Matt Truman

Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial

BACKGROUND The results of FASTACT, a randomised, placebo-controlled, phase 2 study, showed that intercalated chemotherapy and erlotinib significantly prolonged progression-free survival (PFS) in patients with advanced non-small-cell lung cancer. We undertook FASTACT-2, a phase 3 study in a similar patient population. METHODS In this phase 3 trial, patients with untreated stage IIIB/IV non-small-cell lung cancer were randomly assigned in a 1:1 ratio by use of an interactive internet response system with minimisation algorithm (stratified by disease stage, tumour histology, smoking status, and chemotherapy regimen) to receive six cycles of gemcitabine (1250 mg/m(2) on days 1 and 8, intravenously) plus platinum (carboplatin 5 × area under the curve or cisplatin 75 mg/m(2) on day 1, intravenously) with intercalated erlotinib (150 mg/day on days 15-28, orally; chemotherapy plus erlotinib) or placebo orally (chemotherapy plus placebo) every 4 weeks. With the exception of an independent group responsible for monitoring data and safety monitoring board, everyone outside the interactive internet response system company was masked to treatment allocation. Patients continued to receive erlotinib or placebo until progression or unacceptable toxicity or death, and all patients in the placebo group were offered second-line erlotinib at the time of progression. The primary endpoint was PFS in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00883779. FINDINGS From April 29, 2009, to Sept 9, 2010, 451 patients were randomly assigned to chemotherapy plus erlotinib (n=226) or chemotherapy plus placebo (n=225). PFS was significantly prolonged with chemotherapy plus erlotinib versus chemotherapy plus placebo (median PFS 7·6 months [95% CI 7·2-8·3], vs 6·0 months [5·6-7·1], hazard ratio [HR] 0·57 [0·47-0·69]; p<0·0001). Median overall survival for patients in the chemotherapy plus erlotinib and chemotherapy plus placebo groups was 18·3 months (16·3-20·8) and 15·2 months (12·7-17·5), respectively (HR 0·79 [0·64-0·99]; p=0·0420). Treatment benefit was noted only in patients with an activating EGFR gene mutation (median PFS 16·8 months [12·9-20·4] vs 6·9 months [5·3-7·6], HR 0·25 [0·16-0·39]; p<0·0001; median overall survival 31·4 months [22·2-undefined], vs 20·6 months [14·2-26·9], HR 0·48 [0·27-0·84]; p=0·0092). Serious adverse events were reported by 76 (34%) of 222 patients in the chemotherapy plus placebo group and 69 (31%) of 226 in the chemotherapy plus erlotinib group. The most common grade 3 or greater adverse events were neutropenia (65 [29%] patients and 55 [25%], respectively), thrombocytopenia (32 [14%] and 31 [14%], respectively), and anaemia (26 [12%] and 21 [9%], respectively). INTERPRETATION Intercalated chemotherapy and erlotinib is a viable first-line option for patients with non-small-cell lung cancer with EGFR mutation-positive disease or selected patients with unknown EGFR mutation status. FUNDING F Hoffmann-La Roche.

Detection and Dynamic Changes of EGFR Mutations from Circulating Tumor DNA as a Predictor of Survival Outcomes in NSCLC Patients Treated with First-line Intercalated Erlotinib and Chemotherapy

Purpose: Blood-based circulating-free (cf) tumor DNA may be an alternative to tissue-based EGFR mutation testing in NSCLC. This exploratory analysis compares matched tumor and blood samples from the FASTACT-2 study. Experimental Design: Patients were randomized to receive six cycles of gemcitabine/platinum plus sequential erlotinib or placebo. EGFR mutation testing was performed using the cobas tissue test and the cobas blood test (in development). Blood samples at baseline, cycle 3, and progression were assessed for blood test detection rate, sensitivity, and specificity; concordance with matched tumor analysis (n = 238), and correlation with progression-free survival (PFS) and overall survival (OS). Results: Concordance between tissue and blood tests was 88%, with blood test sensitivity of 75% and a specificity of 96%. Median PFS was 13.1 versus 6.0 months for erlotinib and placebo, respectively, for those with baseline EGFR mut+ cfDNA [HR, 0.22; 95% confidence intervals (CI), 0.14–0.33, P < 0.0001] and 6.2 versus 6.1 months, respectively, for the EGFR mut− cfDNA subgroup (HR, 0.83; 95% CI, 0.65–1.04, P = 0.1076). For patients with EGFR mut+ cfDNA at baseline, median PFS was 7.2 versus 12.0 months for cycle 3 EGFR mut+ cfDNA versus cycle 3 EGFR mut− patients, respectively (HR, 0.32; 95% CI, 0.21–0.48, P < 0.0001); median OS by cycle 3 status was 18.2 and 31.9 months, respectively (HR, 0.51; 95% CI, 0.31–0.84, P = 0.0066). Conclusions: Blood-based EGFR mutation analysis is relatively sensitive and highly specific. Dynamic changes in cfDNA EGFR mutation status relative to baseline may predict clinical outcomes. Clin Cancer Res; 21(14); 3196–203. ©2015 AACR.

Pharmacokinetics, efficacy, and safety of mycophenolate mofetil in combination with standard-dose or reduced-dose tacrolimus in liver transplant recipients

The pharmacokinetics of mycophenolate mofetil (MMF) in liver transplant recipients may change because of pharmacokinetic interactions with coadministered immunosuppressants or because changes in the enterohepatic anatomy may affect biotransformation of MMF to mycophenolic acid (MPA) and enterohepatic recirculation of MPA through the hydrolysis of mycophenolate acid glucuronide to MPA in the gut. In the latter case, the choice of formulation (oral versus intravenous) could have important clinical implications. We randomized liver transplant patients (n = 60) to standard (10–15 ng/mL) or reduced (5–8 ng/mL) trough levels of tacrolimus plus intravenous MMF followed by oral MMF (1 g twice daily) with corticosteroids. Pharmacokinetic sampling was performed after the last intravenous MMF dose, after the first oral MMF dose, and at selected times over 52 weeks. The efficacy and safety of the 2 regimens were also assessed. Twenty‐eight and 27 patients in the tacrolimus standard‐dose and reduced‐dose groups, respectively, were evaluated. No significant differences between the tacrolimus standard‐dose and reduced‐dose groups were seen in dose‐normalized MPA values of the time to the maximum plasma concentration (1.25 versus 1.28 hours), the maximum plasma concentration (15.5 ± 7.93 versus 13.6 ± 7.03 μg/mL), or the area under the concentration‐time curve from 0 to 12 hours (AUC0–12; 53.0 ± 20.6 versus 43.8 ± 15.5 μg h/mL) at week 26 or at any other time point. No relationship was observed between the tacrolimus trough or AUC0–12 and MPA AUC0–12. Exposure to MPA after oral and intravenous administration was similar. Safety and efficacy were similar in the two treatment groups. In conclusion, exposure to MPA is not a function of exposure to tacrolimus. The similar safety and efficacy seen with MMF plus standard or reduced doses of tacrolimus suggest that MMF could be combined with reduced doses of tacrolimus. Liver Transpl 15:136–147, 2009.

Tumor marker analyses from the phase III, placebo-controlled, FASTACT-2 study of intercalated erlotinib with gemcitabine/platinum in the first-line treatment of advanced non-small-cell lung cancer.

OBJECTIVES The FASTACT-2 study of intercalated erlotinib with chemotherapy in Asian patients found that EGFR mutations were the main driver behind the significant progression-free survival (PFS) benefit noted in the overall population. Further exploratory biomarker analyses were conducted to provide additional insight. MATERIALS AND METHODS This multicenter, randomized, placebo-controlled, double-blind, phase III study investigated intercalated first-line erlotinib or placebo with gemcitabine/platinum, followed by maintenance erlotinib or placebo, for patients with stage IIIB/IV non-small cell lung cancer (NSCLC). Provision of samples for biomarker analysis was encouraged but not mandatory. The following biomarkers were analyzed (in order of priority): EGFR mutation by cobas(®) test, KRAS mutation by cobas(®)KRAS test, HER2 by immunohistochemistry (IHC), HER3 by IHC, ERCC1 by IHC, EGFR gene copy number by fluorescence in-situ hybridization (FISH) and EGFR by IHC. All subgroups were assessed for PFS (primary endpoint), overall survival (OS), non-progression rate and objective response rate. RESULTS Overall, 256 patients provided samples for analysis. Considerable overlap was noted among biomarkers, except for EGFR and KRAS mutations, which are mutually exclusive. Other than EGFR mutations (p<0.0001), no other biomarkers were significantly predictive of outcomes in a treatment-by-biomarker interaction test, although ERCC1 IHC-positive status was predictive of improved OS for the erlotinib arm versus placebo in EGFR wild-type patients (median 18.4 vs 9.5 months; hazard ratio [HR] HR=0.32, 95% confidence intervals [CI]: 0.14-0.69, p=0.0024). CONCLUSION Activating EGFR mutations were predictive for improved treatment outcomes with a first-line intercalated regimen of chemotherapy and erlotinib in NSCLC. ERCC1 status may have some predictive value in EGFR wild-type disease, but requires further investigation.

A multi‐centre, single‐arm, open‐label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R‐ITP1000 study)

The efficacy of a fixed‐dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 × 109/l and ≤50 × 109/l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed‐up on weeks 1–8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 × 109/l) or partial response (PR; platelet count >50 × 109/l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 × 109/l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m2 four‐dose schedule in relapsed/chronic ITP.

Safety and efficacy of bevacizumab plus standard-of-care treatment beyond disease progression in patients with advanced non-small cell lung cancer: the AvaALL randomized clinical trial.

Importance Bevacizumab treatment beyond progression has been investigated in breast and metastatic colorectal cancers. Avastin in All Lines Lung (AvaALL) is the first randomized phase 3 study of bevacizumab across multiple lines of treatment beyond progression in non–small cell lung cancer (NSCLC). Objective To assess the efficacy and safety of continuous bevacizumab treatment beyond first progression in NSCLC. Design, Setting, and Participants AvaALL was a randomized, open-label, phase 3b trial, conducted from 2011 to 2015 in 123 centers worldwide. Patients with nonsquamous NSCLC previously treated with first-line bevacizumab plus platinum-doublet chemotherapy and at least 2 cycles of bevacizumab maintenance were randomized (1:1) at first progression to receive bevacizumab plus standard of care (SOC) or SOC alone. Interventions Patients received bevacizumab (7.5 or 15 mg/kg intravenously every 21 days) and/or investigator’s choice of SOC. For subsequent lines, patients treated with bevacizumab received SOC with or without bevacizumab; the SOC arm received SOC only. Main Outcomes and Measures The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival from first to second (PFS2) and third progression (PFS3), time to second (TTP2) and third progression (TTP3), and safety. Results Between June 2011 and January 2015, 485 patients (median age, 63.0 years [range, 26-84 years]; 293 [60.4%] male) were randomized. Median OS was not significantly longer with bevacizumab plus SOC vs SOC alone: 11.9 (90% CI, 10.2-13.7) vs 10.2 (90% CI, 8.6-11.9) months (hazard ratio [HR], 0.84; 90% CI, 0.71-1.00; P = .104). Median PFS2 was numerically longer with bevacizumab plus SOC vs SOC alone: 5.5 (90% CI, 4.2-5.7) vs 4.0 (90% CI, 3.4-4.3) months (HR, 0.83; 90% CI, 0.70-0.98; P = .06). Median PFS3 appeared longer with bevacizumab plus SOC vs SOC alone: 4.0 (90% CI, 2.9-4.5) vs 2.6 (90% CI, 2.3-2.9) months (HR, 0.63; 90% CI, 0.49-0.83), as did TTP2 and TTP3. Grade 3/4 adverse events were more frequent with bevacizumab plus SOC (186 [76.5%]) vs SOC alone (140 [60.3%]). No new safety signals were observed. Conclusions and Relevance The primary end point was not met; however, OS was underpowered according to initial statistical assumptions. Continued therapy beyond first progression led to improved PFS3 (but not PFS2), TTP2, and TTP3. Although a result with P = .06 for PFS2 would conventionally be considered significant at a specified 2-sided &agr; of .10, in the absence of adjustments for multiplicity, this result could be a chance finding. No new safety signals were identified with bevacizumab treatment beyond progression. Trial Registration clinicaltrialsregister.eu Identifier: 2010-022645-14; ClinicalTrials.gov identifier: NCT01351415

Effectiveness of biologics in Australian patients with rheumatoid arthritis: a large observational study: REAL: bDMARD effectiveness in Australia

The comparative effectiveness of biologic treatment regimens in a real world Australian population is unknown.

SAT0165 Reasons for bdmard cessation and subsequent persistence of second line treatment in a large real world rheumatoid arthritis registry

Background: The current recommendations for treating Rheumatoid Arthritis (RA) patients (pts) who fail on conventional disease modifying anti-rheumatic drugs (DMARDs) is to use biologic (b) or targeted synthetic (ts) DMARDs. Pts who fail first (1st) line b/tsDMRADs are recommended to go on other b/tsDMARDs; however, reasons for stopping or switching between bDMARDs according to mode of action and the persistence on treatment are not well characterized in real world patient populations. Objectives: The primary objective was to identify the reasons for stopping 1st line b/tsDMARDs in RA pts treated in the clinical practice setting. The secondary objectives were to identify second (2nd) line b/tsDMARDs choices in pts who stop TNF inhibitors (TNFis) within 6 months (mo) due to lack of efficacy and the persistence on these treatments. Methods: Pts ≥18 years with confirmed RA who were treated with 1st line b/tsDMARDs, from 1 August 2010 to 30 June 2017, by physicians participating in the OPAL-QUMI database, were included in the analyses. Reasons for stopping b/tsDMARDs were recorded by the treating physician during routine visits. The following b/tsDMARDs were included abatacept (ABA), adalimumab, certolizumab pegol, etanercept, golimumab, infliximab and tocilizumab (TCZ), rituximab (RTX) and tofacitinib (TFB). Data were analysed using descriptive statistics for continuous variables and frequency counts for categorical variables. Persistence on treatment was summarised using Kaplan-Meier (K-M) methodology. Individual TNFis were combined for simplicity. Abstract Sat0165 – Table 1 Patients receiving 1st line treatment by mechanism of action. Abstract Sat0165 – Table 2 K-M estimates of persistence on 2nd line b/tsDMARDs after discontinuation of 1st line TNFis due to lack of efficacy. Results: A total of 6914 pts received 1st line b/tsDMARDs. Median age was 61 years, median disease duration (RA onset to last visit) was 10 years. The majority (75%) were females. Treatment was stopped in 2656 pts (38%); 914 (34%) of these stopped within 6 mo of treatment initiation. The highest and lowest percentage of pts stopping treatment within 6 mo was in pts receiving TFB (54%) and TCZ (17%), respectively (table 1). The most common reasons for stopping therapy within 6 mo were lack of efficacy (45%>ABA, 44%>TNFis, 33%>TFB and 27%>TCZ) and adverse reactions (21%>TFB, 20%>TCZ, 15%>TNFis, 13%>ABA). Stopping due to lack of efficacy-primary failure was highest for TFB (23%). The percentage of pts remaining on 2nd line b/tsDMARD treatment after stopping 1st line TNFis due to lack of efficacy was the highest for TCZ (78%) at 6 mo and RTX (75%) at 12 mo (table 2). Median time to stopping 2nd line treatment was 48 mo (95% CI:17–74) for RTX, 21 mo (95% CI:11–62) for TCZ, 21 mo (95% CI:6–21) for TFB; 11 mo (95% Cl:8–22) for ABA and 9 mo (95% CI:7–12) TNFis. Conclusions: The primary failure rate is lower than previously reported. In pts who failed 1st line TNFis within 6 mo of commencement due to lack of efficacy, 2nd line TNFis resulted in the lowest treatment persistence. These real world data will assist clinicians with treatment choices post primary TNFis failure. Acknowledgements: Sponsored by Roche Products, Pty. Limited. Medical Writing provided by Dr Joseline Ojaimi from Roche. Disclosure of Interest: P. Youssef: None declared, B. Marcal Employee of: Roche Products, Pty. Limited, P. Button Consultant for: Roche Products, Pty. Limited, M. Truman Consultant for: Roche Products, Pty. Limited, P. Bird: None declared, H. Griffiths: None declared, L. Roberts Consultant for: AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Roche Products, Pty. Limited, UCB, K. Tymms Consultant for: AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Roche Products, Pty. Limited, UCB, G. Littlejohn Consultant for: AbbVie, Bristol-Myers Squibb, Janssen, Pfizer, Roche Products, Pty. Limited, UCB

AB0344 A Retrospective Non-Interventional Study on The Use of Biologics in The Treatment of Australian Patients with Rheumatoid Arthritis-The Real Study

Background Medication choices offered to rheumatoid arthritis (RA) patients are based in part on results from randomised controlled trials (RCTs). While these trials form a valuable evidence-base for rational prescribing, extrapolation of RCTs data to every day clinical practice is hampered by the highly selected patient (pt) groups that are accepted into RCTs. The comparative effectiveness of biologic treatment regimens in a real world Australian population is unknown. Objectives To assess effectiveness of biologic (b) DMARDs, as monotherapy, in combination with conventional (c) DMARDs other than MTX and in combination with cDMARDs regimens including MTX in the Australian OPAL database. Methods A retrospective non-interventional study. Data was extracted from participating Australian rheumatology centres using point of care software. Pts ≥18 years (yrs) with probable/definite RA, who had been prescribed a bDMARD and have had a visit recorded 12 months prior to and at least 12–40 weeks (wks) after commencement of a bDMARD were included. Bouts of treatment (BTs) refer to cycles of continuous, individual biologics prescribing in individual pts; if pts change biologics then this was defined as a new BT. Wk12 (-4/+8) analyses included any measurement between wk8 and wk20 post bDMARDs initiation and wk24 (-4/+8) included any measurements between wk20 and wk32. Results 2971 pts met criteria; median age 60 yrs (min 19, max 94) and median disease duration prior to 1st bDMARD of 6.1 yrs (min 0.2, max 58.3). Median number of bDMARDs per pt was 1 (min 1, max 8). At least 1 bDMARD was taken by 2971 pts, 1177 received 2 bDMARDs and 507 received 3 or more. There were 4923 bDMARD BTs recorded for this population with median treatment duration of 0.7 yrs (min 0, max 11.8). Median duration of 1st bDMARD (n=2971 pts)=0.8 yrs (min 0, max 11.8); 2nd bDMARD (n=1177)=0.6 yrs (min 0, max 9.9) and 3rd bDMARD (n=507)=0.6 yrs (min 0, max 6.4). The most commonly used bDMARDs were etanercept (n=1358), adalimumab (n=1098), abatacept (n=642) and tocilizumab (n=629); median duration of BTs=0.7 (min 0, max 11.8), 0.8 (min 0, max 10.5), 0.7 (min 0, max 6.1) and 1.0 (min 0, max 7.4) yrs respectively. bDMARD monotherapy (no cDMARD overlap) was administered in 10% BTs (n=488); bDMARDs + MTX +/− other cDMARD(s) were administered in 74% BTs (n=3639) and bDMARDs + cDMARD(s) other than MTX were administered in 16% BTs (n=796). Median CDAI and DAS28 by biologic presented in Table 1. Conclusions The majority in this cohort of Australian RA pts receive 1 line of bDMARD. Pts tend to persist longer on 1st bDMARD than subsequent biologics. bDMARDs as monotherapy or in combination (+/− MTX) are valid treatment strategies in the real world. Acknowledgement The study was sponsored by Roche Products Pty. Limited. Medical writing was provided by Dr Joseline Ojaimi from Roche. Disclosure of Interest D. Nicholls: None declared, H. Griffiths: None declared, R. Barrett Employee of: Roche Products, Pty. Limited, P. Button Employee of: Roche Products, Pty. Limited, M. Truman Employee of: Roche Products, Pty. Limited, P. Bird: None declared, L. Roberts: None declared, K. Tymms: None declared, G. Littlejohn: None declared