KRAS promotes GLI2-dependent transcription during pancreatic carcinogenesis.

Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma (PDAC). However, the mechanistic link with established drivers of this disease remains in part elusive. Here, using a new genetically-engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of PDAC development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared to the KrasG12D only expressing mice. Analysis of the mechanism using RNA-seq demonstrate higher levels of GLI2 targets, particularly tumor growth promoting genes including Ccnd1, N-Myc and Bcl2, in KrasG12D mutant cells. Further, ChIP-seq studies showed that in these cells KrasG12D increases the levels of H3K4me3 at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.

Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma.

PURPOSE: To investigate the molecular characteristics of and potential for precision medicine in KRAS wildtype pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We investigated 27 patients with KRASWT PDAC at our institution. Clinical data were obtained via chart review. Tumor specimens for each subject were interrogated for somatic single nucleotide variants, insertion and deletions, and copy number variants by DNA sequencing. Gene fusions were detected from RNA-seq. A patient-derived organoid (PDO) was developed from a patient with a MET translocation and expanded ex vivo to predict therapeutic sensitivity prior to enrollment in a phase 2 clinical trial. RESULTS: Transcriptomic analysis showed our cohort may be stratified by the relative gene expression of the KRAS signaling cascade. The PDO derived from our patient harboring a TFG-MET rearrangement was found to have in vitro sensitivity to the multi-tyrosine kinase inhibitor crizotinib. The patient was enrolled in the phase 2 SPARTA clinical trial and received monotherapy with vebrelitinib, a c-MET inhibitor, and achieved a partial and durable response. CONCLUSIONS: KRASWT PDAC is molecularly distinct from KRASMUT and enriched with potentially actionable genetic variants. In our study, transcriptomic profiling revealed that the KRAS signaling cascade may play a key role in KRASWT PDAC. Our report of a KRASWT PDAC patient with TFG-MET rearrangement who responded to a cMET inhibitor further supports the pursuit of precision oncology in this sub-population. Identification of targetable mutations, perhaps through approaches like RNA-seq, can help enable precision-driven approaches to select optimal treatment based on tumor characteristics.

Transforming the oncology data paradigm by creating, capturing, and retrieving structured cancer data at the point of care: A Mayo Clinic pilot.

INTRODUCTION: Structured data capture requires defined languages such as minimal Common Oncology Data Elements (mCODE). This pilot assessed the feasibility of capturing 5 mCODE categories (stage, disease status, performance status (PS), intent of therapy and intent to change therapy). METHODS: A tool (SmartPhrase) using existing and custom structured data elements was Built to capture 4 data categories (disease status, PS, intent of therapy and intent to change therapy) typically documented as free-text within notes. Existing functionality for stage was supported by the Build. Participant survey data, presence of data (per encounter), and time in chart were collected prior to go-live and repeat timepoints. The anticipated outcome was capture of >50% sustained over time without undue burden. RESULTS: Pre-intervention (5-weeks before go-live), participants had 1390 encounters (1207 patients). The median percent capture across all participants was 32% for stage; no structured data was available for other categories pre-intervention. During a 6-month pilot with 14 participants across three sites, 4995 encounters (3071 patients) occurred. The median percent capture across all participants and all post-intervention months increased to 64% for stage and 81%-82% for the other data categories post-intervention. No increase in participant time in chart was noted. Participants reported that data were meaningful to capture. CONCLUSIONS: Structured data can be captured (1) in real-time, (2) sustained over time without (3) undue provider burden using note-based tools. Our system is expanding the pilot, with integration of these data into clinical decision support, practice dashboards and potential for clinical trial matching.

A Phase I Trial of Nab-Paclitaxel/Bevacizumab (AB160) Nano-Immunoconjugate Therapy for Gynecologic Malignancies.

PURPOSE: AB160 is a 160-nm nano-immunoconjugate consisting of nab-paclitaxel (ABX) nanoparticles noncovalently coated with bevacizumab (BEV) for targeted delivery into tissues expressing high levels of VEGF. Preclinical data showed that AB160 resulted in greater tumor targeting and tumor inhibition compared with sequential treatment with ABX then BEV. Given individual drug activity, we investigated the safety and toxicity of AB160 in patients with gynecologic cancers. PATIENTS AND METHODS: A 3+3 phase I trial was conducted with three potential dose levels in patients with previously treated endometrial, cervical, and platinum-resistant ovarian cancer to ascertain the recommended phase II dose (RP2D). AB160 was administered intravenously on days 1, 8, and 15 of a 28-day cycle (ABX 75-175 mg/m2, BEV 30-70 mg/m2). Pharmacokinetic analyses were performed. RESULTS: No dose-limiting toxicities (DLT) were seen among the three dose levels tested. Grade 3/4 toxicities included neutropenia, thromboembolic events, and leukopenia. DL2 (ABX 150 mg/m2, BEV 60 mg/m2) was chosen as the RP2D. Seven of the 19 patients with measurable disease (36.8%) had confirmed partial responses (95% confidence interval, 16.3%-61.6%). Pharmacokinetic analyses demonstrated that AB160 allowed 50% higher paclitaxel dosing and that paclitaxel clearance mirrored that of therapeutic antibodies. CONCLUSIONS: The safety profile and clinical activity of AB160 supports further clinical testing in patients with gynecologic cancers; the RP2D is DL2 (ABX 150 mg/m2, BEV 60 mg/m2).

Neoadjuvant cobimetinib and atezolizumab with or without vemurafenib for high-risk operable Stage III melanoma: the Phase II NeoACTIVATE trial.

Both targeted therapies and immunotherapies provide benefit in resected Stage III melanoma. We hypothesized that the combination of targeted and immunotherapy given prior to therapeutic lymph node dissection (TLND) would be tolerable and drive robust pathologic responses. In NeoACTIVATE (NCT03554083), a Phase II trial, patients with clinically evident resectable Stage III melanoma received either 12 weeks of neoadjuvant vemurafenib, cobimetinib, and atezolizumab (BRAF-mutated, Cohort A, n = 15), or cobimetinib and atezolizumab (BRAF-wild-type, Cohort B, n = 15) followed by TLND and 24 weeks of adjuvant atezolizumab. Here, we report outcomes from the neoadjuvant portion of the trial. Based on intent to treat analysis, pathologic response (≤50% viable tumor) and major pathologic response (complete or near-complete, ≤10% viable tumor) were observed in 86.7% and 66.7% of BRAF-mutated and 53.3% and 33.3% of BRAF-wild-type patients, respectively (primary outcome); these exceeded pre-specified benchmarks of 50% and 30% for major pathologic response. Grade 3 and higher toxicities, primarily dermatologic, occurred in 63% during neoadjuvant treatment (secondary outcome). No surgical delays nor progression to regional unresectability occurred (secondary outcome). Peripheral blood CD8 + TCM cell expansion associated with favorable pathologic responses (exploratory outcome).

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Introduction: Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. Methods: In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. Results: The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Conclusion: Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Real-world outcomes with immuno-oncology therapies in advanced melanoma: final results of the OPTIMIzE registry study.

Aim: The OPTIMIzE registry study evaluated real-world outcomes in patients with advanced melanoma receiving immuno-oncology therapies. Materials and methods: Data were collected for patients treated with anti-programmed death 1 (PD-1) monotherapy (nivolumab or pembrolizumab; n = 147) or nivolumab plus ipilimumab (n = 81) from 2015-2017 and followed for ≥3 years. Results: Nivolumab plus ipilimumab versus anti-PD-1 monotherapy was associated with a nonsignificantly lower risk of death (adjusted HR: 0.83; 95% CI: 0.54-1.28; p = 0.41), higher disease control rate (72 vs 56%; p = 0.04), and stable quality of life, but more grade 3-4 treatment-related adverse events (54 vs 26%; p < 0.0001). Conclusion: These results support the use of immuno-oncology therapy in advanced melanoma.

Melanoma is a serious form of skin cancer that develops from melanocytes, which are pigment cells that give the skin, hair, and other tissues their color. At advanced stages of spread, melanoma can be life-threatening. However, immunotherapy, a type of therapy that helps the body's immune system to destroy cancer cells, allows some patients with advanced melanoma to live longer. The OPTIMIzE study looked at how well patients with advanced melanoma did when treated with different immunotherapies. These patients were treated in a real-world setting, such as a doctor's office, and were not participating in a clinical trial. Compared with clinical trials, real-world studies like the OPTIMIzE study may include a more varied group of patients because of the less selective study enrollment requirements. In the OPTIMIzE study, patients were treated with either a single immunotherapy (nivolumab or pembrolizumab alone) or a combination of two immunotherapies (nivolumab plus ipilimumab). Both single and combination immunotherapies were effective and tolerable. Patients receiving nivolumab plus ipilimumab had greater tumor shrinkage than patients receiving nivolumab or pembrolizumab alone, but with more side effects from their treatment. Despite the occurrence of side effects with both single and combination immunotherapies, patients reported that their quality of life remained stable while being treated. The OPTIMIzE study shows that immunotherapy is effective and tolerable for patients with advanced melanoma in the real-world setting. This information may help doctors with selecting treatments for their patients with advanced melanoma. Clinical Trial Registration: NCT02780089 (ClinicalTrials.gov).

Metastatic site and clinical outcome of patients with deficient mismatch repair metastatic colorectal cancer treated with an immune checkpoint inhibitor in the first-line setting.

PURPOSE: Only one-half of deficient mismatch repair (d-MMR) metastatic colorectal cancers (mCRC) demonstrate durable responses to immune checkpoint inhibitors (ICIs). Given preclinical data indicating that liver metastases sequester activated CD8+ T cells from systemic circulation, we examined clinical outcome by metastatic site. PATIENTS AND METHODS: In a retrospective cohort of patients with d-MMR mCRCs treated at multiple centers in France (n = 66), we sought to validate data from a U.S. cohort, and performed pooled analysis (n = 104). All patients received first-line ICI monotherapy. Metastatic site was analyzed in relationship to tumor response (RECIST version 1.1), and with progression-free survival (PFS) by multivariable stratified Cox regression after adjustment for covariates. RESULTS: Objective responses were achieved in 38/66 (58%) of patients in the validation cohort. Best tumor response included 13 (20%) complete responses (CR), 25 (38%) partial responses (PR), 16 (25%) stable disease, and 11 (17%) progressive disease (PD). One-year and 5-year PFS rates were 73% and 67%, respectively; 18 (27%) patients progressed during immunotherapy. Best tumor response was attenuated in patients with liver metastasis (P = 0.03). Presence of liver metastasis, but not other sites, was associated with significantly poorer PFS after adjustment for covariates (HRadj 2.82; 95%CI, 1.08-7.39; Padj=0.03). In a pooled analysis, liver metastasis remained significantly and independently associated with poorer PFS (HRadj 3.18; 95%CI, 1.52-6.67; Padj=0.002) and with attenuated tumor best response (P = 0.01). CONCLUSIONS: Metastasis to the liver, but not other sites, was validated as an independent factor associated with poorer response and survival after ICI treatment in d-MMR mCRCs. These data underscore the need for novel therapeutic strategies in these patients.

Early vs conventional onset pancreatic ductal adenocarcinoma: analysis of surgical and oncologic outcomes in patients undergoing curative intent resection.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) impacts patients in their 60s, but its incidence in younger patients is increasing. We hypothesize that younger patients may have worse oncologic outcomes. METHODS: Patients who underwent curative pancreatic resection for PDAC between January 2011 and December 2021 at a single institution were analyzed. Early-onset pancreatic cancer (EOPC) was defined as pancreatic cancer diagnosed in patients ≤50 years. Clinical and survival outcomes were compared between EOPC and Conventional Onset Pancreas Cancer (COPC). RESULTS: A total of 1133 patients were identified, 65 (5.7%) were EOPC. Preoperative patient characteristics including sex, smoking status, alcohol habitus, diabetes mellitus, CA 19-9, and neoadjuvant therapy were similar between EOPC and COPC (p > 0.05). EOPC patients were more likely non-white (p = 0.03), had lower ASA scores (p = 0.02) and larger median tumor size (33 vs 28 mm, p = 0.04), but had similar pathological stages and rate of R0 resections (p > 0.05). Postoperative outcomes were similar (p > 0.05). There was no statistically significant difference in overall (HR 0.93, CI 0.64, 1.33; p = 0.68) or recurrence free (HR 1.05, CI 0.75, 1.48; p = 0.77) survival between the EOPC and COPC after adjusting for significant factors. CONCLUSION: Patients with EOPC who underwent surgical resection had similar oncological outcomes compared to patients with COPC.

A phase I oncolytic virus trial with vesicular stomatitis virus expressing human interferon beta and tyrosinase related protein 1 administered intratumorally and intravenously in uveal melanoma: safety, efficacy, and T cell responses.

Introduction: Metastatic uveal melanoma (MUM) has a poor prognosis and treatment options are limited. These patients do not typically experience durable responses to immune checkpoint inhibitors (ICIs). Oncolytic viruses (OV) represent a novel approach to immunotherapy for patients with MUM. Methods: We developed an OV with a Vesicular Stomatitis Virus (VSV) vector modified to express interferon-beta (IFN-ß) and Tyrosinase Related Protein 1 (TYRP1) (VSV-IFNß-TYRP1), and conducted a Phase 1 clinical trial with a 3 + 3 design in patients with MUM. VSV-IFNß-TYRP1 was injected into a liver metastasis, then administered on the same day as a single intravenous (IV) infusion. The primary objective was safety. Efficacy was a secondary objective. Results: 12 patients with previously treated MUM were enrolled. Median follow up was 19.1 months. 4 dose levels (DLs) were evaluated. One patient at DL4 experienced dose limiting toxicities (DLTs), including decreased platelet count (grade 3), increased aspartate aminotransferase (AST), and cytokine release syndrome (CRS). 4 patients had stable disease (SD) and 8 patients had progressive disease (PD). Interferon gamma (IFNγ) ELIspot data showed that more patients developed a T cell response to virus encoded TYRP1 at higher DLs, and a subset of patients also had a response to other melanoma antigens, including gp100, suggesting epitope spreading. 3 of the patients who responded to additional melanoma antigens were next treated with ICIs, and 2 of these patients experienced durable responses. Discussion: Our study found that VSV-IFNß -TYRP1 can be safely administered via intratumoral (IT) and IV routes in a previously treated population of patients with MUM. Although there were no clear objective radiographic responses to VSV-IFNß-TYRP1, dose-dependent immunogenicity to TYRP1 and other melanoma antigens was seen.

Anorectal melanoma.

Anorectal melanoma is an aggressive mucosal melanoma subtype with a poor prognosis. Although recent advancements have been seen for cutaneous melanoma, the optimal treatment paradigm for management of anorectal melanoma is evolving. In this review, we highlight differences in the pathogenesis of mucosal versus cutaneous melanoma, new concepts of staging for mucosal melanoma, updates to surgical management of anorectal melanoma, and current data for adjuvant radiation and systemic therapy in this unique patient population.

Phase II Trial of Trifluridine/Tipiracil Plus Irinotecan in Patients with Advanced, Refractory Biliary Tract Carcinoma.

BACKGROUND: We sought to determine the safety and efficacy of trifluridine/tipiracil in combination with irinotecan in a phase II trial setting for refractory, advanced unresectable biliary tract carcinoma (BTC). METHODS: A total of 28 patients (27 were evaluable) with advanced BTCs who progressed on at least one prior systemic therapy were enrolled and were treated with trifluridine/tipiracil 25 mg/m2 (days 1-5 of 14-day cycle) and irinotecan 180 mg/m2 (day 1 of the 14-day cycle). The primary endpoint for the study was 16-week progression-free survival (PFS16) rate. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety were pre-specified secondary endpoints. RESULTS: Of 27 patients, PFS16 rate was 37% (10/27; 95% CI: 19%-58%), thereby meeting the criteria for success for the primary endpoint. The median PFS and OS of the entire cohort were 3.9 months (95% CI: 2.5-7.4) and 9.1 months (95% CI: 8.0-14.3), respectively. In the patients evaluable for tumor response (n = 20), the ORR and DCR were 10% and 50%, respectively. Twenty patients (74.1%) had at least one grade 3 or worse adverse event (AE), and 4 patients (14.8%) had grade 4 AEs. A total of 37% (n = 10/27) and 51.9% (n = 14/27) experienced dose reductions in trifluridine/tipiracil and irinotecan, respectively. Delay in therapy was noted in 56% of the patients while 1 patient discontinued the therapy, primarily due to hematologic AEs. CONCLUSION: The combination of trifluridine/tipiracil plus irinotecan is a potential treatment option for patients with advanced, refractory BTCs with good functional status and no targetable mutations. A larger randomized trial is needed to confirm these results. (ClinicalTrials.gov Identifier: NCT04072445).

Preoperative Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

SALVO: Single-Arm Trial of Ipilimumab and Nivolumab as Adjuvant Therapy for Resected Mucosal Melanoma.

PURPOSE: Mucosal melanoma is a rare, aggressive form of melanoma with extremely high recurrence rates despite definitive surgical resection with curative intent. Currently there is no consensus on adjuvant therapy. Data on checkpoint inhibitors for adjuvant therapy are lacking. PATIENTS AND METHODS: We performed a single-arm, multicenter clinical trial using "flip dose" ipilimumab (1 mg/kg q3w × 4 cycles), and nivolumab (3 mg/kg q3w × 4 cycles), then nivolumab 480 mg q4w × 11 cycles to complete a year of adjuvant therapy. Participants must have had R0/R1 resection ≤90 days before registration, no prior systemic therapy (adjuvant radiotherapy allowed), ECOG 0/1, and no uncontrolled autoimmune disease or other invasive cancer. Patients were recruited through the Midwest Melanoma Partnership/Hoosier Oncology Network. RESULTS: From September 2017 to August 2021, 35 patients were enrolled. Of these, 29 (83%) had R0 resections, and 7 (20%) received adjuvant radiotherapy. Median age was 67 years, 21 (60.0%) female. Recurrence-free survival (RFS) rates at 1 and 2 years were 50% [95% confidence interval (CI), 31%-66%] and 37% (95% CI, 19%-55%), respectively. Overall survival rates at 1 and 2 years were 87% (95% CI, 68%-95%) and 68% (95% CI, 46%-83%), respectively. Median RFS was 10.3 months (95% CI, 5.7-25.8). Most common grade 3 toxicities were diarrhea (14%), hypertension (14%), and hyponatremia (11%), with no grade 4/5 toxicities. CONCLUSIONS: Flip-dose ipilimumab and nivolumab after resection of mucosal melanoma is associated with outcomes improved over that of surgical resection alone. Long-term follow-up, subgroup analyses and correlative studies are ongoing.

Association Between Survival and Metastatic Site in Mismatch Repair-Deficient Metastatic Colorectal Cancer Treated With First-line Pembrolizumab.

Importance: Metastatic colorectal cancer (mCRC) with deficient DNA mismatch repair (dMMR) shows frequent and durable responses to programmed cell death 1 blockade. While most of these tumors are sporadic and observed in older patients, first-line pembrolizumab data are limited to findings from the KEYNOTE-177 trial (A Phase III Study of Pembrolizumab [MK-3475] vs Chemotherapy in Microsatellite Instability-High [MSI-H] or Mismatch Repair Deficient [dMMR] Stage IV Colorectal Carcinoma). Objective: To investigate outcome with first-line pembrolizumab monotherapy in mostly older patients with dMMR mCRC at a multisite clinical practice. Design, Setting, and Participants: This cohort study included consecutive patients with dMMR mCRC who received pembrolizumab monotherapy between April 1, 2015, and January 1, 2022, at Mayo Clinic sites and the Mayo Clinic Health System. Patients were identified from review of electronic health records at the sites, which included the evaluation of digitized radiologic imaging studies. Intervention: Patients with dMMR mCRC received first-line pembrolizumab, 200 mg, every 3 weeks. Main Outcomes and Measures: The primary study end point was progression-free survival (PFS), which was analyzed using the Kaplan-Meier method and a multivariable stepwise Cox proportional hazards regression model. Clinicopathological features, including metastatic site and molecular data (BRAF V600E and KRAS), were also analyzed along with tumor response rate, which was determined using Response Evaluation Criteria in Solid Tumors, version 1.1. Results: The study cohort included 41 patients (median [IQR] age at treatment initiation, 81 [76-86] years; 29 females [71%]) with dMMR mCRC. Of these patients, 30 (79%) had the BRAF V600E variant and 32 (80%) were classified as having sporadic tumors. Median (range) follow-up was 23 (3-89) months. Median (IQR) number of treatment cycles was 9 (4-20). Overall response rate was 49% (20 of 41 patients), including 13 patients (32%) with complete responses and 7 (17%) with partial responses. Median (IQR) PFS was 21 (95% CI, 6-39) months. Liver as a site of metastasis was associated with significantly poorer PFS vs nonliver metastasis (adjusted hazard ratio, 3.40; 95% CI, 1.27-9.13; adjusted P = .01). Complete and partial responses were observed in 3 patients (21%) with liver metastasis vs 17 patients (63%) with nonliver metastases. Treatment-related grade 3 or 4 adverse events were observed in 8 patients (20%), 2 of whom discontinued therapy; there was 1 treatment-related death. Conclusions and Relevance: This cohort study found a clinically significant prolongation of survival in older patients with dMMR mCRC who were treated with first-line pembrolizumab in routine clinical practice. Furthermore, liver vs nonliver metastasis was associated with poorer survival in this patient population, which suggests that the metastatic site has implications for survival outcome.

Understanding Suboptimal Response to Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs), as a novel class of anticancer therapy, can be more efficacious and less toxic than chemotherapy, but their clinical success is confined to certain tumor types. Elucidating their targets, mechanisms and scope of action, and potential synergism with chemotherapy and/or targeted therapies are critical to widen their clinical indications. Treatment response to an ICI targeting programmed death-1 (anti-PD-1) is sought to be understood here by conducting a preplanned correlative analysis of a phase II clinical trial in patients with small bowel adenocarcinoma (SBA). The cytolytic capacity of circulating immune cells in cancer patients using a novel ex vivo cytotoxicity assay is evaluated, and the utility of circulating biomarkers is investigated to predict and monitor the treatment effect of anti-PD-1. Baseline expression of Bim and NKG7 and upregulation of CX3CR1 in circulating T cells are associated with the clinical benefit of anti-PD-1 in patients with SBA. Overall, these findings suggest that the frequency and cytolytic capacity of circulating, effector immune cells may differentiate clinical response to ICIs, providing a strong rationale to support immune monitoring using patient peripheral blood.

Pancreatic involvement due to immune checkpoint inhibitors: a proposed classification.

BACKGROUND: Drug-induced acute pancreatitis (AP) is uncommon and pancreatic involvement due to immune checkpoint inhibitors (ICI) in published reports relied on the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE). CTCAE definition of AP differs from the revised Atlanta classification diagnostic criteria. This study aims to classify the spectrum of pancreatic involvement in patients receiving ICI therapy into categories built on the revised Atlanta classification. METHODS: A retrospective cohort study of cancer patients receiving cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) inhibitors between 2011 and 2020. Pancreas-specific immune-related adverse events (irAEs) were categorized into AP and pancreatic injury. RESULTS: Forty-seven patients on ICI therapy met selection criteria. Twenty patients (43%) had AP, while 27 (57%) had pancreatic injury. Fifteen patients (75%) developed mild AP. Five patients progressed to pancreatic atrophy, and two patients (4%) developed exocrine pancreatic insufficiency. In both groups, most patients received nivolumab therapy (70% vs. 67%, p = 0.08) with no difference in mean number of nivolumab doses (9 vs. 10, p = 0.69). There was no correlation between the mean number of nivolumab or pembrolizumab doses and AP events (OR 0.94, p = 0.26, and OR 0.98, p = 0.86), but the duration of ICI therapy was significantly related to pancreatic atrophy (OR 1.01, p = 0.05; 95% CI 1.00-1.02). CONCLUSION: Based on the novel classification, majority of pancreatic irAEs were classified as asymptomatic pancreatic injury but with some risk of pancreatic atrophy. This classification can help in assessing patterns of pancreatic involvement, pathogenesis, and treatment decisions.

Cytoreduction with Hyperthermic Intraperitoneal Chemoperfusion for Pancreatic Cancer with Low-Volume Peritoneal Metastasis: Results from a Prospective Pilot Study.

INTRODUCTION: Resection of oligometastatic pancreatic ductal adenocarcinoma (PDAC) has historically been ineffective, however modern systemic chemotherapy has improved survival. Thus, re-evaluating safety and outcomes of surgical resection in selected patients with limited peritoneal metastasis (PM) warrants consideration. METHODS: From 2018 to 2021, patients with PDAC and positive cytology or limited PM without extraperitoneal metastasis and who had an objective response to ≥ 6 months of systemic chemotherapy were enrolled. Patients underwent laparoscopic hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin/mitomycin C. If amenable to a complete cytoreduction, patients went on to cytoreduction and HIPEC. RESULTS: Overall, 18 patients were enrolled and received a median of 14 (interquartile range [IQR] 12-17) cycles of chemotherapy; 16 (89%) patients received chemoradiation. Laparoscopic HIPEC was completed in 17 patients, with a median length of stay of 1 day, and no grade III complications or hematological toxicities were observed. All 18 patients subsequently underwent a complete cytoreduction (CC-0) along with definitive treatment of the primary tumor, with formal resection (7/18), irreversible electroporation (IRE; 10/18), or intraoperative radiation therapy (IORT; 1/18). Median PCI was 2 (IQR 0-4), median LOS was 7 days (IQR 6-8), and 7 (39%) patients were readmitted. Eight (44%) patients experienced grade 3 or higher complications, including one 30-day mortality. At a median follow-up of 16 months, the median progression-free survival was 20 months and the median overall survival was 26 months. CONCLUSION: Cytoreduction and HIPEC for selected patients with low-volume PM from PDAC is safe and feasible with favorable short-term outcomes. A phase II trial (NCT04858009) is now enrolling to further assess this multimodality approach in select patients.

FDG-PET Predicts Neoadjuvant Therapy Response and Survival in Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.

BACKGROUND: Neoadjuvant therapy (NAT) is used in borderline resectable/locally advanced (BR/LA) pancreatic ductal adenocarcinoma (PDAC). Anatomic imaging (CT/MRI) poorly predicts response, and biochemical (CA 19-9) markers are not useful (nonsecretors/nonelevated) in many patients. Pathologic response highly predicts survival post-NAT, but is only known postoperatively. Because metabolic imaging (FDG-PET) reveals primary tumor viability, this study aimed to evaluate our experience with preoperative FDG-PET in patients with BR/LA PDAC in predicting NAT response and survival. METHODS: We reviewed all patients with resected BR/LA PDAC who underwent NAT with FDG-PET within 60 days of resection. Pre- and post-NAT metabolic (FDG-PET) and biochemical (CA 19-9) responses were dichotomized in addition to pathologic responses. We compared post-NAT metabolic and biochemical responses as preoperative predictors of pathologic responses and recurrence-free survival (RFS) and overall survival (OS). RESULTS: We identified 202 eligible patients. Post-NAT, 58% of patients had optimization of CA 19-9 levels. Major metabolic and pathologic responses were present in 51% and 38% of patients, respectively. Median RFS and OS times were 21 and 48.7 months, respectively. Metabolic response was superior to biochemical response in predicting pathologic response (area under the curve, 0.86 vs 0.75; P<.001). Metabolic response was the only univariate preoperative predictor of OS (odds ratio, 0.25; 95% CI, 0.13-0.40), and was highly correlated (P=.001) with pathologic response as opposed to biochemical response alone. After multivariate adjustment, metabolic response was the single largest independent preoperative predictor (P<.001) for pathologic response (odds ratio, 43.2; 95% CI, 16.9-153.2), RFS (hazard ratio, 0.37; 95% CI, 0.2-0.6), and OS (hazard ratio, 0.21; 95% CI, 0.1-0.4). CONCLUSIONS: Among patients with post-NAT resected BR/LA PDAC, FDG-PET highly predicts pathologic response and survival, superior to biochemical responses alone. Given the poor ability of anatomic imaging or biochemical markers to assess NAT responses in these patients, FDG-PET is a preoperative metric of NAT efficacy, thereby allowing potential therapeutic alterations and surgical treatment decisions. We suggest that FDG-PET should be an adjunct and recommended modality during the NAT phase of care for these patients.

Outcomes following FGFR Inhibitor Therapy in Patients with Cholangiocarcinoma.

BACKGROUND: Sequencing efforts in patients with cholangiocarcinoma (CCA) have provided insights into molecular mechanisms including fibroblast growth factor receptor (FGFR) alterations. There is a lack of data on outcomes of patients following cessation of FGFR inhibitor (FGFRi) therapy. OBJECTIVE: We describe the clinical outcomes following initial FGFRi treatment in CCA harboring FGFR alterations. PATIENTS AND METHODS: We conducted a multicentric, retrospective analysis of patients with FGFR-altered CCA diagnosed between 2010 and 2021. Median overall survival (OS) and progression-free survival (PFS) analyses were performed using the Kaplan-Meier method. RESULTS: We identified 88 advanced or metastatic CCA patients, 28 males (31.8%) and 60 females (68.2%), harboring FGFR alterations who received FGFRi. Median PFS on initial FGFRi was 6.6 months (95% confidence interval (CI): 5.5-8.3). Following cessation of first FGFRi therapy, 55% patients received systemic therapy as next line: 67% received chemotherapy or targeted treatment and 33% received another FGFRi. Median PFS for patients who received chemotherapy or targeted agent was 2.1 months (95% CI 1.6-5.7) and for patients who received a second FGFRi was 3.7 months (95% CI 1.5-not evaluable). OS was 2.0 months for patients who did not receive any therapy compared to 8.7 months with chemotherapy and 8.6 months with another FGFRi. In addition, one patient treated with pemigatinib developed FGFR2 M540_I541insMM alteration at time of resistance, which has not been functionally characterized and its effect on protein function remains unknown. CONCLUSIONS: Understanding the mechanisms of resistance with FGFRi is essential to understand sequencing of treatments. In this study, patients received standard chemotherapy in the first line and were fit enough to be considered for subsequent therapy with an FGFRi. Almost half of the patients become ineligible to receive further systemic therapy following progression on FGFRi. As more agents are being introduced, detailed understanding of outcomes following treatment with an FGFRi, including subsequent FGFRi, is essential.