Longer PFS Research Articles

Prognostic value of SOX2 and CD8+TIL in limited stage small cell lung cancer.

e21108 Background: SOX2 is a transcriptional factor that drives embryonic stem cell to neuroendocrine cells in lung development and is highly expressed in SCLC. The serum SOX2 antibody in SCLC has been known to mediate neurologic paraneoplastic syndrome. In this study, we evaluated the expression of SOX2 and CD8+ tumor infiltrating lymphocyte (TIL) in LS-SCLC from clinical tumor tissue and their impact on PFS and OS. Methods: Among the total 245 patients with SCLC treated between 2010 and 2018, 75 patients with LS-SCLC with available tumor tissue were enrolled. SOX2 and CD8+ TIL were evaluated by immunohistochemistry. High SOX2 expression was defined as above 100 of H score that was derived from multiplying intensity by the proportion of stained tumor cells. The number of CD8+TILs was counted under high magnification (x400) with four fields in intratumoral area. The cut value for high CD8+TIL was the above the median of total case. Results: 64 patients (85.4%) received etoposide/platinum and definite local therapy (radiation therapy or surgery) and 18 patients (24.0%) received surgical resection. High expression of CD8+ TIL was related to significantly longer PFS (13.9 vs. 8.0 months, P = 0.014) and tended to related to longer OS (32.1 vs. 17.4 months, P = 0.056) than low expression. High expression of SOX2 was tended to related with longer OS and PFS compared to low expression of SOX2 (median, 21.7 vs. 17.1 months, P = 0.118; 12.7 vs. 9.0 months, P = 0.110, respectively) without statistical significance. 29 patients with high CD8+TIL among 52 patients with high SOX2 had significantly longer PFS and OS compared to the other groups (median PFS 19.3 vs. 8.4 months, P = 0.002 and median OS 35.7 vs. 17.4 months, P = 0.004, respectively). Multivariate Cox regression analysis showed that combined high expression SOX2 and CD8+ TIL was an independent good prognostic factor for OS (HR = 0.449, P = 0.018) and PFS of SCLC (HR = 0.481, P = 0.021). Conclusions: In our study, high expression level of combined SOX2 and CD8+ TIL were related to longer OS and PFS, and it could be used as a prognostic biomarker for LS-SCLC. [Table: see text]

A phase Ib/II study of eribulin with cyclophosphamide (EC) in patients (pts) with advanced breast cancer (ABC).

e13079 Background: Eribulin is an effective microtubule inhibitor for the treatment of ABC. Based on encouraging efficacy with docetaxel/cyclophosphamide, we hypothesized that eribulin combined with cyclophosphamide (EC) would be effective with tolerable toxicity. The aim of the study was to determine the maximum tolerated dose (MTD) of EC, followed by a dose expansion study to estimate the clinical benefit rate (CBR) of EC in pts with ABC. Methods: Study eligibility included pts with histologically confirmed ABC with any number of prior lines of therapy. Pts were treated using a dose escalation strategy with cohort expansion once MTD was determined. Dose level 0 (DL0): E 1.1 mg/m2 on days 1 and 8, C 600 mg/m2 on day 1 of a 21-day cycle. DL1: E 1.4 mg/m2 on days 1 and 8, C 600 mg/m2 on day 1 of a 21-day cycle. Phase II expanded enrollment at DL1. The primary objective of the phase II study was CBR [(complete response (CR), partial response (PR), and stable disease (SD)]. Secondary objectives were response rate (RR), duration of response (DOR), time to progression (TTP), and safety. Using a 2-stage design, responses in 3 of the first 22 pts allowed continued enrollment to a planned 40. Results: No dose limiting toxicities (DLT) were identified in phase Ib (n = 6). 3 pts were treated at DL0 and 3 at DL1, the MTD. 44 pts with ABC were enrolled at the MTD and are included in the analysis. 31 pts had HR+/HER2- disease, 12 pts had triple negative disease (TNBC), 1 pt had HR+/HER2+ disease. Median age was 56 yrs, prior treatment (rx) for ABC included a median of 1 line of hormone rx (range 0-6) and 2 lines of prior chemorx (range 0-7). CBR was 79.5% (35/44; 7 PR, 28 SD) and median PFS 16.4 wks (95%CI:13.8-21.1 wks). Longer PFS was observed in those with HR+ disease vs TNBC (18.1 vs 10.8 wks; P = 0.067). Adverse events (AE) of any grade included fatigue (68.2%, n = 30), neutropenia (ntp) (59.1%, n = 26), nausea (56.8%, n = 25), constipation (50%, n = 22), peripheral neuropathy (47.7%, n = 21), dyspnea (40.9%, n = 18), headache (36.4%, n = 16), and anorexia (36.4%, n = 16). The most common grade 3/4 AE ntp (47.7%, n = 21); 3 pts had febrile ntp. Dose reductions due to ntp were required to 500 mg/m2 C (n = 17) and to 1.1 mg/m2 in eribulin (n = 12). Conclusions: EC in heavily pretreated ABC resulted in an encouraging CBR of 79.5% and PFS of 16.4 wks, comparing favorably to single agent E (PFS 14.8 wks). Dose reduction and delays were due primarily to ntp. EC is an effective combination therapy with manageable toxicity in ABC. Clinical trial information: NCT01554371 .

Longitudinal and personalized detection of circulating tumor DNA (ctDNA) for monitoring efficacy of atezolizumab plus bevacizumab in patients with unresectable hepatocellular carcinoma (HCC).

3531 Background: ctDNA has emerged as a promising biomarker for noninvasive monitoring of treatment response and disease progression in many tumor types. However, the clinical use of ctDNA in patients with HCC has not been established. Here, we evaluated longitudinal and personalized detection of ctDNA for monitoring the treatment response to atezolizumab (atezo) + bevacizumab (bev) in patients with unresectable HCC not previously treated with systemic therapy. Methods: A subset (n = 48) of 104 patients with HCC who enrolled in Arm A of GO30140 (NCT02715531; Phase 1b) and received atezo + bev treatment were included in this study. These patients had 10 CR, 11 PR, 12 SD and 15 PD per IRF-assessed RECIST 1.1. Serial plasma samples were collected at baseline (Cycle [C]1 Day [D]1), during treatment (C2D1, C4D1) and at disease progression. Somatic mutations in individual tumors were identified via whole exome sequencing of archival tumor tissues or fresh biopsies collected before treatment. Personalized ctDNA assays (Signatera 16-plex multiplex PCR next-generation sequencing assay) specific to each patient’s tumor mutational signatures were successfully designed for 47 of 48 patients. Results: At C1D1, a median of 25.7 ng of cell-free DNA was extracted from 2-mL plasma samples. ctDNA was detected in 45 of 47 patients (96%), with a median of 70.6 mean tumor molecules/mL of plasma (MTM/mL) and a median of 1.8% mean variant allele frequency (mean VAF) in plasma. Higher ctDNA levels detected at C1D1 appeared to be associated with increased tumor burden ( P < 0.03). Dynamic changes in ctDNA levels post-treatment were associated with response at C4D1. ctDNA status changed from positive at baseline to negative in 7 of 10 CR (70%), 3 of 11 PR (27%), 1 of 11 SD (9%) and 0 of 11 PD (0%) patients. Longer PFS was observed in patients whose ctDNA became undetectable post-treatment. The median PFS in patients with ctDNA present vs cleared at C4D1 was 6.5 months and not reached, respectively (HR, 12 [1.7-93], log-rank P < 0.00029). Conclusions: Our study showed that Signatera, a personalized and tumor-informed ctDNA assay, could be used as a sensitive method for detecting ctDNA in patients with unresectable HCC. More importantly, our results illustrate the promise of ctDNA as an emerging biomarker that may potentially help to monitor treatment responses and disease progression in patients with HCC.

Tumor mutational load, microsatellite instability and actionable mutations in metastatic colorectal cancer: Results from the TRIBE2 study.

4077 Background: In the TRIBE2 study molecularly unselected and untreated mCRC patients were randomized to receive FOLFOXIRI/bevacizumab (bev) followed by the same agents after disease progression (PD) or FOLFOX/bev followed by FOLFIRI/bev after PD. We performed a comprehensive NGS analysis of samples from randomized patients in order to investigate the prognostic impact of tumor mutational load (TML), its additional value with respect to the assessment of microsatellite instability (MSI), and the overall prevalence of potentially actionable alterations. Methods: Tumor DNA was obtained from formalin-fixed, paraffin-embedded blocks from primary tumors of 296 (44%) out of 679 randomized patients and underwent NGS analysis using the Caris MI TumorSeek panel, assessing 592 genes. TML was defined low, intermediate or high if < 7, 7-16 or > 16 mutations/Mb were found. MSI status was determined both by NGS and by IHC. Results: TML and MSI were successfully determined by NGS in 224 (76%) cases. NGS and IHC results were concordant in 221 (99%) cases. TML was low, intermediate or high in 56 (25%), 157 (70%) and 11 (5%) cases, respectively. When compared with TML low and intermediate tumors, TML high were more frequently right-sided (p = 0.013), mucinous (p < 0.001) and MSI-high (p < 0.001). TML high tumors were MSI-high or MSS in 8 (73%) and 3 (27%) cases, respectively. Two out of 3 TML high and MSS tumours showed a pathogenic POLE mutation (p.S459F and p.P286R). The other TML high, MSS and POLE wt tumor was dMMR at IHC (loss of MSH6 expression) and showed a pathogenic MSH6 mutation (p.F1040fs). As compared with low and intermediate TML, high TML was associated with longer PFS (median PFS: 17.3 vs 10.6; HR: 0.54 [95%CI: 0.35-1.09], p = 0.098) and OS (median OS: not reached vs 23.7: HR: 0.45 [95%CI:0-28-1.13], p = 0.106). No interaction effect between TML and treatment arm was observed, and no difference between TML low and intermediate tumors was reported in terms of baseline characteristics and prognosis. Actionable alterations ( HER2 mutations [N = 2] and amplifications [N = 4], KRAS G12C [N = 10] and BRAF V600E mutation [N = 39]) were found in 55 (19%) out of 296 cases. No NTRK/ROS/ALK or MET amplification was found. Conclusions: TML high tumors are not limited to MSI-high ones but showed POLE or MSH6 somatic mutation and shower longer PFS and OS. No differences are reported between TML low and intermediate tumors. Molecular alterations predictive of benefit from targeted strategies currently available are detectable only in a small percentage of mCRCs.

Prognostic role of T3/T4 ratio in metastatic renal cell carcinoma (mRCC): Preliminary results of the threeFOUR multicenter study (Meet-Uro 14).

e17093 Background: Thyroid hormones metabolism can be altered in patients (pts) with chronic diseases and/or undergoing cancer treatments. The prognostic role of T3/T4 ratio has been investigated in metastatic colorectal cancer pts in whom a high T3/T4 ratio predicted longer survival. No data are available in mRCC. Methods: We retrospectively reviewed the clinical charts of pts with mRCC treated in first line for metastatic disease at 8 Italian Oncology Units before March 2017, having at least one response assessment and baseline complete thyroid panel data available. T3/T4 was calculated as the ratio of the two value of hormones and categorized in tertiles. Results: We identified 96 pts, median age 62 years (range 27-82), 72% males. Sunitinib wad administered in 56% of pts, pazopanib in 38%, nivolumab and ipilimumab in 6%. According to Heng Score, 33% of the pts were at favorable risk, 58% at intermediate risk, 9% at poor risk. With a median follow-up time of 42.8 months, median PFS was 24.8 months, estimated median OS was 71.6 months. Tertile distribution of patients was 36.4% in the high, 29.1% in the medium and 34.5% in the low subgroup. A baseline high tertile value (≥ 0.35) predicted longer PFS (39.4 vs 21.8 1vs 4.5 months, p = 0.01), while median OS has not been reached in the three tertiles, with survival at 24 months being 69.7%, 82.1% and 91.4%, respectively in the low, medium, high group (p = ns). The high T3/T4 ratio is also strongly associated with the chance to achieve a partial or complete response (42.8% vs 39.9% vs 21%, X squared test, p < 0.001). Heng prognostic model retained its prognostic role in this cohort (median OS was 77.1 vs 48.4 vs 22.3 months, p < 0.001, respectively for favorable, intermediate or poor risk group) and also predicted PFS (median PFS 38.2 vs 17.2 vs 8.4 months, p = 0.004). Baseline NLR ≥ 3 predicted shorter OS (46.5 vs 77.1 months, p = 0.02) in the whole group. Conclusions: In our retrospective multicenter experience, a high T3/T4 ratio was associated with longer PFS and a higher probability to respond to the treatment. Median OS had not been reached for all the subgroups, probably due to a favorable patients selection. A longer follow-up is needed to validate the prognostic value of T3/T4 ratio in this cohort.

Clonal dominance of EGFR and efficacy of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC.

e21501 Background: Though EGFR mutations in lung cancer are identified most often on the trunks of tumor phylogenetic trees in early stage, whether EGFR would always be the dominant clone in the advanced stage is unknown, as cancer evolution often follows a branched trajectory, with divergent subclones evolving simultaneously. The impact of clonal dominance of EGFR on outcomes with targeted therapies has not been explored. Methods: Paired tumor and plasma samples at diagnosis were obtained from systemic treatment naïve patients with advanced NSCLC in the clinical trial (NCT03059641). cfDNA and tumor DNA were sequenced by target-capture deep sequencing of 1021 genes related to solid tumors, with blood cells as the germline control. Clonal dominance analysis was performed on the basis of the CCF determined for SNVs and clustered in plasma or tumor sequencing data using a modified version of Pyclone. PFS was estimated using Kaplan-Meier method and compared using log-rank test. Results: From February 2017 to December 2019, 300 advanced NSCLC patients were enrolled prospectively from 14 centers cross China. One hundred and fourteen EGFR mutant patients treated with EGFR-TKI were followed until disease progression (PD). The medium follow-up time was 10 month (1-27 months) and 92 (80.7%) patients have reached PD, with the ORR of 74.6% (85/114), mPFS of 10.5 months. Clonal dominance analysis of EGFR showed 76 patients had EGFR as the dominant clone according to tissue NGS results, and 66 patients as the dominant clone according to plasma cfDNA NGS results (p = 0.04). The ORR was significantly higher for patients with EGFR as dominant clone according to plasma cfDNA NGS results (84.8% vs 60.9%, p = 0.016), and PFS was significantly longer (12 vs 8 months, HR = 2.58). There was no difference when using tissue NGS results to analyze EGFR clonal dominance. However, if comparing patients who were defined as EGFR dominant clone by both tissue and plasma (n = 44) with those defined as EGFR nondominant (n = 9), EGFR dominance was associated with higher ORR (84.1% vs 44.4%, p = 0.01), and longer PFS (11 vs 6 months, HR = 9.88) significantly. Moreover, multivariate Cox proportional hazard ratio analysis demonstrated it as an independent prognostic indicator of EGFR-TKIs. Conclusions: Clonal dominance of EGFR in the pretreatment plasma cfDNA is associated with the efficacy of EGFR-TKIs in NSCLC. This study indicated the importance of evaluating clonal dominance in the current clinical practice and future trial designs. Clinical trial information: NCT03059641.

Estimated clinical efficacy and radiographic response characteristics of PD1 inhibition in newly diagnosed and recurrent glioblastoma in clinical practice: A report from the iRANO Working Group.

2521 Background: Despite concerns of immunotherapy-induced inflammatory response during PD1 inhibition, questions remain as to the true incidence of inflammatory response and potential clinical implications. The goals of the project were to use GBM patients pooled from academic centers to estimate radiographic PFS and OS, as well as determine the incidence of immunotherapy-induced inflammatory response. Methods: 152 patients with newly diagnosed (N = 57) or recurrent (N = 95) GBM treated with either nivolumab or pembrolizumab from Dana-Farber (N = 88), UCLA (N = 35) or UCSF (N = 29) were included in this study. Radiographic progression was defined by a 25% increase in bidirectional measurements according to RANO. Results: Median PFS and OS for newly diagnosed patients was 162 and 520 days, respectively, while median PFS and OS for recurrent patients was 72 and 225 days, respectively. No difference in OS was observed in recurrent patients treated with nivolumab vs. pembrolizumab (P = 0.58), but recurrent patients treated with nivolumab trended toward a longer PFS (P = 0.097). Of the recurrent patients with OS and PFS data available and radiographic progression, 95% of them progressed within 6 mos of starting treatment. Median post-progression survival (PPS) in recurrent patients with PFS < 6 mos was 151 days, while PPS for patients with PFS > 6 mos was 178 days (P = 0.51). In the 77 recurrent patients who progressed within 6 mos, 36.4% had an OS that was > 9 mos, while 63.6% had an OS < 9 mos, suggesting the majority of patients with “early progression” also died early and a minority of patients had what could be considered “immune-related inflammation”. Of the 81 recurrent patients with documented progression, only 2.5% showed stabilization within 3 mos of first progression, 30.9% died before the 3-month confirmation scan could be obtained, 24.7% showed continued tumor growth by 3 months, and 48.1% had no follow-up confirmatory imaging exams. Of the 70 patients who progressed within 6 mos and had documented death, 2.9% had disease stabilization, 31.4% died before the 3-month confirmation, and 75.7% had either documented tumor growth or had no follow-up confirmatory imaging exams. Conclusions: This study suggests immunotherapy-induced inflammation followed by a favorable PPS is uncommon in GBM. While patients treated with other types of immunotherapy may exhibit different imaging characteristics, these data provide an important basis to refine the iRANO criteria.

Association of neutrophil to lymphocyte ratio (NLR) with efficacy from JAVELIN Renal 101.

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 .

Multicenter analysis of treatment outcomes for well differentiated grade 3 neuroendocrine tumors (NET G3).

4607 Background: Well differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications from 2017 and 2019. Retrospective data suggest that commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Therefore, current treatment guidelines suggest alternative first-line treatment protocols like temozolomide-based (TEM), streptozotocin-based (STZ) and FOLFOX which have only been studied in second-line so far. The aim of this multicenter analysis was to evaluate treatment outcomes for NET G3 with a focus on the efficacy of different first-line regimens. Methods: We performed retrospective analysis of all patients with NET G3 in the NEN databases of 3 German cancer centers. All histopathological findings were reviewed by the investigators in order to comply with the most current WHO classification. Results: A total of 131 patients could be identified. Median Ki67 was 30 %, primary tumors were located in the pancreas in 71 % of cases, 20 patients had a history of prior NET G1/G2 diagnosis. Median overall survival (OS) was 138.1 months with a median follow-up of 20.4 months. 125 patients received palliative first-line therapy: PE n = 34, FOLFOX n = 36, TEM (mostly temozolomide+capecitabine) n = 21, STZ n = 19, other (including targeted agents, somatostatin analogues, PRRT and multimodal combination approaches) n = 15. Overall response (ORR) and disease control rate was 35.3 % and 67.6 % for PE, 52.8 % and 80.6 % for FOLFOX, 28.6 % and 66.7 % for TEM, 47.4 % and 68.4 % for STZ, 20.0 % and 73.3 % for other respectively. Median progression-free survival for PE was 5.2 months. Compared to PE, PFS in the other treatment groups was 6.0 months for FOLFOX (p = 0.164), 12.0 months for TEM (p = 0.059), 5.7 months for STZ (p = 0.519), 14.1 months for other (p = 0.003). All non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 vs. 5.2 months; p = 0.011). 89 patients received second-line systemic therapy with a median PFS of 5.3 months. Conclusions: In this first multicenter analysis of different treatment strategies for NET G3, patients receiving upfront treatment with non-PE regimens had a significantly prolonged PFS. Of the single defined protocols, FOLFOX showed the highest ORR, and TEM the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this newly defined tumor entity is needed.

Polymorphisms of Drug-Metabolizing Enzymes and Transporters Contribute to the Individual Variations of Erlotinib Steady State Trough Concentration, Treatment Outcomes, and Adverse Reactions in Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Patients.

BackgroundErlotinib is presently the first line treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) active mutation. An increasing number of evidences show that the treatment efficacy and toxicities are considerably heterogeneous among individuals. Hence, it is necessary to find biological predictors for further individualized treatment of erlotinib in NSCLC patients.MethodsOur present study enrolled 87 cases of NSCLC patients who had been administrated erlotinib with a fixed dose (150 mg/d). Eleven polymorphisms in seven genes of drug-metabolizing enzymes and transporters were genotyped and the steady state trough concentrations were also determined.ResultsThere were significant variances in the steady-state erlotinib trough plasma concentrations, ranging from 315.6 ng/ml to 4479.83 ng/ml. Erlotinib steady state trough concentration was remarkably lower in current smoking patients. The steady state trough concentration of GG in rs1048943 of CYP1A1 was significantly higher than that of AA allele carriers. The polymorphism of CYP1A2 was significantly associated with the severity of skin rash, and the development of diarrhea was associated with SNPs in ABCB1 and CYP3A5. We also observed that GG allele in CYP1A1 was accompanied with a longer PFS in our study.ConclusionA large variability of erlotinib steady state trough concentration was found among Chinese Han population. SNPs in CYP1A1 appeared to influence the steady state trough concentration of erlotinib. Correlation between CYP1A2 polymorphisms and severity of skin rash was observed, together with the correlation between the development of diarrhea and SNPs in ABCB1 and CYP3A5.

The role of 11C-methionine PET in patients with negative diffusion-weighted magnetic resonance imaging: correlation with histology and molecular biomarkers in operated gliomas.

To compare 11C-methionine (11C-METH) PET with diffusion-weighted MRI (DWI-MRI) diagnostic accuracy and prognostic value in patients with glioma candidate to neurosurgery. We collected and analyzed data from 124 consecutive patients (n = 124) investigated during preoperative work-up. Both visual and semiquantitative parameters were utilized for image analysis. The reference standard was based on histopathology. The median follow-up was 14.3 months. Overall, 47 high-grade gliomas (HGG) and 77 low-grade gliomas (LGG) were diagnosed. On visual assessment, sensitivity and specificity for differentiating HGG from LGG were 80.8 and 59.7% for DWI-MRI, versus 95.7 and 41.5% for 11C-METH PET, respectively. On semiquantitative analysis, the sensitivity, specificity, and area under the curve were 78.7, 71.4, and 80.4% for SUVmax, 78.7, 70.1, and 81.1% for SUVratio, and 74.5, 61, and 76.7% for MTB (metabolic tumor burden), respectively. In patients with negative DWI-MRI and IDH-wild type, SUVmax and SUVratio were higher compared to IDH-mutated (P = 0.025 and P = 0.01, respectively). In LGG, patients with 1p/19q codeletion showed higher SUVmax (P = 0.044). In all patients with negative DWI-MRI, median PFS was longer for SUVmax <3.9 (median not reached vs 34.2 months, P = 0.004), SUVratio <2.3 (median not reached vs 21.5 months, P < 0.001), and MTB <3.1 (median not reached vs 45.7 months, P = 0.05). In LGG patients with negative DWI-MRI, only SUVratio <2.3 and MTB <3.1 were associated with longer PFS (P = 0.016 and P = 0.024, respectively). C-METH PET was found highly sensitive for glioma differentiation and molecular characterization. In DWI-negative patients, PET parameters correlated with molecular profile were associated with clinical outcome.

Abstract P5-01-12: Plasma thymidine kinase 1 activity and outcome of ER+ HER2- metastatic breast cancer patients treated with palbociclib and endocrine therapy

Abstract Background: Thymidine kinase 1 (TK1) has a crucial role in DNA synthesis and cell proliferation. Prior cohort studies reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC) treated by endocrine therapy. We report here the prognostic impact of pTKa, assessed in a prospective study on ER+ HER2- MBC patients treated by endocrine therapy and CDK4/6 inhibitor. Patients and methods: Patients were included after written informed consent into the prospective, ethically approved ALCINA study (NCT02866149), investigating the feasibility of the analysis of circulating tumor markers in blood in various early- or advanced-stage malignancies. Eligibility criteria were patients aged &amp;gt;18 years with ER+ HER2- MBC, treated at the Institut Curie with endocrine therapy (aromatase inhibitor or fulvestrant) and palbociclib. Plasma samples were obtained at baseline (prior to treatment start) and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden), following the manufacturer recommendations and with blinded patient characteristics and outcomes. We investigated the association between baseline and 4 weeks pTKa, patient characteristics and outcomes (progression-free survival-PFS and overall survival-OS). “Low” and “high” pTKa were defined using the median level of pTKa at each time point. Quantitative pTKa were compared using the Mann-Whitney test. Survival curves were compared by an unstratified log-rank test. Results: From 05.2016 to 08.2018, 103 patients treated with endocrine therapy and palbociclib were included. Median age was 64 years (range 26-89). Patients had received a median of 2 prior systemic therapies for MBC (range 0-10). After a median follow-up of 13.8 months (range 6-31), 73 relapses (71%) and 25 deaths (24%) were observed, with median PFS and OS of 9.6 months (95%CI[7-11.3]) and 27.9 months (95%CI[22.5-33.2]), respectively. Median baseline pTKa was 292 Du/L (range 0-27312 Du/L, IQR[89-853]). In univariate analysis, a low baseline pTKa was significantly associated with longer PFS and OS compared with high baseline pTKa (11.7 months (95%CI[7.4-16]) vs 9.1 months [4.4-14]; p=0.02, and NR vs 24.8 months [16-33]; p=0.05, respectively). After 4 weeks (N=85 patients), median pTKa was 134 Du/L (range 0-3877 Du/L, IQR[43-595]). In univariate analysis, a low pTKa at 4 weeks was also associated with longer PFS and OS compared with high pTKa (10.4 months [7.9-13] vs 4.7 months [1.2-8.3]; p=0.02, and NR vs 20 months [16-23]; p&amp;lt;0.001, respectively). Patients with a PFS below 6months had a significantly higher pTKa level at 4w (median 256 Du/L versus 100Du/L, p=0.046). After adjusting for prognostic factors (i.e. number of previous lines of systemic treatments, endocrine resistance, presence of visceral metastases, performance status, age, de novo MBC): baseline pTKa and 4w pTKa remained significant prognostic factors for both PFS and OS (p&amp;lt;0.001). Sensitivity analyses suggested that pTKa changes between baseline and 4w had no significant prognostic impact and that 4w pTKa had a superior prognostic impact than baseline pTKa. Conclusion: pTKa demonstrated its clinical validity as a new dynamic circulating prognostic marker for ER+ HER2- MBC patients treated with endocrine therapy and palbociclib. The clinical utility of this promising biomarker has to be determined in a adequately designed prospective trial of combined targeted and endocrine therapies. Citation Format: Luc Cabel, Marie Laure Tanguy, Florence Lerebours, Etienne Brain, Delphine Loirat, Mattias Bergqvist, Paul Cottu, Anne Donnadieu, Anne Bethune, Manuel Rodrigues, Jean-Yves Pierga, François-Clément Bidard. Plasma thymidine kinase 1 activity and outcome of ER+ HER2- metastatic breast cancer patients treated with palbociclib and endocrine therapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-01-12.

Abstract P1-19-40: Apatinib in the treatment of HER-2 negative advanced breast cancer with chest wall metastasis multicenter phase II clinical study

Abstract Background: Angiogenesis is a key mechanism of tumour growth. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptor 2 (VEGFR-2) and blocks downstream signalling and inhibiting tumour angiogenesis. It was approved in China to treat gastric cancer in October 2014. However, as breast cancer with a chest wall metastasis (CWM) has rich vascular distribution, whether Apatinib is also effective for breast cancer with a chest wall metastasis remains unknown. Therefore, we designed this clinical study to address this question. Method: The trial involved four centres in China from September 2016 to July 2019. It enrolled patients (pts) who were diagnosed of HER2 negative breast cancer with CWM and experienced first line or could not afford standard treatment. The patients were given Apatinib 500mg/day (single or combined with endocrine therapy if hormone receptor positive (HR+)) until progression or side effect not tolerated. Each patient had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1.This study was approved by ethics committee at the Ethics Committee of Beijing Cancer Hospital, and all participants provided written informed consent. The trial was also Register to clinicaltrial.gov ( NCT02878057). Results: 30 pts were enrolled in the study with a median age of 50 (range 35-69) years old. Among the 30 pts, there were 23 ER positive pts (76.7%). 17 pts (56.7%) had more than 2 sites of metastasis, and 5 pts had invasive metastasis (16.6%). 15 pts (50%) were multi pre-treated. The response of 19 pts (63.3%) could be evaluated, and the overall response rate was 57.9% (no CR, 11 cases reached PR, 2 in HR-, 9 in HR+). and the median PFS was 8.6 months (range 0.5-29.5; 95% CI 0.0-18.7). The tumour in chest wall shrunk obviously. Side effects also existed. 15 pts (50%) had hypertension (grade 3: 6.7%); 10 pts (33.3%) had proteinuria (grade 3: 20%); 4 pts (13.3%) had fatigue (grade 3: 3.3%); 3 pts (10%) had bilirubin increase (grade 3: 6.7%). 8 pts discontinued the treatment due to side effects and 3 due to personal reasons. The Apatinib dose was reduced from 500mg to 250mg for most pts 18/30 (60%), and some pts took 500 mg and 250 mg every other day 10/30 (33.3). Conclusion: Apatinib was effective for pts with chest wall metastasis and pts could benefit from longer PFS. However, the side effects should be pay more attention from start on apatinib treatment. Citation Format: Huiping Li, Cuizhi Geng, Guohong Song, Hanfang Jiang, Zhongshen Tong, Junlan Yang, Ran Ran, Ruyan Zhang, Yaxin Liu, Xinyu Gui, Maorong Wei, Lu Xue. Apatinib in the treatment of HER-2 negative advanced breast cancer with chest wall metastasis multicenter phase II clinical study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-40.

T-cell receptor diversity as a prognostic biomarker in melanoma patients.

There is increasing evidence that T-cell receptor (TCR) repertoire diversity can be a predictive biomarker of immune responses in cancer patients. However, the characteristics of the T-cell repertoire together with its prognostic significance in melanoma patients and impact on disease progression remain unknown. We investigated the combinatorial TCR repertoire diversity by semi-quantitative multi-N-plex PCR in peripheral blood samples from 44 melanoma patients together with seven matched metastatic lymph nodes and explored its potential predictive value on clinical prognosis. The diversity was quantified by calculating both richness (number of different specificities) and evenness (relative abundance of the different specificities). Our results revealed that a higher TCR repertoire diversity in blood of patients was associated with a longer PFS, while divpenia (low repertoire diversity) was linked with poor prognosis. The diversity was significantly higher in patients undergoing late relapse and long survival compared to patients who progressed rapidly. Interestingly, the TCR repertoire diversity in tumor may have a potential prognostic value. Thus, our study highlights that the TCR repertoire diversity is a prognostic indicator of clinical outcome in patients with melanoma.

Efficacy and safety of nab-paclitaxel plus S-1(nab-P/S-1) versus nab-paclitaxel plus gemcitabine (nab-P/Gem) for first-line chemotherapy in advanced pancreatic ductal adenocarcinoma (aPDAC): A randomized study.

717 Background: Nab-P/Gem significantly improved survival compared with gem in patients (pts) with metastatic PDAC, but the ORR was limited to 23% with increased myelosuppression. Two phase II trials demonstrated high ORR of 50.0-53.1% with nab-P/S-1 and showed less hematologic toxicity. Methods: A randomized (1:1) phase II trial was conducted. Eligibility required treatment-naïve pts with unresectable PDAC. Pts received nab-P 125mg/m2on day 1 + S-1 80-120mg orally per day on day 1-7 every 2 weeks or nab-P 125mg/m2+ Gem 1000mg/m2 on days 1,8 every 3 weeks. With an increase of ORR from 25% to 50%, 100 pts were required for 90% power at a two-sided significance level of 0.05. We enrolled 40 pts for a pilot study. Primary endpoints were ORR and 6-month PFS rate. Secondary endpoints were ORR of primary lesion, DCR, PFS, OS and safety. Results: 40 pts were enrolled between 06/2018 and 06/2019, including locally advanced (27.5%) and metastatic (72.5%) PDACs. 42.5% were male and the median age was 61 (range, 36-75) years old. The median duration of treatment was 2.3 months in nab-P/S-1 (n = 20) and 2.7 months in nab-P/Gem (n = 20). In the intention-to-treat (ITT) population, the ORR and DCR were 35.0% vs 25.0% ( P= 0.49) and 70.0% vs 70.0%, respectively.The ORR of primary lesion was 30.0% vs 25.0% ( P= 0.72). In the evaluable pts (nab-P/S-1 n = 18, nab-P/Gem n = 18), the ORR, DCR and the ORR of primary lesion were 38.9% vs 27.8%, 77.8% vs 77.8% and 35.3% vs 29.4%, respectively.With the median follow-up of 5.0 (range 0.3-11.4) months, the median PFS and 6-month PFS rate was 6.3 vs 5.7 months and 56.1% vs 36.2%( P= 0.61) for nab-P/S-1 and nab-P/Gem, respectively. The median OS have not reached. Grade 3/4 toxicities occurred in 30.0% nab-P/S-1 and 30.0% nab-P/Gem: leukopenia/neutropenia(15.0% vs 25.0%), febrile neutropenia (0 vs 5.0%), rash (0 vs 5.0%) and diarrhea (10.0% vs 0). Conclusions: Compared with nab-P/Gem, nab-P/S-1 had higher ORR, ORR of primary lesion and longer PFS without significant difference. Nab-P/S-1 developed a trend towards less hematologic toxicity. Follow up for survival is ongoing. Clinical trial information: 03636308.

Gefitinb along with methotrexate as palliative therapy in PS 3 and above in metastatic esophagus squamous cell carcinoma with focus on Q-TWIST.

355 Background: Metronomic therapy is proven method for treatment of terminally ill patients with malignancy, who are not fit for chemotherapy. The median PFS was significantly superior in responders in previous Indian experiences. However most of them were done in head and neck cancers.The prognosis of patients with metastatic esophageal cancer remains poor with only option being symptomatic care. As the previous experiences show metronomic therapy is safe among various options and there is no study focusing on Quality-Adjusted Time Without Symptoms or Toxicity (Q-TWiST) in southern Indian population,we thought of evaluating the same. Methods: Details of 42 subjects with refractory or progressive metastatic squamous cell carcinoma esophagus having PS &gt; 2 were evaluated. Case records between 2017 September and 2018 September were analyzed for TWIST and QOL. Patients received Gefitinib (250 mg/day), Methotrexate 15 mg IM weekly or in combination. Patients were stratified into those with improved PS and those without. The subjects without PS improvement were continued on the single agent and those with improvement were offered additional chemotherapy based on physician/ patient preference. Metronomic therapy could be continued beyond disease progression- if there is TWIST/QOL improvement. Results: Out of 42 subjects, 29 had improvement in the PS and were continued later. 9 had stable PS and disease. 4 had worsening of PS. 34 subjects have clinically meaningful response (stable disease + complete + partial responses) and had symptomatic improvement. The median number of cycles was 6 (4–11). The median PFS was 198 days (95% CI, 174 to 214), and the median improvement in QOL was 6 points on a scale of 25. Grade II/IV toxicities were observed in 21 (50%) cases predominantly skin rash, stomatitis and diarrhea. Conclusions: Metronomic therapy is well tolerated and may have a role in the treatment of advanced cancers with poor performance status. 67% of the patients who are otherwise not eligible for any active therapy became eligible and had better QOL and longer PFS, which re-emphasizes role of metronomic therapy in advanced squamous cell carcinoma of esophagus.

Genetic variants involved in bromodomain-containing protein 4 (BRD4) regulating pathway to predict outcomes in patients with metastatic colorectal cancer: Results from FIRE3 and MAVERICC trials.

232 Background: BRD4 plays an important role in transcription, DNA repair and drug resistance. High expression and polymorphisms of BRD4 regulating pathways were reported to be related to worse prognosis in colorectal cancer. Therefore, we hypothesized that genetic variants in BRD4 regulating pathway may predict first-line treatment outcome in mCRC pts. Methods: The impact on outcome of 22 SNPs in 7 genes involved in BRD4 regulating pathway (BRD4, SIPA1, MYC, 53BP1, H2AX, BATF, CD47) was analyzed through the OncoArray, a customized array manufactured by Illumina, on genomic DNA from blood samples of pts enrolled in 2 randomized trials. MAVERICC FOLFIRI/bevacizumab (bev) arm served as discovery cohort (N = 107), FIRE3 FOLFIRI/bev arm as validation (N = 107) and FOLFIRI/cetuximab (cet) arm as control (N = 129). Results: In the discovery cohort, right(R)-sided pts with BRD4 rs4808272 any G allele (N = 46) showed significantly shorter PFS (9.5 vs 18 m) compared to carriers of A/A (N = 21) in both uni- and multi-variable analysis ( p &lt; .01); R-sided pts carrying any T allele of BATF rs7161377 (N = 50) showed longer PFS (12.3 vs 6.8 m) compared to carriers of C/C (N = 14) in univariate analysis ( p &lt; .05) and had a strong trend in multivariable analysis ( p = .06). These findings were all validated in R-sided pts in FIRE3 bev arm (BRD4 rs4808272, PFS 9.8 vs 18.7 m; BATF rs7161377, PFS 15.1 vs 4.2 m) in uni- (both p &lt; .01) and multi-variable ( p = .08 and p &lt; .05 respectively) analysis. No significant association was observed in the control arm. Interestingly, pts carrying CD47 rs3206652 any C allele (N = 13) only showed significant longer PFS (9.0 vs 3.0 m, univariable p &lt; .01 and multivariable p = .07) in the R-sided pts of FIRE3 cet cohort, but no association was observed in the bev-based treatment. Conclusions: Our study demonstrates for the first time that BRD4 and BATF polymorphisms may predict outcomes of bev-based treatment in R-sided mCRC pts; Meanwhile CD47 polymorphism could predict outcomes of cet-based treatment in R-sided mCRC pts. This finding supports a possible role of BRD4 regulating pathway in contributing to resistance to anti-VEGF/EGFR treatment.

CCR5 Δ32 mutation and gene expression to predict outcome in patients (pts) with metastatic colorectal cancer (mCRC): Data from FIRE-3 and MAVERICC phase III trials.

170 Background: Germline polymorphisms in CCR5 have been associated with treatment outcome in pts with mCRC receiving regorafenib and cetuximab-based treatment. CCR5 Δ32, a loss of function deletion, plays a key role in infectious diseases but data in CRC are scarce. We tested whether CCR Δ32 and CCR5 gene expression may be associated with outcome in mCRC pts receiving first-line treatment. Methods: The impact of CCR5 Δ32 was evaluated in 614 pts enrolled in the randomized FIRE-3 trial (FOLFIRI/cetuximab, cet, n = 313; FOLFIRI/bevacizumab, bev, n = 301). Gene expression was evaluated in 102 pts in the FOLFIRI/cet arm from FIRE-3 and 155 pts treated in the MAVERICC trial (FOLFIRI/bev, n = 76; FOLFOX6/bev, n = 79) from tumor tissue by HTG EdgeSeq Oncology Biomarker Panel and NanoString expression panel, respectively. The association between CCR5 Δ32 and clinical outcomes was evaluated using Cox regression and log-rank tests. Gene expression was dichotomized using an optimal cutoff and P-values computed using a permutation-based approach. Results: In FIRE-3, CCR5 Δ32 was significantly associated with worse PFS in patients with right-sided tumors (RT) receiving FOLFIRI/cet (n = 32; median PFS 3.41 vs 7.84 mo; HR 4.39, 95%CI 1.12-17.24; P= .022;). These associations were not observed in left-sided tumors or pts treated with bev. Lower levels of CCR5 expression trended to be associated with shorter PFS and OS in the same subgroup of RT treated in the cet arm ( P= .096 and P= .063 for PFS and OS, respectively). Lower CCR5 expression was associated with longer PFS in pts treated with FOLFIRI/bev in the MAVERICC trial, regardless of tumor side (mPFS 17.91 vs 11.04 mo; P= .03). A significant interaction between the impact of CCR5 expression levels on PFS and chemotherapy backbone was observed ( P= .019). Low CCR5 expression was associated with worse PFS in pts with RT treated with oxaliplatin (11.10 vs 13.80 mo; P= 0.023). Conclusions: Our results provide the first evidence that CCR5 Δ32 and CCR5 gene expression levels may predict outcomes in mCRC pts receiving first-line treatment with a differential effect depending on tumor location, biologic agent and chemotherapy backbone.

Oligometastatic colorectal cancer: Prognostic implications of tumor load, role of locoregional treatments, and of first-line therapy intensification—A pooled analysis of TRIBE and TRIBE2 studies by GONO.

12 Background: According to the ESMO guidelines a metastatic spread involving up to 2 or occasionally 3 sites with 5 or sometimes more metastases (mts) is defined as oligometastatic disease (OMD) and the possibility to offer locoregional treatments (LRTs) should be carefully considered. Tumor load and treatment’s objective (cytoreduction vs disease control) are included among factors affecting the choice of the intensity of the upfront chemotherapy (CT). Nevertheless, no data from clinical trials adopting this definition are currently available, so that the prognostic effect of tumor load, the impact of LRTs and the magnitude of benefit from the CT-intensification in OMD remain unclear. Here we assess the effect of FOLFOXIRI/bev compared to doublets (FOLFOX or FOLFIRI)/bev and the impact of LRTs according to tumor load (OMD vs non-OMD) in a pooled analysis of two randomized phase III studies (TRIBE and TRIBE2). Methods: Subgroup analyses for ORR, PFS and OS were performed according to tumor load at baseline. OMD was defined as up to 5 mts, up to 3 mts in one organ, up to 3 affected organs, mts size ≤ 3 cm, absence of ascites and peritoneal, bone and central nervous system mts. Results: Among 1187 patients (pts) enrolled, 1158 were classifiable: 126 as OMD (11%) and 1032 as non-OMD (89%). Pts with OMD had longer PFS (14.3 vs 10.5 months (mos); p &lt; 0.01) and OS (44.3 vs 24.0 mos; p &lt; 0.01) compared with those with non-OMD. These results were confirmed in multivariable models (p &lt; 0.01). Also among pts who underwent LRTs with curative intent during first line (N = 202), those with OMD at baseline (N = 35) reported longer OS than those with non-OMD (59.6 vs 50.6 mos; p = 0.04). The benefit provided by FOLFOXIRI/bev compared to doublets/bev was confirmed in the OMD subgroup with no interaction effect between treatment arm and tumor load in terms of ORR, PFS and OS (p for interaction = 0.10, 0.58 and 0.23, respectively). Conclusions: OMD is confirmed as a positive prognostic factor and is associated with a higher magnitude of long-term benefit from LRTs than non-OMD. The positive impact of the intensification of the upfront CT is independent of tumor load.

Treatment of Advanced Gastro-Entero-Pancreatic Neuro-Endocrine Tumors. A Systematic Review and Network Meta-Analysis of Phase III Randomized Controlled Trials

Background: Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) in the last twenty years. However, the question about which is the most effective and safest approach for treating advanced well-differentiated GEP-NENs remained unanswered. Methods: In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more therapies for unresectable GEP-NENs. Network metanalysis was used to overcome the multi-arm problem. The last search was carried out on October 1st, 2020. For each arm, we described the surface under the cumulative ranking (SUCRA) curves. The primary endpoints were the progression-free survival and grade 3-4 of toxicity. Findings: We included nine studies involving a total of 2362 patients and five intervention arms: SSA alone, two IFN-α plus SSA, two Everolimus alone, one Everolimus plus SSA, one Sunitinib alone, one 177 Lu-Dotate plus SSA, and one Bevacizumab plus SSA. 177Lu-Dotatate plus SSA had the highest probability (99.6%) of being associated with the longest PFS. This approach was followed by Sunitinib use (64.5%), IFN-α plus SSA one (53.0%), SSA alone (46.6%), Bevacizumab plus SSA one (45.0%), and Everolimus ± SSA one (33.6%). The placebo administration had the lowest probability of being associated with the longest PFS (7.6%). Placebo or Bevacizumab use has the highest probability of being the safest (73.7% and 76.7%), followed by SSA alone (65.0%), IFN-α plus SSA (52.4%), 177Lu-Dotatate plus SSA (49.4%), and Sunitinib alone (28.8%). The Everolimus-based approach had the lowest probability of being the safest (3.9%). Interpretation: The best approaches were: SSA alone or combined with 177Lu-Dotatate. Funding Statement: The authors did not receive funds for this article. Declaration of Interests: None to declare