Pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in patients with B-cell malignancies: analysis of the Richter transformation subgroup from the multicentre, open-label, phase 1/2 BRUIN study.

BACKGROUND: Richter transformation usually presents as an aggressive diffuse large B-cell lymphoma, occurs in up to 10% of patients with chronic lymphocytic leukaemia, has no approved therapies, and is associated with a poor prognosis. Pirtobrutinib has shown promising efficacy and tolerability in patients with relapsed or refractory B-cell malignancies, including those who progress on covalent Bruton tyrosine kinase (BTK) inhibitors. This study aims to report the safety and activity of pirtobrutinib monotherapy in a subgroup of patients with Richter transformation from the multicentre, open-label, phase 1/2 BRUIN study. METHODS: This analysis included adult patients (aged ≥18 years) with histologically confirmed Richter transformation, an Eastern Cooperative Oncology Group performance status score of 0-2, and no limit of previous therapies, with patients receiving first-line treatment added in a protocol amendment (version 9.0, Dec 15, 2021). Pirtobrutinib 200 mg was administered orally once a day in 28-day cycles. The primary endpoint of phase 1 of the BRUIN trial as a whole, which has been previously reported, was to establish the recommended phase 2 dose for pirtobrutinib monotherapy and the phase 2 primary endpoint was overall response rate. Safety and activity were measured in all patients who received at least one dose of pirtobrutinib monotherapy. This BRUIN phase 1/2 trial was registered with ClinicalTrials.gov and is closed to enrolment (NCT03740529). FINDINGS: Between Dec 26, 2019, and July 22, 2022, 82 patients were enrolled, of whom five were enrolled during phase 1 and 77 during phase 2. All but one patient received a starting dose of 200 mg pirtobrutinib once a day as the recommended phase 2 dose. The remaining patient received 150 mg pirtobrutinib once a day, which was not escalated to 200 mg. The median age of patients was 67 years (IQR 59-72). 55 (67%) of 82 patients were male and 27 (33%) were female. Most patients were White (65 [79%] of 82). 74 (90%) of 82 patients received at least one previous Richter transformation-directed therapy. Most patients (61 [74%] of 82) had received previous covalent BTK inhibitor therapy for chronic lymphocytic leukaemia or Richter transformation. The overall response rate was 50·0% (95% CI 38·7-61·3). 11 (13%) of 82 patients had a complete response and 30 (37%) of 82 patients had a partial response. Eight patients with ongoing response electively discontinued pirtobrutinib to undergo stem-cell transplantation. The most common grade 3 or worse adverse event was neutropenia (n=19). There were no treatment-related deaths. INTERPRETATION: Pirtobrutinib shows promising safety and activity among patients with Richter transformation, most of whom received previous Richter transformation-directed therapy, including covalent BTK inhibitors. These data suggest that further investigation is warranted of pirtobrutinib as a treatment option for patients with relapsed or refractory Richter transformation after treatment with a covalent BTK inhibitor. FUNDING: Loxo Oncology.

Mixed-methods research to support the use of new lymphoma-specific patient-reported symptom measures derived from the EORTC item library.

BACKGROUND: No specific measures exist to assess patient-reported symptoms experienced by individuals with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL). This study was conducted to elicit patient-reported CLL/SLL- and MCL-related symptoms and their impact on patients' lives. The study qualitatively and quantitatively evaluated sets of conceptually-selected EORTC Item Library items for assessing CLL/SLL- and MCL-related symptoms. METHODS: The qualitative component of the research included a literature review, clinician consultations, and patient interviews. Concepts important to patients were identified and coded; cognitive debriefing of the selected library items was completed with patients. CLL/SLL and MCL-related symptoms and impacts were organized in a structured conceptual model, which was mapped to item sets from the Item Library. The quantitative component comprised exploratory macro-level Rasch measurement theory (RMT) analysis conducted to provide supportive quantitative insight on the item sets. RESULTS: 41 patients (21-MCL; 20-CLL/SLL) and 5 clinicians participated in the qualitative study; 57 unique patients (30-MCL; 27-CLL/SLL) completed the EORTC items. The conceptual models generated from the qualitative work included symptoms and functional impacts of CLL/SLL and MCL. Symptom domains included swollen lymph nodes, B symptoms, abdominal issues, pain, fatigue, subjective cognitive impairment, anemia-related symptoms, bleeding, infection, and other issues (appetite loss, temperature fluctuation, rash, weight gain, sleep problems, cough). Impacts included physical function, role function, and other functions (psychological, social). Cognitive debriefing demonstrated that the separate item sets for CLL/SLL and MCL-related symptoms were well understood and aligned with patients' experiences. All selected items were included in the conceptual models. The exploratory RMT analysis showed that the item sets provided adequate coverage of the continuum of CLL/SLL- and MCL-related symptom severity. CONCLUSIONS: This study gathered qualitative and early quantitative evidence supporting use of the EORTC Item Library to assess CLL/SLL- and MCL-related symptoms and impacts. These items are promising candidates for measurement of patient-reported disease symptoms in these populations. A larger sample size will be essential to establish the psychometric properties necessary to support use in clinical trials. Patients who suffer from rare cancers of the blood, bone marrow, and lymph nodes can experience chronic and debilitating symptoms. At present, however, there are no dedicated instruments for assessing the patient's experience of symptoms of conditions like chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) or mantle cell lymphoma (MCL), or for assessing their impact on patients' lives. This research project aimed to address that need. The researchers selected relevant and clinically meaningful symptoms from the EORTC Item Library that assess fatigue, B symptoms, and CLL/SLL- and MCL-specific symptoms. Using patients and clinician interviews as well as quantitative analyses, the research revealed no major concerns with using these item sets to assess symptoms of CLL/SLL and MCL. Interviews with patients demonstrated that the separate item sets for CLL/SLL and MCL-related symptoms were well understood and aligned with patients' experiences. All selected items were included in the conceptual models. Item sets identified in this study can potentially be used to assess patient-reported symptom endpoints in clinical trial settings in these disease areas.

Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

Pirtobrutinib in Covalent Bruton Tyrosine Kinase Inhibitor Pretreated Mantle-Cell Lymphoma.

PURPOSE: Pirtobrutinib is a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). We report the safety and efficacy of pirtobrutinib in patients with covalent Bruton tyrosine kinase inhibitor (cBTKi) pretreated mantle-cell lymphoma (MCL), a population with poor prognosis. METHODS: Patients with cBTKi pretreated relapsed/refractory (R/R) MCL received pirtobrutinib monotherapy in a multicenter phase I/II trial (BRUIN; ClinicalTrials.gov identifier: NCT03740529). Efficacy was assessed in the first 90 consecutively enrolled patients who met criteria for inclusion in the primary efficacy cohort. The primary end point was overall response rate (ORR). Secondary end points included duration of response (DOR) and safety. RESULTS: The median patient age was 70 years (range, 46-87), the median prior lines of therapy was 3 (range, 1-8), 82.2% had discontinued a prior cBTKi because of disease progression, and 77.8% had intermediate- or high-risk simplified MCL International Prognostic Index score. The ORR was 57.8% (95% CI, 46.9 to 68.1), including 20.0% complete responses (n = 18). At a median follow-up of 12 months, the median DOR was 21.6 months (95% CI, 7.5 to not reached). The 6- and 12-month estimated DOR rates were 73.6% and 57.1%, respectively. In the MCL safety cohort (n = 164), the most common treatment-emergent adverse events (TEAEs) were fatigue (29.9%), diarrhea (21.3%), and dyspnea (16.5%). Grade ≥3 TEAEs of hemorrhage (3.7%) and atrial fibrillation/flutter (1.2%) were less common. Only 3% of patients discontinued pirtobrutinib because of a treatment-related adverse event. CONCLUSION: Pirtobrutinib is a first-in-class novel noncovalent (reversible) BTKi and the first BTKi of any kind to demonstrate durable efficacy after prior cBTKi therapy in heavily pretreated R/R MCL. Pirtobrutinib was well tolerated with low rates of treatment discontinuation because of toxicity.

Exploratory Analysis of Patients With Gastric/Gastroesophageal Junction Adenocarcinoma With or Without Liver Metastasis From the Phase 3 RAINBOW Study.

PURPOSE: Liver metastasis (LM) is reported in approximately 40% of patients with advanced/metastatic gastric/gastroesophageal junction adenocarcinoma (metastatic esophagogastric adenocarcinoma; mGEA) and is associated with a worse prognosis. This post-hoc analysis from the RAINBOW trial reported the efficacy, safety, and biomarker outcomes of ramucirumab and paclitaxel combination treatment (RAM+PAC) in patients with (LM+) and without (LM-) LM at baseline. MATERIALS AND METHODS: Patients (n=665) were randomly assigned on a 1:1 basis to receive either RAM+PAC (LM+: 150, LM-: 180) or placebo and paclitaxel (PL+PAC) (LM+: 138, LM-: 197). The overall survival (OS) and progression-free survival (PFS) were evaluated using stratified Kaplan-Meier and Cox regression models. The correlation of dichotomized biomarkers (VEGF-C, D; VEGFR-1,2) with efficacy in the LM+ versus LM- subgroups was analyzed using the Cox regression model with reported interaction P-values. RESULTS: The presence of LM was associated with earlier progression than those without LM, particularly in patients receiving PL+PAC (hazard ratio [HR], 1.68). RAM+PAC treatment improved OS and PFS irrespective of LM status but showed greater improvement in LM+ than that in LM- (OS HR, 0.71 [LM+] vs. 0.88 [LM-]; PFS HR, 0.47 [LM+] vs. 0.76 [LM-]). Treatment-emergent adverse events were similar between patients with and without LM. No predictive relationship was observed between biomarker levels (VEGF-C, D; VEGFR-1,2) and efficacy outcome (OS, PFS) (all interaction P-values >0.05). CONCLUSIONS: RAM provided a significant benefit, irrespective of LM status; however, its effect was numerically stronger in patients with LM. Therefore, RAM+PAC is a clinically meaningful therapeutic option for patients with mGEA and LM. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01170663.

Optimizing the Dosing Regimen of Cetuximab and Ramucirumab Using the Model-Informed Drug Development Paradigm.

Model-informed drug development (MIDD) is a process that integrates drug exposure-based, biological, and statistical models to enhance the benefit-risk balance in drug development. The US Food and Drug Administration (FDA) MIDD Paired Meeting Pilot Program provides a platform to apply MIDD approaches to drug development and to seek regulatory feedback in a collaborative and streamlined process prior to submission for approval. Eli Lilly and Company (Lilly) participated in the Pilot Program to seek agency alignment to enhance the initial approved dosing regimens of cetuximab (Erbitux; Eli Lilly and Company, Indianapolis, IN) and ramucirumab (Cyramza; Eli Lilly and Company) without conducting additional clinical trials. Here, we describe the overall MIDD strategy at Lilly, the process with the FDA, and the impact of implementing the approach.

Clinical outcomes among patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who received treatment with a covalent BTK and BCL2 inhibitor in the United States: a real-world database study.

This retrospective study using the nationwide de-identified Flatiron Health electronic health record-derived database was designed to evaluate clinical outcomes among patients with chronic lymphocytic leukemia (CLL) who previously received both a covalent Bruton's tyrosine kinase inhibitor (cBTKi) and B-cell lymphoma 2 inhibitor (BCL2i) in a real-world setting. Outcomes for the immediate next line of therapy following the latter of the cBTKi or BCL2i treatment included: real-world response rate of 34.4% (using methods most consistent with clinical trials); median duration of real-world response of 13.3 months; and median real-world progression-free survival of 9.2 months. Median overall survival was 25.5 months from the start of the immediate next line of therapy. There remains a need for more effective therapies after cBTKi and BCL2i therapy for patients with CLL.

Preclinical characterization of pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor.

Bruton tyrosine kinase (BTK), a nonreceptor tyrosine kinase, is a major therapeutic target for B-cell-driven malignancies. However, approved covalent BTK inhibitors (cBTKis) are associated with treatment limitations because of off-target side effects, suboptimal oral pharmacology, and development of resistance mutations (eg, C481) that prevent inhibitor binding. Here, we describe the preclinical profile of pirtobrutinib, a potent, highly selective, noncovalent (reversible) BTK inhibitor. Pirtobrutinib binds BTK with an extensive network of interactions to BTK and water molecules in the adenosine triphosphate binding region and shows no direct interaction with C481. Consequently, pirtobrutinib inhibits both BTK and BTK C481 substitution mutants in enzymatic and cell-based assays with similar potencies. In differential scanning fluorimetry studies, BTK bound to pirtobrutinib exhibited a higher melting temperature than cBTKi-bound BTK. Pirtobrutinib, but not cBTKis, prevented Y551 phosphorylation in the activation loop. These data suggest that pirtobrutinib uniquely stabilizes BTK in a closed, inactive conformation. Pirtobrutinib inhibits BTK signaling and cell proliferation in multiple B-cell lymphoma cell lines, and significantly inhibits tumor growth in human lymphoma xenografts in vivo. Enzymatic profiling showed that pirtobrutinib was highly selective for BTK in >98% of the human kinome, and in follow-up cellular studies pirtobrutinib retained >100-fold selectivity over other tested kinases. Collectively, these findings suggest that pirtobrutinib represents a novel BTK inhibitor with improved selectivity and unique pharmacologic, biophysical, and structural attributes with the potential to treat B-cell-driven cancers with improved precision and tolerability. Pirtobrutinib is being tested in phase 3 clinical studies for a variety of B-cell malignancies.

Outcomes for Patients With Chronic Lymphocytic Leukemia (CLL) Previously Treated With Both a Covalent BTK and BCL2 Inhibitor in the United States: A Real-World Database Study.

PURPOSE: This study describes the treatment patterns and outcomes of patients with CLL/SLL in a de-identified real-world oncology electronic health records database. METHODS: Adult patients with CLL/SLL were eligible if they had received cBTKi therapy, both a cBTKi and a BCL2i, or all 4 drug classes (cBTKi, BCL2i, rituximab, and chemotherapy) at any time during the first 5 lines of therapy. Time-to-event outcomes were evaluated using Kaplan Meier method. No statistical comparisons were conducted; all analyses were descriptive and conducted using SAS Enterprise. RESULTS: A total of 9578 patients were eligible: 52.0% (n = 4983) received at least one cBTKi, 6.1% (n = 581) received both a cBTKi and BCL2i, and 2.3% (n = 218) received all four therapies (cBTKi, BCL2i, rituximab, and chemotherapy). Of those who discontinued these treatments, only 39.5% (n = 1 206/3 577), 59.7% (n = 228/382), and 55.0% (n = 82/149) received subsequent therapy (post-cBTKi, post-cBTKi/post-BCL2i, and post-all 4 therapies, respectively). Median time from treatment discontinuation of these therapies to the discontinuation of subsequent therapy or death was 9.5 months (all patients who discontinued the cBTKi) 5.6 months (those who discontinued both a cBTKi and BCL2i) and 3.9 months (patients who discontinued all four therapies). The median duration of the next treatment among those who received additional therapy was post-cBTKi treatment duration = 4.1 months; post-cBTKi/post-BCL2i treatment duration = 5.5 months; and median duration of the immediate next therapy after discontinuation of all 4 therapies = 5.1 months. CONCLUSIONS: The poor outcomes observed across cohorts in this study demonstrate the need for effective treatments that can improve outcomes in patients with CLL/SLL.

Prognostic and Predictive Factors in Patients with Advanced HCC and Elevated Alpha-Fetoprotein Treated with Ramucirumab in Two Randomized Phase III Trials.

PURPOSE: Ramucirumab is an effective treatment for patients with advanced hepatocellular carcinoma (aHCC) and baseline alpha-fetoprotein (AFP) ≥400 ng/mL. We aimed to identify prognostic and predictive factors of response to ramucirumab in patients with aHCC with AFP ≥400 ng/mL from the phase III REACH and REACH-2 randomized trials. PATIENTS AND METHODS: Patients with aHCC, Child-Pugh class A with prior sorafenib treatment were randomized in REACH and REACH-2 (ramucirumab 8 mg/kg or placebo, biweekly). Meta-analysis of individual patient-level data (pooled population) from REACH (AFP ≥400 ng/mL) and REACH-2 was performed. A drug exposure analysis was conducted for those with evaluable pharmacokinetic data. To identify potential prognostic factors for overall survival (OS), multivariate analyses were performed using a Cox proportional hazards regression model. To define predictors of ramucirumab benefit, subgroup-by-treatment interaction terms were evaluated. RESULTS: Of 542 patients (316 ramucirumab, 226 placebo) analyzed, eight variables had independent prognostic value associated with poor outcome (geographical region, Eastern Cooperative Oncology Group performance score ≥1, AFP >1,000 ng/mL, Child-Pugh >A5, extrahepatic spread, high neutrophil-to-lymphocyte ratio, high alkaline phosphatase and aspartate aminotransferase). Ramucirumab survival benefit was present across all subgroups, including patients with very aggressive HCC [above median AFP; HR: 0.64; 95% confidence interval (CI): 0.49-0.84] and nonviral aHCC (HR: 0.56; 95% CI: 0.40-0.79). While no baseline factor was predictive of a differential OS benefit with ramucirumab, analyses demonstrated an association between high drug exposure, treatment-emergent hypertension (grade ≥3), and increased ramucirumab benefit. CONCLUSIONS: Ramucirumab provided a survival benefit irrespective of baseline prognostic covariates, and this benefit was greatest in patients with high ramucirumab drug exposure and/or those with treatment-related hypertension.

Outcomes among Patients with Mantle Cell Lymphoma Post-Covalent BTK Inhibitor Therapy in the United States: A Real-World Electronic Medical Records Study.

Purpose: There remains a lack of consensus among experts regarding the optimal therapeutic approach for Mantle cell lymphoma (MCL) after failure of covalent Bruton Tyrosine Kinase inhibitor (cBTKi)-based therapy. This study was designed to examine patient characteristics, current treatment patterns, and clinical outcomes using a real-world database to evaluate how MCL is currently managed post-cBTKi therapy in the U.S. Methods: A large, deidentified U.S. electronic medical record (EMR) oncology database (ConcertAI) with data from January 2011 to July 2021 was utilized for this study. Eligible patients were adults with MCL who had received at least one cBTKi. Descriptive statistics were used to evaluate patient characteristics and treatment patterns. Time-to-event real-world outcomes of duration of therapy, time to next treatment discontinuation, and overall survival was evaluated using the Kaplan-Meier method. Results: A total of 946 patients met eligibility criteria. Of these, 739 (78.1%) discontinued cBTKi treatment before the end of the follow-up period, while the remaining 207 (21.9%) were still receiving cBTKi therapy at the end of the follow-up period. Among those who had discontinued the cBTKi, 352 (47.6%, 352/739) received at least one subsequent (post-cBTKi) treatment. The median duration of the immediate post-cBTKi therapy was 2.6 months (n = 352). Among the 739 patients who discontinued cBTKi treatment, the median time from cBTKi discontinuation to next treatment discontinuation or death was 3.9 months and the median overall survival was 10.3 months. Conclusions: This study demonstrates the poor outcomes experienced by patients after cBTKi therapy. There is an urgent need for safe and effective treatments for patients with recurrent or progressive MCL.

Ramucirumab for Patients with Intermediate-Stage Hepatocellular Carcinoma and Elevated Alpha-Fetoprotein: Pooled Results from Two Phase 3 Studies (REACH and REACH-2).

BACKGROUND: Intermediate-stage hepatocellular carcinoma (HCC), as defined by Barcelona Clinic Liver Cancer (BCLC) stage B, is heterogeneous in terms of liver function and tumor burden. REACH and REACH-2 investigated ramucirumab in patients with HCC after prior sorafenib, with REACH-2 enrolling only patients with baseline α-fetoprotein (AFP) ≥400 ng/mL. An exploratory analysis of outcomes by BCLC stage was performed. METHODS: A pooled meta-analysis of independent patient data (stratified by study) from REACH (AFP ≥ 400 ng/mL) and REACH-2 was performed. All patients had Child-Pugh A, Eastern Cooperative Oncology Group performance status 0-1, prior sorafenib treatment, and either HCC BCLC stage B (refractory/not amenable to locoregional therapy) or BCLC stage C. Patients were randomized to ramucirumab 8 mg/kg or placebo every 2 weeks. Median overall survival (OS) and progression-free survival were estimated by the Kaplan-Meier method. Treatment effects in BCLC stage B and C were evaluated by Cox proportional-hazards model; prognosis of BCLC staging for OS was evaluated by multivariate Cox proportional-hazards model. Tumor responses were evaluated according to Response Evaluation in Solid Tumors v1.1. Liver function was assessed with albumin-bilirubin score. RESULTS: Baseline characteristics were generally balanced between treatment arms in each BCLC stage. BCLC staging trended as an independent prognostic factor for OS (B vs. C; hazard ratio [HR] 0.756 [95% CI 0.546-1.046]). Consistent treatment benefit was observed for ramucirumab versus placebo across BCLC stages. Median OS for ramucirumab versus placebo was 13.7 versus 8.2 months; HR (95%): 0.43 (0.23-0.83) and 7.7 versus 4.8 months; HR (95%): 0.72 (0.59-0.89) for BCLC stage B and C, respectively. Adverse events (AEs) were consistent with observations from both studies; hypertension was the most frequent grade ≥3 AE. Liver function was preserved throughout the study and similar between treatment arms in both BCLC stages. CONCLUSIONS: Ramucirumab provided a better survival benefit irrespective of BCLC stage and was well tolerated without compromising liver function during treatment.

Clinical development and evaluation of a VEGF-D assay in plasma from patients with metastatic colorectal cancer in the RAISE study.

BACKGROUND: Vascular endothelial growth factor (VEGF)-D was identified as a potential predictive biomarker for ramucirumab efficacy in second-line metastatic colorectal cancer using a research use only (RUO) assay. We describe results with a new assay for detecting VEGF-D in human plasma. METHODS: In RAISE (Clinical Trial Registration: NCT01183780), 1072 patients were randomized 1:1 to ramucirumab or placebo plus FOLFIRI. All patients were then randomized 1:2 to marker exploratory (ME) and marker confirmatory (MC) groups, and those with plasma samples were analyzed accordingly. A new assay validated for investigational use only (IUO) was used to measure VEGF-D levels in plasma, which were analyzed for correlation with overall and progression-free survival (OS/PFS). IUO assay data were compared with historical RUO assay data. RESULTS: ME subset analyses determined the optimal cutpoint of 5.4 ng/mL for defining high/low VEGF-D subgroups. In the combined ME/MC placebo arms, OS/PFS were numerically greater for patients with low vs high VEGF-D (OS: 12.8 vs 11.1 months; PFS: 5.6 vs 4.2 months). In patients with high VEGF-D, ramucirumab vs placebo demonstrated a numerically greater improvement in OS and PFS. Differential efficacy by VEGF-D level was statistically significant for PFS, but not OS. CONCLUSION: In patients with high VEGF-D, ramucirumab demonstrated a greater improvement in OS and PFS vs placebo; however, baseline VEGF-D level was not predictive of ramucirumab OS benefit using VEGF-D assay for IUO. The RAISE intent-to-treat results remain valid.

Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: Impact of liver disease aetiology.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load. METHODS: Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study). RESULTS: Baseline characteristics were generally balanced between arms in each subgroup (HBV: N = 225, HCV: N = 127, Other: N = 190). No significant difference in treatment effect by aetiology subgroup was detected (OS interaction P-value = .23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74, 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82, 95% CI 0.55-1.23) for HCV and 8.5 versus 5.4 (HR 0.56, 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function and liver-specific adverse events. CONCLUSIONS: Ramucirumab improved survival across aetiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.

Early Weight Loss as a Prognostic Factor in Patients with Advanced Gastric Cancer: Analyses from REGARD, RAINBOW, and RAINFALL Phase III Studies.

BACKGROUND: Weight loss is common in advanced gastric and gastroesophageal junction adenocarcinoma (G/GEA); however, the prognostic implications of weight loss during the first cycle (C1) of chemotherapy remain poorly characterized. In this study, we investigated the impact of early weight loss during systemic treatment as a potential prognostic factor for overall survival (OS) in patients with advanced G/GEA. MATERIALS AND METHODS: We performed a post hoc analysis of three phase III studies of ramucirumab. Patients were categorized into two groups: weight loss of ≥3% and <3% based on weight change during C1 (3-4 weeks) of treatment. OS by weight groups was assessed for each study and as a pooled meta-analysis. The effect of C1 weight change on patient survival was evaluated using univariate and multivariate Cox models. RESULTS: A total of 1,464 patients with weight data at the end of C1 were analyzed: REGARD (n = 311), RAINBOW (n = 591), and RAINFALL (n = 562). For all three studies, there were fewer patients in the weight loss ≥3% than <3% group. OS was numerically shorter for patients with weight loss of ≥3% than for patients with weight loss of <3% during C1 irrespective of treatment arm. Similar treatment independent effects of early weight loss on OS were observed in the meta-analysis. Overall, early weight loss ≥3% was associated with shorter survival in patients receiving active drug as well as placebo/best supportive care. CONCLUSION: This large post hoc analysis demonstrated that weight loss of ≥3% during C1 was a negative prognostic factor for OS in patients with advanced G/GEA. IMPLICATIONS FOR PRACTICE: This comprehensive analysis examining early weight loss during systemic treatment as a predictor of survival outcomes in patients with advanced gastric and gastroesophageal junction adenocarcinoma (G/GEA) includes a large sample size, reliable on-treatment data reported in well-conducted phase III clinical trials, and global representation of cancer patients with advanced G/GEA. Understanding the impact of on-treatment weight loss is clinically relevant and may represent an opportunity for targeted interventions.

Ramucirumab in patients with advanced hepatocellular carcinoma and elevated α-fetoprotein: Outcomes by treatment-emergent ascites.

AIM: The REACH and REACH-2 trials investigated ramucirumab versus placebo in patients with advanced hepatocellular carcinoma (HCC). Ascites is common in HCC and is associated with poorer outcomes. This exploratory, pooled meta-analysis of patients with baseline α-fetoprotein (AFP) ≥400 ng/ml investigated outcomes by treatment-emergent (TE) ascites in REACH and REACH-2. METHODS: A pooled meta-analysis of independent patient data for participants (N = 542) with baseline AFP ≥400 ng/ml (stratified by study) from REACH and REACH-2 was carried out. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier estimator, and OS further assessed by Cox models. The effect of TE ascites on OS was evaluated by multivariate Cox models. RESULTS: Treatment-emergent ascites developed in 66 patients (20.9%) in the ramucirumab group and 33 patients (14.8%) in the placebo group. When adjusted for treatment duration, the incidence rates per 100 patient-years of any grade TE ascites were 59.1 and 71.9 for the ramucirumab and placebo groups, respectively, and the incidence of grade ≥3 TE ascites were 13.4 and 19.6, respectively. Treatment-emergent ascites was associated with TE hypoalbuminemia (odds ratio 4.9; 95% confidence interval 2.5-9.3), but not TE proteinuria or hypertension. One patient discontinued ramucirumab treatment due to TE ascites. Ramucirumab treatment improved OS and PFS compared with placebo, irrespective of TE ascites. CONCLUSIONS: When adjusted for treatment duration, the incidence of TE ascites was no higher in patients who received ramucirumab than in those who received placebo. Ramucirumab was well tolerated and provided a survival benefit irrespective of the development of TE ascites.

Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab.

BACKGROUND: Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2). METHODS: Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed. RESULTS: Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6-12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354-0.574; p < 0.0001). CONCLUSIONS: AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, REACH (NCT01140347) and REACH-2 (NCT02435433).

Evaluating clinical impact of a shortened infusion duration for ramucirumab: a model-based approach.

PURPOSE: We investigated the impact of infusion duration (30 and 60 min) on the pharmacokinetic profile of ramucirumab using a population pharmacokinetic (PopPK) modeling approach. We also assessed the relationship between infusion rate and incidence of immediate infusion-related reactions (IRRs; occurring on the day of administration) using ramucirumab phase II/III study data. METHODS: The impact of different infusion durations (30 vs. 60 min) on the time-course of ramucirumab concentration profiles were evaluated using a PopPK model, established using ramucirumab pharmacokinetic data from 2522 patients. Logistic regression was used to evaluate the association between ramucirumab infusion rate and incidence of immediate IRRs in clinical trials. RESULTS: Ramucirumab time-course concentration profiles were equivalent following a 30- or 60-min infusion. In the pooled clinical study dataset, 254 of 3216 (7.9%) patients receiving ramucirumab experienced at least one immediate IRR (any grade). When grouped according to infusion rate quartile, the incidence of immediate IRRs (any grade or grade ≥ 3) was similar across quartiles; findings were confirmed in sensitivity analyses. The risk of immediate IRRs was not found to be associated with infusion rate based on multivariate logistic analysis. CONCLUSION: Shortening the infusion duration of ramucirumab from 60 to 30 min has no impact on ramucirumab exposure. Analysis of trial data found no relationship between an increased risk of immediate IRRs and a faster infusion rate. Such a change in infusion duration is unlikely to affect the clinical efficacy or overall safety profile of ramucirumab.

Effect of ramucirumab on ALBI grade in patients with advanced HCC: Results from REACH and REACH-2.

BACKGROUND & AIMS: The albumin-bilirubin (ALBI) grade/score is derived from a validated nomogram to objectively assess prognosis and liver function in patients with hepatocellular carcinoma (HCC). In this post hoc analysis, we assessed prognosis in terms of survival by baseline ALBI grade and monitored liver function during treatment with ramucirumab or placebo using the ALBI score in patients with advanced HCC. METHODS: Patients with advanced HCC, Child-Pugh class A with prior sorafenib treatment were randomised in REACH trials to receive ramucirumab 8 mg/kg or placebo every 2 weeks. Data were analysed by trial and as a meta-analysis of individual patient-level data (pooled population) from REACH (alpha-fetoprotein ≥400 ng/ml) and REACH-2. Patients from REACH with Child-Pugh class B were analysed as a separate cohort. The ALBI grades and scores were calculated at baseline and before each treatment cycle. RESULTS: Baseline characteristics by ALBI grade were balanced between treatment arms among patients in the pooled population (ALBI-1, n = 231; ALBI-2, n = 296; ALBI-3, n = 7). Baseline ALBI grade was prognostic for overall survival (OS; ALBI grade 2 vs. 1; hazard ratio [HR]: 1.38 [1.13-1.69]), after adjusting for other significant prognostic factors. Mean ALBI scores remained stable in both treatment arms compared with baseline and were unaffected by baseline ALBI grade, macrovascular invasion, tumour response, geographical region, or prior locoregional therapy. Baseline ALBI grades 2 and 3 were associated with increased incidence of liver-specific adverse events and discontinuation rates in both treatments. Ramucirumab improved OS in patients with baseline ALBI grade 1 (HR 0.605 [0.445-0.824]) and ALBI grade 2 (HR 0.814 [0.630-1.051]). CONCLUSIONS: Compared with placebo, ramucirumab did not negatively impact liver function and improved survival irrespective of baseline ALBI grade. LAY SUMMARY: Hepatocellular carcinoma is the third leading cause of cancer-related death worldwide. Prognosis is affected by many clinical factors including liver function both before and during anticancer treatment. Here we have used a validated approach to assess liver function using 2 laboratory parameters, serum albumin and bilirubin (ALBI), both before and during treatment with ramucirumab in 2 phase III placebo-controlled studies. We confirm the practicality of using this more simplistic approach in assessing liver function prior to and during anticancer therapy, and demonstrate ramucirumab did not impair liver function when compared with placebo.

Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab.

BACKGROUND & AIMS: Radiological progression patterns to first-line sorafenib have been associated with post-progression and overall survival in advanced hepatocellular carcinoma, but these associations remain unknown for therapies in second- and later-line settings. This post hoc analysis of REACH and REACH-2 examined outcomes by radiological progression patterns in the second-line setting of patients with advanced hepatocellular carcinoma treated with ramucirumab or placebo. METHODS: Patients with advanced hepatocellular carcinoma, Child-Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive ramucirumab 8mg/kg or placebo every 2 weeks. Among 625 patients with ≥1 progression pattern (new extrahepatic lesion [including new macrovascular invasion], new intrahepatic lesion, extrahepatic growth or intrahepatic growth), data were analysed by trial and for pooled individual patient data for REACH-2 and REACH (alpha-fetoprotein ≥400 ng/mL). Cox models evaluated prognostic implications of progression patterns on overall and post-progression survival. RESULTS: Post-progression survival was worse among those with new extrahepatic lesions in REACH (HR 2.33, 95% CI 1.51-3.60), REACH-2 (HR 1.49, 95% CI 0.72-3.08) and the pooled population (HR 1.75, 95% CI 1.12-2.74) compared to other progression patterns. Overall survival was also significantly reduced in those with new extrahepatic lesions across studies. Ramucirumab provided an overall survival benefit across progression patterns, including patients with new extrahepatic lesions (HR 0.56, 95% CI 0.39-0.80) in the pooled population. CONCLUSIONS: The emergence of new extrahepatic lesions in the second-line setting is a poor prognostic factor for post-progression survival. The benefit of ramucirumab for overall survival was consistent across progression patterns.