Second-line Therapy Regimens Research Articles

Second-line therapy for patients with steroid-refractory aGVHD: systematic review and meta-analysis of randomized controlled trials.

Steroids-refractory (SR) acute graft-versus-host disease (aGVHD) is a life-threatening condition in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), but the optimal second-line therapy still has not been established. We aimed to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of different second-line therapy regimens. Literature search in MEDLINE, Embase, Cochrane Library and China Biology Medicine databases were performed to retrieve RCTs comparing the efficacy and safety of different therapy regimens for patients with SR aGVHD. Meta-analysis was conducted with Review Manager version 5.3. The primary outcome is the overall response rate (ORR) at day 28. Pooled relative risk (RR) and 95% confidence interval (CI) were calculated with the Mantel-Haenszel method. Eight eligible RCTs were included, involving 1127 patients with SR aGVHD and a broad range of second-line therapy regimens. Meta-analysis of 3 trials investigating the effects of adding mesenchymal stroma cells (MSCs) to other second-line therapy regimens suggested that the addition of MSCs is associated with significantly improvement in ORR at day 28 (RR = 1.15, 95% CI = 1.01-1.32, P = 0.04), especially in patients with severe (grade III-IV or grade C-D) aGVHD (RR = 1.26, 95% CI = 1.04-1.52, P = 0.02) and patients with multiorgan involved (RR = 1.27, 95% CI = 1.05-1.55, P = 0.01). No significant difference was observed betwwen the MSCs group and control group in consideration of overall survival and serious adverse events. Treatment outcomes of the other trials were comprehensively reviewed, ruxolitinib showed significantly higher ORR and complete response rate at day 28, higher durable overall response at day 56 and longer failure-free survival in comparison with other regimens; inolimomab shows similar 1-year therapy success rate but superior long-term overall survial in comparison with anti-thymocyte globulin, other comparisons did not show significant differences in efficacy. Adding MSCs to other second-line therapy regimens is associated with significantly improved ORR, ruxolitinib showed significantly better efficacy outcomes in comparison with other regimens in patients with SR aGVHD. Further well-designed RCTs and integrated studies are required to determine the optimal treatment. https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022342487.

The epidemiologic impact and cost-effectiveness of new tuberculosis vaccines on multidrug-resistant tuberculosis in India and China

BackgroundDespite recent advances through the development pipeline, how novel tuberculosis (TB) vaccines might affect rifampicin-resistant and multidrug-resistant tuberculosis (RR/MDR-TB) is unknown. We investigated the epidemiologic impact, cost-effectiveness, and budget impact of hypothetical novel prophylactic prevention of disease TB vaccines on RR/MDR-TB in China and India.MethodsWe constructed a deterministic, compartmental, age-, drug-resistance- and treatment history-stratified dynamic transmission model of tuberculosis. We introduced novel vaccines from 2027, with post- (PSI) or both pre- and post-infection (P&PI) efficacy, conferring 10 years of protection, with 50% efficacy. We measured vaccine cost-effectiveness over 2027–2050 as USD/DALY averted-against 1-times GDP/capita, and two healthcare opportunity cost-based (HCOC), thresholds. We carried out scenario analyses.ResultsBy 2050, the P&PI vaccine reduced RR/MDR-TB incidence rate by 73% (UI:66–76) and 72% (UI:65–77), and the PSI vaccine by 29% (UI: 27–31) and 47% (UI: 37–58) in China and India, respectively.In India, we found both USD 10 P&PI and PSI vaccines cost-effective at the 1-times GDP and upper HCOC thresholds and P&PI vaccines cost-effective at the lower HCOC threshold. In China, both vaccines were cost-effective at the 1-times GDP threshold. P&PI vaccine remained cost-effective at the lower HCOC threshold with 49% probability and PSI vaccines at the upper HCOC threshold with 21% probability. The P&PI vaccine was predicted to avert 1.0 million (UI: 0.6–1.3) and 0.8 million (UI: 0.5–1.4) second-line therapy regimens in China and India between 2027 and 2050, respectively.ConclusionsNovel TB vaccination is likely to substantially reduce the future burden of RR/MDR-TB, while averting the need for second-line therapy. Vaccination may be cost-effective depending on vaccine characteristics and setting.

Phase II Study of Pembrolizumab Plus GVD As Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma

Phase II Study of Pembrolizumab Plus GVD As Second-Line Therapy for Relapsed or Refractory Classical Hodgkin Lymphoma

Patient Characteristics and Outcomes of Relapsed/Refractory Multiple Myeloma in Patients Treated with Proteasome Inhibitors in Germany

Introduction: Real-world data reflects treatments and outcomes in clinical practice in contrast with controlled clinical trials. This study evaluates real-life multiple myeloma (MM) patients receiving proteasome inhibitor (PI)-based treatments in the second or third therapy line in 2017 in Germany. Methods: This is a retrospective chart review on adult relapsed/refractory MM patients treated with ≥1 dose of a PI-based regimen in either the second or the third line of therapy. Participating physicians had ≥3 years of clinical experience in treating symptomatic MM patients and used PI according to the label. Results: Distinct patient profiles for each PI-based regimen emerged. Younger, fitter, transplant-eligible patients received novel PI triplets such as carfilzomib in combination with lenalidomide and dexamethasone (KRd) or IRd. Patients receiving lenalidomide in first-line therapy mostly received lenalidomide-free regimens in second-line therapy. In high-risk patients, no clear treatment patterns could be ascertained. The complete response rates were highest with KRd (13.0%), followed by carfilzomib in combination with dexamethasone (Kd) (5.7%) and bortezomib (4.8%). The very good partial response rates were highest with IRd (76.9%), followed by KRd (53.7%), Kd (25.7%), and bortezomib (20.5%). None of the KRd- or IRd-treated patients responded below a partial response. Discussion/Conclusion: Clear patient profiles for each PI type were observed. In second-line therapy, younger, fitter, transplant-eligible patients received novel-PI-based triplets, e.g., KRd or IRd. Patients treated with lenalidomide in first-line therapy mostly received lenalidomide-sparing regimens in second-line therapy. In high-risk patients no clear treatment patterns could be ascertained due to the limited sample size.

High Complete Response Rate Observed with Second-Line Chemo-Immunotherapy with Pembrolizumab and GVD (Gemcitabine, Vinorelbine, and Liposomal Doxorubicin) in Relapsed and Refractory Classical Hodgkin Lymphoma

High Complete Response Rate Observed with Second-Line Chemo-Immunotherapy with Pembrolizumab and GVD (Gemcitabine, Vinorelbine, and Liposomal Doxorubicin) in Relapsed and Refractory Classical Hodgkin Lymphoma

Lenalidomide Maintenance Does Not Negatively Impact Overall and Progression Free Survival Using Lenalidomide-Based Regimens for Multiple Myeloma in First Relapse

BACKGROUNDOutcomes in multiple myeloma have improved dramatically over the last decade however, optimal sequencing of therapy remains unknown. Specifically, in an era where post-transplant lenalidomide (L) maintenance is now as established standard of care, questions remain around the utility of full dose L-based regimens in second line therapy. In this series, we sought to evaluate the impact of different regimens used at first relapse in patients who received autologous stem cell transplant (ASCT) in the frontline setting treated with and without lenalidomide maintenance (LM). We focused on the impact of L-based therapies in patients relapsing on LM.METHODSUsing our prospectively maintained institutional MM database we retrospectively analyzed patients treated at the Cross Cancer Institute from January, 2005 to January, 2016 to ensure 2 years of follow-up for surviving patients. 4 categories were identified based on 2 variables: receipt of LM following 1st line therapy (yes or no) and receipt of L-based 2nd line therapy (yes or no). The primary endpoint was 2nd PFS defined as time of initiation of second line therapy to relapse, death or last follow-up. OS was defined as time of initiation of first line induction therapy to death or last follow-up. Second OS was defined as time of initiation of second line therapy to death or last follow-up. Survival statistics were determined using the Kaplan-Meier method with SPSS software. A p - value of <0.05 was considered significant.RESULTS213 patients received standard bortezomib-based induction and ASCT of which 132 (62%) received LM. Median follow up for the LM patients was 48 months compared to 74.6 months in non-LM patients. 103 patients (48%) required treatment with second line therapy. Forty-four percent patients were treated with LM while 56% were not. Sixty-nine percent received L-based therapy at relapse, 21% received PI-based therapy and 8% were treated with a PI-IMID combination (table 1).Focusing on the cohort of relapsed patients who received LM (n=44), the median 2nd PFS was 9.3 months in those that received L-based second line therapy vs 4.1 months in those that did not (p = 0.28, figure 1b]. In patients who did not receive LM (n = 55) the median 2nd PFS was 14.0 months in those who received L-based second line therapy vs 6.9 months in those who did not (p = 0.19, figure 1a. Examining all patients who received L-based therapy at relapse there was no difference in 2nd PFS based on whether LM was given (p = 0.42).The median 2nd OS was not statistically significant between the groups (p = 0.39, figure 1b. Patients on LM had a median 2nd OS of 34 months with L-based therapy at relapse compared to 39.2 months without. The median 2nd OS in non-LM patients was 34.5 months in those receiving L-based therapy at first relapse and 23.4 months in those that did not (p=0.10).There was no statistically significant differences in median OS between the 4 groups (p = 0.83). For patients who received LM the median OS was not reached in those receiving L-based therapies at relapse and was 78.1 months in patients who did not. In patients who did not receive LM the median OS was 78.0 months in those receiving L-based therapies at relapse and 69.3 months in those who did not.CONCLUSIONOur data suggests that receiving LM does not negatively impact survival outcomes after receiving full dose L-based therapy at relapse. Both median 2nd PFS and 2nd OS were similar with L-based therapies regardless of prior LM. While the 2nd PFS at relapse does fall short of recently published trials in relapsed MM there are some notable confounders here. Firstly, this real-world data includes frailer patients with potentially greater co-morbidities possibly influencing choice and duration of therapy as well as reflect more aggressive disease biology. Secondly, given the relatively short median follow-up of the relapsed LM patients to date, the cohort may be enriched with “early” relapsers (< 2-years) also potentially indicative of biologically more aggressive disease. As such, this may underestimate the true impact of L-based therapies in patients relapsing on LM. Larger series with longer follow-up are necessary to formally examine whether multi-agent L-based regimens confer additional benefit over L-Dexamethasone or non-L based regimens. Real world registries will be useful as prospective trials are unlikely to be done. DisclosuresSandhu:Novartis: Honoraria; Bioverativ: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Venner:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Takeda: Honoraria.

Three fluoropyrimidine-based regimens in second-line therapy following nab-paclitaxel plus gemcitabine in metastatic pancreatic cancer: Efficacy and tolerance in clinical practice.

370 Background: Combination of nab-paclitaxel plus gemcitabine (N+G) has recently become a valid first-line treatment (1L) in metastatic pancreatic adenocarcinoma (MPA) in patients (pts) with performance status (PS) of 0,1 or 2, but there is currently no standard second-line treatment (2L) after this new 1L option. We evaluated survival outcomes and tolerability of three usual fluoropyrimidine-based regimens: FOLFOX, FOLFIRI or FOLFIRI.3 (FOLFIRI1/3), and FOLFIRINOX after N+G failure in MPA pts. Methods: We prospectively identified 138 pts from 11 French centers who received 1L N+G for unresectable pancreatic adenocarcinoma. After disease progression or unacceptable toxicity, we excluded pts with locally advanced cancer, or who underwent secondary resection/chemoradiotherapy. Three subgroups of 2L chemotherapy were identified: FOLFOX, FOLFIRI1/3 and FOLFIRINOX regimens. Response was evaluated by RECIST criteria, progression-free survivals (PFS1, PFS2), and overall survival (OS1, OS2) were calculated using Kaplan-Meier method and compared with the Log-rank test. Results: 61 pts with MPA received a 2L. Persistent neuropathy was present in 27% of pts. Median age was 71.7 years [41-83]. PS was 0, 1 or 2. Median 1L duration, number of metastatic sites, PS, CA19.9, albumin, and bilirubin levels, and persistent neuropathy grade were statistically comparable between the 3 subgroups. Median OS for all 2L pts was 6.0 months [4-8]. Third line regimen was used in 32.8% of 2L pts without statistical significance between the subgroups. Main grade 3/4 adverse events reported were thrombocytopenia (18%), anemia (7.7%), neutropenia (21.4%) and nausea (5.4%). No toxic deaths occurred. Conclusions: This study suggests a clinical benefit and a manageable toxicity profile of 2L fluoropyrimidine-based regimens after N+G failure in patients with MPA, in particularly combined with irinotecan.[Table: see text]

Efficacy of Different Second-line Therapy Regimens in Metastatic Urothelial Carcinoma

Introduction: Metastatic Urothelial Cancer (UC) has a reported survival from platinum based chemotherapy of 15 months. Second line chemotherapy is considered relatively ineffective. Recently, new immuno-oncology drugs have been introduced. Objectives: Aim of this study was to analyze the survival by regimen and metastatic sites of second line treatment for UC. Methods: We analysed 70 patient receiving second line therapy between January 2010 and December 2016 at Heidelberg University Hospital. Median age was 60.9 years, male to female distribution was 74,3% to 25,7%. Regimens used were vinflunine (n=40, 57,1%) taxane based (n=20, 28,6%) and immunotherapy (n=9, 12,9%). Results: Median overall survival (OS) from first line therapy over all lines was 28,0 months. Median OS from second line was 14,7 months (95% CI, 11,4-18,0). No significant differences between regimens could be detected. OS of patients with lymphonodal only involvement (n=16, 22,5%) was 35.5 months (95% CI 0.0-73.9), OS with visceral metastases excluding liver was 14.7 months (95% CI 9.8-19.6) .and OS with any liver involvement was 9.4 months (95% CI 0.0-20.9). Conclusion: Second line therapy for UC of selected patients leads to a prolonged survival compared to historical data. The choice of regimen appears not to influence OS. Lymphnodal only involvement is associated with the best prognosis.

Predictors of Second-Line Treatment Choice with Triplet Therapy in Routine Care Among Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

BackgroundBeginning with the IFM 2005-04/MMVAR trial, three-drug combinations (TCs) have demonstrated superior clinical outcomes compared with two-drug regimens among patients with RRMM (Garderet JCO 2012). TCs are emerging as the standard of care at first relapse. We assessed factors that influenced treatment choice with TCs in a cohort of patients with RRMM who were managed in routine care.MethodsWe identified adult patients with MM between January 2008 and February 2014 in a large, national, US healthcare claims database of commercially insured and Medicare Advantage beneficiaries. Newly diagnosed patients were followed from the first claim with an ICD-9 code for MM (with a 12-month wash-out period). To ensure completeness of claim history, patients with continuous enrollment from 12 months pre-diagnosis through at least initiation of second-line therapy (SLT) for RRMM were included. Those with claims for transplants were excluded. Front-line therapy (FLT) began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 days of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 months of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 months between end of FLT and start of a second regimen (retreatment or switch), 2) start of a follow-up regimen (retreatment) with a treatment gap of >3 and up to 6 months after end of FLT, or 3) a switch to another drug combination after FLT regimen. The first claim for SLT was the index date. SLT ended at the earliest of: start of a new drug, death, or end of study period (February 2014). Patients were grouped into those receiving one-/two-(1-2) vs three-/four-drug (3+) combinations based on the number of unique cancer therapy agents received within the start and end date of SLT. A logistic multivariable model was used to identify factors independently associated with receipt of 1-2 vs 3+ SLT regimens.ResultsBaseline characteristics among 249 RRMM patients on SLT are shown in Table 1 according to receipt of 1-2 vs 3+ SLT regimens. Among 62 patients who initiated SLT in 2013-14, 14 (23%) received a 3+ SLT regimen (vs 19 (10%) prior to 2013). Adjusting for gender and CRAB symptoms (hypercalcemia, renal insufficiency, anemia, and bone disease), predictors of 3+ SLT included: younger age (<65 years), early relapse (time to next therapy [TTNT], interval from start of FLT to start of SLT, <6 months), 3+ agents in FLT and index year of SLT initiation (in 2013-14). Charlson Comorbidity Index (CCI) was not independently associated with receipt of 3+ SLT.ConclusionsA majority of patients do not receive triplet-based SLT in routine care. Younger age, and not comorbidity status, appears to be the discriminatory patient characteristic for triplet therapy choice. Introduction of triplets with a favorable toxicity profile and assessment for comorbidity status in routine practice represent steps towards optimizing treatment choices in RRMM.Table 1Baseline Characteristics among Patients with RRMM According to SLT Type (N=249)N (%)Monotherapy/Doublet (1-2) (N=216)Triplet/Quadruplet (3+) (N=33)Total (N=249)TTNT<6 months44 (20.4%)14 (42.4%)58 (23.3%)≥6 months172 (79.6%)19 (57.6%)191 (76.7%)Age, years<6553 (24.5%)17 (51.5%)70 (28.1%)65-7464 (29.6%)8 (24.2%)72 (28.9%)≥7599 (45.8%)8 (24.2%)107 (43%)Male105 (48.6%)16 (48.5%)121 (48.6%)CCI060 (27.8%)10 (30.3%)70 (28.1%)152 (24.1%)3 (9.1%)55 (22.1%)2+104 (48.1%)20 (60.6%)124 (49.8%)CRAB symptoms147 (68.1%)26 (78.8%)173 (69.5%)Number of agents in FLT regimen1-2147 (68.1%)12 (36.4%)159 (63.9%)3+69 (31.9%)21 (63.6%)90 (36.1%)Table 2Predictors of 3+ SLT in RRMM (N=249)Odds Ratio (OR) for 3+ vs 1-2 SLT(95% CI for OR)Age, years<65 65-74 ≥753.10 1.36 Reference(1.13 - 8.51)* (0.45 - 4.09) -Male1.13(0.51 - 2.51)Index year2008-2012 ≥2013Reference 3.42- (1.42 - 8.21)**TTNT, months≥6 <6Reference 2.54- (1.05 - 6.17)*CRAB symptoms at baseline1.69(0.63 - 4.58)CCI0 1 2+Reference 0.41 0.98- (0.10 - 1.62) (0.39 - 2.46)Number of agents in FLT regimen1-2 3+Reference 2.77- (1.20 - 6.42)**significant at 5%; **significant at 1% DisclosuresRomanus:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Takeda Pharmaceutical Company Limited: Equity Ownership; Sanofi: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Treatment Patterns and Outcomes Among Patients Who Initiate Therapy for Relapsed/Refractory Multiple Myeloma (RRMM) in Routine Care

BackgroundMultiple myeloma (MM) is the second most common hematologic cancer in adults. Novel agents, including thalidomide, bortezomib, and lenalidomide, have led to improved overall survival (OS) in MM, but the disease remains generally incurable with the majority of patients inevitably relapsing after front-line therapy (FLT). In a multi-center observational analysis of 383 MM patients (treated between 2007 and 2010), median progression-free survival (PFS) and OS from treatment after first relapse were 13 and 35 mos (Durie ASCO 2012; abs 8095). According to NCCN guidelines, retreatment with primary therapy may be considered if relapse occurs more than 6 mos after discontinuation of primary therapy, otherwise a switch in regimen is recommended (NCCN MM Guidelines v.4 2015). Treatment patterns and outcomes in RRMM remain to be elucidated. We examined treatment use, retreatment and therapy switch patterns, and outcomes among patients with RRMM initiating second-line therapy (SLT).MethodsWe conducted a retrospective cohort study using a large, national, US claims database. Adult patients with MM who initiated cancer-specific systemic therapy between Jan 2008 and Feb 2014, without evidence of transplantation, were identified. Newly diagnosed MM patients were followed from the first claim for MM. Continuous enrollment in the health plan for 12 mos pre-diagnosis (with no claim for MM) through at least the start of SLT was required. FLT began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 days of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 mos of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 mos between end of FLT and start of a second regimen (retreatment or switch), 2) start of a follow up regimen (retreatment) with a treatment gap of >3 and up to 6 mos after end of FLT, or 3) a switch to another drug combination after FLT regimen. Analyses were conducted from the first claim for SLT. SLT ended at the earliest of start of a new drug, death, or end of study period (Feb 2014). MM drug combinations were based on all unique MM systemic therapy agents received within start and end date for SLT. Vital status information was ascertained from the Social Security Death Index.ResultsWe identified 249 patients with RRMM receiving SLT. Approximately half (49%) were male; 29% and 43% were aged 65-74 and 75 years or older, respectively. SLT regimens were: lenalidomide±dexamethasone (R±d, n=70 [28%]), bortezomib±d (V±d 61 [25%]), other (58 [23%], see Table 1), V+other (25 [10%]), R+other (14 [6%]), V-cyclophosphamide±d (VC±d, 13 [5%]), and VR±d (8 [3%]). The switch and retreatment patterns from FLT to SLT are depicted in Table 1. Among patients with treatment-free interval (TFI, time from end of FLT to start of SLT) >6 mos (n=64) vs ≤6 mos (n=185), 18 (28%) vs 17 (9%) were retreated with the same primary regimen in SLT, respectively. Median duration of SLT was 6.3 (95% CI: 5.6, 6.9) mos (Fig. 1) and of FLT was 6.8 (95% CI: 6.0, 7.8) mos. The 1-year OS probability from initiation of SLT for RRMM was 82% (95% CI: 76%, 86%).ConclusionsAmong patients with RRMM treated in the USA, V- and R-based regimens were the most common at first relapse. The vast majority of patients (91%) with TFI ≤6 mos switched therapy at time of relapse in concordance with NCCN guidelines. The relatively short duration of SLT (median 6.3 mos) in this study compared with PFS from treatment after first relapse (median 13 mos, Durie ASCO 2012; abs 8095) in a cohort of patients with RRMM, suggests that the majority of patients discontinue SLT prior to disease progression. These findings highlight the need for newer SLT regimens that are effective and more sustainable compared with current treatment choices.Table 1Switch and Retreatment Patterns from FLT to SLT among Patients with RRMM. SLTV-basedR-basedVR-basedOtherFLTV-based41 (41%)49 (58%)4 (50%)15 (26%)R-based33 (33%)13 (15%)2 (25%)12 (21%)VR-based9 (9%)6 (7%)2 (25%)19 (33%)Other*16 (16%)16 (19%)0 (0%)12 (21%)Total99 (100%)84 (100%)8 (100%)58 (100%)*Other combinations consisted of a subset of the following agents: cyclophosphamide, melphalan, vincristine, doxorubicin, interferon-alpha, pomalidomide, thalidomide, carfilzomib, dexamethasone, prednisone [Display omitted] DisclosuresRomanus:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Sanofi: Equity Ownership; Takeda Pharmaceutical Company Limited: Equity Ownership; Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment.

Healthcare Resource Use and Costs Among Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM)

BackgroundFew studies have assessed HRU and costs in RRMM. A prior study reported 1-yr total healthcare costs of $113,000 (2013 US $) among non-transplant patients with newly diagnosed MM (DaCosta Byfield ASCO 2015). Real-world data on economic burden in the era of new MM therapeutic options could provide insight for directing efficient resource utilization. We examined HRU and costs associated with second-line therapy (SLT) in RRMM.MethodsWe identified adult pts with MM between Jan 2008 and Feb 2014 in a large, national, healthcare claims database of commercially insured and Medicare Advantage beneficiaries. Newly diagnosed pts were followed from first claim for MM (+12-mo wash out period). Pts with continuous enrollment from 12 mos pre-diagnosis through 12 mos post-initiation of SLT for RRMM were included (including pts who died within 12 mos post SLT start). Those with a claim for transplants were excluded. Front-line therapy (FLT) began with the first claim for MM-directed systemic cancer therapy. Unique agents administered within 90 d of FLT initiation constituted a regimen. Continuation of FLT regimen (or part thereof) or monotherapy within 3 mos of the end of the initial regimen was considered part of FLT. SLT after first relapse for RRMM was identified accordingly: 1) a treatment gap >6 mos between end of FLT and start of a 2nd regimen (retreatment or switch), 2) start of a follow-up regimen (retreatment) with treatment gap >3 and ≤6 mos after end of FLT, or 3) a switch to another drug combination after FLT. The first claim for SLT was the index date. Healthcare costs and HRU were determined for the 1-yr period following SLT start. Healthcare costs were calculated as total reimbursed amount to the provider paid by the health plan, the pt, and other payers, including treatment with subsequent lines of therapy if falling within the 1-yr period. Drug and drug-administration costs were captured from a) all pharmacy claims for MM-directed systemic therapy, and b) medical claims with CPT codes indicating chemotherapy drug administration if, on the same date of service, there was a claim with a HCPCS for any drug of interest.ResultsWe identified 160 of 249 pts receiving SLT. The majority (55%) were female, 72% were aged ≥65 yrs, 10% received triplet SLT, and 53% were enrolled in a Medicare Advantage plan. Most common SLT regimens were bortezomib- (39%) or lenalidomide-based (38%) (Table 1).RRMM pts averaged 58 ambulatory visits and 1.2 hospitalizations in the yr following start of SLT, with 5.1 ICU and 7.9 non-ICU days. Mean 1-yr healthcare costs were $123,922 with 59% of total costs attributable to non-drug costs (mean: $72,718; Table 2).ConclusionsThe healthcare and economic burden of illness among pts with RRMM receiving SLT is substantial. The main cost driver in RRMM was non-drug related. While this research did not examine indirect costs, rates of ambulatory visits and hospitalization days occurring within 1 yr of the start of SLT were high and likely correlated with indirect costs to both the pt and caregiver. New treatment options with a more favorable side-effect and efficacy profile may mitigate this burden. At study completion, a statistical analysis will be conducted to assess the determinants and drivers of economic burden in RRMM.Table 1RRMM pt Characteristics and SLT patternsTotal (N=160)n (%)*Died during 1-yr following start of SLT36 (22.5)Age, yrs<6545 (28.1)65-7445 (28.1)≥7570 (43.8)Male72 (45)Insurance typeCommercial76 (47.5)Medicare Advantage84 (52.5)SLT regimensBortezomib-based62 (38.8)IMiD-based60 (37.5)Bortezomib + IMiD3 (1.9)Other†35 (21.9)Start of a new regimen within 1 yr (3rd line)68 (42.5)*unless otherwise noted †including cyclophosphamide, melphalan, vincristine, doxorubicin, interferon-alpha, pomalidomide, thalidomide, carfilzomib, dexamethasone, prednisone ‡among non-censored ptsTable 2Healthcare costs and encounters among pts with RRMM after initiation of SLT1-yr healthcare costs (2014 US$)Mean (SD)(N=160)Total123,922 (114,052)Drug51,204 (40,997)Non-drug72,718 (102,169)Total123,922 (114,052)During SLT81,590 (90,151)After 3rd Line initiation*33,573 (64,832)SLT end to start of 3rd Line8,759 (28,046)Healthcare encounters per ptAmbulatory visits58.5 (32.6)ER visits1.7 (2.2)Hospitalizations1.2 (1.7)Inpatient length of stay, days13.0 (26.6)Non-ICU7.9 (21)ICU5.1 (12.7)*censored at 12 mos after SLT initiation DisclosuresRomanus:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Seal:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jhaveri:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Takeda Pharmaceutical Company Limited: Equity Ownership; Sanofi: Equity Ownership. Labotka:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Henk:Optum (a consulting firm retained by Takeda to conduct the reasearch pertaining to this abstract): Employment.

Correction: Raltegravir Non-Inferior to Nucleoside Based Regimens in SECOND-LINE Therapy with Lopinavir/Ritonavir over 96 Weeks: A Randomised Open Label Study for the Treatment Of HIV-1 Infection

Correction: Raltegravir Non-Inferior to Nucleoside Based Regimens in SECOND-LINE Therapy with Lopinavir/Ritonavir over 96 Weeks: A Randomised Open Label Study for the Treatment Of HIV-1 Infection

Raltegravir non-inferior to nucleoside based regimens in second-line therapy with lopinavir/ritonavir over 96 weeks: a randomised open label study for the treatment of HIV-1 infection.

ObjectiveTo determine the durability over 96 weeks of safety and efficacy of lopinavir/ritonavir (LPV/r) and raltegravir (RAL) which was demonstrated to have non-inferior efficacy relative to a regimen of LPV/r with nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs) (Control) in primary analysis at 48 weeks.DesignOpen label, centrally randomised trial.SettingRecruitment was from 37 primary and secondary care sites from Africa, Asia, Australia, Europe and Latin America.Subjects541 HIV-1 infected adults virologically failing first-line non-NRTI + 2N(t)RTI, with no previous exposure to protease inhibitors or integrase strand transfer inhibitors were analysed, 425 completed 96 weeks follow up on randomised therapy.InterventionRandomisation was 1:1 to Control or RAL.Main outcome measuresDifferences between the proportion of participants with plasma HIV-1 RNA (VL) <200 copies/mL by intention to treat were compared with a non-inferiority margin of −12%. Differences in biochemical, haematological and metabolic changes were assessed using T-tests.ResultsVL <200 copies/mL at 96 weeks was: RAL 80.4%, Control 76.0% (difference: 4.4 [95%CI −2.6, 11.3]) and met non-inferiority criteria. The RAL arm had a significantly higher mean change (difference Control-RAL; 95%CI) in haemoglobin (−2.9; −5.7, −1.1), total lymphocytes (−0.2; −0.3, −0.0), total cholesterol (−0.5; −0.8, −0.3), HDL cholesterol (−0.1; −0.1, −0.0) and LDL cholesterol (−0.3; −0.5, −0.2).ConclusionAt 96 weeks, both RAL and Control maintained efficacy greater than 75% and continued to demonstrate similar safety profiles. These results support the use of a combination LPV/r and RAL regimen as an option following failure of 1st line NNRTI + 2N(t)RTIs.Trial RegistrationClinicalTrials.gov NCT00931463

709P - Single-Agent or Doublets As Second-Line Chemotherapy After Folfirinox in Patients with Locally Advanced or Metastatic Pancreatic Cancer

ABSTRACT Aim: FOLFIRINOX represents an active regimen in first-line treatment of advanced pancreatic adenocarcinoma (PDAC) patients (pts) with good performance status (PS). Currently, there are no accepted standard regimens in second-line therapy for patients with disease progression and data about efficacy of chemotherapy after FOLFIRINOX failure are lacking. Methods: We retrospectively investigated clinical and laboratory characteristics (including blood count, LDH, CEA and CA19.9) of PDAC pts treated between June 2011 and April 2014 in four Italian institutions with either doublet or single agent as second-line therapy after FOLFIRINOX failure. Survival estimates were quantified using Kaplan Meier curves, and differences between groups were compared with the log-rank test. Results: Among 96 pts treated with FOLFIRINOX as first-line chemotherapy, 50 pts received second-line treatment (52%). Median age at diagnosis was 60 years (range 36-76); 66 pts were males (72%). PDAC was locally advanced in 15 (30%) and metastatic in 35 pts (70%). Patients who received second line single agent (gemcitabine, docetaxel or nab-paclitaxel) or doublets (gemcitabine with either abraxane, capecitabine, cisplatin or docetaxel) were 24 (48%) and 26 (52%), respectively. According to RECIST criteria, 2 pts achieved PR (4%), 10 (20%) SD for ≥9 wks and 38 (76%) PD. Median progression-free survival (PFS) was 2.7 months and median overall survival (OS) was 3.4 months. No differences were found in terms of OS (5.0 vs 3.1, p = 0.489) or PFS (4.0 vs 2.7 p = 0.182) between patients treated with single-agent or doublets as second-line. At multivariate analysis, ECOG ≥ 2 was the only independent prognostic factor for worst OS (p = 0.002) and PFS (p = 0.020). Conclusions: Our findings suggest that the choice of second line therapy in patients treated with first-line FOLFIRINOX should be carefully evaluated. ECOG ≥ 2 was significantly associated with poor prognosis, while pre-treatment CA 19-9, LDH, Hb, neutrophil and platelet counts were not prognostic factors for OS, although these data should be confirmed in perspective studies. Disclosure: All authors have declared no conflicts of interest.

Second-line Chemotherapy and Its Survival Analysis of 181 Patients with Extensive-stage Small Cell Lung Cancer in a Single Institute

背景与目的小细胞肺癌（small cell lung cancer, SCLC）是恶性程度极高的神经内分泌肿瘤，对放化疗敏感，但大多数接受一线化疗的患者在1年-2年内复发。一旦疾病复发，预后不良。目前，广泛期SCLC的一线标准化疗方案为铂类联合依托泊苷方案，二线化疗方案尚无定论。该研究分析二线化疗预后的影响因素；比较不同二线化疗方案的近期疗效、不良反应和远期生存情况的差异。方法回顾性分析接受二线化疗的181例广泛期SCLC患者的临床资料。根据不同化疗方案分为6组，采用χ2检验比较计数资料和各组组成差异。采用Kaplan-Meier法分析总生存时间（overall survival, OS）和无进展生存时间（progression-free survival, PFS）。采用单因素和Cox回归多因素分析方法分析生存期的影响因素。结果二线化疗的中位OS为7.0个月，单因素和多因素的分析结果表明吸烟情况（P=0.004）、ECOG评分（P < 0.001）、肝转移（P=0.019）和骨转移（P=0.028）是影响二线化疗OS的独立影响因素；二线化疗的中位PFS为3.0个月，吸烟（P=0.034）、ECOG评分（P=0.011）和骨转移（P=0.005）是二线化疗PFS的独立影响因素。6组有效率有明显差异（χ2=12.413, P=0.017），两两比较各组无明显差异；副反应方面，伊立替康组胃肠道反应的发生率明显高于其它组；6组的OS和PFS无统计学差异（χ2=1.491, P=0.914; χ2=6.133, P=0.293）。结论ECOG评分是影响广泛期SCLC二线化疗预后的最重要因素。广泛期SCLC的二线化疗尚无疗效确切的最优方案。

Phase II Trial Alternating FOLFOX-6 and FOLFIRI Regimens in Second-Line Therapy of Patients with Metastatic Colorectal Cancer (FIREFOX Study)

We assessed a schedule alternating 4 FOLFOX and 4 FOLFIRI cycles in 39 patients with 5-FU resistant metastatic colorectal cancer. Patients alternatively received 4 FOLFOX-6 cycles (oxaliplatin 100 mg/m2, leucovorin 200 mg/m2 d1 followed by bolus 400 mg/m2 5-FU and by a 46-hour 2,400 mg/m2 5-FU infusion, every 2 weeks), and 4 FOLFIRI cycles (oxaliplatin replaced by irinotecan 180 mg/m2 d1) until progression or limiting toxicity. Eigteen patients achieved an objective response (46.1 percent). Median progression-free and overall survivals were 8.8 and 18.7 months, respectively. Only 2 patients (5.1 percent) had Grade 3 oxaliplatin-related sensory-neuropathy. This schedule had so promising efficacy and safety.