Longer PFS Research Articles

Utility of FDG-PET/CT in Patients with Advanced Renal Cell Carcinoma with Osseous Metastases: Comparison with CT and 99mTc-MDP Bone Scan in a Prospective Clinical Trial

Objective: Compare FDG-PET/CT, CT, and bone scan for detecting and monitoring bone metastases’ response in metastatic renal cell cancer (mRCC). Methods: Patients with mRCC prospectively underwent FDG-PET/CT, CT, and bone scans at baseline and after 8 weeks of therapy. Tumor visibility and metabolic activity were retrospectively recorded. Response was evaluated by PERCIST, RECIST, and MD Anderson bone criteria. Kaplan-Meier methodology estimated event-time distributions for PFS, OS, and time to symptomatic skeletal event (SSE). Log-rank test tested differences in event-time distributions between response at 8 weeks by response criteria. Results: Sixteen patients (n = 30; 53%) were evaluable. Baseline FDG-PET/CT detected more osseous metastases (n = 55) than CT (n = 45) or bone scan (n = 34). From baseline to 8 weeks, metabolic activity of lesions decreased >20%, while qualitative and quantitative CT and bone scan parameters were unchanged for most patients. Partial metabolic responders by PERCIST had longer PFS and OS (n = 5, 20+ months) versus those with stable (n = 9; PFS = 9.2 mos, OS = 8.7 mos) and progressive (n = 2; PFS = 5.4 mos, OS = 12.1 mos) metabolic disease, p = 0.09 and 0.42, respectively. By RECIST, longer PFS and OS was seen for stable (n = 12, PFS = 8.3 mos, OS = 17.7 mos) versus progressive (n = 4; PFS = 3.7 mos, OS = 7.5 mos) disease, p = 0.16, 0.02, respectively. OS was not reached, but estimated ≥20 mos, for 4 patients with RECIST SD and PERCIST PMR, compared to OS of 17.7 mos for other patients with RECIST SD. Conclusions: FDG-PET/CT identified more bone metastases and greater numbers of quantitative and qualitative treatment responses in mRCC compared to CT and bone scan. FDG-PET/CT also may identify a sub-group of patients with better outcomes than predicted by standard imaging modalities.

Abstract A052: Detection of serum protein levels for predicting clinical benefit in advanced non-small-cell lung cancer patients treated with immune checkpoint inhibitors

Abstract Background: Though PD-ligand 1 (PD-L1) expression on tumor tissue has been established as companion diagnostics in non-small-cell lung cancer (NSCLC) for anti-PD-1 treatment, additional biomarkers are critically needed. While immune related adverse events (irAEs) have been reported to be associated with efficacy, there are no established biomarkers to predict irAEs onset. Here, we measured multiple serum proteins in NSCLC patients treated with immune checkpoint inhibitors (ICIs) and explored the potential of predicting clinical response and irAE onset. Patients and Methods: Advanced NSCLC patients received nivolumab, pembrolizumab or atezolizumab until progressive disease (PD) or unacceptable toxicity. Serum samples were collected at baseline and after the treatment (at week 4 or week 6). Durable clinical benefit (DCB) was defined as patients whose response was lasting over 6 months. Using Luminex technology, serum levels of 41 proteins consisting of cytokines, chemokines, growth factors, and angiogenesis factors were measured. All statistical analyses were carried out using JMP Pro software (ver. 14.0). Cut-off value of serum protein levels were estimated with receiver operating characteristic curve. Results: Ninety-eight patients were registered in the study between January 2016 and May 2019 at Wakayama Medical University Hospital and 97 were included in the final analysis. Demographics of the patients were as follows: median age 70 (range, 49 to 91); male 78%; stage III/IV 31/69%; squamous/non-squamous/unknown 29/69/2%; previous treatment: 0/≥1 22/78%; ICI: nivolumab/pembrolizumab/atezolizumab 46/41/13%. Objective response rate was 24.7% (24/97), and disease control rate was 46.4% (45/97). Among 41 serum proteins measured serially, IL-8 levels at baseline were significantly lower in DCB patients than non-DCB patients in entire cohort (p < 0.05). Among those, Kaplan-Meier analysis revealed lower levels of IL-8 were significantly associated with longer PFS (cut-off, 11.9217 pg/ml; median PFS, 293 vs 59 days; p < 0.01). In second or later line subset, GRO-α, IL-8, IP-10, PLGF and VEGF-D were significantly lower in DCB patients than non-DCB-patients at baseline (p < 0.05). Lower levels of those proteins except for VEGF-D were significantly associated with longer PFS ((cut-off, 1.073 ng/ml, 11.9217 pg/ml, 480.8 pg/ml, and 14.83 pg/ml; median PFS, 183 vs 49, 293 vs 49, 133 vs 42 , and 153 vs 49 days; 95% CI, 56-322 days, 69 days-not reached, 58-211 days and 52-293 days; p < 0.05, 0.01, 0.05, 0.01). Follistatin which we previously reported to be associated with DCB upon nivolumab treatment, also showed significant association with longer PFS both in entire cohort (cut-off, 572.5; median PFS, 160 vs 59 days; 95% CI, 68-322 days, p < 0.05) and 2nd or later line subset (cut-off, 572.5; median PFS, 100 vs 49 days; 95% CI, 39-322 days, p < 0.05), though it was not significantly different between DCB and non-DCB. Regarding irAEs, GRO-α levels were significantly increased between baseline and the second sampling point in patients who acquired irAEs both in entire cohort and 2nd or later line subset (p < 0.01). Conclusions: We identified potential serum protein markers associated with clinical benefit and irAEs in advanced NSCLC treated with ICIs by multiplex protein-based assay. Citation Format: Jun Oyanagi, Yasuhiro Koh, Hiroaki Akamatsu, Koichi Sato, Shunsuke Teraoka, Kuninobu Kanai, Atsushi Hayata, Nahomi Tokudome, Yuichi Ozawa, Keiichiro Akamatsu, Masanori Nakanishi, Hiroki Ueda, Nobuyuki Yamamoto. Detection of serum protein levels for predicting clinical benefit in advanced non-small-cell lung cancer patients treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A052. doi:10.1158/1535-7163.TARG-19-A052

Immune-related toxicities in NSCLC: Real-world experience from a tertiary cancer center

Abstract Background Immune checkpoint inhibitors (ICIs) are key in the treatment of advanced non-small cell lung cancer (NSCLC). However, there is a paucity of large real-world case series on timing and severity of immune-related adverse events (irAEs) that could inform treatment service provision. Methods A retrospective study of patients with advanced NSCLC treated with ICIs at The Clatterbridge Cancer Centre between 2016 and 2018 was conducted to review irAEs in the context of therapeutic efficacy. Kaplan Meier analysis, Mann-Whitney and chi-squared tests were used. Results 303 patients were identified. Median age was 68 years; 83 patients (27%) had a performance status (PS) of 0; 85 (28%) had an ACE-27 comorbidity score ≥2. 277 (91%) had pembrolizumab (107 (35%) first line), 21 (7%) nivolumab and 5 (2%) atezolizumab. Median number of cycles was 6 (range 1-29). Median progression-free and overall survival (PFS/OS) were 5.0 and 10.0 months. IrAEs were reported in 40% of patients and 13% experienced multiple irAEs; 11% were ≥G3. The most common irAEs were dermatitis (12%), dysthyroidism (9%), colitis (6%), hepatitis (5%), arthralgia (5%), pneumonitis (5%); the most common ≥G3 irAEs were pneumonitis (3%), hepatitis (2%) and colitis (2%). Treatment was discontinued due to irAEs in 12% of patients. Median time to irAEs onset by system involved varied between 46 days (hyperthyroidism) and 122 days (arthralgia). There was no association between irAEs and age (p = 0.16), PS (p = 0.46), or ACE-27 score (p = 0.68). 83% of irAEs occurred within 6 months of initiating ICIs; no clear correlation between irAEs incidence and time on treatment was found. Patients with irAEs within 6 months of treatment had longer PFS (7.1 vs. 3.9 months, HR 0.70, p = 0.014) and OS (15.6 vs. 7.7 months, HR 0.48, p Conclusion In our large real-world retrospective cohort study the incidence of irAEs reflected that seen in clinical trials. There appears to be a toxicity-efficacy relationship with irAEs; however, larger studies are required to validate this. Legal entity responsible for the study The Clatterbridge Cancer Centre NHS Foundation Trust. Funding Has not received any funding. Disclosure A.C. Olsson-Brown: Honoraria (self): MSD; Honoraria (self), Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Research grant / Funding (self): Eli Lily; Research grant / Funding (self): Novartis. C. Escriu: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb; Advisory / Consultancy, Research grant / Funding (self): Boeringher Ingelheim; Speaker Bureau / Expert testimony: Pfizer. All other authors have declared no conflicts of interest.

The Prognostic Value of Circulating Tumor Cells in Asian Neuroendocrine Tumors

Circulating tumor cells (CTC) play important roles in various cancers; however, few studies have assessed their clinical utility in neuroendocrine tumors. This study aimed to prospectively evaluate the prognostic value of CTC counts in Asian patients with neuroendocrine tumors before and during anti-cancer therapy. Patients who were diagnosed with unresectable histological neuroendocrine tumors between September 2011 and September 2017 were enrolled. CTC testing was performed before and during anti-cancer therapy using a negative selection protocol. Chromogranin A levels were also assessed. Univariate and multivariate Cox’s proportional hazard model with forward LR model was performed to investigate the impact of independent factors on overall survival and progression-free survival. Kaplan–Meier method with log-rank tests were used to determine the difference among different clinicopathological signatures and CTC cutoff. The baseline CTC detection rate was 94.3% (33/35). CTC counts were associated with cancer stages (I-III vs. IV, P = 0.015), liver metastasis (P = 0.026), and neuroendocrine tumor grading (P = 0.03). The median progression-free survival and overall survivals were 12.3 and 30.4 months, respectively. In multivariate Cox regression model, neuroendocrine tumors grading and baseline CTC counts were both independent prognostic factors for progression-free survival (PFS, P = 0.005 and 0.015, respectively) and overall survival (OS, P = 0.018 and 0.023, respectively). In Kaplan-Meier analysis, lower baseline chromogranin A levels were associated with longer PFS (P = 0.024). Baseline CTC counts are associated with the clinicopathologic features of neuroendocrine tumors and are an independent prognostic factor for this malignancy.

Analysis of the association between prior chemotherapy regimens and outcomes of subsequent anti-PD-(L)1 monotherapy in advanced non-small cell lung cancer

Immune checkpoint inhibitor (ICI) monotherapy targeting PD-1/PD-L1 has been a prominent option for the patients with advanced non-small cell lung cancer (NSCLC), which is now commonly used in second- or later-line settings after the failure of conventional chemotherapy. Chemotherapy can modulate tumor immunity in drug-dependent manner, suggesting pre-ICI chemotherapeutic regimens might influence the efficacy of immunotherapy. Therefore, it is of interest to investigate the associations between the types of pre-ICI chemotherapy and the outcomes of patients receiving ICIs treatment. The data from NSCLC patients who received anti-PD-1/PD-L1 ICI monotherapy after the failure of first-line chemotherapy were retrospectively reviewed. Clinical outcomes of the patients following ICIs monotherapy were compared according to different pre-ICI chemotherapeutic regimens. Eighty-nine cases receiving ICI monotherapy immediately after the failure of first-line chemotherapy were included into final analysis. The patients in Gem group had the longest PFS (median: 6.50 m) following ICIs treatment (P=0.031), compared to Pem group and Tax group (median: 3.49 and 3.30 m, respectively). Pre-ICI chemotherapy with Gem retained independently associated with favorable PFS (P=0.014, HR 0.52; 95% CI, 0.31-0.88) in multivariate analysis after adjusting for other covariates. The patients in Gem group also achieved better objective response rate (ORR) (P=0.046) and disease control rate (DCR) (P=0.005) following ICIs treatment compared to those in Pem/Tax group. The differences in depth of response to ICIs between Gem and Pem/Tax groups were also compared. Of the 48 patients who achieved controlled disease and had ≥1 measurable target lesion during ICIs treatment, no greater tumor shrinkage was observed in Gem group (P=0.374), however, Gem group trended to have shorter TTM (P=0.074). Prior-line chemotherapy regimens might influence outcomes of the following ICIs monotherapy. Patients received pre-ICI gemcitabine-containing chemotherapy are significantly correlated with longer PFS and better response to ICIs treatment.

Evaluating Isatuximab Interference with Monoclonal Protein Detection By Immuno-Capture and Liquid Chromatography Coupled to High Resolution Mass Spectrometry in the Pivotal Phase 3 Multiple Myeloma Trial, Icaria-MM

Recent advances in multiple myeloma (MM), have seen the advent of several therapeutic monoclonal antibodies (mAb) targeting antigens on malignant plasma cells such as CD38 and SLAMF7. Evaluation of depth of response through quantification of M-Protein, by Serum Protein Electrophoresis (SPEP) and Immuno-Fixation Electrophoresis (IFE) presents a particular challenge for clinical laboratories when therapeutic mAbs are used. Specifically, therapeutic mAbs can confound SPEP and IFE measurements when they overlap with patient serum M-protein. Such interference could lead to an inaccurate determination of depth of response according to International Myeloma Working Group (IMWG) criteria Isatuximab (Isa), an IgG-kappa, anti-CD38 mAb, binds a specific epitope on CD38, which is widely expressed on MM cells. ICARIA-MM was a phase 3, prospective, randomized, open-label, active-controlled, multicenter study comparing isatuximab in combination with pomalidomide plus dexamethasone (Isa-Pd) to pomalidomide plus dexamethasone (Pd) in patients with relapsed/refractory multiple myeloma (RRMM). ICARIA-MM enrolled patients who had received ≥2 prior lines of therapy, including lenalidomide (len) and a proteasome inhibitor (PI). ICARIA-MM demonstrated that Isa-Pd significantly improved PFS, overall response and depth of response with a trend in overall survival benefit and a manageable toxicity profile in these patients. To overcome the potential interference of isatuximab with M-Protein in patients enrolled in ICARIA-MM, we developed and validated a hybrid assay using Immuno-Capture and Liquid Chromatography coupled to High Resolution Mass Spectrometry (IC-LC-HRMS). This method enriches for serum immunoglobulins by immuno-capture. Heavy chains (HC) and light chains (LC) are then dissociated and sorted using Liquid Chromatography. M-Protein and isatuximab LC are analyzed using HRMS which allows to differentiate their monoisotopic intact mass. A small number of patients (24/154; 15.6% in the Isa-Pd arm and 5/153; 3.3% in the Pd arm) fulfilled all criteria for CR (100% M-protein reduction on SPEP, bone marrow <5% plasma cells), but remained IFE positive as per IRC (near-CR category). Serial serum samples from 22 of 24 patients in the Isa-Pd arm were available for MS analysis. Separation of the M-protein and isatuximab signals was performed by IC-LC-HRMS. Using a semi-quantitative approach and applying a sensitivity threshold of 0.25g/dL for IFE-positivity (sensitivity threshold of IFE test per Covance central lab), we identified 11 of 22 patients as having M-protein levels below the threshold for IFE positivity, indicating that the true CR-rate was underestimated in the ICARIA-MM study due to interference. Of the 11 patients with MS M-protein values below the IFE sensitivity threshold, 10 were IgG (8 IgGκ, 2 IgGλ) and one was lambda LC disease with undetectable baseline HC. Baseline myeloma isotype distribution was different in patients with MS M-protein values above IFE sensitivity threshold (4 IgA, 6 IgG, 1 kappa light chain). This confirms that M-protein interference mediated by isatuximab, an IgG kappa mAb, is predominantly seen in patients with IgG isotype (mainly IgGκ), and in LC patients in whom a detectable IgG heavy chain can now be identified. At primary analysis, 4 of 11 patients with MS M-protein values above IFE sensitivity level, versus 2 of 11 patients with MS M-protein values below IFE sensitivity level had progressed. Median PFS was 13.9mo in patients with MS M-protein values above IFE sensitivity level, versus 15.21mo in patients with MS M-protein values below IFE sensitivity level. In conclusion, MS can be successfully used to separate endogenous M-protein from therapeutic isatuximab serum levels. In this subpopulation with excellent response to Isa-Pd, while most patients are still progression-free, a trend can be observed towards longer PFS in patients who would be considered IF negative after MS versus patients remaining IF positive. Disclosures Finn: Sanofi Oncology: Employment. Macé:Sanofi Oncology: Employment. Campana:Sanofi: Employment. Le-Guennec:Sanofi: Employment. Muccio:Sanofi Oncology: Employment. Tavernier:Sanofi Oncology: Employment. Rouchon:Sanofi Oncology: Employment. Roccon:Sanofi Oncology: Employment. Dai:Sanofi Oncology: Employment. Boutet:Sanofi Oncology: Employment. Mouret:Sanofi Oncology: Employment. Pradeilles:Sanofi Oncology: Employment. Hugla:Sanofi Oncology: Employment. Engelvin:Sanofi Oncology: Employment. DiNoto:Sanofi Oncology: Employment. van de Velde:Sanofi: Employment. Fedeli:Sanofi Oncology: Employment. OffLabel Disclosure: Isatuximab is an investigational agent and has not yet been approved by the US Food and Drug administration or any other regulatory agency.

Exposure-Response Analyses and Disease Modeling for Selection and Confirmation of Optimal Dosing Regimen of Isatuximab in Combination Treatment in Patients with Multiple Myeloma

Background: Isatuximab (Isa) is an anti-CD38 monoclonal antibody with multiple modes of action for killing tumor cells through direct tumor targeting and immune cell engagement. Exposure-Response (E-R) analysis and disease modelling of tumor burden were performed to evaluate the relationship between Isa exposure and efficacy outcomes. This analysis also supports the Isatuximab dosing regimen selection/confirmation when administered in combination in relapsed/refractory multiple myeloma (RRMM) patients. Methods: To determine the optimal dose for the Phase 3 ICARIA-MM study, E-R analyses were conducted in 44 and 52 RRMM evaluable patients from two Phase 1 trials of Isa in combination with pomalidomide/dexamethasone (Pd) (NCT02283775) or with lenalidomide/dexamethasone (Rd) (NCT01749969), respectively. Isa was administered intravenously at doses from 3 to 20 mg/kg every 2 weeks or weekly for 4 weeks then every 2 weeks (QW/Q2W). In the E-R analyses, several Isa exposure parameters were tested to evaluate if they were predictors of response (partial response [PR] or better). Baseline covariates were also considered in the model to evaluate potential confounding effects. In addition, a second type of analysis was performed on 2 pooled datasets of 153 (single agent and combination with Pd) and 162 (single agent and combination with Rd) evaluable RRMM patients: disease response was also captured by modeling the dynamics of the serum M-protein using a joint model of tumor growth inhibition and drop-out. Trial simulations were then performed to evaluate different dosing regimens of interest. To confirm the dose, E-R analyses were conducted in 297 evaluable RRMM patients from the phase 3 trial (ICARIA-MM; NCT02990338) comparing Isa-Pd (N=148) and Pd (N=149). Isa was administered intravenously at 10 mg/kg QW/Q2W in the Isa-Pd arm. Cox and Weibull (Progression-Free Survival [PFS]) or logistic regression (overall response rate [ORR]) models were used. Results: In the two combination Phase 1 trials, Isa appeared to be well tolerated with no clear dose response relationship between 10 and 20 mg/kg. E-R analyses suggested that higher Isa exposure represented by log Ctrough at 4 weeks (CT4W) was associated with increased ORR. Both models predicted an increased ORR with decreased beta-2 microglobulin and lower number of prior lines of therapy (Rd only), together with higher log CT4W. Clinical trial simulations showed that the probability of success to reach the targeted ORR was high with 10 mg/kg QW/Q2W for both Pd (83% for ORR ≥60%) and Rd (96% for ORR ≥50%). Serum M-protein reduction was greater at doses ≥10 mg/kg compared to doses <10 mg/kg, with minimal differences between 10 and 20 mg/kg QW/Q2W. These analyses supported the rationale for 10 mg/kg QW/Q2W selection for the Phase 3 combination study. In the Phase 3 ICARIA-MM study, the E-R analysis showed that higher CT4W was associated with higher ORR (predicted ORR below and above the median CT4W being 52% and 72%, respectively). The final model also included time since diagnosis and Revised International Staging System (R-ISS) stage at baseline and an interaction between time since diagnosis and R-ISS; ORR increased as time since diagnosis increased and decreased with higher R-ISS stage. For PFS, in addition to CT4W, the model included plasmacytomas, serum albumin level and R-ISS at baseline. The predicted distribution of PFS indicated that patients with greater Isa CT4W had longer PFS, patients with R-ISS Stage III and plasmacytomas had shorter PFS. Matched analyses to Pd indicated that even patients with concentrations ≤median CT4W benefited from Isa treatment (PFS hazard ratio: 0.773). Conclusion: Model-based drug development was successfully applied to support Phase 3 Isa dosing regimen selection for use in combination with Pd in RRMM patients. E-R and clinical data from the Phase 3 ICARIA-MM study confirmed the efficacy and safety of 10 mg/kg QW/Q2W dose/regimen selected. Disclosures Rachedi: Sanofi: Employment. Koiwai:Sanofi: Employment. Gaudel-Dedieu:Sanofi: Employment. Sebastien:Sanofi: Employment. Thai:Sanofi: Employment. El-Cheikh:Sanofi: Employment. Brillac:Sanofi: Employment. Fau:Sanofi: Employment. Nguyen:Sanofi: Employment. Liu:Sanofi: Employment. Campana:Sanofi: Employment. van de Velde:Sanofi: Employment. Semiond:Sanofi: Employment.

Brentuximab Vedotin and Nivolumab for Relapsed or Refractory Classic Hodgkin Lymphoma: Long-Term Follow-up Results from the Single-Arm Phase 1/2 Study

Brentuximab Vedotin and Nivolumab for Relapsed or Refractory Classic Hodgkin Lymphoma: Long-Term Follow-up Results from the Single-Arm Phase 1/2 Study

271P - Comparison between CHOP like regimens and DAEPOCH with or without Rituximab in adult high grade B cell lymphoma NOS; A retrospective study from a tertiary cancer hospital in South India

BackgroundHigh grade B cell lymphomas (HGBCL) are aggressive lymphomas, grouped into two entities according to whether or not they express double hit/double expresser phenotype. Entity without double hit/expresser phenotype is termed as HGBCL NOS. Best therapeutic approach to patients with HGBCL NOS is not known; treated with either regimens ideal for DLBCL or with more intensive Burkitt’s like regimens. MethodsHospital records of patients diagnosed with HGBCL NOS were retrieved. 34 patients had been non randomly assigned to receive CHOP like regimens (CHOP [20], COP [2], CHOP+HD MTX [5]) or dose adjusted (DA) EPOCH [7] with or without Rituximab[13]. Response rate (RR) to chemoimmunotherapy, toxicity profiles, PFS at 20 months of follow up and OS were noted. Results76.4 %(26) were diagnosed with advanced stage. 76.4%(26) had extra-nodal involvement. overall RR to first line therapy was 100%( CR = 58.8%, PR = 29.4%, SD = 11.8%). 48.1% CR and 37.0% PR in the CHOP like regimen arm and 100% CR rate in patients receiving DAEPOCH. At 20 months follow up, the mean and median PFS was 14.8 months and 11 months. DAEPOCH was associated with highest mean and median PFS (23.7 and 30 months) and same for CHOP were (10.31 and 9 months) at 20months of follow up(p = 0.039). Median OS not reached at 20 months of follow up. Use of Rituximab was associated with improved median PFS (30m vs 10m; p = 0.038) at 20 months, in univariate analysis. On an average 1.54 episodes of grade 3-4 neutropenia and 0.65 episodes of febrile neutropenia occurred per patient. Corresponding values for DAEPOCH and CHOP like regimens were (3.7, 1.5) and ( 0.92, 0.40). 2(5.88%)cases had treatment related death, one each in DAEPOCH(14.2%) and CHOP like regimen arm (3.7%) arm. 21(61.76%) patients relapsed at one year. ConclusionsRegimens like CHOP or DAEPOCH with Rituximab has high response rates but substantial proportion of patients may relapse. Grade 3-4 neutropenia occurs more frequently with DAEPOCH than CHOP, but treatment related mortality is low for both the regimens. Good PS patients do tolerate intensive regimens. Intensive regimens may be associated with longer PFS that may lead to longer OS. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Alteration in TET1 as potential biomarker for immune checkpoint blockade in multiple cancers

BackgroundImmune checkpoint inhibitors (ICIs) have achieved impressive success in different cancer types, yet responses vary and predictive biomarkers are urgently needed. Growing evidence points to a link between DNA methylation and anti-tumor immunity, while clinical data on the association of genomic alterations in DNA methylation-related genes and ICI response are lacking.MethodsClinical cohorts with annotated response and survival data and matched mutational data from published studies were collected and consolidated. The predictive function of specific mutated genes was first tested in the discovery cohort and later validated in the validation cohort. The association between specific mutated genes and tumor immunogenicity and anti-tumor immunity was further investigated in the Cancer Genome Altas (TCGA) dataset.ResultsAmong twenty-one key genes involving in the regulation of DNA methylation, TET1-mutant (TET1-MUT) was enriched in patients responding to ICI treatment in the discovery cohort (P < 0.001). TET1 was recurrently mutated across multiple cancers and more frequently seen in skin, lung, gastrointestinal, and urogenital cancers. In the discovery cohort (n = 519), significant differences were observed between TET1-MUT and TET1-wildtype (TET1-WT) patients regarding objective response rate (ORR, 60.9% versus 22.8%, P < 0.001), durable clinical benefit (DCB, 71.4% versus 31.6%, P < 0.001), and progression-free survival (PFS, hazard ratio = 0.46 [95% confidence interval, 0.25 to 0.82], P = 0.008). In the validation cohort (n = 1395), significant overall survival (OS) benefit was detected in the TET1-MUT patients compared to TET1-WT patients (hazard ratio = 0.47 [95% confidence interval, 0.25 to 0.88], P = 0.019), which was, importantly, independent of tumor mutational burden and high microsatellite instability; as well as not attributed to the prognostic impact of TET1-MUT (P > 0.05 in both two non-ICI-treated cohorts). In TCGA dataset, TET1-MUT was strongly associated with higher tumor mutational burden and neoantigen load, and inflamed pattern of tumor-infiltrating T lymphocytes, immune signatures and immune-related gene expressions.ConclusionsTET1-MUT was strongly associated with higher ORR, better DCB, longer PFS, and improved OS in patients receiving ICI treatment, suggesting that TET1-MUT is a novel predictive biomarker for immune checkpoint blockade across multiple cancer types.

Clinical significance of radiotherapy before and/or during nivolumab treatment in hepatocellular carcinoma.

BackgroundThis study aimed to investigate the clinical significance of previous and/or concurrent application of radiotherapy (RT) in the course of nivolumab treatment for advanced hepatocellular carcinoma (HCC).MethodsPatients with advanced HCC who received nivolumab treatment between March 2017 and May 2018. were included. Nivolumab treatment was indicated in patients who did not respond to conventional therapy including locoregional therapy and/or sorafenib. RT was performed when necessary for curative/palliative purpose.ResultsAmong the 76 HCC patients who received nivolumab, 54 (71.1%) had received RT for HCC before and/or during the treatment. The period from initial HCC diagnosis to nivolumab treatment was significantly longer (P = .007) and the rate of undergoing transarterial chemoembolization (TACE; P = .006) and sorafenib treatment (P = .007) was significantly higher in patients who received previous/concurrent RT than in those who did not. Nivolumab‐related toxicities were generally tolerable regardless of the history of RT. During the follow‐up, 39 (51.3%) patients died and 54 (71.1%) patients experienced disease progression according to the RECIST v1.1. Patients who had received previous/concurrent RT had a significantly longer progression‐free survival (PFS; P = .008) and overall survival (OS; P = .007) than those who did not receive RT; however, this trend was not observed in patients with a history of radiofrequency ablation or TACE (all P > .05).ConclusionPrevious and/or concurrent application of RT in the course of nivolumab treatment was related with longer PFS and OS in advanced HCC patients. Nonetheless, further clinical studies are warranted to confirm our findings.

530PD - Association between transit-amplifying signature and outcomes of patients treated with anti-epidermal growth factor receptor (EGFR) therapy in colorectal cancer

BackgroundIn CRC, the transit-amplifying (TA) subtype is enriched for tumours sensitive to anti-EGFR agents. At the same time, the presence of TA gene signature in tumours belonging to other subtypes may suggest potential anti-EGFR benefit. Hence, we evaluated the association between the TA signature (presence - class 1; absence - class 2) and outcomes in CRC patients (pts) treated with anti-EGFR therapy. MethodsFormalin-fixed, paraffin-embedded samples from a retrospective discovery cohort (D) and an independent clinical trial cohort (CO.20 study, validation (V)) were classified into the two TA classes using our published nCounter assay (NanoString Technologies). A subset of pts with extended RAS/BRAF wild-type (WT) tumours, cell lines, and pts-derived xenografts (PDXs) were also evaluated. Biomarker portability was evaluated in primary/metastatic samples and different platforms (microarrays). ResultsUp to 295 quality samples were included (D-84; V-121; 30 matched pts and control/treated PDXs). Class 1 pts had significantly longer progression-free survival [PFS; D – adjusted (adj) HR 1.95 (1.15-3.31) p<0.01; V – adj HR 1.59 (1.07-2.37) p<0.02] and higher disease control rate (DCR) [D – adj p<0.0001; V adj p<0.001]. In D cohort (unselected for RAS/BRAF) classes were significantly associated with sidedness (left 71% class 1; right 58% class 2). In 71WT pts, class 1 was associated with significantly higher DCR (83% vs. 39%, adj p: 0.003); and trend towards longer PFS and response. This association was more pronounced in a clinically relevant cohort of 51WT and left-sided pts (class 2 vs. class 1 median PFS: 2 vs. 5.62 months; HR: 1.88 (0.99-3.57) p: 0.049; response rate (class 2 vs. class 1, 8% vs. 33%, odds ratio 0.17(0.02-1.41) p: 0.09, adj (for age, gender) p: 0.14)). WT PDXs and cell lines showed similar response (Wilcoxon test; PDXs p-value: 0.04; cell lines p-value: 0.007). The TA classes were further validated using microarray data from metastatic samples (Khambata-Ford; PFS p<0.0001). ConclusionsThe detection of TA signature in primary or metastatic samples may further refine the selection of WT CRC pts for anti-EGFR therapy and may explain the differential benefit behind sidedness. Clinical trial identificationNCT00640471. Legal entity responsible for the studyThe authors. FundingNIHR Biomedical Research Centre at The Royal Marsden and the ICR; Cancer Research UK, MedTech SuperConnector. DisclosureD. Cunningham: Research grant / Funding (institution): Amgen; AstraZeneca; Bayer; Celgene; MedImmune; Merck Serono; Merrimack; Sanofi. N. Starling: Research grant / Funding (institution): AstraZeneca; Verastem. A. Sadanandam: Research grant / Funding (institution): Bristol-Myers Squibb; Licensing / Royalties: PCT/IB2013/060416. All other authors have declared no conflicts of interest.

Treatment and long-term outcomes in pituitary carcinoma: a cohort study.

Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit. We describe a single-center multidisciplinary experience in managing PC patients over a 22-year period and review previously published PC series. Seventeen patients were identified. Median age at PC diagnosis was 44 years (range 16-82 years), and the median time from PA to PC transformation was 5 years (range 1-29 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervous system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest PFS in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year survival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy. PC management benefits from multidisciplinary care and multimodality therapy. TMZ-based regimens were associated with high survival rates and long disease control.

EP1.14-10 Investigation of Mechanisms of Acquired Resistance to Afatinib with Plasma DNA in Non-Small Cell Lung Cancer Patients

Afatinib, the 2nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) has been evidenced better efficacy compared to 1st generation EGFR-TKI by phase III studies, but the problem is to acquire resistance approximately one year after treatment. The detail mechanisms of acquired resistance to afatinib has not clarified, although T790M was also detected at time to acquired resistance. Recently, the 3rd generation EGFR-TKI, osimertinib has been approved as the first line setting. As for the mechanisms of acquired resistance to osimertinib as 1st line, various kinds of pathway beside EGFR contributed, suggesting difficulty to select next treatment strategy after osimertinib. Considering how to use 1st, 2nd and 3rd approximately, it has been reported that longer PFS was shown among the patients who were treated with osimertinib following afatinib, compared to 1st generation EGFR-TKI. Based on these evidences, we hypothesize that mechanisms of acquired resistance to afatinib may be less genetic alterations compared to osimertinib, and these alterations could be limited to EGFR pathway, resulting in EGFR-TKI sequencing, from afatinib to osimertinib showed better prognosis. Because the concept of tumor evolution showed that the number and kind of genetic alterations were increased after treatment modifications, comprehensive assay system is indispensable for evaluation of acquired resistance. Moreover, non-invasive assay system such as liquid biopsy is needed since distant metastases are often observed in advanced lung cancer patients. Guardant360™, a high sensitive digital sequencing system with plasma DNA has been developed by Guardant Health, enable to detection of SNV of 73 genes, in/del of 23 genes, amplification of 18 genes, and fusions of 6 genes. The assay system enables us to detect 0.03% allele fraction. The purpose of this study is to clarify mechanism of acquired resistance to afatinib with liquid biopsy to determine best EGFR-TKI sequencing. Study Design Prospective observational study Primary objective To determine mechanisms of acquired resistance to afatinib with plasma DNA Target sample size 40. We are planning to compare with the results of patients who acquired resistance to osimertinib with liquid biopsy performed in FLAURA. So far, 29 patients acquired resistance to afatinib, and we collected these blood samples. Sample preparation Collection of samples 1. before afatinib treatment and at PD to afatnib 2. collection of 5ml blood with sodium citrate collection tube Genomic examinations NGS is performed in Guardant Health. This study had finished enrollment and under analysis now. Comprehensive analysis are needed to clarify the mechanisms of acquired resistance to afatinib to facilitate consideration of the best sequence of EGFR-TKI.

880P - Impact of treatment sequence in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Data from the prospective PROREPAIR-B study

880P - Impact of treatment sequence in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Data from the prospective PROREPAIR-B study

1613P - Gefitinib along with methotrexate as palliative therapy in PS 3 and above in metastatic squamous cell carcinoma head and neck cancer patients

BackgroundMetronomic chemotherapy is one of the proven methods for treatment of terminally ill patients with malignancy, who are otherwise not fit for chemotherapy. The literature (IJMPO 2013:34 11-15) suggested that it has been used in patients with PS1/2. However, it was never used in PS 3 and above and it is worth exploring the same as the adverse event profile was very limited with the treatment. With encouraging results of above publications, we explored the possibility of using Gefitinib methotrexate 15mg either alone or in combination in patients with advanced head and neck cancers in view of the limited options and literature availability for subjects with PS 3 and more. MethodsAim- Analysis of Gefitinib 250mg once a day vs methotrexate 15mg once a week vs combination in patients with advanced head and neck cancers safety and efficacy. We collected the details of the 78 subjects with pre-treated advanced refractory or progressive solid tumors having PS of more than 2. Case records between 2017 September and 2018 September were analyzed, 78 patients were found suitable for analysis. Patients received gefitinib (250mg/day), methotrexate as 15mg intramuscular weekly or a combination. Patients were stratified into those with improved PS and those without. The subjects without PS improvement were continued on the single agent and those with improvement were offered additional chemotherapy based on the primary site. ResultsOut of 78 subjects, 49 had improvement in the PS and were continued later. 19 subjects had stable PS and disease. 10 subjects had worsening of PS. Fifty-two subjects have clinically meaningful response (stable disease + complete + partial responses) and had symptomatic improvement. The median PFS was 248 days (95% CI, 104 to 282), and the median improvement in QOL was 9 points on a scale of 30. ConclusionsGefitinib 250mg once a day, methotrexate 15mg once a week, or combination is well tolerated and may have a role in the treatment of advanced cancers with poor performance status. Majority of the patients who are otherwise not eligible beyond palliative care now had better QOL and longer PFS, which re-emphasizes role of metronomic therapy in advanced squamous cell carcinoma of head and neck regions. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Relationship between p53 rs1625895 polymorphism and prognosis in diffuse large B-cell lymphoma

OBJECTIVE p53 gene, as guardian of the genome, is the most widely studied tumor suppressor gene. Previous studies have shown that about 50 percent of tumors have P53 dysfunction. This article aims to retrospectively analyze the correlation between p53 rs1625895 polymorphism and the prognosis of patients with diffuse large B-cell lymphoma (DLBCL). METHODS PCR combined with Sanger sequencing were used to detect rs1625895 genotype in 384 DLBCL patients. The relationship between rs1625895 polymorphisms and the clinical characteristics, first-line therapeutic effects and the prognosis of the patients were analyzed. RESULTS Among all the patients, 2 (0.5%) patients with AA genotype, 34 (8.9%) patients with AG genotype and 348 (90.6%) patients with GG genotype were identified. The patients with different rs1625895 genotypes did not have any difference in terms of age, gender, B symptoms (developing any of the following symptoms: unexplained recurrent fever (often above 38 °C), night sweats, and unexplained weight loss of 10% within 6 months ), erythrocyte sedimentation rate (ESR), international prognostic index (IPI) and molecular subtype (P>0.05). The overall response rate (ORR) was 82.9% and 82.8% in AA/AG and GG, respectively. There was no significant difference between the first-line therapeutic effects of the two groups (P>0.05). And there was also no difference between A allele carriers and homozygous G allele carriers for the 5-year progressionfree survival rate (PFS) (71.8% vs. 62.3%, χ2=1.351, P=0.245) and 5-year overall survival rate (OS) (72.2% vs. 64.1%, χ2=1.267, P=0.260). But in the subgroup with Germinal Center B-cell (GCB) type, the patients carrying A allele for rs1625895 had an obviously longer PFS (91.7% vs. 72.7%, χ2=4.493, P=0.034) and OS (91.7% vs. 76.7%, χ2=4.246, P=0.039) compared with the patients homozygous for the G allele. As for the patients with non-GCB subtype, there was no significant difference in PFS and OS between different rs1625895 genotypes (P>0.05). According to whether the first-line regimen contained rituximab or not, the patients were divided into two groups treated with cyclophosphoramide, doxorubicin, vincristine and prednisone (CHOP) or with rituximab and CHOP (R-CHOP). But in both subgroups, there was no significant difference in the 5-year PFS and OS between the AA/AG and GG patients, too (P>0.05). CONCLUSION For DLBCL patients receiving CHOP regimen chemotherapy in the first line, p53 rs1625895 cannot predict the clinical efficacy and prognosis of the patients, but in the patients with GCB subtype, this polymorphism may be a prognostic indicator.

Therapeutic relevance of targeted sequencing in management of patients with advanced biliary tract cancer: DNA damage repair gene mutations as a predictive biomarker

PurposeIn biliary tract cancer (BTC), standard chemotherapy has limited benefit and no molecular targeted agents have been approved. This study investigated the genetic profile of BTC to identify potential new therapeutic targets and predictive biomarkers. MethodsTargeted exome sequencing was performed for 124 patients with BTC [gallbladder cancer (GBC), 25; intrahepatic cholangiocarcinoma (ICC), 55; extrahepatic cholangiocarcinoma (ECC), 44]. Survival analysis was performed in 112 patients who received palliative chemotherapy for locally unresectable or metastatic disease. ResultsGenetic alterations were observed in 104 patients (83.8%); the most commonly mutated genes were TP53 (44.4%), KRAS (29.0%), ARID1A (12.1%) and IDH1 (9.7%). IDH1/2 mutations appeared more frequently in ICC (23.6%, P = 0.0002) than in GBC (4.0%) or ECC (2.3%), while ERBB2/3 mutations were found only in GBC (20.0%) and ECC (11.4%). Patients harbouring TP53 mutations had shorter overall survival (OS; median 15.2 vs. 37.8 months, P = 0.018), while IDH1 mutations showed a tendency for longer progression-free survival (PFS; 10.6 vs. 6.1 months, P = 0.124). Potentially actionable genetic alterations were found in 54.8%, and 7.1% received appropriate molecular targeted therapy in the clinical trial setting. Germline or somatic mutations in DNA damage repair (DDR) genes were found in 63.5% of patients and were significantly associated with longer PFS (6.9 vs. 5.7 months, P = 0.013) and OS (21.0 vs. 13.3 months, P = 0.009) in patients who received first-line platinum-containing chemotherapies (n = 88). ConclusionsA subgroup of patients with BTC may benefit from targeted therapy by the aid of genetic information. In particular, DDR alterations may be a predictive biomarker for response to platinum-containing chemotherapy in patients with BTC.

Cytological-negative pleural effusion can be an alternative liquid biopsy media for detection of EGFR mutation in NSCLC patients

ObjectiveThough the possibility of using malignant pleural effusions (MPEs) as alternatives for tumor tissues in epidermal growth factor receptor (EGFR) mutation test has been examined, the diagnosis of MPE is often clinically challenging, especially if the cytology is negative for malignancy. The aim of this study was to examine whether cytological-negative PE (CNPE) is useful in detecting EGFR mutation and evaluated its feasibility for predicting clinical outcomes. MethodIn this study, we performed capture-based targeted sequencing using a panel consisting of 520 lung cancer-related genes to detect EGFR mutation status in 121 MPEs and 40 CNPE samples from 161 advanced lung adenocarcinoma patients. Patients underwent TKI treatment with gefitinib, icotinib or erlotinib if EGFR sensitizing mutations were detected at their tumor biopsies or pleural effusion sediment. ResultsWe revealed a mutation detection rate of 99.2% and 100% for MPE and CNPE, respectively (p = 1). The maximum allelic fraction (maxAF) of MPE and CNPE were 57.4% and 56.8%, respectively (p = 0.77). CNPE supernatant is comparable to MPE in reflecting the mutational profile of lung adenocarcinoma. EGFR activating mutations were detected in 47.5% (19/40) of CNPE supernatant sample and 32.5% (13/40) of matched tumor biopsies. CNPE sample is superior to tumor tissues in identifying EFGR mutation. Among the 72 EGFR-TKI treated patients, 51 were cytology positive and the remaining 21 were cytology negative. Our data showed that MPE patients exhibited comparable PFS (p = 0.41) and OS (p = 0.26) with CNPE patients treated with EGFR-TKI. Among the 21 CNPE patients received TKI treatment, patients harboring either L858R or exon 19 deletion had longer PFS than patients without a detectable mutation (p = 0.036). ConclusionCollectively, we demonstrated that CNPE supernatant provided a comprehensive profile of NSCLC, and can serve as a reliable lipid biopsy media for EGFR mutational detection.

Lung cavitation in lung metastases of gastric and non-small-cell lung cancer patients treated with apatinib

In one of the latest issues of Translational Lung Cancer Research ( TLCR ), Jiang et al. have reported on the frequent cavitation of lung metastases in metastatic lung and gastric cancer patients following treatment with apatinib. It has been recognized that anti-angiogenic compounds surface among the anti-cancer therapies, inducing lung cavitation. Although lung cavitation was not found to influence PFS and OS in previous studies (1), the study of Man Jiang, directed by Xiaochun Zhang, has shown that apatinib induces cavitation of lung metastases in a significant number of patients treated with apatinib. Detection of cavitation of lung metastases was associated with longer PFS and OS.