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PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option. PATIENTS AND METHODS: Multicenter Phase 1b/2 randomized clinical trial in patients with metastatic PDAC, untreated (Cohort A) or previously received gemcitabine-based chemotherapy (Cohort B) (NCT03611556). During escalation, patients received oleclumab 1500 or 3000 mg, durvalumab 1500 mg, and gemcitabine plus nab-paclitaxel (GnP) (Cohort A; n=14) or modified FOLFOX (Cohort B; n=11). During expansion, Cohort A patients (n=170) were randomized to: GnP (Arm A1), oleclumab (recommended Phase 2 dose; RP2D) with GnP (Arm A2), or oleclumab (RP2D) with durvalumab plus GnP (Arm A3). Primary objectives were safety (escalation) and objective response rate (ORR) (expansion). Secondary objectives included progression-free survival (PFS) and overall survival (OS). RESULTS: During escalation, 1/11 patients from Cohort B (oleclumab 3000 mg) experienced two dose-limiting toxicities. Oleclumab RP2D was 3000 mg. During expansion, Grade ≥3 treatment-related adverse events occurred in 67.7% (42/62) of patients in A1, 73.7% (28/38) in A2, and 77.1% (54/70) in A3. ORR was 29.0%, 21.1%, and 32.9% in A1, A2, and A3, respectively (A1 vs A3; p=0.650). PFS (hazard ratio [HR]=0.72; 95% confidence interval [CI]: 0.47, 1.11) and OS (HR=0.75; 95% CI: 0.50, 1.13) were similar for A3 versus A1. Patients with high CD73 expression had improved PFS and OS in A3 versus A1, although this should be interpreted with caution. CONCLUSIONS: Although the safety profile was acceptable, this study did not meet its primary efficacy endpoint.
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Gastroesophageal (GE) and pancreatobiliary (PB) cancers represent a significant clinical challenge. In this context, it is critical to understand the key molecular targets within these malignancies including how they are assayed for as well as the clinical actionability of these targets. Integrating biomarkers into the standard of care presents a critical avenue for refining treatment paradigms. This review aims to explore these complexities, offering insights into the optimal sequencing of chemotherapy and targeted therapies and their utility in the management of GE and PB cancers. The timely integration of promising investigational therapies into clinical practice has broader implications around strategies for future clinical trial designs, which would pave the way for advancements in the management of GE and PB cancers. This review provides guidance in navigating the evolving landscape of GE and PB cancer care, which ultimately will drive forward progress in the field and lead to improved patient outcomes.
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Biomarcadores de Tumor , Terapia Molecular Dirigida , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/tratamiento farmacológico , Neoplasias Esofágicas/terapia , Neoplasias Gástricas/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/terapia , Toma de Decisiones Clínicas , Neoplasias del Sistema Biliar/genética , Neoplasias del Sistema Biliar/tratamiento farmacológico , Neoplasias del Sistema Biliar/terapiaRESUMEN
BACKGROUND: Camonsertib is a selective oral inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase with demonstrated efficacy in tumors with DNA damage response gene deficiencies. On-target anemia is the main drug-related toxicity typically manifesting after the period of dose-limiting toxicity evaluation. Thus dose/schedule optimization requires extended follow-up to assess prolonged treatment effects. METHODS: Long-term safety/tolerability and antitumor efficacy of three camonsertib monotherapy dose levels/schedules were assessed in the TRESR study dose-optimization phase: 160 mg once daily (QD) 3 days on/4 off (160 3/4; the preliminary recommended phase II dose [RP2D]) and two step-down groups of 120 mg QD 3/4 (120 3/4) and 160 mg QD 3/4, 2 weeks on/1 off (160 3/4, 2/1w). Safety endpoints included incidence of treatment-related adverse events (TRAEs), dose modifications, and transfusions. Efficacy endpoints included overall response rate, clinical benefit rate, progression-free survival, and circulating-tumor-DNA (ctDNA)-based molecular response rate. RESULTS: The analysis included 119 patients: 160 3/4 (n = 67), 120 3/4 (n = 25), and 160 3/4, 2/1w (n = 27) treated up to 117.1 weeks as of the data cutoff. The risk of developing grade 3 anemia was significantly lower in the 160 3/4, 2/1w group compared with the preliminary RP2D group (HR = 0.23, 2-sided P = .02), translating to reduced transfusion and dose reduction requirements. The intermittent weekly schedule did not compromise antitumor activity. CONCLUSION: The 160 3/4, 2/1w dose was established as an optimized regimen for future camonsertib monotherapy studies offering significantly reduced anemia incidence without any compromise to efficacy.
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BACKGROUND: There is currently limited literature assessing the real-world treatment patterns and clinical outcomes of patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination repair (HRR) mutations. METHODS: Medical charts were abstracted for mCRPC patients with ≥ 1 of 12 HRR somatic gene alterations treated at US oncology centers participating in the American Association for Cancer Research Project Genomics Evidence Neoplasia Information Exchange. Treatment patterns and clinical outcomes were assessed from the initiation of first-line or later (1L+) mCRPC therapy received on or after July 1, 2014. RESULTS: Among 138 patients included in the study, the most common somatic HRR mutations were CDK12 (47.8%), BRCA2 (22.5%), and ATM (21.0%). Novel hormonal therapy and taxane chemotherapy were most commonly used in 1L; taxane use increased in later lines. Median overall survival (95% confidence interval [CI]) was 36.3 (30.7-47.8) months from initiation of 1L therapy and decreased for subsequent lines. Similarly, there was a trend of decreasing progression-free survival and prostate-specific antigen response from 1L to 4L+ therapy. CONCLUSIONS: Treatment patterns identified in this study were similar to those among patients with mCRPC regardless of tumor HRR mutation status in the literature.
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Proteína BRCA2 , Mutación , Neoplasias de la Próstata Resistentes a la Castración , Reparación del ADN por Recombinación , Humanos , Masculino , Anciano , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Proteína BRCA2/genética , Persona de Mediana Edad , Proteínas de la Ataxia Telangiectasia Mutada/genética , Taxoides/uso terapéutico , Taxoides/administración & dosificación , Quinasas Ciclina-Dependientes/genética , Resultado del Tratamiento , Anciano de 80 o más Años , Antígeno Prostático Específico/sangre , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios Retrospectivos , Metástasis de la NeoplasiaRESUMEN
PURPOSE: Camonsertib is a highly selective and potent inhibitor of ataxia telangiectasia and Rad3-related (ATR) kinase. Dose-dependent anemia is a class-related on-target adverse event often requiring dose modifications. Individual patient risk factors for the development of significant anemia complicate the selection of a "one-size-fits-all" ATR inhibitor (ATRi) dose and schedule, possibly leading to suboptimal therapeutic doses in patients at low risk of anemia. We evaluated whether early predictors of anemia could be identified to ultimately inform a personalized dose-modification approach. PATIENTS AND METHODS: On the basis of preclinical observations and a mechanistic understanding of ATRi-related anemia, we identified several potential factors to explore in a multivariable linear regression modeling tool for predicting hemoglobin level ahead of day 22 (cycle 2) of treatment. RESULTS: In patients treated with camonsertib monotherapy (NCT04497116), we observed that hemoglobin decline is consistently preceded by reticulocytopenia, and dose- and exposure-dependent decreases in monocytes. We developed a nomogram incorporating baseline and day 8 hemoglobin and reticulocyte values that predicted the day 22 hemoglobin values of patients with clinically valuable concordance (within 7.5% of observations) 80% of the time in a cross-validation performance test of data from 60 patients. CONCLUSIONS: The prediction of future hemoglobin decrease, after a week of treatment, may enable a personalized, early dose modification to prevent development of clinically significant anemia and resulting unscheduled dose holds or transfusions.
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Anemia , Ataxia Telangiectasia , Humanos , Proteínas de la Ataxia Telangiectasia Mutada , Nomogramas , Anemia/tratamiento farmacológico , Anemia/etiología , HemoglobinasRESUMEN
PURPOSE: This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor]. EXPERIMENTAL DESIGN: Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks). RESULTS: A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR. CONCLUSIONS: Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors. SIGNIFICANCE: PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.
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Neoplasias , Receptor de Muerte Celular Programada 1 , Humanos , Receptor de Muerte Celular Programada 1/uso terapéutico , Neoplasias/tratamiento farmacológico , Diarrea , NáuseaRESUMEN
Predictive biomarkers of response are essential to effectively guide targeted cancer treatment. Ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) have been shown to be synthetic lethal with loss of function (LOF) of ataxia telangiectasia-mutated (ATM) kinase, and preclinical studies have identified ATRi-sensitizing alterations in other DNA damage response (DDR) genes. Here we report the results from module 1 of an ongoing phase 1 trial of the ATRi camonsertib (RP-3500) in 120 patients with advanced solid tumors harboring LOF alterations in DDR genes, predicted by chemogenomic CRISPR screens to sensitize tumors to ATRi. Primary objectives were to determine safety and propose a recommended phase 2 dose (RP2D). Secondary objectives were to assess preliminary anti-tumor activity, to characterize camonsertib pharmacokinetics and relationship with pharmacodynamic biomarkers and to evaluate methods for detecting ATRi-sensitizing biomarkers. Camonsertib was well tolerated; anemia was the most common drug-related toxicity (32% grade 3). Preliminary RP2D was 160 mg weekly on days 1-3. Overall clinical response, clinical benefit and molecular response rates across tumor and molecular subtypes in patients who received biologically effective doses of camonsertib (>100 mg d-1) were 13% (13/99), 43% (43/99) and 43% (27/63), respectively. Clinical benefit was highest in ovarian cancer, in tumors with biallelic LOF alterations and in patients with molecular responses. ClinicalTrials.gov registration: NCT04497116 .
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Ataxia Telangiectasia , Neoplasias Ováricas , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Inhibidores de Proteínas Quinasas/farmacocinética , Daño del ADN , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/metabolismoRESUMEN
OBJECTIVE: To develop and evaluate task-based radiomic features extracted from the mesenteric-portal axis for prediction of survival and response to neoadjuvant therapy in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Consecutive patients with PDAC who underwent surgery after neoadjuvant therapy from two academic hospitals between December 2012 and June 2018 were retrospectively included. Two radiologists performed a volumetric segmentation of PDAC and mesenteric-portal axis (MPA) using a segmentation software on CT scans before (CTtp0) and after (CTtp1) neoadjuvant therapy. Segmentation masks were resampled into uniform 0.625-mm voxels to develop task-based morphologic features (n = 57). These features aimed to assess MPA shape, MPA narrowing, changes in shape and diameter between CTtp0 and CTtp1, and length of MPA segment affected by the tumor. A Kaplan-Meier curve was generated to estimate the survival function. To identify reliable radiomic features associated with survival, a Cox proportional hazards model was used. Features with an ICC ≥ 0.80 were used as candidate variables, with clinical features included a priori. RESULTS: In total, 107 patients (60 men) were included. The median survival time was 895 days (95% CI: 717, 1061). Three task-based shape radiomic features (Eccentricity mean tp0, Area minimum value tp1, and Ratio 2 minor tp1) were selected. The model showed an integrated AUC of 0.72 for prediction of survival. The hazard ratio for the Area minimum value tp1 feature was 1.78 (p = 0.02) and 0.48 for the Ratio 2 minor tp1 feature (p = 0.002). CONCLUSION: Preliminary results suggest that task-based shape radiomic features can predict survival in PDAC patients. KEY POINTS: ⢠In a retrospective study of 107 patients who underwent neoadjuvant therapy followed by surgery for PDAC, task-based shape radiomic features were extracted and analyzed from the mesenteric-portal axis. ⢠A Cox proportional hazards model that included three selected radiomic features plus clinical information showed an integrated AUC of 0.72 for prediction of survival, and a better fit compared to the model with only clinical information.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Masculino , Humanos , Estudios Retrospectivos , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/terapia , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/terapia , Tomografía Computarizada por Rayos X/métodos , Neoplasias PancreáticasRESUMEN
BACKGROUND: Targeting programmed cell death protein 1 (PD-1) and indoleamine 2,3-dioxygenase (IDO1) pathways is an appealing option for cancer treatment. METHODS: The open-label, phase 1/2 ECHO-203 study evaluated the safety, tolerability, and efficacy of the IDO1 inhibitor epacadostat in combination with durvalumab, a human anti-PD-L1 monoclonal antibody in adult patients with advanced solid tumors. RESULTS: The most common treatment-related adverse events were fatigue (30.7%), nausea (21.0%), decreased appetite (13.1%), pruritus (12.5%), maculopapular rash (10.8%), and diarrhea (10.2%). Objective response rate (ORR) in the overall phase 2 population was 12.0%. Higher ORR was observed in immune checkpoint inhibitor (CPI)-naïve patients (16.1%) compared with patients who had received previous CPI (4.1%). Epacadostat pharmacodynamics were evaluated by comparing baseline kynurenine levels with those on therapy at various time points. Only the 300-mg epacadostat dose showed evidence of kynurenine modulation, albeit unsustained. CONCLUSIONS: Epacadostat plus durvalumab was generally well tolerated in patients with advanced solid tumors. ORR was low, and evaluation of kynurenine concentration from baseline to cycle 2, day 1, and cycle 5, day 1, suggested >300 mg epacadostat twice daily is needed to ensure sufficient drug effect. CLINICAL TRIAL INFORMATION: A study of epacadostat (INCB024360) in combination with durvalumab (MEDI4736) in subjects with selected advanced solid tumors (ECHO-203) (NCT02318277).
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Neoplasias Primarias Secundarias , Neoplasias , Adulto , Humanos , Oximas , Sulfonamidas , Anticuerpos Monoclonales/efectos adversos , Neoplasias/patología , Neoplasias Primarias Secundarias/etiología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Importance: Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC. Objectives: To assess whether the addition of atezolizumab to capecitabine and bevacizumab therapy improves progression-free survival (PFS) among patients with refractory mCRC and to perform exploratory analyses among patients with microsatellite-stable (MSS) disease and liver metastasis. Design, Setting, and Participants: This double-blind phase 2 randomized clinical trial enrolled 133 patients between September 25, 2017, and June 28, 2018 (median duration of follow-up for PFS, 20.9 months), with data cutoff on May 4, 2020. The study was conducted at multiple centers through the Academic and Community Cancer Research United network. Adult patients with mCRC who experienced disease progression while receiving fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-epidermal growth factor receptor antibody therapy (if the patient had a RAS wild-type tumor) were included. Interventions: Patients were randomized (2:1) to receive capecitabine (850 or 1000 mg/m2) twice daily on days 1 to 14 and bevacizumab (7.5 mg/kg) on day 1 plus either atezolizumab (1200 mg; investigational group) or placebo (placebo group) on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary end point was PFS; 110 events were required to detect a hazard ratio (HR) of 0.65 with 80% power (1-sided α = .10). Secondary end points were objective response rate, overall survival (OS), and toxic effects. Results: Of 133 randomized patients, 128 individuals (median age, 58.0 years [IQR, 51.0-65.0 years]; 77 men [60.2%]) were assessed for efficacy (82 in the investigational group and 46 in the placebo group). Overall, 15 patients (11.7%) self-identified as African American or Black, 8 (6.3%) as Asian, 1 (0.8%) as Pacific Islander, 101 (78.9%) as White, 1 (0.8%) as multiple races (Asian, Native Hawaiian/Pacific Islander, and White), and 2 (1.6%) as unknown race or unsure of race. Microsatellite-stable disease was present in 110 patients (69 in the investigational group and 41 in the placebo group). Median PFS was 4.4 months (95% CI, 4.1-6.4 months) in the investigational group and 3.6 months (95% CI, 2.2-6.2 months) in the placebo group (1-sided log-rank P = .07, a statistically significant result; HR, 0.75; 95% CI, 0.52-1.09). Among patients with MSS and proficient mismatch repair, the HR for PFS was 0.66 (95% CI, 0.44-0.99). The most common grade 3 or higher treatment-related adverse events in the investigational vs placebo groups were hypertension (6 patients [7.0%] vs 2 patients [4.3%]), diarrhea (6 patients [7.0%] vs 2 patients [4.3%]), and hand-foot syndrome (6 patients [7.0%] vs 2 patients [4.3%]). One treatment-related death occurred in the investigational group. In the investigational group, the response rate was higher among patients without liver metastasis (3 of 13 individuals [23.1%]) vs with liver metastasis (4 of 69 individuals [5.8%]). The benefit of atezolizumab for PFS and OS was greater among patients without vs with liver metastasis (primary analysis of PFS: HR, 0.63 [95% CI, 0.27-1.47] vs 0.77 [95% CI, 0.51-1.17]; OS: HR, 0.33 [95% CI, 0.11-1.02] vs 1.14 [95% CI, 0.72-1.81]). Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to capecitabine and bevacizumab therapy provided limited (ie, not clinically meaningful) clinical benefit. Patients with MSS and proficient mismatch repair tumors and those without liver metastasis benefited more from dual inhibition of the vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 pathways. Trial Registration: ClinicalTrials.gov Identifier: NCT02873195.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Bevacizumab/uso terapéutico , Capecitabina/uso terapéutico , Neoplasias Colorrectales , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/administración & dosificación , Bevacizumab/efectos adversos , Capecitabina/administración & dosificación , Capecitabina/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin ProgresiónRESUMEN
PURPOSE: TIGIT (T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain) is a co-inhibitory receptor of T-cell and natural killer cell activity. Targeting TIGIT with or without PD-1/PD-L1 checkpoint inhibition may enhance antitumor immunity. PATIENTS AND METHODS: This Phase 1a/b trial was a first-in-human, open-label, multicenter, dose-escalation and -expansion study in patients with locally advanced or metastatic solid tumors. Using 3 + 3 design, patients underwent 14-day treatment cycles with anti-TIGIT antibody etigilimab alone (Phase 1a; 0.3, 1.0, 3.0, 10.0, 20.0 mg/kg intravenously) or in combination with anti-PD-1 antibody nivolumab (Phase 1b; 3.0, 10.0, 20.0 mg/kg etigilimab and 240 mg nivolumab). Primary objective was safety and tolerability. RESULTS: Thirty-three patients were enrolled (Phase 1a, n = 23; Phase 1b, n = 10). There were no dose-limiting toxicities (DLT). MTD for single and combination therapy was not determined; maximum administered dose was 20 mg/kg. The most commonly reported adverse events (AE) were rash (43.5%), nausea (34.8%), and fatigue (30.4%) in Phase 1a and decreased appetite (50.0%), nausea (50.0%), and rash (40%) in Phase 1b. Six patients experienced Grade ≥3 treatment-related AEs. In Phase 1a, 7 patients (30.0%) had stable disease. In Phase 1b, 1 patient had a partial response; 1 patient had prolonged stable disease of nearly 8 months. Median progression-free survival was 56.0 days (Phase 1a) and 57.5 days (Phase 1b). Biomarker correlative analyses demonstrated evidence of clear dose-dependent target engagement by etigilimab. CONCLUSIONS: Etigilimab had an acceptable safety profile with preliminary evidence of clinical benefit alone and in combination with nivolumab and warrants further investigation in clinical trials.
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Exantema , Neoplasias Primarias Secundarias , Anticuerpos Monoclonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Exantema/inducido químicamente , Exantema/tratamiento farmacológico , Humanos , Náusea/inducido químicamente , Neoplasias Primarias Secundarias/tratamiento farmacológico , Nivolumab/uso terapéuticoRESUMEN
Background Current imaging methods for prediction of complete margin resection (R0) in patients with pancreatic ductal adenocarcinoma (PDAC) are not reliable. Purpose To investigate whether tumor-related and perivascular CT radiomic features improve preoperative assessment of arterial involvement in patients with surgically proven PDAC. Materials and Methods This retrospective study included consecutive patients with PDAC who underwent surgery after preoperative CT between 2012 and 2019. A three-dimensional segmentation of PDAC and perivascular tissue surrounding the superior mesenteric artery (SMA) was performed on preoperative CT images with radiomic features extracted to characterize morphology, intensity, texture, and task-based spatial information. The reference standard was the pathologic SMA margin status of the surgical sample: SMA involved (tumor cells ≤1 mm from margin) versus SMA not involved (tumor cells >1 mm from margin). The preoperative assessment of SMA involvement by a fellowship-trained radiologist in multidisciplinary consensus was the comparison. High reproducibility (intraclass correlation coefficient, 0.7) and the Kolmogorov-Smirnov test were used to select features included in the logistic regression model. Results A total of 194 patients (median age, 66 years; interquartile range, 60-71 years; age range, 36-85 years; 99 men) were evaluated. Aside from surgery, 148 patients underwent neoadjuvant therapy. A total of 141 patients' samples did not involve SMA, whereas 53 involved SMA. A total of 1695 CT radiomic features were extracted. The model with five features (maximum hugging angle, maximum diameter, logarithm robust mean absolute deviation, minimum distance, square gray level co-occurrence matrix correlation) showed a better performance compared with the radiologist assessment (model vs radiologist area under the curve, 0.71 [95% CI: 0.62, 0.79] vs 0.54 [95% CI: 0.50, 0.59]; P < .001). The model showed a sensitivity of 62% (33 of 53 patients) (95% CI: 51, 77) and a specificity of 77% (108 of 141 patients) (95% CI: 60, 84). Conclusion A model based on tumor-related and perivascular CT radiomic features improved the detection of superior mesenteric artery involvement in patients with pancreatic ductal adenocarcinoma. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Do and Kambadakone in this issue.
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Adenocarcinoma/cirugía , Carcinoma Ductal Pancreático/cirugía , Márgenes de Escisión , Arteria Mesentérica Superior/diagnóstico por imagen , Arteria Mesentérica Superior/patología , Neoplasias Pancreáticas/cirugía , Tomografía Computarizada por Rayos X/métodos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Conductos Pancreáticos/cirugía , Proyectos Piloto , Cuidados Preoperatorios/métodos , Reproducibilidad de los Resultados , Estudios Retrospectivos , Neoplasias PancreáticasRESUMEN
Pancreatic adenocarcinoma commonly presents as metastatic disease and harbors a dire prognosis due to its aggressive behavior, propensity for resistance to therapies, and lack of targetable driver mutations. Additionally, despite advances in other cancers, immunotherapy has been ineffective in this disease thus far and treatment remains centered around cytotoxic chemotherapy. Here, we present a case of a patient with pancreatic adenocarcinoma harboring both high microsatellite instability (MSI-H) and HER2 amplification. After an initial response to standard-of-care chemotherapy with FOLFIRINOX followed by progression, she was treated with dual immune checkpoint blockade, which resulted in a period of disease control. This was complicated by the development of autoimmune hypophysitis and an incidental finding of brain metastasis on magnetic resonance imaging (MRI). Her extracranial disease progressed while receiving stereotactic radiosurgery, with findings of lymphangitic spread in her lungs, and her treatment was changed to gemcitabine/nab-paclitaxel with trastuzumab. This resulted in a degree of extracranial disease control, though she experienced progressive brain metastases despite radiation and therapeutic switch to lapatinib and trastuzumab. Ultimately, the patient developed leptomeningeal disease which was not controlled by intrathecal trastuzumab. Given the rarity of central nervous system metastasis, HER2 amplification, and MSI in pancreatic cancer, this patient's presentation represents a confluence of multiple unique features. This case highlights the clinical value of up-front next-generation sequencing in metastatic pancreatic cancer and the ability of pancreatic cancer with actionable molecular variants to develop atypical sites of disease and adaptive resistance.
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Background Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally active, allosteric mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, in pancreas cancer patients with somatic KRASG12R mutations. Methods In this two-stage, phase II study (NCT03040986) patients with advanced pancreas cancer harboring somatic KRASG12R variants who had received at least one standard-of-care systemic therapy regimen received 75 mg selumetinib orally twice a day until disease progression or unacceptable toxicity occurred. The primary outcome of the study was best objective response (BOR). Results From August 2017 to February 2018 a total of 8 patients with confirmed somatic KRASG12R mutations and a median age of 61.5 years were treated with selumetinib. Seven out of eight (87.5%) had received two or more lines of prior systemic chemotherapy. After a median follow-up period of 8.5 months (range 2 to 20), three patients had stable disease for more than 6 months while receiving selumetinib. No patients achieved an objective partial response. Median progression-free survival (PFS) was 3.0 months (95% CI, 0.8-8.2) and median overall survival (OS) 9 months (95% CI, 2.5-20.9). Conclusion This study in heavily pre-treated pancreatic adenocarcinoma patients suggests alternative strategies beyond single agent MEK inhibition are required for this unique, molecular subset of pancreatic cancer patients. The trial was registered on February 2nd, 2017 under identifier NCT03040986 with ClinicalTrials.gov .
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Adenocarcinoma/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Bencimidazoles/uso terapéutico , MAP Quinasa Quinasa 1/antagonistas & inhibidores , MAP Quinasa Quinasa 2/antagonistas & inhibidores , Neoplasias Pancreáticas/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Adenocarcinoma/mortalidad , Administración Oral , Anciano , Antineoplásicos/efectos adversos , Bencimidazoles/efectos adversos , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/mortalidad , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: The immunosuppressive desmoplastic stroma of pancreatic cancer represents a major hurdle to developing an effective immune response. Preclinical studies in pancreatic cancer have demonstrated promising anti-tumor activity with Bruton tyrosine kinase (BTK) inhibition combined with programmed cell death receptor-1 (PD-1) blockade. METHODS: This was a phase II, multicenter, open-label, randomized (1:1) clinical trial evaluating the BTK inhibitor acalabrutinib, alone (monotherapy) or in combination with the anti-PD-1 antibody pembrolizumab (combination therapy). Eligible patients were adults with histologically confirmed metastatic or locally advanced unresectable pancreatic ductal adenocarcinoma with an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤1 who had received at least one prior systemic therapy. Oral acalabrutinib 100 mg twice daily was administered with or without intravenous pembrolizumab 200 mg on day 1 of each 3-week cycle. Peripheral blood was analyzed for changes in immune markers, and tumors from exceptional responders were molecularly analyzed. RESULTS: A total of 77 patients were enrolled (37 monotherapy; 40 combination therapy) with a median age of 64 years; 77% had an ECOG PS of 1. The median number of prior therapies was 3 (range 1-6). Grade 3-4 treatment-related adverse events were seen in 14.3% of patients in the monotherapy arm and 15.8% of those in the combination therapy arm. The overall response rate and disease control rate were 0% and 14.3% with monotherapy and 7.9% and 21.1% with combination therapy, respectively. Median progression-free survival was 1.4 months in both arms. Peripheral blood flow analysis demonstrated consistent reductions in granulocytic (CD15+) myeloid-derived suppressor cells (MDSCs) over time. Two exceptional responders were found to be microsatellite stable with low tumor mutation burden, low neoantigen load and no defects in the homologous DNA repair pathway. CONCLUSIONS: The combination of acalabrutinib and pembrolizumab was well tolerated, but limited clinical activity was seen with either acalabrutinib monotherapy or combination therapy. Peripheral reductions in MDSCs were seen. Efforts to understand and target the pancreatic tumor microenvironment should continue. TRIAL REGISTRATION NUMBER: NCT02362048.
Asunto(s)
Agammaglobulinemia Tirosina Quinasa/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Benzamidas/administración & dosificación , Carcinoma Ductal Pancreático/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Pirazinas/administración & dosificación , Administración Intravenosa , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas/efectos adversos , Carcinoma Ductal Pancreático/diagnóstico , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/mortalidad , Esquema de Medicación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Células Supresoras de Origen Mieloide/efectos de los fármacos , Células Supresoras de Origen Mieloide/inmunología , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/mortalidad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Prueba de Estudio Conceptual , Pirazinas/efectos adversos , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunologíaRESUMEN
PURPOSE: This study was conducted to define the maximum tolerated dose (MTD), recommended phase two dose (RPTD), and toxicities of gemcitabine + dasatinib (GD) and gemcitabine + dasatinib + cetuximab (GDC) in advanced solid tumor patients. METHODS: This study was a standard phase I 3 + 3 dose escalation study evaluating two combination regimens, GD and GDC. Patients with advanced solid tumors were enrolled in cohorts of 3-6 to either GD or GDC. Gemcitabine was dosed at 1000 mg/m2 weekly for 3 of 4 weeks, dasatinib was dosed in mg PO BID, and cetuximab was dosed at 250 mg/m2 weekly after a loading dose of cetuximab of 400 mg/m2. There were two dose levels for dasatinib: (1) gemcitabine + dasatinib 50 mg ± cetuximab, and (2) gemcitabine + dasatinib 70 mg ± cetuximab. Cycle length was 28 days. Standard cycle 1 dose-limiting toxicity (DLT) definitions were used. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities that would increase the risk of toxicity. Serum, plasma, and skin biopsy biomarkers were obtained pre- and on-treatment. RESULTS: Twenty-five patients were enrolled, including 21 with pancreatic adenocarcinoma. Three patients received prior gemcitabine. Twenty-one patients were evaluable for toxicity and 16 for response. Four DLTs were observed: Grade (Gr) 3 neutropenia (GDC1, n = 1), Gr 3 ALT (GD2, n = 2), and Gr 5 pneumonitis (GDC2, n = 1). Possible treatment-emergent adverse events (TEAEs) in later cycles included: Gr 3-4 neutropenia (n = 7), Gr 4 colitis (n = 1), Gr 3 bilirubin (n = 2), Gr 3 anemia (n = 2), Gr 3 thrombocytopenia (n = 2), Gr 3 edema/fluid retention (n = 1), and Gr 3 vomiting (n = 3). Six of 16 patients (3 of whom were gemcitabine-refractory) had stable disease (SD) as best response, median duration = 5 months (range 1-7). One gemcitabine-refractory patient had a partial response (PR). Median PFS was 2.9 months (95% CI 2.1, 5.8). Median OS was 5.8 months (95% CI 4.1, 11.8). Dermal wound biopsies demonstrated that dasatinib resulted in a decrease of total and phospho-Src levels, and cetuximab resulted in a decrease of EGFR and ERBB2 levels. CONCLUSIONS: The MTD/RPTD of GD is gemcitabine 1000 mg/m2 weekly for 3 of 4 weeks and dasatinib 50 mg PO BID. The clinical activity of GD seen in this study was modest, and does not support its further investigation in pancreatic cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cetuximab/administración & dosificación , Dasatinib/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/patología , Neoplasias Pancreáticas/patología , Resultado del Tratamiento , GemcitabinaRESUMEN
Pancreatic cancer is a devastating disease with a universally poor prognosis. In 2015, it is estimated that there will be 48,960 new cases of pancreatic cancer and that 40,560 people will die of the disease. The 5-year survival rate is 7.2% for all patients with pancreatic cancer; however, survival depends greatly on the stage at diagnosis. Unfortunately, 53% of patients already have metastatic disease at diagnosis, which corresponds to a 5-year survival rate of 2.4%. Even for the 9% of patients with localized disease confined to the pancreas, the 5-year survival is still modest at only 27.1%. These grim statistics highlight the need for ways to identify cohorts of individuals at highest risk, methods to screen those at highest risk to identify preinvasive pathologic precursors, and development of effective systemic therapies. Recent clinical and translational progress has emphasized the relationship with diabetes, the role of the stroma, and the interplay of each of these with inflammation in the pathobiology of pancreatic cancer. In this article, we will discuss these relationships and how they might translate into novel management strategies for the treatment of this disease.
Asunto(s)
Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/terapia , Transformación Celular Neoplásica , Terapia Combinada , Diabetes Mellitus/epidemiología , Diabetes Mellitus/metabolismo , Manejo de la Enfermedad , Humanos , Neoplasias Pancreáticas/epidemiología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Factores de Riesgo , Células del Estroma/metabolismo , Células del Estroma/patologíaRESUMEN
The decision about who may derive benefit from adjuvant chemotherapy in colon cancer is often a difficult one for clinicians. While multiple trials have demonstrated that adjuvant chemotherapy reduces the risk of recurrence and improves overall survival in patients with stage III disease, the data supporting the use of adjuvant chemotherapy in patients with stage II disease are not as compelling. Because adjuvant therapy can have significant toxicity, tools to help clinicians determine who may derive a benefit from therapy are of the utmost importance. Recent advances in high throughput technologies have led to the identification of molecular biomarkers-including microsatellite instability (MSI), loss of heterozygosity (LOH), p53, Kirsten rat sarcoma viral oncogene homolog (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), thymidylate synthase (TS), and excision repair cross-complementation group 1 (ERCC1)--as well as various multigene assays that are being studied for their ability to offer both prognostic and predictive information to clinicians. Here we review the current knowledge about molecular biomarkers that may aid the clinician in offering personalized cancer therapy based on the genetic landscape of an individual patient's tumor.
Asunto(s)
Biomarcadores , Recurrencia Local de Neoplasia , Animales , Quimioterapia Adyuvante , Neoplasias del Colon/genética , Humanos , Inestabilidad de Microsatélites , Recurrencia Local de Neoplasia/tratamiento farmacológico , PronósticoRESUMEN
The peroxisome proliferator-activated receptors (PPARalpha, PPARdelta, and PPARgamma) constitute a family of nuclear receptors that regulates metabolic processes involved in lipid and glucose homeostasis. Although generally considered to function as ligand-regulated receptors, all three PPARs exhibit a high level of constitutive activity that may result from their stimulation by intracellularly produced endogenous ligands. Consequently, complete inhibition of PPAR signaling requires the development of inverse agonists. However, the currently available small molecule antagonists for the PPARs function only as partial agonists, or their efficacy is not sufficient to inhibit the constitutive activity of these receptors. Due to the lack of efficacious antagonists that interact with the ligand-binding domain of the PPARs, we decided to target an interaction that is central to nuclear receptor-mediated gene transcription: the nuclear receptor-coactivator interaction. We utilized phage display technology to identify short LXXLL-containing peptides that bind to the PPARs. Analysis of these peptides revealed a consensus binding motif consisting of HPLLXXLL. Cross-screening of these peptides for binding to other nuclear receptors enabled the identification of a high-affinity PPAR-selective peptide that has the ability to repress PPARgamma1-dependent transcription of transfected reporter genes. Most importantly, when introduced into HepG2 cells, the peptide inhibited the expression of endogenous PPARgamma1 target genes, adipose differentiation-related protein and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase 2. This work lends support for the rational development of peptidomimetics that block receptor-mediated transcription by targeting the nuclear receptor-coactivator interaction surface.