Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor (TKI). Durvalumab is an anti–programmed death ligand 1 monoclonal antibody. The phase III open-label CAURAL trial (NCT02454933) ...investigated osimertinib plus durvalumab versus osimertinib monotherapy in patients with EGFR-TKI sensitizing and EGFR T790M mutation–positive advanced NSCLC and disease progression after EGFR-TKI therapy.
Patients were randomly assigned 1:1 to receive orally administered osimertinib (80 mg once daily) with or without durvalumab (10 mg/kg administered intravenously every 2 weeks) until progression. Treatment could continue beyond progression, providing clinical benefit continued (judged by the investigator). The amended primary objective was to assess the safety and tolerability of osimertinib plus durvalumab; efficacy was an exploratory objective.
CAURAL recruitment was terminated early because of increased incidence of interstitial lung disease–like events in the osimertinib plus durvalumab arm from the separate phase Ib TATTON trial (NCT02143466). At termination of CAURAL recruitment, 15 patients had been randomly assigned to treatment with osimertinib and 14 to treatment with osimertinib plus durvalumab. The most common AEs were diarrhea (53% grade ≥3 in 6% of patients) in the osimertinib arm and rash (67% grade ≥3 in 0 patients) in the combination arm. One patient who had been randomized to the combination arm reported grade 2 interstitial lung disease while receiving osimertinib monotherapy (after discontinuing durvalumab therapy after one dose). The objective response rates were 80% in the osimertinib arm and 64% in the combination arm.
Limited patient numbers preclude formal safety and efficacy comparisons between the two treatment arms. The combination of programmed cell death 1/programmed death ligand 1 inhibitors and EGFR-TKIs as therapy for NSCLC is not well understood, but it requires a careful approach if considered in the future.
Cancer cachexia worsens the treatment outcomes of patients with small-cell lung cancer (SCLC). However, no reliable biomarker of cancer cachexia is yet known.
We retrospectively evaluated male SCLC ...patients who received induction chemotherapy or concurrent chemoradiotherapy. The cachexia index (CXI) was calculated as skeletal muscle index × serum albumin level (g/dL)/neutrophil-to-lymphocyte ratio. The CXI cutoff according to tumor stage was determined based on a time-dependent receiver operating characteristic curve, and all patients were divided into low- and high-CXI groups.
Of 267 patients, 83 and 24 patients with limited-stage disease (LD) and 123 and 37 patients with extensive-stage disease (ED) were assigned to the high- and low-CXI groups, respectively. Only one of 24 patients (4.2%) with LD in the low-CXI group achieved a complete response (CR), whereas 30 of 83 patients (36.1%) with LD in the high-CXI group achieved CRs (p = 0.004). More low-CXI patients required early discontinuation of treatment because of treatment-related toxicity compared to the high-CXI patients (37.5% vs. 16.9%, respectively, p = 0.030, for LD patients; 27.0% vs. 11.4%, respectively, p = 0.019, for ED patients). The median progression-free survival (PFS) and overall survival (OS) were significantly shorter in the low-CXI group than the high-CXI group (6.3 vs. 11.1 months and 7.5 vs. 20.6 months, respectively, both p < 0.001 for LD patients; 2.9 vs. 6.3 months and 5.8 vs. 12.8 months, respectively, both p < 0.001, for ED patients). On multivariate analysis, low-CXI status was an independent poor prognostic factor for both PFS and OS regardless of the tumor stage.
A low CXI was associated with treatment intolerance, poor treatment response rate, and poor prognosis in SCLC.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background The endothelial activation and stress index (EASIX) score has been reported to predict overall survival (OS) in hematological cancers. However, it has not been validated as a prognostic ...marker for diffuse large B-cell lymphoma (DLBCL) to date. Methods The records of 265 patients who presented with DLBCL in the Republic of Korea between January 07, 2004, and March 05, 2020 were retrospectively reviewed. For all included patients, EASIX scores were calculated using serum lactate dehydrogenase (LDH) and creatinine levels and the platelet count measured at diagnosis as follows: LDH (U/L) x creatinine (mg/dL)/platelet count (10.sup.9/L). Results The median age of the patients was 64 years. The optimal cutoff value of EASIX according to the receiver operating characteristic analysis for OS was 1.33. All the patients were treated with cyclophosphamide, doxorubicin, vincristine, and prednisone combined with rituximab. The 1-year OS and progression-free survival (PFS) rates were lower in the high-EASIX group than in the low EASIX group (63.8% vs. 84.4%, p < 0.001 and 54.0% vs. 79.6%, p < 0.001, respectively). A high EASIX was an independent poor prognostic factor for OS and PFS (hazard ratio, 1.606; 95% CI, 1.077-2.395; p = 0.020 and hazard ratio, 1.621; 95% CI, 1.066-2.464; p = 0.024, respectively). Conclusions EASIX is a readily available and cheaply obtainable parameter in clinical studies and shows considerable potential as a new prognostic marker for patients with newly diagnosed DLBCL. Keywords: Lymphoma, Large B-cell, Diffuse, Endothelial Activation and Stress Index, Prognosis, Drug-related side effects and adverse reactions
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Cancer cachexia is known to adversely affect the clinical course in patients with malignant lymphoma. The cachexia index (CXI) is a potential biomarker of cancer cachexia, and its ...implications for the prognosis and treatment outcome of lung cancer and aggressive lymphoma has been assessed in previous studies.
Methods
A total of 267 patients diagnosed with diffuse large B‐cell lymphoma who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) immunochemotherapy were retrospectively reviewed. The CXI was calculated as the skeletal muscle index (SMI) × serum albumin/neutrophil–lymphocyte ratio (NLR). Although previous studies measured the SMI using the muscles of the L3 vertebral level, the present study used both the L3 vertebral muscles and the pectoralis muscles (PM) at the T4 vertebral level to measure the SMI. Depending on the type of muscles used, the CXI was termed the L3‐CXI or PM‐CXI. Using sex‐specific cutoff values for CXI, the patients were categorized as follows: (i) high‐CXI group (high L3‐CXI and high PM‐CXI), (ii) intermediate‐CXI group (high L3‐CXI and low PM‐CXI), and (iii) low‐CXI group (low L3‐CXI and low PM‐CXI).
Results
Complete responses to R‐CHOP were obtained in 145/173 (83.8%), 25/36 (69.4%), and 27/57 (47.4%) patients in the high‐CXI, intermediate‐CXI, and low‐CXI groups, respectively (P < 0.001). Treatment‐related anaemia (15.6%, 30.6%, and 26.3%, P = 0.038), thrombocytopenia (21.4%, 36.1%, and 43.9%, P < 0.001), febrile neutropenia (23.7%, 44.4%, and 36.8%, P = 0.022), and any nonhaematologic toxicity (31.2%, 44.4%, and 54.4%, P = 0.001) of Grade 3 or more were more common in the lower CXI groups than in the higher‐CXI groups. Early treatment discontinuation for reasons other than lymphoma progression also occurred more frequently in the low‐CXI group (24/57, 42.1%) compared with the intermediate‐CXI (5/36, 13.9%) and high‐CXI (18/173, 10.4%) groups (P < 0.001). Median overall survival in the high‐CXI, intermediate‐CXI, and low‐CXI groups was not reached, 50.6 months, and 14.5 months, respectively (p < 0.001). Multivariable analysis showed that low CXI was an independent negative prognostic factor for overall survival (hazard ratio 2.103, 95% confidence interval 1.278–3.460, P = 0.003).
Conclusions
We suggest that in patients with diffuse large B‐cell lymphoma, the CXI is a biomarker for cancer cachexia that can predict survival, treatment response, treatment‐related toxicity, and compliance with R‐CHOP. Patients were more clearly stratified by this new CXI category compared with the classifications described in previous studies.
Background
Sarcopenia is known to be related to an increased risk of chemotherapy toxicity and to a poor prognosis in patients with malignancy. We assessed the prognostic role of sarcopenia in ...patients with diffuse large B‐cell lymphoma (DLBCL).
Methods
In total, 187 consecutive patients with DLBCL treated with induction rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R‐CHOP) immunochemotherapy were reviewed. Sarcopenia was defined as the lowest sex‐specific quartile of the skeletal muscle index, calculated by dividing the pectoralis muscle area by the height. Clinical outcomes were compared between the sarcopenic and non‐sarcopenic groups. A nomogram was constructed from the Cox regression model for overall survival (OS).
Results
Treatment‐related mortality (21.7 vs. 5.0%, P = 0.002) and early discontinuation of treatment (32.6 vs. 14.9%, P = 0.008) were more common in the sarcopenic group than in the non‐sarcopenic group. The 5 year progression‐free survival (PFS) rates were 35.3% in the sarcopenic group and 65.8% in the non‐sarcopenic group (P < 0.001). The 5 year OS rates were 37.3% in the sarcopenic group and 68.1% in the non‐sarcopenic group (P < 0.001). Sarcopenia and the five variables of the International Prognostic Index (IPI) were independent prognostic factors in a multivariate analysis for PFS and OS and were used to construct the nomogram. The calibration plot showed good agreement between the nomogram predictions and actual observations. The c index of the nomogram (0.80) was higher than those of other prognostic indices (IPI, 0.77, P = 0.009; revised‐IPI, 0.74, P < 0.001; National Comprehensive Cancer Network‐IPI, 0.77, P = 0.062).
Conclusions
Sarcopenia is associated with intolerance to standard R‐CHOP chemotherapy as well as a poor prognosis. Moreover, sarcopenia itself can be included in prognostic models in DLBCL.
Systemic inflammation and cachexia are associated with adverse clinical outcomes in diffuse large B-cell lymphoma (DLBCL). The Geriatric Nutritional Risk Index (GNRI) is one of the main parameters ...used to assess these conditions, but its efficacy in DLBCL is inconclusive.
We retrospectively reviewed 228 DLBCL patients who were treated with R-CHOP immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The patients were stratified according to GNRI score (> 98, 92 to 98, 82 to < 92, and < 82) as defined in previous studies. Additionally, the extent of sarcopenia was categorized as sarcopenia-both, sarcopenia-L3/PM alone, and non-sarcopenia-both according to skeletal muscle index.
Survival curves plotted against a combination of GNRI and sarcopenia scores revealed two clear groups as follows: high cachexia risk (HCR) group (GNRI < 82, sarcopenia-both, or GNRI 82-92 with sarcopenia-L3/PM alone) and low cachexia risk (LCR) group (others). The HCR group had a lower complete response rate (46.5% vs. 86.6%) and higher frequency of treatment-related mortality (19.7% vs. 3.8%) and early treatment discontinuation (43.7% vs. 8.3%) compared with the LCR group. The median progression-free survival (PFS) (not reached vs. 10.3 months, p < 0.001) and overall survival (OS) (not reached vs. 12.9 months, p < 0.001) were much shorter in the HCR group than in the LCR group. On multivariable analyses, the HCR group was shown to be an independent negative prognostic factor for PFS and OS after adjusting the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI).
A combined model of GNRI and sarcopenia may provide prognostic information independently of the NCCN-IPI in DLBCL.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
On the basis of the benefits of frontline radiation in early-stage, extranodal, natural killer (NK)/T-cell lymphoma (ENKTL), we conducted a phase II trial of concurrent chemoradiotherapy (CCRT) ...followed by three cycles of etoposide, ifosfamide, cisplatin, and dexamethasone (VIPD).
Thirty patients with newly diagnosed, stages IE to IIE, nasal ENKTL received CCRT (ie radiation 40 to 52.8 Gy and cisplatin 30 mg/m(2) weekly). Three cycles of VIPD (etoposide 100 mg/m(2) days 1 through 3, ifosfamide 1,200 mg/m(2) days 1 through 3, cisplatin 33 mg/m(2) days 1 through 3, and dexamethasone 40 mg days 1 through 4) were scheduled after CCRT.
All patients completed CCRT, which resulted in 100% response that included 22 complete responses (CRs) and eight partial responses (PRs). The CR rate after CCRT was 73.3% (ie, 22 of 30 responses; 95% CI, 57.46 to 89.13). Twenty-six of 30 patients completed the planned three cycles of VIPD, whereas four patients did not because they withdrew (n = 2) or because they had an infection (n = 2). The overall response rate and the CR rate were 83.3% (ie; 25 of 30 responses; 95% CI, 65.28 to 94.36) and 80.0% (ie, 24 of 30 responses; 95% CI, 65.69 to 94.31), respectively. Only one patient experienced grade 3 toxicity during CCRT (nausea), whereas 12 of 29 patients experienced grade 4 neutropenia. The estimated 3-year, progression-free and overall survival rates were 85.19% (95% CI, 72.48 to 97.90) and 86.28% (95% CI, 73.97 to 98.59), respectively.
Patients with newly diagnosed, stages IE to IIE, nasal ENKTL are best treated with frontline CCRT.
Primary gastrointestinal (PGI) diffuse large B cell lymphoma (DLBCL) is a relatively common disease. Recent studies indicate that measurement of maximum standardized uptake value (SUVmax) on ...pretreatment for 18F‐fluorodeoxyglucose PET is an important prognostic factor in PGI DLBCL. However, there is still an association between initial tumor burden and prognosis. Thus, in the present study, we investigated whether tumor volume by PET could have a potential prognostic value to predict the outcome. From 2006 to 2009, 165 Stage I E/II E PGI DLBCL patients were enrolled in the study. One hundred and five patients received cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R‐CHOP) only, whereas 60 patients underwent surgery plus R‐CHOP. Metabolic tumor volume (MTV) was defined initial tumor burden as target GI lesion above SUV, 2.5 by PET as a contouring border. Over a median follow‐up period of 36.6 months, receiver operating characteristic (ROC) analysis indicated that the best cut‐off values for MTV and SUVmax were 160.1 cm3 and 12.0, respectively. The estimated area under the ROC curve was higher for MTV than SUVmax. Thus, MTV was a better predictor for survival than SUVmax. In patients with a low MTV (<160.1 cm3), there were no significant differences in survival between patients undergoing R‐CHOP alone and surgery plus R‐CHOP (P = 0.347 for progression‐free survival PFS; P = 0.148 for overall survival OS). Conversely, in patients with a high MTV (>160.1 cm3), survival was longer in those who underwent surgery plus R‐CHOP than in those treated with R‐CHOP alone (P < 0.001 for PFS; P < 0.001 for OS). Multivariate analysis revealed that high MTV is an independent factor for predicting survival. Even in the era of rituximab, treatment of PGI DLBCL is not easy in patients with a high MTV. (Cancer Sci 2012; 103: 477–482)
Patients with EGFR-mutated non-small-cell lung cancer (NSCLC) given EGFR tyrosine kinase inhibitors (TKIs) inevitably become resistant to first-generation or second-generation drugs. We assessed the ...safety, tolerability, pharmacokinetics, and activity of lazertinib—an irreversible, third-generation, mutant-selective, EGFR TKI—in patients with advanced NSCLC progressing after EGFR TKI therapy.
This first-in-human, open-label, multicentre, phase 1–2 study had three parts: dose escalation, dose expansion, and dose extension; here, we report results on dose escalation and dose expansion. The study was done in 14 hospitals in Korea. Eligible patients were aged 20 years or older and had advanced NSCLC harbouring an activating EGFR mutation and progressing after first-generation or second-generation EGFR TKI treatment, a defined tumour T790M mutation status, an Eastern Cooperative Oncology Group performance status of 0–1, at least one measurable extracranial lesion, defined according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, and adequate organ function. Patients were enrolled to seven dose-escalation cohorts according to a rolling six design; five cohorts were expanded. Patients were given oral lazertinib 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, 240 mg, or 320 mg once daily continuously in 21-day cycles. Primary endpoints were safety and tolerability and secondary endpoints included objective response in evaluable patients. This study is registered with ClinicalTrials.gov, NCT03046992, and the phase 2 extension study is ongoing.
Between Feb 15, 2017, and May 28, 2018, 127 patients were enrolled into the dose escalation group (n=38) and dose expansion group (n=89). No dose-limiting toxicities occurred. There was no dose-dependent increase in adverse events. The most commonly reported adverse events were grade 1–2 rash or acne (in 38 30% of 127 patients) and pruritus (in 34 27%). Grade 3 or grade 4 adverse events occurred in 20 (16%) patients, with the most common being grade 3 pneumonia (four 3%). Treatment-related grade 3 or 4 adverse events occurred in four (3%) patients; treatment-related serious adverse events were reported in six patients (5%). There were no adverse events with an outcome of death and no treatment-related deaths. The proportion of patients achieving an objective response by independent central review assessment was 69 (54%; 95% CI 46–63) of 127.
Lazertinib had a tolerable safety profile and showed promosing clinical activity in patients with NSCLC progressing on or after EGFR TKI therapy. Our findings provide a rationale for further clinical investigations.
Yuhan Corporation.
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