Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

Asia; Colorectal cancer; PembrolizumabAsia; Cáncer colorrectal; PembrolizumabÀsia; Càncer colorectal; PembrolizumabThe phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002

Nutritional index for immune-checkpoint inhibitor in patients with metastatic gastro-esophageal junction/gastric cancer

Background: Nutritional status is strongly associated to prognosis in mGOJ/GC patients. The aim of the present study was to develop an ICI-specific nutritional index (NI).Methods: Ten serum and anthropometric nutritional markers derived from blood tests or CT scans were analyzed at baseline in patients treated with second-line ICI and correlated with overall survival (OS). An ICI-specific NI (the NUTRIICI) was developed with its specificity assessed in an independent group of patients treated with standard second-line chemotherapy.Results: From June 2014 to December 2018, 57 mGOJ/GC patients (14 females, 43 males) with a median(m) age of 61 years (range 29-85) received ICI as second-line therapy (Pembrolizumab n=26, Nivolumab n=1 6, Avelumab n=15). Among the 10 analyzed variables, Onodera's prognostic NI (PNI) <= 33 and waist-to-hip (WHR) <1 were independent predictors of OS and used to build the NUTRIICI. Patients with both favorable factors (i.e., PNI >33 and WHR >= 1, comparator group) had a mOS of 18.0 vs. 6.7 months of patients with one unfavorable factor (either PNI <= 33 or WHR <1, Hazard Ratio, HR 3.06), vs. 1.3 months of patients with both unfavorable factors (HR 17.56), overall P<0.0001. In the independent group of patients treated with standard chemotherapy NUTRIICI was not associated with prognosis (P=0.57).Conclusions: NUTRIICI is the first ICI-specific NI for mOGJ/GC patients receiving second-line ICI. A validation in larger cohorts is strongly encouraged

Pembrolizumab in Asian patients with microsatellite-instability-high/mismatch-repair-deficient colorectal cancer

The phase 3 KEYNOTE-177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite-instability-high (MSI-H)/mismatch-repair-deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression-free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE-177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n =?22; chemotherapy, n =?26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1?57.8) months with pembrolizumab and 43.9 (range 36.6?55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months?NR) with pembrolizumab versus 10.4 (95% CI 6.3?22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26?1.20). Median OS was NR (range 13.8 months?NR) versus 30.0 (14.7?NR) months (HR 0.65, 95% CI 0.27?1.55) and ORR was 50% (95% CI 28?72) versus 46% (95% CI 27?67). Grade 3/4 treatment-related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune-mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first-line pembrolizumab as a standard of care for patients from Asia with MSI-H/dMMR mCRC. ClinicalTrials.gov identifier: NCT02563002.FUNDING INFORMATION: The study was designed under the responsibility of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA, in conjunction with the steering committee. The study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. Pembrolizumab was provided by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. All authors had full access to all of the data in the study and had final responsibility for the decision to submit for publication. ACKNOWLEDGMENTS: This work was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. We thank the patients and their families and caregivers for participating in this trial, and all investigators and site personnel. Medical writing and editorial assistance were provided by Jemimah Walker, PhD, Mehak Aggarwal, PharmD, and Doyel Mitra, PhD, CMPP, of ApotheCom (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

Comprehensive Examination of Cholangiocarcinoma Patients Treated with Novel Targeted Therapies after Extended Molecular Profiling on Liquid Biopsies

Background: Cholangiocarcinoma (CCA) is associated with poor outcomes and limited treatment options, leading to increased use of targeted therapies for its management. Here, we performed one of the largest single-centre reviews evaluating outcomes following personalised targeted agents in CCA patients. Methods: All consecutive CCA patients receiving systemic therapy between January 2010 and April 2023 at UCLH were included. The primary objective of this study was to evaluate treatment response, survival outcomes and predictors of clinical benefit in CCA patients treated with molecularly guided therapies. Patient demographic factors, disease characteristics and survival outcomes were evaluated using the Kaplan–Meier method and Cox proportional-hazards models. Results: Of the 227 consecutive CCA patients, 162 (71%) had molecular profiling, of whom 56 (35%) were eligible and 55 received molecular-targeted treatment. CCA histological classifications comprised intrahepatic (N = 32), extrahepatic (N = 11), hilar (N = 4) and unknown (N = 9) subtypes. Most patients received targeted agents based on genomic profiling in a second treatment line setting (N = 34). Frequently observed genomic alterations occurred in the FGFR2 (N = 21), IDH1 (N = 7) and BRCA2 (N = 6) genes. Median progression-free survival (PFS) following first-, second- and third-line systemic therapy and overall survival (OS) were 8.44 (95% CI, 7.49–12.78), 5.65 (95% CI, 3.71–7.13), 5.55 (2.79–12.58) and 29.01 (24.21–42.91) months, respectively. CCA subtype and FGFR/BRCA molecular aberration status were not associated with PFS or OS. However, a prior CCA-related surgical history was predictive of OS (p = 0.02). Stratification by best overall response to second-line targeted agents demonstrated an association with PFS (p = 0.002) and OS (p = 0.02). Duration of treatment with second-line targeted therapy was associated with OS (p < 0.001). Conclusions: Patients receiving targeted therapeutics achieved promising outcomes, especially those attaining a favourable treatment response and those receiving targeted agents for longer periods. Liquid biopsies can reliably provide information on extended molecular profiling to aid patient selection for personalised therapies

Gastric Inflammatory Prognostic Index (GIPI) in Patients with Metastatic Gastro-Esophageal Junction/Gastric Cancer Treated with PD-1/PD-L1 Immune Checkpoint Inhibitors

Background Immune checkpoint inhibitors (ICIs) demonstrated improved overall survival (OS) in heavily pretreated unselected patients with metastatic gastro-esophageal junction (mGOJ)/gastric cancer (GC). Attempts to select patients based on programmed death-ligand 1 (PD-L1) expression appear to be suboptimal. A strong rationale suggests a prognostic role for inflammatory biomarkers for ICI-treated patients with mGOJ/GC. Objective Our objective was to assess whether inflammatory markers are associated with survival in ICI-treated patients with mGOJ/GC. Methods Ten inflammatory markers were retrospectively analyzed at baseline in 57 patients with mGOJ/GC with unknown PD-L1 status treated with second-line ICIs and correlated with OS. Selected variables were then analyzed in a multivariate Cox-regression model and used to build a GIPI nomogram. Results Neutrophil/lymphocyte ratio (NLR) and C-reactive protein (CRP) as continuous variables and albumin categorized as less than versus greater than 30 g/dL were the most significant predictors of OS and were used to build the GIPI nomogram. Nomogram-based lowest, mid-low, mid-high, and highest risk quartiles were associated with median OS (mOS) of 14.9, 7.1, 5.6, and 2.1 months, respectively (hazard ratio [HR] of highest vs. lowest risk 4.94; p = 0.0002). By optimally dichotomizing CRP and NLR, patients with one or more of the risk factors NLR &gt; 6, CRP &gt; 15 mg/L, and albumin &lt; 30 g/dL (n = 29) had an mOS of 3.9 versus 14.2 months for patients with no risk factor (n = 28) (HR 2.48; p = 0.0015). Conclusions GIPI, combining NLR, CRP, and albumin, is the first inflammatory index with a significant prognostic value in patients with mOGJ/GC receiving ICIs. GIPI merits validation in independent cohorts and prospective clinical trials

Functional characterization of the 19q12 amplicon in grade III breast cancers

Introduction: The 19q12 locus is amplified in a subgroup of oestrogen receptor (ER)-negative grade III breast cancers. This amplicon comprises nine genes, including cyclin E1 (CCNE1), which has been proposed as its 'driver'. The aim of this study was to identify the genes within the 19q12 amplicon whose expression is required for the survival of cancer cells harbouring their amplification. Methods: We investigated the presence of 19q12 amplification in a series of 313 frozen primary breast cancers and 56 breast cancer cell lines using microarray comparative genomic hybridisation (aCGH). The nine genes mapping to the smallest region of amplification on 19q12 were silenced using RNA interference in phenotypically matched breast cancer cell lines with (MDA-MB-157 and HCC1569) and without (Hs578T, MCF7, MDA-MB-231, ZR75.1, JIMT1 and BT474) amplification of this locus. Genes whose silencing was selectively lethal in amplified cells were taken forward for further validation. The effects of cyclin-dependent kinase 2 (CDK2) silencing and chemical inhibition were tested in cancer cells with and without CCNE1 amplification. Results: 19q12 amplification was identified in 7.8% of ER-negative grade III breast cancer. Of the nine genes mapping to this amplicon, UQCRFS1, POP4, PLEKHF1, C19ORF12, CCNE1 and C19ORF2 were significantly overexpressed when amplified in primary breast cancers and/or breast cancer cell lines. Silencing of POP4, PLEKHF1, CCNE1 and TSZH3 selectively reduced cell viability in cancer cells harbouring their amplification. Cancer cells with CCNE1 amplification were shown to be dependent on CDK2 expression and kinase activity for their survival. Conclusions: The 19q12 amplicon may harbour more than a single 'driver', given that expression of POP4, PLEKHF1, CCNE1 and TSZH3 is required for the survival of cancer cells displaying their amplification. The observation that cancer cells harbouring CCNE1 gene amplification are sensitive to CDK2 inhibitors provides a rationale for the testing of these chemical inhibitors in a subgroup of patients with ER-negative grade III breast cancer

Trifluridine/Tipiracil in Metastatic Colorectal Cancer:A UK Multicenter Real-world Analysis on Efficacy, Safety, Predictive and Prognostic Factors

BACKGROUND: The orally administered combination trifluridine/tipiracil has been approved as third line treatment in mCRC, demonstrating survival benefit and acceptable toxicity profile in the phase III RECOURSE study.PATIENT AND METHODS: We performed a multicenter retrospective real-world analysis of patients with mCRC receiving trifluridine/tipiracil between 2016 and 2019 in eight cancer centers across the United Kingdom.RESULTS: A total of 236 patients were included with median age of 69 years. All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 10% of patients had ECOG ≥ 2. Median duration of trifluridine/tipiracil treatment was 3 months with an ORR of 2.1% and disease control rate of 21.6%. Median OS was 7.6 and median PFS 3.3 months. A dose reduction was required in 27% of patients, while 7.6% discontinued treatment due to toxicity. The most common grade 3 toxicities were neutropenia (34%), fatigue (10%), anemia (9%) and febrile neutropenia (5%). Baseline NLR &lt;5 and CEA &lt;200 had favorable prognostic (HR: 0.52 and 0.39, P≤ .001) and predictive value (OR: 4.1 and 6.7, P&lt; .05). Development of grade 3 neutropenia predicted treatment response (OR: 0.32, P&lt; .001). Following treatment with trifluridine/tipiracil 41% were referred for phase I trial or rechallenged with chemotherapy.CONCLUSION: Trifluridine/tipiracil is well tolerated in refractory mCRC patients with comparable efficacy and toxicity profile to that of the phase III RECOURSE. Pretreatment NLR and CEA could serve as potential markers for patient selection, while treatment-induced grade 3 neutropenia predicted response. Prospective validation is needed.</p