根据患者初发时的年龄、日常生活能力评分、日常生活能力量表、Charlson合并症指数，按照Palumbo等提出的健康评估系统，将评分为0分的归为健康，评分为1分的归为中等健康，评分≥2分的归为健康状况差。分析三组患者的治疗反应率、疾病无进展生存（PFS）时间以及总生存（OS）时间。结果93例患者中，健康、中等健康、健康状况差组分别为15例、31例和47例，三组完全缓解（CR）率分别为60.0%、22.6%、12.8%（Fisher χ2＝12.398，P＝0.002）。三组的中位PFS时间分别为31、24和13个月（χ2＝17.832，P<0.001），中位OS时间分别为未达到、58个月和25个月（χ2＝40.678，P<0.001）。在47例健康状况差的患者中，应用含有新药（蛋白酶体抑制剂或免疫调节剂）化疗方案的较未应用新药的患者可获得更长PFS时间（17个月对9个月，χ2＝6.454，P＝0.011）；CR患者PFS和OS时间均明显长于未达CR的患者（PFS：24个月对12个月，χ2＝4.117，P＝0.042；OS：37个月对25个月，χ2＝6.507，P＝0.011）。结论健康状况影响老年MM患者的治疗反应率、PFS及OS。对健康状况差的老年MM患者，使用含有新药的化疗方案可延长PFS时间，且获得CR的患者PFS及OS时间更长。

Circulating tumor cells as a predictive biomarker in patients with small cell lung cancer undergoing chemotherapy

BackgroundThere are no biomarkers for assessment of disease burden or activity of therapy in SCLC. Patients and methodsWe conducted a prospective study enumerating serial CTCs in patients with newly diagnosed limited disease (LD) and extensive stage (ED) SCLC. CTCs demonstrating DNA damage and apoptosis based on γH2AX and M30 staining were also assessed. We correlated CTC number with disease stage, survival outcomes and tumor burden by RECIST. ResultsBetween 03/2011-10/2013, 50 evaluable patients were enrolled (20 LD). Baseline CTC number was higher for ED (median CTC 71 vs. 1.5 for LD; p 0.0004). Patients with <5 CTC had longer PFS but not OS (11 vs. 6.7 months, p 0.0259 and 15.5 vs. 12.9 months, p 0.4357). A higher cutoff (CTC<50 or CTC≥50) was significantly correlated with both OS (20.2 vs. 11.8 months, p 0.0116) and PFS (10 vs. 4.8 months, p 0.0002). Patients with <5 CTC on day 1 of cycle 2 had longer PFS (10 vs. 3.17 months, p<0.001) and OS (18 vs. 9 months, p 0.0001). Patients with an increase in γ2HAX-positive CTCs after chemotherapy had longer OS compared to patients without an increase (25.3 vs. 9 months, p 0.15). ConclusionsThis study demonstrates that CTCs at baseline and Cycle 2 of chemotherapy correlate with disease stage and survival in patients with SCLC, suggesting that CTCs may be used as a surrogate biomarker for clinical response. Confirmatory prospective clinical trials are needed before we can incorporate routine evaluation of CTCs into clinical practice.

Highlights of This Issue

Defects in homologous recombination repair genes (e.g., BRCA1 and BRCA2 mutations) can sensitize tumors to poly(ADP-ribose) polymerase (PARP) inhibition through synthetic lethality. This phase I–II study was the first to evaluate single-agent oral rucaparib, a potent PARP inhibitor, at multiple doses in patients with advanced solid tumors (Part 1; phase I), establish the recommended phase II dose (RP2D) of 600 mg twice daily, and evaluate the RP2D in patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation (Part 2A; phase II). Rucaparib was tolerable and had robust antitumor activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC.Germinal center B-cell (GCB) has a better prognosis than non-GCB diffuse large B-cell lymphoma (DLBCL) to upfront therapy. Cell-of-origin (COO) determination using gene expression profiling (GEP) is more sensitive, reproducible, and robust than immunohistochemistry. Czuczman and colleagues designed a randomized study using COO-based subtyping to elucidate differences in activity of lenalidomide over salvage monotherapy in relapsed/refractory DLBCL. Lenalidomide elicited higher ORR and longer PFS in non-GCB patients (most pronounced in ABC-designated patients). These results provide an additional rationale for the ongoing phase 3 trial, ROBUST (NCT02285062), of lenalidomide plus immunochemotherapy versus immunochemotherapy alone in patients with treatment-naive GEP-selected ABC-subtype DLBCL.The improvement of imaging and therapeutic targeting of tumors requires the identification of novel target-specific tracers. To address HNSCC tumors, Altmann and colleagues performed alternating biopanning on membrane proteome of HNO97 tumor cells fractionated by the ProteomeLab PF2D system and corresponding HNO97 cells using a sunflower trypsin inhibitor1-based phage display (SFTI8Ph) library. A novel ITGαvβ6-binding peptide (SFITGv6) was identified providing high stability and demonstrating affinity for ITGαvβ6-positive HNSCC and other carcinomas. SFITGv6 accumulated in tumor tissues but not in normal tissues or inflammatory lesions, and thus represents a promising tracer for imaging and endoradiotherapy.Deubiquitylating (DUB) enzymes have emerged as potential therapeutic targets. Das and colleagues examined the functional significance of DUB enzyme USP1 in multiple myeloma (MM) using an irreversible USP1 inhibitor SJB3-019A. USP1 is highly expressed in patient multiple myeloma (MM) cells. USP1 blockade with SJB3-019A decreases the viability of MM cells, inhibits DNA repair and USP1/ID/Notch/Sox pathways, and overcomes bortezomib-resistance. SJB induced generation of more mature and differentiated plasma cells. Combination of SJB with bortezomib, ACY1215, lenalidomide, or pomalidomide triggers synergistic anti-MM activity. These preclinical data provide basis for clinical evaluation of USP1 inhibitors in MM to overcome proteasome inhibitor resistance.