In the phase III HIMALAYA study (NCT03298451) in unresectable hepatocellular carcinoma (uHCC), STRIDE (Single Tremelimumab Regular Interval Durvalumab) significantly improved overall survival (OS) ...versus sorafenib; durvalumab monotherapy was noninferior to sorafenib for OS. Results reported herein are from a 4-year updated OS analysis of HIMALAYA.
Participants with uHCC and no previous systemic treatment were randomized to STRIDE (n = 393), durvalumab (n = 389), or sorafenib (n = 389). The updated data cut-off was 23 January 2023. OS and serious adverse events (AEs) were assessed. Additionally, baseline characteristics and subsequent therapies were analyzed in long-term survivors (≥36 months beyond randomization).
For STRIDE, durvalumab, and sorafenib, median 95% confidence interval (CI) follow-up was 49.12 months (46.95-50.17 months), 48.46 months (46.82-49.81 months), and 47.31 months (45.08-49.15 months), respectively. OS hazard ratio (95% CI) for STRIDE versus sorafenib was 0.78 (0.67-0.92). The 36-month OS rate for STRIDE was 30.7% versus 19.8% for sorafenib. The 48-month OS rate remained higher for STRIDE at 25.2%, versus 15.1% for sorafenib. The long-term OS benefit of STRIDE was observed across clinically relevant subgroups and was further improved in participants who achieved disease control. Long-term survivors with STRIDE (n = 103) included participants across clinically relevant subgroups, and 57.3% (59/103) had no reported subsequent anticancer therapy. No new serious treatment-related AEs occurred with STRIDE from the primary analysis (17.5%; 68/388). Durvalumab maintained OS noninferiority to sorafenib and no late-onset safety signals were identified.
These data represent the longest follow-up to date in phase III studies in uHCC. The unprecedented 3- and 4-year OS rates reinforce the sustained long-term OS benefit of STRIDE versus sorafenib. STRIDE maintained a tolerable yet differentiated safety profile from other current uHCC therapies. Results continue to support the long-term benefits of STRIDE in a diverse population, reflective of uHCC globally.
•This updated analysis of the phase III HIMALAYA study in uHCC showed sustained OS benefit with STRIDE vs sorafenib.•Four-year OS rates were 25.2% with STRIDE vs 15.1% with sorafenib.•STRIDE improved OS vs sorafenib across subgroups and further improved 3- and 4-year OS rates in those with disease control.•Subsequent anticancer systemic therapy was more common in the sorafenib vs STRIDE arm.•No new serious treatment-related AEs occurred after the primary analysis for STRIDE.
BACKGROUNDIn KEYNOTE-119 (ClinicalTrials.gov, NCT02555657), overall survival (primary end-point) was similar between pembrolizumab and chemotherapy in patients with previously treated metastatic ...triple-negative breast cancer (TNBC), although the pembrolizumab treatment effect increased with tumour PD-L1 expression. We report results of prespecified health-related quality of life (HRQoL) analyses from KEYNOTE-119.METHODSEligible patients were randomised 1:1 to pembrolizumab 200 mg Q3W intravenously for up to 35 cycles or treatment of physician's choice per local/country guidelines. Prespecified exploratory end-points were the change from baseline in HRQoL (EORTC QLQ-C30, QLQ-BR23) and to characterise utilities (EQ-5D-3L). Time to deterioration (TTD) was the time from start of treatment to first onset of a ≥10-point worsening from baseline.RESULTSHRQoL analyses included 187 patients with tumour PD-L1 combined positive score (CPS) ≥10. Changes from baseline at 6 weeks (primary analysis time point) were directionally better with pembrolizumab versus chemotherapy for QLQ-C30 GHS/QoL (between-group difference in least-squares mean scores of 4.21 95% CI, -1.38 to 9.80), QLQ-C30 functional scales (physical, role, cognitive, social), QLQ-C30 symptom scales/items (fatigue, nausea/vomiting, dyspnoea, appetite loss), and QLQ-BR23 symptom scales/items (systemic therapy side-effects, upset by hair loss). Median TTD was directionally longer for pembrolizumab versus chemotherapy for QLQ-C30 QHS/QoL (4.3 versus 1.7 months), QLQ-C30 nausea/vomiting (7.7 versus 4.8 months), and QLQ-BR23 systemic therapy side-effects (6.1 versus 3.4 months). Minimal treatment differences were observed for other HRQoL end-points.CONCLUSIONSHRQoL results were consistent with clinical outcomes and appeared to be driven by results for patients with tumour PD-L1 CPS ≥10.
In KEYNOTE-355 (NCT02819518), the addition of pembrolizumab to chemotherapy led to statistically significant improvements in progression-free survival and overall survival in patients with advanced ...triple-negative breast cancer with tumor programmed cell death ligand 1 (PD-L1) combined positive score of at least 10. We report patient-reported outcomes from KEYNOTE-355.
Patients were randomly assigned 2:1 to pembrolizumab 200 mg or placebo every 3 weeks for up to 35 cycles plus investigator's choice chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin). The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30), Breast Cancer-Specific Quality of Life Questionnaire, and EuroQol 5-Dimension questionnaire visual analog scale were prespecified. Patient-reported outcomes were analyzed for patients who received at least 1 dose of study treatment and completed at least 1 patient-reported outcome assessment. Changes in patient-reported outcome scores from baseline were assessed at week 15 (latest time point at which completion and compliance rates were at least 60% and at least 80%, respectively). Time to deterioration in patient-reported outcomes was defined as time to first onset of at least a 10-point worsening in score from baseline.
Patient-reported outcome analyses included 317 patients with tumor PD-L1 combined positive score of at least 10 (pembrolizumab plus chemotherapy: n = 217; placebo plus chemotherapy: n = 100). There were no between-group differences in change from baseline to week 15 in QLQ-C30 global health status/quality of life (QOL; least-squares mean difference = -1.81, 95% confidence interval CI = -6.92 to 3.30), emotional functioning (least-squares mean difference = -1.43, 95% CI = -7.03 to 4.16), physical functioning (least-squares mean difference = -1.05, 95% CI = -6.59 to 4.50), or EuroQol 5-Dimension questionnaire visual analog scale (least-squares mean difference = 0.18, 95% CI = -5.04 to 5.39) and no between-group difference in time to deterioration in QLQ-C30 global health status/QOL, emotional functioning, or physical functioning.
Together with the efficacy and safety findings, patient-reported outcome results from KEYNOTE-355 support pembrolizumab plus chemotherapy as a standard of care for patients with advanced triple-negative breast cancer with tumor PD-L1 expression (combined positive score ≥10).
Background
PF-05280014 was compared with trastuzumab sourced from the European Union (trastuzumab-EU), each plus paclitaxel, as first-line treatment for human epidermal growth factor receptor ...2-positive metastatic breast cancer in a phase III study. Equivalence between treatment groups was demonstrated.
Objective
The aim of this study was to report long-term safety and overall survival (OS) over 6 years after the first patient was screened.
Patients and methods
Randomized patients received intravenous PF-05280014 or trastuzumab-EU, each plus paclitaxel, until objective disease progression. OS, long-term safety, subgroup safety (patients ongoing after day 378), and time-to-treatment discontinuation (TTD) were assessed based on the final statistical analysis plan amended for the ad-hoc analyses.
Results
Of 707 randomized patients (
n
= 352, PF-05280014;
n
= 355, trastuzumab-EU), 252 (71.6%) in the PF-05280014 and 251 (70.7%) in the trastuzumab-EU group discontinued treatment due to objective progression. Overall, 451 (63.8%) patients completed the study. Between groups (PF-05280014; trastuzumab-EU), estimated median TTDs were 12.25 and 12.06 months (
p
= 0.692); 61 (17.3%) and 67 (18.9%) patients died; stratified hazard ratio for OS was 0.929 (95% confidence interval 0.656–1.316;
p
= 0.339); estimated survival rates were 82.3 and 77.4% at 2 years and 77.2 and 75.3% at 3 years. The incidences of treatment-emergent adverse events (TEAEs) overall (98.6%; 96.6%) and for grades ≥3 (41.0%; 43.1%) were comparable between groups. In patients (
n
= 265;
n
= 264) ongoing after day 378, the incidences of any TEAEs, grade ≥3 TEAEs, and serious TEAEs were comparable between the treatment groups.
Conclusion
Long-term safety and OS were consistent with previous results and demonstrated no clinically meaningful differences between treatment groups.
Trial registration
ClinicalTrials.gov: NCT01989676 (21 November 2013); and EudraCT: 2013-001352-34 (18 December 2013).
This randomized, double-blind trial compared proposed biosimilar LA-EP2006 with reference pegfilgrastim in women receiving chemotherapy for breast cancer (PROTECT-1).
Women (≥18 years) were ...randomized to receive LA-EP2006 (n = 159) or reference (n = 157) pegfilgrastim (Neulasta(®), Amgen) for ≤6 cycles of (neo)-adjuvant TAC chemotherapy. Primary end point was duration of severe neutropenia (DSN) during cycle 1 (number of consecutive days with absolute neutrophil count <0.5 × 10(9)/l) with equivalence confirmed if 90% and 95% CIs were within a ±1 day margin.
For DSN, LA-EP2006 was equivalent to reference (difference: 0.07 days; 90% CI: -0.09-0.23; 95% CI: -0.12-0.26).
LA-EP2006 and reference pegfilgrastim showed no clinically meaningful differences regarding efficacy and safety in breast cancer patients receiving chemotherapy.
Methods: RTXM83 is a proposed biosimilar developed by mAbxience S.A. to the reference medicine product rituximab (MabThera®/ Rituxan®). A prospective, multicenter, double-blind, randomized trial ...compared the efficacy in terms of non-inferiority, pharmacokinetics (PK), pharmacodynamics (PD), safety and immunogenicity of RTXM83 vs rituximab (Mabthera®/Rituxan®), both in combination with CHOP chemotherapy (RTXM83-CHOP vs R-CHOP), as first-line treatment in patients with previously untreated CD20+ Diffuse Large B Cell Lymphoma (DLBCL). Adults aged ≥18 and ≤65 years, with a disease stage of I (only with bulky disease) to IV according to the Cotswolds modification of the Ann Arbor classification, and ECOG performance status ≤2 were included, and randomized (1:1) to receive up to a total of six cycles of either RTXM83-CHOP or R-CHOP. Patients were stratified according to study center and age-adjusted IPI scores (0 versus 1), which are based on: disease stage, ECOG, and lactate dehydrogenase (LDH) levels.
The primary endpoint was to assess the response rate (RR) (complete response + partial response) achieved after cycle 6 of treatment by the International Working Group (IWG) criteria. PK, PD, safety and immunogenicity were assessed as secondary study endpoints. For PK, the systemic exposure (AUC and Cmax) were assessed at Cycle 1 and steady-state at Cycle 6 using a population PK (Pop PK) model approach. The serum levels of CD20+/CD19+ cells for PD profile, and of anti-drug antibodies (ADA) for immunogenicity assessment were analysed at different time points: start of treatment (Cycle 1 Day 1, pre-dose), at Cycle 5 Day 1 (pre-dose), at Cycle 6 Day 21 and during the follow-up period: FU 1 (3 months after last dose of treatment) and follow-up 3 if available (9 months after last dose of treatment).
Results: A total of 241 patients, 123 in the RTXM83-CHOP arm and 118 R-CHOP arm, from 58 sites in 12 countries were eligible. Demographic and baseline characteristics were well balanced between arms. A difference of 3.9% in the RR in favour of the RTXM83-CHOP arm was achieved in the per protocol population (RR: 84.7% vs 80.8% in RTXM83-CHOP and the R-CHOP arm, respectively). The lower bound of the 95% CI of this difference (-6.20% to 14.03%) was above the non-inferiority margin of -13% that was set for the study.
The Pop PK comprised a total of 5341 samples from 251 patients. Geometric least square means ratios (GLSMR) with the 90% CI of RXTM83/rituximab were 99.2% (93.6-105) for AUC and 99.6% (93.9-105) for Cmax,sd at Cycle 1 whereas, at steady-state the GLSMR were 103% (98.5-107) for AUC and 104% (99.5-109) for Cmax,ss. RXTM83 and rituximab exhibited a comparable serum concentration-time profile and the GLSMR were within the predefined margins of 80-125%. PD profile in terms of time of onset, magnitude and duration of response was similar between RTXM83 and rituximab.
Safety assessment shows no obvious differential safety profile of RXTM83 and rituximab in terms of nature, frequency and severity of the adverse events (AE); being infections and blood and lymphatic system disorders the most common SAEs reported.
A low and similar ADA incidence was observed in both treatment arms, with no relationship with efficacy, safety or PK/PD data was observed.
Conclusion: These results demonstrate that RTXM83 has comparable efficacy to rituximab in terms of tumour response, and displays a similar PK profile, PD activity, safety profile and immunogenicity in the first line treatment of patients with newly diagnosed DLBCL, which supports the claim that RTXM83 is highly similar to the reference medicine rituximab (MabThera® / Rituxan®).
Gonzalez:Lab Eticos: Other: Principal Investigator. Radhakrishnan:Cancer Institute Adyar Chennai India: Employment. Schusterschitz:Libbs: Research Funding. Perez:Mabxience SA: Employment.
Background: Rituximab (R) is a chimeric IgG1 mAb antibody directed against the CD20 antigen, expressed on greater than 90% of all B-cell lymphomas. Despite the encouraging results, responses to R ...monotherapy are usually partial and of limited duration. Therefore, new strategies to increase the clinical effectiveness of R are being explored. Antibody-dependent cellular cytotoxicity (ADCC) is an important mechanism of Rituximab's activity. Studies (Dunne et al. J Immunol 2001; 167:3129–3138) have provided evidence that rIL-2 can augment ADCC and thereby enhance the efficacy of antitumor antibodies such as R.
Methods: A multicenter Phase II trial was conducted to evaluate the efficacy of rIL-2+R compared to R alone. Subjects were R naïve with follicular lymphoma who were relapsed or unresponsive to previous chemotherapy. Subjects were randomized 1:1 to either IV R (375 mg/m2) monotherapy (n=29) once weekly (weeks 1–4) or the same dose and schedule of R in combination with SC rIL-2 (n=27) three times weekly at 14 MIU (weeks 2–5) followed by 10 MIU (weeks 6–9). The primary and secondary objectives were to compare overall response rate (ORR) and time to progression (TTP) for subjects receiving rIL-2+R with those receiving R monotherapy. A further objective was to evaluate the safety of an 8-week SC administration of rIL-2 with 4 week IV administration of R. From October 2004 until May 2005, 69 participating centres enrolled 56 patients.
Results: Twenty-seven subjects in the combination arm received a mean cumulative dosage of 82.8 MIU (range: 0–96) of rIL-2. The most common adverse events (AEs) observed in this arm were fever, chills and injection site reactions. Safety was comparable in the combination and monotherapy arms for grade 1 (33 vs. 38%) and grade 3 (11 vs. 13%) AEs. Treatment related grade 2 AEs were more common in the combination arm (44% vs 0%) with most related to skin and subcutaneous tissue reactions. No grade 4 AEs were reported. Five patients were withdrawn from the study, three in the combination arm and two in R alone group for disease progression (2 subjects in the combination arm and 1 in the R monotherapy), adverse event (1 in the combination arm related to a R reaction) and withdrawal of consent (1).
Conclusions: This preliminary data confirm that the addition of rIL-2 to R therapy appears to be safe and well tolerated. The majority of the subjects were able to receive the total dose of rIL-2. The observed adverse events were manageable and related to skin reactions and flu-like symptoms, as expected with rIL-2. The main reason for study treatment discontinuation was disease progression. Trial assessment is ongoing.
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