Trend For Longer Overall Survival Research Articles

Real-World Clinical Outcomes in Patients with Relapse and Refractory Multiple Myeloma Received VTD-PACE Treatment in the Era of Monoclonal Antibody

The treatment outcomes of multiple myeloma (MM) have drastically improved with the use of novel agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies. However, ultimately, the disease relapses and results in a fatal outcome. Even in cases of relapse, treatment outcomes have improved with the use of novel agents. However, in situations where novel agents have been exhausted or when the disease rapidly progresses, bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) is frequently utilized, with reported effectiveness. However, its outcomes in the era of monoclonal antibodies remain unclear. Therefore, this retrospective cohort study assessed the clinical outcomes of 60 patients with RRMM (median four prior treatment lines) administered VTD-PACE at the Japanese Red Cross Medical Center between June 2016 and April 2023. The characteristics of the 60 patients are shown in Table 1. The VTD-PACE regimen consisted of 1 mg/m 2 of bortezomib on days 1, 4, 8, and 11 administered subcutaneously; 200 mg of thalidomide administered orally on days 1-4; 40 mg of dexamethasone administered orally on days 1-4; and a 4-day continuous intravenous infusion of 10 mg/m 2 cisplatin, 40 mg/m 2 cyclophosphamide, 40 mg/m 2 etoposide, and 10 mg/m 2 doxorubicin. The cisplatin dose was adjusted based on renal function, as determined by the treating physician. The responses were evaluated according to the International Myeloma Working Group response criteria. High-risk cytogenetic abnormalities (HRCA) included del (17p), t(4;14), and t(14;16). Double-class refractory disease was defined as refractoriness to PIs and IMiDs, whereas triple-class refractory disease was defined as refractoriness to PIs, IMIDs, and anti-CD38 monoclonal antibodies. Penta-drug refractory disease was defined as refractoriness to bortezomib, carfilzomib, lenalidomide, pomalidomide, and anti-CD38 antibodies. The median follow-up period was 11.1 months (range, 0.5-72.0 months), during which they received a median of two cycles of VTD-PACE. The overall response (ORR), stringent complete response, complete response, and very good partial response rates were 66.7% (40 patients), 13.3% (8 patients), 5% (3 patients), and 20% (12 patients), respectively. The results of univariate analysis for factors associated with response rate are shown in Table 2. The ORRs in patients with ≥4 and ≤3 prior lines were 53.1% and 82.1%, respectively ( P = 0.027). Extramedullary disease (EMD), refractoriness to anti-CD38 antibody, HRCA, and triple-class/penta-drug refractory disease did not significantly reduce the ORR. The median overall survival (OS) was 17 months with a median progression-free survival (PFS) of 9.8 months. The median PFS in patients with and without receiving hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE were 9.8 and 5.1 months, respectively ( P = 0.023). The median OS in patients with and without renal dysfunction were 10.7 months and 21.5 months, respectively ( P = 0.0091). A trend for longer OS was observed in patients with HSCT or CART following VTD-PACE (P = 0.18). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response is expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use. However, the response rate decreased in late lines; therefore, its use in early lines is recommended.

Eosinophilia in patients with melanoma under treatment with immune checkpoint inhibitor-based regimens.

e21528 Background: Immune-related eosinophilia (irEo) has been described as an adverse event of immune checkpoint inhibitors (ICI), but its rate, severity, duration, clinical significance, diagnostic approach, and management have not been analysed. In the present study we analyse these features in patients with melanoma. Methods: We reviewed the files of patients with advanced/metastatic melanoma treated with ICI-based regimens in a tertiary university referral centre, to describe the rate of eosinophilia, along with the baseline disease characteristics, severity, type of treatment, time on treatment, maximum eosinophil count, and symptoms, as well as its diagnostic evaluation and management, course, and prognostic implications. Results: A total of 249 patients were included in the analysis. Eosinophilia was present in 61 (24.5%) and there was no correlation with gender, age, histologic type, stage, or BRAF mutation status. The median time interval from treatment initiation to the onset of eosinophilia was 55 days (10-534), while the median eosinophil count at first presentation was 0.70x109/L (0.50-4.53x109/L), and the maximum eosinophil count was 1.07x109/L (0.50-13.22 x109/L). The rate of eosinophilia was significantly higher in patients treated with nivolumab plus bempegaldesleukin (50.0%), followed by nivolumab plus ipilimumab (21.7%). Symptomatic patients [N = 15, mostly pruritus, rash, arthralgia] and/or patients with hypereosinophilia (eosinophil count > 1.5x109/L, N = 3 at first presentation, N = 20 during the course of eosinophilia) were assessed for organ involvement and for the cause of eosinophilia (CBC with blood smear, biochemistry profile including LDH, and uric acid, cardiac troponin, chest X-ray, and heart ultrasound). Further evaluation was performed according to the clinical scenario and the findings of the initial evaluation. In none of the patients a definitive diagnosis of eosinophilia was reached; thus, all cases were deemed irEo. None of the patients was acutely ill. Patients without findings or hypereosinophilia did not require medical intervention, while the remaining were managed with low-to-medium doses of corticosteroids (N = 2), antihistamines (N = 11), or local treatment (N = 4). Two patients had to delay treatment, and one (max count 13.2x109/L) had to permanently discontinue bempegaldesleukin and continue on nivolumab monotherapy. Eosinophilia relapsed in 21 patients when rechallenged with the same or different immunotherapy regimen. There was a non-significant trend for longer overall survival in patients with eosinophilia (64.5 months vs 33.4 months, p = 0.16). Conclusions: This is the first study evaluating the association between the type of immunotherapy and the rate of eosinophilia in patients with melanoma and analysing the baseline characteristics of the patients as well as their diagnostic evaluation and management, course, and prognosis.

The prognostic value of [18F]FDG PET/CT based response monitoring in metastatic melanoma patients undergoing immunotherapy: comparison of different metabolic criteria

PurposeTo investigate the prognostic value of [18F]FDG PET/CT as part of response monitoring in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs).MethodsSixty-seven patients underwent [18F]FDG PET/CT before start of treatment (baseline PET/CT), after two cycles (interim PET/CT) and after four cycles of ICIs administration (late PET/CT). Metabolic response evaluation was based on the conventional EORTC and PERCIST criteria, as well as the newly introduced, immunotherapy-modified PERCIMT, imPERCIST5 and iPERCIST criteria. Metabolic response to immunotherapy was classified according to four response groups (complete metabolic response [CMR], partial metabolic response [PMR], stable metabolic disease [SMD], progressive metabolic disease [PMD]), and further dichotomized by response rate (responders = [CMR] + [PMR] vs. non-responders = [PMD] + [SMD]), and disease control rate (disease control = [CMR] + [PMR] + [SMD] vs. [PMD]). The spleen-to-liver SUV ratios (SLRmean, SLRmax) and bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were also calculated. The results of PET/CT were correlated with patients’ overall survival (OS).ResultsMedian patient follow up [95% CI] was 61.5 months [45.3 – 66.7 months]. On interim PET/CT, the application of the novel PERCIMT demonstrated significantly longer survival for metabolic responders, while the rest criteria revealed no significant survival differences between the different response groups. Respectively on late PET/CT, both a trend for longer OS and significantly longer OS were observed in patients responding to ICIs with metabolic response and disease control after application of various criteria, both conventional and immunotherapy-modified. Moreover, patients with lower SLRmean values demonstrated significantly longer OS.ConclusionIn patients with metastatic melanoma PET/CT-based response assessment after four ICIs cycles is significantly associated with OS after application of different metabolic criteria. The prognostic performance of the modality is also high after the first two ICIs cycles, especially with employment of novel criteria. In addition, investigation of spleen glucose metabolism may provide further prognostic information.

Real-world Outcomes With Cumulative Bortezomib Dose and Efficacy in the Treatment of Transplant-ineligible Multiple Myeloma With Cyclophosphamide, Bortezomib, and Dexamethasone.

Higher cumulative dose of bortezomib, a key component of Multiple Myeloma (MM) treatment regimens, has been shown to improve outcomes in MM patients, but must be balanced with toxicities including peripheral neuropathy. In this study, we studied the effect of cumulative bortezomib dose on survival, depth of response, and discontinuation rate in transplant ineligible MM patients. Data from 70 patients treated with Cyclophsophamide, Bortezomib, and Dexamethasone (CyBorD) in a single Canadian center were grouped according to above vs below median cumulative bortezomib dose and analyzed for progression-free survival (PFS), overall survival (OS), depth of response, and discontinuation rate. There was a trend for lower discontinuation rate (45.7% vs. 68.6%, P=.052) and significantly lower rate of neuropathy-related discontinuation (5.7% vs. 22.9%, P=.035) in patients who received higher than 43.1 mg/m² of bortezomib. The higher-dose group showed a trend for higher rate of complete response (14.3% vs. 5.7%, P=.225) and significantly higher rate of very good partial response or better (77.1% vs. 51.4%, P=.024). There was significantly longer PFS (24.3 vs. 9.1 months, P=.012) and a trend for longer OS (22.4 vs. 61.3 months, P=.061) in the higher-dose group. In landmark analysis after 180 days, PFS (23.5 vs. 24.3 months, P=.941) and OS were similar in both groups. Higher cumulative bortezomib dose showed a lower rate of discontinuation, longer survival, and deeper response. Determining risk of treatment intolerance remains important for treatment.

The impact of claudin-18.2 expression in patients with advanced gastric cancer treated with nivolumab.

439 Background: Claudin-18.2 (CLDN 18.2) is the components of tight junction and one of the therapeutic targets in advanced gastric cancer (AGC). It has been reported that the tumor microenvironment in CLDN18.2 high AGC contains more PD-1 negative CD8+ T cells than in CLDN18.2 low, which may make anti-PD-1 antibodies less effective. However, the data on the association between CLDN18.2 expression and prognosis in patients with AGC treated with nivolumab (NIVO) is limited. Methods: Patients who received NIVO monotherapy as third- or later-line treatment (NIVO group) and those who received only fluoropyrimidine, platinum and taxanes (non-NIVO group) at our hospital between 2015 and 2019 were enrolled. High CLDN18.2 expression was defined as ≥40% positive tumor cells with moderate to strong membranous staining on immunohistochemistry. Overall survival (OS) and progression-free survival (PFS) were compared according to CLDN18.2 expression and combined positivity score (CPS). Results: There were 71 and 50 patients in the NIVO and non-NIVO groups, respectively. Patient characteristics at first-line chemotherapy in the NIVO/non-NIVO groups were median age 67 (range, 34-83)/64.5 (29-80) years; performance status 0, 22 (31%)/23 (46%); peritoneal metastasis 38 (54%)/26 (52%); liver metastasis 15 (21%)/6 (12%); CLDN18.2 high 31 (44%)/25 (50%). In the NIVO group, patient characteristics did not differ between CLDN18.2 high and low except for peritoneal metastasis (25 [81%]/22 [55%]). Nine patients (29%) were CLDN18.2 high with CPS≥1, and 14 (35%) were CLDN18.2 low with CPS≥1. OS from first-line chemotherapy did not differ between CLDN18.2 high and low in the non-NIVO group (median, 18.4 months [95%CI, 10.7-32.4] vs. 16.9 months [95%CI, 14.8-21.4], HR 0.94 [95%CI, 0.50-1.78], p=0.847). In the NIVO group, OS from first-line chemotherapy and OS and PFS after starting NIVO did not differ between CLDN18.2 high and low; however, patients with CLDN18.2 high and CPS≥1 had longer OS after starting NIVO (median, 14.8 months [95%CI, 4.2-NR] vs. 3.6 months [95%CI, 2.0-6.9], HR 0.27 [95%CI, 0.11-0.68], p=0.012) and PFS after starting NIVO (median, 3.5 months [95%CI, 0.7-NR] vs. 1.7 months [95%CI, 1.1-3.1], HR 0.38 [95%CI, 0.15-0.97], p=0.033) than those with CLDN 18.2 high and CPS<1. Patients with CLDN18.2 high and CPS≥1 had a trend of longer OS from first-line chemotherapy than those with CLDN 18.2 high and CPS<1 (median, 37.4 months [95%CI, 11.1-NR] vs. 14.8 months [95%CI, 9.4-31.2], HR 0.47 [95%CI, 0.17-1.31], p=0.12). In the CLDN18.2 low group, OS and PFS did not differ between CPS≥1 and <1. Conclusions: With CLDN18.2 high, CPS≥1 was associated with longer survival in AGC treated with NIVO.

Response Rate, Event-Free Survival (EFS) and Overall Survival (OS) in Higher-Risk Myelodysplastic Syndromes (HR-MDS): U.S. Food and Drug Administration (FDA) Patient-Level Analyses

Background: Hypomethylating agents (HMAs) have changed the treatment landscape for patients with higher-risk myelodysplastic syndromes (HR-MDS) in the past two decades. However, less than half of patients respond to HMA therapy and even the best responses are transient and non-curative. Therapeutic options for those who have failed HMAs are limited, and these patients have very poor prognosis. To speed the development of novel therapeutics, varying response rate definitions and event-free survival (EFS) have been suggested as clinical benefit endpoints for regulatory approvals. However, the relationship between complete remission (CR), partial remission (PR), hematologic improvement (HI), event-free survival (EFS) and overall survival (OS) in MDS has not been conclusively established. To evaluate the relationship between these endpoints, we conducted patient-level response analyses of MDS trials submitted to the FDA.Methods: We searched for trials submitted with New Drug Applications for treatment of MDS between 2000 and 2020. Trials which supported the efficacy of approved treatments for HR-MDS were included. Patients with chronic myelomonocytic leukemia (CMML), bone marrow blasts ≥ 20%, or missing bone marrow blast information were excluded. A patient-level responder analysis was performed to compare OS and EFS between responders and non-responders, regardless of treatment assignment in the pooled dataset. Separate analyses were formed for CR, PR, and HI. Response rates were defined per protocol; criteria included IWG 2000, IWG 2006, and custom criteria. EFS was defined as time from randomization, or first dose of study drug for single-arm trials, to treatment failure (defined as date of transformation to AML, given availability across trials) or death from any cause. For each trial, the hazard ratio of response vs. no-response on OS and EFS was estimated using a Cox model with response as a time-varying covariate and treatment, sex, age, and percentage blast count as baseline covariates. The resulting hazard ratios were combined assuming a common effect of response on clinical outcome to estimate a pooled hazard ratio. Unadjusted distributions of OS and EFS by response were obtained using the Kaplan-Meier method.Results: We identified 8 trials with a total of 772 patients with HR-MDS investigating 3 experimental agents (azacitidine, decitabine, and decitabine + cedazuridine) for the treatment of HR-MDS. Three trials were randomized trials to assess efficacy (N=116, 124, 215), two were randomized crossover trials to assess bioequivalence (N=116, 61), and 3 were single arm trials (N=29, 34, 77). Across all trials, the population characteristics were: median age 69 years (range: 23-92); 70% male, 67% White, 29% Asian, 2% Black; 17% High Risk per IPSS, 25% Intermediate-1, 33% Intermediate-2, 2% Low Risk, and 24% unknown. IPSS information was missing for 3 trials (187 patients).We assessed the effect of CR vs. PR vs. HI in a pooled analysis. Patients who achieved a CR had better OS (HR=0.40 [95% CI: 0.25-0.64]) and EFS (HR=0.39 [95% CI: 0.24-0.63]) compared with non-responders, defined as patients who failed to achieve CR, PR, or HI. Patients who achieved a PR had better OS (HR=0.51 [95% CI: 0.28-0.92]) and EFS (HR=0.66 [95% CI: 0.37-1.17]) compared to non-responders. Patients who achieved an HI response had better OS (HR=0.60 [95% CI: 0.46-0.76]) and EFS (HR=0.60 [95% CI: 0.47-0.76]) compared to non-responders. Patients who achieved a CR+PR had a trend for longer OS (HR=0.73 [95% CI: 0.49-1.11]) and EFS (HR=0.76 [95% CI: 0.51-1.14]) compared with those who achieved HI alone. Between-study variances of these effects were not able to be reliably estimated due to the low number of responses per trial and low number of trials included in the analysis. Figures 1 and 2 present unadjusted Kaplan-Meier estimates of OS and EFS by response group.Conclusions: Patient-level responder analyses suggest that CR, PR, and HI responders have better OS and EFS compared with non-responders. A limitation of these analyses is that response criteria are not standardized across trials. Future work includes standardizing response criteria across trials. However, our results suggest that CR, PR, and HI may be associated with long-term benefit in patients with HR-MDS. While HI responses had better OS compared to no response, CR and CR+PR remain the response endpoints associated with greatest long-term benefit. [Display omitted] DisclosuresVallejo: AstraZeneca: Other: Spouse is employed by AstraZeneca..

Randomized Phase III Study (ADMYRE) of Plitidepsin in Combination with Dexamethasone Vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma

Randomized Phase III Study (ADMYRE) of Plitidepsin in Combination with Dexamethasone Vs. Dexamethasone Alone in Patients with Relapsed/Refractory Multiple Myeloma

HGG-42. CLINICAL FEATURES AND TREATMENT OUTCOME OF MALIGNANT GLIOMAS IN CHILDREN AND ADOLESCENTS

INTRODUCTIONMalignant gliomas in children and adolescents are rare. They are difficult to treat and are associated with an extremely poor prognosis.SUBJECTS AND METHODSThe treatment and outcomes of WHO grade IV -gliomas and diffuse intrinsic pontine gliomas (DIPG) in children and adolescents (Age 4–39, median 28) treated at our institute since 2001 were retrospectively reviewed. Thirty-five cases were included in this study. Nine cases were located in their brain stem and 2 of them were diagnosed as DIPG clinically without biopsy. Three (brain stem -2, thalamus- 1) cases were diffuse midline glioma H3 K27 M mutant. Remaining 30 cases were diagnosed histologically as glioblastoma. Expect for 2 cases, all were irradiated. Twenty-four cases were treated with temozolomide (TMZ). Bevacizumab (BEV) was administrated as an initial therapy in 10 cases (concomitant with TMZ in 9 cases) and was administrated at the time of relapse in 9 cases. In summary, 19 cases were treated with BEV.RESULTSMedian survival time (MST) of all cases was 16.8 (4.4 -152.3) months. In total, BEV did not prolonged overall survival (OS), MST 16.02 vs 14.44, (p=0.498). Among adolescents (age 15–39), patients treated with BEV had a trend of longer OS but did not reached statistical significance, MST 19.64 vs 10.76 (p=0.167). An extent of resection and KPS =>70 at discharge from hospital were beneficial factors associated with prolonged OS.CONCLUSIONAs well as in elderly cases, multidisciplinary treatment including resection, radiation and chemotherapy including BEV improves outcomes.

Measurable Residual Disease (MRD) in Elderly Acute Myeloid Leukemia (AML): Results from the Pethema-Flugaza Phase III Clinical Trial

The value of measurable residual disease (MRD) in elderly patients with acute myeloid leukemia (AML) is inconsistent between those treated with intensive vs hypomethylating drugs, and unknown after semi-intensive therapy. We investigated the role of MRD in refining complete remission (CR) and treatment duration in the phase 3 FLUGAZA clinical trial, which randomized 283 elderly AML patients to induction and consolidation with fludarabine plus cytarabine (FLUGA) vs 5-azacitidine. After consolidation, patients continued treatment if MRD was ≥0.01% or stopped if MRD was <0.01%, as assessed by multidimensional flow cytometry (MFC). On multivariate analysis including genetic risk and treatment arm, MRD status in patients achieving CR (N = 72) was the only independent prognostic factor for relapse-free survival (RFS) (HR, 3.45; P = .002). Achieving undetectable MRD significantly improved RFS of patients with adverse genetics (HR, 0.32; P = .013). Longer overall survival was observed in patients with undetectable MRD after induction though not after consolidation. Although leukemic cells from most patients displayed phenotypic aberrancies vs their normal counterpart (N = 259 of 265), CD34 progenitors from cases with undetectable MRD by MFC carried extensive genetic abnormalities identified by whole-exome sequencing. Interestingly, the number of genetic alterations significantly increased from diagnosis to MRD stages in patients treated with FLUGA vs 5-azacitidine (2.2-fold vs 1.1-fold; P = .001). This study supports MRD assessment to refine CR after semi-intensive therapy or hypomethylating agents, but unveils that improved sensitivity is warranted to individualize treatment and prolong survival of elderly AML patients achieving undetectable MRD.

PD-L1 expression in malignant pleural effusion samples and its correlation with oncogene mutations in non-small cell lung cancer.

BackgroundProgrammed death ligand 1 (PD-L1) tumor proportion score (TPS) is currently widely used for selection of immune therapies in non-small cell lung cancer (NSCLC). Most of samples for PD-L1 expression were obtained from tumor tissue. However, the feasible of malignant pleural effusion (MPE) cytological samples for PD-L1 detection is poorly reported. And the correlation between oncogene mutations and PD-L1 expression based on high-throughput sequencing is rarely studied.MethodsNSCLC MPE cytological samples and partially paired tumor tissue from our institution analyzed for PD-L1 immunohistochemistry (IHC) using the clone SP263 pharmDx kit and evaluated genomic aberrations in all patients using next generation sequencing (NGS).ResultsOne hundred and twenty-three MPE cell blocks and 29 paired tumor tissue were successfully tested for PD-L1 expression. PD-L1 TPS of ≥50% were seen in 18.7% (23/123) of all samples. The accordance of PD-L1 expression in tumor tissue and MPE samples was 86.2% (50% as cut-off value). PD-L1 TPS ≥50% tumors were significantly associated with EGFR wild-type (P=0.007), but, no correlation between other genes and PD-L1 expression. A trend of longer overall survival (OS) was observed in patients with PD-L1 TPS <50% than those TPS ≥50% (20.0 vs. 13.8 months, P=0.057). No difference of tumor mutational burden (TMB) was observed between patients with PD-L1 ≥50% and <50% (8.2/MB and 7.7/MB, P=0.47).ConclusionsOur results suggest that cytological material is feasible for PD-L1 IHC analysis. Gene alterations could partially contribute to select the samples that with different PD-L1 expression. No correlation between the PD-L1 expression and TMB.

Clinical and molecular factors for selection of nivolumab or irinotecan as third-line treatment for advanced gastric cancer.

Background:The use of nivolumab or irinotecan as the third-line treatment for patients with advanced gastric cancer (AGC) remains controversial.Methods:This study analyzed patients with AGC treated with nivolumab or irinotecan (nivolumab group or irinotecan group, respectively) from May 2016 to April 2019 following two or more previous lines of chemotherapy. Univariate survival analysis was conducted to identify the clinical and molecular factors associated with progression-free survival (PFS).Results:A total of 156 patients (74 treated with nivolumab and 82 treated with irinotecan) were analyzed. The median PFS was 1.9 months in both treatment groups. The median overall survival (OS) was 7.2 and 6.2 months in the nivolumab and irinotecan groups, respectively. Eastern Cooperative Oncology Group performance status of 1 or more, liver metastasis, a large tumor size at baseline, and HER2-positive status were associated with a worse PFS in the nivolumab group compared with the irinotecan group. The nivolumab group showed a significantly longer PFS (median 3.1 versus 2.0 months) and OS (median 12.9 versus 7.8 months) than the irinotecan group in patients with 0 or 1 of these factors, whereas the irinotecan group showed a significantly longer PFS (median 1.0 versus 1.8 months) and a trend of longer OS (median 3.9 versus 6.1 months) in patients with ⩾2 of these factors.Conclusions:Some clinical and molecular factors were associated with outcomes following nivolumab or irinotecan as the third- or later-line treatment in patients with AGC. These factors must be considered while selecting an optimal treatment option.

1323P - Immune checkpoint inhibitors in a cohort of 206 metastatic uveal melanomas patients

BackgroundUveal melanomas (UM) are BRAF-wild type tumors associated with dismal prognosis for which no systemic therapy is active. We report our experience with immune checkpoint inhibitors (ICI) in metastatic UM patients. MethodsAmbispective cohort of metastatic UM patients treated with ICI in eight French centers. Response rate, progression-free survival (PFS) and overall survival were retrieved. Results206 evaluable patients started their first ICI treatment between December 2012 and January 2019. The population consisted of 98 men and 108 women. Median age was 57.5 yo (19; 82). Seventy-four patients had been enucleated, 131 had received proton beam therapy, one had received brachytherapy. The median time to first metastasis was 29.4 months (0-380.4). ICI were first prescribed in first-line in 68 patients, in second-line in 79 patients, in third-line or more in 80 patients. One hundred forty-four patients received pembrolizumab (63%), 58 nivolumab (25%) and 21 ipilimumab (9%). Metastatic sites at initiation of ICI were liver, lung, skin, and bone for 201, three, one and one patients, respectively. Liver was the sole metastatic site in 201 patients. Patients received a median number of four ICI infusions (1-60+). Treatment was suspended because of immune side effects in 21 patients. Nine objective responses were observed (four complete and five partial responses; 4.4%) including one patient with a hypermutated, MBD4-deficient tumor. Fifty-seven patients showed stable disease as best response (27.7%). Median PFS in the whole cohort was 4.1 months (0; 30.4) in 1st line, 4.9 months (0; 42,6) in 2nd line and 3.1 (1; 17.,3) months in 3rd line. Median PFS was 4.1 months in the ICI-resistant population and 27.4 months in the ICI-sensitive population (log-rank p-test < 0.0001). Median overall survival was 25.9 months in the ICI-resistant population (103/197 deaths) and not reached in the ICI-sensitive population (2/9 deaths; log-rank p-test=0.1). ConclusionsICI are associated with a low response rate in UM but with longer PFS and a trend for longer overall survival in ICI-sensitive tumors. Immunotherapies should be investigated in this disease. ICI-sensitive cases are currently being explored to identify biomarkers of response. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Molecular and clinical features of hospital admissions and immunotherapy related adverse events of immune checkpoint inhibitors in thoracic malignancies.

e18192 Background: Immunotherapy related adverse events (irAEs) and hospital admissions with Immune Checkpoint Inhibitors (ICIs) in thoracic malignancies remain poorly characterized. Methods: Admissions after ICIs in all thoracic malignancies patients received ICIs at City of Hope (total 384) were identified as of 11/8/2018. IrAEs, outcomes, pathology and next-generation sequencing (NGS) data were collected, including Tumor mutation burden (TMB) and PD-L1 (22C3). Length of stay (LOS) and overall survival (OS) was calculated. Unpaired T-tests if data passed normality test, Chi-square and Fisher’s exact test, Gehan-Breslow-Wilcoxon test were used for comparison between 2 groups (irAEs VS no irAEs) for LOS, demographics and genetics, and survival respectively. Results: 100 patients had hospital admissions after ICIs therapy and 90 patients (41 women, 49 men) had stage IV disease (63 lung adenocarcinomas, 14 squamous cell lung cancer, 5 small cell lung cancer, 8 others). 28 out of 90 patients had irAEs (10 pneumonitis/pneumonia, 4 adrenal insufficiencies, 4 colitis, 3 liver toxicities, 2 nephritis, 1 heart failure, 1 pancreatitis, 1 diabetic ketone acidosis, and others including multiple irAEs). There was no difference between the patients who had irAEs VS no irAEs in LOS (median 7 days VS 6 days, P = 0.57). Patients with irAEs had more invasive diagnostic procedures than no irAEs (53.6% VS 25.8%, P = 0.02). There was a trend of longer OS in irAEs patients (median 16.4 months VS 6.8 months, P = 0.13) than no irAEs. Male gender (71.4% (20/28) VS 46.8% (29/62), OR = 2.85, P = 0.04) and smoking exposure (89.3% (25/28) VS 58.1% (36/62), OR = 6.0, P &lt; 0.01) were associated with irAEs patients. Genetic alterations of LRP1B gene (83.3% (5/6) VS 26.9% (7/26), OR = 13.6, P = 0.02) and MLL3 gene (66.7% (4/6) VS 19.2% (5/26), OR = 8.4, P = 0.04) were associated with patients who had irAES. No difference was found in age, lines of therapy, TP53, KRAS, EGFR, STK11, PIK3CA, TMB, PD-L1 between the irAEs and no irAEs patients. Conclusions: Hospitalized patients who had irAEs had similar LOS compared with patients without irAEs but potentially longer OS. Gender, smoking status and genes associated with irAEs and ICIs outcomes were explored. Larger dataset for molecular and clinical features was planned.

Prognosis of ovarian cancer in the United States during 1973 to 2015.

e17072 Background: Ovarian cancer is the first leading cause of cancer death among gynecologic malignancies. Despite significant efforts to improve treatment strategies, the prognosis of patients with ovarian cancer remains poor. Different diagnostic period and the occurrence of distant metastases may have different impacts on prognosis. In this study, we sought to describe the impact of distant metastases and different diagnostic period on prognosis of ovarian cancer. Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify patients diagnosed with ovarian cancer from year 1973 to year 2015. Kaplan-Meier method was used to estimate the overall survival (OS) and Log-Rank test was used to compare the difference between groups. Results: Total 152729 patients with ovarian cancer were included. Median age was 62 years. The overall rates of distant lymph node metastases, bone, brain, liver and lung were 2.9%, 1.0%, 0.2%, 6.6% and 5.6%. Median overall survival (OS) was 30 months, 6 months, 9 months, 20 months and 20 months for pure distant lymph node metastases, brain metastases, bone metastases, lung metastases and liver metastases, respectively. Patients who were diagnosed from year 2010 to year 2015 had significantly improved OS compared with patients who were diagnosed from year 1973 to year 2009 (54 months vs. 47 months, P &lt; 0.0001). Patients with pure distant lymph node metastases who were diagnosed from year 2010 to year 2015 also had significantly improved OS compared with patients who were diagnosed from year 1973 to year 2009 (30 months vs. 24 months, P = 0.0002). In addition, we also observed a trend of longer OS in patients with bone metastases diagnosed from year 2014 to year 2015 compared with patients who were diagnosed year 2010 to year 2013 (10 months vs. 7 months, P = 0.05). Conclusions: The results of this analysis indicated an improved prognosis in patients with ovarian cancer from 2010 to 2014, especially for patients with distant lymph node metastases. In addition, novel treatment strategies are needed for patients with distant visceral metastases.

Prognostic value of genomic alterations in DNA damage response (DDR) genes in relapsed/advanced bladder cancer (BCa).

427 Background: DDR defects play an important role in tumorigenesis, progression, treatment response and outcomes of BCa. We previously showed DDR mutations were associated with better prognosis in relapsed/advanced (TxN2-3M0-1) BCa. In this study, we aimed to update and validate our findings in 3 independent datasets. Methods: 81 BCa patients (pts) who had FoundationOne tumor tissue genomic sequencing (315 cancer-related genes) were used as discovery dataset. Validation dataset 1 consisted of additional 91 pts with FoundationOne test. Validation dataset 2 consisted of 129 relapsed/advanced pts from TCGA BCa cohort. Overall survival (OS) was measured from time of initial BCa diagnosis to death or last follow-up. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Logistic regression analysis was performed to calculate odds ratio (OR) and 95% CI. A panel of 32 DDR genes (excluding ATM) were used for analyses because ATM mutation was a negative prognostic factor in our prior study. Results: DDR mutations were present in 76.5% (62/81), 40.7% (37/91) and 51.2% (66/129) pts of the 3 datasets. They were associated with longer OS (adjHR = 0.39, 95% CI 0.21–0.73, p = 0.003) in the discovery dataset, which were confirmed in two validation datasets (Validation 1: adjHR = 0.51, 95% CI 0.26–1.03, p = 0.059; Validation 2: adjHR = 0.62, 95% CI 0.39–0.97, p = 0.038). There was a trend for longer OS with increased number of DDR mutations in individual pts. Pts carrying ≥3 DDR mutations had the best prognosis (data not shown). In 144 cisplatin or carboplatin-treated pts pooled from the 3 cohorts, pts with DDR mutations were more likely to have objective response (OR = 1.81, 95% CI 0.85–3.92 for any DDR mutations; OR = 3.65, 95% CI 0.91–14.7 for ≥3 DDR mutations) and longer overall survival (HR = 0.61, 95% CI 0.38–0.98 for any DDR mutations; HR = 0.49, 95% CI 0.19–1.27 for ≥3 DDR mutations). Conclusions: DDR mutations (excluding ATM gene and especially ≥3) correlated with better outcomes in relapsed/advanced BCa. Further exploration of the deleterious nature and functional impact of alterations is critical along with prospective validation in ongoing trials.

213O Nintedanib + pemetrexed/cisplatin in malignant pleural mesothelioma (MPM): Phase II biomarker data from the LUME Meso study

Background: The randomised Phase II/III LUME-Meso study is evaluating nintedanib + pemetrexed/cisplatin versus placebo + pemetrexed/cisplatin (≤6 cycles), followed by nintedanib or placebo maintenance, in chemonaïve MPM. In the Phase II part, nintedanib treatment led to improved progression-free survival (PFS; hazard ratio [HR] = 0.54; p = 0.010) and a trend for longer overall survival (OS; HR = 0.77; p = 0.319) compared with placebo. Patients with epithelioid tumours derived greatest benefit. Plasma angiogenic factors and genomic markers were explored for potential associations with treatment outcome in the Phase II epithelioid population. Methods: Baseline plasma levels of 58 angiogenic factors were analysed by multiplex immunoassay (Human AngiogenesisMAP®, Myriad RBM). Genes implicated in the nintedanib mode of action and/or mesothelioma pathophysiology (VEGFR1, VEGFR3 and mesothelin) were evaluated for known single-nucleotide polymorphisms (SNPs). Biomarker associations with PFS/OS treatment effects were analysed by Cox regression and interaction tests with false-discovery rate (FDR) adjustment. Analyses were exploratory and hypothesis generating. Results: Angiogenic factor and genomic data were available for 71 and 67 patients, respectively, in the epithelioid population (n = 77). Of the angiogenic factors evaluated, only endoglin showed a possible trend for association with both PFS and OS improvement, with potentially greater benefit in patients with low plasma levels. Major homozygous genotypes for two VEGFR3 SNPs (rs307821 G/G and rs307826 A/A) showed weak association with OS effect, while the VEGFR1 SNP rs9582036 A/A genotype was potentially correlated with PFS benefit. However, all biomarker treatment associations were limited by small subgroup size (especially for minor genotypes) and FDR-adjusted interaction tests were not significant. Conclusions: These first biomarker results for nintedanib-treated MPM showed potential signals for greater PFS/OS benefits in patients with low plasma endoglin and major homozygous VEGFR1/3 genotypes, but no biomarkers showed clear and significant association with nintedanib efficacy. Clinical trial identification: NCT01907100 Legal entity responsible for the study: Boehringer Ingelheim Funding: Boehringer Ingelheim Disclosure: N. Pavlakis: Advisory Boards: Boehringer Ingelheim, MSD, Merck, BMS, Astra Zeneca, Takeda, Bayer, Novartis, Pfizer, Roche, Ipsen Speaking Honoraria: Boehringer Ingelheim, Bayer, Novartis, Pfizer, Roche Travel Support: BMS, Astra Zeneca, Roche. N. Steele: Honoraria: Pfizer, Novartis Consulting/advisory role: MSD, Boehringer Ingelheim, BMS Research funding: Merck Serono, AstraZeneca, Boehringer Ingelheim, BMS, Novartis, Roche Travel, accommodation, expenses: Pfizer, MSD Oncology, Boehringer Ingelheim. A. Nowak: Consulting/Advisory Role: Aduro Biotech, Morphotek, Bayer, AstraZeneca, Sellas Life Sciences, Trizell, Boehringer Ingelheim, Epizyme, Roche Research Funding: Boehringer Ingelheim, AstraZeneca Travel and expenses: Amgen, AstraZeneca, Boehringer Ingelheim. S. Novello: Speakers' Bureau: AstraZeneca, MSD, Bristol-Myers Squibb, Roche, Pfizer, Eli Lilly. S. Popat: Honoraria: Pfizer, Boehringer Ingelheim, Eli Lilly, AstraZeneca, Novartis, Roche Consulting/advisory role: Boehringer Ingelheim, Eli Lilly, Pfizer, Novartis, Roche Research funding: Boehringer Ingelheim, Epizyme, BMS, Clovis Oncology, Eli Lilly, Roche. L. Greillier: Honoraria: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Pfizer, AstraZeneca, Novartis Pharma, Roche Consulting/advisory role: Boehringer Ingelheim, Bristol-Myers Squibb, Roche Research funding: Roche. M. Reck: Honoraria: Boehringer Ingelheim, Proacta, BMS, MSD, Pfizer, Eli Lilly, AstraZeneca, Merck Inc., Celgene, Novartis Consulting/advisory role: Boehringer Ingelheim, Eli Lilly, BMS, MSD, Pfizer, AstraZeneca, Merck Inc., Celgene, Novartis, Roche Speaker's bureau: Roche, Eli Lilly, MSD Oncology, Merck, AstraZeneca, BMS, Boehringer Ingelheim, Celgene, Pfizer, Novartis. T. Kitzing: Employment: Boehringer Ingelheim. G. Scagliotti: Honoraria: Eli Lilly, Pfizer, MSD, AstraZeneca, Roche Consulting/Advisory role: Eli Lilly Speakers' Bureau: Eli Lilly, MSD. All other authors have declared no conflicts of interest.

Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients.

Background:Programmed death-ligand 1 (PD-L1) may be induced by oncogenic signals or can be upregulated via interferon gamma (IFN-γ). We have explored whether the expression of IFNG, the gene encoding IFN-γ, is associated with clinical response to the immune checkpoint blockade in non-small cell lung cancer (NSCLC) and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE, STAT1 and other associated genes has also been examined.Methods:Total RNA from 17 NSCLC and 21 melanoma patients was analyzed by quantitative reverse transcription PCR. STAT3 and Rantes, YAP1 and CXCL5, DNMT1, RIG1 and TET1, EOMES, IFNG, PD-L1 and CTLA4, IKBKE and NFATC1 mRNA were examined. PD-L1 protein expression in tumor and immune cells and stromal infiltration of CD8+ T-cells were also evaluated. Progression-free survival and overall survival were estimated.Results:A total of 17 NSCLC patients received nivolumab and 21 melanoma patients received pembrolizumab. Progression-free survival with nivolumab was significantly longer in NSCLC patients with high versus low IFNG expression (5.1 months versus 2 months, p = 0.0124). Progression-free survival with pembrolizumab was significantly longer in melanoma patients with high versus low IFNG expression (5.0 months versus 1.9 months, p = 0.0099). Significantly longer overall survival was observed for melanoma patients with high versus low IFNG expression (not reached versus 10.2 months p = 0.0183). There was a trend for longer overall survival for NSCLC patients with high versus low IFNG expression.Conclusions:IFN-γ is an important marker for prediction of response to immune checkpoint blockade. Further research is warranted in order to validate whether IFNG is more accurate than PD-L1.

Laboratory and Clinical Investigations to Identify the Optimal Dosing Strategy for Quizartinib (AC220) Monotherapy in FLT3-Itd-Positive (+) Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)

Internal tandem duplications (ITD) are the most commonly observed FLT3 mutations in AML and are associated with decreased survival. In order to achieve meaningful clinical responses with FLT3 inhibitors, sustained inhibition of FLT3 must be achieved [Pratz, Blood 2009]. Quizartinib (Q) is an oral, potent and selective FLT3 inhibitor with an IC50 ≤ 1 nM. In a Phase (Ph) 1 study, the maximum tolerated dose was 200 mg/day (d) in patients (pt) with R/R AML. QTc prolongation was the dose limiting toxicity (Cortes, JCO 2013). In Ph 2 trials, QTc prolongation >500 msec was observed in 15%-17% of pt treated with Q doses of 90 mg/d and 135 mg/d (Cortes ASCO 2013, Martinelli, ASCO 2013). Composite complete response (CRc) rates and overall survival (OS) in FLT3-ITD(+) pt in these studies were similar, respectively. (Levis EHA 2013)] Therefore, we conducted a pre-clinical, pharmacokinetic (PK), and clinical study to find an optimal dosing strategy balancing efficacy with safety for use in future trials.FLT3-inhibitory activity of Q and its major active metabolite with comparable potency, AC886, in human plasma was determined in a FLT3-ITD(+) cell line incubated in human plasma. Results indicated the minimum plasma concentration to fully inhibit FLT3-ITD in peripheral blood (PB) blasts was 200 nM. Less potent FLT3 inhibitors are able to clear blasts from PB when used at MTD, but often have little effect on bone marrow (BM) blasts. Factors contributing to resistance in the BM microenvironment include local metabolism of drug by stromal cell-cytochrome P450 enzymes (Ghiaur, PNAS 2013) and local production of FLT3 ligand (Sato, Blood 2011). To estimate the concentration of Q necessary to inhibit FLT3-ITD in marrow blasts, we conducted concentration-response studies in blasts in suspension culture (as a parallel to PB blasts) vs co-cultured on BM stromal cells. Approximately 5-fold higher levels of Q were needed to achieve the same IC50 in blasts on BM stroma (Figure 1). These results predict that plasma levels between 500 nM-1000 nM would be required to reach complete inhibition of leukemic growth in BM.The PK of 30 mg and 60 mg doses of Q were evaluated in a Ph 2 study of 76 pt with FLT3-ITD(+) R/R AML. PK dose-proportionality was observed, and steady state (SS) was reached by Day 15. The SS geometric mean trough concentrations for Q+AC886 were 346 nM and 947 nM for 30 mg and 60 mg, respectively. FLT3 inhibition in peripheral blood blasts, as determined both directly and by a plasma inhibitory activity (PIA) assay, was comparable between the 2 doses.With regards to clinical activity, a trend for longer OS and duration of CRc (DOR) (Figure 2) was seen with the higher dose: median OS 20.9 and 25.4 wk and median DOR 4.1 (95% CI 3.9, 9.7) and 20.0 wk (95% CI, 4.3, 20) for 30 mg/d and 60 mg/d, respectively. A similar trend was observed when these were compared for high and low PK exposures. Higher exposure with 60 mg/d did not result in increased CRc rate (47% both doses). (Cortes, ASH 2013)In the Ph 2 study, a linear mixed effect model was applied to Fridericia-corrected QT data (QTcF) and time-matched Q and AC886 plasma concentrations to obtain a slope estimate. The model showed that Q plasma concentration, but not AC886, was the significant predictor for QTc prolongation. The model-predicted upper limit of 90% confidence interval of QTcF change from baseline at geometric mean Cmax of 60 mg (869nM) was 22.6 msec, and for 30 mg (332nM) was 8.64 msec. No apparent dose-response relationship was observed for other safety parameters, including myelosuppression or febrile neutropenia. Thus, neither dose was myelosuppressive, but 60 mg/d was associated with somewhat more QTcF prolongation.This novel laboratory and clinical study has identified 60mg/d of Q as the target dose for clinical efficacy as monotherapy. Although differences in DOR and OS were not statistically significant between 30 mg and 60 mg doses, the sample size was small, and trends for increased benefit were observed at the higher dose. In addition, 60 mg/d provides plasma concentrations (Q+AC886) of 500-1000 nM which are predicted to achieve more complete inhibition of BM blasts. To mitigate the risk of QTc prolongation, a dosing regimen that includes a 30 mg/d lead-in period until SS is reached to allow for QT assessment, followed by escalation to 60 mg/d if tolerated, has been adopted for the Ph 3 study of Q monotherapy in FLT3-ITD-(+) R/R AML (QuANTUM-R, NCT02039726). [Display omitted] [Display omitted] DisclosuresLevis:Millennium: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Gammon:Daichi Sankyo Pharma Development: Employment. Trone:Daichi Sankyo Pharma Development: Employment. Kang:Daichi Sankyo Pharma Development: Employment. Li:Daichi Sankyo Pharma Development: Employment.

HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma

BackgroundSorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child–Pugh A status.MethodsAll patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child–Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients.ResultsThe 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child–Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade ≥3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child–Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively.ConclusionsThere was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia–Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing.

1563P - The oncogenic role of FGFR1 depends on the molecular context

The FGFR protein family has been extensively related to oncogenesis in several types of tumors, including lung cancer. In squamous cell lung carcinoma, 20% of patients harbour FGFR1 amplification. However, its role in lung cancer has not yet been thoroughly described. Several lung cell lines with different genetic backgrounds were transfected with plasmids to either overexpress or silence FGFR1. In these models, several tumorigenic abilities were tested in vitro and in vivo. Besides, mRNA from formalin-fixed paraffin-embedded tissue of a cohort of lung cancer patients was extracted and FGFR1 expression levels, as well as other histology-specific differentially expressed genes, were measured and related to clinical characteristics. FGFR1 increases oncogenic properties in SCC cell lines, but exerts the opposite effects in several lung ADC cell lines. This behaviour is a consequence of differentially expressed genes between these two histologies in the cell lines under study. According to this, analysis of FGFR1 mRNA expression, along with the above mentioned differentially expressed genes, in a cohort of lung cancer patients, reinforced our in vitro results. In this patient cohort, high FGFR1 mRNA expression was associated to a shorter overall survival (OS) and progression free survival (PFS) in lung SCC patients. However, a trend for longer OS was observed for the ADC patients with higher FGFR1 mRNA expression. We provide evidence that FGFR1 oncogenic role is dependent of its molecular context, resulting in a differential role for this gene in tumorigenesis. This involves a differential prognostic role of this gene in the two main lung cancer histologies. The characterization of this molecular context may be of interest in order to decide the suitability for a patient to receive anti-FGFR therapy.