Second-line Therapy In Patients Research Articles

Real-world evaluation of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors for managing type 2 diabetes mellitus: a retrospective multi-ethnic cohort study

PurposeSodium-glucose co-transporter-2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors are increasingly used as second-line therapies in patients with type 2 diabetes. The aim of this study was to assess the real-world effects of SGLT2 inhibitors in a multi-ethnic population in Singapore.MethodsThis retrospective cohort study examined patients diagnosed with and treated for diabetes from the Ministry of Health’s administrative database. Differences in outcomes between treatment groups were assessed using Poisson regression. Demographics, clinical characteristics, previous diagnoses and hospitalisations, and diabetes medication history were used for propensity score matching. Subgroup analyses by ethnicity were performed. Effect size was estimated using risk ratios (RRs) with 95% confidence intervals (CIs).ResultsPatients initiating SGLT2 inhibitors were more likely to achieve glycaemic control target than DPP4 inhibitor-treated patients (RR 1.09; 95% CI 1.04, 1.14). This was observed only in patients of Chinese ethnicity. A higher risk of diabetic ketoacidosis in SGLT2 inhibitor initiators was not observed. SGLT2 inhibitors were associated with reduced risk of hypoglycaemia (RR 0.69; 95% CI 0.59, 0.82) and urinary tract infection (RR 0.52; 95% CI 0.43, 0.63) but was not statistically significant for hypoglycaemia in Malay patients. Compared to DPP4 inhibitors, SGLT2 inhibitors were associated with 12% and 34% reduction in any-cause hospitalisation and all-cause mortality, respectively, potentially resulting in more than $50 million savings over 10 years.ConclusionSGLT2 inhibitors were associated with improvements in glycaemic control, reduced risk of complications, and was well tolerated. Ethnicity also plays a role and should be considered in future studies.

Expanding the immunotherapy roadmap for hepatocellular carcinoma.

In a recent Lancet Oncology article, Yau etal. report the CheckMate 459 trial results. This is the first phase III trial comparing the single-agent anti-programmed death protein 1 (PD-1) therapy nivolumab to the tyrosine kinase inhibitor sorafenib for treatment-naive patients with advanced hepatocellular carcinoma.

FOLFIRI plus ramucirumab versus paclitaxel plus ramucirumab as second-line therapy for patients with advanced or metastatic gastroesophageal adenocarcinoma with or without prior docetaxel – results from the phase II RAMIRIS Study of the German Gastric Cancer Study Group at AIO

BackgroundRamucirumab and paclitaxel is the standard second-line therapy in patients with metastatic gastroesophageal adenocarcinoma. We report the efficacy and safety analyses of FOLFIRI and ramucirumab versus paclitaxel and ramucirumab after the failure of a platinum- and fluoropyrimidine-containing chemotherapy. MethodsThis multicenter, investigator initiated, phase II trial randomised patients with gastroesophageal adenocarcinoma to either FOLFIRI plus ramucirumab (RAM) (arm A) or paclitaxel plus RAM (arm B). The primary end-point was 6-month overall survival (OS) rate, with a proportion of ≥65% in arm A considered a positive signal for further investigation. Results111 patients (65% of patients had prior docetaxel) were enrolled and 110 patients qualified for ITT population (arm A, 72; arm B, 38). The study did not meet the primary end-point for the comparison with historical control, as 6-month OS rate in the FOLFIRI plus RAM arm was 54% (95% CI 44–67). In between arm comparison, OS was similar (hazard ratio, HR 0.97 [95% CI 0.62–1.52]), while objective response rates (ORRs) and PFS were numerically better in arm A versus arm B (HR for PFS 0.73; ORR, 22% versus 11%). These differences were largely attributed to favourable efficacy results for arm A in docetaxel-pretreated patients (HR, 0.49; ORR, 25% versus 8%). In the safety population (n = 106), grade 3-5 adverse events were similar between arms (arm A, 75%; arm B, 68%). ConclusionThe RAMIRIS trial demonstrated feasibility of FOLFIRI plus RAM. While the study was formally negative, it provided a signal to further investigate this combination for the group of patients with previous docetaxel therapy. Trial registrationclinicaltrials.gov identifier: NCT03081143.

Abstract OT2-16-01: The SMILE study: A phase 2 trial of onapristone in combination with fulvestrant for patients with ER+ and HER2- metastatic breast cancer after progression on endocrine therapy and CDK4/6 inhibitors

Abstract Background Antiprogestins, including selective progesterone receptor (PgR) modulators (SPRMs) that act as PgR antagonists, are a promising class of therapeutics for overcoming endocrine resistance including in patients who develop activating estrogen receptor 1 (ESR1) mutations after prior endocrine therapy (ET). The SMILE study (NCT04738292) is a multi-institutional phase II clinical trial to determine the efficacy and safety of an antiprogestin, onapristone in combination with fulvestrant as second-line therapy for patients with ER+,PgR+, HER2 -metastatic breast cancer (MBC). Methods Patients with locally advanced or MBC who progress on ≥2 lines of prior therapy with ET as a single agent or in combination with CDK4/6 inhibitors, mTOR inhibitors and one line of chemotherapy in the metastatic setting are eligible. Other criteria include ECOG performance status ≤ 2, measurable disease per RECIST 1.1 criteria, adequate organ function, availability of an archived tumor biopsy block confirming the diagnosis of MBC, optional biopsy at disease progression on trial, and optional 18F-fluorofuranylnorprogesterone (18F-FFNP) PET/CT imaging. Ovarian suppression is allowed. Prior ET with tamoxifen or aromatase inhibitor therapy in the adjuvant or metastatic setting is allowed. Patients with prior exposure to fulvestrant, antiprogestins, or CDK inhibitors in the adjuvant setting are ineligible. Following consent, all subjects will receive fulvestrant at the recommended dosing schedule plus onapristone 50 mg orally, twice daily, until disease progression, unacceptable toxicity, or discontinuation for any other reason. Using the Simon Two-Stage design, a total of 39 patients will be enrolled over two years from 6-8 sites within Wisconsin Oncology Network (WON). In the first stage of the trial, 21 subjects will be enrolled; if ≥2 responses are observed, then 18 additional subjects will be enrolled in the second stage. This design yields a one-sided type I error rate of 5% if the ORR is 7% and power of 80% when the combination's true response rate is 20%. The primary objective is to evaluate the objective response rate; secondary objectives include safety and tolerability, progression-free survival, disease control rate, and duration of response. Other correlates include optional functional imaging of PgR binding with 18F-FFNP PET/CT and biomarker analysis (ER, total PgR, HER2, Ki67, CD24, CD44, LDH1, KLF4, CK 5/6, PhosphoSer294-PgR on tissue samples, ESR1 mutations, and circulating tumor DNA analysis). The study was approved in January 2021, and enrollment is active at the time of this submission. Citation Format: Sailaja Kamaraju, Amy Fowler, Chung Yee Cheng, Lubna N Chaudhary, John Burfeind, Janet Retseck, Amye J Tevaarwerk, Mark Burkard, Elisavet Paplomata, Amanda M Parkes, Julie M Jorns, Sergey Tarima, Douglas Yee, Hallgeir Rui, Carol Lange, Tarek Sahmoud, Kari B Wisinski. The SMILE study: A phase 2 trial of onapristone in combination with fulvestrant for patients with ER+ and HER2- metastatic breast cancer after progression on endocrine therapy and CDK4/6 inhibitors [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-16-01.

Abstract P5-01-07: Patient-derived xenografts (PDXs) generated from hormone receptor-positive breast cancer (BC) before and after cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) treatment: Initial findings from the PROMISE study

Abstract Background: Hormone receptor-positive (HR+) breast cancer (BC) accounts for ~60-70% of all BC cases. CDK4/6i combined with endocrine therapy (ET) is the standard of care for first- and second-line therapy of patients with HR+ metastatic breast cancer (MBC) based on substantial improvements in progression free survival (PFS) and overall survival compared to ET alone. Unfortunately, most patients (pts) develop resistance to CDK4/6i. The mechanisms underlying CDK4/6i resistance have not been fully elucidated. Robust in vivo CDK4/6i resistant animal models from pts with de novo and acquired CDK 4/6i resistance are lacking. Patient-derived xenografts (PDXs) are important preclinical tools in oncology to advance our understanding of cancer biology and to evaluate drug response phenotypes. Unfortunately, the establishment of sustainable PDXs from pts with HR+ BC is much more difficult than from HR-negative BC. In order to obtain clinically relevant models that can be utilized to better understand mechanisms of primary and acquired resistance to ET and CDK4/6i, we report the development of PDXs from a prospective study in which percutaneous biopsies were obtained from women receiving palbociclib for the treatment of HR+ advanced or MBC (PROMISE; NCT03281902). Methods: PROMISE (Prospective Study to Evaluate the Role of Tumor Sequencing in Women Receiving Palbociclib for Advanced Hormone Receptor (HR)-Positive Breast Cancer) is a prospective trial which enrolled pts with HR+, HER2-negative MBC who planned to start treatment with palbociclib and letrozole (1st line [FL]) or palbociclib and fulvestrant (2nd line [SL]). For pts enrolled at Mayo Clinic Rochester (MCR), serial tumor biopsies were obtained prior to the start of treatment and at disease progression to establish PDXs. Because baseline take rate was low, we amended the protocol to attempt PDX generation after the 2nd cycle (C2) of therapy. Tissues were received within an hour of excision and were orthotopically implanted in the mammary fat pad of 6~8-week-old nonobese diabetic (NOD)/SCID/IL-2g-receptor null (NSG) mice. Tumor growth was defined as tumor volume ≥ 50 mm3. Tumor take rate was defined as percent of patients with development of at least one stably transplantable (passed at least for two generations) xenograft that was pathologically confirmed as BC. Results: Of the 50 pts enrolled at MCR, 37 were FL pts (2 ineligible) and 13 were SL pts (1 ineligible). Fresh tumor samples obtained pre-treatment from 43 eligible pts (32 FL), after C2 from 17 eligible pts (13 FL), and at disease progression from 10 eligible pts (5 FL) were implanted. Tumor growth was seen in at least one mouse from a pre-treatment specimen in 1 (3.1%) FL pt (confirmed BC) and 4 (36.4%) SL pts (2 confirmed BC); from end of C2 specimens in 2 (15.4%) FL pts and 2 (50%) SL pts (1 confirmed BC); and at progression in 1 (20%) FL pt and 2 (40%) SL pts (1 confirmed BC). The take rate from pre-treatment samples among FL pts was 1/32 (3.1%; 95% CI: 0.08-16.2%). Take rates in other groups are pending histological review. Discussion: In pts receiving palbociclib for HR+ MBC, the take rate using a pre-treatment percutaneous biopsy was low (3.1%) in the FL setting. However, higher growth rates were seen in the SL setting. The observation of higher growth rates at the end of C2 and at progression may relate to the activation of G1/S that occurs with withdrawal of palbociclib, and should be further studied. PDX remains a valuable tool for the evaluation of tumor biology and the development of new therapeutics, especially for those models established from pts with palbociclib and ET resistance. Proteogenomic and sequencing studies are ongoing to fully characterize these PDXs. Citation Format: Jia Yu, Vera J. Suman, Jun He, Jason P. Sinnwell, Ann M. Moyer, Bo Qin, Yayun Gu, Huan Zhang, Jodi M. Carter, Krishna R. Kalari, Brendan P. McMenomy, Minetta C. Liu, Tufia C. Haddad, Kathryn J. Ruddy, Fergus J. Couch, Alvaro Moreno-Aspitia, Donald W. Northfelt, Richard Weinshilboum, Ciara O'Sullivan, Matthew P. Goetz, Liewei Wang. Patient-derived xenografts (PDXs) generated from hormone receptor-positive breast cancer (BC) before and after cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) treatment: Initial findings from the PROMISE study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-07.

Efficacy and safety of intermittent versus continuous dose apatinib plus docetaxel as second-line therapy in patients with advanced gastric cancer or gastroesophageal junction adenocarcinoma: a randomized controlled study.

BackgroundPrevious studies of the second-line treatment for advanced gastric cancer or gastroesophageal junction adenocarcinoma (GC/GEJAC) had reported that apatinib combined with chemotherapy improved the treatment outcomes. However, the benefits were sometimes limited due to the tolerance of continuous dose regimen. This randomized controlled study aimed to investigate the efficacy and safety of intermittent or continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC.MethodsAdvanced GC/GEJAC patients who failed first-line chemotherapy were recruited (enrollment time: from September 15, 2017 to July 21, 2019), and randomly assigned to either the intermittent dose group (IG group) or the continuous dose group (CG group) (1:1 ratio) using the block randomization method. In the IG group, patients received apatinib 500 mg/d for 5 consecutive days then held for 2 days plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. In the CG group, patients received apatinib 500 mg daily plus docetaxel 60 mg/m2 q3w, in a 3-week cycle. The progression free survival (PFS) was evaluated every two cycles and follow-ups were performed monthly. The primary endpoint was PFS, and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety.ResultsIn total, 76 eligible patients were enrolled and randomly assigned (1:1 ratio). The IG group exhibited similar PFS compared to the CG group [median PFS: 3.88 (95% CI: 1.72–6.03) months vs. 3.98 (95% CI: 1.06–6.90) months, P=0.546] and OS [median OS: 9.00 (95% CI: 5.31–12.70) months vs. 9.40 (95% CI: 5.20–13.59) months, P=0.310]. ORR (21.1% vs. 18.4%, P=0.773) and DCR (60.5% vs. 60.5%, P=1.000) were of not statistically different between the IG and CG groups. As for safety, the IG group exhibited less frequent hypoproteinemia (31.6% vs. 55.3%, P=0.037) and lactate dehydrogenase increased (18.4% vs. 44.7%, P=0.014), while no differences in other adverse events were observed between the two groups.ConclusionsIntermittent dose apatinib plus docetaxel was equally effective and more tolerable than continuous dose apatinib plus docetaxel as a second-line therapy in patients with advanced GC/GEJAC.Trial RegistrationClinicalTrials.gov NCT03334591.

A multicenter phase Ib/II study of liposomal-irinotecan, 5-fluorouracil (5-FU), and leucovorin (LV) with nivolumab as second-line therapy for patients with advanced biliary tract cancer (BilT-03).

438 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy and treatment beyond first-line platinum doublet remains largely investigational. The immunomodulatory properties of conventional cytotoxic therapy, particularly in regard to the upregulation of PD-L1 expression rendering tumor cells less sensitive to T cell-mediated lysis, rapid emergence of chemotherapy resistance, and known modest efficacy of single agent anti-PD-1 antibody in BTC provide a rationale for combination chemoimmunotherapy. We conducted a multi-center, phase Ib/II, single-arm study to investigate the role of liposomal-irinotecan, 5FU and LV in combination with nivolumab as second-line therapy in pts with advanced BTC. Methods: Key eligibility criteria include histologically confirmed unresectable or metastatic BTC after progression or intolerance of first-line systemic therapy, measurable disease per RECISTv1.1, ECOG PS 0-1, and absence of autoimmune disease or chronic steroid use. The limited phase Ib portion evaluated 10 pts to determine the recommended phase 2 dose (RP2D) based on the probability of dose-limiting toxicity (DLT) rate <30% during days 1-29. Study treatment included 5FU 2400 mg/m2 over 46 hrs, LV 400 mg/m2, liposomal-irinotecan 70 mg/m2 at dose level 0 along with nivolumab 240 mg every 2 wks for up to 2 yrs in absence of disease progression or unacceptable toxicity. The primary endpoint was median progression-free survival (PFS) rate with an alternative and null hypothesis of 5.0 mo and 2.9 mo (two-sided alpha 0.05, power 80%), respectively. Secondary endpoints included best overall response rate (ORR) per immune related (ir)RECIST, median overall survival (OS), 75th percentile estimates of PFS and OS, and safety. Exploratory objectives include biomarker analysis using include targeted panel exome/transcriptome and immune cell subsets in tissue. Results: 30 eligible pts (60% men, 83% Caucasian) including 10 pts in phase Ib and 20 pts in phase II with a median age of 63.5 yrs (range 36-75) were enrolled across 4 US sites between June 2019 and July 2021. In phase Ib, one pt experienced DLT (grade 3 enterocolitis); RP2D was confirmed at dose level 0. All 30 pts were included in study reported outcomes with a median follow-up time of 10.7 mo. Median PFS was 4.2 mo (95% CI, 1.9-10.2) and failed to reject the null hypothesis. Median OS was 7.5 mo (95% CI, 5.8-21.4). The 75th percentile estimates for PFS and OS are 10.2 mo (95% CI, 5.4-NE) and 21.4 mo (95% CI, 7.8-21.4). ORR estimates and toxicity data are pending and will be presented at the meeting. Conclusions: The observed median PFS is insufficient to reject the null hypothesis. The 75th percentile estimates for PFS and OS are suggestive of prolonged benefit with chemoimmunotherapy in a small fraction of patients with BTC. Clinical trial information: NCT03785873.

A prospective, multicenter, dose-escalation, and dose-expansion study evaluating apatinib plus chemotherapy in second-line therapy of patients with postoperatively gastric cancer (ACHIEVE).

TPS362 Background: Apatinib, a highly selective small-molecule tyrosinase inhibitor of VEGFR2, is the third-line standard therapy for patients (pts) with advanced gastric cancer. Many previous studies have preliminarily demonstrated the efficacy and safety of apatinib combined with chemotherapy in the second-line treatment of gastric cancer. Comparing with pts who have not undergone surgery, previous pharmacological study has found that pts who have undergone gastric cancer surgery have lower bioavailability and can tolerate higher doses of apatinib (Clin Pharmacokinet. 2017 Jan; 56(1):65-76). However, there is no prospective evidence of apatinib plus chemotherapy for second line treatment in pts with postoperatively gastric cancer. Methods: To explore the efficacy, safety and the maximum tolerated dose (MTD) of apatinib from apatinib+chemotherapy for second line treatment in pts with postoperatively gastric cancer. We designed ACHIEVE as a multicenter, dose-escalation, and dose-expansion trial in pts with gastric or gastroesophageal junction cancer who had prior undergone gastrectomy. In part 1 (dose escalation), pts who had received previously first-line treatment will be assigned to 1 of 3 three dose groups: (1) apatinib (250mg qd) + chemotherapy drug; (2) apatinib (500mg qd) + chemotherapy drug; (3) apatinib (750mg qd) + chemotherapy drug. The therapeutic drugs for second-line chemotherapy are determined by the investigator, it’s recommended to use docetaxel or albumin-bound paclitaxel, and chemotherapeutics are used for up to 6 cycles. In part 2 (dose expansion), pts will be treated with apatinib (MTD determined by dose escalation, qd) + chemotherapy drug. Whether PD-1 or PD-L1 inhibitors have been used in the first-line treatment will be analyzed as a subgroup analysis factor. Primary endpoints are progression-free survival (PFS) and MTD. Secondary endpoints include confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR), overall survival (OS), and safety. AEs will be monitored throughout the study and graded per NCI CTCAE v5.0. Tumor response will be assessed by RECIST v1.1 every 6 weeks in the first 18 weeks, and every 9 weeks thereafter. Clinical trial information: ChiCTR2100048288.

Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): Phase 3 KEYNOTE-394 study.

383 Background: The anti–PD-1 antibody pembro showed efficacy and manageable safety in the global phase 2 KEYNOTE-224 and phase 3 KEYNOTE-240 studies of patients (pts) with previously treated advanced HCC, a population of high unmet need. KEYNOTE-394 is a randomized, double-blind, phase 3 study conducted in Asia to evaluate the efficacy and safety of pembro vs placebo, both given with BSC, as second-line therapy for previously treated advanced HCC (NCT03062358). Methods: Eligible pts in Asia with confirmed advanced HCC and progression on or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomized 2:1 to pembro 200 mg or placebo Q3W for ≤35 cycles plus BSC per local guidelines. The primary endpoint was OS. Secondary endpoints were PFS, ORR, DOR, DCR, and TTP, all assessed per RECIST v1.1 by blinded independent central review, and safety. Treatment differences were assessed using the stratified log-rank test (OS and PFS) or the stratified Miettinen & Nurminen method (ORR). The P value boundary for OS superiority at final analysis (FA) was 0.019307. If OS was superior, PFS and ORR superiority at the second interim analysis (IA2; primary analysis timepoint for these endpoints) could be tested at boundaries of 0.013447 and 0.009139, respectively. Results: 453 pts were randomized to pembro (N = 300) or placebo (N = 153). Baseline characteristics were generally balanced between arms; 90.7% had received sorafenib as first-line therapy. As of the June 30, 2021 cutoff date for FA, median study follow-up was 33.8 mo (range 18.7-49.0). At FA, pembro significantly improved OS vs placebo (HR 0.79, 95% CI 0.63-0.99, P = 0.0180); median (95% CI) OS was 14.6 mo (12.6-18.0) for pembro vs 13.0 mo (10.5-15.1) for placebo and 24-mo OS rate was 34.3% vs 24.9%. At IA2, pembro significantly improved PFS (HR 0.74, 95% CI 0.60-0.92, P = 0.0032) and ORR (estimated difference 11.4%, 95% CI 6.7-16.0, P = 0.00004); median (95% CI) PFS was 2.6 mo (1.5-2.8) for pembro vs 2.3 mo (1.4-2.8) for placebo, 12-mo PFS rates were 15.9% vs 1.4%, and ORR was 12.7% vs 1.3%. At FA, ORR was 13.7% vs 1.3%, median DOR was 23.9 mo vs 5.6 mo, DCR was 52.7% vs 47.7%, and median TTP was 2.7 mo vs 1.7 mo (HR 0.72, 95% CI 0.58-0.90). At FA, treatment-related AEs occurred in 66.9% of pts in the pembro arm and 49.7% in the placebo arm, including 14.4% and 5.9% with grade 3-5 events. 3 pts (1.0%) in the pembro arm and 0 in the placebo arm died of treatment-related AEs. Conclusions: Pembro plus BSC significantly improved OS, PFS, and ORR compared with placebo plus BSC as second-line therapy for patients from Asia with advanced HCC. The pembro safety profile was as expected. Overall, results were consistent with those previously observed in KEYNOTE-224 and KEYNOTE-240 and thus add to the body of evidence supporting the use of pembro as second-line therapy for advanced HCC. Clinical trial information: NCT03062358.

Natural history of patients with advanced cholangiocarcinoma and FGFR2 gene fusions/rearrangements.

391 Background: Cholangiocarcinoma (CCA) is a rare malignancy associated with poor survival. Molecular profiling is important to inform treatment choices and FGFR2 fusions or other rearrangements are common, occurring in 10–16% of patients with intrahepatic CCA (iCCA). There is limited real-world data on the natural history of patients with advanced CCA and FGFR2 fusions/rearrangements receiving therapies for advanced disease. The primary objective of this retrospective, observational natural history study was to compare real-world overall survival in patients with advanced CCA and FGFR2 fusions/rearrangements vs. those with wild-type (WT) FGFR2 from the index date of diagnosis of advanced CCA to date of death. A secondary objective was to analyze overall survival in the subgroup of patients with CCA and FGFR2 fusions/rearrangements from the index date of start of second-line therapy to date of death. Methods: This study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinico-genomic database. Data originated from approx. 280 US cancer clinics (̃800 sites of care). Patients were ≥18 years of age, had chart-confirmed advanced CCA, comprehensive genomic profiling demonstrating FGFR2 fusion/rearrangement, and had ≥2 visits within the Flatiron Health network since January 1, 2011. Results: As of May 2020, 571 patients met the inclusion criteria; 75 patients with FGFR2 fusions/rearrangements (median age 63 years; 64% female; 95% iCCA; 68% stage IV at initial diagnosis), and 496 patients with WT FGFR2 (median age 65 years; 48% female; 74% iCCA; 55% stage IV at initial diagnosis). Median overall survival from the index date of diagnosis was numerically higher, but not statistically different, for patients with FGFR2 fusions/rearrangements vs. WT FGFR2 (12.1 months [95% CI 8.5−17.1] vs. 7.1 months [95% CI 5.7−8.8]; log rank p = 0.184). 50 patients with FGFR2 fusions/rearrangements (median age 62 years; 70% female; 94% iCCA; 70% stage IV at diagnosis) received second-line therapy. Median real-world overall survival from the index date of second-line therapy was 8.5 months (95% CI 4.1−12.4 months). Conclusions: These real-world overall survival findings did not demonstrate a survival advantage for patients with CCA and FGFR2 fusions/rearrangements vs. WT FGFR2 receiving therapies for advanced disease, although a non-significant trend towards longer overall survival was observed in patients with FGFR2 fusions/rearrangements. FGFR2 status was not a significant predictor of overall survival after adjusting for potential prognostic covariates. An additional analysis is ongoing to compare overall survival from the start of second-line therapy in patients with advanced CCA and FGFR2 fusions/rearrangements vs. those with WT FGFR2.

Mycophenolate mofetil as second line treatment in autoimmune hepatitis – A retrospective single center analysis

BackgroundMost patients with autoimmune hepatitis respond to standard treatment with steroids and azathioprine. While the disease is usually fatal if untreated, patients who respond well to therapy have an excellent prognosis. Nevertheless, second-line treatment is necessary in approximately 20% of patients, due to either intolerance or insufficient response to first line treatment.While data for mycophenolate mofetil (MMF) in patients intolerant to azathioprine is encouraging, MMF seems of less benefit in patients with insufficient response to first line treatment, but analyzed data on this issue is limited. AimTo evaluate the efficacy and safety of MMF as a second-line therapy in patients with AIH. MethodsRetrospective analysis of a monocentric database of AIH patients who received medical care from 2000 to 2022. Clinical, immunological and biochemical parameters were assessed at different time points including last follow-up. ResultsOverall, 144 patients with AIH were identified. Fifty out of 144 (35%) AIH patients received MMF. Forty (80%) received MMF due to first line treatment intolerance, while ten (20%) due to insufficient response to first line treatment.Remission with MMF monotherapy was 81.5% in the intolerance group versus 30% in the insufficient response group. Patients switched to MMF because of an insufficient response, more often needed additional prednisolone doses higher than 5 mg/day, a switch to third-line treatment or combination regiments, to achieve disease control. ConclusionsPatients treated with MMF because of intolerance to first line treatment show a good disease control under MMF in the majority of cases. Efficacy is considerably lower in the patients switched to MMF because of an insufficient response to first line treatment.

Pembrolizumab versus chemotherapy for patients with esophageal squamous cell carcinoma enrolled in the randomized KEYNOTE-181 trial in Asia

In the randomized phase III KEYNOTE-181 study, pembrolizumab prolonged overall survival (OS) compared with chemotherapy as second-line therapy in patients with advanced esophageal cancer and programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥10. We report a post hoc subgroup analysis of patients with esophageal squamous cell carcinoma (ESCC) enrolled in KEYNOTE-181 in Asia, including patients from the KEYNOTE-181 China extension study. Three hundred and forty Asian patients with advanced/metastatic ESCC were enrolled in KEYNOTE-181, including the China cohort. Patients were randomly assigned 1 : 1 to receive pembrolizumab 200 mg every 3 weeks for ≤2 years or investigator's choice of paclitaxel, docetaxel, or irinotecan. OS, progression-free survival, response, and safety were analyzed without formal comparisons. OS was evaluated based on PD-L1 CPS expression level. In Asian patients with ESCC, median OS was 10.0 months with pembrolizumab and 6.5 months with chemotherapy [hazard ratio (HR), 0.63; 95% CI 0.50-0.80; nominal P < 0.0001]. Median progression-free survival was 2.3 months with pembrolizumab and 3.1 months with chemotherapy (HR, 0.79; 95% CI 0.63-0.99; nominal P= 0.020). Objective response rate was 17.1% with pembrolizumab and 7.1% with chemotherapy; median duration of response was 10.5 months and 7.7 months, respectively. In patients with PD-L1 CPS <1 tumors (pembrolizumab versus chemotherapy), the HR was 0.99 (95% CI 0.56-1.72); the HR (95% CI) for death was better for patients with PD-L1 CPS cut-offs >1 [CPS ≥1, 0.57 (0.44-0.75); CPS ≥5, 0.56 (0.41-0.76); CPS ≥10, 0.53 (0.37-0.75)]. Treatment-related adverse events were reported in 71.8% of patients in the pembrolizumab group and 89.8% in the chemotherapy group; grade 3-5 events were reported in 20.0% and 44.6%, respectively. Pembrolizumab monotherapy demonstrated promising efficacy in Asian patients with ESCC, with fewer treatment-related adverse events than chemotherapy. PD-L1 CPS ≥1 is an appropriate cut-off and a predictive marker of pembrolizumab efficacy in Asian patients with ESCC.

116TiP KEYNOTE-B98: Phase Ib/II study of pembrolizumab plus investigational agents as second-line treatment for anti–PD-1/PD-L1-refractory extensive-stage small cell lung cancer (ES-SCLC)

Immune checkpoint inhibitors plus platinum chemotherapy are first-line standard-of-care therapy for ES-SCLC. Treatment options for patients who progress after first-line therapy have limited efficacy. The anti–PD-1 monoclonal antibody (mAb) pembrolizumab has demonstrated antitumor activity as monotherapy in patients who have received prior therapy for advanced SCLC in the KEYNOTE-028 and KEYNOTE-158 studies. KEYNOTE-B98 (NCT04938817) is a randomized, phase 1b/2, rolling-arm, multicenter, open-label study evaluating pembrolizumab plus investigational agents as second-line therapy in patients with anti–PD-1/PD-L1 refractory ES-SCLC.

Safety and cost-effectiveness of ponatinib versus other tyrosine kinase inhibitors as second-line therapy in patients with chronic myeloid leukemia in the United States

To evaluate the cost-effectiveness of ponatinib compared with second-line TKIs in the treatment of adult patients with CML who failed, or were intolerant to, first-line TKIs. A Markov state transition model was conducted. Model transition, adverse-effect probabilities, utility data and medical costs were obtained from clinical trials and literature. Measurements included medications, follow-ups, adverse events, allogeneic stem cell transplantation and quality-adjusted life years (QALYs). Univariable and Bayesian multivariable probabilistic sensitivity analyses were conducted using Monte Carlo simulations. Dasatinib resulted in an ICER of $79,086/QALY compared to nilotinib. Ponatinib yielded an ICER of $176,278/QALY and $141,563/QALY compared to dasatinib and nilotinib, respectively. Dasatinib was the optimal treatment at a $100,000/QALY threshold. The probability (36%–40%) for ponatinib or dasatinib optimal treatment was associated with thresholds of $160,000–$180,000/QALY. Dasatinib and ponatinib can be considered cost-effective options and provide clinical benefits compared to other second-line TKIs for CML in the US.

Efficacy and Safety of Ruxolitinib in the Treatment of Elderly Patients with Policythemia Vera Resistant/Intolerant to Hydroxyurea

▪Introduction: Ruxolitinib (Rux) has been recently approved as second-line therapy in patients (pts) with Polycythemia Vera (PV) resistant/intolerant to hydroxyurea (HU). Median age of PV pts enrolled in the pivotal Response trials was around 60 yrs; at present, no data is reported on the use of Rux in elderly pts.Aims: In a real-world cohort of PV pts treated with Rux, we investigated whether the efficacy and safety of Rux were comparable in pts who initiated therapy when aged ≥75 years compared with younger pts.Methods: After IRB approval, clinical/laboratory data of 934 WHO2016-defined PV pts followed in 29 Hematology Centers were retrospectively collected. Of them, 168 (17.9%) were considered resistant/intolerant to HU at any time during follow-up by responsible physician and shifted to Rux as second-line therapy.Results: Among the 168 pts treated with Rux, 42 (25%, median age 78.2 years) were aged ≥75 yrs at Rux start, 74 (44%, median age 67.7) were aged 60-74 and 52 (31%, median age 53) were <60 at Rux start.No significant differences were observed between the 3 groups, apart from a lower need for phlebotomies in pts aged ≥75 yrs and lower presence of palpable spleen in older pts (age ≥60), that more frequently switched to Rux due to HU intolerance (Table 1).Median duration of HU treatment was 41.0 months (IQR 14.6 - 85.8), with a trend for a longer median treatment duration in pts aged ≥75 [61.0 months (IQR 21.5 - 89.6) vs 35.9 months (IQR 13.4 - 79.6), p=0.04]. Rux starting dose was similar across age groups; however, more elderly pts underwent Rux dose reductions during follow-up (45.2% in pts aged ≥75 vs 28.6% in younger pts, p=0.04).Responses during Rux therapy are reported in Table 2, with no significant differences between the 3 groups at any time. In the overall cohort, response on PV-related symptoms at 6 and 12 months was significantly higher in pts who switched to Rux because of HU intolerance; however, this difference was not observed in pts aged ≥75 yrs.As to the most common hematologic Rux-related toxicities, grade 3-4 anemia and thrombocytopenia were observed in only 2 (1.2%) and 5 (3%) pts, with no difference across age groups (p=0.45 and p=0.18). However, any grade anemia and thrombocytopenia during Rux were more frequently observed in pts aged ≥75 (68.3% vs 51.7% of anemia, p=0.06 and 12.2% vs 3.5% of thrombocytopenia in younger pts, p=0.04). Nineteen and 4 pts experienced infectious and thrombotic complications during Rux with incidence rates of 0.59 and 0.12 per 100 patient-months, respectively, comparably in younger and older (≥75) pts (p=0.75 and p=0.29, respectively). Notably, 6 infections were herpes simplex/zoster virus, comparably distributed between the 3 groups (p=0.60).Permanent Rux discontinuation was needed in 14 pts (8.3%) after a median Rux exposure of 7.8 months (IQR 4.6 - 17.6) (incidence: 0.41 per 100 pts/months). Discontinuation was comparable between age groups, with Rux stop in 4 pts aged ≥75 yrs and 10 younger pts (2.4% vs 5.2% at 8 months, log-rank p=0.75). At last follow-up, 2 pts had died (1 from 2 nd neoplasia after 19.1 months from Rux start and 1 from acute leukemia after 3.3 years), both pts aged 60-74 yrs.Conclusions. In this real-world analysis, use of Rux in HU resistant/intolerant elderly PV pts was effective and safe despite the more frequent need for dose reductions. Older age should not discourage Rux therapy, but stricter hematological monitoring may be suggested. [Display omitted] DisclosuresLatagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria. Bonifacio: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Apatinib plus S-1 for previously treated, advanced gastric or gastro-oesophageal junction adenocarcinoma: a phase 2, single-arm, prospective study.

The current management of advanced gastric or gastro-oesophageal junction adenocarcinoma remains unsatisfactory. We investigated the efficacy and safety of the combination therapy of apatinib and S-1, considering the potential advantage of home-based treatment without hospital admission, in patients with platinum-refractory gastric or gastro-oesophageal junction adenocarcinoma. In this open-label, single-arm, phase 2 trial, in each 21-day cycle, eligible patients received apatinib at an initial dose of 500 mg once daily continuously and S-1 at a dose of 40-60 mg twice daily on days 1-14 until the trail was discontinued disease progression, development of intolerable toxicity, or withdrawal of consent. The primary endpoints were progression-free survival. The secondary endpoints were objective response rates, disease control rates, and safety, and overall survival. This study was registered at ClinicalTrials.gov, NCT04338438. Between April 2015 and May 2019, we included 37 patients with advanced gastric or gastro-oesophageal junction adenocarcinoma refractory to first-line platinum-containing therapy. At the data cutoff, the 6-month progression-free survival was 31.5%, the median progression-free survival and overall survival were 4.2 (95% CI: 3.50-4.90) months and 8.2 (95% CI: 4.69-11.71) months, respectively. Of 37 eligible patients, 8 (21.6%) patients reached objective responses, 31 (83.8%) patients reached disease control. Grade 3 or 4 adverse events occurred in 8 (21.6%) patients, including hand-foot syndrome, hypertension, and diarrhea, etc. The combination of Apatinib and S-1 showed promising efficacy and manageable toxicity as a home-based, second-line therapy in patients with advanced gastric or gastro-oesophageal junction adenocarcinoma, especially for the elder patients with poor performance status. NCT04338438.

Second-line pembrolizumab versus chemotherapy in Japanese patients with advanced esophageal cancer: subgroup analysis from KEYNOTE-181

BackgroundSafe and effective treatments for advanced esophageal cancer are an unmet need in Japan. We report results of a subgroup analysis of Japanese patients enrolled in KEYNOTE-181, a randomized, open-label, phase 3 study of pembrolizumab versus chemotherapy as second-line therapy for patients with advanced or metastatic esophageal cancer whose disease progressed after standard first-line therapy.MethodsPatients were randomly assigned 1:1 to receive pembrolizumab 200 mg every 3 weeks or investigator’s choice of paclitaxel, docetaxel, or irinotecan. Efficacy was evaluated in all Japanese patients and in those with programmed death ligand 1 combined positive score ≥ 10.ResultsOf the 152 Japanese patients enrolled (pembrolizumab, n = 77; chemotherapy, n = 75), 150 (98.7%) had squamous cell carcinoma and 79 (52.0%) had combined positive score ≥ 10. At the final analysis, median overall survival was improved among all patients (12.4 vs 8.2 months with pembrolizumab and chemotherapy, respectively; hazard ratio, 0.68; 95% CI 0.48–0.97) and patients with combined positive score ≥ 10 (12.6 vs 8.4 months; hazard ratio, 0.68; 95% CI 0.42–1.10). Fewer patients had any-grade (74.0% vs 95.9%) or grade 3–5 (16.9 vs 50.0%) treatment-related adverse events with pembrolizumab than with chemotherapy.ConclusionConsistent with the global trial results, second-line pembrolizumab therapy showed a survival benefit and a favorable safety profile compared with chemotherapy in Japanese patients with advanced esophageal cancer.

PD-1/PD-L1 Immune Checkpoint Inhibitors after Platinum-based Chemotherapy in Metastatic or Locally Advanced Urothelial Bladder Carcinoma: A Systematic Review and Meta-analysis

Objective: This study aimed to assess the effect of anti-programmed cell death-1/programmed cell death-ligand-1 (PD-1/PD-L1) agents compared with second-line therapy in patients with metastatic or locally advanced urothelial bladder carcinoma following previous platinum-containing chemotherapy.Material and Methods: We systematically searched three electronic databases. The protocol of the study was registered in Prospero (CRD42019142494). Using the Grading of Recommendations Assessment, Development, and Evaluation approach, the certainty of evidence (CoE) was estimated.Results: The search results initially found 8168 publications. For qualitative synthesis, two publications were included. Pooled results indicated that patients treated with anti-PD-1/PD-L1 agents had significantly prolonged overall survival (hazard ratio (HR) 0.80; 95% confidence interval (CI) 0.7-0.9; I2 21.0%; moderate CoE). According to positive PD-L1 expression, PD-1/PD-L1 inhibitors had significantly more survival than chemotherapy (HR 0.75; 95% CI 0.5-0.9, I2 57.0%, low CoE). Furthermore, there was no significant difference in adverse events (AE) between the anti-PD-1/PDL1 agents and second-line chemotherapy (risk ratio 0.68; 95% CI 0.3-1.4; I2 97.0%, low CoE).Conclusion: The present meta-analysis and systematic review provide strong evidence that anti-PD-1/PD-L1 agents could improve overall survival and have similar results in AEs compared with second-line chemotherapy. Further studies will confirm the power of immunotherapy for the treatment of metastatic or locally advanced urothelial bladder carcinoma.

Recent Updates in the Treatment of Erythema Multiforme.

Erythema multiforme (EM) is an immune-mediated condition that classically presents with discrete targetoid lesions and can involve both mucosal and cutaneous sites. While EM is typically preceded by viral infections, most notably herpes simplex virus (HSV), and certain medications, a large portion of cases are due to an unidentifiable cause. EM can be confused with other more serious conditions like Stevens–Johnson syndrome (SJS); however, clinical research has provided significant evidence to classify EM and SJS as separate disorders. Treatment of EM is highly variable, depending on the etiology, the involvement of mucosal sites, and the chronicity (acute vs. recurring) of the disease. If the etiology or causal medication/infection is identified, then the medication is stopped and/or the infection is treated prior to initiating symptomatic treatment. Treatment for acute EM is focused on relieving symptoms with topical steroids or antihistamines. Treatment for recurrent EM is most successful when tailored to individual patients. First line treatment for recurrent EM includes both systemic and topical therapies. Systemic therapies include corticosteroid therapy and antiviral prophylaxis. Topical therapies include high-potency corticosteroids, and antiseptic or anesthetic solutions for mucosal involvement. Second-line therapies for patients who do not respond to antiviral medications include immunosuppressive agents, antibiotics, anthelmintics, and antimalarials

275P A phase II study of LAG525 in combination with spartalizumab (PDR001), PDR001 and carboplatin (Carbo), or Carbo, as first- or second-line therapy in patients (Pts) with advanced (Adv) triple-negative breast cancer (tnbc)

In TNBC, despite high initial response to chemotherapy (CT), many pts relapse, and options for treating recurrence are limited. Combining immunotherapy and CT may synergise to enhance therapeutic efficacy. Here we evaluate LAG525, an anti-LAG-3 antibody (ab), with PDR001, an anti-PD-1 ab, and/or carbo in pts with adv TNBC.