Abstract
Background
The MORPHEUS platform comprises multiple open-label, randomized, phase Ib/II trials designed to identify early efficacy and safety signals of treatment combinations across ...cancers. Atezolizumab (anti-programmed cell death 1 ligand 1 PD-L1) was evaluated in combination with PEGylated recombinant human hyaluronidase (PEGPH20).
Methods
In 2 randomized MORPHEUS trials, eligible patients with advanced, previously treated pancreatic ductal adenocarcinoma (PDAC) or gastric cancer (GC) received atezolizumab plus PEGPH20, or control treatment (mFOLFOX6 or gemcitabine plus nab-paclitaxel MORPHEUS-PDAC; ramucirumab plus paclitaxel MORPHEUS-GC). Primary endpoints were objective response rates (ORR) per RECIST 1.1 and safety.
Results
In MORPHEUS-PDAC, ORRs with atezolizumab plus PEGPH20 (n = 66) were 6.1% (95% CI, 1.68%-14.80%) vs. 2.4% (95% CI, 0.06%-12.57%) with chemotherapy (n = 42). In the respective arms, 65.2% and 61.9% had grade 3/4 adverse events (AEs); 4.5% and 2.4% had grade 5 AEs. In MORPHEUS-GC, confirmed ORRs with atezolizumab plus PEGPH20 (n = 13) were 0% (95% CI, 0%-24.7%) vs. 16.7% (95% CI, 2.1%-48.4%) with control (n = 12). Grade 3/4 AEs occurred in 30.8% and 75.0% of patients, respectively; no grade 5 AEs occurred.
Conclusion
Atezolizumab plus PEGPH20 showed limited clinical activity in patients with PDAC and none in patients with GC. The safety of atezolizumab plus PEGPH20 was consistent with each agent’s known safety profile. (ClinicalTrials.gov Identifier: NCT03193190 and NCT03281369).
In this clinical trial, atezolizumab was evaluated in combination with PEGPH20 to assess clinical activity in patients with pancreatic ductal adenocarcinoma or gastric cancer.
Purpose
Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association ...between CK2 activation and paclitaxel resistance in a gastric cancer (GC).
Experimental design
CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model.
Results
Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%,
p
= 0.017) and shorter progression-free survival (2.8 vs. 4.8 months,
p
= 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities.
Conclusions
These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.
Abstract Background The benefit of cytoreductive nephrectomy (CN) for overall survival (OS) is unclear in patients with synchronous metastatic renal cell carcinoma (mRCC) in the era of targeted ...therapy. Objective To determine OS benefit of CN compared with no CN in mRCC patients treated with targeted therapies. Design, setting, and participants Retrospective data from patients with synchronous mRCC ( n = 1658) from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) were used to compare 982 mRCC patients who had a CN with 676 mRCC patients who did not. Outcome measurements and statistical analysis OS was compared and hazard ratios (HRs) adjusted for IMDC poor prognostic criteria. Results and limitations Patients who had CN had better IMDC prognostic profiles versus those without (favorable, intermediate, or poor in 9%, 63%, and 28% vs 1%, 45%, and 54%, respectively). The median OS of patients with CN versus without CN was 20.6 versus 9.5 mo ( p < 0.0001). When adjusted for IMDC criteria to correct for imbalances, the HR of death was 0.60 (95% confidence interval, 0.52–0.69; p < 0.0001). Patients estimated to survive <12 mo may receive marginal benefit from CN. Patients who have four or more of the IMDC prognostic criteria did not benefit from CN. Data were collected retrospectively. Conclusions CN is beneficial in synchronous mRCC patients treated with targeted therapy, even after adjusting for prognostic factors. Patients with estimated survival times <12 mo or four or more IMDC prognostic factors may not benefit from CN. This information may aid in patient selection as we await results from randomized controlled trials. Patient summary We looked at the survival outcomes of metastatic renal cell carcinoma patients who did or did not have the primary tumor removed. We found that most patients benefited from tumor removal, except for those with four or more IMDC risk factors.
In the primary analysis of the CLEAR study, lenvatinib plus pembrolizumab significantly improved progression-free survival and overall survival versus sunitinib in patients with advanced renal cell ...carcinoma (data cutoff Aug 28, 2020). We aimed to assess overall survival based on 7 months of additional follow-up.
This is a protocol-prespecified updated overall survival analysis (data cutoff March 31, 2021) of the open-label, phase 3, randomised CLEAR trial. Patients with clear-cell advanced renal cell carcinoma who had not received any systemic anticancer therapy for renal cell carcinoma, including anti-vascular endothelial growth factor therapy, or any systemic investigational anticancer drug, were eligible for inclusion from 200 sites (hospitals and cancer centres) across 20 countries. Patients were randomly assigned (1:1:1) to receive lenvatinib (20 mg per day orally in 21-day cycles) plus pembrolizumab (200 mg intravenously every 21 days; lenvatinib plus pembrolizumab group), lenvatinib (18 mg per day orally) plus everolimus (5 mg per day orally; lenvatinib plus everolimus group not reported in this updated analysis) in 21-day cycles, or sunitinib (50 mg per day orally, 4 weeks on and 2 weeks off; sunitinib group). Eligible patients were at least 18 years old with a Karnofsky performance status of 70 or higher. A computer-generated randomisation scheme was used, and stratification factors were geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint was progression-free survival assessed by independent imaging review according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). In this Article, extended follow-up analyses for progression-free survival and protocol-specified updated overall survival data are reported for the intention-to-treat population. No safety analyses were done at this follow-up. This study is closed to new participants and is registered with ClinicalTrials.gov, NCT02811861.
Between Oct 13, 2016, and July 24, 2019, 1417 patients were screened for inclusion in the CLEAR trial, of whom 1069 (75%; 273 26% female, 796 74% male; median age 62 years IQR 55–69) were randomly assigned: 355 (33%) patients (255 72% male and 100 28% female) to the lenvatinib plus pembrolizumab group, 357 (33%) patients (275 77% male and 82 23% female) to the sunitinib group, and 357 (33%) patients to the lenvatinib plus everolimus group (not reported in this updated analysis). Median follow-up for progression-free survival was 27·8 months (IQR 20·3–33·8) in the lenvatinib plus pembrolizumab group and 19·4 months (5·5–32·5) in the sunitinib group. Median progression-free survival was 23·3 months (95% CI 20·8–27·7) in the lenvatinib plus pembrolizumab group and 9·2 months (6·0–11·0) in the sunitinib group (stratified hazard ratio HR 0·42 95% CI 0·34–0·52). Median overall survival follow-up was 33·7 months (IQR 27·4–36·9) in the lenvatinib plus pembrolizumab group and 33·4 months (26·7–36·8) in the sunitinib group. Overall survival was improved with lenvatinib plus pembrolizumab (median not reached 95% CI 41·5–not estimable) versus sunitinib (median not reached 38·4–not estimable; HR 0·72 95% CI 0·55–0·93).
Efficacy benefits of lenvatinib plus pembrolizumab over sunitinib were durable and clinically meaningful with extended follow-up. These results support the use of lenvatinib plus pembrolizumab as a first-line therapy for patients with advanced renal cell carcinoma.
Eisai and Merck Sharp & Dohme.
Background
A subgroup analysis of data from a nationwide study (KCSG-ST19-16) was performed to evaluate the efficacy and safety of second-line ramucirumab plus paclitaxel treatment in patients with ...human epidermal growth factor receptor 2 (HER2)-positive advanced gastric or gastro-esophageal junction (GEJ) adenocarcinoma.
Methods
The KCSG-ST19-16 study enrolled a total of 1063 patients from 56 hospitals in South Korea with advanced gastric or GEJ adenocarcinoma, who had received second-line treatment with ramucirumab plus paclitaxel. HER2 status was known for 994 (93.5%) of these patients, who were thus included in the subgroup analysis.
Results
In total, 163 of 994 patients (16.4%), had HER2-positive gastric or GEJ adenocarcinoma. The objective response rate to ramucirumab plus paclitaxel treatment was significantly higher in patients with HER2-positive disease compared to those with HER2-negative disease (23.0% 95% confidence interval (CI), 15.9–30.1 vs. 15.1% 95% CI, 12.3–17.9,
p
= 0.025). The median progression-free survival was longer in patients with HER2-positive versus HER2-negative disease, but the difference was not statistically significant (4.3 months 95% CI, 3.7–5.3 vs 3.7 months 95% CI, 3.4–4.0,
p
= 0.054). There was no statistically significant difference in median overall survival (OS) between the groups (9.8 months 95% CI, 8.9–12.3 vs 10.1 months 95% CI, 9.2–10.9,
p
= 0.564).
Conclusions
In patients with HER2-positive gastric or GEJ adenocarcinoma, the objective response rate to second-line treatment with ramucirumab plus paclitaxel was significantly higher compared to patients with HER2-negative disease. However, an increased response to treatment was not associated with an improvement in OS.
Purpose
To develop a Cancer Symptom Management System: Symptom Management Improves your LifE (SMILE) and evaluate the effect and feasibility of the system in cancer symptom management.
Methods
The ...Cancer Symptom Management System: SMILE was developed, and a nonblinded, randomized controlled trial was conducted. Cancer patients starting adjuvant or palliative chemotherapy (CTx) were enrolled and randomized to control (symptom monitoring), experimental 1 (Exp 1; symptom monitoring + report), or experimental 2 (Exp 2; symptom monitoring + report + Oncology Nursing Society putting evidence into practice (ONS PEP)–guided evidence-based symptom management education) groups in a 1:2:2 ratio (
N
= 249). To evaluate whether symptom management education provided additional benefit to continuous symptom monitoring, the Exp 1 and Exp 2 groups were compared utilizing Mann-Whitney
U
test and generalized estimating equations (
n
= 199).
Results
Symptom severity (symptom total score) at each measurement point was not different among the three groups (
p
> .05). Fatigue and sleep disturbance changes were different between Exp 1 and Exp 2 among patients receiving adjuvant CTx (
p
= .042 and
p
= .008). Fatigue gradually decreased after a peak at the 1st CTx cycle in Exp 2, whereas Exp 1 experienced increasing fatigue until the 3rd CTx cycle. A gradual decrease in sleep disturbance was observed in Exp 2 after the 2nd CTx cycle, whereas Exp 1 experienced a steady increase in the symptom. Participants were willing to participate in symptom monitoring using the cancer symptom management system. Symptom management education was easy to follow and helpful.
Conclusion
The application of the Cancer Symptom Management System: SMILE incorporating ONS PEP–guided evidence-based symptom management education effectively managed fatigue and sleep disturbance after adjuvant CTx. The feasibility of the system has been demonstrated. Incorporating the system into electronic medical systems and integrating provider input will be necessary.
Abstract Purpose Family caregivers of cancer patients become responsible for many elements of cancer care, usually without preparation or training in provision of care. Their efforts of care generate ...caregiving burden, which could deteriorate caregivers' quality of life (QOL). Method A secondary data analysis of a cross-sectional descriptive study was conducted to describe the influence of caregiving burden on the QOL of family caregivers of cancer patients with consideration of correlates (N = 212). The Korean versions of Zarit Burden Interview and the World Health Organization QOL BREF were used. Multiple regression analyses were applied to analyze the relationship between the caregiving burden and QOL. Results Caregiving burden explained 30.3% of variance of the QOL (β = −0.534, p < 0.001). Caregivers caring for patients with functional deterioration experienced higher burden. Caregivers providing care for hospitalized patients demonstrated lower QOL. The caregiver's educational level was a positively contributing factor for the QOL. Conclusions Caregiving burden was the influential, negatively affecting factor for the QOL. Assessment of caregiving burden with special attention being paid to caregivers caring for patients with functional decline would help to identify caregivers in need of support. Supportive care needs to be sought to alleviate caregiving burden and improve the QOL of caregivers, especially for the caregivers of hospitalized patients.
Objective
Gastric cancer patients generally have a poor outcome, particularly those with advanced-stage disease which is defined by the increased invasion of cancer locally and is associated with ...higher metastatic potential. This study aimed to identify genes that were functional in the most fundamental hallmark of cancer, namely invasion. We then wanted to assess their value as biomarkers of gastric cancer progression and recurrence.
Design
Data from a cohort of patients profiled on cDNA expression arrays was interrogated using K-means analysis. This genomic approach classified the data based on patterns of gene expression allowing the identification of the genes most correlated with the invasion of GC. We evaluated the functional role of a key protein from this analysis in invasion and as a biomarker of recurrence after curative resection.
Results
Expression of secreted frizzled-related protein 4 (SFRP4) was identified as directly proportional to gastric cancer invasion. This finding was validated in multiple, independent datasets and its functional role in invasion was also confirmed using invasion assays. A change in serum levels of SFRP4 after curative resection, when coupled with AJCC stage, can accurately predict the risk of disease recurrence after curative therapy in an assay we termed
PredictR
.
Conclusions
This simple ELISA-based assay can help predict recurrence of disease after curative gastric cancer surgery irrespective of adjuvant therapy. The results require further evaluation in a prospective trial but would help in the rational prescription of cancer therapies and surveillance to prevent under or over treatment of patients after curative resection.
Results from the phase 3 CLEAR study showed that lenvatinib plus pembrolizumab improved progression-free survival and overall survival compared with sunitinib in patients with advanced renal cell ...carcinoma. We aimed to assess the health-related quality-of-life (HRQOL) outcomes from the CLEAR study.
This open-label, randomised, phase 3 study was done across 200 hospitals and cancer centres in 20 countries. Patients were required to be 18 years or older, with advanced clear-cell renal cell carcinoma, and a Karnofsky performance status of 70% or higher. Patients who had received previous systemic anticancer therapy for renal cell carcinoma were not eligible. Patients were randomly assigned (1:1:1) to lenvatinib (oral 20 mg per day) plus pembrolizumab (intravenous 200 mg every 21 days), lenvatinib (oral 18 mg per day) plus everolimus (oral 5 mg per day) in 21-day cycles, or sunitinib (oral 50 mg per day, 4 weeks on followed by 2 weeks off). Patients were assigned to treatments with a computer-generated randomisation scheme and were stratified by geographical region and Memorial Sloan Kettering Cancer Center prognostic groups. The primary endpoint, previously reported, was progression-free survival, and HRQOL was a secondary endpoint. Most HRQOL analyses were done in patients who underwent randomisation, received at least one dose of study treatment, and had any HRQOL data. Completion and compliance analyses were done in the full analysis set. Functional Assessment of Cancer Therapy Kidney Symptom Index-Disease-Related Symptoms (FKSI-DRS), European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), and the EQ-5D-3 Level (EQ-5D-3L) preference questionnaire were administered at baseline and on day 1 of each subsequent 21-day cycle. This study is registered with ClinicalTrials.gov, NCT02811861, and is closed to new participants.
Between Oct 13, 2016, and July 24, 2019, 355 patients were randomly assigned to the lenvatinib plus pembrolizumab group, 357 to the lenvatinib plus everolimus group, and 357 to the sunitinib group. Median follow-up for HRQOL analyses was 12·9 months (IQR 5·6–22·3). Because of the promising efficacy and safety results of lenvatinib plus pembrolizumab in the first-line setting, we focus the HRQOL results in this report on that combination versus sunitinib. Mean change from baseline in the lenvatinib plus pembrolizumab group compared with the sunitinib group was –1·75 (SE 0·59) versus –2·19 (0·66) for FKSI-DRS, –5·93 (0·86) versus –6·73 (0·94) for EORTC QLQ-C30 global health status/quality of life (GHS/QOL), and –4·96 (0·85) versus –6·64 (0·94) for the EQ-5D visual analogue scale (VAS). Median time to first deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 9·14 weeks (95% CI 6·43–12·14) versus 12·14 weeks (9·14–15·29; HR 1·13 95% CI 0·94–1·35, log-rank p=0·20) for FKSI-DRS, 12·00 weeks (7·29–15·14) versus 9·14 weeks (6·29–12·14; 0·88 0·74–1·05, log-rank p=0·17) for EORTC QLQ-C30 GHS/QOL, and 9·43 weeks (6·43–12·29) versus 9·14 weeks (6·29–12·00; 0·83 0·70–0·99, log-rank p=0·041) for the EQ-5D VAS. Median time to definitive deterioration in the lenvatinib plus pembrolizumab group compared with the sunitinib group was 134·14 weeks (95% CI 120·00–not estimable) versus 117·43 weeks (90·14–131·29; HR 0·70 95% CI 0·53–0·92, log-rank p=0·0081) for FKSI-DRS, 114·29 weeks (102·14–153·29) versus 75·14 weeks (57·29–105·14; 0·60 0·47–0·77, log-rank p<0·0001) for EORTC QLQ-C30 GHS/QOL, and 124·86 weeks (94·71–134·57) versus 74·86 weeks (54·14–96·00; 0·67 0·53–0·85, log-rank p=0·0012) for the EQ-5D VAS. No outcomes on any of the instruments significantly favoured sunitinib over lenvatinib plus pembrolizumab. Most HRQOL comparisons of lenvatinib plus everolimus versus sunitinib were similar or favoured sunitinib.
These HRQOL results demonstrate that patients given lenvatinib plus pembrolizumab treatment had similar or favourable scores compared with patients given sunitinib, particularly with respect to time to definitive deterioration. These results support the efficacy and safety profile of lenvatinib plus pembrolizumab as first-line therapy for patients with advanced renal cell carcinoma.
Eisai (Nutley, NJ, USA) and Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA).
The PD-1/PD-L1 axis plays a paramount role in the immune escape of tumor cells by negative regulation of T-cell functions. The aim of the present study was to characterize the PD-L1 expression ...pattern and its clinical implication in soft-tissue sarcomas (STS).
We analyzed PD-L1 expression in 82 STS patients with 5 subtypes: rhabdomyosarcoma, synovial sarcoma, Ewing sarcoma, epithelioid sarcoma, and mesenchymal chondrosarcoma.
The median age at diagnosis was 26 (range: 1-78) and the male to female ratio was 1.6. The majority (80 %) of patients showed locoregional disease rather than metastatic disease at diagnosis. Thirty-five cases (43 %) showed PD-L1 expression and the proportion of PD-L1 expression was significantly different according to histologic subtypes (P = 0.004); highest in epithelioid sarcoma (100 %, 7/7), followed by synovial sarcoma (53 %, 10/19), rhabdomyosarcoma (38 %, 12/32), and Ewing sarcoma (33 %, 6/18), while it was not expressed in mesenchymal chondrosarcoma (0 %, 0/6). STS patients with PD-L1 expression had worse overall survival compared with those without PD-L1 expression (5-year survival rate: 48 % vs. 68 %, P = 0.015). The Cox proportional hazard model adjusted for histologic subtype, initial metastasis, and PD-L1 expression showed that PD-L1 expression was significantly associated with shorter overall survival (P = 0.037, HR 2.57, 95 % CI 1.060-6.231).
We have confirmed PD-L1 expression in various STS of young population and demonstrated its independent negative prognostic role, thereby suggesting the PD-1/PD-L1 axis as a potential therapeutic target for the treatment of young STS patients.
PDF
