SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer.

INTRODUCTION: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer. METHODS: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity. RESULTS: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure). CONCLUSIONS: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer. CLINICAL TRIAL REGISTRATION: NCT02834013 (ClincialTrials.gov). PLAIN LANGUAGE SUMMARY: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.

Selective internal radiation therapy using yttrium-90 microspheres for treatment of localized and locally advanced intrahepatic cholangiocarcinoma.

OBJECTIVES: To evaluate safety and effectiveness of selective internal radiation therapy (SIRT) using yttrium-90 for localized and locally advanced intrahepatic cholangiocarcinoma (iCCA). METHODS: A retrospective review was performed of patients with localized iCCA treated with SIRT at a single institution. Overall survival (OS), local tumor response, progression-free survival (PFS), and toxicity were collected. Stratified analysis was performed based on surgical resection. Predictor analysis of OS was performed using the Fine-Grey regression analysis model with patients bridged to surgery regarded as competing events. RESULTS: A total of 28 consecutive patients with localized iCCA were treated with a total of 38 sessions of SIRT (17 segmental, 13 lobar, and 8 combined deliveries) and a mean dominant target dose per session of 238.4 ± 130.0 Gy. The cumulative radiologic response rate was 16/28 (57.1%) with a median PFS of 265 days. Median survival time (MST) was 22.9 months for the entire cohort with 1-year and 3-year survival of 78.4% and 45.1%, respectively. Ten patients (34.5%) were downstaged to surgical intervention (7 resection, 3 transplant) and showed longer OS (p = 0.027). The 1-year and 3-year OS for patients who received surgery were 100% and 62.5% (95% CI: 14.2-89.3%), respectively. Age (p = 0.028), Eastern Cooperative Oncology Group performance status (p = 0.030), and objective radiologic response (p=0.014) are associated with OS. Two ≥grade 3 hyperbilirubinemia, anemia, and one pleuro-biliary fistula occurred post-SIRT. CONCLUSIONS: SIRT for localized iCCA is safe and effective in achieving radiological response, downstaging to surgery and transplant, and resulting in pathologic necrosis. CLINICAL RELEVANCE STATEMENT: Selective internal radiation therapy should be considered for patients with localized and locally advanced intrahepatic cholangiocarcinoma. KEY POINTS: • The effectiveness of radioembolization for intrahepatic cholangiocarcinoma (iCCA) can be underestimated given the inclusion of extrahepatic disease. • Radioembolization is safe and effective for local and locally advanced iCCA. Age, Eastern Cooperative Oncology Group performance status, and radiologic response are associated with survival. • Radioembolization should be considered for patients with localized and locally advanced iCCA.

Modified Radiation Lobectomy Strategy of Radioembolization for Right-Sided Unresectable Primary Liver Tumors.

PURPOSE: To assess the safety and effectiveness of using modified radiation lobectomy (mRL) to treat primary hepatic tumors located in the right hepatic lobe (Segments V-VIII) and to determine future liver remnant (FLR) hypertrophy. MATERIALS AND METHODS: A retrospective review was performed at a single institution to include 19 consecutive patients (7 females, 12 males) who underwent single-session mRL for right-sided primary hepatic tumors: 15 received segmentectomy plus lobectomy (segmental dose of >190 Gy and lobar dose of >80 Gy); 4 were treated with the double-segmental approach (dominant segments of >190 Gy and nondominant segments of >80 Gy). Treated tumors included 13 hepatocellular carcinoma (HCC), 4 cholangiocarcinoma (CCA), and 2 mixed-type HCC-CCA with a median dominant tumor size of 5.3 cm (interquartile range [IQR], 3.7-7.3 cm). FLR of the left hepatic lobe was measured at baseline, T1 (4-8 weeks), T2 (2-4 months), T3 (4-6 months), and T4 (9-12 months). RESULTS: Objective tumor response and tumor control were achieved in 17 of the 19 (89.5%) and 18 of the 19 (94.7%) patients, respectively. FLR hypertrophy was observed at T1 (median, 47.8%; P = .025), T2 (median, 48.4%; P = .012), T3 (median, 50.4%; P = .015), and T4 (median, 59.1%; P < .001). Patients without cirrhosis demonstrated greater hypertrophy by 6 months (median, 55.8% vs 47.2%; P = .031). One patient developed a Grade 3 adverse event (ascites requiring paracentesis) at 1-month follow-up. Grade ≥2 serum toxicities were associated with worse baseline Child-Pugh Score, serum albumin, and total bilirubin (P < .05). Among 7 patients who underwent neoadjuvant mRL, 2 underwent resection and 1 received liver transplant. CONCLUSIONS: mRL appears safe and effective for treatment of right-sided primary hepatic tumors with the benefit of promoting FLR hypertrophy.

Survival Outcomes of Radiofrequency Ablation for Intrahepatic Cholangiocarcinoma from the SEER Database: Comparison with Radiotherapy and Resection.

PURPOSE: To determine effectiveness of radiofrequency ablation for treatment of intrahepatic cholangiocarcinoma (iCCA) using a population-based database. MATERIALS AND METHODS: Data was extracted from Surveillance, Epidemiology, and End Results database from 2000 to 2020 to include 194 patients who underwent ablation for iCCA. Patient demographics, overall survival (OS), and cancer-specific survival (CSS) were retrieved. Factors associated with survival were evaluated. Comparison between ablation and surgical resection (n=2653) or external beam radiotherapy (n=1068) were performed. RESULTS: In the ablation group, atients diagnosed and treated after 2010 demonstrated improved OS than the 2000-2009 subgroup (mOS 32 versus 21 months, HR: 0.50 [95%CI: 0.33-0.75], p=0.001). Additional factors associated with OS included tumor size (≤3cm versus >3cm, p=0.049) and tumor stage (p<0.001). For patients diagnosed after 2010, the 1-, 3-, and 5-year OS were 82.8% (95%CI: 74.8-88.4%), 43.5% (95%CI: 33.5-53.1%), and 23.7% (95%CI: 15.3-33.5%), respectively. Patients with local disease (1-year OS: 87.8% [95%CI: 78.6-93.3%]) demonstrated improved OS than regional (1-year OS: 81.3% [95%CI: 52.5-93.5%]) and distant disease (50.2% [95%CI: 34.0-78.8%], p<0.001). For tumors ≤3cm, ablation and surgical resection offered comparable survival benefits (p=0.561), although both were better than radiotherapy (p<0.0001). CONCLUSION: Survival of iCCA patients who underwent thermal ablation has improved over the last 10 years. For tumors ≤3cm, ablation could be as effective as resection with careful candidate selection, and may be considered as front line compared to radiotherapy in certain patient populations. Patient selection based on tumor size and disease stage could improve survival outcomes.

COMPANION-002 A clinical trial of investigational drug CTX-009 plus paclitaxel vs paclitaxel in second line advanced BTC.

Treatment options for patients with biliary tract cancer are limited, and the prognosis is poor. CTX-009, a novel bispecific antibody targeting both DLL4 and VEGF-A, has demonstrated antitumor activity in patients with advanced cancers as both a monotherapy and in combination with chemotherapy. In a phase II study of patients with advanced biliary tract cancer who had received one or two prior therapies, CTX-009 with paclitaxel demonstrated a 37.5% overall response rate (ORR). Described here is the design of and rationale for COMPANION-002, a randomized phase II/III study, which will evaluate the safety and efficacy of CTX-009 in combination with paclitaxel versus paclitaxel alone as second-line treatment for patients with advanced biliary tract cancer. The primary end point is ORR, and crossover is allowed.Clinical Trial Registration: NCT05506943 (ClinicalTrials.gov).

Looking for new options for patients with advanced biliary tract cancer? Explore COMPANION-002, Compass Therapeutics' phase II/III study of CTX-009 + paclitaxel as a second line treatment.#CMPX #biotech #healthcare #rarecancer.

Yttrium-90 Radioembolization and Concomitant Systemic Gemcitabine, Cisplatin, and Capecitabine as the First-Line Therapy for Locally Advanced Intrahepatic Cholangiocarcinoma.

PURPOSE: To determine the safety and effectiveness of yttrium-90 transarterial radioembolization (TARE) combined with systemic gemcitabine, cisplatin, and capecitabine for the first-line treatment of locally advanced intrahepatic cholangiocarcinoma (iCCA). MATERIALS AND METHODS: Data of 13 patients with treatment-naïve, locally advanced iCCA treated with a downstaging protocol using gemcitabine, cisplatin, TARE, and capecitabine were retrospectively reviewed. Overall survival (OS), local tumor response (modified Response Evaluation Criteria in Solid Tumors), progression-free survival (PFS), technical adverse events, and toxicity were measured. RESULTS: Calculated from the time of diagnosis, the median OS was 29 months (95% confidence interval [CI], 15 to not reached), with a 1-year OS of 84.6% (95% CI, 52.2%-95.9%) and 2-year OS of 52.9% (95% CI, 20.3%-77.5%). The median OS values were 24 months (95% CI, 8 to not reached) and 21 months (95% CI, 5 to not reached) from the time of initial cycle of chemotherapy and TARE, respectively. Patients who were downstaged to surgery (n = 7, 53.8%) had a more favorable OS (median OS, not reached vs 15 months; P = .0221). Complete and partial radiologic responses were achieved in 5 (38.5%) and 6 (46.2%) patients, respectively. The median PFS was 13 months (95% CI, 12 to not reached). Although no serum toxicity with Grade >2 occurred within 3 months after TARE, 1 patient was no longer a surgical candidate given suboptimal nutrition status despite successful downstage on imaging studies. Two patients required a reduced dose or delay of post-TARE chemotherapy. CONCLUSIONS: First-line combination therapy with TARE and systemic gemcitabine, cisplatin, and capecitabine is an effective treatment with an acceptable safety profile for iCCA with a high rate of downstaging to resection.

Segmental Yttrium-90 Radioembolization Using Glass Microspheres Greater than 400 Gray for the Treatment of Intrahepatic Cholangiocarcinoma: A Preliminary Experience.

Radiation segmentectomy with a dose of >190 Gy using yttrium-90 (90Y) glass microspheres for intrahepatic cholangiocarcinoma (iCCA) has been shown to be safe and effective. The present study further increased the dose to >400 Gy for treatment of iCCA as complete pathologic necrosis has been shown in hepatocellular carcinoma using this ablative approach. A total of 10 patients with 13 tumors (median size, 5.3 cm; range, 1.5-13.6 cm) at a single institution underwent >400-Gy segmental radioembolization. Objective response was achieved in all tumors (13 of 13, 100%). One patient developed a Grade 3 or greater major adverse event (stroke and hepatic decompensation). One patient was bridged to transplant (>95% pathologic necrosis), whereas another underwent resection (>99% necrosis). Contralateral hypertrophy was observed in 6 out of 6 patients treated with modified lobectomy dosing, with a functional liver reserve increase from a median of 31.5% to 57.1%. The present report suggests that segmental transarterial radioembolization with >400 Gy is feasible in terms of safety and effectiveness for treating iCCA.

Phase II Prospective, Open-Label Randomized Controlled Trial Comparing Standard of Care Chemotherapy With and Without Sequential Cytoreductive Interventions for Patients with Oligometastatic Foregut Adenocarcinoma and Undetectable Circulating Tumor Deoxyribose Nucleic Acid (ctDNA) Levels.

BACKGROUND: Metastatic adenocarcinomas of foregut origin are aggressive and have limited treatment options, poor quality of life, and a dismal prognosis. A subset of such patients with limited metastatic disease might have favorable outcomes with locoregional metastasis-directed therapies. This study investigates the role of sequential cytoreductive interventions in addition to the standard of care chemotherapy in patients with oligometastatic foregut adenocarcinoma. METHODS: This is a single-center, phase II, open-label randomized clinical trial. Eligible patients include adults with synchronous or metachronous oligometastatic (metastasis limited to two sites and amenable for curative/ablative treatment) adenocarcinoma of the foregut without progression after induction chemotherapy and having undetectable ctDNA. These patients will undergo induction chemotherapy and will then be randomized (1:1) to either sequential curative intervention followed by maintenance chemotherapy versus routine continued chemotherapy. The primary endpoint is progression-free survival (PFS), and a total of 48 patients will be enrolled to detect an improvement in the median PFS in the intervention arm with a hazard ratio (HR) of 0.5 with 80% power and a one-sided alpha of 0.1. Secondary endpoints include disease-free survival (DFS) in the intervention arm, overall survival (OS), ctDNA conversion rate pre/post-induction chemotherapy, ctDNA PFS, PFS2, adverse events, quality of life, and financial toxicity. DISCUSSION: This is the first randomized study that aims to prospectively evaluate the efficacy and safety of surgical/ablative interventions in patients with ctDNA-negative oligometastatic adenocarcinoma of foregut origin post-induction chemotherapy. The results from this study will likely develop pertinent, timely, and relevant knowledge in oncology.

Deep learning prediction of BRAF-RAS gene expression signature identifies noninvasive follicular thyroid neoplasms with papillary-like nuclear features.

Noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTP) are follicular-patterned thyroid neoplasms defined by nuclear atypia and indolent behavior. They harbor RAS mutations, rather than BRAFV600E mutations as is observed in papillary thyroid carcinomas with extensive follicular growth. Reliably identifying NIFTPs aids in safe therapy de-escalation, but has proven to be challenging due to interobserver variability and morphologic heterogeneity. The genomic scoring system BRS (BRAF-RAS score) was developed to quantify the extent to which a tumor's expression profile resembles a BRAFV600E or RAS-mutant neoplasm. We proposed that deep learning prediction of BRS could differentiate NIFTP from other follicular-patterned neoplasms. A deep learning model was trained on slides from a dataset of 115 thyroid neoplasms to predict tumor subtype (NIFTP, PTC-EFG, or classic PTC), and was used to generate predictions for 497 thyroid neoplasms within The Cancer Genome Atlas (TCGA). Within follicular-patterned neoplasms, tumors with positive BRS (RAS-like) were 8.5 times as likely to carry an NIFTP prediction than tumors with negative BRS (89.7% vs 10.5%, P < 0.0001). To test the hypothesis that BRS may serve as a surrogate for biological processes that determine tumor subtype, a separate model was trained on TCGA slides to predict BRS as a linear outcome. This model performed well in cross-validation on the training set (R2 = 0.67, dichotomized AUC = 0.94). In our internal cohort, NIFTPs were near universally predicted to have RAS-like BRS; as a sole discriminator of NIFTP status, predicted BRS performed with an AUC of 0.99 globally and 0.97 when restricted to follicular-patterned neoplasms. BRAFV600E-mutant PTC-EFG had BRAFV600E-like predicted BRS (mean -0.49), nonmutant PTC-EFG had more intermediate predicted BRS (mean -0.17), and NIFTP had RAS-like BRS (mean 0.35; P < 0.0001). In summary, histologic features associated with the BRAF-RAS gene expression spectrum are detectable by deep learning and can aid in distinguishing indolent NIFTP from PTCs.

Cytoreductive Surgery for Selected Patients Whose Metastatic Gastric Cancer was Treated with Systemic Chemotherapy.

BACKGROUND: The authors hypothesized that cytoreductive surgery (CRS, comprising gastrectomy combined with metastasectomy) in addition to systemic chemotherapy (SC) is associated with a better survival than chemotherapy alone for patients with metastatic gastric adenocarcinoma (MGA). METHODS: Patients with MGA who received SC between 2004 and 2016 were identified using the National Cancer Database (NCDB). Nearest-neighbor 1:1 propensity score-matching was used to create comparable groups. Overall survival (OS) was compared between subgroups using Kaplan-Meier analyses. Immortal bias analysis was performed among those who survived longer than 90 days. RESULTS: The study identified 29,728 chemotherapy-treated patients, who were divided into the following four subgroups: no surgery (NS, n = 25,690), metastasectomy alone (n = 1170), gastrectomy alone (n = 2248), and CRS (n = 620) with median OS periods of 8.6, 10.9, 14.8, and 16.3 months, respectively (p < 0.001). Compared with the patients who underwent NS, the patients who had CRS were younger (58.9 ± 13.4 vs 62.0 ± 13.1 years), had a lower proportion of disease involving multiple sites (4.6% vs 19.1%), and were more likely to be clinically occult (cM0 stage: 59.2% vs 8.3%) (p < 0.001 for all). The median OS for the propensity-matched patients who underwent CRS (n = 615) was longer than for those with NS (16.4 vs 9.3 months; p < 0.001), including in those with clinical M1 stage (n = 210). In the Cox regression model using the matched data, the hazard ratio for CRS versus NS was 0.56 (95% confidence interval [CI], 0.49-0.63). In the immortal-matched cohort, the corresponding median OS was 17.0 versus 9.5 months (p < 0.001). CONCLUSIONS: In addition to SC, CRS may be associated with an OS benefit for a selected group of MGA patients meriting further prospective investigation.

Novel Application of Iterative Hyperthermic Intraperitoneal Chemotherapy for Unresectable Peritoneal Metastases from High-Grade Appendiceal Ex-Goblet Adenocarcinoma.

BACKGROUND: Peritoneal metastases (PMs) from appendiceal ex-goblet adenocarcinoma (AEGA) are associated with a poor prognosis. While cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to prolong survival, the majority of patients are ineligible for complete cytoreduction. We describe a novel approach to the management of such patients with iterative HIPEC (IHIPEC). METHODS: Patients with signet ring/poorly differentiated AEGA with high Peritoneal Cancer Index (PCI) and extensive bowel involvement underwent IHIPEC with mitomycin C at 6-week intervals for a total of three cycles. Survival outcomes for these patients were compared with patients with high-grade appendiceal tumors matched for tumor burden who were treated with other conventional approaches, i.e. systemic chemotherapy only (SCO) or complete CRS + HIPEC. RESULTS: Between 2016 and 2019, seven AEGA patients with high PCI (median 32.5 [range 21-36]) underwent 18 IHIPEC cycles (median cycles per patient 3 [2-3]) in combination with systemic chemotherapy (median 2 lines [1-3], 12 cycles [10-28]). IHIPEC was delivered laparoscopically in 14/18 cases. Postoperatively, the median length of stay was 1 day (1-8 days), no procedure-related complications were reported, and five (28%) 90-day readmissions for bowel obstruction were documented. Median overall survival after IHIPEC was better compared with a matched group of patients (n = 16) receiving SCO (24.6 vs. 7.9 months; p = 0.005), and similar to those (n = 7) who underwent CRS + HIPEC (24.6 vs. 16.5 months; p = 0.62). CONCLUSIONS: IHIPEC in combination with systemic chemotherapy is tolerable, safe, and may be associated with encouraging survival outcomes compared with SCO in selected patients with high-grade, high-burden AEGA PM.

Targeted therapies in hepatocellular carcinoma: past, present, and future.

Targeted therapies are the mainstay of systemic therapies for patients with advanced, unresectable, or metastatic hepatocellular carcinoma. Several therapeutic targets, such as c-Met, TGF-ß, and FGFR, have been evaluated in the past, though results from these clinical studies failed to show clinical benefit. However, these remain important targets for the future with novel targeted agents and strategies. The Wnt/ß-catenin signaling pathway, c-Myc oncogene, GPC3, PPT1 are exciting novel targets, among others, currently undergoing evaluation. Through this review, we aim to provide an overview of previously evaluated and potentially novel therapeutic targets and explore their continued relevance in ongoing and future studies for HCC.

Peptide Receptor Radionuclide Therapy versus Capecitabine/Temozolomide for the Treatment of Metastatic Pancreatic Neuroendocrine Tumors.

Background: Peptide Receptor Radionuclide Therapy (PRRT), a form of Radioligand Therapy (RLT), and Capecitabine/Temozolomide (CAPTEM) are cornerstones of systemic therapy for metastatic pancreatic neuroendocrine tumors (PNETs). Data regarding comparative efficacy are lacking. Herein, we compare the efficacy of PRRT vs. CAPTEM as second-line/beyond regimens and treatment sequencing. Methods: Clinicopathologic, radiographic, and genomic data were captured for metastatic PNETs seen in our multi-disciplinary NET clinic between 2013 and 2023. The primary outcome was progression-free survival (PFS) after progression on a previous line of systemic therapy. The secondary outcomes were objective response rate (ORR), time to response (TTR), and overall survival (OS). Results: Fifty-nine cases were included. PFS was similar in the PRRT (n = 29) and CAPTEM (n = 30) groups (PRRT = 21.90 months vs. CAPTEM = 20.03 months; HR 0.99; p = 0.97). On subgroup analysis, PRRT had longer PFS in cases without extrahepatic metastases (26.47 months vs. 17.67 months; p = 0.03) and cases with a mutation in the MEN1, DAXX, and/or ATRX genes (28.43 months vs. 18.67 months; p = 0.03). PRRT had reduced PFS in patients with grade 3 disease (7.83 months vs. 16.33 months; p = 0.02). ORR did not vary significantly (34.78% vs. 40.91%; p = 0.67). CAPTEM responders showed shorter TTR (6.03 months vs. 11.15 months; p = 0.03). In patients who received both, OS did not vary based on the sequence (HR 1.20; p = 0.75). Conclusions: PFS, ORR, and OS are similar when using PRRT vs. CAPTEM as second-line-and-beyond therapy for patients with metastatic PNETs. However, patients with MEN1, DAXX, and/or ATRX mutations or without extrahepatic metastases might better benefit from PRRT and patients with grade 3 disease from CAPTEM. Candidates for surgical debulking or with tumor-induced symptoms may benefit from initial treatment with CAPTEM due to shorter TTR.

MEN1/DAXX/ATRX mutations enhance progression-free survival in gastroenteropancreatic neuroendocrine tumors treated with peptide receptor radionuclide therapy.

Pre-clinical data suggest that mutations in the MEN1, DAXX, and/or ATRX genes may potentially increase radiation efficacy in cancer cells. Herein, we explore the association between response to peptide receptor radionuclide therapy (PRRT) and those mutations in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). We analyzed tissue-based next generation sequencing (NGS) assay results and clinicopathologic data from 28 patients with GEP-NETs treated with PRRT. Findings were correlated with progression-free survival (PFS) and objective response rate (ORR). Patients with mutations in MEN1, DAXX, and/or ATRX (n = 13) had a longer median PFS (26.47 vs 12.13 months; P = 0.014) than wild-type (n = 15) patients when adjusted for surgery prior to PRRT, tumor grade, and presence of TP53 mutation. Alterations in MEN1 along with a concurrent mutation in either DAXX or ATRX (n = 6) trended toward longer PFS compared to patients without concurrent mutations (31.53 vs 17.97 months; P = 0.09). ORR was higher in patients with a mutation in MEN1, DAXX, or ATRX (41.67% vs 15.38%). In pancreatic NET patients, these target mutations also showed a longer PFS (28.43 vs 9.83 months; P = 0.04). TP53 alterations showed a shorter PFS than wild-type cases (11.17 vs 20.47 months; P = 0.009). Mutations in MEN1/DAXX/ATRX are associated with improved PFS in patients with GEP-NETs receiving PRRT and might be used as a biomarker for treatment response.

Surgery enhances the effectiveness of peptide receptor radionuclide therapy in metastatic gastroenteropancreatic neuroendocrine tumors.

BACKGROUND: With the advent of peptide receptor radionuclide therapy, the timing and sequence of surgery in the treatment of metastatic gastroenteropancreatic neuroendocrine tumors merits further study. We hypothesized that surgery before peptide receptor radionuclide therapy might enhance its effectiveness in patients with metastatic gastroenteropancreatic neuroendocrine tumors. METHODS: Eighty-nine patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors treated with 177Lutetium-dotatate peptide receptor radionuclide therapy between 2018 and 2023 were included. Fifty-six patients underwent surgery (primary tumor resection and/or liver debulking) before peptide receptor radionuclide therapy and 33 patients did not. Primary outcome was progression-free survival according to Response Evaluation Criteria in Solid Tumors. Pretreatment dotatate positron emission tomography/computed tomography was used to calculate tumor volumes. RESULTS: The surgery and no-surgery groups were well-matched. Median progression-free survival after peptide receptor radionuclide therapy was 15.6 months (interquartile range, 9.1-22.7 months) in the no-surgery group compared with 26.1 months (interquartile range, 12.7-38.1 months) in the surgery group (P = .04). On subgroup analysis, median progression-free survival was 18.1 months (interquartile range, 11.9-38.4 months) in patients who underwent primary tumor resection only compared with 26.2 months (interquartile range, 14.0-38.1 months) in patients who underwent liver debulking (P = .04). Tumor volume was lowest in patients who underwent liver debulking (median 146.07 mL3) compared with no surgery (median 626.42 mL3) (P = .001). On univariable analysis, a tumor volume <138.8 mL3 was associated with longer progression-free survival (hazard ratio, 2.03; 95% confidence interval, 0.95-4.34, P = .05), with a median progression-free survival of 38.1 months (interquartile range, 16.9-41.3 months) compared with 17.8 months (interquartile range, 10.8-28.7 months). CONCLUSION: Surgery may enhance the effectiveness of 177Lutetium-dotatate in the treatment of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors. This positive effect may be the result of a lower tumor volume in patients after surgery. Our findings fortify the concept of using surgical debulking to improve systemic therapies such as peptide receptor radionuclide therapy.

Single center outcomes from parenchymal-sparing resections and microwave ablations for neuroendocrine tumor liver metastases.

BACKGROUND: Reported outcomes after surgical debulking in patients with advanced neuroendocrine tumor liver metastases (NETLM) are sparse. METHODS: NETLM patients that underwent surgical debulking from 2019 to 2021 were reviewed. Trends in perioperative liver function, complications, symptom response, and progression-free survival were examined. RESULTS: 1069 liver lesions were debulked from 53 patients using a combination of parenchymal-sparing resections (PSR) and ultrasound-guided microwave ablations (MWA). Post-operative transaminitis and thrombocytopenia were common, and severity correlated with increasing number of lesions. Laboratory markers for synthetic liver function did not differ according to the number of lesions debulked. 13% of patients sustained a Clavien-Dindo grade 3 or 4 complication which was not associated with the number of lesions targeted. All patients with preoperative symptoms had improvement after surgery. Median time to progression was 10.9 months. CONCLUSIONS: PSR with MWA for large numbers of NETLM is safe and effective for symptom control and does not affect synthetic liver function.

Multi-Institutional Study Evaluating the Role of Circulating Tumor DNA in the Management of Appendiceal Cancers.

PURPOSE: Conventional surveillance methods are poorly sensitive for monitoring appendiceal cancers (AC). This study investigated the utility of circulating tumor DNA (ctDNA) in evaluating systemic therapy response and recurrence after surgery for AC. METHODS: Patients from two specialized centers who underwent tumor-informed ctDNA testing (Signatera) were evaluated to determine the association between systemic therapy and ctDNA detection. In addition, the accuracy of ctDNA detection during surveillance for the diagnosis of recurrence after complete cytoreductive surgery (CRS) for grade 2-3 ACs with peritoneal metastases (PM) was investigated. RESULTS: In this cohort of 94 patients with AC, most had grade 2-3 tumors (84.0%) and PM (84.0%). Fifty patients completed the assay in the presence of identifiable disease, among which ctDNA was detected in 4 of 7 (57.1%), 10 of 16 (62.5%), and 19 of 27 (70.4%) patients with grade 1, 2, and 3 diseases, respectively. Patients who had recently received systemic chemotherapy had ctDNA detected less frequently (7 of 16 [43.8%] v 26 of 34 [76.5%]; odds ratio, 0.22 [95% CI, 0.06 to 0.82]; P = .02). Among 36 patients with complete CRS for grade 2-3 AC-PM, 16 (44.4%) developed recurrence (median follow-up, 19.6 months). ctDNA detection was associated with shorter recurrence-free survival (median 11.3 months v not reached; hazard ratio, 14.1 [95% CI, 1.7 to 113.8]; P = .01) and showed high accuracy for the detection of recurrence (sensitivity 93.8%, specificity 85.0%). ctDNA was more sensitive than carcinoembryonic antigen (62.5%), CA19-9 (25.0%), and CA125 (18.8%) and was the only elevated biomarker in four (25%) patients with recurrence. CONCLUSION: This study revealed a reduced ctDNA detection frequency after systemic therapy and accurate recurrence assessment after CRS. These findings underscore the role of ctDNA as a predictive and prognostic biomarker for grade 2-3 AC-PM management.

A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .