Repair-deficient Cancer Research Articles

Interspatial Distribution of Tumor and Immune Cells in Correlation with PD-L1 in Molecular Subtypes of Gastric Cancers.

Simple SummaryThe majority of gastric cancers are negative for the Epstein–Barr virus (EBV) and mismatch repair-proficient, or microsatellite stable. Molecular subtyping currently does not influence clinical decision making, and accurate response prediction towards immunotherapy remains a major challenge. We therefore analyzed PD-L1 expression, tumor-infiltrating lymphocytes, and their spatial relationship to tumor cells in EBV-negative mismatch repair-proficient gastric cancers compared to EBV-positive and mismatch repair-deficient tumors to identify an immunogenic phenotype that is susceptible to immunotherapy in this large group. We demonstrated a close relationship between the total number of tumor-infiltrating lymphocytes, their proximity to tumor cells, and the expression of PD-L1 across all subtypes, including the EBV-negative and mismatch repair-proficient cancers. However, we also identified a subgroup of PD-L1-negative, EBV-negative, and mismatch repair-proficient cancers with high numbers of tumor-associated CD8+ lymphocytes. This is indicative of an immunoreactive phenotype in a subgroup of gastric cancers along or independent of PD-L1 status and molecular type.(1) Background: EBV-positive and mismatch repair-deficient (MMRd) gastric cancers (GCs) show higher levels of tumor-infiltrating lymphocytes (TILs) and PD-L1 expression and thus a more profound response to immunotherapy. However, the majority of GCs are EBV-negative (EBV−) and MMR proficient (MMRp). We analyzed PD-L1 expression and TILs in EBV-MMRpGCs in comparison to EBV-positive (EBV+) and MMRdGCs to identify an immunogenic phenotype susceptible to immunotherapy. (2) Methods: A next-generation tissue microarray of 409 primary resected GCs was analyzed by Epstein-Barr encoding region (EBER) in situ hybridization for MSH1, PMS2, MSH2, MSH6, PD-L1, and CD8 immunohistochemistry. PD-L1 positivity was defined as a combined positive score (CPS) of ≥1. CD8+ TILs and their proximity to cancer cells were digitally analyzed on the HALO™ image analysis platform. (3) Results: Eleven cases were EBV+, 49 cases MMRd, and 349 cases EBV-MMRpGCs. The highest rate of PD-L1 positivity was seen in EBV+GCs, followed by MMRdGCs and EBV-MMRpGCs (81.8%, 73.5%, and 27.8%, respectively). EBV+ and MMRdGCs also demonstrated increased numbers and proximity of CD8+ TILs to tumor cells compared to EBV-MMRpGCs (p < 0.001 each). PD-L1 status positively correlated with the total numbers of CD8+ TILs and their proximity to tumor cells in all subtypes, including EBV-MMRpGCs (p < 0.001 each). A total of 28.4% of EBV-MMRpGCs showed high CD8+ TILs independent of PD-L1. (4) Conclusions: PD-L1 and CD8 immunohistochemistry, supplemented by digital image analysis, may identify EBV-MMRpGCs with high immunoreactivity indices, indicating susceptibility to immunotherapy.

Clinical outcomes of neoadjuvant treatment strategies in localized mismatch repair-deficient rectal cancer.

192 Background: Rectal cancer treatment paradigm has been evolving over time. Historically, for locally advanced rectal cancer, standard therapy (ST) consisted of neoadjuvant chemoradiation followed by surgery and adjuvant chemotherapy. Recently, total neoadjuvant treatment (TNT) approach that delivers both neoadjuvant chemotherapy (CAPOX or FOLFOX) and chemoradiation (or radiation only) prior to surgery is increasingly being utilized. The prognostic and predictive values of mismatch repair deficient (dMMR) in rectal cancer is not well characterized. Most dMMR patients receive the same treatment as MMR proficient (pMMR) patients although there is limited data that dMMR rectal cancer patients may not have the same level of benefits from neoadjuvant treatment. This retrospective study aims to evaluate the clinicopathological/molecular characteristics, disease response, and clinical outcomes in dMMR localized rectal cancer patients. Methods: A retrospective analysis was conducted on consecutive adult patients with a diagnosis of dMMR rectal cancer who were treated at Mayo Clinic between January 2000 to September 2021. Patients who presented with concurrent primary non-colorectal malignancies were excluded. The distributions of demographics, clinicopathological features, biomarkers, and outcome data were collected. Survival was assessed using Kaplan-Meier curves and Cox models were stratified by treatment arms to determine significance of treatment strategies. Results: Forty-one patients were identified with a median age of 45.3 years. Thirty (73.2%) pts were male. The most common MMR were loss of MSH2 and MSH6 (12/42; 29.3%) followed by loss of MLH1 and PMS2 (10/42; 24.4%) and solitary loss of MSH2 (4/42; 9.8%). The treatment, pathological response, and clinical outcomes are listed in table. With a median follow up of 101 months, only 6 patients (14.3%) died and median overall survival was not reached. Conclusions: Our findings showed dMMR localized rectal cancer responded to both ST and TNT with good clinical outcomes.[Table: see text]

One-year duration of nivolumab plus ipilimumab in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC): Long-term follow-up of the GERCOR NIPICOL phase II study.

13 Background: Optimal treatment duration with immune checkpoint inhibitors (ICI) for MSI/dMMR mCRC pts remains to be determined. Different durations are used, usually a fixed duration of 2 years or treatment until progression or toxicity. The GERCOR NIPICOL phase II study evaluated 1 year of therapy with nivolumab plus ipilimumab for MSI/dMMR mCRC pts. Here, we present the efficacy data with 16 months of additional follow-up since the primary analysis. Methods: MSI/dMMR mCRC pts previously treated with fluoropyrimidine, oxaliplatin, and irinotecan ± targeted therapies received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W for 4 cycles, then nivolumab 3 mg/kg Q2W until progression or a maximum of 20 cycles. Second course of nivolumab was permitted for pts who completed the predefined year of treatment and had later progressive disease (PD). Objectives were to evaluate response rates, progression-free survival (PFS) per iRECIST, and overall survival (OS). A landmark analysis was performed for PFS in pts who remained alive and progression-free at 1 year (theoretical end of treatment). Results: Of 57 pts included between Dec 2017 and Nov 2018, 36 (63%) completed the predefined 1-year duration of treatment. Reasons of premature treatment discontinuation were PD or death (n = 13), adverse event (n = 7), and the pt wish (n = 1). Overall median follow-up was 34.5 months. One, 2, and 3-year PFS rates were respectively 75.4% (95% CI 62.0-84.6), 70.0% (95% CI 56.2-80.1), and 70.0% (95% CI 56.2-80.1). One, 2, and 3-year OS rates were 84.1 (95% CI 71.7-91.4), 78.4% (95% CI 65.1-87.1), and 73.1% (95% CI 58.4-83.4), respectively. 42/57 pts were progression-free and alive at 1 year. Among them, median follow-up was 35.0 months and the 24-month PFS rate was 92.9% (95% CI 79.5-97.6%). PD was observed in three pts whose 12-month status was stable disease (SD). These three pts received a second course of nivolumab: two achieved PR and one had PD. Conclusions: Nivolumab plus ipilimumab with a fixed duration of 1 year continued to show durable activity in pts with chemoresistant MSI/dMMR mCRC after 3 years of follow-up. Reexposure to nivolumab seems to provide additional antitumor activity for pts experiencing late resistance after discontinuation of immunotherapy. Clinical trial information: NCT033501260.

Complete Pathologic Response to Neoadjuvant Chemoimmunotherapy and Oxaliplatin-Induced Fever Associated With IL-6 Release in a Patient With Locally Advanced Colon Cancer

Neoadjuvant systemic therapy is a preferred treatment approach for a number of tumor types due to many potential advantages over upfront surgery, including tumor downstaging, early treatment of micrometastatic disease, and providing an in vivo test of tumor biology. For colon cancer, current standard of care is upfront surgery followed by adjuvant systemic therapy in high-risk patients. Concerns about inaccurate radiological staging and tumor progression during preoperative treatment, as well the lack of randomized data demonstrating benefit, are among the reasons for the limited use of neoadjuvant therapy in this disease. Locally advanced colon cancer, defined as primary colon cancer with direct invasion into the adjacent structures or extensive regional lymph node involvement, is not always amenable to pathological complete resection, and when attempted it comes with high incidence of postoperative morbidity and mortality because of the required multivisceral resection. Clinical trials of neoadjuvant chemotherapy for colon cancer to date have been promising with downstaging of disease and higher rates of R0 resection. Here, we report a case of a patient with locally advanced, unresectable, mismatch repair deficient sigmoid colon cancer who was treated with neoadjuvant chemoimmunotherapy followed by surgical resection leading to a complete pathologic response after preoperative systemic chemoimmunotherapy.

Emerging Treatment Options for Advanced or Recurrent Endometrial Cancer.

Endometrial cancer is the most common cancer of the female reproductive organs. The American Cancer Society estimates that there will be over 65,950 new cases diagnosed in 2022. According to the National Comprehensive Cancer Network (NCCN) Guidelines, response rates in the front-line setting are approximately 40% to 62%. Prior to the recent U.S. Food and Drug Administration (FDA) approvals of immunotherapy, there had been no standard of care for women after failing front-line carboplatin and paclitaxel. In May 2017, the FDA approved single-agent pembrolizumab in microsatellite instability high (MSI-H)/mismatch repair deficient (dMMR) endometrial cancer patients following failure of systemic therapy. Then, in September 2019, the FDA approved pembrolizumab and lenvatinib for women who are not MSI-H or are MMR-proficient. This approval was based on KEYNOTE-146 and Study 111. Among 94 non–MSI-H women, 80% of those treated with pembrolizumab and lenvatinib had tumor shrinkage, and 38.3% had objective response by RECIST 1.1 as assessed by an independent radiology committee. The median duration of response was not reached, with 69% being progression free at 6 months. Grade 3/4 treatment-related adverse events (AEs) occurring in > 20%, including fatigue, hypertension, and gastrointestinal AEs. With supportive care, early identification, and intervention, the side effect profile was manageable, with only 21% discontinuing treatment due to AEs.

New Drug Update: Dostarlimab, Loncastuximab Tesirine, and Aducanumab.

Three new drugs are presented: dostarlimab, loncastuximab tesirine, and aducanumab. Product information, clinical trials, and recommendations are provided. Dostarlimab (Jemperli®) is FDA-indicated for the treatment of adult patients with mismatch repair deficient (dMMR - an abnormality that affects DNA repair) recurrent or advanced endometrial cancer (EC). Loncastuximab tesirine (Zynlonta®) is FDA-indicated for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, DLBCL arising from low grade lymphoma, and high-grade B-cell lymphoma. Aducanumab (Aduhelm®) is FDA-indicated for the treatment of Alzheimer's disease. It is an amyloid beta-directed antibody developed by Biogen of Cambridge, Massachusetts. This indication was approved on June 7, 2021, under the accelerated approval based on the reduction in amyloid beta plaques in patients treated with the drug.

European-Australasian consensus on the management of advanced gastric and gastro-oesophageal junction cancer: current practice and new directions.

Gastric carcinoma and gastro-oesophageal junction (GC/GEJ) carcinoma remain a significant global problem, with patients presenting with symptoms often found to have advanced or metastatic disease. Treatment options for these patients have broadened in recent years with new chemotherapy agents, agents targeting angiogenic pathways and the development of immune checkpoint inhibitors (ICIs). Most initial advances have occurred in the refractory setting, where it is important to balance treatment benefits versus toxicity and patient quality of life. In the first-line treatment of advanced/metastatic GC/GEJ, platinum- and fluoropyrimidine-based chemotherapy protocols remain the backbone of therapy (with or without HER2-targeted therapy), with the FOLFIRI regimen offering an alternative in patients deemed unsuitable for a platinum agent. Microsatellite instability-high or mismatch repair-deficient cancers have been shown to benefit most from ICIs. In unselected patients previously treated with doublet or triplet platinum- and fluoropyrimidine-based chemotherapy and second-line chemotherapy with irinotecan or taxanes have formed the backbone of therapy with or without the addition of the vascular endothelial growth factor receptor-2 inhibitor ramucirumab in addition to paclitaxel. Beyond this, efficacy has been demonstrated with oral trifluridine/tipiracil and with single-agent nivolumab, in selected refractory patients. In this review, we highlight the positive evidence from key trials that have led to our current practice algorithm, with particular focus on the refractory advanced disease setting, discussing the areas of active research and highlighting the factors, including biomarkers and the influence of ethnicity, that contribute to therapeutic decision-making.

Opportunities for Utilization of DNA Repair Inhibitors in Homologous Recombination Repair-Deficient and Proficient Pancreatic Adenocarcinoma.

Pancreatic cancer is rapidly progressive and notoriously difficult to treat with cytotoxic chemotherapy and targeted agents. Recent demonstration of the efficacy of maintenance PARP inhibition in germline BRCA mutated pancreatic cancer has raised hopes that increased understanding of the DNA damage response pathway will lead to new therapies in both homologous recombination (HR) repair-deficient and proficient pancreatic cancer. Here, we review the potential mechanisms of exploiting HR deficiency, replicative stress, and DNA damage-mediated immune activation through targeted inhibition of DNA repair regulatory proteins.

Cost-Effectiveness of First-Line Versus Second-Line Pembrolizumab or Chemotherapy in Patients With Microsatellite-Instability-High/Mismatch Repair-Deficient Advanced Colorectal Cancer.

Background: Pembrolizumab is a guideline-recommended, both first- and second-line treatment option for microsatellite-instability-high (MSI-H)/mismatch repair-deficient (dMMR)advanced colorectal cancer patients. The aim of the present study is to investigates the health and economic outcomes of three treatment strategies with or without pembrolizumab in MSI-H/dMMR advanced colorectal cancer to define the best treatment strategy from the perspective of the US payer. Methods: A microsimulation model was developed to estimate the cost and effectiveness of three treatment strategies: 1) pembrolizumab used as first-line, 2) pembrolizumab used as second-line and, 3) chemotherapy. Life years (LYs), quality-adjusted LYs (QALYs) and lifetime costs were estimated. Results: The model projected that patients receiving pembrolizumab in the first-line setting gained 5.579 QALYs; this value was 1.501 and 3.941 QALYs more than that for patients receiving pembrolizumab in the second-line setting and chemotherapy, respectively. First-line pembrolizumab strategy dominated second-line pembrolizumab strategy. Compared with chemotherapy, first-line pembrolizumab strategy yielded an incremental cost of $50613.7, which resulted in an ICER of $13441 per QALY. Conclusion: For patients with MSI-H/dMMR advanced colorectal cancer, reserving pembrolizumab for second-line line use is dominated by its first-line use, and first-line use of pembrolizumab is cost-effective compared with chemotherapy.

Distinct Hypoxia-Related Gene Profiling Characterizes Clinicopathological Features and Immune Status of Mismatch Repair-Deficient Colon Cancer.

Despite dramatic responses to immune checkpoint inhibitors (ICIs) in patients with colon cancer (CC) harboring deficient mismatch repair (dMMR), more than half of these patients ultimately progress and experience primary or secondary drug resistance. There is no useful biomarker that is currently validated to accurately predict this resistance or stratify patients who may benefit from ICI-based immunotherapy. As hypoxic and acidic tumor microenvironment would greatly impair tumor-suppressing functions of tumor-infiltrating lymphocytes (TILs), we sought to explore distinct immunological phenotypes by analysis of the intratumoral hypoxia state using a well-established gene signature. Based on the Gene Expression Omnibus (GEO) (n = 88) and The Cancer Genome Atlas (TCGA) (n = 49) databases of patients with CC, we found that dMMR CC patients could be separated into normoxia subgroup (NS) and hypoxia subgroup (HS) with different levels of expression of hypoxia-related genes (lower in NS group and higher in HS group) using NMF package. Tumoral parenchyma in the HS group had a relatively lower level of immune cell infiltration, particularly CD8+ T cells and M1 macrophages than the NS group, and coincided with higher expression of immune checkpoint molecules and C-X-C motif chemokines, which might be associated with ICI resistance and prognosis. Furthermore, three genes, namely, MT1E, MT2A, and MAFF, were identified to be differentially expressed between NS and HS groups in both GEO and TCGA cohorts. Based on these genes, a prognostic model with stable and valuable predicting ability has been built for clinical application. In conclusion, the varying tumor-immune microenvironment (TIME) classified by hypoxia-related genes might be closely associated with different therapeutic responses of ICIs and prognosis of dMMR CC patients.

Efficacy of Immune Checkpoint Inhibitors in Patients with Mismatch Repair-Deficient or Microsatellite Instability-High Metastatic Colorectal Cancer: Analysis of Three Phase-II Trials.

Programmed cell death ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) inhibitors are increasingly used in a variety of solid tumors. In patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer, their efficacy has been demonstrated in recently published phase-II trials. However, an indirect comparison of effectiveness between pembrolizumab, nivolumab, and nivolumab+ipilimumab is not yet available.After a standard literature search, we analyzed four overall survival (OS) curves from three phase-II trials. Individual patient data were reconstructed from each curve using a specific web-based technique (Shiny method). Indirect statistical comparisons were made based on hazard ratio (HR) and restricted mean survival time (RMST).Nivolumab+ipilumumab had a better HR compared with pembrolizumab (0.65, 95% confidence interval [CI], 0.43 to 1.002, p=0.051); the difference being close to statistical significance. In the analysis based on RMST, the combination of nivolumab+ipilimumab showed a significantly longer OS than pembrolizumab (improvement in RMST, 1.08 mos; 95%CI, 0.11 to 2.06; p=0.029). The other two pairwise differences in RMST (nivolumab vs. pembrolizumab and nivolumab+ ipilimumab vs. nivolumab) had a smaller magnitude (0.25 mos, 95%CI, -0.99 to 1.48, and 0.84 mos, 95%CI, -0.40 to 2.07, respectively) and were far from statistical significance.Our results favoring the combination of nivolumab+ipilimumab in metastatic colorectal cancer must be viewed with caution owing to the indirect nature of our statistical comparisons. With this limitation in mind, the magnitude of the incremental benefit for the above combination treatment was estimated to be around one month over a follow-up of 15 months.

Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial

PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers. The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Eligible patients were aged 18-75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3-T4 or any T with lymph node positivity (N+), Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1), without any stratification or balanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle, for six cycles before surgical resection. Adjuvant treatment with toripalimab with or without celecoxib was permitted at the investigators' discretion. The primary endpoint was the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampled regional lymph nodes. All efficacy and safety analyses were assessed in the modified intention-to-treat population, which included all patients who were randomly assigned to treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov, NCT03926338, and is ongoing. Between May 1, 2019, and April 1, 2021, 53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14·9 months (IQR 8·8-17·0). All patients received study treatment and underwent surgical resection; there were no treatment-related surgical delays. All 34 patients had an R0 resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64-99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38-86]) in the toripalimab monotherapy group had a pathological complete response. All patients continued to receive adjuvant toripalimab with or without celecoxib for a total perioperative duration of 6 months and were alive and free of recurrence at data cutoff. During neoadjuvant treatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalimab monotherapy group had grade 1-2 treatment-related adverse events. Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, had a grade 3 or higher treatment-related adverse event during the neoadjuvant phase, which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase, only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had a grade 3 or higher treatment-related adverse events, which was grade 3 increased aspartate aminotransferase and alanine aminotransferase levels. Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high, locally advanced, colorectal cancer. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise surgery. Longer term follow-up is needed to assess effects on survival-related endpoints. The National Key R&D Program of China, the National Natural Science Foundation of China, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. For the Chinese translation of the abstract see Supplementary Materials section.

Hyperprogression of a mismatch repair-deficient colon cancer in a humanized mouse model following administration of immune checkpoint inhibitor pembrolizumab.

Immunotherapy is an established treatment modality in oncology. However, in addition to primary or acquired therapy resistance with immune checkpoint blockade (ICB), hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. A validated and predictive animal model would help investigate HPD/HP to develop new approaches for this challenging clinical entity. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immunodeficient NCRU-nude athymic mice bearing mismatch repair-deficient (MMR-d) human colon carcinoma HCT116 p53-null (but not wild-type p53) tumor xenograft, we observed accelerated tumor growth after PD-1 blockade with pembrolizumab administration. There was increased colon tumor cell proliferation as determined by immunohistochemical Ki67 staining of tumor sections. There was no increase in MDM2 or MDM4/MDMX in the p53-null HCT116 cells versus the wild-type p53-expressing isogenic tumor cells, suggesting the effects in this model may be MDM2 or MDM4/MDMX-independent. Human cytokine profiling revealed changes in IFN-γ, TRAIL-R2/TNFRSF10B, TRANCE/TNFSF11/RANK L, CCL2/JE/MCP-1, Chitinase 3-like 1, IL-4 and TNF-α. This represents a novel humanized HPD mouse model with a link to deficiency of the p53 pathway of tumor suppression in the setting of MMR-d. Our novel humanized preclinical TALL-104/p53-null HCT116 mouse model implicates p53-deficiency in an MMR-d tumor as a possible contributor to HPD/HP and may help with evaluating therapeutic strategies in cancer immunotherapy to extend clinical benefits of ICB’s in a broader patient population.

Durable Response After Immune Checkpoint Inhibitor-Related Diabetes in Mismatch Repair-Deficient Pancreatic Cancer

Mismatch repair protein deficiency occurs in 0.8-2% of pancreatic ductal adenocarcinomas and confers susceptibility to immunotherapy. Herein, we report the case of a patient with Lynch syndrome-associated, locally advanced mismatch repair protein deficiency pancreatic ductal adenocarcinomas who demonstrated a sustained response to second-line treatment with pembrolizumab, but eventually developed immune-related diabetic ketoacidosis requiring discontinuation of treatment. He has since remained in remission, off treatment, over the following 3years, with regular surveillance showing no clinical or radiographic evidence of disease progression. The patient's unusual disease course raises the question of whether this serious immune-related adverse event affecting the organ of malignant involvement may have predicted his remarkable and durable response.

Interim analysis of the immune-related endpoints of the mismatch repair deficient (dMMR) and proficient (MMRp) endometrial cancer cohorts from the GARNET study

<h3>Objectives:</h3> Dostarlimab is a humanized programmed death (PD)-1 receptor monoclonal antibody that blocks interaction with the PD-1 ligands. GARNET (NCT02715284) is a phase 1 study assessing antitumor activity and safety of dostarlimab monotherapy in patients (pts) with solid tumors. Here, we report efficacy endpoints by irRECIST based on investigator assessment (IA) for the endometrial cancer (EC) cohorts. <h3>Methods:</h3> This is a multicenter, open-label, single-arm, dose-escalation and cohort-expansion study. Here, we report on 2 independent expansion cohorts of pts with recurrent or advanced EC (dMMR EC and MMRp EC, determined by immunohistochemistry [IHC]) that progressed on or after a platinum-based chemotherapy regimen. Pts received 500 mg dostarlimab IV Q3W for 4 cycles, then 1000 mg Q6W until disease progression, discontinuation, or withdrawal. The primary endpoints of objective response rate (ORR) and duration of response (DOR) by blinded independent central review (BICR) using RECIST v1.1, and safety have been reported previously.1 Immune-related endpoints (irORR and irDOR by irRECIST) are based on IA, and are prespecified secondary endpoints. <h3>Results:</h3> In total, 126 dMMR and 145 MMRp pts identified by IHC were enrolled and dosed. Of these, 103 dMMR and 142 MMRp pts had measurable disease at baseline by BICR, and sufficient follow-up time (6 mo) for the primary efficacy analyses. 110 dMMR and 144 MMRp pts had measurable disease at baseline by IA and sufficient follow-up time (6 mo) and were included for efficacy analysis of irORR and irDOR; some additional pts were considered to have measurable disease at baseline by IA. Efficacy data based on irRECIST are shown in the table. irORR was 45.5% in dMMR pts, and 13.9% in MMRp pts. <h3>Conclusions:</h3> Efficacy endpoints reported by RECIST v1.1 and irRECIST show similar results. irDCR was particularly of interest in the MMRp cohort, a group with a poorer prognosis. The potential benefit seen in this single-arm trial awaits confirmation in ongoing randomized controlled studies. <b>Reference:</b> [1] Oaknin, A, et al. Annals of Oncology (2020) 31 (suppl_4): S1142-S1215. 10.1016/annonc/annonc325. LBA36. <h3>Funding:</h3> GlaxoSmithKline.

Identification of Lynch syndrome-associated DNA mismatch repair-deficient bladder cancer in a Japanese hospital-based population.

The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated. Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor. Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68years (63-79years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS. The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6-1.1% among unselected BC cases.

SO-27 Nivolumab plus low-dose ipilimumab in previously treated patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: 4-year follow-up from CheckMate 142

In the phase 2 multicohort CheckMate 142 study (NCT02060188), nivolumab plus low-dose (1 mg/kg) ipilimumab provided robust and durable clinical benefit with a manageable safety profile in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) at a median follow-up of 13.4 months (Overman M et al. J Clin Oncol 2018;36:773–779). At 25.4 months of follow-up, nivolumab plus low-dose ipilimumab continued to provide robust and durable clinical benefit with deepening of response, and no new safety signals were identified (Overman M et al. J Clin Oncol 2019;37:635). Here, we present results from the 4-year follow-up of these patients. Patients received nivolumab (3 mg/kg) + low-dose (1 mg/kg) ipilimumab Q3W (4 doses) followed by nivolumab (3 mg/kg) Q2W until disease progression. Primary endpoint was investigator-assessed objective response rate (ORR; per RECIST v1.1). Other key endpoints reported here include disease control rate (DCR, per investigator), duration of response (DOR, per investigator), progression-free survival (PFS, per investigator), overall survival (OS), and safety. For the 119 treated patients, median age was 58 years, 59% were male, 76% had ≥ 2 prior lines of therapy, 55% had ECOG performance status (PS) 1, 25% had BRAF mutation, 37% had KRAS mutation, and 26% were BRAF/KRAS wild type. Median follow-up was 50.9 months (range, 46.9–62.7 months). Investigator-assessed ORR (95% CI) increased from 55% (45–64) at 13.4 months to 65% (55–73) at 50.9 months; DCR (95% CI) at 50.9 months was 81% (72–87). Complete response (CR) rate increased with longer follow-up from 3% at 13.4 months to 13% at 50.9 months. Partial responses (PR) were observed in 52% of patients; 21% had stable disease (SD), and 12% had progressive disease (PD) as best response. Median time to response was 2.8 months (range, 1.1–37.1 months) and median DOR was not reached (range, 1.4+ to 58.0+ months). At data cutoff, 37 (48%) patients had ongoing responses. Median PFS was not reached (95% CI, 38.4 to not estimable [NE]) and median OS was not reached (95% CI, NE). The 48-month rates of PFS (95% CI) and OS (95% CI) were 53% (43–62) and 70.5% (61.4–77.9), respectively. ORR benefit was observed across evaluated subgroups by BRAF/KRAS mutation status, ECOG PS, age, and sex, and each was consistent with that in the overall population. Grade 3-4 treatment-related adverse events (TRAEs) were observed in 32% of patients; 10% (grade 3-4) and 13% (any grade) of patients had TRAEs leading to discontinuation. Nivolumab plus low-dose ipilimumab provided durable clinical benefit (ORR, PFS, and OS) over 13.4, 25.4, and 50.9 months of follow-up. Extended follow-up showed increasing ORR and deepening of response. The safety profile was manageable with no new safety signals. These results demonstrate long-term benefit of nivolumab plus low-dose ipilimumab for previously treated patients with MSI-H/dMMR mCRC.

PARP inhibitors and immunotherapy in ovarian and endometrial cancers.

Advanced ovarian and endometrial cancers have historically been associated with poor prognosis and few treatment options, limited to single or doublet chemotherapy regimens. The introduction of novel target therapies has transformed the management of these cancers. In contrast to chemotherapy, which inhibits DNA replication and mitosis, targeted therapies target cancer signalling pathways, stroma, immune-microenvironment and vasculature in tumour tissues. The most notable advances in gynaecological cancers have come from the introduction of PARP inhibitors and immune checkpoint inhibitors for ovarian and endometrial cancer, respectively. Several PARP inhibitors, which target defective DNA repair, have been approved as maintenance therapy for advanced ovarian cancer in both the first line and platinum-sensitive relapsed settings. Immune checkpoint inhibitors such as anti-PD-1/PD-L1 antibodies have proven successful in advanced mismatch repair deficient endometrial cancers with use now being investigated beyond this population. This review will explore the biological rationale and clinical evidence behind the use of PARP inhibitors and immunotherapy in ovarian and endometrial cancers.

Prediction of mismatch repair deficient biliary tract cancer: Role of morphological features and host immune response detected by routine hematoxylin-eosin staining.

The objective of this study was to determine the frequency and predictors of biliary tract cancer (BTC) with deficient DNA mismatch repair (dMMR) in Japan. Immunostaining and microsatellite instability analysis were performed for mismatch repair-related proteins in tissue specimens from 662 patients who underwent surgery for BTC between 2001 and 2017 to identify dMMR-BTC. We compared dMMR-BTC and proficient MMR (pMMR)-BTC based on patient demographics, pathological features, and host immune responses characterized by the percentage of stromal tumor infiltrating lymphocytes (sTIL percentage) and tertiary lymphoid structures (TLS). The incidence of dMMR-BTC was 2.3%. Significant predictors of dMMR-BTC were its primary lesion being intrahepatic cholangiocarcinoma (odds ratio [OR] 6.34, P=.004), presence of signet ring cell component (OR 35.62, P<.001), sTIL percentage ≥40% (OR 3.43, P=.038), and presence of TLS (OR 22.22, P<.001). The sensitivity, specificity, and negative likelihood ratio for any one or more of these four variables to be positive were 93.3%, 57.8%, and 0.12, respectively. Evaluation of histopathological findings and host immune response based on conventional histochemical staining is useful for efficient and inexpensive diagnostic screening of dMMR-BTC patients.

P0439 - Cisplatin tolerance is elevated in mismatch repair deficient prostate cancer cell lines but independent of acquired resistance to irradiation or docetaxel

P0439 - Cisplatin tolerance is elevated in mismatch repair deficient prostate cancer cell lines but independent of acquired resistance to irradiation or docetaxel