Median PFS For Patients Research Articles

Toxicity Management and Efficacy Evaluation of BCMA-CART in the Treatment of Relapsed and Refractory Multiple Myeloma

To investigate the toxicity management and efficacy evaluation of BCMA-chimeric antigen receptor T cells(CART) in the treatment of relapsed and refractory multiple myeloma (MM). The efficacy and adverse reactions of 21 patients with MM who received BCMA-CART treatment at the First Affiliated Hospital of Wenzhou Medical University from December 2017 to September 2020 were evaluated, and the efficacy assessment and survival analysis for high-risk patients and non-high-risk patients were evaluated. After infusion of BCMA-CART cells in 21 MM patients, the number of effective cases was 17, of which the complete remission (sCR/CR) was 10, and the partial remission (VGPR/PR) was 7. The median OS time for all patients was 19.4 months, and the median PFS time was 7.9 months. The number of patients with extramedullary disease(EMD), high-risk genetics, and ISS stage Ⅲ were 5, 15 and 8, and the effective number was 3, 11 and 6, respectively. The treatment of 3 patients without high-risk factors was effective. The median OS and median PFS of patients with EMD were 14.2 and 2.5 months, respectively, which were shorter than those of patients without EMD (19.4 months and 8.9 months, respectively). The median OS and median PFS of patients with high-risk cytogenetic factors and ISS Ⅲ were not significantly different from those of non-high-risk patients. Cytokine release syndrane (CRS) occurred in 20 patients, of which 14 cases were Grade 1 CRS, while 6 were Grade 2, no CRS of Grade 3 or above occurred. IL-6 receptor inhibitors were used in 9 patients. All CRS were controlled effectively, and no patients had neurological toxicity. BCMA-CART is a certain curative effect in the treatment of relapsed and refractory multiple myeloma, and the adverse reactions can be well controlled through close monitoring and timely treatment.

High score of LDH plus dNLR predicts poor survival in patients with HER2-positive advanced breast cancer treated with trastuzumab emtansine

ObjectiveTo investigate the prognostic value of derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) in patients with advanced HER2 positive breast cancer treated with trastuzumab emtansine.MethodsFifty one patients with advanced HER2 positive breast cancer who received T-DM1 treatment in Harbin Medical University Cancer Hospital were selected. The clinical data and blood test indexes were collected, and the ROC curve determined the optimal cut-off value. Kaplan-Meier survival curve and Cox regression model was used to analyze the effect of different levels of dNLR,LDH,LNI (dNLR combined with LDH index) before and after T-DM1 treatment on the survival of patients.ResultsThe median PFS and OS of the patients with advanced HER2 positive breast cancer who received T-DM1 treatment were 6.9 months and 22.2 months, respectively. The optimal cut-off value of LDH and dNLR before T-DM1 treatment was 244 U / L (P = 0.003) and 1.985 (P = 0.013), respectively. Higher LDH and dNLR were significantly correlated with shorter median PFS and OS (P < 0.05). The median PFS of patients with LNI (0), LNI (1) and LNI (2) were 8.1 months, 5.5 months and 2.3 months, respectively, P = 0.007. Univariate and multivariate analysis showed that LDH > 244 U / L, dNLR > 1.985, LNI > 0, ECOG ≥1 and HER-2 (IHC2 +, FISH+) before the T-DM1 treatment were the poor prognostic factors. LDH uptrend after the T-DM1 treatment also predicted poor prognosis.ConclusionSerum LDH > 244 U / L and dNLR > 1.985 before the T-DM1 treatment were prognostic risk factors for patients with advanced HER2 positive breast cancer receiving T-DM1 treatment. The higher LNI score was significantly associated with shorter PFS and OS. LDH uptrend after T-DM1 treatment was also related to the poor prognosis.

RADT-13. SPARE TRIAL: SCALP-SPARING RADIATION WITH CONCURRENT TEMOZOLOMIDE AND TUMOR TREATING FIELDS FOR PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract INTRODUCTION Current adjuvant treatment for patients with newly diagnosed glioblastoma includes concurrent chemoradiation and maintenance temozolomide with Tumor Treating Fields (TTFields). We report our clinical trial evaluating feasibility and tolerability of scalp-sparing radiation with concurrent temozolomide and TTFields. METHODS Adult patients (age ≥ 18 years) with newly diagnosed glioblastoma with a KPS of ≥ 60 were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions) with temozolomide (75 mg/m2 daily) and TTFields (200 kHz). Maintenance therapy included temozolomide and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. The primary endpoint was safety and toxicity of tri-modality treatment within 30 days of completion of chemoradiation treatment. RESULTS Thirty patients were enrolled. Twenty were male and ten were female, with a median age of 58 years (range 19 to 77 years). Median follow-up was 10.8 months (range 1.6 to 21.3 months). Twenty (66.7%) patients had unmethylated MGMT promotor and ten (33.3%) patients had methylated promoter. Scalp dose constraints were achieved for all patients. Skin adverse events (erythema, dermatitis, irritation, folliculitis) were noted in 83.3% of patients, however, these were limited to Grade 1 or 2 events, which resolved spontaneously or with topical medications. No patient had radiation treatment interruption due to skin AEs. Other Grade 1 events included pruritus (33.3%), fatigue (30%), nausea (13.3%), headache (10%), dizziness (6.7%), and cognitive impairment (3.3%). Other Grade 2 events included headache (3.3%). The median PFS for the entire cohort was 9.1 months (at least 8.5 months, 95% confidence). The median PFS for patients with MGMT promoter methylation status was 11.4 months (at least 9.5 months, 95% confidence). Overall survival was not reached. CONCLUSIONS Concurrent TTFields with scalp-sparing chemoradiation is feasible treatment option with limited toxicity. Future randomized prospective trials are warranted to define therapeutic advantages of concurrent TTFields with chemoradiation.

Palliative Biliary Drainage Has No Effect on Survival in Pancreatic Cancer: Medical Oncology Perspective.

Removal of obstructive jaundice in metastatic pancreatic cancer is an important part of palliative therapy. However, it is not known whether invasive procedures reduce cancer-related mortality. In this study, the effect of palliative biliary drainage on survival outcomes in pancreatic cancer patients was evaluated. Patients diagnosed with pancreatic cancer and undergoing biliary drainage in two different centers between 2010 and 2019 were evaluated retrospectively. Biliary drainage was applied to 73 patients, constituting 20.6% of 355 patients included in the study. The median progression-free survival (PFS) of patients with biliary stent was 5months, while the medianPFS of patients without stenting was 5.5months and the median overall survival (OS) was11.1 and 11.5months, respectively (p: 0.424, p: 0.802). A positive effect of palliative biliary drainage on median PFS and OS could not be demonstrated in our study group. In pancreatic cancer, predictive markers are needed to select patients who can derive a survival benefit from biliary drainage.

Inferior Outcomes for Multiple Myeloma (MM) Patients (pts) Harbouring t(11;14) and the Promise of Venetoclax, Real-World Australian Retrospective

Introduction/ BackgroundTraditionally, MM harbouring t(11;14) is considered standard risk disease. In the era of novel therapies, however, pts with t(11;14) are reported to have inferior outcomes to other standard risk pts. Evidence of response to the BCL-2 inhibitor, Venetoclax (Ven), has further increased interest in understanding outcomes of t(11;14) pts. In this study, we aimed to describe the historical outcomes of t(11;14) MM and response to Ven in a real-world cohort of Australian pts.MethodsThis was a retrospective, multicentre study conducted by members of the Australasian Leukaemia and Lymphoma Group, Myeloma Working Party. Cases were identified by interrogation of cytogenetics/FISH database from 2010 to 2019 inclusive. Baseline patient and disease characteristics, treatment exposure and outcomes were extracted from hospital medical records. Descriptive statistics, and survival analyses were performed as appropriate.ResultsSeventy-four pts [median age 65 years (yrs), range (43-85)] were identified across seven centres. 43% pts had ISS Stage III MM with 88% harbouring additional cytogenetic abnormalities, incl. 13% with gain in 1q and 12% with del(17p). The majority (81%) of pts received proteasome inhibitor (PI)-based 1 st line therapy with 60% having an upfront autologous stem cell transplant (ASCT) and 54% having immunomodulatory drug (IMiD)-based maintenance therapy. Two patients received an allogeneic stem cell transplant after ASCT. The overall response rate (ORR) was 86% with 38% achieving very good partial response (VGPR) or better. The median progression free survival-1 (PFS-1) was 1.91 yrs (95% CI 1.73-2.56) [PI-based, n=60, PFS 1.84yrs (95% CI 1.61-2.41) vs IMiD-based, n=5, PFS 4.58yrs (95% CI 1.16-5.51), HR 0.68 p=0.45] The median overall survival (OS) was 5.35 yrs (95% CI 4.12-6.56). Second and third line therapy was predominantly IMiD-based (see Table 1) with recent introduction of anti-CD38 monoclonal antibodies (mAbs). Median PFS-2 was 0.77 yrs (95% CI 0.39-0.98) while median PFS-3 was 0.65 yrs (95% CI 0.34-1.16). Eleven pts (median 3 prior lines of therapy) were given Ven [Six pts in combination with PI, three with PI and mAbs and two with dexamethasone]. ORR to Ven was 55% with 45% achieving VGPR or better. Median PFS with Ven was 0.54 yrs (85% CI 0.05-2.17). Median PFS for patients with 1-4 lines (n=6) was 1.22 years and median PFS for patients with 5 lines or more (n=5) was 0.54 years, HR 0.56 (95% CI 0.12-2.5).ConclusionFor pts harbouring t(11;14), the duration of response to PI-based 1 st line therapy is suboptimal even with the use of ASCT consolidation in the majority of patients. Despite multiple prior lines of therapy, Venetoclax shows promising results and every effort should be made for early identification of this cytogenetic lesion. Further studies are required to examine the impact of novel triplet and quadruplet combination therapy and use of venetoclax early in the disease course of this sub-group of patients. [Display omitted] DisclosuresTalaulikar: Takeda: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jansenn: Honoraria, Research Funding; Roche: Honoraria, Research Funding; EUSA Pharma: Honoraria, Research Funding. Gibbs: Janssen, Celgene, Amgen, Takeda, BMS and Pfizer: Consultancy, Honoraria; AbbVie: Consultancy.

P-215: A phase I/II study of Pomalidomide, Ixazomib, Clarithromycin and Dexamethasone (PICd) in patients with relapsed or refractory Multiple Myeloma (RRMM)

P-215: A phase I/II study of Pomalidomide, Ixazomib, Clarithromycin and Dexamethasone (PICd) in patients with relapsed or refractory Multiple Myeloma (RRMM)

P-051: Inferior outcomes for Multiple Myeloma (MM) patients (pts) harbouring t(11;14) and the promise of venetoclax, real-world Australian retrospective

<h3>Background</h3> Traditionally, MM harbouring t(11;14) is considered standard risk disease. In the era of novel therapies however, pts with t(11;14) are reported to have inferior outcomes to other standard risk pts. Evidence of response to the BCL-2 inhibitor, Venetoclax (Ven), has further increased interest in understanding outcomes of t(11;14) pts. Here we aim to describe the historical outcomes of t(11;14) MM and response to Ven in a real-world cohort of Australian pts. <h3>Methods</h3> This was a retrospective, multicentre study conducted by members of the Australasian Leukaemia and Lymphoma Group, Myeloma Working Party. Cases were identified by interrogation of cytogenetics/FISH database from 2010 to 2019 inclusive. Baseline patient and disease characteristics, treatment exposure and outcomes were extracted from hospital medical records. Descriptive statistics, and survival analyses were performed as appropriate. <h3>Results</h3> Seventy-four pts [median age 65 years (yrs), range (43-85)] were identified across seven centres. 43% pts had ISS Stage III MM with 88% harbouring additional cytogenetic abnormalities, incl. 13% with gain in 1q and 12% with del(17p). The majority (81%) of pts received proteasome inhibitor (PI)-based 1st line therapy with 60% having an upfront autologous stem cell transplant (ASCT) and 54% having immunomodulatory drug (IMiD)-based maintenance therapy. Two patients received an allogeneic stem cell transplant after ASCT. The overall response rate (ORR) was 86% with 38% achieving very good partial response (VGPR) or better. The median progression free survival-1 (PFS1) was 1.91 yrs (95% CI 1.73-2.56) [PI-based, n=60, PFS 1.84yrs (95% CI 1.61-2.41) vs IMiD-based, n=5, PFS 4.58yrs (95% CI 1.16-5.51), HR 0.68 p=0.45] The median overall survival (OS) was 5.35 yrs (95% CI 4.12-6.56). Second and third line therapy was predominantly IMiD-based with recent introduction of anti-CD38 monoclonal antibodies (mAbs). Median PFS-2 was 0.77 yrs (95% CI 0.39-0.98) while median PFS-3 was 0.65 yrs (95% CI 0.34-1.16). Eleven pts (median 3 prior lines of therapy) were given Ven [Six pts in combination with PI, three with PI and mAbs and two with dexamethasone]. ORR to Ven was 55% with 45% ≥ VGPR. Median PFS with Ven was 0.54 yrs (85% CI 0.05-2.17). Median PFS for patients with 1-4 lines (n=6) was 1.22 years and median PFS for patients with 5 lines or more (n=5) was 0.54 years, HR 0.56 (95% CI 0.12-2.5). <h3>Conclusion</h3> For pts harbouring t(11;14), the duration of response to PI-based 1st line therapy is suboptimal even with the use of ASCT consolidation in the majority of patients. Despite multiple prior lines of therapy, Venetoclax shows promising results and every effort should be made for early identification of this cytogenetic lesion. Further studies are required to examine the impact of novel triplet and quadruplet combination therapy and use of venetoclax early in the disease course of this sub-group of patients.

P-179: Immunoparesis remains a negative prognostic factor in newly diagnosed Multiple Myeloma by competing risk analysis

<h3>Background</h3> Recent reports describe worst outcome in patients with multiple myeloma (MM) and immunoparesis (IP). However, infections can be considered a competing event when analyzing the impact of IP on overall survival (OS). Here, we analyzed the prognostic impact of IP in newly diagnosed MM (NDMM) with a different approach. <h3>Methods</h3> This is a single-center retrospective study of NDMM patients diagnosed between 2000 to 2018. We defined IP as suppression of both uninvolved polyclonal immunoglobulins in IgG and IgA MM or three uninvolved polyclonal immunoglobulins in light-chain MM. <h3>Results</h3> A total of 651 patients with NDMM were diagnosed and treated at our institution. Median age at diagnosis was 65 years old (56 – 74). The M-protein isotype was IgG in 355 (55%) patients, IgA in 184 (28%), light – chain in 98 (15%) and IgD in 14 (2%). At diagnosis, IP was present in 318 (47%) patients, and increased with each ISS stage (37% in ISS-1, 54% in ISS-2 and 63% in ISS-3; p<0.01). 347 (53%) patients were fit for autologous stem cell transplant (ASCT). With a median follow-up of 5 years, median PFS in patients with IP was shorter compared to those without IP (22 vs. 27 months; p<0.01). Cox univariate analysis for known risk factors of progression showed that high β2-microglobulin (≥3.5 mg/L, HR 1.4; p<0.01), low serum albumin (< 35 g/L, HR 1.2; p=0.1), high LDH (≥ 450 U/L, HR 1.6; p<0.01) and IP (HR 1.3; p<0.01) had similar negative impact on PFS. Multivariate analysis showed that high β2-microglobulin, high LDH and IP were the main risk factors with independent negative impact on PFS. Given this data, we aimed to create a prediction model on PFS by two different approaches. The first one consisted of evaluating all possible equations (Stata 16.0. College Station, TX) with AIC and C-Harrell as main criteria, and the second used backward stepwise elimination process. Both resulted in a parsimonious model that contained high β2-microglobulin, high LDH and IP. At the time of this analysis, 45% patients were still alive. Severe infection as a cause of death was seen in 7% patients. Cox univariate analysis showed that patients with IP at diagnosis had negative impact on OS (HR 1.2; p=0.04). To evaluate the impact of IP on OS, we included severe infections deaths as competing events. With this approach, risk of death among patients with or without IP did not change significantly, maintaining its prognostic value both in eligible and non-eligible patients for ASCT (Peppe and Mori test; p=0.12 and p=0.08 respectively). These results suggest that severe infections do not play a major role in OS of patients with NDMM and IP. <h3>Conclusion</h3> In patients with NDMM, IP is an important negative biomarker with shorter median PFS. Its prognostic impact was similar to other known potent risk factors of progression. Regarding OS, IP kept its negative impact even in the presence of severe infections deaths as competing events.

Outcomes in primary cutaneous diffuse large B-cell lymphoma, leg type.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is a rare, aggressive lymphoma characterized by skin involvement predominantly in the lower extremities. Immunochemotherapy with or without involved-site radiation therapy (ISRT) is considered standard front-line therapy. Over-expression of PD-L1/PD-L2 is seen in a high proportion of PCDLBCL, LT cases, but efficacy of immune checkpoint inhibitors (ICI) in relapsed/refractory, PCDLBCL, LT has not been thoroughly studied. We conducted a retrospective cohort study of patients diagnosed with PCDLBCL, LT seen at Mayo Clinic from 1 January 2000 to 31 December 2020. Using the Kaplan-Meier method, we calculated progression-free survival, duration of response, and overall survival in patients who received front-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with and without ISRT, and salvage ICI therapy for relapsed/refractory disease. A total of 28 patients with PCDLBCL, LT were identified. The median PFS in patients treated with R-CHOP plus ISRT was 58 months (95% CI: 18-112) compared to 14 months (95% CI: 5-not reached; p=0.04) in those treated with R-CHOP without ISRT. The median PFS from salvage ICI therapy was 10 months (95% CI: 4-not reached), and median DOR from salvage ICI therapy was 23 months [95% CI: 4-26]. R-CHOP with ISRT had a significantly longer median PFS compared to R-CHOP without ISRT as front-line therapy for PCDLBCL, LT. ICIs may have a role in treating relapsed/refractory disease as reasonable activity in heavily pre-treated patients was observed in this study.

Olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency status: secondary efficacy results from the phase II LIGHT study

<h3>Objectives:</h3> LIGHT (NCT02983799) evaluated olaparib treatment in patients with platinum-sensitive relapsed (PSR) ovarian cancer by <i>BRCA</i> mutation (<i>BRCA</i>m) and homologous recombination repair deficiency (HRD) status; the primary analysis demonstrated objective response rates (ORRs) of 69%, 64%, 29%, and 10% in cohorts of patients with a germline (g) <i>BRCA</i>m, with tumors with somatic (s) <i>BRCA</i>m, HRD-positive (non<i>-BRCA</i>m), and HRD-negative status, respectively (Cadoo K <i>et al.</i> ASCO 2020). Here, we report pre-specified secondary efficacy endpoints and subgroup analyses. <h3>Methods:</h3> In this open-label, non-randomized study, patients with PSR ovarian cancer and ≥1 prior line of platinum-based chemotherapy received olaparib monotherapy (300 mg bid). Patients were assigned to one of four cohorts based on whether they had a g<i>BRCA</i>m, tumors with s<i>BRCA</i>m, had HRD-positive (non<i>-BRCA</i>m) tumors, or HRD-negative tumors. Testing for g<i>BRCA</i>m was completed using Myriad BRACAnalysis CDx; s<i>BRCA</i>m testing was done with Myriad myChoice CDx. Genomic instability (GI) was assessed using the Myriad myChoice HRD test; tumors were deemed HRD-positive if they had a GI score ≥42. Secondary efficacy endpoints included investigator-assessed progression-free survival (PFS; RECIST v1.1) and cancer antigen (CA)-125 response. Time to any progression (TTAP) was calculated from the date of the first dose of olaparib until the earliest date of RECIST v1.1 or CA-125 disease progression, or death. <h3>Results:</h3> The analysis was timed ~6 months after the last patient was enrolled (data cut-off, Aug 27, 2019). Of 271 enrolled patients who had received olaparib, 270 had measurable disease at baseline and were included in efficacy analyses (13 patients whose Myriad test result was failed or missing could not be assigned to a cohort; efficacy in these patients was analyzed separately). ORR and PFS by prior line of chemotherapy, CA-125 response, and TTAP are summarized in the Table. ORRs ~60-70% were observed in the gBRCAm and sBRCAm cohorts and ~30% in the HRD-positive (non-BRCAm) cohort, both in patients with 1 or ≥2 prior lines of chemotherapy. Similarly, median PFS in patients was ~10-11 months in the <i>BRCA</i>m cohorts, and ~5-7 months in the HRD-positive (non<i>-BRCA</i>m) cohort, both in patients with 1 or ≥2 prior lines of chemotherapy. In the <i>BRCA</i>m cohorts, a high proportion of patients achieved a CA-125 response and complete response (CR), with a CA-125 CR rate of 60% and 68% in the <i>BRCA</i>m cohorts and 29% in the HRD-positive non<i>-BRCA</i>m cohort. Median TTAP was ~11 months in the <i>BRCA</i>m cohorts, and 7.2 months in the HRD-positive (non<i>-BRCA</i>m) cohort. <h3>Conclusions:</h3> Secondary efficacy data and subgroup analyses from the LIGHT study of olaparib monotherapy as treatment for PSR ovarian cancer support the primary analysis. Efficacy was observed in all cohorts, particularly in the gBRCAm and sBRCAm cohorts, where similar efficacy was observed. For patients without a <i>BRCA</i>m, greater efficacy was seen in the HRD-positive cohort.

Bendamustine and Bortezomib-Containing Regimens Produce Higher Response Rates and More Durable Responses Versus Cyclophosphamide-Based Therapy in Frontline Waldenstrom Macroglobulinemia

Background: Waldenstrom macroglobulinemia (WM) is an incurable IgM-secreting lymphoplasmacytic lymphoma. Primary therapy for symptomatic WM patients often consists of combination therapy with an alkylating agent or proteasome inhibitor with rituximab. However, randomized studies comparing these treatment regimens are lacking in WM patients.Methods: We retrospectively searched our database for WM patients who received primary therapy with bendamustine-rituximab (Benda-R), bortezomib-dexamethasone-rituximab (BDR), or cyclophosphamide-dexamethasone-rituximab (CDR) between 2005 and 2016. Pertinent clinical data were collected. Response was assessed based on current criteria. Univariate and multivariate regression models were fitted to evaluate the association between clinical variables and response. Time to events was estimated using the Kaplan-Meier method. The Cox regression method was used to fit univariate and multivariate models for progression-free (PFS) and overall survival (OS). P<0.05 was considered statistically significant.Results: 182 patients with WM were identified who received frontline therapy with Benda-R (n=57), BDR (n=88), and CDR (n=37). No differences in sex, hemoglobin level, platelet count, B2M, bone marrow involvement, IPSSWM, and MYD88 and CXCR4 mutational status were observed between treatment groups (p>0.05 for all comparisons). Patients treated with BDR were more likely <65 years, have serum IgM >4,000 mg/dl, and receive treatment for symptomatic hyperviscosity versus patients treated with Benda-R and CDR. Patients with extramedullary disease and peripheral neuropathy were more likely to be treated with Benda-R and CDR, respectively (p<0.01 for all comparisons). 116 patients (64%) received maintenance rituximab, and did not differ between treatment regimens (p=0.68). Rates of CR, VGPR, PR, minor response and no response to therapy were 12% (n=22), 27% (n=48), 47% (n=84), 6% (n=10), and 8% (n=14), respectively. The rate of major response (PR+) was 86%, and the rate of deep response (VGPR+) was 39%. No difference in response was observed between treatment regimens (p=0.45). In the multivariate logistic analysis, patients with serum IgM >4,000 mg/dl had lower odds of major response to therapy (OR 0.3, 95% CI 0.1-0.8; p=0.02), whereas patients who received maintenance rituximab had higher odds of both a major response (OR 13.9, 95% CI 4.4-44.1; p<0.001) and deep response (OR 2.1, 95% CI 1.1-4.0; p=0.02). For patients treated with Benda-R, BDR, and CDR, the median PFS was 5.5 years (95% CI 4.9-not reached [NR]), 5.8 years (95% CI 4.4-7.4), and 4.9 years (95% CI 2.8-7.0), respectively. In the multivariate regression analysis, an increased risk of progression was associated with B2M >3 mg/l (HR 2.33, 95% CI 1.37-3.96; p=0.002) and serum IgM level >4,000 mg/dl (HR 1.85, 95% CI 1.08-3.20; p=0.02). A decreased risk of progression was associated with both Benda-R (HR 0.2, 95% CI 0.1-0.5; p<0.001) and BDR (HR 0.6, 95% CI 0.3-1.0; p=0.05) when compared to CDR. Maintenance rituximab was also associated with a decreased risk of progression (HR 0.11, 95% CI 0.06-0.21; p<0.001), and the median PFS for patients who did and did not receive maintenance rituximab was 6.8 years (95% CI 5.9-NR) versus 2.8 years (95% CI 2.1-4.1), respectively. No difference in the risk of progression was observed between BDR and Benda-R (p=0.13). The estimated 5- and 10-year OS for all patients was 92% and 79%, respectively; median OS has not been reached. The estimated 5-year OS among patients treated with Benda-R, BDR, and CDR was 95%, 96%, and 81%, respectively; p=0.06). For patients treated with BDR and CDR, the estimated 10-year OS was 87% and 61%, respectively, and was not evaluable for patients treated with Benda-R. Treatment with BDR (HR 0.16, 95% CI 0.04-0.59; p=0.006) and maintenance rituximab (HR 0.17, 95% CI 0.05-0.61; p=0.006) were independently associated with a decreased risk of death.Conclusions: Primary therapy with Benda-R, BDR, and CDR produces high response rates and durable PFS in patients with WM. The risk of progression is lower in patients treated with Benda-R and BDR when compared to CDR. Maintenance rituximab is associated with both major and deep responses to therapy as well as superior PFS and OS. DisclosuresCastillo:Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding; Janssen: Consultancy, Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

Efficacy of AI and palbociclib in ER+ HER2- advanced breast cancer patients relapsing during adjuvant tamoxifen: An exploratory analysis of the PADA-1 trial.

1070 Background: In PADA-1 (NCT03079011), a phase III trial testing the clinical utility of ESR1mut detection, ER+ HER2- advanced breast patients (ABC pts) received Aromatase Inhibitor (AI) and Palbociclib (Pal) +/- LHRH agonist as first line therapy. PADA-1 was open to “AI-sensitive” pts, including those with de novo stage IV disease or metastatic relapse after adjuvant endocrine therapy but also pts with metastatic relapses during adjuvant tamoxifen (TAM). In this subsidiary analysis, we report the efficacy of AI+PAL as first line therapy in patients relapsing on adjuvant TAM. Methods: Main inclusion criteria in PADA-1 are: pre- or post-menopausal pts with ER+ HER2- ABC, who did not receive any prior therapy for ABC and who had no adjuvant AI or completed adjuvant AI for &gt; 12 months or who had disease recurrence while on adjuvant TAM. Results: From 04/2017 to 01/2019, 1017 ABC pts have been included in PADA-1, of which 115 (11.3%) had a metastatic relapse while on adjuvant TAM (TAM only (N = 112) or TAM+GnRH agonist (N = 3)). Median age at inclusion was 46 years (range 25-81), and 58 (50.4%) patients had visceral disease. The median PFS under AI+PAL was 20.4 months (95%CI16.1;27.8) in patients relapsing during adjuvant TAM. In contrast, median PFS in patients with de novo metastatic disease and metastatic relapses after the completion of adjuvant endocrine therapy were 30.6 months (95%CI26.7;Not reached) and 27.8 months (95%CI24.1;30.)], respectively. A subgroup analysis among patients relapsing on adjuvant TAM showed that those relapsing during the first two years of adjuvant TAM had a shorter PFS (11.4 months 95%CI[8.7;20.7]) than those relapsing after 2 years of adjuvant TAM (23.8 months 95%CI[20.2;Not reached]). Conclusions: To our knowledge, these are the first data on first line AI+CDK4/6 inhibitor in patients relapsing on adjuvant TAM. While PFS on AI + PAL appears primarily driven by endocrine resistance status, our data show that AI+PAL is a valuable option also in patients relapsing during adjuvant TAM. Clinical trial information: NCT03079011 .

Side effects of CDK4/6 inhibitors in the treatment of HR+/HER2- advanced breast cancer: a systematic review and meta-analysis of randomized controlled trials.

Although combination of cyclin-dependent kinase 4 and 6(CDK4/6) inhibitors with endocrine therapy for advanced breast cancer (ABC) prolongs PFS in patients, but also has associated toxic side effects. However, few previous studies have summarized the toxic and side effects of CDK4/6 inhibitors. Therefore, this study summarized the corresponding toxic and side effects of CDK/6 inhibitors, which is of great importance for doctors and patients to understand how to balance the high survival rate brought by drugs with the decreased quality of life and improve the management of BC. PubMed, Embase, The Cochrane Library, and VIP databases were systematically searched to collect randomized controlled trials (RCTs) of CDK4/6 inhibitors combined with endocrine therapy for advanced breast cancer from January 2010 to December 2019.Two investigators independently reviewed the literatures. Before using the RevMan 5.3 software for a meta-analysis, date were extracted and the risk of bias with the include studies were assessed. A total of 64 RCTs involving 3685 patients were included. Compared with placebo combined with endocrine therapy, CDK4/6 inhibitors combined with endocrine therapy could improve the median progression free survival rate (hazard ratio 0.54, 95% confidence interval (CI):0.50-0.60, P<0.00001). In terms of adverse reactions, CDK4/6 inhibitors combined with endocrine therapy had higher rates of neutropenia, leukopenia, thrombocytopenia, anemia, fatigue, diarrhea, febrile neutropenia, nausea and increased alanine aminotransferase (ALT). CDK4/6 inhibitors have strong specification in the treatment of ABC because of their role in regulating the cell cycle. Although CDK4/6I combined with endocrine therapy can improve the effective rate and median PFS of patients with HR+/HER2-ABC, this treatment regimen increases the incidence of adverse reactions such as neutropenia, leukopenia, thrombocytopenia, anemia, fatigue, diarrhea, febrile neutropenia, nausea and increased ALT. Further research into improving the survival rate while reducing or even avoiding the side effects of CDK4/6Isis needed for better clinical management of BC. PROSPERO (CRD42020171112).

Dynamic cfDNA Analysis by NGS in EGFR T790M-Positive Advanced NSCLC Patients Failed to the First-Generation EGFR-TKIs.

PurposeCirculating cell-free DNA (cfDNA) level has been demonstrated to be associated with efficacy in first generation EGFR TKIs in non-small cell lung cancer (NSCLC). However, the role of dynamic cfDNA analysis using next-generation sequencing (NGS) in patients with subsequent third-generation EGFR TKIs remains unclear.MethodsFrom 2016 to 2019, 81 NSCLC patients with EGFR T790M mutation either in tissue or plasma who received third-generation EGFR TKIs treatment were enrolled. CfDNA were sequenced by NGS with a 425-gene panel. The association of clinical characteristics, pretreatment, dynamic cfDNA and T790M level with outcomes in patients treated with the third-generation TKIs were analyzed.ResultsIn univariate analysis, the median PFS of patients with undetectable cfDNA level during treatment was significantly longer than those with detectable cfDNA (16.97 vs. 6.10 months; HR 0.2109; P < 0.0001). The median PFS of patients with undetectable T790M level during treatment was significantly longer than those with detectable T790M (14.1 vs. 4.4 months; HR 0.2192; P < 0.001). Cox hazard proportion model showed that cfDNA clearance was an independent predictor for longer PFS (HR 0.3085; P < 0.001) and longer OS (HR 0.499; P = 0.034). The most common resistant mutations of the third-generation TKIs were EGFR C797S (24%). CDK6 CNV, GRIN2A, BRCA2, EGFR D761N, EGFR Q791H, EGFR V843I, and ERBB4 mutation genes may possibly be new resistant mechanisms.ConclusionsPatients with undetectable cfDNA during the third-generation EGFR TKI treatment have superior clinical outcomes, and dynamic cfDNA analysis by NGS is valuable to explore potential resistant mechanisms.

Clinical Characteristics and Prognostic Significance of BCOR/BCORL1 Gene Mutation in Patients with Myelodysplastic Syndromes

To investigate the clinical characteristics and prognostic significance of myelodysplastic syndrome (MDS) patients with BCOR/BCORL1 mutation. The clinical characteristics of 135 patients diagnosed as de novo MDS in People's Hospital of Xinjiang Uygur Autonomous Region from September 2015 to September 2019 were analyzed retrospectively. Next-generation sequencing was used to detect 34 kinds of myeloid-tumor-related gene in MDS patients. The clinical characteristics of BCOR/BCORL1 mutation and its effect to progression-free survival(PSF) and overall survival (OS) in MDS patients were analyzed. Among MDS patients, BCOR/BCORL1 mutation was found in 34(25.2%) patients, including 16(11.9%) BCOR mutation and 18(13.3%) BCORL1 mutation. Patients with BCOR/BCORL1 mutation were more common in women and showed lower neutrophil count ［0.75(0.08-22.20) vs 1.27(0.06-35.71)×109/L, P=0.047］ as compared with those without BCOR/BCORL1 mutation. There were no significant difference in the rate of BCOR/BCORL1 mutation in different IPSS-R subgroups, the IPSS-R lower risk group and the IPSS-R higher risk group, different genetic groups, and conversion or non-conversion to leukemia group(P=0.725, P=0.713, P=0.273, P=0.165). BCOR/BCORL1 mutation was associated with DNMT3A, NF1, STAG2, U2AF1, and EZH2 mutation (P=0.003, P=0.007, P=0.000, P=0.004, P=0.024). While the median PFS of patients with BCOR/BCORL1 mutation showed no significantly different as compared with MDS patients without BCOR/BCORL1 mutation (P=0.210), but the median OS was significantly shorter ［16(3-32) vs 22(0.2-48) months, P=0.039］. BCOR/BCORL1 mutation is more common in MDS patients and often company with other genes co-mutations. BCOR/BCORL1 mutation is not associated with disease progression and AML transformation in MDS patients, but it predicts poor overall survival.

The Relative Risk of Prognostic Factors of Age Stratified Multiple Myeloma

Background: Age is a pivotal prognostic factor for multiple myeloma (MM). The risk of evolving from MGUS and SMM to symptomatic MM steadily increases with age. And there are nuances in clinical manifestations and cytogenetic characteristics between young and old patients. The aim of this study is to delineate the clinical and laboratory features and determine the relative contribution of ISS, performance status and cytogenetic abnormalities in each age MM patients. Methods: In this study, 778 MM patients were enrolled in the prospective, non-randomized BDH2008/02 clinical trial between January, 2008 and December, 2016. Briefly, the patients accepted bortezomib or thalidomide-based induction therapy. Transplantation eligible patients accepted ASCT, otherwise they accepted the original regimen consolidation therapy. Subsequently, unless intolerance, patients received either thalidomide-based or lenalidomide-based maintenance therapy for two years. Conventional FISH panel included del(13q), del(17p), gain(1q), t(11;14), t(4;14), t(14;16), and t(14;20). The positive cut-off value for chromosome deletion or gain was 20%, and for chromosome translocation was 10%. A multivariate Cox proportional-hazards model was developed to assess the variables with significant effects on PFS and OS. Explained variation of variables was quantified by RD2. Statistical analysis was conducted by Stata/MP 16.0 (Stata Corp., TX, USA) and SPSS 26.0 (IBM Corp., Chicago, Illinois, USA). Results: Among 778 patients with complete data, 59.5% (463/778) were younger than 60 years old, 31.4% (244/778) were 61-70 years old, and only 9.1% (71/778) were over 71 years old. The median PFS of patients≤60, 61-70 and ≥71 years of age was 36.3, 32.6 and 23.1 months, respectively (P&amp;lt;0.001). The median OS in each age group was 86.2, 60.7 and 34.9 months, respectively (P&amp;lt;0.001) (Figure A-D). The median evaluated glomerular filtration rate of the three groups was 89.1, 74.0 and 66.4 ml/min (P&amp;lt;0.001), respectively. The serum β2-microglobulin level gradually increased with age (P&amp;lt;0.001), along with the proportion of patients with ISS 3 stage. Patients ≥71 years old had a higher proportion of ECOG performance status score 3-4, twice than that of patients ≤60 years old. The incidence of high-risk IgH translocation decreased with age, and was 25.4%, 21.3% and 14.3% across age groups. The incidence of gain(1q) increased with age, and was 43.9%, 47.1% and 54.8%, respectively. The incidence of del(17p) and del(13q) seldom changed with age (Figure E). With age, the risk of high-risk cytogenetic abnormalities did not change significantly, accounting for about 50% in each age group. The risk of ISS gradually decreased, accounting for 36%, 27%, and 14% in ≤60, 61-70 and ≥71 year subgroups, respectively. The risk of the ECOG performance status gradually increased with age, accounting for 10%, 17%, and 36% in the three subgroups (Figure F). The overall response rate of induction treatment gradually decreased with age, and were 90.2%, 81.9%, and 69.2%, respectively (P&amp;lt;0.001). Elderly patients with impaired renal function or more than one high-risk cytogenetic abnormalities might benefit more from bortezomib based treatment than younger patients (Figure G). Conclusion: Age is an important prognostic factor in MM. With age, the risk of MM progression or death steadily grows. Cytogenetic abnormalities are equally important in every age group. The risk of poor performance status increases in elderly patients with a reduction risk in ISS. Elderly patients should focus on the status of frailty and molecular events to determine treatment. Figure Disclosures No relevant conflicts of interest to declare.

Fulvestrant in the treatment of luminal metastatic breast cancer: the balance of effectiveness and safety

The review presents the results of studies of fulvestrant in metastatic breast cancer (MBC). Hormone therapy is an effective method of treating hormone-positive metastatic breast cancer even in the presence of visceral metastases in the absence of a visceral crisis and without detected resistance to endocrine therapy. During the COVID-19 pandemic, hormone therapy is safer for patients with hormone-positive MBC than chemotherapy, since it does not lead to immunosuppression. Fulvestrant is a “pure antiestrogen”, it has a greater affinity for estrogen receptors than tamoxifen. Fulvestrant is both a competitive antagonist and a selective estrogen receptor degrader (SERD), this mechanism of action provides complete blocking of the estrogen signaling pathway. In the phase III CONFIRM study, the optimal dose of fulvestrate was determined to be 500 mg once every 28 days, with a loading dose of 500 mg on day 15 of the first month of therapy. In the FALCON phase III study (n = 462), which included postmenopausal MBC patients who had not previously received any endocrine therapy, fulvestrant 500 mg was compared with the aromatase inhibitor anastrozole. Significant improvement in PFS was achieved with fulvestrant therapy compared to anastrozole: 16.6 months in the fulvestrant group versus 13.8 months with anastrozole [OR = 0.797; 95% CI 0.637–0.999; p = 0.0486]. A subgroup analysis showed that patients without visceral metastases can benefit most from taking fulvestrant. In all studies fulvestrant 500 mg has demonstrated a good toxicity profile, so it is being studied as a component of combined endocrine therapy. In the PALOMA-3 study the combination of fulvestrant with palbociclib (CDK4/6 inhibitor) demonstrated a median PFS 9.5 months, compared with monotherapy with fulvestrant – 4.6 months (HR = 0.46, p &lt; 0.0001). In the MONALEESA-3 study, the median PFS in patients receiving ribociclib with fulvestrant was significantly higher compared to those taking placebo with fulvestrant: 20.5 months and 12.8 months, respectively (HR = 0.593; 95% CI: 0.480–0.732; p &lt; 0.001). In the MONARCH-2 study the combination of fulvestrant and abemaciclib was studied in the second line of therapy, the median PFS was 16.4 months in the group of fulvestrant and abemaciclib, and 9.3 months in the group of fulvestrant and placebo (HR = 0.553; 95% CI 0.449-0.681; p &lt; 0.0001). Fulvestrant has a satisfactory toxicity profile, does not require supporting therapy, and is included in the clinical recommendations for monotherapy and combination therapy.

P-212 Factors affecting median PFS in patients with advanced, non-resectable well differentiated pancreatic neuroendocrine tumors treated initially with octreotide LAR - real world data

Somatostatin analogues (SSA) are widely used in the treatment of patients with functioning and non-functioning well-differentiated neuroendocrine tumors (NET). The antiproliferative activity of SSA in NETs has been confirmed in two randomized placebo-controlled trials. The PROMID trial was the study assessing the effect of octreotide LAR on the control of tumor growth in patients with metastatic, well-differentiated mostly G1 midgut NETs, but not pancreatic NET. The Clarinet trial evaluated the effect of another analogue of SST - lanreotide autogel (AG) 120mg sc in patients with metastatic, well- or moderately differentiated, non-functional enteropancreatic NETs including also pancreatic NET G1/G2 (Ki-67 index < 10%), nonfunctioning, SSTR-positive There are only a few retrospectives study evaluated the efficacy of octreotide LAR 30mg in pan NET.

Impact of proteasome inhibitor vs. IMiD maintenance therapy on outcomes of patients with high-risk multiple myeloma (HRMM).

e20557 Background: The ideal choice of maintenance therapy in patients with HRMM high-risk multiple myeloma remains unknown. We analyzed the outcomes of patients with HRMM undergoing transplant receiving different maintenance approaches. Methods: Patients with MM undergoing their first ASCT from 2012-19 within 1 year of diagnosis were identified from the prospectively maintained database of patients undergoing ASCT. HRMM was defined as having t(4;14), t(14;16), t(14;20), del17p13, or gain 1q detected on fluorescent in situ hybridization (FISH). Results: Of the 412 patients undergoing ASCT within 1 year of diagnosis, 333 had FISH data available and of these, 37% (124/333) patients had high-risk cytogenetics. Distribution of HR cytogenetics was as follows: deletion 17p: 37% (n = 46), t(4;14): 27% (n = 34), t(14;16) or t(14;20): 12% (n = 26), gain1q: 31% (n = 41). 9% (n = 12) had more than one HR abnormality. In patients with HRMM, median age at transplant was 59 years (range: 39 to 73), and 61% (n = 103) were males. 64% (n = 107) of high-risk patients received post-transplant maintenance therapy. Maintenance therapy in this group included a proteasome inhibitor (PI) in 34% (n = 29), immunomodulatory drug (IMiD) in 59% (n = 51), or both in 7% (n = 6). There was no difference in baseline characteristics of HRMM patients receiving PI vs. IMiD maintenance, except that patients with del17p were more likely to receive PI maintenance therapy (55% vs 28%, p = 0.01). (Table) After a median follow-up of 3.1 years from diagnosis, patients with HRMM had inferior PFS compared to patients with standard risk disease, with median PFS of 3 vs. 4.8 years, p &lt; 0.001. Amongst the 86 HRMM patients receiving maintenance therapy, median PFS in patients receiving PI vs. IMiD vs. both PI + IMiD maintenance was 3 vs. 3.2 vs. 2.2 years, respectively, log-rank p = 0.7. In the sub-group of patients with 17p deletion, median PFS in the three groups was 3 vs. 2.9 vs. 2.2 years, respectively, log-rank p = 0.7. Conclusions: Patients with HRMM have inferior PFS compared to patients with standard risk disease. We observed similar outcomes in HRMM patients post-transplant regardless of the choice of maintenance therapy. [Table: see text]

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

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