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PURPOSE: Outcome for patients with nonmetastatic, microsatellite instability (MSI) colon cancer is favorable: however, high-risk cohorts exist. This study was aimed at developing and validating a nomogram model to predict freedom from recurrence (FFR) for patients with resected MSI colon cancer. PATIENTS AND METHODS: Data from patients who underwent curative resection of stage I, II, or III MSI colon cancer in 2014-2021 (model training cohort, 384 patients, 33 events; median follow-up, 38.8 months) were retrospectively collected from institutional databases. Variables associated with recurrence in multivariable analysis were selected for inclusion in the clinical calculator. The calculator's predictive accuracy was measured with the concordance index and validated using data from patients who underwent treatment for MSI colon cancer in 2007-2013 (validation cohort, 164 patients, eight events; median follow-up, 84.8 months). RESULTS: T category and number of positive lymph nodes were significantly associated with recurrence in multivariable analysis and were selected for inclusion in the clinical calculator. The calculator's concordance index for FFR in the model training cohort was 0.812 (95% CI, 0.742 to 0.873), compared with 0.759 (95% CI, 0.683 to 0.840) for the staging schema of the eighth edition of the American Joint Committee on Cancer Staging Manual. The concordance index for the validation cohort was 0.744 (95% CI, 0.666 to 0.822), confirming robust predictive accuracy. CONCLUSION: Although in general patients with nonmetastatic MSI colon cancer had favorable outcome, patients with advanced T category and multiple metastatic lymph nodes had higher risk of recurrence. The clinical calculator identified patients with MSI colon cancer at high risk for recurrence, and this could inform surveillance strategies. In addition, the model could be used in trial design to identify patients suitable for novel adjuvant therapy.
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Neoplasias do Colo , Instabilidade de Microssatélites , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Humanos , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/cirurgia , Neoplasias do Colo/diagnóstico , Feminino , Masculino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Pessoa de Meia-Idade , Idoso , Nomogramas , Estudos Retrospectivos , Prognóstico , AdultoRESUMO
BACKGROUND: To determine whether the addition of durvalumab (anti-PD-L1) and oleclumab (anti-CD73) to standard-of-care treatment (FOLFOX and bevacizumab) enhances the anti-tumour effect in patients with metastatic colorectal cancer (mCRC). METHODS: COLUMBIA-1 (NCT04068610) was a Phase Ib (feasibility; Part 1)/Phase II (randomised; Part 2) trial in patients with treatment-naïve microsatellite stable mCRC. Patients in Part 2 were randomised to receive standard-of-care (control arm) or standard-of-care plus durvalumab and oleclumab (experimental arm). Primary objectives included safety and efficacy. RESULTS: Seven patients were enrolled in Part 1 and 52 in Part 2 (n = 26 in each arm). Grade ≥3 treatment-emergent adverse events (TEAE) occurred in 80.8% and 65.4% of patients in the control and experimental arms of Part 2, respectively, with 26.9% and 46.3% experiencing serious TEAEs. The confirmed objective response rate (ORR) was numerically higher in the experimental arm compared with the control arm (61.5% [95% confidence interval (CI), 40.6-79.8] vs 46.2% [95% CI, 26.6-66.6]) but did not meet the statistically significant threshold in either arm. CONCLUSION: The safety profile of FOLFOX and bevacizumab in combination with durvalumab and oleclumab was manageable; however, the efficacy results do not warrant further development of this combination in patients with microsatellite stable mCRC. REGISTRATION: NCT04068610.
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Microsatellite stable metastatic colorectal cancer (MSS mCRC; mismatch repair proficient) has previously responded poorly to immune checkpoint blockade. Botensilimab (BOT) is an Fc-enhanced multifunctional anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody designed to expand therapy to cold/poorly immunogenic solid tumors, such as MSS mCRC. BOT with or without balstilimab (BAL; anti-PD-1 antibody) is being evaluated in an ongoing expanded phase 1 study. The primary endpoint is safety and tolerability, which was evaluated separately in the dose-escalation portion of the study and in patients with MSS mCRC (using combined dose-escalation/dose-expansion data). Secondary endpoints include investigator-assessed RECIST version 1.1-confirmed objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and progression-free survival (PFS). Here we present outcomes in 148 heavily pre-treated patients with MSS mCRC (six from the dose-escalation cohort; 142 from the dose-expansion cohort) treated with BOT and BAL, 101 of whom were considered response evaluable with at least 6 months of follow-up. Treatment-related adverse events (TRAEs) occurred in 89% of patients with MSS mCRC (131/148), most commonly fatigue (35%, 52/148), diarrhea (32%, 47/148) and pyrexia (24%, 36/148), with no grade 5 TRAEs reported and a 12% discontinuation rate due to a TRAE (18/148; data fully mature). In the response-evaluable population (n = 101), ORR was 17% (17/101; 95% confidence interval (CI), 10-26%), and DCR was 61% (62/101; 95% CI, 51-71%). Median DOR was not reached (NR; 95% CI, 5.7 months-NR), and median PFS was 3.5 months (95% CI, 2.7-4.1 months), at a median follow-up of 10.3 months (range, 0.5-42.6 months; data continuing to mature). The combination of BOT plus BAL demonstrated a manageable safety profile with no new immune-mediated safety signals and encouraging clinical activity with durable responses. ClinicalTrials.gov identifier: NCT03860272 .
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Cibisatamab is a bispecific antibody-based construct targeting carcinoembryonic antigen (CEA) on tumour cells and CD3 epsilon chain as a T-cell engager. Here we evaluated cibisatamab for advanced CEA-positive solid tumours in two open-label Phase 1 dose-escalation and -expansion studies: as a single agent with or without obinutuzumab in S1 (NCT02324257) and with atezolizumab in S2 (NCT02650713). Primary endpoints were safety, dose finding, and pharmacokinetics in S1; safety and dose finding in S2. Secondary endpoints were anti-tumour activity (including overall response rate, ORR) and pharmacodynamics in S1; anti-tumour activity, pharmacodynamics and pharmacokinetics in S2. S1 and S2 enrolled a total of 149 and 228 patients, respectively. Grade ≥3 cibisatamab-related adverse events occurred in 36% of S1 and 49% of S2 patients. The ORR was 4% in S1 and 7% in S2. In S2, patients with microsatellite stable colorectal carcinoma (MSS-CRC) given flat doses of cibisatamab and atezolizumab demonstrated an ORR of 14%. In S1 and S2, 40% and 52% of patients, respectively, developed persistent anti-drug antibodies (ADAs). ADA appearance could be mitigated by obinutuzumab-pretreatment, with 8% of patients having persistent ADAs. Overall, cibisatamab warrants further exploration in immunotherapy combination strategies for MSS-CRC.
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Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Complexo CD3 , Antígeno Carcinoembrionário , Neoplasias , Humanos , Anticorpos Biespecíficos/uso terapêutico , Anticorpos Biespecíficos/farmacocinética , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Complexo CD3/imunologia , Adulto , Antígeno Carcinoembrionário/imunologia , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinéticaRESUMO
Background: Oncologists are prescribing checkpoint inhibitors with greater frequency, and an awareness of and ability to recognize immune-related adverse events (irAEs) is a key part of the safe administration of these drugs. Case Description: Herein, we report the case of a 26-year-old male diagnosed with de novo metastatic right-sided colon cancer to the liver, with tumor immunohistochemistry demonstrating loss of MSH2 and MSH6, and a pathogenic mutation in MSH2 identified on germline testing, consistent with Lynch Syndrome. The patient received first-line treatment with pembrolizumab. Following 7 months of immune checkpoint blockade (ICB), new pulmonary findings on routine imaging were felt to be concerning for disease progression, despite ongoing excellent clinical status, disease control in the liver, and stable tumor markers. An endobronchial biopsy of one of the mediastinal lymph nodes demonstrated granulomatous inflammation consistent histologically with sarcoidosis, and a diagnosis of sarcoid-like reaction (SLR) secondary to immunotherapy was established. Pembrolizumab was discontinued, and the patient continued active monitoring off of active therapy, with durable cancer control. After 8 months of watchful waiting, new hepatic lesions and increasing abdomino-pelvic lymphadenopathy were identified on imaging, concerning for progression of disease. Inguinal lymph node biopsy demonstrated findings consistent with ongoing SLR. The patient remains with durable cancer control, now 24 months since receipt of ICB. In addition, he remains asymptomatic of the SLR. Conclusions: This case highlights the propensity of SLRs to imitate progression of disease, and the importance of awareness of this adverse effect, to prompt appropriate investigation and management.
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BACKGROUND: Resistance to immune checkpoint inhibitors and targeted treatments for cancer is common; thus, novel immunotherapy agents are needed. Urelumab is a monoclonal antibody agonist that binds to CD137 receptors expressed on T cells. Here, we report two studies that evaluated urelumab in combination with cetuximab or nivolumab in patients with select, advanced solid tumors. METHODS: CA186-018: Patients with metastatic colorectal cancer or metastatic squamous cell carcinoma of the head and neck (SCCHN) were treated in a dose-evaluation phase with urelumab 0.1 mg/kg (urelumab-0.1) every 3 weeks (Q3W)+cetuximab 250 mg/m2 (cetuximab-250) weekly; and in a dose-expansion phase with urelumab 8 mg flat dose (urelumab-8) Q3W+cetuximab-250 weekly. CA186-107: The dose-escalation phase included patients with previously treated advanced solid tumors (or treated or treatment-naive melanoma); patients received urelumab 3 mg flat dose (urelumab-3) or urelumab-8 every 4 weeks+nivolumab 3 mg/kg (nivolumab-3) or 240 mg (nivolumab-240) every 2 weeks. In the expansion phase, patients with melanoma, non-small cell lung cancer, or SCCHN were treated with urelumab-8+nivolumab-240. Primary endpoints were safety and tolerability, and the secondary endpoint included efficacy assessments. RESULTS: CA186-018: 66 patients received study treatment. The most frequent treatment-related adverse events (TRAEs) were fatigue (75%; n=3) with urelumab-0.1+cetuximab-250 and dermatitis (45%; n=28) with urelumab-8+cetuximab-250. Three patients (5%) discontinued due to TRAE(s) (with urelumab-8+cetuximab-250). One patient with SCCHN had a partial response (objective response rate (ORR) 5%, with urelumab-8+cetuximab-250).CA186-107: 134 patients received study treatment. Fatigue was the most common TRAE (32%; n=2 with urelumab-3+nivolumab-3; n=1 with urelumab-8+nivolumab-3; n=40 with urelumab-8+nivolumab-240). Nine patients (7%) discontinued due to TRAE(s) (n=1 with urelumab-3+nivolumab-3; n=8 with urelumab-8+nivolumab-240). Patients with melanoma naive to anti-PD-1 therapy exhibited the highest ORR (49%; n=21 with urelumab-8+nivolumab-240). Intratumoral gene expression in immune-related pathways (CD3, CD8, CXCL9, GZMB) increased on treatment with urelumab+nivolumab. CONCLUSIONS: Although the addition of urelumab at these doses was tolerable, preliminary response rates did not indicate an evident additive benefit. Nevertheless, the positive pharmacodynamics effects observed with urelumab and the high response rate in treatment-naive patients with melanoma warrant further investigation of other anti-CD137 agonist agents for treatment of cancer. TRIAL REGISTRATION NUMBERS: NCT02110082; NCT02253992.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Melanoma , Humanos , Nivolumabe/farmacologia , Nivolumabe/uso terapêutico , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Neoplasias Pulmonares/induzido quimicamente , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológicoRESUMO
Purpose: Colorectal liver metastases (CLMs) represent a radioresistant histology. We aimed to investigate CLM radiation therapy (RT) outcomes and explore the association with treatment parameters. Methods and Materials: This retrospective analysis of CLM treated with RT at Memorial Sloan Kettering Cancer Center used Kaplan-Meier analysis to estimate freedom from local progression (FFLP), hepatic progression-free, progression-free, and overall survival (OS). Cox proportional hazards regression was used to evaluate association with clinical factors. Dose-response relationship was further evaluated using a mechanistic tumor control probability (TCP) model. Results: Ninety patients with 122 evaluable CLMs treated 2006 to 2019 with a variety of RT fractionation schemes with a median biologically effective dose (α/ß = 10; BED10) of 97.9 Gy (range, 43.2-187.5 Gy) were included. Median lesion size was 3.5 cm (0.7-11.8 cm). Eighty-seven patients (97%) received prior systemic therapy, and 73 patients (81%) received prior liver-directed therapy. At a median follow-up of 26.4 months, rates of FFLP and OS were 62% (95% CI, 53%-72%) and 75% (66%-84%) at 1 year and 42% (95% CI, 32%-55%) and 44% (95% CI, 34%-57%) at 2 years, respectively. BED10 below 96 Gy and receipt of ≥3 lines of chemotherapy were associated with worse FFLP (hazard ratio [HR], 2.69; 95% CI, 1.54-4.68; P < .001 and HR, 2.67; 95% CI, 1.50-4.74; P < .001, respectively) and OS (HR, 2.35; 95% CI, 1.35-4.09; P = .002 and HR, 4.70; 95% CI, 2.37-9.31; P < .001) on univariate analyses, which remained significant or marginally significant on multivariate analyses. A mechanistic Tumor Control Probability (TCP) model showed a higher 2-Gy equivalent dose needed for local control in patients who had been exposed to ≥ 3 lines of chemotherapy versus 0 to 2 (250 ± 29 vs 185 ± 77 Gy for 70% TCP). Conclusions: In a large single-institution series of heavily pretreated patients with CLM undergoing liver RT, low BED10 and multiple prior lines of systemic therapy were associated with lower local control and OS. These results support continued dose escalation efforts for patients with CLM.