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BACKGROUND: A minority subset of immunotherapy patients manifests hyperprogressive disease (HPD), with the disparity in melanoma subtypes yet to be reported. This study aimed to delineate the proportion and prognosis of HPD in patients receiving anti-PD-1 monotherapy and to identify patient with HPD clinical characteristics across melanoma subtypes to inform clinical decision making. METHODS: Utilizing 4 established HPD definitions, the incidence of HPD in patients with advanced melanoma on anti-PD-1 monotherapy was determined. The incidence rates and prognostic abilities of various HPD definitions were compared to elect the most effective one. This facilitated a comparative analysis of subtypes and clinical features between patients with HPD and traditional progression. RESULTS: A total of 262 patients with advanced melanoma treated with anti-PD-1 monotherapy from 5 prospectively registered clinical trials were included in the study. The objective response rate (ORR) and disease control rate (DCR) was 21% and 58%, respectively, with 42% showcasing progression disease. The HPD incidences by 4 definitions were 13.2%, 16.8%, 10.8%, and 28.2%. All definitions effectively segregated HPD patients, with significantly poorer outcome than other progressive patients. The Delta TGRâ >â 100 definition was the most indicative of a reduced overall survival, corroborated by the highest hazard ratio and statistical significance. The number of metastatic organs over 2 is a risk factor for HPD (ORâ =â 4.18, Pâ =â .0103). Mucosal melanoma was the HPD prevalent subtype (ORâ =â 3.13, Pâ =â .0489) in multivariable analysis, which is also indicated by RECIST criteria (Pâ =â .005). CONCLUSION: A delta TGR exceeding 100 best identified HPD patients in the advanced melanoma population treated with anti-PD-1 monotherapy. Hyperprogression was notably prevalent in mucosal melanoma patients with multiple metastatic organs. Caution against HPD is warranted when applying anti-PD-1 monotherapy in mucosal subtype.
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BACKGROUND: Acral melanoma, the most common subtype of melanoma in Asians, is often diagnosed at an advanced stage and responds poorly to current programmed cell death protein 1 (PD-1) inhibitors. OBJECTIVES: To evaluate the safety and efficacy of TQB2450 and anlotinib in patients with advanced acral melanoma in a phase Ib study (NCT03991975). METHODS: Patients received TQB2450 (1200 mg every 3 weeks) and anlotinib (10 mg or 12 mg once daily, 2-week on/1-week off) in the dose-escalation and dose-expansion phases. The primary endpoints were dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and objective response rate (ORR). RESULTS: Nineteen patients were enrolled between June 2019 and June 2022. The majority of patients (16 of 19 patients) received anlotinib and TQB2450 as first-line treatment. No DLTs were observed, and MTD was not reached. Eighteen (94.7%) out of 19 patients experienced treatment-related adverse events (TRAEs), but most were grade 1 or 2. Grade 3 or greater TRAEs occurred in seven patients (36.8%). The ORR was 26.3% (two complete responses and three partial responses). The disease control rate was 73.7%. The median duration of response was 30.3 months [95% confidence interval (CI): 5.8-NA]. The median progression-free survival (PFS) was 5.5 months (95% CI: 2.8-NA), and median overall survival was 20.3 months (95% CI: 14.8-NA). Whole-exome sequencing suggested that acquired drug resistance might be attributed to activation of the MAPK signalling pathway and transformation to an immunosuppressive tumour environment. CONCLUSIONS: TQB2450 combined with anlotinib showed favourable tolerance and promising anti-tumour activity with a prolonged PFS compared with anti-PD1 monotherapy in patients with advanced acral melanoma.
Subject(s)
Antibodies, Monoclonal , Immune Checkpoint Inhibitors , Indoles , Melanoma , Quinolines , Skin Neoplasms , Humans , Antibodies, Monoclonal/therapeutic use , Immune Checkpoint Inhibitors/therapeutic use , Indoles/adverse effects , Melanoma/drug therapy , Quinolines/adverse effects , Skin Neoplasms/drug therapyABSTRACT
BACKGROUND: The frequency of HER2 overexpression in bladder cancer is reported as 9%-61%. HER2 alteration correlates with aggressive disease in bladder cancer. Traditional anti-HER2 targeted therapy has failed to show clinical benefits in patients with advanced urothelial carcinoma . METHODS: The information on pathologically proven patients with urothelial carcinoma with detected HER2 status was collected from the database of Peking University Cancer Hospital. The HER2 expression, as well as its association with clinical characteristics and prognosis, was analyzed. RESULTS: A total of 284 consecutive patients with urothelial carcinoma were enrolled. HER2 was positive (IHC 2+/3+) in 44% of urothelial carcinoma. HER2 positivity was found more frequent in UCB than in UTUC (51% vs. 38%). Stage, radical surgery, and histological variant were associated with survival (P < .05). For metastatic patients, multivariate analysis shows that 3 indicators, including liver metastasis, the number of involved organs, and anemia, are independent risk factors of prognosis. Receiving immunotherapy or disitamab vedotin (DV) treatment is an independent protecting factor. The survival of patients with low HER2 expression was also significantly improved by the treatment of DV (P < .001). HER2 expression (IHC 1+, 2+, 3+) was associated with a better prognosis in this population. CONCLUSION: DV has improved the survival of patients with urothelial carcinoma in the real world. With the new-generation anti-HER2 ADC treatment, HER2 expression is no longer a poor prognostic factor.
Subject(s)
Carcinoma, Transitional Cell , Urinary Bladder Neoplasms , Humans , Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/therapy , East Asian People , Prognosis , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/therapyABSTRACT
BACKGROUND: Pucotenlimab is a novel recombinant humanized anti-PD-1 (Programmed death-1) monoclonal antibody, which belongs to the human IgG4/kappa subtype, and can selectively block the binding of PD-1 with its ligands PD-L1 and PD-L2. METHODS: In this phase 2 trial, patients with locally advanced or metastatic melanoma who had failed conventional treatment (chemotherapy, targeted therapy, interferon, IL-2, et al.) were recruited. The patients were administrated with Pucotenlimab of 3 mg/kg every 3 weeks until disease progression, intolerable toxicity, or treatment discontinuation for any other reasons. The primary endpoint was the overall response rate (ORR). The secondary endpoints were disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: One-hundred and nineteen patients were enrolled and followed up for 19.32 (ranging from 15.901 to 24.608) months by the cutoff date of July 30th, 2021. The ORR was 20.17% (24/119, 95% CI, 13.370%-28.506%) based on both independent review committee (IRC) and the investigator's assessment per RECIST v1.1. The median PFS were 2.89 (95% CI, 2.037-4.074) months and 2.46 (95% CI, 2.004-4.008) months based on IRC and investigator's assessment, respectively, per RECIST v1.1. The median OS was 16.59 (95% CI, 13.963-26.973) months. Treatment-related adverse events (TRAEs) occurred in 77.3% (92/119) of the patients. The incidence of Grade ≥ 3 TRAEs was 15.1% (18/119). In addition, none of the patients died because of TRAEs. As for biomarker analysis, Eotaxin (CCL11) and MCP-1 (CCL2) were related to treatment response, while TNF-α and VEGF were related to treatment failure. CONCLUSIONS: Pucotenlimab as a ≥ 2nd line therapy showed promising efficacy and tolerable toxicity for patients with locally advanced or metastatic melanoma. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04749485 (registered retrospectively on 11/02/2021).
Subject(s)
Antibodies, Monoclonal, Humanized , Melanoma , Humans , Retrospective Studies , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal/adverse effects , Melanoma/pathology , Immunoglobulin G/therapeutic use , Immune Checkpoint Inhibitors/therapeutic useABSTRACT
BACKGROUND: Acral melanoma (AM) is less responsive to immunotherapy than nonacral cutaneous melanoma. Variable responses are seen during immunotherapy, including pseudoprogression, hyperprogressive disease (HPD) and heterogeneous responses. There are currently no studies on the response patterns of patients with AM treated with immunotherapy and the impact on the outcome. OBJECTIVES: To evaluate the response patterns and prognosis of patients with AM treated with anti-programmed death (PD)-1 antibodies. METHODS: Patients with advanced AM treated prospectively in five clinical trials of anti-PD-1 monotherapy at Peking University Cancer Hospital were included. Responses of individual metastases and heterogeneous responses were evaluated during immunotherapy. Cox proportional hazards regression analysis was conducted to identify the possible predictive factors and generate a nomogram to predict the risk of 1-year and 2-year mortality. RESULTS: The overall response rate was 18·0%, the disease control rate was 36·1%, median progression-free survival was 3·5 months [95% confidence interval (CI) 1·7-5·3] and median overall survival was 17·5 months (95% CI 15·1-19·9) for anti-PD-1 monotherapy. Overall, 9·8% of patients met the criteria of HPD, and displayed a dramatically worse outcome than patients without HPD. In total, 369 metastatic lesions were assessed, with the highest response rate in lymph nodes (20·4%) and the lowest in the liver (5·6%). Homogeneous response, heterogeneous response and heterogeneous or homogeneous progression had different prognoses from the best to the worst. A predictive model was constructed and achieved good accuracy with a C-index of 0·73 (95% CI 0·63-0·84) in the training set and 0·74 (95% CI 0·61-0·86) in the validation set. CONCLUSIONS: HPD during immunotherapy serves as an essential biomarker of poor prognosis in advanced AM. Metastases in different sites respond distinctively to immunotherapy. Clinically heterogeneous responses to immunotherapy affect the outcome of patients. A predictive model was built to distinguish the prognosis of acral melanoma under immunotherapy.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/pathology , Skin Neoplasms/pathology , Prognosis , Progression-Free Survival , Retrospective Studies , Immunotherapy , Melanoma, Cutaneous MalignantABSTRACT
OBJECTIVES: To evaluate the anti-tumour activity and safety of anti-programmed death receptor-1 (PD-1) antibody plus epidermal growth factor receptor blockade combined with platinum-based chemotherapy (PEP) as first-line therapy for stage IV penile squamous cell carcinoma (PSCC). PATIENTS AND METHODS: We conducted a retrospective review of 17 patients with stage IV PSCC undergoing first-line PEP at Sun Yat-sen University Cancer Center between January 2018 and September 2021. Clinical responses were assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Adverse events (AEs) were graded according to Common Terminology Criteria for Adverse Events version 5.0. RESULTS: Of 17 patients who received first-line PEP, 13 were observed to have partial responses. Twelve patients subsequently received consolidated surgery. Nine of these achieved pN0 status, of whom six with locally advanced PSCC achieved pathological complete response. The median (range) follow-up time was 24.87 (3.63-29.40) months. Median PFS and median OS were not reached, with 2-year PFS and OS rates being 68.4% (95% confidence interval [CI] 48.7-96.1) and 62.9% (95% CI 41.6-95), respectively. Eight patients experienced Grade 3 or 4 treatment-related AEs. No Grade 5 AEs or death associated with treatment was observed. CONCLUSIONS: Anti-PD-1 antibody plus epidermal growth factor receptor blockade and platinum-based chemotherapy showed promising anti-tumour activity, acceptable toxicity, and satisfying long-term survival for stage IV PSCC. Larger clinical trials are needed to validate our findings.
Subject(s)
Carcinoma, Squamous Cell , Lung Neoplasms , Penile Neoplasms , Male , Humans , Penile Neoplasms/drug therapy , Penile Neoplasms/pathology , ErbB Receptors , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Progression-Free Survival , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Receptors, Death Domain , Lung Neoplasms/drug therapy , Lung Neoplasms/metabolism , Lung Neoplasms/pathologyABSTRACT
BACKGROUND: There is no widely employed staging system for mucosal melanoma (MuM) that incorporates all anatomic sites. We hypothesized that MuM patients arising from different anatomical sites could be staged using a common approach. METHODS: A prospective database contained 1814 MuM patients with a median follow-up of 5.14 years was employed. Overall survival (OS) was calculated from the time of pathological diagnosis to the date of death from any cause. Multivariate analyses of prognostic variables and OS were performed using the Cox proportional hazard model. RESULTS: For localized MuM, the most significant median OS differences were primary tumors invading submucosa (i.e., T1) versus deeper (i.e., T2/T3/T4): 4.3 versus 3.4, 3.1, and 2.9 years, respectively (p < 0.001). For patients only with regional node metastasis at presentation, the most significant were: 1 versus ≥ 2 regional nodes (N1 vs. N2, 2.5 vs. 2.1 years, p < 0.001). For patients with distant metastasis at presentation, the median OS was 1.5, 1.2, 0.8, and 0.6 years respectively for skin/subcutaneous tissue/distant lymph nodes (M1a), lung metastasis (M1b), all other visceral sites except brain (M1c), and brain (M1d) (p < 0.001). Based on these results, the staging system for MuM is proposed: (1) Stage I: T1N0M0 (median OS, 4.3 years); (2) Stage II: T2-4N0M0 (3.1 years); (3) Stage IIIA: T1-4N1M0 (2.5 years), Stage IIIB: T1-4N2M0 (2.1 years); (4) Stage IV: TanyNanyM1 (0.9 years) (p < 0.001). CONCLUSIONS: A single, unified, staging system for mucosal melanoma inclusive of all anatomical primary tumor sites can harmonize staging of MuM and the design of clinical trials.
Subject(s)
Lung Neoplasms , Melanoma , Humans , Lung Neoplasms/pathology , Lymph Nodes/pathology , Melanoma/pathology , Neoplasm Staging , PrognosisABSTRACT
BACKGROUND: Anti-programmed cell death receptor-1 (PD-1) monotherapy is the standard treatment for metastatic melanoma in current. Camrelizumab is a humanized IgG4 anti-PD-1 monoclonal antibody whose safety and efficacy have not been reported in advanced Asian melanoma patients. METHODS: This phase I study investigated the safety, activity, and pharmacokinetics of camrelizumab in Chinese patients with advanced melanoma. The study included two phases, the dose-escalation phase ("3 + 3" design at 60 mg, 200 mg, and 400 mg) and the dose-expansion phase. RESULTS: No dose-limiting toxicities were recorded over the dose-escalation phase, and the maximum tolerated dose was not reached. The most common treatment-related adverse events (TRAEs) in 36 patients were reactive cutaneous capillary endothelial proliferation, followed by rash, fever, hypothyroidism, hyperthyroidism, vitiligo, and fatigue. Five grade 3 or above TRAEs were reported (13.9%), including two cases of elevated γ-glutamyltransferase and blood triglycerides without clinical symptoms, and one liver injury recovered after symptomatic treatment. The confirmed overall response rate was 13.9% (95%CI: 4.7, 29.5%) and disease control rate was 38.9% (95%CI: 23.1, 56.5%). The median progression-free survival was 1.8 months (95%CI: 1.1, 2.4) and the median overall survival was 11.1 months (95%CI: 6.8, 15.4). CONCLUSIONS: Camrelizumab had acceptable tolerability and similar anti-tumor activity compared with other anti-PD-1 antibodies in advanced Asian melanoma patients. TRIAL REGISTRATION: ClinicalTrials.gov identification: NCT02738489. Registered on 14/04/2016, prospectively registered.
Subject(s)
Antibodies, Monoclonal, Humanized , Melanoma , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Humans , Melanoma/drug therapy , Melanoma/pathology , Progression-Free SurvivalABSTRACT
PURPOSE: RC48 contains the novel humanized anti-HER2 antibody hertuzumab conjugated to MMAE via a cleavable linker. A phase I study was initiated to evaluate the toxicity, MTD, PK, and antitumor activity of RC48 in patients with HER2-overexpressing locally advanced or metastatic solid carcinomas, particularly gastric cancer. PATIENTS AND METHODS: This was a 2-part phase I study. Successive cohorts of patients received escalating doses of RC48 (0.1 mg/kg, 0.5 mg/kg, 1.0 mg/kg, 2.0 mg/kg, 2.5 mg/kg, and 3.0 mg/kg). Dose expansion proceeded at the dose of 2.0 mg/kg Q2W. The efficacy and safety set included all patients who received at least one dose of RC48. RESULTS: Fifty-seven patients were enrolled, the MTD was unavailable due to termination of 3.0 mg/kg cohort; 2.5 mg/kg Q2W was declared the RP2D. RC48 was well tolerated, the most frequent grade 3 or worse TRAEs included neutropenia (19.3%), leukopenia (17.5%), hypoesthesia (14.0%), and increased conjugated blood bilirubin (8.8%). Four deaths occurred during the whole study, three of which were believed to be related to RC48. Overall, ORR and DCR were 21.0% (12/57) and 49.1% (28/57). Notably, patients who were HER2 IHC2+/FISH- responded similarly to those who were IHC2+/FISH+ and IHC3+, with ORRs of 35.7% (5/14), 20% (2/10), and 13.6% (3/22), respectively. In patients who were pretreated with HER2-targeted drugs, RC48 also showed promising efficacy, with ORR of 15.0% (3/20) and DCR of 45.0% (9/20). CONCLUSION: RC48 was well tolerated and showed promising antitumor activity in HER2-positive solid tumors, including gastric cancer with HER2 IHC 2+/FISH- status. CLINICAL TRIAL INFORMATION: NCT02881190.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Agents, Immunological/administration & dosage , Immunoconjugates/administration & dosage , Receptor, ErbB-2/immunology , Stomach Neoplasms/drug therapy , Adult , Aged , Antibodies, Monoclonal, Humanized/immunology , Antineoplastic Agents, Immunological/immunology , Female , Humans , Immunoconjugates/immunology , Male , Maximum Tolerated Dose , Middle Aged , Oligopeptides/immunology , Stomach Neoplasms/immunology , Treatment OutcomeABSTRACT
BACKGROUND: The clinicopathological and survival profiles across primary sites in acral melanoma (AM) are still controversial and unclear. METHODS: This is a multi-center retrospective study. Clinicopathological data of AM patients diagnosed between 1 January 2000 and 31 December 2017 from 6 large tertiary hospitals in China were extracted. Chi square tests were used to compare basic characteristics between primary sites of sole, palm and nail bed. Melanoma-specific survival (MSS) differences based on primary sites were compared by log-rank tests and multivariate Cox regressions were used to identify prognostic factors for MSS. RESULTS: In total, 1157 AM patients were included. The sole group had a more advanced initial stage, deeper Breslow thickness, higher recurrence rate and distant metastases risk (all P < 0.05). The proportion of age < 65 years and ulceration were statistically lower in nail bed and palm groups, respectively. A total of 294 patients underwent sentinel lymph node biopsy and rates of positive SLN status had no statistical difference across primary sites. Among 701 patients with genetic profiles, the mutational frequency of BRAF, C-KIT, and PDGFRA were similar except for NRAS (higher in sole group, P = 0.0102). The median MSS of sole, nail bed and palm patients were 65.0 months, 112.0 months, and not reached, respectively (log-rank P = 0.0053). In multivariate analyses, primary site, initial stage, ulceration and recurrence were the prognostic factors for MSS in overall population, but the statistical significance varied over primary sites. CONCLUSIONS: Substantial clinicopathological and survival heterogeneities exist across different primary sites in the AM population. Sole melanoma has worse prognosis compared with palm and nail bed subtypes.
Subject(s)
Melanoma , Skin Neoplasms , Aged , China , Female , Foot , Hand , Humans , Kaplan-Meier Estimate , Lymphatic Metastasis , Male , Melanoma/genetics , Melanoma/mortality , Melanoma/pathology , Melanoma/surgery , Middle Aged , Nails , Neoplasm Recurrence, Local , Prognosis , Retrospective Studies , Sentinel Lymph Node Biopsy , Skin Neoplasms/genetics , Skin Neoplasms/mortality , Skin Neoplasms/pathology , Skin Neoplasms/surgery , Survival RateABSTRACT
BACKGROUND: We performed a pooled analysis of the COMPARZ study assessing efficacy and safety of pazopanib versus sunitinib in treatment-naïve Chinese patients with locally advanced and/or metastatic renal cell carcinoma (a/mRCC). METHODS: In the COMPARZ study, patients were randomized (1:1) to receive pazopanib 800 mg once daily (QD) continuously or sunitinib 50 mg QD in 6-week cycles (4 weeks on, 2 weeks off). The primary endpoint was progression-free survival (PFS); secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. PFS and ORR were assessed by independent review committee (IRC) and local investigators. RESULTS: Of the 209 Chinese patients (pazopanib, [n = 109] and sunitinib, [n = 100]), 155 (74%) were males and median age was 57 years (range, 18-79). Median PFS was 13.9 months for pazopanib versus 14.3 months for sunitinib per investigator assessment and 8.3 months in both arms per IRC assessment; PFS hazard ratio was 1.17 (investigator) and 0.99 (IRC). Median OS was not reached in pazopanib arm and was 29.5 months in sunitinib arm. ORR was significantly higher in pazopanib arm versus sunitinib arm (investigator: 41% versus 23% [P = 0.0052]; IRC: 35% versus 20% [P = 0.0203]). Pazopanib was generally well tolerated in Chinese patients with a/mRCC. Most frequent AEs in the pazopanib arm were diarrhea and hair color changes whereas the most frequent AEs in the sunitinib arm were decreased platelets, decreased neutrophil count, and thrombocytopenia. CONCLUSION: The results of the pooled analysis were consistent with the overall population in the COMPARZ study, and confirmed similar PFS and OS of pazopanib and sunitinib in the Chinese patients. TRIAL REGISTRATION: clinical trials.gov, NCT00720941 (August 14, 2008) and NCT01147822 (May 19, 2010).
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Pyrimidines/therapeutic use , Sulfonamides/therapeutic use , Sunitinib/therapeutic use , Adolescent , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Carcinoma, Renal Cell/epidemiology , China/epidemiology , Female , Humans , Indazoles , Kidney Neoplasms/epidemiology , Male , Middle Aged , Progression-Free Survival , Pyrimidines/administration & dosage , Pyrimidines/adverse effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Sunitinib/administration & dosage , Sunitinib/adverse effects , Young AdultABSTRACT
Here we reported the development of a novel immuno-SPECT tracer, namely 99mTc-JS001, to non-invasively image PD-1 expression in mice. The JS001 antibody was directly labeled by the most widely used SPECT radionuclide 99mTc with a radiochemical yield of 90%, and the specific activity was ≤74â¯GBq/mmol. After the radiolabeling, 99mTc-JS001 exhibited a similar immnuoaffinity to PD-1 in vitro. 99mTc-conjugated JS001 maintained intact in 5% HSA system for 24â¯h. S180 sarcoma xenograft-bearing Kunming mice and BGC823 gastric cancer orthotopic tumor model were built. Bio-distribution and/or immuno-SPECT studies with 99mTc-JS001 showed the antibody maintained in the blood, liver, kidneys and tumors at 1.5 ID%/g, 1.4 ID%/g, 2.0 ID%/g and 0.5 ID%/g, respectively. Also, there was a higher uptake in the BGC823 orthotopic tumor than that in the adjunct stomach. These results demonstrated that 99mTc-JS001 might have capacity to monitor the PD-1 expression in vivo, which might facilitate the anti-PD-1 antibodies treatment in preclinical models.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Programmed Cell Death 1 Receptor/chemistry , Technetium/therapeutic use , Animals , Antibodies, Monoclonal/pharmacology , Humans , Mice , Technetium/pharmacologyABSTRACT
AIM: Efficacy/safety of first-line axitinib in Asian patients with metastatic renal cell carcinoma. METHODS: Patients were assigned (2:1) to 5-mg axitinib (n = 48) or 400-mg sorafenib (n = 24) twice daily. Primary end point was progression-free survival. Objective response rate, overall survival and adverse events were also assessed. RESULTS: For axitinib versus sorafenib, hazard ratio for progression-free survival was 0.652 (95% CI: 0.340-1.252; p = 0.0989), objective response rate was higher (35.4 vs 16.7%; p = 0.0495), overall survival longer (hazard ratio: 0.739; 95% CI: 0.397-1.375; p = 0.1683). Palmar-plantar erythrodysesthesia (57.4%), diarrhea (55.3%), hypertension (51.1%) were commonest adverse events with axitinib; palmar-plantar erythrodysesthesia (50.0%) with sorafenib. CONCLUSION: Axitinib improved efficacy in Asian patients with metastatic renal cell carcinoma; adverse events were consistent with previous findings.
Subject(s)
Antineoplastic Agents/therapeutic use , Axitinib/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Sorafenib/therapeutic use , Adult , Aged , Antineoplastic Agents/adverse effects , Asian People , Axitinib/adverse effects , Carcinoma, Renal Cell/mortality , Carcinoma, Renal Cell/pathology , Female , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Kidney Neoplasms/pathology , Male , Middle Aged , Sorafenib/adverse effects , Treatment OutcomeABSTRACT
G2 and S-phase expressed 1 (GTSE1) regulates cell cycle progression in human cancers. However, its significance and mechanism of action in acral melanoma (AM) remain unknown. In the present study, we found that GTSE1 expression was upregulated in advanced stage/metastatic AM tissues and metastatic cell lines, and correlated with higher stage (P = .028) and poor disease-free survival (DFS) in patients with AM (P = .003). Cox regression assays validated GTSE1 expression to be an independent prognostic factor of DFS for patients with AM (P = .004). Ectopic expression of GTSE1 enhanced primary AM cell proliferation, invasion, and migration. Loss-of-function in GTSE1 attenuated metastatic AM cell proliferation and metastatic ability in vitro and in vivo. We additionally observed that inhibition of migration and invasion occurred concomitantly with a GTSE1 knockdown-mediated increase in E-cadherin and decreases in N-cadherin and Slug. We further showed that integrin subunit alpha 2 (ITGA2) interacts with GTSE1 and is a downstream effector of GTSE1. Further, ITGA2 levels were positively correlated with GTSE1 expression in human AM tissues. Ectopic ITGA2 expression rescued siGTSE1-mediated inhibition of migration and invasion, thereby restoring epithelial-to-mesenchymal transition (EMT). In conclusion, GTSE1 expression promotes AM progression and correlates with clinical outcomes of patients with AM, and may represent a promising therapeutic target to suppress AM progression.
Subject(s)
Gene Expression Regulation, Neoplastic , Melanoma/genetics , Microtubule-Associated Proteins/genetics , Skin Neoplasms/genetics , Animals , Cell Line, Tumor , Cell Movement/genetics , Disease Progression , Female , Humans , Male , Melanoma/metabolism , Melanoma/pathology , Mice, Inbred NOD , Mice, SCID , Microtubule-Associated Proteins/metabolism , Middle Aged , Neoplasm Staging , Prognosis , RNA Interference , Skin Neoplasms/metabolism , Skin Neoplasms/pathology , Survival Analysis , Transplantation, HeterologousABSTRACT
PURPOSE: This study was designed to evaluate the efficacy of isolated limb infusion (ILI) treatment in Chinese patients with in-transit melanoma and to identify factors predictive of the outcome. METHODS: A total of 150 patients with in-transit melanoma who received a single ILI between 2007 and 2016 were identified from a prospectively collected database. RESULTS: All patients had AJCC Stages IIIb, IIIc, and IV disease. Acral lentiginous melanoma (ALM) accounted for 79% of patients, and 59% had a high burden of disease (BOD). The complete response (CR) and partial response (PR) rates were 6 and 35%, respectively. Forty-five percent of patients experienced grade III-IV limb toxicities, but no grade V toxicity was observed. Patients with a low BOD, high limb temperature, high peak creatine phosphokinase (CK) level, and grade III-IV limb toxicity achieved higher response rates. Stage IV disease and high BOD were associated with worse infield progression-free survival (PFS) and overall survival (OS), whereas patients with CR or PR to ILI had better infield PFS and OS. Multivariate analyses showed that disease stage, BOD, and a CR were independent predictors of infield PFS, whereas disease stage and a response to ILI were independent predictors of OS. CONCLUSIONS: ILI is well-tolerated but the response rate in Chinese patients was lower than that reported in US and Australian studies. The prevalence of the ALM histological type, advanced disease stages, and a high BOD may be the main reasons for this. A response to ILI, BOD, and disease stage are prognostic factors for survival.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Chemotherapy, Cancer, Regional Perfusion/mortality , Extremities/pathology , Melanoma/drug therapy , Melanoma/pathology , Adolescent , Adult , Aged , Aged, 80 and over , China , Dactinomycin/administration & dosage , Female , Follow-Up Studies , Humans , Male , Melphalan/administration & dosage , Middle Aged , Prospective Studies , Survival Rate , Treatment Outcome , Young AdultABSTRACT
BACKGROUND: The hypothesis that mucosal melanomas from different anatomic sites would have different prognostic features and survival outcome was tested in a multifactorial analysis. METHODS: Complete clinical and pathological information from 706 mucosal melanoma patients from different anatomical sites was compared for overall survival (OS) and prognostic factors. RESULTS: Mucosal melanomas arising from different anatomical sites did not have any significant differences in OS in a multivariate analysis (p = 0.721). Among all 706 stage I-IV mucosal melanoma patients, depth of tumor invasion (p < 0.001), number of lymph node metastases (p < 0.001), and sites of distant metastases (p < 0.001) were independent prognostic factors for OS; among 543 stage I-III patients, depth of tumor invasion (p < 0.001) and number of lymph node metastases (p < 0.001) were independent prognostic factors for OS; and among 547 stage IV patients, depth of tumor invasion (p = 0.009), number of lymph node metastases (p < 0.001), and combined distant metastases and elevation of serum lactate dehydrogenase (LDH; p < 0.001) were independent prognostic factors for OS. The presence of c-KIT or BRAF mutations was not predictive of survival. CONCLUSIONS: This is the first large-scale study comparing outcomes of mucosal melanomas from different anatomic sites in a multifactorial analysis. There were no significant survival differences among mucosal melanomas arising at different sites when matched for staging and prognostic and molecular factors, thus rejecting our hypothesis. We concluded that prognostic characteristics of mucosal melanomas can be staged as a single histological group, regardless of the anatomic site of the primary tumor.
Subject(s)
Adenocarcinoma, Mucinous/mortality , Melanoma/mortality , Mucous Membrane/pathology , Neoplasm Recurrence, Local/mortality , Adenocarcinoma, Mucinous/secondary , Adenocarcinoma, Mucinous/surgery , Adult , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , Male , Melanoma/pathology , Melanoma/surgery , Middle Aged , Mucous Membrane/surgery , Neoplasm Invasiveness , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/surgery , Prognosis , Prospective Studies , Survival RateABSTRACT
BACKGROUND: To compare the efficacy of sorafenib and sunitinib with regard to overall survival (OS) and progression free survival (PFS) in Chinese patients with metastatic renal cell carcinoma (mRCC). METHODS: A multicenter, retrospective study was performed to elucidate the relationship between clinical variables and prognosis comparing sorafenib and sunitinib as first-line treatment agents in Chinese patients with mRCC. Between September 2006 and December 2014, 845 patients received either sorafenib (400 mg bid; n = 483) or sunitinib (50 mg q.d; n = 362). The primary end point was OS and PFS. RESULTS: The percentage of patients with low and moderate risk according to Memorial Sloan-Kettering Cancer Centre (MSKCC) score was significantly higher in sunitinib group, and that with high risk was significantly higher in sorafenib group (15.1 vs. 5.2%; p < 0.001). Median OS was similar in sorafenib and sunitinib group (24 vs. 24 months; p = 0.298). Sorafenib group exhibited higher mPFS compared to sunitinib group (11.1 vs. 10.0 months; p = 0.028). Treatment (sorafenib vs sunitinib), pathology, Eastern Cooperative Oncology Group (ECOG) performance status, MSKCC scores, Heng's criteria of risk, and number of metastases were identified as significant predictors for OS and along with liver metastasis for PFS. Clinical outcomes in terms of mOS was significantly better with sorafenib in patients ≥65 years of age (p = .041), ECOG 0 (p = 0.0001), and median MSKCC risk score (p = 0.008). CONCLUSIONS: Sorafenib and sunitinib are both effective in treating mRCC. However, sorafenib might be more effective in elderly patients (≥65 years) and in patients with an ECOG status of 0, classified under MSKCC moderate risk.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Pyrroles/therapeutic use , Adult , Aged , Aged, 80 and over , Asian People , Carcinoma, Renal Cell/mortality , Disease-Free Survival , Female , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/mortality , Male , Middle Aged , Niacinamide/therapeutic use , Prognosis , Proportional Hazards Models , Retrospective Studies , Sorafenib , Sunitinib , Treatment OutcomeABSTRACT
OBJECTIVE: To investigate the efficacy and safety of sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) on a 2 weeks on/1 week off intermittent dosing schedule. METHODS: A total of 11 mRCC patients were enrolled to receive sunitinib 50 mg/day in 2 weeks on/1 week off schedule per 6 weeks till disease progression or intolerable toxicity occurred. The primary end point was progression free survival (PFS), the secondary end points were overall survival (OS), incidence of adverse effects and objective response. RESULTS: The objective response rate in the 11 cases was 45.5% and disease control rate 72.7% (partial response n = 5, stable disease n = 3). Till the last follow up on Dec 2013, the median PFS was 17.0 months (95% CI 7.3 to 26.7 months), and median OS 26.0 months (95% CI 2.2 to 49.8 months). The common adverse events included leucopenia, thrombocytopenia, diarrhea, mucositis and hand-foot skin reaction. Dose reduction to 37.5 mg was seen only in 2 patients without discontinuation. CONCLUSIONS: Sunitinib on an intermittent dosing schedule 2 weeks on /1 week off as first-line therapy for mRCC patients shows a good efficacy and tolerance, with less grade 3-4 drug-related toxicities and a tendency of prolonged PFS in mRCC patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Indoles/therapeutic use , Kidney Neoplasms/drug therapy , Pyrroles/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/pharmacology , Disease-Free Survival , Drug Administration Schedule , Humans , Indoles/administration & dosage , Indoles/pharmacology , Pilot Projects , Pyrroles/administration & dosage , Pyrroles/pharmacology , Sunitinib , Treatment OutcomeABSTRACT
OBJECTIVE: To evaluate the efficacy and safety of sorafenib in Chinese patients with advanced renal cell carcinoma. METHODS: The data of 174 advanced renal cell carcinoma patients orally taking sorafenib in our single center from October 2006 to October 2013 was retrospectively collected. Progression free survival (PFS), overall survival (OS) of these patients and drug-related side effects were analyzed. RESULTS: Disease control rate was 92% for the whole group. The median PFS of patients taking standard dose (400 mg bid) was (8.0±0.6) months, the median PFS of patients taking increased dose (600 mg bid) after progression was (5.0±1.0) months, the median PFS of patients taking increased dose (800 mg bid) after second-progression was (2.0±0.4) months. The median OS was (24.0±2.8) months. The common side effects included hand-foot reaction (70%), fatigue (57.4%), diarrhea (45.2%), rash (39.9%) and hypertension (21.8%). CONCLUSIONS: Sorafenib has good efficacy and safety in Chinese patients with advanced renal cell carcinoma. Increased dose could bring clinical benefit after standard dose failed.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Antineoplastic Agents , Diarrhea , Disease-Free Survival , Fatigue , Humans , Niacinamide/analogs & derivatives , Phenylurea Compounds , Retrospective Studies , Sorafenib , Treatment OutcomeABSTRACT
BACKGROUND: The incidence of renal cell cancer (RCC) has been increasing for the past decade, and the 5-year survival for patients with metastatic RCC (mRCC) is rather low. Everolimus (RAD001), a new inhibitor for mammalian target of rapamycin (mTOR), is generally well tolerated, and demonstrates clinical benefit to patients with anti-VEGF-refractory mRCC. However, factors for selection of patients who may benefit from everolimus remain largely unknown. Here we aimed to explore potential molecular indicators for mRCC patients who may benefit from everolimus treatment. METHODS: Paraffin-embedded tumor tissue specimens derived from 18 mRCC patients before everolimus treatment, who participated the phase 1b trial of everolimus in VEGF receptor (VEGFR)-tyrosine kinase inhibitor (TKI)-refractory Chinese patients with mRCC (clinicaltrials.gov, NCT01152801), were examined for the expression levels of phosphorylated AKT, mTOR, eukaryotic initiation factor 4E (eIF4E) binding protein-1 (4EBP1) and 40S ribosomal protein S6 (S6RP) by immunohistochemistry. Clinical benefit rate (complete response [CR], partial response [PR], plus stable disease [SD] ≥ 6 months) and progression-free survival time (PFS) were correlated with expression levels of these mTOR-associated molecules. RESULTS: In these 18 patients, there were 1 PR, 15 SDs (including 9 SDs ≥ 6 months), and 2 progressive diseases (PD). The clinical benefit rate (CBR) was 55.6% (10/18), and the median PFS time was 8.4 months. Patients with positive expression of phospho-mTOR showed a better CBR (71.4% versus 0%, P = 0.023) and PFS time (11.3 versus 3.7 months, P = 0.001) than those patients with negative expression. The median PFS of patients with positive phospho-S6RP expression was longer (11.3 versus 3.7 months, P = 0.002) than that of patients negative for phospho-S6RP expression. However, expression levels of phospho-4EBP1 and phospho-AKT were unassociated to efficacy of everolimus treatment with respect to CBR and PFS. Co-expression of phosphorylated mTOR, S6RP and/or 4EBP1 may improve the predictive value of the biomarkers for patients treated with everolimus. CONCLUSIONS: The expression levels of phospho-mTOR and phospho-S6RP may be potential predictive biomarkers for efficacy of everolimus in patients with mRCC. Combining examinations of phosphorylated mTOR, S6RP and/or 4EBP1 may be a potential strategy to select mRCC patients sensitive to mTOR inhibitor treatment.