1st-line Platinum-based Chemotherapy Research Articles

Optimising utility of selective internal radiation therapy in metastatic pancreatic adenocarcinoma.

622 Background: Selective internal radiation therapy (SIRT) using Yttrium-90 containing microspheres has established benefit for a number of cancers but there is limited data available on the utility of SIRT for the treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Methods: In this retrospective audit we identified 32 patients who received SIRT using Yttrium-90 microspheres for metastatic PDAC in 2 treatment centres. All patients received SIRT in combination with chemotherapy. Data was analysed from electronic medical records. Results: Thirty two patients with metastatic PDAC who had SIRT were identified. Patients received SIRT (median activity 1.6 GBq) in combination with chemotherapy (platinum-based; n = 23, non-platinum-based; n = 9). Three patients remain alive and 29 patients were included in the survival analysis. For the entire group, the median OS was 15 months (range 4-49), median survival from time of SIRT was 9 months (range 1-48) and median PFS from time of SIRT was 4 months (range 1-25). Median PFS (6 vs 2 months, p=0.0011) and OS (13 vs 4 months, p=0.0004) from SIRT was significantly better when SIRT was given with 1st-line therapy vs with 2nd-line and beyond. Median PFS from SIRT was significantly better (10 vs 2 months, p=0.0020) when combined with 1st line platinum-based chemotherapy (n=14) vs non-platinum based treatment (n=6). 18 month survival was 40% (n=13) with 9/13 patients having had SIRT with 1st line with platinum-based therapy. 24 month survival was 22% (n=7) with 7/7 patients having had SIRT with 1st line with platinum-based therapy. SIRT was well-tolerated with no associated 30-day all-cause mortality. Grade 3 adverse events were liver abscess (7%, n = 2), gastritis (7%, n = 2) and duodenitis (7%, n=2). Conclusions: This is the first report to analyse optimum utility of SIRT with chemotherapy in metastatic PDAC. Our data suggest SIRT in combination with 1st-line platinum agents contribute to the best outcomes in the setting and warrants further study.

Phase 2 small cell lung cancer (SCLC) cohort of a phase 1b/2 trial of a liposomal formulation of eribulin in combination with nivolumab.

8593 Background: E7389-LF is a liposomal formulation of the microtubule dynamics inhibitor eribulin. Combining E7389-LF with an immune checkpoint inhibitor (ICI; eg, nivolumab) may improve antitumor response via vascular remodeling. The phase 1b part of the open-label Study 120 evaluated the dosing and safety of E7389-LF in combination with nivolumab in patients (pts) with solid tumors. The phase 2 part assessed efficacy and safety in disease cohorts; herein, we report results from the SCLC cohort. Methods: Pts with unresectable and measurable SCLC who had progression during or after 1st-line (1L) platinum-based chemotherapy with/without an ICI were enrolled to the SCLC cohort of the phase 2 part of Study 120. Pts received E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg IV Q3W. The primary objective of the phase 2 part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory objectives included the disease control rate (DCR), overall survival (OS), and biomarker analysis. Tumor response was assessed by investigators per RECIST v1.1 Q6W. All adverse events (AEs) were monitored and recorded. Results: In the SCLC cohort, 34 pts were enrolled; the median age was 66.0 years (range 46–81). At data cutoff (May 31, 2022), 5 pts (14.7%) were undergoing treatment. Discontinuations occurred in 29 pts (85.3%)—26 (76.5%) primarily due to disease progression, 3 (8.8%) due to an AE. Efficacy analyses included 33 pts, as 1 pt had their diagnosis of SCLC changed to a different cancer type after being enrolled. Of the 33 evaluable pts, 27 (81.8%) had an ICI as part of their prior 1L therapy. The ORR of E7389-LF in combination with nivolumab was 24.2% (95% CI 11.1–42.3) in the evaluable population; the DCR was 75.8% (95% CI 57.7–88.9). Median PFS was 3.98 mos (95% CI 2.63–4.40); the 6-mo PFS rate was 27.7% (95% CI 13.0–44.6). At a median follow-up period of 10.6 mos, median OS was not reached (95% CI not estimable); the 6-mo OS rate was 90.9% (95% CI 74.4–97.0). Treatment-related, treatment-emergent (TE)AEs of any grade and of grade ≥3 severity occurred in 97.1% (n = 33) and 82.4% (n = 28) of the 34 enrolled pts, respectively; the most common treatment-related TEAE was neutropenia (any grade: 58.8% [n = 20]; grade ≥3: 52.9% [n = 18]). The neutrophil count nadir occurred around cycle 1 day 8. TEAEs led to dose reduction of E7389-LF in 19 pts (55.9%). Withdrawal of E7389-LF or nivolumab occurred in 5 pts (14.7%): acute kidney injury, cough, myocarditis, pneumonitis, and radiation pneumonitis (n = 1 each). Changes in vascular and immune-related plasma markers were observed. Conclusions: E7389-LF in combination with nivolumab showed notable antitumor activity as 2L therapy in pts with SCLC, as evidenced by the notable ORR of 24.2%. No new safety signals were observed for this combination. Clinical trial information: NCT04078295 .

Efficacy of avelumab in the treatment of oncourological malignances. Results of registration studies and own experience

Background. In the JAVELIN Bladder 100 trial, 1st line maintenance with avelumab in combination with best supportive care significantly increased (9.2 months) overall survival compared to best supportive care in patients with locally advanced or metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy: 29.7 months versus 20.5 months, respectively. Trial results led to inclusion of avelumab into the international guidelines as a standard of care with the highest level of evidence. Combined therapy with avelumab + axitinib in patients with previously untreated metastatic renal cell carcinoma showed higher progression-free survival and objective response rate compared to sunitinib in all IMDC (International Metastatic Renal Cancer Database Consortium) groups. Avelumab + axitinib is one of the immuno-oncology combinations with proven effectiveness for progression-free survival and objective response rate.Aim. To evaluate the effectiveness of avelumab in treatment of oncological urological diseases in routine clinical practice. Materials and methods. At the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology - branch of the National Medical Research Radiology Center, 12 patients with locally advanced inoperable and metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy in combination with gemcitabine received maintenance avelumab therapy. Median follow-up was 10 months. Primary endpoints were overall survival from the start of avelumab maintenance therapy and safety.Combined therapy with avelumab + axitinib was administered in 18 patients with metastatic renal cell carcinoma. Median follow-up was 9 (3-16) months. Overall survival, progression-free survival, response rate and safety in the overall population and according to IMDC groups were evaluated.Results. At data cut-off (March 2023) with median follow-up of 10 months, overall survival was 100 %, progression-free survival was 66.7 % (among patients who received more than 3 infusions - 100 %). Progression-free survival was higher in patients with tumors of the lower urinary tract compared to upper (72.5 % versus 60 %), complete response to induction platinum-based chemotherapy compared to partial response and stable disease (100 % versus 66.7 %) and presence of metastases in the lymph nodes only compared to visceral and bone metastases (100 % versus 66.7 %). Adverse events were observed in 4 (66.7 %) patients.Among 18 patients who received avelumab + axitinib, complete response was observed in 2 (11.1 %) patients, partial response in 6 (33.3 %) patients, stable disease in 9 (50 %) patients, disease progression in 1 (5.6 %) patient. Response to therapy was observed in patients of all prognosis groups; for large (>5 cm) metastases in the lungs, soft tissues, lymph nodes and bones response was observed 3 months after treatment start. Overall survival for this follow-up duration was 100 %, progression-free survival was 96.4 ± 11.2 %. Adverse events were observed in 8 (44.4 %) patients, and in 6 (75 %) of them they were grade I—II and did not require infusion regimen correction or axitinib dose reduction.Conclusion. Avelumab maintenance therapy in the 1st line is the standard of care for patients with locally advanced and metastatic urothelial cancer without disease progression during 1st line platinum-based chemotherapy. Maintenance therapy allows to achieve better overall survival and progression-free survival irrespective of the choice of platinum regimen (cisplatin or carboplatin), response to platinum-based chemotherapy, number of chemotherapy cycles, tumor localization and advancement.Experience of the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology confirms results of the JAVELIN Bladder 100 trial on the effectiveness of avelumab maintenance therapy in routine clinical practice. Combination drug therapy with avelumab and axitinib in patients with metastatic renal cell carcinoma is an effective and safe treatment method which allows to achieve fast objective response and has good tolerability in patients irrespective of IMDC group or metastasis location. Effectiveness and favorable safety profile of avelumab + axitinib combination were proven in the context of routine clinical practice.

1030P Anlotinib plus docetaxel in the treatment of non-small cell lung cancer (NSCLC) after failure of previous immune checkpoint inhibitors (ICIs) therapy: Updated results from a pooled analysis of two phase II trials

ICIs are widely used in 1st -line or 2nd -line treatment of advanced NSCLC, but effective treatment after resistance to ICIs is still controversial. We previously reported some results of the pooled analysis of ALTER-L016 and ALTER-L018, which demonstrated that anlotinib plus docetaxel had encouraging efficacy and manageable toxicity in advanced NSCLC patients (pts) who had been pre-treated with ICIs. Here, we continued to update the efficacy and safety of the combination in the pooled analysis of ALTER-L016 and ALTER-L018. Efficacy and safety data from 2 multi-institutional, randomized, controlled comparative, phase II trials of 73 advanced NSCLC pts who had progressed after 1st-line platinum-based chemotherapy were pooled for this analysis. The studies shared similar dosing intervals and doses, pts were randomly allocated to receive anlotinib (10/12 mg QD from day 1 to 14 of a 21-day cycle) plus docetaxel (60/75 mg/m2 Q3W) (group A+D) or docetaxel (60/75 mg/m2 Q3W) only (group D). Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests. As of 30 April, 2022, 73 pts were available for efficacy and safety analysis (demographics are shown in Table). The median (m) PFS was 5.20 months (m) (95%Cl: 2.96-7.44) vs 2.20 m (95%Cl: 1.06-3.34) in group A+D and group D, respectively (HR: 0.29; 95%Cl: 0.16-0.52, p<0.0001). The mOS has not been reached. For tumor response, the ORR was 34.90% vs 13.30% and the DCR was 93.02% vs 60.00% in group A+D and group D, respectively. The most common grade 3/4 TRAEs were neutropenia (5, 11.6%) and leukopenia (2, 4.7%) in group A+D, and dysphagia (1, 3.3%) in group D.Table: 1030PDemographicsExperimental (anlotinib + docetaxel) (n=43)Control (docetaxel) (n=30)Median age, years62 (31-74)60 (41-73)Age group, years, n (%)< 6018 (41.86)14 (46.67)≥ 6025 (58.14)16 (53.33)Sex, n (%)Men40 (93.02)24 (80.00)Women3 (6.98)6 (20.00)Disease stage, n (%)III5 (11.63)2 (6.67)IV38 (88.37)28 (93.33)ECOG PS, n (%)013 (30.23)9 (30.00)130 (69.77)21 (70.00)Histologic subtype, n (%)ADC20 (46.51)13 (43.33)Non-ADC23 (53.49)17 (56.67)Smoking history, n (%)Never smoker9 (20.93)10 (33.33)Current/ Former smoker34 (79.07)20 (66.67)Brain metastasis, n (%)Yes6 (13.95)4 (13.33)No37 (86.05)26 (86.67) Open table in a new tab Anlotinib plus docetaxel continued to show better clinical efficacy with manageable safety profile in advanced NSCLC pts who had been pre-treated with ICIs.

Capecitabine in pretreated metastatic pulmonary lymphoepithelioma-like carcinoma: A retrospective study.

9093 Background: Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare disease, sharing common histological features with the undifferentiated subtype of nasopharyngeal carcinoma (NPC), and being under-represented in non-small cell lung cancer trials and clinical guidelines. While gemcitabine-based platinum doublet chemotherapy is more established in 1st line treatment of stage IV disease, there is limited evidence for subsequent treatment strategy. Oral capecitabine is one of the active agents in metastatic NPC, and was observed to have encouraging outcomes in pulmonary LELC. Methods: All consecutive patients with pulmonary LELC in 2010 – 2019 treated in a tertiary institution were reviewed. Patients with metastatic disease who progressed after gemcitabine-based platinum doublets and treated with capecitabine were included. Capecitabine was given at 1250 mg/m2 twice daily for 14 days followed by 7 days of rest in each cycle. Treatment response was monitored by clinical history, physical examination and imaging. Treatment was continued till drug holiday, intolerance or disease progression. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Clinical predictors for PFS and OS were analyzed using log-rank test and the Cox proportional hazard model. Results: Of the 140 LELC patients identified, 36 patients satisfied the above inclusion criteria (14 male, 22 female). Median age was 58.6 years old (range 41.5 – 75.6). All patients had an ECOG performance score of 0 or 1. 16 patients (44.4%) received 2 or more lines of prior systemic treatment. Median capecitabine cycles received was 5 (range 2 – 68). Objective response rate was 27.8% (complete response: 5.6%; partial response: 22.2%), disease control rate was 75.0%. With a median follow-up of 15.3 months (range 1.8 – 82.6), the median PFS and OS were 5.4 months (95% CI, 2.1 – 8.8) and 15.4 months (95% CI, 10.0 – 20.7) respectively. Capecitabine was generally well tolerated, with 22.2% grade 3 or above side effects, and 5.6% treatment termination due to intolerance. Bone and distant lymph node (LN) involvement were significant predictors of poorer PFS on multivariate analyses (bone: HR 3.24, 95% CI 1.44 – 7.29, p=0.004; distant LN: HR: 2.62, 95% CI 1.14 – 6.02, p=0.024). Age, sex, smoking history, number of treatment lines, and other sites of disease involvement were not significant predictors. Conclusions: This is to date the largest reported cohort of capecitabine in pre-treated metastatic pulmonary LELC. Capecitabine is effective and well tolerated, and should be considered as a treatment option after 1st line platinum-based chemotherapy. Future studies are warranted to delineate the optimal treatment pathway of this rare disease entity.

Platinum Re-Exposure as a Non-Small Cell Lung Cancer (NSCLC) Treatment Strategy in the Age of Immunotherapy

IntroductionImmunotherapy has prolonged the time that NSCLC patients are off platinum-based (PB) chemotherapy. However, the significance of the platinum-free-interval (PFI) is unclear. We evaluated whether an optimal PFI exists in NSCLC for PB re-exposure in contemporary treatment settings. MethodsWe conducted a retrospective cohort study of patients with metastatic NSCLC treated with 1st-line PB chemotherapy with or without immunotherapy. Using multivariable Cox models stratified by treatment strategies, we evaluated whether salvage PB vs. nonPB chemotherapy resulted in superior outcomes and whether this was modulated by the PFI. ResultsA total of 751 patients treated with salvage chemotherapy after PB chemoimmunotherapy were identified in 2 treatment strategy cohorts: 3rd-line after sequential chemotherapy and immunotherapy (Sequential Chemo IO, n = 604); 2ndline after chemoimmunotherapy (Concurrent ChemoIO, n = 147). An optimal PFI of 5 and 6 months was identified in the Sequential Chemo IO and Concurrent ChemoIO cohorts, respectively, but there was no overall survival or progression free survival advantage for PB vs. nonPB chemotherapy in long or short PFI groups. ConclusionAn optimal PFI was identified in this contemporary NSCLC cohort treated with two common immunotherapy-containing treatment approaches, but PFI threshold did not predict benefit from platinum re-exposure as it has in other malignancies.

Emerging clinical phenotype of bone metastatic urothelial cancer (mUC): Association of early osseous metastases (EOM) and outcomes.

e17007 Background: Outcomes of patients (pts) with mUC with EOM have not thoroughly been described in the age of immuno-oncology. We hypothesized that EOM is associated with worse outcomes when compared to pts with non-osseous metastases (NOM). Methods: We used a multi-institutional database of pts with mUC who received systemic treatment (trt) between March 2005 and August 2019, to assess survival and palliative outcomes of pts with EOM vs NOM at the time of metastatic diagnosis (met dx). Wilcoxon rank-sum and chi-square tests were performed. Survival was estimated by Kaplan-Meier method, Cox regression analysis was performed. Results: We identified 270 pts, 72% men, mean age 67 ± 11 years, 28% never smokers. At met dx, 27% (n = 72) had ≥ 1 EOM; these pts were more likely to have de novo metastases vs. those with recurrent metastases (42% vs 19%, p &lt; 0.001). Pts with EOM were more likely to have a change or stop in 1st line trt due to clinical progression (30.6% vs 15.7%, p = 0.006), and received fewer total lines of systemic trt, median of 1.0 (1.0-5.0) vs. 2.0 (1.0-8.0), p = 0.05. Pts with EOM had shorter median overall survival (OS) vs. those with NOM, (6.1 vs 13.7 months, p &lt; .0001), HR = 2.79 (95% CI:1.95-3.97, p &lt; .0001). Median OS was shorter for pts with EOM who received 1st line immune checkpoint inhibitor (n = 14) vs platinum-based chemotherapy (n = 43), (1.6 vs 9.1 months, p = 0.003). Pts with EOM received higher opioid analgesic doses at the first and last oncology outpatient visits compared to pts with NOM with mean morphine milligram equivalent (MME) dose of 60 ± 91 vs 28 ± 65 at first visit, p = 0.004, and 171 ± 214 vs. 94 ± 229 at last visit, p &lt; 0.001. Conclusions: The presence of EOM in mUC is associated with worse outcomes vs. pts with NOM. Pts with EOM may benefit from 1st line platinum-based chemotherapy vs. checkpoint immunotherapy. Furthermore, pts with EOM experience more pain than pts with NOM and may benefit from early engagement with palliative care. Pts with EOM represent a population with a highly unmet need for systemic, targeted and/or radiation interventions. Molecular subtypes may further define these pts and analysis is planned. We encourage ongoing clinical trials to report outcomes in pts with EOM. A consensus on reporting of non-measurable disease is also needed. [Table: see text]

Response to immunotherapy, platinum-based chemotherapy or their combination in metastatic urothelial carcinoma (MUC) with or without FGFR-3 alterations: Single cohort experience.

560 Background: Fibroblast growth factor receptor-3 (FGFR-3) is a promising target therapy in metastatic urothelial carcinoma. Its role in patient’s clinical outcome and treatment response is unclear. We present data for overall survival (OS) and response to platinum-based treatment, immunotherapy and combination (platinum plus immunotherapy) in MUC. Methods: Enrolled patients were diagnosed with muscle-invasive urothelial cancer (MIUC) between 2/2009-6/2019 at Clinic Hospital of Barcelona, Spain. All have been screened for FGFR-3 alterations using next-generation sequencing or qualitative real-time polymerase chain reaction-based assays in tumour or blood. Demographic, pathology, treatments and treatment response were collected retrospectively. Results: 101 patients with MIUC were screened, 99% had progressed to metastatic stage. At diagnosis 32.67% were metastatic. 77% were man and median age was 68y (38-85y). Median follow-up (FU) since metastatic disease was 16.25 months (1.2-89.72m) with 69.31% of patients had died at cut-off. 32% presented FGFR-3 alteration (fusion =1 and mutation=31). FGFR-3 altered more frequently had papillary histology than FGFR-3 wild type tumours (69 vs 26%, p&lt;0.05). No statistical differences were detected between both groups for gender, age, stage at diagnosis, median FU, primary tumour site (upper vs lower tract) or previous history of non-invasive urothelial carcinoma. 58% patients received 1st line platinum-based chemotherapy, 25% immunotherapy and 8% the combination of both (9% with other therapies). FGFR-3 altered tended to present more benefit (complete, partial response or stable disease) with platinum-based chemotherapy than FGFR-3 wild type (81% vs 62%) but without reach statistical significance. No differences were detected for immunotherapy or combination therapies. Moreover, OS was similar for FGFR-3 altered (median 14.6m) and FGFR-3 wild- type (median 17.1 m) (HR 0.76, p=0.3). Conclusions: In our series, no significant differences related to response to first line therapy or survival was observed.

Evaluating maintenance therapies in advanced oesophago-gastric adenocarcinoma (OGA): Interim analysis and biomarker results from the PLATFORM study.

282 Background: Advanced OGA patients (pts) are treated with platinum-based 1st line chemotherapy but the role of maintenance therapy once disease control is obtained is unknown. Methods: PLATFORM is a prospective, open-label, adaptive phase II trial assessing maintenance therapy in OGA. HER2 negative pts with advanced OGA achieving response or stable disease on completion of 1st line platinum-based chemotherapy were initially randomised to surveillance (A1), capecitabine (A2) and durvalumab (A3). Rucaparib (A4) and capecitabine+ramucirumab (A5) were subsequently added as part of adaptive design. Primary endpoint is progression-free survival with target recruitment of 154pts/arm. A pre-planned futility interim analysis (IA) is triggered when 61 pts/arm are recruited and evaluable using 12-week progression-free rate (PFR). Individual arms will continue accrual if the upper limit of 1-sided 95% CI difference is &gt; 0 when compared to A1. Biomarker analyses of A1 and A3 IA patients include: PDL1 as tumour and immune cell combined proportion (TIP), multiplex IHC of tumour infiltrating lymphocytes (TILs), TMB and MSI status by whole exome sequencing. Results: To date, 1053 pts have registered prior to or during 1st line therapy and 356 pts randomised. Primary attrition was due to disease progression. Baseline demographics in the IA population (arms A1 to A3, n = 183) were male (81%); median age 65 yrs; metastatic disease (92%); oesophageal (40%), OG junction (28%) and gastric (32%) primary. 12-week PFR were A1: 51% (95%CI: 38-64%); A2: 52% (95%CI: 40-65%); A3: 49% (95%CI: 36-62%). PFR differences to arm A1 were A2: 1.6% (95%CI: -13.2 to 16.5%); A3: -1.6% (95%CI: -16.5 to 13.3%). In A1, PFR was 53% vs 43% in PDL1 TIP &lt; 10% and ≥10% respectively. In A3, PFR was 51% vs 100% in PDL1 TIP &lt; 10% and ≥10% respectively. 3 pts in A3 had partial response; none were seen in A1 and A2. Density of TILs subsets, TMB and MSI data will be presented. Conclusions: PLATFORM IA did not indicate futility in maintenance capecitabine or durvalumab compared to surveillance in advanced OGA and will continue to target accrual. Incremental radiological responses were observed with maintenance durvalumab only. Clinical trial information: NCT02678182.

1922P - Circulating microRNAs related to DNA damage response as predictors of survival in metastatic non- small cell lung cancer patients treated with platinum-based chemotherapy

BackgroundAberrant miRNA expression has been associated with DNA damage response (DDR) pathways that modulate tumor response to platinum agents. We assessed the expression of miR-21, miR-128, mir-155 and miR-181 involved in DDR pathways, in the plasma of metastatic non- small cell lung cancer (mNSCLC) patients receiving 1st-line platinum-based chemotherapy (CMT) and the levels were correlated with patients’ outcomes. We also performed bioinformatics analysis to identify putative target genes of the above miRNAs. MethodsPlasma samples were obtained from patients (n=128) before 1st-line CMT. miR-21, miR-128, miR-155 and miR-181 expression levels were assessed by RT-qPCR and expression was classified as high or low according to the median values. Pathway analysis was performed by Diana-Tarbase algorithm. ResultsMir-128 (p<0.001), miR-155 (p<0.001) and miR-181 (p=0.012) were higher in mNSCLC patients compared to healthy donors. Patients with high miR-128 and miR-155 expression had shorter overall survival (OS) (p=0.028 and p=0.035, respectively). In multivariate analysis performance status of 2 and high miR-128 expression independently predicted for shorter OS in the whole group of patients (p=0.003 and p=0.026, respectively). No differences in miRNA expression were revealed among patients with adenocarcinoma (n=79) and squamous carcinoma (SCC; n=41). However, in the SCC subgroup, besides miR-128 and miR-155, high miR-21 and miR-181 expression were associated with shorter OS (p=0.021, p=0.015, p=0.004 and p=0.028, respectively). In multivariate analysis, miR-155 high expression independently predicted for decreased OS (p=0.004). Integrated function and pathway analysis on miRNA predicted genes revealed that pathways related to cancer, cell cycle, apoptosis and drug resistance were significantly enriched. ConclusionsDifferential expression levels of DDR related miRNAs are encountered in mNSCLC patients before 1st-line platinum-based CMT and independently predict patients’ outcomes. The association of miR-155 with the prognosis of patients with SCC merits further investigation. Legal entity responsible for the studyThe authors. FundingHESMO. DisclosureAll authors have declared no conflicts of interest.

Association of early bone metastases and outcomes of the bone predominant metastatic urothelial carcinoma (BP mUC) phenotype.

e16016 Background: Prior analyses demonstrated worse outcomes with the BP mUC clinical phenotype. UC molecular subtypes that may correlate with the BP phenotype have been defined, however molecular subtyping is not a readily available standard practice. We hypothesized that BP mUC has worse prognosis vs. non-BP (NBP) mUC and evaluated patient (pt) characteristics associated with the mUC subtype, responses and outcomes. Methods: We searched the electronic medical record (EMR) to identify pts with mUC who received systemic therapy in the metastatic setting. Demographic, clinicopathologic, treatment (trt), response, progression-free survival (PFS), overall survival (OS ) from start of first line trt. Imaging was reviewed to identify NBP or BP disease. Logistic regression, Cox proportional-hazards and Kaplan-Meier analyses were performed. Results: 149 mUC pts were identified (64% male, 68% smokers ), median age at 1st line trt was 68 years. 70% had de-novo mets, 46% to lung and 27% to liver. 22% of pts were BP, of these, 36% were de-novo metastatic. In non- de-novo metastatic pts (70% of pts), first progression of disease to bone was associated with development of the BP phenotype (OR = 30.46, 95% CI 6.37 to 145.61; p &lt; 0.0001). BP pts had higher rate of death (HR = 2.28, 95% CI 1.45 to 3.58, p = 0.0004), shorter PFS from 1st line trt, (11.7 vs 14.9 weeks, p = 0.032) as well as shorter OS from 1st line trt (24.6 vs 56.6 weeks, p = 0.002) compared to NBP pts. There was no difference in PFS between BP and NBP groups for pts treated with 1st line platinum-based chemotherapy (11.8 vs 18.3 weeks, p = 0.091) or for BP pts treated with 1st line immunotherapy vs platinum-based chemotherapy (11.71 vs 11.86 weeks, p = 0.135). Conclusions: Early bone metastases are associated with the development of the BP metastatic phenotype. BP pts have worse PFS and OS from 1st line trt compared to NBP pts. PFS remains poor when BP pts are treated with either platinum-based chemotherapy or immunotherapy in the first line setting. Imaging to determine the presence of bone metastases may routinely be pursued and careful attention paid on follow up imaging. Clinical trials and prospective registries focusing on efficacy endpoints for BP mUC are needed.

Analysis of real-world data (RWD) on treatment (tx) sequencing in patients with advanced non-small cell lung cancer (aNSCLC).

e20642 Background: While optimal sequencing of systemic therapy in aNSCLC is critical to achieve maximal clinical benefit, it is practically challenging to study tx sequencing through clinical trials. RWD allow retrospective, observational studies to examine tx patterns and associated clinical outcomes. Methods: 1,609 aNSCLC patients who received systemic therapies at Mount Sinai hospitals were analyzed for the number of line of therapy (LOT), therapeutic modalities (chemotherapy, targeted therapy and immunotherapy), and the sequence in which treatments were given when LOT &gt; 1. Time to tx discontinuation (TTD) was used as a surrogate clinical endpoint for outcomes. Results: 578 of the 1,609 (36%) patients received more than one LOT. 356 (22%) received tyrosine kinase inhibitors (TKIs), and 297 (16%) received immune checkpoint inhibitors (CPIs). Kaplan-Meier analysis revealed that among 297 patients who received CPIs, median TTD was longer in the 1st line setting (295 days, 95% CI 169 to 523; n=132) than when LOT &gt; 1 (169 days, 95% CI 113 to 269; n=165), although the difference was not statistically significant (P=0.092, log-rank test). No difference of TTD on TKIs was observed between LOT = 1 and LOT &gt; 1 (P=0.51). With respect to tx sequencing, when patients (n=94) received TKIs as the 1st LOT, 60%, 35%, and 5% of them received another TKI, chemotherapy, or a CPI-containing regimen, respectively, as the 2nd LOT. Among patients (n=370) who progressed on 1st line platinum-based chemotherapy, 52%, 32%, and 16% received another chemo regimen, a CPI-containing regimen, or a targeted therapy, respectively, as the 2nd LOT; these percentages shifted significantly toward more CPIs (24%, 66%, 10% for chemo, CPI, targeted, respectively) when only 2016-2018 data were examined. In the 2nd line setting after platinum therapy, TTD was significantly longer in the CPI group (332 days, 95% CI 169-484) compared to the chemo group (88 days, 95% CI 65-100; P&lt;0.0001), consistent with results from pivotal clinical trials. Conclusions: As the tx algorithm of aNSCLC has been evolving rapidly, we observed diverse tx patterns in RWD. Various tx sequences may impact patient outcomes, and therefore warrant further investigation.

Tracking plasma KRAS mutations (mu) in lung adenocarcinoma (LUAC) patients (p) and branching evolution.

9055 Background: KRAS m in LUAC p are recalcitrant to therapy. In mice models and p, STK11 m confer poor prognosis. Patients with KRAS, or KRAS with TP53 m, benefit from immunotherapy (IO). We used a cell free DNA (cfDNA) sequencing platform to sub-group 53 LUAC p with KRAS m from the Spanish Lung Liquid versus Invasive biopsy Program (SLLIP, NCT03248089), according to the coexistence of TP53 and STK11 m. We evaluated the treatment outcome in the KRAS subgroups and we explored the mutational evolution at 2 weeks (w), and at the end of the study (EOS). Methods: SLLIP was a multi-center observational study in patients with treatment-naïve metastatic LUAC. Genotyping, with a clinically validated cfDNA assay (Guardant360) was performed at 3 time points: before start of treatment, at 2 w, and upon progression or at 12 months (mo). Oncoprints were constructed based on mutation status and variant allele frequency (VAF). Results: 53 p with KRAS alterations were included. 36 male; median age 59; 46 current/ex-smokers; 64% received 1st line platinum-based chemotherapy (CT), 4% platinum-based CT+IO, 8% platinum-based CT plus bevacizumab, and 24% other or no therapy. 13 p had only KRAS m (K-only group), 25 p had KRAS + TP53 m (KP group), and 15 p had KRAS + STK11 with or without TP53 m (KS group). Median progression-free survival was 3.5 mo for all 53 p, 4.8 mo for the K-only group, 4.4 mo for the KP group, and only 2.6 mo for the KS group (p = 0.05 for KS versus K-only). The average VAF for K-only, KP, and KS groups at EOS were 6.4%, 9.7%, and 46%, respectively. When looking at p with cfDNA analysis at the three time points, the following were observed: In the K-only group, 25% lost KRAS m at 2 w and 50% at EOS. 50% and 75% gained TP53 m, at 2 w and EOS, respectively. None gained STK11 at the 2 time points. In the KP group, 40% lost KRAS m at 2 w but all had KRAS m at EOS. 20% and 10% lost TP53 m, at 2 w and EOS, respectively. 10% gained STK11 m at the 2 time points. In the KS group, 33% lost KRAS m at the 2 time points. All and 33% lost STK11 m at 2 w and EOS, respectively. 66% gained TP53 at the 2 time points. Conclusions: Subgroups of KRAS m traced in cfDNA confirm dismal prognosis to 1st line therapies. These findings prompt us to tailor IO for K-only or KP subgroups. For p with STK11 m, restoration of the STK11 function is warranted. Clinical trial information: NCT03248089.

Efficacy of PD-1 monoclonal antibody SHR-1210 plus apatinib in patients with advanced nonsquamous NSCLC with wild‐type EGFR and ALK.

9112 Background: Our preclinical study suggested combination of PD-1 monoclonal antibody SHR-1210 and VEGFR 2 inhibitor apatinib significantly improved antitumor effects. This was an open-label, multi-center, phase 1/2 study of intravenous SHR-1210 plus oral apatinib in patients with advanced NSCLC. Here, we reported preliminary efficacy and safety outcomes of SHR-1210 plus apatinib in patients with wild‐type EGFR and ALK. Methods: In dose-escalation phase, advanced non-squamous NSCLC patients (pts) previously treated with at least 2nd line chemotherapy were enrolled to explore 2 dose levels of apatinib (250, 375mg/d) + SHR-1210 (200mg, q2w). 250mg/d of apatinib was selected to be combined with SHR-1210 in phase II trial. Pts previously treated with 1st line platinum-based chemotherapy were enrolled. Primary endpoint was ORR per RECIST 1.1. Archived or fresh tumor tissues and blood samples were taken before the treatment, PD-L1 expression and tumor mutation burden (TMB) were tested and correlated with efficacy. TMB was detected by Oseq-pan cancer panel (including 636 genes and 1.95Mb), and then calculated by in-house algorithm developed by BGI Genomics Co., Ltd. Results: 96 pts with advanced non-squamous NSCLC harboring wild‐type EGFR and ALK were recruited . 23 had ≥2 prior lines of systemic treatment, and 73 had 1 prior line of treatment. Median age was 57, male 79.8%, adenocarcinoma 93.9%, ex-smokers 56.7%. ORR and DCR in 91evaluable pts were 29.7% and 81.3%, respectively. Blood TMB (bTMB) test was available in 80/91 evaluable patients and the cut-point was 1.54 muts/Mb as determined by receiver operating characteristic curve. ORR in pts with high bTMB was 50% (19/38). At data cutoff of 20 Jan 2019, 20/27 responders were still on treatment (table). Across all 96pts, 54(56.2%) grade ≥3 TRAEs. AEs of grade ≥3 occurring in 2 or more pts included hypertension, hand-foot syndrome, gamma-glutamyl transferase increase, proteinuria, abnormal hepatic function and alkaline phosphatase increase. Conclusions: SHR-1210 plus apatinib demonstrated promising anti-tumor activity with acceptable safety in patients with non-squamous NSCLC, especially in those with high bTMB. Prospective study is needed to validate the clinical outcome and bTMB as a predictor of efficacy. Clinical trial information: NCT03083041. [Table: see text]

A phase II randomized study of avelumab plus entinostat versus avelumab plus placebo in patients (pts) with advanced epithelial ovarian cancer (EOC).

5511 Background: Preclinical evidence suggests that combining avelumab (A), a human anti-PD-L1 monoclonal antibody, and entinostat (E), a class I selective histone deacetylase (HDAC) inhibitor, may increase tumor immunogenicity and responsivity to checkpoint inhibition. This study evaluated whether A+E would lead to improved progression free survival (PFS) vs A in pts with advanced EOC. Methods: Pts with EOC which had progressed or recurred after 1st-line platinum-based chemotherapy and received 3- 6 lines of therapy were randomized 2:1 to receive A (10 mg/kg IV Q2W) plus E (5 mg PO QW) or A plus placebo (P). Treatment continued until disease progression (PD) or unacceptable toxicity. The primary endpoint was PFS (investigator-assessed, RECIST 1.1), stratifying on the presence/absence of bulky disease (tumor ≥ 50 mm) and platinum-refractory disease. The hypothesis was that the combination would reduce the hazard of PD or death by 43%, representing a 75% improvement in median PFS. 97 events (from 120 pts) provided 90% power with 1-sided significance level of 0.10. Secondary endpoints included ORR, duration and time to response, toxicity, clinical benefit rate, and OS. Results: 126 pts were enrolled, median age 63 yrs (range 43-82), median 4 prior lines, 83% serous histology. Median PFS was 1.64 and 1.51 mos for A+E and A+P, respectively (p = 0.31; HR 0.90, 95% CI: 0.58-1.39). No significant differences in ORR (6% vs 5%), or OS (NE vs 11.3 mos) were observed. 4 pts (3%) had clear cell EOC, with no responses observed. The incidence of related adverse events (AEs) was higher in the A+E arm compared to A+P (any grade: 93% vs 78%, Grade 3/4: 41% vs 10%), and the most frequent (≥20%) related AEs with A+E were fatigue (46%), nausea (31%), diarrhea (26%), anemia (26%), and chills (20%). Grade 3/4 related AEs occurring in ≥5% with A+E were fatigue (9%), and neutropenia (8%). 47% of pts in A+E arm required E dose holds/reductions. Discontinuations due to AEs were similar between arms (21% vs 17.5% for A+E and A+P, respectively), as was duration of study therapy (median 4 and 5 cycles started). Conclusions: In pts with heavily pretreated EOC, median PFS was not prolonged when E was added to A compared to A alone and the combination resulted in greater toxicity. Clinical trial information: NCT02915523.

Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182.

4504 Background: Platinum-based chemotherapy for 1st-line treatment of pts with metastatic urothelial cancer (mUC) is typically administered for a fixed duration followed by observation until recurrence. PD-1 blockade with pembro improves survival of pts with mUC progressing despite platinum-based chemotherapy. We explored the potential benefit of earlier use of PD-1 blockade using a "switch maintenance" approach. Methods: Pts with mUC achieving at least stable disease after up to 8 cycles of 1st-line platinum-based chemotherapy were enrolled. Pts were randomized 1:1 to pembro 200 mg IV q3 weeks versus placebo for up to 24 months; pts progressing on placebo could cross over to pembro. Randomization was stratified based on pre-chemotherapy visceral metastases (Y/N) and response to 1st-line chemotherapy (CR/PR vs. SD). The primary objective was to determine the progression-free survival (PFS) as per irRECIST among pts treated with pembro versus placebo. Results: Between 12/2015 and 11/2018, 107 pts were randomized to placebo (n=52) versus pembro (n=55). The baseline pt characteristics are shown in the Table. Pts randomized to placebo and pembro received a median of 6 and 8 cycles, respectively. Excluding patients with baseline CRs, the objective response rate was 12% (5/42) on placebo and 22% (10/46) on pembro. Grade 3-4 treatment emergent adverse events occurred in 48% of pts on placebo and 56% on pembro. At a median follow-up of 14.7 months, 41 pts have died and 26/52 pts randomized to placebo have crossed over to pembro. PFS was significantly longer in patients randomized to pembro vs. placebo (Maximum Efficiency Robust Test p=0.036; log-rank p = 0.038). The 18-month restricted mean progression-free survival time was 5.6 months with placebo and 8.2 months with pembro (p=0.023). Conclusions: Switch maintenance pembro may “deepen” responses achieved with 1st-line chemotherapy. Switch maintenance pembro prolongs PFS in pts with mUC completing 1st-line platinum-based chemotherapy. Clinical trial information: NCT02500121. [Table: see text]

A multicenter phase II trial of rucaparib in combination with nivolumab as maintenance therapy for patients with advanced biliary tract cancer.

TPS4153 Background: Patients (pts) with advanced biliary tract cancers (BTC) have a poor prognosis with a median overall survival (OS) less than 12 months. Using whole exome NGS, 26 (49%) pts in a 53 pt cohort had either DNA damage repair (DDR) pathway mutations (somatic and/or germline, n = 18), or isocitrate dehydrogenase 1 (IDH1) mutations (n = 8), and may have potentially benefited from PARP inhibition. Further, disruption of the mutated DDR pathways with a PARP inhibitor may result in increased mutational burden and neoantigens leading to immunogenicity, thus providing the rationale for combination with a PD-1 antibody. This phase 2 trial is designed to investigate the role of a PARP inhibitor in combination with a PD-1 antibody in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed advanced, unresectable biliary adenocarcinoma (intra- or extra-hepatic, and gallbladder) without progression after 4-6 months of 1st line platinum-based systemic chemotherapy, measurable disease per RECIST v1.1, ECOG PS 0-1, Child-Pugh A or B7, and absence of autoimmune disease or chronic steroid use. Primary objective is to evaluate progression-free survival (PFS) rate at 4 months. Secondary objectives include evaluation of objective response rate per immune related (ir)RECIST criteria, median PFS and OS, and safety in this patient population. Exploratory objectives include identification of predictive biomarkers of response and mechanisms of resistance through serial biopsies and blood collection (pre, on and post therapy), including sequential whole exome/transcriptomic analysis with immune cell subset analysis. Treatment includes rucaparib 600 mg PO BID on days 1-28 with nivolumab 240 mg on days 1, 15 Q4 weeks. In absence of disease progression, pts may continue therapy up to 2 years. Accrual goal is 32 evaluable pts. Using a null hypothesis value of a 63% PFS rate at 4 months, and an 85% alternative hypothesis, this ongoing study has 80% power, with a one-sided alpha of 0.05 to identify treatment efficacy in the study arm. Clinical trial information: NCT03639935.

Real-world treatment outcome of advanced Chinese NSCLC EGFR exon 20 insertion patients.

9043 Background: Treatment outcome of advanced EGFR exon20 insertion (ex20ins) patients with 1st- or 2nd-line chemotherapy and EGFR TKIs remains limited. Methods: Retrospective real-world analysis of clinical, molecular, and treatment outcome of a web-based patient registry and hospital chart review. Results: Between 9/13/18-10/22/18, 165 EGFR ex20ins NSCLC patients treated in 99 hospitals from 26 different regions in China were registered. Data cutoff was 12/20/18. EGFR ex20ins were determined by commercial NGS (84%) or PCR (16%). 41 different molecular subtypes of EGFR ex20ins were identified. Ala767_Val769dupASV was the most common (23.0%) followed by Ser768_Asp770dupSVD (17.6%). 61% were females, 77% never-smokers, and CNS mets occurred in 22.4% of patients at time of diagnosis. Median PFS was significantly longer in patients who received 1st-line platinum-based chemotherapy (N = 105) (6.4m; 95% CI:5.7-7.1) vs. EGFR TKI (all generations, N = 23) (2.9m; 95%CI:1.5-4.3; P &lt; 0.001) or vs. EGFR TKI (1G, N = 14) (2.6m; 95%CI:0.8-4.4; P &lt; 0.001). Median PFS was numerically longer in patients who received 2nd-line paclitaxel-based chemotherapy (N = 34) (4.1m; 95%CI:3.3-4.9) versus patients who received 2nd-line EGFR TKIs (N = 18) (2.0m; 95%CI:0.8-3.2; P = 0.342). Patients with CNS mets (N = 21) had shorter median PFS with 1st-line chemotherapy than those without CNS mets (N = 84) (5.5m; 95%CI:0.7-10.3 vs. 6.4m; 95%CI:5.8-7.0; P = 0.694). Patients with CNS mets had numerically shorter median PFS with 1st-line EGFR TKI (N = 7) than those without CNS mets (N = 16) (2.0m; 95%CI:0.8-3.2 vs. 2.9m; 95%CI:2.1-3.7; P = 0.077). Conclusions: Chemotherapy is superior to current approved EGFR TKIs as 1st- or 2nd-line treatment of EGFR ex20ins. Patients with CNS mets had numerically poorer PFS with chemotherapy and EGFR TKI treatment. Targeted therapy against EGFR ex20ins with CNS activity is needed.

Maintenance With Niraparib In Patients With Advanced Urothelial Cancer After 1st-line Platinum-based Chemotherapy

Maintenance With Niraparib In Patients With Advanced Urothelial Cancer After 1st-line Platinum-based Chemotherapy

P1.04-007 Rovalpituzumab Tesirine Maintenance Therapy Following 1st Line Platinum-Based Chemotherapy Small Cell Lung Cancer

SCLC embodies 15-20% of lung cancers. Patients (pts) are staged with either limited or extensive disease; the standard front-line treatment for the latter is chemotherapy with carbo- or cisplatin combined with etoposide or irinotecan. Response rates are high with limited duration. Recurrence may be attributable to chemo-resistant tumor initiating cells (TICs). Delta-like protein 3 (DLL3) is an inhibitory Notch receptor ligand identified as a novel target in SCLC TICs. DLL3 is highly expressed in SCLC but not normal tissue.