Duration of immunotherapy in dMMR/MSI-H metastatic colorectal cancer patients.

BACKGROUND: Immune checkpoint blockade (ICB) has revolutionized treatment of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). However, there is no evidence on the optimal treatment duration. We aimed to compare outcomes of different immunotherapy durations. METHODS: An international multicenter retrospective cohort study of immunotherapy-naïve dMMR/MSI-H mCRC patients who received immunotherapy between 2014-2024. Fixed treatment duration of two years was compared to treatment duration beyond two years. Fixed treatment duration of one year was compared to treatment duration beyond one year. Subgroup analysis was performed for patients who experienced CR. Kaplan-Meier analysis and Cox proportional hazard regression model were used to analyze the effect of all exposure variables on OS. RESULTS: The study cohort included 757 dMMR/MSI-H mCRC patients treated with ICB. Median follow-up time was 46.7 months (IQR 28.5-70.3). There was no statistically significant difference in OS between patients treated for a two-year fixed-duration (n = 83) and those treated beyond two years (n = 139) in both the univariable and multivariable analysis (HR=0.65 95 %CI 0.14-3.07 p = 0.59 and HR=0.61 95 %CI 0.12-3.10 p = 0.6, respectively). The comparison between one-year fixed-duration versus continuing treatment beyond one year included 27 and 330 patients, respectively. For patients who achieved CR, discontinuing treatment after one year was not associated with a negative impact on OS (p = 0.5). CONCLUSIONS: Discontinuing immunotherapy after two years is a reasonable option for dMMR/MSI-H mCRC patients with ongoing response. Treatment discontinuation after one year may be considered for patients achieving CR. Further prospective studies are needed to define the most appropriate duration of therapy.

Budget impact of dostarlimab plus carboplatin-paclitaxel for primary advanced or recurrent endometrial cancer from a third-party US payer perspective.

AIM: Dostarlimab plus carboplatin-paclitaxel (CP) significantly increased progression-free survival in patients with primary advanced or recurrent endometrial cancer (pA/rEC) vs CP alone in the RUBY trial (NCT03981796). This analysis estimated the per-member-per-month (PMPM) costs of introducing dostarlimab + CP as a treatment alternative from a third-party US payer perspective. MATERIALS AND METHODS: A budget impact model was developed to estimate the costs of introducing dostarlimab + CP into commercial and Medicare health plans over a 3-year time horizon (2023-2025). Costs were sourced from relevant literature and US-specific databases and were calculated using epidemiology data, clinical inputs, treatment costs, and market share estimates. Clinical inputs were sourced from primary clinical trials for each respective treatment (i.e. dostarlimab + CP, CP, pembrolizumab, pembrolizumab plus lenvatinib, bevacizumab + CP, and pembrolizumab + CP). Current and future market shares assumed dostarlimab + CP reduced the market share of CP only. Analyses were performed in mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations using a US 2023 cost year. RESULTS: For a commercial plan, the model estimated (dMMR/MSI-H and overall populations) that 7 and 26 patients would be treated with dostarlimab + CP, respectively; average annual budget impacts per patient treated were $118,257 and $116,094; average budget impacts per patient treated per month (PPPM) were $9,855 and $9,675; average budget impacts PMPM were $0.02 and $0.06. For a Medicare plan, the model estimated that 28 and 93 patients, respectively, would be treated with dostarlimab + CP. Average annual budget impacts per patient treated and PPPM were the same as those for the commercial plan in both populations; average budget impacts PMPM were $0.07 and $0.22, respectively. CONCLUSIONS: Introducing dostarlimab + CP as a first-line treatment for patients with pA/rEC results in minimal budget impact PMPM from a US third-party payer's perspective. Together with the efficacy and safety results from RUBY, these results support the use of dostarlimab + CP as a treatment option.

Dostarlimab with carboplatin­paclitaxel is a recently approved treatment for newly diagnosed advanced or recurrent endometrial cancer. This analysis was done to estimate the added costs that US commercial and Medicare health plans would have over 3 years if this treatment was covered. This analysis found that the budget increase for covering dostarlimab with carboplatin­paclitaxel was small ($0.02­$0.06 per commercial plan member per month; $0.07­$0.22 per Medicare plan member per month).

Clinical, pathological, and adjuvant chemotherapy use differences among microsatellite unstable and microsatellite stable colon cancers.

Background: Colon cancers are categorized into mismatch repair deficient/microsatellite unstable (MSI-H) and mismatch repair proficient/microsatellite stable (MSS) cancers. This study aims to compare the disease characteristics and trends in the utilization of cancer therapies across different age groups and stages in these two groups. Methods: MSI-H and MSS colon adenocarcinomas from 2010 to 2016 were identified using the National Cancer Database. We compared patient and disease characteristics between the two groups and evaluated the use of adjuvant chemotherapy across age groups and cancer stages. Within MSI-H and MSS groups, we conducted a landmark analysis after propensity score matching for adjuvant chemotherapy versus no chemotherapy to determine its effect on survival. Results: Of the 542,368 patients that met inclusion criteria, 120,751 (22%) had mismatch repair results available-out of these 96,928 (80%) had MSS colon cancers while 23,823 (19.7%) had MSI-H cancers. MSI-H disease had a bimodal age distribution (<40 years = 22%; ≥75 years = 26%) and was frequent among females (22%) and non-Hispanic Whites (20%). Among those < 65 years, 15% of low-risk stage 2 MSI-H patients and 40% of high-risk stage 2 MSI-H patients received adjuvant chemotherapy. More than two-thirds of stage 3 patients <65 years received adjuvant chemotherapy in both groups. After conducting propensity-score matching for age, gender, and co-morbidities, we found that adjuvant chemotherapy use had a trend towards lower overall survival (OS) in low-risk stage 2 MSI-H (HR = 1.8 [95% CI, 0.8-4.02]) and high-risk stage 2 MSI-H (HR = 1.42 [95% CI, 0.96-2.12]) groups. Adjuvant chemotherapy significantly improved OS in stage 3 colon cancer patients irrespective of microsatellite status or risk category of disease. Conclusions: MSI-H colon cancer had bimodal age distribution. Among stage 2 MSI-H patients <65 years, a notable proportion received adjuvant chemotherapy. Among MSI-H stage 2 patients, adjuvant chemotherapy use was associated with lower survival while it significantly improved survival for stage 3 patients, irrespective of MSI status.

RPL22 is a tumor suppressor in MSI-high cancers and a splicing regulator of MDM4.

Microsatellite instability-high (MSI-H) tumors are malignant tumors that, despite harboring a high mutational burden, often have intact TP53. One of the most frequent mutations in MSI-H tumors is a frameshift mutation in RPL22, a ribosomal protein. Here, we identified RPL22 as a modulator of MDM4 splicing through an alternative splicing switch in exon 6. RPL22 loss increases MDM4 exon 6 inclusion and cell proliferation and augments resistance to the MDM inhibitor Nutlin-3a. RPL22 represses the expression of its paralog, RPL22L1, by mediating the splicing of a cryptic exon corresponding to a truncated transcript. Therefore, damaging mutations in RPL22 drive oncogenic MDM4 induction and reveal a common splicing circuit in MSI-H tumors that may inform therapeutic targeting of the MDM4-p53 axis and oncogenic RPL22L1 induction.

Unique miRNA Expression Profile in MSI- and EMAST-Unstable Sporadic Colon Cancer.

MicroRNAs (miRNAs) are critical post-transcriptional gene regulators and their involvement in sporadic colon cancer (CRC) tumorigenesis has been confirmed. In this study we investigated differences in miRNA expression in microsatellite stable (MSS/EMAST-S), microsatellite unstable marked by high elevated microsatellite alterations at selected tetranucleotide repeats (MSS/EMAST-H), and high microsatellite unstable (MSI-H/EMAST-H) tumor subgroups as well as in tumors with different clinicopathologic characteristics. An RT-qPCR analysis of miRNA expression was carried out on 45 colon cancer and adjacent normal tissue samples (15 of each group). Overall, we found three differentially expressed miRNAs between the subgroups. miR-92a-3p and miR-224-5p were significantly downregulated in MSI-H/EMAST-H tumors in comparison to other subgroups. miR-518c-3p was significantly upregulated in MSS/EMAST-H tumors in comparison to stable and highly unstable tumors. Furthermore, we showed that miR-143-3p and miR-145-5p were downregulated in tumors in comparison to normal tissues in all subgroups. In addition, we showed overexpression of miR-125b-5p in well-differentiated tumors and miR-451a in less advanced tumors. This is the first report on differences in miRNA expression profiles between MSS/EMAST-S, MSS/EMAST-H, and MSI-H/EMAST-H colorectal cancers. Our findings indicate that the miRNA expression signatures differ in CRC subgroups based on their instability status.

Neoadjuvant Immunotherapy for Patients With Microsatellite Instability-High or POLE-Mutated Locally Advanced Colorectal Cancer With Bulky Tumors: New Optimization Strategy.

OBJECTIVE: To evaluate the efficacy and safety of neoadjuvant immunotherapy for patients with microsatellite instability-high (MSI-H) or DNA polymerase ε (POLE)-mutated locally advanced colorectal cancer (LACRC) with bulky tumors.  PATIENTS: We retrospectively reviewed 22 consecutive patients with MSI-H or POLE-mutated LACRC with bulky tumors (>8 cm in diameter) who received preoperative programmed death-1 blockade, with or without CapOx chemotherapy.  MAIN OUTCOME MEASURES: Pathological complete response (pCR), clinical complete response (cCR), toxicity, R0 resection rate, and complications were evaluated. Survival outcomes were analyzed using the Kaplan-Meier method. Multiplex immunofluorescence analysis were performed before and after treatment.  RESULTS: The incidence of immune-related adverse events (irAEs) was 36.4% (8/22). Five of 22 patients presented with surgical emergencies, most commonly perforation or obstruction. The 22 patients underwent a median 4 (1-8) cycles. Two patients were evaluated as cCR and underwent a watch and wait strategy. The R0 resection rate was 100.0% (20/20) and pCR rate was 70.0% (14/20). Twelve of 14 cT4b patients (85.7%) avoided multivisceral resection, and 10 of them achieved pCR or cCR. In the two patients with POLE mutations, one each achieved pCR and cCR. No Grade III/IV postoperative complications occurred. The median follow-up was 16.0 months. Two-year event-free and overall survival for the whole cohort was both 100%.  CONCLUSIONS: Preoperative immunotherapy is the optimal option for MSI-H or POLE-mutated LACRC with bulky tumors, especially cT4b. Preoperative immunotherapy in patients with T4b CRC can reduce multivisceral resection and achieve high CR rate.

Minimal residual disease monitoring via ctDNA: a case report of Lynch syndrome with synchronous colorectal cancer and review of literature.

Background: The investigation of circulating tumor DNA (ctDNA) as a substitute for minimal residual disease (MRD) has been a central focus in various clinical trials, with findings highlighting its effectiveness as a sensitive marker for detecting recurrence. In 2018, a joint review by the American Society of Clinical Oncology and the College of American Pathologists acknowledged a lack of current evidence guiding clinical decisions regarding ctDNA. Nevertheless, there are a multitude of ongoing studies exploring the future applications of ctDNA and its role in clinical decision making for select patient populations. Case Description: The case presented involves a patient with Lynch syndrome who developed synchronous left-sided colorectal cancers (CRC). Each primary malignancy exhibited a distinct mutational profile, introducing complexity to the personalized tumor-informed assays used for quantifying ctDNA levels. Initial ctDNA levels were negative until the assay was calibrated to the transverse colon primary tumor. Unfortunately, surveillance imaging showed radiographic recurrence coinciding with positive ctDNA findings. Treatment with the anti-PD-1 inhibitor pembrolizumab was initiated, resulting in the clearance of ctDNA after just four cycles. As of now, there is no radiographic or biologic evidence indicating disease recurrence. Conclusions: This case study sheds light on the evolving landscape and current limitations of ctDNA as a surrogate for MRD. We describe a patient with synchronous CRC who had radiographic recurrence and a negative MRD assay. Current tumor-informed assays are limited in their capacity to detect a single tumor, and by nature can miss both synchronous and metachronous malignancies. Assays tailored to multiple tumors or utilizing tumor agnostic methods should be a part of clinical decision making in this patient population.

Neoadjuvant Immunotherapy Effectiveness in Patients With Microsatellite Instability-High (MSI-H) Gastric Cancer.

Purpose This research work evaluates monotherapy with checkpoint inhibitors (CPI). as a neoadjuvant treatment for patients with Microsatellite Instability-High (MSI-H) locally advanced gastric cancer. Methods Here we present the results of the retrospective study from Napalkov Cancer Center over 4.5 years on patients with MSI-H locally advanced gastric cancer. A total of 566 patients were analyzed, 18 of whom were included in the research, focusing on clinical response rate, surgical pathology, 'watch and wait' strategy, and safety outcomes on an exploratory basis. Patients were assigned to four to eight neoadjuvant cycles of CPI, followed by surgery. Results The objective response to neoadjuvant CPI in patients with MSI-H gastric cancer was 77.8%. Complete response was achieved in five (27.8%) and partial response in nine (50%) patients, accordingly. Surgery was performed on 14 patients. Complete margin-free (R0) resection rates were 100%. Downstaging was observed in 12 out of 14 patients. Histopathologic complete response rates (pathologic complete response or Tumor Regression Grade-major response (TRG1)) were achieved in eight (57.1%) patients. No disease progression was detected with a median follow-up of 33.7 months (4.4-55.7 months). Clinically significant adverse events were not observed. Conclusion CPI in a neoadjuvant setting for patients with MSI-H locally advanced gastric cancer is highly effective and safe.

Target-Driven Tissue-Agnostic Drug Approvals-A New Path of Drug Development.

The regulatory approvals of tumor-agnostic therapies have led to the re-evaluation of the drug development process. The conventional models of drug development are histology-based. On the other hand, the tumor-agnostic drug development of a new drug (or combination) focuses on targeting a common genomic biomarker in multiple cancers, regardless of histology. The basket-like clinical trials with multiple cohorts allow clinicians to evaluate pan-cancer efficacy and toxicity. There are currently eight tumor agnostic approvals granted by the Food and Drug Administration (FDA). This includes two immune checkpoint inhibitors, and five targeted therapy agents. Pembrolizumab is an anti-programmed cell death protein-1 (PD-1) antibody that was the first FDA-approved tumor-agnostic treatment for unresectable or metastatic microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors in 2017. It was later approved for tumor mutational burden-high (TMB-H) solid tumors, although the TMB cut-off used is still debated. Subsequently, in 2021, another anti-PD-1 antibody, dostarlimab, was also approved for dMMR solid tumors in the refractory setting. Patients with fusion-positive cancers are typically difficult to treat due to their rare prevalence and distribution. Gene rearrangements or fusions are present in a variety of tumors. Neurotrophic tyrosine kinase (NTRK) fusions are present in a range of pediatric and adult solid tumors in varying frequency. Larotrectinib and entrectinib were approved for neurotrophic tyrosine kinase (NTRK) fusion-positive cancers. Similarly, selpercatinib was approved for rearranged during transfection (RET) fusion-positive solid tumors. The FDA approved the first combination therapy of dabrafenib, a B-Raf proto-oncogene serine/threonine kinase (BRAF) inhibitor, plus trametinib, a mitogen-activated protein kinase (MEK) inhibitor for patients 6 months or older with unresectable or metastatic tumors (except colorectal cancer) carrying a BRAFV600E mutation. The most recent FDA tumor-agnostic approval is of fam-trastuzumab deruxtecan-nxki (T-Dxd) for HER2-positive solid tumors. It is important to identify and expeditiously develop drugs that have the potential to provide clinical benefit across tumor types.

Use of Chemoimmunotherapy for Locally Advanced Deficient Mismatch Repair (dMMR) Gastric Adenocarcinoma With Curative Intent: A Case Report.

The standard of care for patients with operable gastric adenocarcinoma is perioperative chemotherapy and surgical resection. The deficient mismatch repair (dMMR)/microsatellite instability (MSI-H) phenotype is a major predictive biomarker for immune checkpoint inhibitors (ICIs) efficacy in advanced disease. Several phase II and III trials suggest a promising future role of immunotherapy with or without chemotherapy in the neoadjuvant/adjuvant setting, especially in MSI-H localized gastric adenocarcinomas. We present a 38-year-old man diagnosed in March 2022 with poorly differentiated gastric adenocarcinoma clinical stage III (cT4 N0 M0) with deficiency of MLH1 and PMS2, combined positive score (CPS) of 100 and negative HER2 immunohistochemistry, had poor tumor response to preoperative 5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT). It was considered unresectable because of the involvement of the colon, mesocolon, duodenum, pancreas, and retroperitoneum. Then, first-line systemic treatment with 5-FU, leucovorin, and oxaliplatin (FOLFOX)-nivolumab was initiated in August 2022, with a significant radiologic tumor reduction after six cycles, allowing a curative surgery in March 2023 with complete pathologic tumor response, followed by capecitabine and nivolumab for one year, maintaining radiological remission in the last follow-up in April 2024. With this case report, we conclude that it is likely that chemoimmunotherapy or immunotherapy alone may be alternative neoadjuvant treatment choices for MSI-H locally advanced gastric cancer patients.

Treatment of Microsatellite-Unstable Rectal Cancer in Sporadic and Hereditary Settings.

Microsatellite instability is rare in rectal cancer and associated with younger age of onset and Lynch syndrome. All rectal cancers should be tested for microsatellite instability prior to treatment decisions. Patients with microsatellite instability are relatively resistant to chemotherapy. However, recent small studies have shown dramatic response with neoadjuvant immunotherapy. Patients with Lynch syndrome have a hereditary predisposition to cancer and thus an elevated risk of metachronous cancer. Therefore, while "watch and wait" is a well-established practice for sporadic rectal cancers that obtain a complete clinical response after chemoradiation, its safety in patients with Lynch syndrome has not yet been defined. The extent of surgery for patients with Lynch syndrome and rectal cancer is controversial and there is significant debate as to the relative advantages of a segmental proctectomy with postoperative endoscopic surveillance versus a therapeutic and prophylactic total proctocolectomy. Surgical decision making for the patient with Lynch syndrome and rectal cancer is complex and demands a multidisciplinary approach, taking into account both patient- and tumor-specific factors. Neoadjuvant immunotherapy show great promise in the treatment of these patients, and further maturation of data from prospective trials will likely change the current treatment paradigm. Patients with Lynch syndrome and rectal cancer who do not undergo total proctocolectomy require yearly surveillance colonoscopies and should consider chemoprophylaxis with aspirin.

Identification of 8 candidate microsatellite instability loci in colorectal cancer and validation of the ACVR2A mechanism in the tumor progression.

This study probes the utility of biomarkers for microsatellite instability (MSI) detection and elucidates the molecular dynamics propelling colorectal cancer (CRC) progression. We synthesized a primer panel targeting 725 MSI loci, informed by The Cancer Genome Atlas (TCGA) and ancillary databases, to construct an amplicon library for next-generation sequencing (NGS). K-means clustering facilitated the distillation of 8 prime MSI loci, including activin A receptor type 2A (ACVR2A). Subsequently, we explored ACVR2A's influence on CRC advancement through in vivo tumor experiments and hematoxylin-eosin (HE) staining. Transwell assays gauged ACVR2A's role in CRC cell migration and invasion, while colony formation assays appraised cell proliferation. Western blotting illuminated the impact of ACVR2A suppression on CRC's PI3K/AKT/mTOR pathway protein expressions under hypoxia. Additionally, ACVR2A's influence on CRC-induced angiogenesis was quantified via angiogenesis assays. K-means clustering of NGS data pinpointed 32 MSI loci specific to tumor and DNA mismatch repair deficiency (dMMR) tissues. ACVR2A emerged as a pivotal biomarker, discerning MSI-H tissues with 90.97% sensitivity. A curated 8-loci set demonstrated 100% sensitivity and specificity for MSI-H detection in CRC. In vitro analyses corroborated ACVR2A's critical role, revealing its suppression of CRC proliferation, migration, and invasion. Moreover, ACVR2A inhibition under CRC-induced hypoxia markedly escalated MMP3, CyclinA, CyclinD1, and HIF1α protein expressions, alongside angiogenesis, by triggering the PI3K/AKT/mTOR cascade. The 8-loci ensemble stands as the optimal marker for MSI-H identification in CRC. ACVR2A, a central element within this group, deters CRC progression, while its suppression amplifies PI3K/AKT/mTOR signaling and angiogenesis under hypoxic stress.

The Prognostic Nutritional Index in patients with microsatellite instability-high metastatic gastric or gastroesophageal cancers receiving immune checkpoint inhibitors.

BACKGROUND: Microsatellite instability high (MSI-H) and/or mismatch repair deficient (dMMR) status is the strongest predictive factor for immune checkpoint inhibitors (ICIs) benefit in patients with metastatic gastroesophageal cancer (mGC). Primary resistance to ICIs is a relevant issue, but prognostic and predictive factors are lacking. MATERIALS AND METHODS: In this multinational, retrospective cohort of patients with MSI-H/dMMR mGC treated with ICIs without chemotherapy we collected baseline laboratory values to establish the prognostic nutritional index (PNI). We evaluated the association between baseline PNI with the activity and efficacy of ICIs. RESULTS: At a median follow-up of 31.6 months, median progression-free survival (PFS) and 2-year PFS rate were not reached and 73.6 % in the PNI-high subgroup versus 6.3 months and 38.3 % in the PNI-low one (HR 0.32, 95 % CI: 0.16-0.61, p < .001). Median overall survival (OS) and 2-year OS rate were not reached and 81.9 % in the PNI-high subgroup versus 24.4 months and 50.5 % in the PNI-low one (HR 0.26, 95 % CI: 0.12-0.56, p < .001). In multivariable models, high PNI was associated with longer PFS and OS (HR 0.30, 95 % CI: 0.15-0.61, p <0.001 and 0.37, 95 % CI: 0.15-0.91, p = .031). CONCLUSIONS: High PNI is associated with longer PFS and OS, in patients with MSI-H mGC receiving ICIs. Patients with low baseline PNI may benefit from intensive therapeutic approaches.

Non-operative management after immune checkpoint inhibitors for early-stage, dMMR/MSI-H gastrointestinal cancers.

Surgery is a standard treatment for early-stage gastrointestinal cancers, often preceded by neoadjuvant chemo(radio)therapy or followed by adjuvant therapy. While leading to cure in a proportion of patients, it has some drawbacks such as intra/post-operative complications, mutilation and life-long functional sequelae. Further to the unprecedented efficacy data from studies of immune checkpoint inhibitors for advanced mismatch repair deficient/microsatellite instable (dMMR/MSI-H) tumours, a strong interest has recently emerged for the investigation of such agents in the neoadjuvant setting. Although limited by the exploratory design and small sample size, trials of neoadjuvant immune checkpoint inhibitors for early-stage dMMR/MSI-H gastrointestinal cancers have consistently reported complete response rates ranging from 70 % to 100 %. As a result, the question has arisen as to whether surgery is still needed or organ-preserving strategies should be offered to this especially immuno-sensitive population. In this article, we discuss the available evidence for neoadjuvant immune checkpoint inhibitors in dMMR/MSI-H gastrointestinal cancers and analyse opportunities and challenges to the implementation of non-operative management approaches in this setting.

Pancreatic cancer biomarkers: A pathway to advance in personalized treatment selection.

Pancreatic cancer is one of the tumors with the worst prognosis, and unlike other cancers, few advances have been made in recent years. The only curative option is surgery, but only 15-20% of patients are candidates, with a high risk of relapse. In advanced pancreatic cancer there are few first-line treatment options and no validated biomarkers for better treatment selection. The development of targeted therapies in pancreatic cancer is increasingly feasible due to tumor-agnostic treatments, such as PARP inhibitors in patients with BRCA1, BRCA2 or PALB2 alterations or immunotherapies in patients with high microsatellite instability/tumor mutational burden. In addition, other therapeutic molecules have been developed for patients with KRAS G12C mutation or fusions in NTRK or NRG1. Consequently, there has been a growing interest in biomarkers that may help guide targeted therapy in pancreatic cancer. Therefore, this review aims to offer an updated perspective on biomarkers with therapeutic potential in pancreatic cancer.

Clinical evidence for efficacy of pembrolizumab in MSI-H and TMB-H advanced solid tumor: results from three cancer centers in China.

BACKGROUND: Pembrolizumab has been indicated in the treatment of solid tumors with high frequency microsatellite instability (MSI-H) or high tumor mutational burden (TMB-H); however, real-world data on the effectiveness of pembrolizumab with or without chemotherapy in this molecular subset remain limited. Our retrospective study evaluated the clinical efficacy and safety of pembrolizumab in treating advanced solid tumors with either MSI-H or TMB-H. METHODS: This retrospective study analyzed data from 116 patients with MSI-H or TMB-H advanced solid cancers who received pembrolizumab with or without chemotherapy regardless of treatment setting. We analyzed objective response rate (ORR) and progression-free survival (PFS). RESULTS: The top three cancer types were colorectal (48.6% MSI-H, 6.5% TMB-H), lung (15.4% MSI-H, 84.4% TMB-H), and gastric (15.4% MSI-H, 5.1% TMB-H). The ORR with pembrolizumab was 52.6%, including complete response (CR) observed in 8.6% (n = 10) of cases and partial responses (PR) in 43.9% (n = 51). Of the 93 patients who received first-line pembrolizumab, 52 patients achieved objective response (10 CR, 42 PR), with a median PFS of 14.0 months (95% confidence intervals [CI] 6.6-21.4). Of the 23 who received subsequent-line pembrolizumab, the ORR was 39.1%, disease control rate was 91.3%, and median PFS was 5.7 months (95% CI 3.9-7.5). Treatment-related adverse events were observed in 32 patients (27.6%), with no reported treatment-related fatal adverse events. CONCLUSION: Our study provides real-world evidence on the clinical effectiveness of pembrolizumab with or without chemotherapy in the treatment of patients with MSI-H and TMB-H advanced solid cancers.

Pembrolizumab in patients from China with microsatellite instability-high/mismatch repair deficient tumors: KEYNOTE-158.

Aim: To evaluate pembrolizumab in patients of Chinese descent with microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR) tumors enrolled in KEYNOTE-158 (Cohort L). Methods: Patients with MSI-H/dMMR advanced tumors received pembrolizumab 200 mg IV Q3W. Primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS) and overall survival (OS). Results: 24 patients were enrolled (20 were evaluable for efficacy). With median follow-up of 12.4 months, the ORR was 70%. DOR, PFS and OS were all not reached. A total of 19 (79%) patients had a treatment-related adverse event (AE; grade ≥3 in 4 [17%]), and 8 (33%) had an immune-mediated AE (grade ≥3 in (4 [17%]). Conclusion: Pembrolizumab provided meaningful and durable responses with manageable safety. These results are consistent with those reported for the global trial.

Neoadjuvant Immunotherapy With Ipilimumab Plus Nivolumab in Mismatch Repair Deficient/Microsatellite Instability-High Colorectal Cancer: A Preliminary Report of Case Series.

BACKGROUND: Although ipilimumab plus nivolumab have significantly improved the survival of metastatic colorectal cancer (CRC) with mismatch repair deficient (dMMR) /microsatellite instability-high (MSI-H), the data on neoadjuvant setting is limited. PATIENTS AND METHODS: We enrolled 11 patients with advanced dMMR/MSI-H CRC. 10 patients were locally advanced and 1 was metastatic. Ten patients were treated with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg), and 1 patient was treated with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg) with 2 cycles. All the patients underwent surgery after immunotherapy. The aim of the study was to evaluate the safety and short-term efficacy of this strategy. RESULTS: Pathologic responses were observed in 11/11 (100%) dMMR/MSI-H tumors, with 9/11 (81.8%) achieving complete responses. Among these 9 cases with complete responses, 1 achieved a radiological noncomplete response after treatment with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg), so another cycle of treatment with 1 dose of ipilimumab (1 mg/kg) and 2 doses of nivolumab (3 mg/kg) was administered, followed by surgery. The postoperative pathological evaluation was a complete response. Seven patients (63.6%) developed grade I/II adverse events. No patients developed grade III/IV adverse events or postoperative complications. CONCLUSION: Neoadjuvant immunotherapy with ipilimumab plus nivolumab induced tumor regression with a major clinical and pathological response in advanced dMMR/MSI-H CRC. Notably, patients do not achieve a complete response to neoadjuvant immunotherapy, additional neoadjuvant immunotherapy may offer benefits. Further research is needed to assess the long-term efficacy of this strategy.

The current status and prospect of immunotherapy in colorectal cancer

Metastatic colorectal cancer (mCRC) is a heterogeneous disease. We reviewed the current clinical trials on immunotherapy in metastatic colorectal cancer with high microsatellite instability and microsatellite stability. Owing to the advances in immunotherapy, its use has gradually expanded from second- and third-line therapies to first-line, early neoadjuvant, and adjuvant therapies. Based on current research results, immunotherapy has shown very good results in dMMR/MSI-H patients, whether it is neoadjuvant therapy for operable patients or first-line or multi-line therapy for advanced patients. KEYNOTE 016 study also showed that patients with MSS were basically ineffective in single immunotherapy. Moreover, immunotherapy for colorectal cancer may also require identification of new biomarkers (AU)