Tazemetostat Is Associated with Lower Risk for Safety Outcomes Versus the PI3-Kinases Idelalisib, Duvelisib and Copanlisib, in Patients with Relapsed/Refractory Follicular Lymphoma Who Have Received at Least 2 Prior Systemic Treatments: A Matching-Adjusted Indirect Comparison of Single-Arm Trials

Background: Tazemetostat, a first-in-class, oral enhancer of zeste homolog 2 (EZH2) inhibitor was recently approved by the US Food and Drug Administration in patients with relapsed/refractory (R/R) follicular lymphoma (FL) after demonstrating single-agent, antitumor activity in patients with wild-type (WT) or mutant (MT) EZH2. The PI3K inhibitors idelalisib, duvelisib, and copanlisib are indicated for third-line or later (3L+) treatment of R/R FL, but they are associated with safety concerns, and clinical studies with these agents did not include grade 3B or transformed FL. However, tazemetostat idelalisib, duvelisib, and copanlisib were all approved based on single-arm studies and have not been compared in head-to-head randomized trials for the treatment of 3L+ R/R FL. Here, we present an indirect treatment comparison (ITC) of tazemetostat with idelalisib, duvelisib, and copanlisib for the treatment of 3L+ R/R FL. Methods: A systematic literature review identified clinical trial publications for idelalisib (DELTA), duvelisib (DYNAMO), and copanlisib (CHRONOS-1 Part B) for use in an ITC with tazemetostat for 3L+ treatment of R/R FL. Matching-adjusted indirect comparison (MAIC) methodology was selected as all comparator trials were single-arm and individual patient data (IPD) were available for the tazemetostat E7438-G000-101 trial (n=99). Three MAIC analyses were conducted by weighting individual patients treated with tazemetostat to baseline characteristics reported from each comparator trial. FL subpopulation baseline characteristics and outcomes data were available for matching idelalisib (n=72); full trial mixed-NHL populations were reported for duvelisib (n=129, 64% FL) and copanlisib (n=142, 73% FL). Baseline characteristics for matching-adjustment were chosen using clinical advice, an evaluation of prognostic factors associated with outcomes, and published data availability. Characteristics included: age, ECOG performance status, disease stage, histology (tumor grade, transformed FL), number of prior lines of treatment, prior stem cell therapy, and refractory status (to last therapy). Only the tazemetostat trial included patients with grade 3b or transformed FL, or recorded EZH2 mutation status. Safety and efficacy outcome definitions were similar across trials. Primary safety outcomes included risk of any grade ≥3 treatment-emergent adverse event (TEAE), any treatment-emergent serious adverse event (TESAE), and TEAEs leading to dose reduction, drug discontinuation, or interruption. The primary efficacy outcome was objective response rate (ORR), reported across all trials. Rates of individual grade ≥3 TEAEs also were compared. Limitations of such indirect methods include inability to account for any unmeasured covariates that may be effect modifiers, and reductions in the effective sample size. Results: After matching, all baseline characteristics were successfully balanced. Matched patients treated with tazemetostat had lower relative risk for all safety outcomes compared with all treatments, including any grade ≥3 TEAE (vs idelalisib: RR=0.45; vs duvelisib: RR=0.35; vs copanlisib: RR=0.37; all, P<0.001), any TESAE, and any TEAE leading to dose reduction, drug discontinuation, or interruption. These results were statistically significant (where comparator data were reported) for all but 2 safety outcomes (Figure). Several grade ≥3 TEAEs occurred at a significantly lower incidence with tazemetostat compared with matched patients treated with idelalisib, duvelisib, or copanlisib, including neutropenia (vs idelalisib: 3% vs 22%; vs duvelisib: 3% vs 25%; vs copanlisib: 4% vs 24%; all, P<0.05). The ORR was similar after matching for tazemetostat versus all treatments, with no statistically significant difference between therapies (vs idelalisib: 43% vs 56%, P=0.16; vs duvelisib: 48% vs 47%, P=0.91; vs copanlisib: 49% vs 61%, P=0.11). Conclusion: More tolerable treatment options are needed for 3L+ treatment of R/R FL because patients in this setting are often elderly and have exhausted multiple prior lines of treatment. Results from this ITC indicate that, after adjusting for baseline population differences, tazemetostat addresses this unmet need, as it is associated with lower relative risk for safety outcomes versus idelalisib, duvelisib, or copanlisib while achieving similar efficacy outcomes. Disclosures Proudman: Analysis Group, Inc.: Consultancy. Nellesen:Analysis Group, Inc.: Consultancy. Gupta:Analysis Group, Inc.: Consultancy. Adib:Epizyme, Inc.: Consultancy; Alacrita: Current Employment. Yang:Epizyme, Inc.: Current Employment. Keith:Epizyme: Current Employment, Current equity holder in publicly-traded company. Mamlouk:Epizyme: Current Employment, Current equity holder in publicly-traded company.

Download Full-text

A Matching-Adjusted Indirect Comparison of Sonidegib and Vismodegib in Advanced Basal Cell Carcinoma

Journal of Skin Cancer ◽

10.1155/2017/6121760 ◽

2017 ◽

Vol 2017 ◽

pp. 1-7 ◽

Cited By ~ 13

Author(s):

Dawn Odom ◽

Deirdre Mladsi ◽

Molly Purser ◽

James A. Kaye ◽

Eirini Palaka ◽

...

Keyword(s):

Basal Cell ◽

Comparative Effectiveness ◽

Small Sample Size ◽

Objective Response ◽

Locally Advanced ◽

Indirect Comparison ◽

Small Sample ◽

Curative Surgery ◽

Adjusted Indirect Comparison ◽

Baseline Characteristics

Objectives. Based on single-arm trial data (BOLT), sonidegib was approved in the US and EU to treat locally advanced basal cell carcinomas (BCCs) ineligible for curative surgery or radiotherapy. Vismodegib, the other approved targeted therapy, also was assessed in a single-arm trial (ERIVANCE). We examined the comparative effectiveness of the two drugs using a matching-adjusted indirect comparison (MAIC) versus an unadjusted indirect comparison. Methods. After comparing trials and identifying potential prognostic factors, an MAIC was conducted to adjust for differences in key patient baseline characteristics. Due to BOLT’s small sample size, the number of matching variables was restricted to two. Efficacy results for sonidegib were generated so that selected baseline characteristics matched those from ERIVANCE and were compared with published ERIVANCE results. Results. Matching variables were baseline percentages of patients receiving prior radiotherapy and surgery. After weighting, sonidegib objective response rate (ORR) and median progression-free survival (PFS) were effectively unchanged (prematched versus postmatched ORR and PFS, 56.1% versus 56.7% and 22.1 versus 22.1 months, resp.). Vismodegib’s ORR and PFS were 47.6% and 9.5 months. Conclusions. Comparative effectiveness of sonidegib versus vismodegib remains unchanged after adjusting BOLT patient-level data to match published ERIVANCE baseline percentages of patients receiving prior surgery and radiotherapy.

Download Full-text

Nivolumab-Induced, Late-Onset, Steroid-Sensitive, High-Grade Pneumonitis and Durable Tumor Suppression in Metastatic Renal Cell Carcinoma: A Case Report

Case Reports in Oncological Medicine ◽

10.1155/2019/6759472 ◽

2019 ◽

Vol 2019 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Vincent Louie Mendiola ◽

Meghana Kesireddy ◽

Bagi Jana

Keyword(s):

Renal Cell Carcinoma ◽

Adverse Event ◽

Case Report ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Late Onset ◽

Drug Discontinuation ◽

Related Adverse Event ◽

Grade 3

Nivolumab, an antiprogrammed death-1 checkpoint inhibitor, has been approved for use in unresectable/metastatic renal cell carcinoma (RCC). Nivolumab-induced pneumonitis, a rare, but often severe and potentially life-threatening immune-related adverse event, has been reported, typically, early during the treatment. Due to its low incidence, more studies are needed to better elucidate this condition and its possible effects on cancer progression. We now present a 57-year-old Hispanic male patient with metastatic RCC-clear cell type who, after his 34th cycle of nivolumab (16 months after being on nivolumab), developed a late-onset, immune-related adverse event (IRAE) including a grade 3 pneumonitis, which resolved completely, clinically, and on serial lung imaging with steroids and drug discontinuation. His cancer remained stable with no progression for 18 months despite discontinuation of nivolumab which showed tumor progression resistance. This case report is aimed at providing further information regarding the rare phenomena of a late-onset IRAE, in particular, a grade 3 nivolumab-induced pneumonitis which also responded rapidly to treatment, as well as at discussing this immunotherapy’s durable tumor suppressive effect and a possible associated factor to this phenomenon.

Download Full-text

Incidence and risk of colitis with programmed death-1 versus programmed death-ligand 1 inhibitors for the treatment of cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e15087 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e15087-e15087

Author(s):

Hirotaka Miyashita ◽

Takahisa Mikami ◽

Sera Satoi ◽

Christina Cruz ◽

Matt D. Galsky

Keyword(s):

Adverse Event ◽

Relative Risk ◽

Fixed Effects ◽

Meta Analysis ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Significant Difference ◽

Programmed Death 1 ◽

Grade 3 ◽

Meta Analyses

e15087 Background: Programmed death 1 (PD-1) inhibitors and Programmed Death-Ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) approved for treatment of several different cancers. Colitis is a major immune-related adverse event associated with ICIs, but the risk of colitis with PD-1 versus PD-L1 inhibitors is not well characterized. Methods: We performed a meta-analysis for the incidence of all grade and grade 3-4 colitis with PD-1 inhibitor (nivolumab, pembrolizumab, and cemiplimab) or PD-L1 inhibitor (atezolizumab, avelumab, and durvalumab) monotherapy using a fixed effects model. We also conducted subgroup meta-analyses of non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) trials, and a network meta-analysis of randomized trials comparing PD-1 or PD-L1 inhibitors with docetaxel for NSCLC. We analyzed Food and Drug Administration Adverse Event Reporting System (FAERS) database to estimate the reporting odds ratio (ROR) of each medication, which provides the estimated relative risk most valid in spontaneous report database. Results: We identified 88 studies that met inclusion for the analysis. PD-1 inhibitors were associated with higher incidence of all grade and grade 3-4 colitis compared to PD-L1 inhibitors in the analysis of all cancer types (1.49% vs 0.83%, relative risk (RR); 1.80, 95% confidence interval (CI); 1.22-2.67 for all grade colitis, and 0.85% vs 0.34%, RR; 2.52, 95% CI; 1.46-4.37 for grade 3-4 colitis). The meta-analyses on NSCLC and UC, and the network meta-analysis on NSCLC also showed the tendency that PD-1 inhibitors are associated with higher risk of all grade and grade 3-4 colitis, though only the analysis on UC for all grade colitis showed a significant difference. (1.95% vs 0.64%, RR; 3.05, 95% CI; 1.18 - 7.88) Retrospective analysis showed ROR of 16.78 (95% CI; 15.8-17.8) for PD-1 inhibitors, and 12.93 (95% CI; 10.74-15.42) for PD-L1 inhibitors. We found that ROR of PD-1inhibitors was 1.17 (95% CI; 0.97-1.43) compared to PD-L1 inhibitors. Conclusions: Our study showed that PD-1 inhibitors have higher risk of colitis than PD-L1 inhibitors.

Download Full-text

Indirect Comparisons to Assess the Relative Efficacy of Carfilzomib + Lenalidomide + Dexamethasone Versus Panobinostat + Bortezomib + Dexamethasone and Bortezomib + Dexamethasone: A Matching Adjusted Indirect Comparison

Blood ◽

10.1182/blood.v126.23.5622.5622 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5622-5622

Author(s):

Michael Rael ◽

Agnes Benedict ◽

Jack Ishak ◽

Sarah Cadarette ◽

Marco Campioni ◽

...

Keyword(s):

Indirect Comparison ◽

Phase Iii ◽

Novel Treatments ◽

Prior Therapy ◽

Hazard Ratios ◽

Phase Iii Study ◽

Adjusted Indirect Comparison ◽

Equity Ownership ◽

Baseline Characteristics ◽

Indirect Comparisons

Abstract Background: Several novel treatments have recently been approved for the treatment of relapsed multiple myeloma (RMM). In the absence of head-to-head comparisons between these novel treatments, clinicians and payers must rely on statistical indirect comparisons. The objective of this analysis is to derive measures of relative effectiveness for carfilzomib + lenalidomide + dexamethasone (KRd) against bortezomib + dexamethasone (Vd), and the recently approved combination of panobinostat + bortezomib + dexamethasone (PVd) in patients with RMM who have been treated with at least one prior therapy. Methods: A matching-adjusted indirect comparison (MAIC) (Signorovitch, 2010) for progression-free survival (PFS) and overall survival (OS) was conducted between the KRd arm of the phase III study ASPIRE (Stewart et al., 2015) versus the PVd and Vd arms of the phase III study PANORAMA 1 (San-Miguel et al., 2014). The MAIC utilized patient level data from ASPIRE, and adjusted for reported patient population differences. An MAIC uses a propensity score type equation to assign case weights to the KRd patients so that their weighted baseline characteristics match the baseline of the PVd or Vd population. This re-weighting process attempts to answer the question: What would the outcomes be if KRd had been administered to a population matching the characteristics of the PVd or Vd arms? Adjustments were made for age, gender, ECOG status, history of autologous stem cell transplant, disease duration, number of prior regimens, ISS stage, prior bortezomib use, and creatinine clearance rate. Cox PH models were fitted to estimate hazard ratios (HRs) for PFS and OS. Weibull survival curves best fit the adjusted survival data and were used to estimate median survival times. A simulated treatment comparison (STC) (Ishak et al., 2015), which adjusts for reported patient population differences using regression equations, was conducted as a cross validation. Results: The KRd arm in ASPIRE included 396 patients and the PVd and Vd arms in PANORAMA 1 included 387 and 381 patients, respectively. After successfully matching, the effective sample size of the KRd population was 131 for the PVd comparison and 138 for the Vd comparison. See Figure 1 for the MAIC adjusted PFS and OS Kaplan-Meier curves. Hazard ratios (95% CIs) from the Cox models for PFS and OS outcomes were 0.317 (0.228, 0.44) and 0.582 (0.394, 0.86) for KRd vs PVd, respectively and 0.208 (0.153, 0.283) and 0.472 (0.324, 0.688) for KRd vs Vd, respectively. Corresponding hazard ratios from the STC were similar and validate the MAIC results. Estimates of median PFS and OS in months were 29.5 and 65.2 for KRd compared to 12.0 and 40.9 for PVd, respectively. Corresponding estimates were 29.7 and 57.3 for KRd compared to 8.2 and 33.0 for Vd. Figure 1. Conclusion: This MAIC analysis suggests that KRd provides a consistent and statistically significant PFS and OS benefit relative to PVd and Vd in RMM patients who have been treated with at least one prior therapy. Beyond the patient characteristics available from PANORAMA 1, other variables that may potentially influence outcomes were not adjusted for in the analysis. This analysis did not compare KRd to PVd in patients who have received at least 2 prior regimens including bortezmib and an IMiD (panobinostat's FDA-approved indication) due to lack of published data on the baseline characteristics of this patient subset studied in PANORAMA 1. Disclosures Rael: Onyx: Consultancy; Evidera: Employment. Benedict:Onyx: Consultancy; Evidera: Employment. Ishak:Onyx: Consultancy; Evidera: Employment. Cadarette:Evidera: Employment; Onyx: Consultancy. Campioni:Amgen: Employment, Equity Ownership. Panjabi:Onyx Pharmaceuticals Inc., An Amgen Subsidiary: Employment, Equity Ownership.

Download Full-text

Updated Safety and Efficacy Results of Phase 1 Study of Olverembatinib (HQP1351), a Novel Third-Generation BCR-ABL Tyrosine Kinase Inhibitor (TKI), in Patients with TKI-Resistant Chronic Myeloid Leukemia (CML)

Blood ◽

10.1182/blood-2021-153065 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 311-311

Author(s):

Jiang Qian ◽

Dayu Shi ◽

Zongru Li ◽

Yazhen Qin ◽

Ting Zhao ◽

...

Keyword(s):

Adverse Event ◽

Research Funding ◽

Phase 1 ◽

Third Generation ◽

Publicly Traded ◽

Safety And Efficacy ◽

Grade 3 ◽

Cutoff Date

Abstract Background: Management of CML using TKIs is often constrained by treatment resistance, which portends a poor prognosis. Treatment failure may be due to therapeutic resistance (BCR-ABL1 mutation-dependent or independent), intolerance, and/or suboptimal adherence. The BCR-ABL1 T315I ("gatekeeper") genotype is insensitive to first- and second-generation TKIs, while compound mutations complicate management with all TKIs (including third-generation TKI ponatinib). HQP1351 (olverembatinib) is a novel, third-generation, orally active BCR-ABL1 TKI with evidence of antitumor activity against CML regardless of genotype (Ren X et al. Med Chem 2013;56:879-94) and a preliminary favorable safety profile in clinical trials (Jiang Q et al. Blood 2020;136:50-1). Methods: This Chinese, open label, multicenter, phase 1 trial evaluated the safety and efficacy of olverembatinib in adults with CML in chronic phase (CML-CP) or accelerated phase (CML-AP). Eligible patients have CML-CP or CML-AP that is resistant or intolerant to first- or second-generation TKIs. Patients with severe cardiovascular diseases, hypertension, and pulmonary arterial hypertension were excluded. Olverembatinib is orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg. This study reports data on patients with long-term follow-up. Results: From October 26, 2016, through February 2, 2021 (data cutoff date), 101 patients with CP-CML (n = 86) and AP-CML (n = 15) were enrolled and treated with olverembatinib. Seventy-one (70.3%) patients were male, the median age was 40 (range, 20-64) years, and median (range) interval from diagnosis to initial olverembatinib treatment was 6.0 (0.3-15.2) years. Eighty-four (83.2%) patients received ≥ 2 prior lines of TKI-therapy, and 63 (62.4%) harbored T315I mutation. At baseline, compound mutations were detected in 11 (10.9%) patients, of whom 7 (63.6%) had the BCR-ABL1 T315Igenotype. A total of 20 (19.8%) patients had 2 (n = 13) or ≥ 3 (n = 7) mutations. The median follow-up was 30.8 (1.2-51.8) months. As of the data cutoff date, 81 (80.2%) of 101 patients continued on treatment and 20 (14 CP-CML and 6 AP-CML) discontinued because of disease progression, intolerance, or occurrence of a secondary cancer. The cumulative median (range) drug exposure was 13,635 (1,650-20,975) mg. Of 101 patients, 18 (17.8%) were treated for > 3 years and 5 (5%) for > 4 years. Of evaluable patients without baseline responses, 97.0% had complete hematologic responses (CHR), 62.1% complete cytogenetic responses (CCyR), and 51.0% major molecular responses (MMR). Most evaluable patients with T315I mutations experienced 100% for CHR, 83.7% for MCyR, and 71.2% for MMR among patients in CP-CML, as well as 80.0% for CHR and 54.5% each for MCyR and MMR in AP-CML. At 36 months, the PFS rate (95% CI) was 96.3% (89.1%-98.8%) in patients with CP-CML and 71.4% (40.6%‒88.2%) in those with AP-CML. Treatment responses were durable and unaffected by baseline BCR-ABL1 mutational status. Corresponding values in patients with > 4 years of treatment were 100% (CHR), 80% (CCyR), and 60% (MMR). The mean (95% confidence interval) PFS rate was 100% (100%-100%) at 36 months, 100% at 48 months, and not reached (NR-NR) at 60 months. Most treatment-related adverse events were grade 1 or 2. The most frequent nonhematologic adverse event was (mostly grade 1 or 2) skin hyperpigmentation (86.1%). Grade ≥ 3 nonhematologic AEs included hypertriglyceridemia (10.9%), pyrexia (6.9%), and proteinuria (5.0%). The most common hematologic treatment-related adverse event was thrombocytopenia in 78 (77.2%) patients, including 52 (51.5% of total population) with grade ≥ 3 and 6 (5.9%) with serious adverse events. Leukopenia was grade ≥ 3 in 21 (20.8%) patients but not serious, while anemia was grade 3 or higher in 16 (15.8%) patients and serious in 4 (4.0%). Conclusions: In patients with TKI-resistant CML-CP or CML-AP and long-term treatment, olverembatinib was efficacious and well tolerated. Internal study identifier HQP1351-SJ002. Figure 1 Figure 1. Disclosures Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Wang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

Download Full-text

A weighted-adjusted indirect comparison of everolimus (EVE) versus axitinib (AXI) in second-line metastatic renal cell carcinoma (mRCC) patients who previously failed sunitinib therapy.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.491 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 491-491

Author(s):

Steven A. Sherman ◽

Xufang Wang ◽

Billy Amzal ◽

Roman Casciano ◽

Haitao Gao ◽

...

Keyword(s):

Indirect Comparison ◽

Progression Free Survival ◽

Similar Efficacy ◽

Phase Iii ◽

Second Line ◽

Two Phase ◽

Phase Iii Clinical Trials ◽

Kaplan Meier ◽

Adjusted Indirect Comparison ◽

Baseline Characteristics

491 Background: Both EVE and AXI have been approved for second-line treatment of mRCC after VEGFR-TKI therapy failure. No head-to-head clinical trial has compared clinical outcomes between EVE and AXI in this setting. This study aims to compare progression free survival (PFS) from two phase III clinical trials among mRCC patients with SUN as their only prior antineoplastic therapy and subsequently treated with EVE in the RECORD-1 trial vs. AXI in the AXIS trial, after adjusting for cross-trial differences. Methods: A weighted-adjusted indirect comparison using patient-level data from RECORD-1 and summary data from the AXIS trial publication was performed to align baseline characteristics from both trials and compare PFS (central review). A subset of N=43 second-line SUN -refractory mRCC patients treated with EVE were identified in RECORD-1 to correspond to a similar subset of patients (N=194) treated with AXI in AXIS. Logistic regression was used to identify factors predicting PFS in RECORD-1. The RECORD-1 subset was weighted to align the distributions of these key factors (i.e., MSKCC risk, gender, and time on prior SUN) with the AXIS subset. Weights were calculated for each patient using the following equation: Wi = [Pi (AAXIS)/Pi (ARECORD-1)] * [Pi (BAXIS)/Pi (BRECORD-1)] * [Pi (CAXIS)/Pi (CRECORD-1)], where A=Gender, B=MSKCC risk, and C=time on prior SUN. A weighted median PFS estimate with 95% bootstrap confidence interval (CI) and corresponding Kaplan-Meier (KM) curve were derived for EVE patients. Results: After weighting, the three key baseline characteristics were mostly comparable between the two studies, with the exception of MSKCC where a higher proportion of poor risk patients was evident in RECORD-1 (42%) vs. AXIS (33%). A median PFS of 5.1 months (95% CI: 3.6-10.7) was observed for weighted EVE patients compared to 4.8 months (95% CI: 4.5-6.4) reported in AXIS. Conclusions: The PFS estimates suggest similar efficacy between EVE and AXI in SUN-refractory mRCC patients. Further research is needed to confirm these results, which should be interpreted as those from an observational study.

Download Full-text

A Matching-Adjusted Indirect Comparison of Pembrolizumab + Chemotherapy vs. Nivolumab + Ipilimumab as First-Line Therapies in Patients with PD-L1 TPS ≥1% Metastatic NSCLC

Cancers ◽

10.3390/cancers12123648 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3648

Author(s):

Balazs Halmos ◽

Thomas Burke ◽

Chrysostomos Kalyvas ◽

Ralph Insinga ◽

Kristel Vandormael ◽

...

Keyword(s):

Indirect Comparison ◽

Stage Iv ◽

Risk Difference ◽

Base Case ◽

First Line ◽

Multiple Endpoints ◽

Estimated Risk ◽

Adjusted Indirect Comparison ◽

Baseline Characteristics ◽

Nsclc Patients

Background: In the absence of head-to-head trials, this study indirectly compared the effectiveness of pembrolizumab + chemotherapy vs nivolumab + ipilimumab for the first-line treatment of metastatic stage IV NSCLC patients with PD-L1 tumor proportion score (TPS) ≥1%. Methods: An anchored matching-adjusted indirect comparison (MAIC) was conducted using pooled individual patient data (IPD) from the ITT population in KEYNOTE-021G, KEYNOTE-189 and KEYNOTE-407 (n = 816) and published aggregate data of nivolumab + ipilimumab from CheckMate 227 Part 1A (n = 793). To adjust for cross-trial differences in baseline characteristics, data from KEYNOTE-021G/KEYNOTE-189/KEYNOTE-407 were re-weighted to match the baseline characteristics of CheckMate 227 Part 1A. Outcomes included OS, PFS and ORR. Base case analyses were restricted to patients with PD-L1 TPS ≥1%, with sub-group analyses in PD-L1 TPS ≥50% and 1–49%. Results: The estimated HR (95% CI) of pembrolizumab + chemotherapy vs nivolumab + ipilimumab was 0.80 (0.59,1.09) and 0.53 (0.41,0.68) for OS and PFS, respectively. For ORR, the estimated risk ratio was 1.8 (1.3,2.4) for pembrolizumab + chemotherapy vs nivolumab + ipilimumab and the risk difference was 25.5% (15.0,36.0). PD-L1 TPS ≥50% and 1–49% sub-groups showed an OS HR of 0.89 (0.58,1.36) and 0.68 (0.46,1.01), respectively. Conclusion: These MAIC results suggest that pembrolizumab + chemotherapy leads to a greater clinical benefit vs nivolumab + ipilimumab in patients with PD-L1 TPS ≥1% across multiple endpoints.

Download Full-text

Tisagenlecleucel versus historical standard therapies for pediatric relapsed/refractory acute lymphoblastic leukemia

Journal of Comparative Effectiveness Research ◽

10.2217/cer-2020-0069 ◽

2020 ◽

Vol 9 (12) ◽

pp. 849-860

Author(s):

Qiufei Ma ◽

Jie Zhang ◽

Elliott O'Brien ◽

Amber L Martin ◽

Andrea Chassot Agostinho

Keyword(s):

Overall Survival ◽

Acute Lymphoblastic Leukemia ◽

Survival Benefit ◽

Lymphoblastic Leukemia ◽

Indirect Comparison ◽

Standard Of Care ◽

Salvage Chemotherapy ◽

Adjusted Indirect Comparison ◽

Baseline Characteristics ◽

Combination Regimens

Aim: We compared outcomes from a single-arm study of tisagenlecleucel with standard of care (SOC) regimens in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Methods: The analysis included one tisagenlecleucel study, one blinatumomab study, one clofarabine monotherapy study, three studies of clofarabine combination regimens and two studies of other salvage chemotherapy. Matching-adjusted indirect comparison analyses were conducted. Results: After adjusting for baseline characteristics, tisagenlecleucel was associated with significantly prolonged overall survival compared with blinatumomab (hazard ratio [95% CI], 0.32 [0.16–0.64]); clofarabine monotherapy (0.24 [0.13–0.42]); clofarabine combination regimens (0.26 [0.15–0.45]); two salvage therapies (0.15 [0.09–0.25] and 0.27 [0.15–0.49]). Conclusion: The analysis demonstrated tisagenlecleucel was associated with substantially greater survival benefit versus all SOC regimens.

Download Full-text

Matching-Adjusted Indirect Comparison (MAIC) of Lisocabtagene Maraleucel (liso-cel) Vs Axicabtagene Ciloleucel (axi-cel) and Tisagenlecleucel in Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Blood ◽

10.1182/blood-2020-137719 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 18-19

Author(s):

David G. Maloney ◽

John Kuruvilla ◽

Christopher P Fox ◽

Guillaume Cartron ◽

Daniel Li ◽

...

Keyword(s):

Safety Profile ◽

Research Funding ◽

Treatment Effects ◽

Tumor Burden ◽

Publicly Traded ◽

Cns Involvement ◽

Bridging Therapy ◽

Safety Outcomes ◽

Grade 3 ◽

Ecog Ps

Introduction: Chimeric antigen receptor T cell therapies have shown encouraging, durable responses in patients with R/R LBCL, yet no head-to-head clinical trials comparing options exist to date. We conducted 2 separate pair-wise MAICs to compare treatment effects of liso-cel vs both axi-cel and tisagenlecleucel. Methods: MAICs were used to estimate population-adjusted relative treatment effects associated with liso-cel (TRANSCEND NHL 001 [TRANSCEND]; NCT02631044; N = 256) vs axi-cel (ZUMA-1; NCT02348216; N = 101) and vs tisagenlecleucel (JULIET; NCT02445248; N = 111). Outcomes of interest included efficacy (overall and complete response rates [ORR/CRR], overall survival [OS], and progression-free survival [PFS]) and safety (cytokine release syndrome [CRS] by Lee criteria, neurological events [NEs], aphasia, encephalopathy, infections, hypogammaglobulinemia, and prolonged cytopenia). Individual patient data (IPD) from TRANSCEND were adjusted to match the marginal distribution (eg, mean, variance) of clinical factors among patients from ZUMA-1 and JULIET. Patients from TRANSCEND were removed from the IPD set if they did not satisfy eligibility criteria specified in the comparator trial for each MAIC. IPD for patients who remained in the TRANSCEND data set were weighted using a method-of-moments propensity score model. Baseline characteristic and outcome definitions were aligned with those in ZUMA-1 or JULIET. Clinically relevant prognostic factors (identified from literature, TRANSCEND data, and 5 independent clinical experts) were adjusted collectively in a stepwise fashion by ranked order. Key matched and adjusted variables in 1 or both comparisons included: disease histology, Eastern Cooperative Oncology Group performance status (ECOG PS), central nervous system (CNS) involvement, prior allogeneic/autologous hematopoietic stem cell transplant (HSCT), tumor burden, International Prognostic Index score, response to last therapy, bulky disease, and age. Efficacy outcomes in patients without bridging therapy were evaluated; however, ZUMA-1 and TRANSCEND treatment protocols differed in bridging therapy use (not allowed in ZUMA-1) and time to product availability (median, 17 vs 24 days, respectively). Results : After aligning definitions of baseline characteristics among trials, substantial differences were noted for ECOG PS of 2, tumor burden, active CNS involvement, number of prior lines of therapy, prior allogeneic HSCT, and history of hematologic comorbidities between studies. Overall, TRANSCEND included a larger sample size and broader patient population vs comparator trials, allowing for successful MAIC adjustments. When comparing TRANSCEND to ZUMA-1, MAIC-weighted efficacy outcomes were comparable between trials: odds ratios (ORs [95% CI]) for ORR and CRR with liso-cel vs axi-cel were 0.85 (0.48-1.52) and 0.78 (0.47-1.27), respectively; hazard ratios (HRs [95% CI]) for OS and PFS were 1.15 (0.80-1.65) and 1.30 (0.96-1.77), respectively (Figure). When limited to patients without bridging therapy, differences between trials remained statistically insignificant. MAIC-weighted safety outcomes showed a favorable safety profile for liso-cel, with a statistically significant lower odds of CRS, NEs (including aphasia and encephalopathy), and infections vs axi-cel. ORs (95% CI) for all-grade and grade ≥3 CRS with liso-cel vs axi-cel were 0.06 (0.03-0.13) and 0.16 (0.06-0.47), respectively; ORs for all-grade and grade ≥3 NEs were 0.21 (0.13-0.35) and 0.31 (0.18-0.54), respectively. When comparing TRANSCEND to JULIET, liso-cel showed a statistically significant higher ORR/CRR and longer OS/PFS than tisagenlecleucel. ORs (95% CI) for ORR and CRR achieved with liso-cel vs tisagenlecleucel were 2.78 (1.63-4.74) and 2.01 (1.22-3.30), respectively; HRs (95% CI) for OS and PFS were 0.67 (0.47-0.95) and 0.65 (0.47-0.91), respectively. Adjusted safety outcomes showed generally comparable profiles with lower ORs (95% CI) for all-grade and grade ≥3 CRS with liso-cel vs tisagenlecleucel: 0.53 (0.32-0.89) and 0.10 (0.03-0.31), respectively. Conclusions : MAIC-weighted outcomes suggest that liso-cel may provide a more well-balanced overall efficacy and safety profile for the treatment of R/R LBCL, with better efficacy compared with tisagenlecleucel and better safety compared with axi-cel. Disclosures Maloney: A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Bioline Rx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding. Kuruvilla:Bristol-Myers Squibb Company: Consultancy; AbbVie: Consultancy; Antengene: Honoraria; TG Therapeutics: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Seattle Genetics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Celgene Corporation: Honoraria; Amgen: Honoraria; Roche: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca Pharmaceuticals LP: Honoraria, Research Funding. Fox:AstraZeneca: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Adienne: Honoraria, Research Funding; Atarabio: Research Funding. Cartron:F. Hoffmann-La Roche: Consultancy, Honoraria; Abbvie: Honoraria; Sanofi: Honoraria; Celgene: Consultancy, Honoraria; Gilead: Honoraria; Jansen: Honoraria. Li:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Hasskarl:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Bonner:Eversana: Current Employment. Zhang:Eversana: Current Employment. Liu:Bristol-Myers Squibb: Current Employment, Current equity holder in publicly-traded company.

Download Full-text

Comparative Effectiveness of Pegcetacoplan Versus Ravulizumab in Patients with Paroxysmal Nocturnal Hemoglobinuria Previously Treated with Eculizumab: A Matching-Adjusted Indirect Comparison

Blood ◽

10.1182/blood-2020-141667 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 37-38

Author(s):

Rachel Y Bhak ◽

Nikita Mody-Patel ◽

Scott B. Baver ◽

Colin Kunzweiler ◽

Christopher Yee ◽

...

Keyword(s):

Comparative Effectiveness ◽

Research Funding ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Indirect Comparison ◽

Publicly Traded ◽

Phase 3 ◽

Fatigue Score ◽

Study Results ◽

Adjusted Indirect Comparison ◽

Previously Treated

INTRODUCTION Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematological disease characterized by complement-mediated hemolysis, resulting in anemia, thrombosis, and bone marrow failure. Currently available treatment options for PNH include the C5 inhibitors eculizumab and ravulizumab, which target intravascular hemolysis through terminal complement inhibition. Pegcetacoplan is a targeted C3 inhibitor being developed to control both intravascular and extravascular hemolysis, to improve hematologic and clinical outcomes. There is no head-to-head study of pegcetacoplan vs ravulizumab in patients with PNH. We assessed the comparative effectiveness of pegcetacoplan to ravulizumab through comparison of phase 3 study results, using matching-adjusted indirect comparison (MAIC) methodology, anchoring on the common comparator arm in the studies, eculizumab. We also acknowledge inherent limitations to MAIC (eg, lack of generalizability beyond the analyzed population). METHODS Individual patient data from PEGASUS, an ongoing, randomized, phase 3 study comparing pegcetacoplan and eculizumab among patients with PNH previously treated with eculizumab, were used to adjust for baseline differences compared to aggregate, published results from the randomized 302 study (Kulasekararaj AG, et al. Blood. 2019;133(6):540-549), which compared ravulizumab and eculizumab among patients with PNH with previous eculizumab. Both studies had similar eligibility criteria. However, PEGASUS also required hemoglobin <10.5 g/dL and absolute reticulocyte count >1.0× the upper limit of normal; these criteria were not applicable in the 302 study. To adjust for cross-study differences in baseline characteristics, propensity score weighting was used to balance demographic and clinical characteristics. Outcomes assessed included transfusion avoidance, total number of units of packed red blood cells (PRBCs) transfused, hemoglobin stabilization, and change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score. Outcomes were assessed from PEGASUS at week 16 and from the 302 study at week 26. Unadjusted mean and least-squares mean change in FACIT-Fatigue score were compared for PEGASUS and the 302 study, respectively. Weighted Wald tests and 95% confidence intervals (CIs) were computed for comparisons of categorical and continuous outcomes (ie, chi-square and z tests, respectively). RESULTS Sixty-eight patients from PEGASUS (36 pegcetacoplan; 32 eculizumab) and 195 from the 302 study (97 ravulizumab; 98 eculizumab) were included. Among pegcetacoplan and ravulizumab patients, mean age was 46.4 years, 48.5% were female, and 51.5% were white. Overall, 51.5% received ≥4 transfusions in the 12 months before screening in PEGASUS. The adjusted difference in proportion of transfusion avoidance was 71.4% (95% CI, 53.5-89.3%; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 71.4% more transfusion avoidance than ravulizumab. The difference in mean number of units of PRBCs transfused during follow-up was -5.7 units (95% CI, -7.2 to -4.2; P < 0.0001) for pegcetacoplan vs ravulizumab, indicating that pegcetacoplan is associated with 5.7 fewer units of PRBCs transfused during treatment than ravulizumab. The adjusted difference in proportion of hemoglobin stabilization was 75.5% (95% CI, 56.4-94.6%; P < 0.0001), suggesting that pegcetacoplan is associated with 75.5% more patients who achieved hemoglobin stabilization than ravulizumab. The adjusted difference in mean change from baseline in FACIT-Fatigue score was 8.8 points (95% CI, 4.2-13.3; P < 0.0001), suggesting that pegcetacoplan is associated with an improvement ~3 times greater than the clinically meaningful improvement of 3 points than ravulizumab. See the Figure for additional details. CONCLUSIONS MAIC methodology allowed the examination of the comparative effectiveness of pegcetacoplan vs ravulizumab in the absence of a head-to-head trial. Results suggest an improvement in transfusion avoidance, hemoglobin stabilization, and fatigue and a reduction in the total number of units of PRBCs transfused for patients who received pegcetacoplan, a C3 inhibitor, in PEGASUS, vs patients who received ravulizumab, a C5 inhibitor, in the 302 study. As PEGASUS progresses, week 26 data will be used to refresh these analyses. Disclosures Bhak: Apellis: Research Funding. Mody-Patel:Apellis: Current Employment, Current equity holder in publicly-traded company. Baver:Apellis: Current Employment, Current equity holder in publicly-traded company. Kunzweiler:Apellis: Research Funding. Yee:Apellis: Research Funding. Sundaresan:Apellis: Research Funding. Swartz:Apellis: Research Funding. Duh:Pharmacyclics: Research Funding; Takeda Oncology: Research Funding; GlaxoSmithKline: Research Funding; AstraZeneca: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Shire: Research Funding; Apellis: Research Funding; Merck: Research Funding. Krishnan:Apellis: Current Employment, Current equity holder in publicly-traded company. Sarda:Apellis: Current Employment, Current equity holder in publicly-traded company. OffLabel Disclosure: Pegcetacoplan is an investigational drug for the treatment of paroxysmal nocturnal hemoglobinuria

Download Full-text