3rd Line Treatment Research Articles

Single center experience with alpelisib-fulvestrant in heavily pretreated women with HR(+), HER-2 (−) metastatic breast cancer.

e13034 Background: HR-positive, Her2-negative metastatic breast cancer patients harboring PIK3CA mutations are associated with resistance to endocrine therapy and worse prognosis. Results from the phase III SOLAR-1 trial demonstrate improved PFS for patients treated with Alpelisib-Fulvestrant after failure on first or second line treatment with aromatase inhibitor. Methods: Within an early access program for Alpelisib in a single oncology center, patients diagnosed with metastatic HR-positive, Her2 -negative breast cancer were screened for PIK3CA mutations. New generation sequencing (NGS) was the preferred technique to identify carriers with PIK3CA mutations on soft tissue or liquid biopsy. Patients who progressed and carried PIK3CA mutations received Alpelisib and fulvestrant as subsequent line of therapy. Results: Among 32 patients (pts) screened, 13 (40,6%) had a PIK3CA mutation. In total, 11 pts received alpelisib. Median age at diagnosis was 57.5 years (range, 39-69). Eight pts (72.7%) had been operated for early-stage breast cancer, 6 (54.5%) had received adjuvant chemotherapy and 5 (45.5%) had received adjuvant radiotherapy. Of 11 pts with evaluable histology, 3 pts (27.3%) had high grade tumors at diagnosis. Ten pts (90.9%) had PR positive tumors. Median Ki67 was 20% (range, 2-80). Eight pts (72.7%) had PIK3CA exon 20 and 3 (27.3%) had exon 9 mutations. Six pts (54.5%) had received prior chemotherapy in the metastatic setting and 10 (90.9%) prior CDK4/6 inhibitor. Three pts (27.3%) received Alpelisib as 2nd line and all remaining patients received alpelisib beyond 3rd line treatment. All pts (100%) had metastasis to the bones, 8 pts (72.7%) to the liver, 6 pts (54.5%) to the lungs and 2 pts (18.2%) to the brain. Until the date of last assessment, Alpelisib was administered for a median of 5.1 months (range, 0.4-21.3). Ten pts were evaluable for response to treatment with Alpelisib. One (10%) had CR, 5 (50%) SD and 4 (40%) PD as best response. Median duration of disease control was not reached. Baseline characteristics were not associated with disease control. Adverse events noticed were thrombocytopenia grade II (1/11), diarrhea grade II (2/11), skin rash grade I &II (4/11), weakness grade III (1/11) and hyperglycemia (3/11). Conclusions: Prevalence of PIK3CA mutations is consistent with published data. Furthermore, combination of Alpelisib-Fulvestrant is a highly active line of therapy even in heavily pretreated patients.

A cohort study of the efficacy and safety of immune checkpoint inhibitors plus anlotinib versus immune checkpoint inhibitors alone as the treatment of advanced non-small cell lung cancer in the real world.

BackgroundAnlotinib is a new multi-target tyrosine kinase inhibitor (TKI) and has been shown to have antitumor effects and synergistic antitumor effects with immunotherapy only in animal studies and in the 2nd-line treatment in small clinical trials. A real-world study with large sample to compare the efficacy and safety of anlotinib plus immune checkpoint inhibitors (ICIs) with ICIs alone in the multiline treatment of advanced non-small cell lung cancer (NSCLC) was urgently needed.MethodsThe data of 535 advanced NSCLC patients were collected from January 1, 2018, to December 31, 2021. The patients were divided into 2 groups: (I) ICI monotherapy (230 patients); (II) ICI + anlotinib (305 patients). After propensity-score matching (PSM) to reduce the effects of biases and confounding variables, the progression-free survival time (PFS), occurrence of adverse events, disease control rate (DCR), and objective response rate (ORR) of the 2 groups were compared. The effects of clinical factors, including age, gender, gene mutations, tumor proportion score, metastases, and combined radiotherapy, were also analyzed.ResultsAfter PSM, the baseline clinical characteristics were well balanced and the 2 group had a good comparability. Patients in the ICI + anlotinib group had significantly longer median PFS in both the 2nd-line treatment (7.73 vs. 4.70 months; P=0.003) and 3rd-line treatment (5.90 vs. 3.37 months; P=0.020), but the difference lacked statistical significance in the 1st-line treatment (8.40 vs. 5.20 months; P=0.229). The overall median PFS of patients in the ICI + anlotinib group was also much longer than that of patients in the ICI monotherapy group (6.37 vs. 3.90 months; P<0.001). The ICI + anlotinib group also tended to have a higher DCR, a higher ORR, and a higher probability of severe adverse drug reactions during the treatment than the ICI monotherapy group, but the differences were not statistically significant. Combining ICI + anlotinib could improve the outcomes of patients with bone metastasis.ConclusionsAnlotinib + ICI therapy could have greater efficacy in the treatment of advanced NSCLC patients than ICI monotherapy. The probability of adverse events might increase in the combined treatment, but could be controlled.

Patient, caregiver, and physician preferences for treatment of relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL).

e18710 Background: Relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) patients ineligible for transplantation face complex, preference-sensitive treatment decisions. Shared decision making (SDM) can improve patient engagement and treatment satisfaction, despite limited data on patient preferences and values in treatment decision-making, particularly for 2nd and 3rd-lines. We conducted a primary qualitative research study to better understand R/R DLBCL treatment decision-making in patients, caregivers, and physicians. Methods: We conducted 1-hour semi-structured interviews with 14 adult R/R DLBCL patients, 8 paired caregivers, and 8 oncologists of R/R DLBCL patients to understand perceived patient and caregiver involvement in treatment-related decisions, 2nd and 3rd-line preferences and goals, treatment satisfaction, and current SDM practices. We used template analysis to code transcripts from 6 a priori codes. 2 interviewers double-coded 8 interviews to ensure interrater reliability &gt; 75% and independently coded the remaining 22 interviews. Results: Patients said rapid-moving care and shock of diagnosis or failing treatment impeded individual and caregiver involvement in treatment decision-making, and thus relied on physician recommendations for 1st line treatment. All patients felt they followed a well-established standard of care, adding to low self-efficacy for SDM in 71% of patients and 38% of caregivers. Caregivers also perceived treatment decisions as directives. While physicians believe patients should have total control over their treatment decisions, they agreed on barriers for involving patients in decision-making (i.e., limited treatment options, established standard of care, lack of patient understanding). Patients found that cumulative treatment experience shaped preferences and considerations in 2nd and 3rd-line treatment; 43% perceived higher autonomy over decision-making and had clearer expectations. 10 patients (71%) said their oncologists shared educational materials around treatment options, but some wanted resources to address ancillary concerns (e.g., mental health, fertility). Patients found caregivers helpful in enhancing their understanding of treatment-related discussions, and all physicians encouraged caregiver inclusion in treatment planning. 71% of patients felt satisfied with their treatment experience, but 21% would have liked a more individualized approach. Conclusions: Results suggest while 2nd- and 3rd-line R/R DLBCL treatment options may be limited, patient preferences and goals can be incorporated into long-term treatment planning. Opportunities for improvement include developing tailored educational materials for caregivers to establish them as trusted messengers and physician tools to support integration of patients’ lived experiences into their clinical workflow.

VOYAGER (KSCC1902): A single-arm, multicenter, phase II study of early induction of nivolumab during second-line treatment with taxane ± ramucirumab for advanced gastric or gastro-esophageal junction cancer.

4028 Background: Although nivolumab prolonged overall survival in 3rd or later line treatment for advanced gastric cancer in the ATTRACTION-2 study, only a small number of patients respond or achieve stable disease. Previous reports have shown that low tumor burden at the start of treatment was potentially associated with efficacy to immunotherapy in some types of tumors, but it has not been studied in advanced gastric cancer. We conducted a clinical trial to evaluate the early induction of nivolumab. Methods: Eligible patients were unresectable advanced or recurrent gastric or gastro-esophageal junction cancer, histologically confirmed to be adenocarcinoma regardless of PD-L1 expression. Patients who were refractory to or intolerant of fluoropyrimidines had a complete or partial response after at least three cycles of taxane ± ramucirumab, and were confirmed to be either of the following conditions; disease progression by imaging tests, an increase of tumor markers, exacerbation of symptoms, and intolerant of pretreatment. Patients received 240mg/body nivolumab every 2 weeks. The primary endpoint was the rate of progression-free survival (PFS) at 6 months (M), and the secondary endpoints included safety, overall survival (OS), response rate (RR), time to treatment failure (TTF), and duration of response (DOR). Based on assuming a threshold PFS at 6M of 16% and an expected PFS of 30% with the early induction of nivolumab, 39 patients were required for a power of 0.8 with a one-sided α of 0.1. Results: Between September 2019 and February 2021, 42 patients were enrolled in this study. The characteristics of patients were male/female: 28/14, median age: 71 years (range: 39-87), and performance status 0/1/2: 21/19/2. The PFS at 6M was 35.7% (80% confidence interval 26.4-45.1%), which means this trial met the primary endpoint. The median PFS and OS were 4.0M (95%CI:2.3–5.7) and 10.9M (95%CI:9.9–16.0), respectively. Of 34 patients with baseline target legions, RR was 17.5% (all confirmed partial response) and the rate of stable disease was 41.2%. TTF, and DOR were 3.6M (95%CI:2.2–5.1), and 14.3M (95%CI:3.9–14.3), respectively. No new safety signals were observed. Conclusions: This study demonstrated an improvement of PFS at 6M in patients with advanced gastric cancer and might justify the strategy of early induction of nivolumab. Clinical trial information: jRCTs071190025.

P-79 Precision oncology without biomarkers: Assessing drug sensitivity in patient-derived tumoroids to guide mCRC 3rd line therapy

“Precision Oncology” refers to strategies and tools to find the best treatment for a specific patient. This concept is often reduced to the combination of targeted therapies with molecular biomarkers. Nevertheless, most options indicated in guidelines for 3rd line treatment of mCRC patients do not have associated biomarkers. In vitro assessment of tumor drug sensitivity based on patient-derived 3D tumoroids can be used to guide therapy decision-making. Furthermore, it can inform the “off label” use of drugs susceptible of improving patient’s PFS.

Efficacy of dacomitinib in patients with non-small cell lung cancer carrying complex EGFR mutations: a real-world study.

BackgroundDacomitinib is a first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations; however, clinical evidence of its activity on NSCLC with complex EGFR mutations is limited.MethodsPatients harboring complex (common mutations co-existing with uncommon mutations), or common (comparison cohort) EGFR mutations, who were treated with dacomitinib, were retrospectively evaluated in the Chinese National Cancer Center and the China PLA hospital between August 2019 and August 2021.ResultsIn total, 72 patients with NSCLC harboring complex (C+U group, n=18) or common (C group, n=54) EGFR mutations and being treated with dacomitinib were enrolled. In the C+U group, 16 cases (88.9%) harbored L858R mutations co-existing with uncommon mutations located from exon 18 to exon 25 of EGFR (mostly E709X), and two cases harbored exon 19 deletion co-existing with G724S or K754E. Among the 15 evaluable patients, the objective response rate (ORR) was 40% (6/15), and the disease control rate (DCR) was 73.3% (11/15). The median progression-free survival (PFS) was 7.5 months [95% confidence interval (CI), 4.4–10.6 months]. Except for the application line of dacomitinib (P=0.039), no significant statistical differences were found in other characteristics and adverse events between the two groups. The Kaplan-Meier method revealed no significant differences in PFS (P=0.889) and overall survival (OS) (P=0.703). However, the stratified analysis found worse PFS in the C+U group than that observed in the C group when receiving 1st and ≥3rd line dacomitinib treatment, while its OS was worse than that of group C when receiving ≥3rd line treatment. Furthermore, in a multivariate analysis, complex mutation status was an independent prognostic factor for OS (P=0.038) in the entire cohort.ConclusionsThis study indicated a worse response and prognosis of patients with NSCLC harboring complex EGFR mutations than those harboring common EGFR mutations when treated with dacomitinib. Further studies and data are needed to confirm this conclusion.

Long-term botulinum therapy for overactive bladder: myths and reality

The review article presents data on the efficacy and tolerability of intravesical injections of botulinum toxin in patients with overactive bladder. The pharmacological bases of the use of botulinum therapy in this category of patients are described in detail. Data on the history of the use of botulinum toxin for medical purposes are presented. Experience to date shows that intravesical botulinum toxin injections are highly effective and well tolerated in patients with refractory overactive bladder. Botulinum therapy is included in domestic and foreign clinical guidelines as a 3rd line treatment for idiopathic and neurogenic overactive bladder. Indications for its implementation are the inefficiency and/or poor tolerability of oral pharmacotherapy. It is noted that the only botulinum toxin recommended for use in clinical practice for the treatment of overactive bladder is onabotulinumtoxin A (Botox). The results of clinical studies are presented, showing that the effectiveness and safety of botulinum therapy do not decrease over time.

Cost-effectiveness analysis of infliximab for the treatment of Kawasaki disease refractory to the initial treatment: A retrospective cohort study

BackgroundInfliximab (IFX) treatment is approved in Japan for health insurance coverage in patients with Kawasaki disease (KD). This study aimed to compare the cost-effectiveness of IFX and other therapeutic strategies for KD refractory to initial treatment, including intravenous immunoglobulin (IVIG), steroids, immunosuppressants, and plasma exchange therapy. MethodsThis multicenter, retrospective cohort study utilized data from the public medical insurance system of Japan. The target population included those who received treatment for KD between April 2012 and March 2019. Eligibility criteria were as follows: 1) initial onset of KD, 2) age < 15 years at onset, and 3) administration of 3rd line treatment if the 1st line treatment was IVIG alone or 2nd line treatment if the 1st line treatment was a combination of IVIG and steroids, in accordance with Japanese guidelines (2012). Those with KD-related cardiovascular complications before admission and those with congenital cardiac disease were excluded. The primary outcome was cost-effectiveness, which was calculated based on the number of admission events per annum divided by medical expenses per annum (times/10,000 US dollars). The Wilcoxon test was applied to analyze the difference in cost-effectiveness between patients who had received IFX and those who had not. ResultsAmong 1267 patients with KD, 25 received IFX treatment, while 206 received another treatment after the disease was designated refractory to initial treatment. The frequency of steroid use during initial IVIG treatment (a predictor of severity) was higher in the non-IFX group than in the IFX group (70.4% vs. 32.0%, p < 0.001) but became comparable after propensity-score matching. Our analysis indicated that IFX was more cost-effective than other treatments [1.04 (0.86, 1.34) vs. 1.38 (1.03, 1.79) (times/10,000 US dollars), p = 0.006]. ConclusionsIFX treatment may be more cost-effective than non-IFX treatment for patients with KD that is refractory to initial treatment.

Persistence, effectiveness and safety of ustekinumab compared to TNF inhibitors in psoriatic arthritis within the Italian PsABio cohort.

To compare real-world persistence, effectiveness and tolerability of ustekinumab versus TNF inhibitors (TNFi) in psoriatic arthritis (PsA). One-year data from Italian subjects enrolled in the PsABio study (PsA patients receiving 1st- to 3rd-line treatment with ustekinumab or TNFi) were evaluated. Treatment persistence was analysed using Kaplan-Meier curves; hazard ratios (HR) of stopping treatment, and the corresponding 95% confidence intervals (CI), were computed through Cox regression models. Proportions of patients reaching clinical effectiveness endpoints were analysed using logistic regression, including propensity score (PS) adjustment for imbalanced baseline covariates, and non-response imputation if treatment was stopped/switched. Among 222 participants with follow-up data (effectiveness set), 101 received ustekinumab and 121 TNFi. In the ustekinumab group, 74.3% continued treatment up to 12±3 months compared to 63.6% in the TNFi group. Ustekinumab showed better persistence than TNFi, overall and in specific subgroups (females, monotherapy without methotrexate, BMI <25 or >30 kg/m2, patients receiving ustekinumab as 2nd-line treatment instead of a second TNFi). Overall, the PS-adjusted HR of treatment discontinuation was 0.46 (95% CI: 0.26-0.82) for ustekinumab vs. TNFi. cDAPSA LDA/remission was achieved in 43.5% of ustekinumab and 43.6% of TNFi-treated patients, while MDA was achieved in 24.2% and 28.0% of patients, respectively. After PS adjustment, odds ratios of clinical effectiveness did not differ significantly. Both treatments showed an acceptable safety profile. This prospective, real-life study found a better persistence of ustekinumab than TNFi in PsA patients. At 1 year, both treatments showed similar effectiveness.

Hairy Cell Leukemia Patients Have a Normal Life Expectancy-A 35-Year Single-Center Experience and Comparison with the General Population.

Simple SummaryClassic hairy cell leukemia (HCL) is a rare, chronic B-cell malignancy with long-term remissions after standard treatment with purine analogues introduced in the 1990s. Although nearly all patiently ultimately relapse after up to 20 years from therapy requiring retreatment, overall survival prognosis remains insufficiently defined as life expectancyhas rarely been corrected for that of the general population. The aim of this single-center retrospective analysis was to report the long-term clinical outcomes of 83 consecutive HCL patients and compare overall survival with a matched cohort from the general population. We show that HCL patients may look forward to a normal lifespan when treated with purine analogues irrespectively of their pretreatment history, age at diagnosis, or whether they were treated until or after the year 2000.Classic hairy cell leukemia (HCL) is an uncommon hematologic malignancy characterized by an excellent prognosis since purine analogues (PA), such as cladribine (2-CdA), have been introduced in the 1990s. However, most data on long-term outcomes is gathered from patients treated with PA first-line or include limited information on previous treatment outcomes, i.e., Interferon-α (IFN-α). Survival curves from previous series did not reach a plateau, indicating that nearly all patients ultimately relapse. Yet, overall survival (OS) data were rarely corrected for life expectancy of the general population. We here report 83 consecutive HCL patients treated between 1983 and 2017 at the University Center in Innsbruck, Austria. Median follow-up was 170 months (1–498). IFN-α, the first-line treatment of choice before 1990, was administered to 24 patients, achieving an overall response rate (ORR) of 86% and an unconfirmed complete remission (CRu) in 23%. All these patients relapsed after a median progression-free survival (PFS) of 30 months (3–80), but either remained drug-sensitive upon re-exposure to IFN-α or were successfully salvaged with PA. All 42 patients exposed to first-line 2-CdA responded (ORR of 100%). Sixteen patients received two to four successive courses of PA with a continuous decrease in the response quality (CRu rate 85.7% 1st-line vs. 41.5% 3rd-line treatment). Median PFS was not reached in both treatment-naïve patients and those retreated at first relapse. Although pretreatment with IFN-α was associated with a shortened median PFS of 81 months (43–118) after PA therapy, this tendency of inferior PFS did not result in inferior OS. OS of all 83 patients was excellent and equivalent to that of age-, sex-, and diagnostic period-matched controls from the Tyrolean general population (standardized mortality ratio 0.8), regardless of their age at diagnosis or whether they were diagnosed until or after the year 2000. These results confirm that HCL patients may look forward to a normal lifespan when treated with PA irrespective of their pretreatment history.

Prognostic and predictive factors of eribulin in patients with heavily pre-treated metastatic breast cancer.

A predictive marker for efficacy of eribulin administered as different lines of treatment in metastatic breast cancer (MBC) has not been identified. We aimed to determine the predictive factors for efficacy of eribulin administered as different lines of treatment in MBC patients.This restrospective cohort study included 49 heavily pre-treated MBC patients who received either eribulin monotherapy or combination therapy with eribulin and anti-Her2 therapy. Associations between clinical response of eribulin-based treatment, time-to-treatment failure (TTF), and possible predictive markers were investigated.Patients’ median age was 55 years; 65% were ER+; 43% were HER2+; and 16% were triple-negative. Median TTF was 5.23 months and longer in non-visceral metastases patients. Eastern Cooperative Oncology Group (ECOG) status was 0–1; eribulin as ≥2nd-line treatment; eribulin combined with dual blockades; lymphocyte-monocyte ratio (LMR) ≥3; and monocyte-lymphocyte ratio (MLR) <0.4. In patients with eribulin as >3rd-line treatment, univariate analysis showed that ECOG status was 0–1, and LMR ≥3 and MLR <0.4 were associated with a low risk of TTF. Multivariate analysis showed that ECOG status 0–1 was an independent protective factor. Leukopenia and neutropenia were the most common manageable adverse events.ECOG status is an independent predictor for TTF, while LMR and MLR may have an interactive effect with other biomarkers (e.g., ECOG status) to predict response in MBC patients receiving eribulin as ≥2nd-line treatment.

Prognostic Factors of Idiopathic Hypereosinophilic Syndrome: A Nationwide Survey in Japan

Prognostic Factors of Idiopathic Hypereosinophilic Syndrome: A Nationwide Survey in Japan

Previous/Concurrent Radiation Enhanced the Response of Toripalimab in Advanced and Recurrent Liver Cancer: A Pilot Study

Anti-programmed death-1 (PD-1) is an emerging paradigm for treating metastatic malignancies. However, limited response rate and unsatisfactory results of PD-1 inhibitor as monotherapy in advanced liver cancer prompted the exploration of combination strategies. Preclinical studies demonstrated that combination of radiation and PD-1 inhibitors can synergistically augment the anti-tumor efficacy induced by both agents. This study addressed the hypothesis that the application of radiation combined with Toripalimab, an anti-PD-1 agent, may foster immune efficacy in metastatic and recurrent liver cancer.We did this study in patients with stage IV (defined by the American Joint Committee on Cancer 8th edition staging system) or recurrent liver cancer in 2nd-line or 3rd-line treatment, with an Eastern Cooperative Oncology Group performance score of 0-2, child-Pugh grade of A-B. All enrolled patients received radiation at doses of 40-60Gy. Toripalimab (240mg per day, 21 days per cycle) was delivered during and/or after radiation until progression or severe toxicities. The primary endpoint was progression-free survival and the secondary endpoints were objective response, overall survival and toxicities. Survivals were calculated from the beginning of immunotherapy.From April 2017 to September 2020, 17 patients were enrolled and evaluable. Sixteen patients (94.1%) were male and 1(5.9%) was female. The median age was 56 years old (range 36-74 years old). Ten patients (58.8%) had hepatocellular carcinoma. Sixteen patients (94.1%) were with Child-Pugh grade A. Fifty-two lesions, including 15 venous tumor emboli, 13 metastatic bones, 12 lymph nodes, 11 liver malignancies and 2 other sites, received radiation. The median radiation dose is 53Gy (40-60Gy, 2-4Gy per fraction). Sixteen patients received targeted therapy (9 patients with sorafenib, 3 patients with lenvatinib, 3 patients with regorafenib and 1 patient with apatinib) during the treatment of immunotherapy and radiotherapy. The objective response rate and disease control rate were 64.7% (the complete response was 5.9% and partial response was 58.8%) and 88.2%. Grade≥3 adverse events were observed in 5 patients (29.4%), including 3 with thrombocytopenia (2 with grade 4, 1 with grade 3),1 with gastrointestinal event and 1 with infection. All the adverse events were cured after treatment. The median follow-up time was 15.9 months. At the last follow up, 6 patients died. No in-field relapse was recorded. Progression-free survival was 43.3% at 1 year and 21.6% at 2 years, overall survival was 60% at 1 year and 24% at 2 years. The median survival time and progression free survival time were 12.1 months and 11.1 months, respectively.For patients with advanced or recurrent liver cancer, toripalimab in combination with concurrent or previous radiotherapy is an effective treatment with tolerable toxicities. A prospective trial with large number of patients is warranted.

289P A retrospective population-based observational study in metastatic HER2-positive breast cancer patients in Denmark previously treated with T-DM1

Current Danish guidelines in HER2-positive metastatic breast cancer (mBC) recommend the combination of trastuzumab with one of several chemotherapeutic agents for 3rd line or later treatments. This study aims to describe treatment of HER2-positive mBC in 3rd line or later after previous treatment with T-DM1 for mBC in a Danish real-world setting.

MO5-3 Nivolumab monotherapy in 3rd-line treatment for HER2 positive or negative advanced gastric cancer

Trastuzumab deruxtecan (DS-8201) showed clinical benefit among HER2 positive (H+) advanced gastric cancer (AGC) patients who received at least two previous therapies. Subgroup analysis of ATTRACTION-2 trial showed that nivolumab was efficacious regardless of prior Trastuzumab use. Little is known about proper use of nivolumab, trifluridine/tipiracil, and DS-8201 in 3rd-line treatment. The purpose of this study is to compare nivolumab efficacy between H+ and HER2 negative (H-) AGC patients in clinical practice. We retrospectively reviewed the medical record of 38 AGC patients who received nivolumab monotherapy in 3rd-line treatment at our institution until August 2020. The baseline characteristics of H+ group (n=10)/ H- group (n=28) were as follows: median age, 71/69 years; male, 90%/68%; ECOG PS 0-1, 80%/79%; previous gastrectomy, 20%/29%; intestinal type, 60%/43%; liver meta, 50%/32%; and ascites, 40%/54%. All H+ patients had received trastuzumab. Among 6 in H+ group/ 16 in H- group who had measurable lesions, objective response rate was 33%/19%. Median progression-free survival and median overall survival were 3.5/1.8 months and 8.2/7.5 months, respectively. The frequencies of immune-related adverse events between two groups were similar (20%/14%). H+ was associated with better outcome of nivolumab monotherapy compared with H-, although this study was small sample size and single institutional retrospective analysis.

Real World Management of Multiple Myeloma in Asia: Treatment Pattern and Cost

Introduction:Multiple myeloma (MM) is the second most common hematologic malignancies in the world. New approved therapeutic agents have improved the survival rates of myeloma patients. However, it is often unclear what is the best treatment in different settings, and the treatment cost is rising. In this study, we assess the way MM is treated in a developed country in Asia.Methods:A retrospective study of newly diagnosed MM patients from June 2009 to April 2017 from Singapore was conducted. The analysis focused on the age of patient, medication regimes used for different lines of treatment, whether autologous stem cell transplant (SCT) was received and the estimated cost of treatment. Treatment free period (TFP) was measured as time from the end date of previous treatment to the start date for the next treatment. The time to next treatment (TTNT) was measured from the start date of the first treatment to the start date of the next line of treatment.Results:A total of 143 patients were included in the analysis. Among the 96 (67.1%) patients under 65 years old, only 73 (76%) received autologous SCT treatment. Overall, 56 (39.2%) of the patients progressed and received second (2nd) line treatment, while 21 (14.7%) and 9 (6.3%) received 3rd and 4th line treatment respectively. The most frequently used drugs for 1st line treatment were Bortezomib (75.5%), Dexamethasone (87.4%), Thalidomide (63.6%) and Cyclophosphamide (53.8%). This reflects that the 2 most commonly used regimens for 1st line treatment are VCD and VTD. For 2nd line treatment, Lenalidomide (50%) and Dexamethasone (94.6%) were the main drugs used, reflecting that RD was the predominant regimen used in this phase. For 3rd line treatment, Dexamethasone (100%), Pomalidomide (38.1%), Cyclophosphamide (33.3%) and Lenalidomide (33.3 %) were the main drugs used.Focusing on individual drugs, while Lenalidomide was only used 7.7% of the time for 1st line treatment, usage increased to 50% and 33.3% for 2nd and 3rd line treatment respectively. For Pomalidomide, while usage was low at 0% and 7.1% for 1st and 2nd line treatment respectively, it increased to 38.1% for 3rd line treatment. Bortezomib, Thalidomide and Cyclophosphamide were predominantly used as 1st line treatment choices, with usage rates of 75.5%, 63.6% and 53.8% respectively. Their usage rates were significantly reduced in 2nd and 3rd line treatment.The average treatment cost per TFP (weeks) among 56 patients who progressed to 2nd line treatment was $673.81/week. The average cost increased to $2,239/week and $11,556.56/week for the patients who received 3rd and 4th line treatment respectively. For SCT patients (30 patients progressed to 2nd line, 7 patients to 3rd line, and 4 patients to 4th line), the average cost per TFP was $705.87/week, $2,078.66/week and $35,854.20/week for 2nd, 3rd and 4th line of treatment respectively. For non-SCT patients (26 patients progressed to 2nd line, 14 patients to 3rd line, and 5 patients to 4th line), the average cost per TFP was $603.64/week, $2,333.25/week and $5,959.72/week for 2nd, 3rd and 4th line of treatment respectively.The average TTNT per patient for 1st, 2nd and 3rd treatment line progression was 128.8, 58.7 and 75.5 weeks respectively. The average TTNT per SCT patient was 142.4, 65.6 and 74.9 weeks for 1st, 2nd and 3rd treatment line progression respectively, as compared to 113.1, 55.2 and 75.9 weeks for non-SCT patients. Overall, the average treatment cost per week of TTNT was $409.18, $798.10 and $2,167.92 for 1st, 2nd and 3rd treatment line progression respectively - the average cost for SCT patients was $496.91, $736.23 and $2,855.34, while the average cost for non-SCT patients was $281.81, $834.81 and $1,625.58 respectively.Conclusions:Treatment for multiple myeloma remains expensive. While the benefits of subsequent lines of treatment decreases, the average treatment cost increases. With the increasing availability of expensive but yet more effective treatments, these could be incorporated early into the treatment regimen to maximise therapeutic benefit. Despite the higher cost of these drugs, cost-effectiveness could be improved, or at least remain similar if TTNT can be greatly prolonged. [Display omitted] DisclosuresChng:Janssen China R&D: Research Funding.

Navigating the Changing Multiple Myeloma (MM) Treatment Landscape: Real-World Data on Clinical Practice Patterns in 287 MM Patients Treated in and Outside German DSMM (Deutsche Studiengruppe Multiples Myelom) Study Group Trials

Introduction: Over the last decade MM diagnosis and therapy have greatly improved; notably due to an increasing number of “novel agents” (NA; e.g. PIs, IMiDs, mAbs, HDAC-, PD1/PD-L1-inhibitors). Anti-MM-therapy has gained complexity; orientation towards “state of the art” chemotherapy (CTx) protocols and international guidelines, as well as their continuous evaluation is highly important. According to the international literature, analyses of CTx management and particularly the use of novel substances have mainly been performed in the context of clinical trials (CT), therefore in a selected minority of patients (pts). In order to determine, whether guideline recommendations on MM therapy are thoroughly implemented in- and outside CT settings, we performed a real-world data analysis on clinical MM practice patterns. Substance use was analyzed in view of treatment lines and evaluated for “MM-pathway conformity”.Methods: We performed a detailed analysis of 287 myeloma pts treated at our University Medical Center, part of the DSMM study group in 2014/15. The pt cohort was defined using the hospital pharmacy and tumor documentation (TBD) databases. TBD analysis enabled the detailed acquisition of pt characteristics, such as age at initial diagnosis (ID), gender, Durie and Salmon (D&S) and International Staging System stage (ISS). Status of transplantation (Tx), comorbidity (via Revised Myeloma Comorbidity Index [R-MCI]), CT data, treatment line/cycle and the year of CTx application were collected using electronic medical records, TBD and CTx management tools. Basic data on therapy composition was collected for the years 2005 to 2017, separating two treatment periods for 1st, 2nd and 3rd-line therapy of 2005-2012 and 2013-2017. This cut-off was carefully chosen to discriminate best between NA- and non-NA-based regimens, and between first generation PI- (bortezomib (BOR) and IMiD-use (thalidomide (THAL), lenalidomide (LEN)) and second generation NA.Results: Pt characteristics were representative for tertiary centers with a median age of 63 years (27-89), 54% were 60-79 and 14% >80 years old. The male:female gender ratio was 58%:42% and ISS predominantly advanced (II/III:62%). Pts showed substantial comorbidities and were classified as fit, intermediate-fit and frail according to R-MCI in 33%, 56% and 11%, respectively. Of interest, 33% of pts could be enrolled in CTs and 88% received 1st line treatment at our center. 275 pts received 1st-line, 149 pts 2nd-line and 97 pts 3rd-line treatment (Fig.1). As expected, numbers of pts decreased with subsequent lines of treatment, albeit the median time to 2nd line therapy due to progression amounted to 2 years. As depicted in Fig.1, 1st line conventional CTx (cCTx) alone was rare and substantially declined over time from 12% 2005-2012 to 1% in 2013-2017. 200 pts (73%) were treated with BOR in 1st line, 63 of 106 reinduced pts received BOR in 2nd or 3rd line. IMiD 2nd and 3rd line treatment was also common within different regimens and the combination of 2 NA of both PI+IMiD increased over time (BOR+THAL, BOR+LEN). The use of second generation NA in 2nd and 3rd line treatment notably increased in 2013 to 2017 in line with their approval. Our analysis revealed that 44% of second generation NA protocols were administered outside CT settings, mainly due to tight inclusion and wide CT exclusion criteria. Maintenance was performed in 57% of pts, predominantly with LEN (60%) and within DSMM CT protocols.Conclusion: Our analyses demonstrate that NA combinations are used predominantly today, whereas the use of cCTx alone is substantially declining. While BOR plays an important role in induction, LEN was subsequently used for maintenance and in outpatient-regimens. BOR-reinduction as a validated treatment option is also reflecting the substantial amount of BOR-based protocols worldwide. A significant percentage of second generation NA are administered outside CT settings, representing the fast and effective implementation of guideline recommendations into the real-world clinical practice at our and other MM centers. Currently, we are assessing the percentage of pts discussed in our weekly MM tumorboard, the evidence level of therapeutic interventions, PFS and OS. Results will be shown at the meeting, including the comparison of our data with others in a detailed review of the literature. [Display omitted] DisclosuresEngelhardt:German Cancer Aid (#11424): Other: Educational Grant; Janssen Cilag GmbH: Other: Educational Grant; Celgene GmbH: Other: Educational Grant; Amgen GmbH: Other: Educational Grant.

Outcomes after Sequential Tyrosine Kinase Inhibitors Treatment in Chronic Phase Chronic Myeloid Leukemia

Introduction: Tyrosine kinase inhibitors (TKIs) made great success in chronic myeloid leukemia (CML) treatment. However, TKIs often need to be changed due to not only adverse events but also suboptimal response or treatment failure. Currently, 5 TKIs, imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) are approved for CML, and the sequential TKI treatment outcomes has not been well studied. Thus, we sought to evaluate outcomes of CP CML in an era where several TKIs are available.Method: Record of CP-CML who were referred to Winship Cancer Center between January 2005 and April 2016 were reviewed. We excluded patients who did not initiate TKI as first-line within 6 months after diagnosis.Results: A total 206 patients were included and followed up median 48.8 (1.4-190.1) months. Clinical characteristics were summarized in table 1. Age at diagnosis was 50 (11-88), and male/female was 105/101. Risk scores was calculated in 110 patients (53.4%), and low/(intermediate)/high of Sokal, Hasford, and EUTOS were 64/27/19, 66/38/6, and 95/15, respectively. Four-teen patients (6.8%) showed additional chromosomal abnormality at initial diagnosis. A total 76 patients (36.9%) were treated with one TKI, 73 (35.4%) were 2 TKIs and rest of them (27.7%), more than 3 TKIs (3 TKIs, n=33; 4 TKIs, n=17; 5 TKIs, n=7). Eight-teen patients (8.7%) reused same TKIs in different treatment lines. IM was the most frequently used in 1st line treatment (n=145, 70.4%), DAS in 2nd line treatment (n=68, 52.3%), NIL in 3rd line treatment (n=21, 32.3%), and PON in 4th and 5th line treatment (n=11, 36.7%, and n=4, 40%), respectively. Reason for switching TKIs or discontinuation included resistant (49.8%), intolerance or adverse event (43.5%), and others (insurance, clinical trial, or reason are not available, 6.7%). ABL domain mutation were tested in 71 (34%) patients, and mutations were detected in 25 patients (35%). Nine patients had more than one mutation, and T315I were detected in 36% of them (n=9).Median 39.0 (3.8-119.8) months after diagnosis, 19 (9.2%) were progressed to advanced phase (AP, n=6; myeloid BC (MBP), n=4; lymphoid BP (LBP), n=9). Eight patients underwent allogeneic HSCT due to TKI failure (n=2), presence of T315I mutation (n=1), persistent neutropenia after imatinib (n=1), and progression to LBP (n=3) and AP (n=1), and 1 did autologous HSCT due to progression to MBP with CSF involvement. Ten patients were expired because of complication of allogenic HSCT (n=3), refractory disease (n=6) and acute myocardial infarction (n=1).Estimated cumulative PFS at 5- and 10-year were 92% and 81%, and OS at 5- and 10-year were 94% and 87% respectively. Fifteen patients of progressed patients were treated with median 1.5 (1-3) more TKIs after disease progression, number of used TKIs for PFS and for OS are not same. According to number of used TKI, PFS rates were not different between groups (Figure 1A, p=0.051), but OS rate were different (Figure 1B, p=0.002). OS at 10 years of 1 TKI was 100% (n=76), 2TKI, 82% (n=73), 3TKIs, 87% (n=33), 4 TKIs, 75% (n=16), and 5TKIs, 55% (n=7), respectively. In univariate analysis, female (p=0.008), ABL kinase mutation (p<0.001), optimal response at 3, 6, and 12 months were related PFS (p<0.001, p=0.002, and 0.037, respectively) (Figure 2 A, C, and E), and Hasford (p<0.001), EUTOS (p=0.047), optimal response at 3 and 6 months (p=0.002 and 0.013) predicted OS. (Figure 2 B and D). Age, race, Sokal score, additional chromosomal abnormality, and 1st line TKI (IM vs newer generation TKIs) did affect neither PFS nor OS.Conclusion: In the era of multiple TKIs, 63% of CP-CML patients were treated more than one TKIs. The best OS was observed in patients tolerating and responding to first and second-line TKI, but OS of 5 TKIs treated patients at 10 years were still 55%, showing potential for long term survival. PFS and OS can be predicted by early molecular response. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical Outcomes of Patients with 3rd or Higher Relapsed Classical Hodgkin Lymphoma: Results from the German Hodgkin Study Group

Introduction: In classical Hodgkin lymphoma (cHL), new agents are initially investigated after several relapses in pre-treated patients. Evidence regarding disease status, treatment sequence, and survival after 3rd or higher relapse of cHL is limited. The aim of this study was to describe clinical outcomes of a historical group of European patients from the German Hodgkin Study Group (GHSG) trial database.Methods: Subjects with at least three consecutive tumor-related events, either progressive/refractory or relapsed disease, were identified in the GHSG database. Two sub-cohorts, further analyzed, included patients (pts) suffering from 3rd relapse after autologous stem-cell transplantation (ASCT; cohort A); and 3rd relapse after salvage therapy without ASCT (cohort B). Overall survival (OS) was the main and progression free survival (PFS) a key secondary endpoint of this study. Adverse events (AEs) were collected in case they had been reported by treating physicians.Results: More than 12,000 HL patients were identified from the GHSG database between the years 1993 and 2013; of which a total of 69 cHL patients with 3 or more relapsed/refractory disease events were included in the analysis. (A, N=50; B, N=8). Majority were males (n=51; 74%). Mean age at the time of 3rd relapse was 39.2 years (standard deviation = 14.0 years; range from 20 to 79 years), with the majority presenting with stage III or IV disease (67%). Time from end of 3rd-line treatment to 3rd relapse was ≤ 3 months (i.e. GHSG definition of refractory disease) in 15 pts (22%), ≤ 12 months (early relapse) in 19 pts (28%) and > 12 months (late relapse) in 35 pts (51%). All 69 pts were pretreated with chemotherapy (ctx), 35 pts (50.7%) with BEACOPP, 30 pts (43.5%) with ABVD and no BEACOPP, and 32 pts (46.4%) with other types of ctx. The number of prior ctx ranged from one to three (median 3). Pretreatment with radiotherapy was observed in 57 pts (82.6%), with salvage ctx aimed to induce a remission prior to stem-cell transplantation (SCT) in 58 pts (84.1%), and with high-dose ctx followed by ASCT in 50 pts (72.5%). Four pts (5.8%) had received allogeneic SCT as 3rd-line treatment. None of the pts had received brentuximab vedotin or anti-PD1 antibodies before 3rd relapse. Among 18 pts with AE records, 16 had a therapy-related AE >/= grade 3. Of the total 69 pts, objective response was obtained in 22 pts (31.9%, 95% CI 21%-44%). With a median observation time of 63.3 months for OS after 3rd relapse, 45 pts (65%) had died and 60 pts (87%) had another PFS event. Twelve months after the 3rd relapse, OS was 73.2% (95% CI 62.6%-83.8%; A, 69.4 % [95% CI 56.5%-82.4%]; B, 62.5 % [95% CI 29.0%-96.0%];) and PFS 50.8% (95%>CI 38.9% to 62.8%; A, 44.9 % [95% CI 31.0%-58.8%]; B, 50.0 % [95% CI 15.4%-84.6%]; Table 1).Conclusion: Pts with a 3rd relapse or progression of cHL were young (mean age 39.2 years) and had poor clinical outcomes. More than 50% of the pts had a PFS event and a quarter of the patient population died within a year. The present data helps to further elucidate the patient-relevant value of new treatment options in a European health service context, and beyond and warrants the need for new treatment options to improve outcomes for these heavily affected pts. [Display omitted] DisclosuresBroeckelmann:Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria, Research Funding. Kaskel:MSD; Merck & Co., Inc.: Employment, Other: stock/stock options. Metterlein:MSD: Employment. Giezek:MSD: Employment. Balakumaran:Merck & Co., Inc.: Employment, Other: stock/stock options. Raut:Merck & Co., Inc.: Employment, Other: stock/stock options. Engert:Amgen: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. von Tresckow:MSD: Consultancy, Research Funding; Takeda: Consultancy, Other: Travel, Housing, Congress Fees, Research Funding; Novartis: Honoraria, Other: Travel, Housing, Congress Fees, Research Funding; BMS: Other: Travel, Housing, Congress Fees.

Anti-Interleukin-17 Therapy of Severe Psoriatic Patients Results in an Improvement of Serum Lipid and Inflammatory Parameters’ Levels, but Has No Effect on Body Composition Parameters

BACKGROUND: Psoriasis is frequently accompanied by metabolic syndrome. Effect of anti-tumor necrosis factor therapies on increases in body weight is well-known. Data on the effects of interleukin-17 inhibitors are limited. Authors determined the effect of anti-interleukin-17 therapies on the body composition and serum lipid and inflammatory parameters among severe psoriatic patients. METHODS: Thirty-five severe psoriatic patients were enrolled. Twenty-two received secukinumab and 13 received ixekizumab as their 2nd-or 3rd-line biological treatment. Before treatment initiation and 6 months later, laboratory examinations measuring metabolic and inflammatory panels and body composition analyses were performed. RESULTS: After 6 months, a significant reduction was observed in psoriasis area severity index (p < 0.001) from 18 to 0, in c-reactive protein (p < 0.001) from 6.6 to 4.00 mg/L, in low-density lipoprotein-cholesterol (p = 0.004) from 3.69 to 3.19 mmol/L, and an improvement in high-density lipoprotein-cholesterol (p = 0.022) from 1.31 to 1.40 mmol/L. Median baseline body mass index was 32.80 kg/m2. The body composition parameters did not show any significant changes. CONCLUSIONS: Anti-interleukin-17 therapy of severe psoriatic patients does not cause significant changes in body composition parameters. Improvements in the lipid and inflammatory parameters might have a beneficial effect on patients’ cardiometabolic status. This effect might be detectable in high-risk obese psoriatic patients.