Phase 1a dose escalation study of ivonescimab (AK112/SMT112), an anti-PD-1/VEGF-A bispecific antibody, in patients with advanced solid tumors.

BACKGROUND: Studies showed that vascular endothelial growth factor (VEGF) inhibitors could improve therapeutic efficacy of PD-1/PD-L1 antibodies by transforming the immunosuppressive tumor microenvironment (TME) into an immunoresponsive TME. Ivonescimab is a first-in-class, humanized tetravalent bispecific antibody targeting PD-1 and VEGF-A simultaneously. Here, we report the first-in-human, phase 1a study of ivonescimab in patients with advanced solid tumors. METHODS: Patients with advanced solid tumors were treated with ivonescimab 0.3, 1, 3, 10, 20 or 30 mg/kg intravenously every 2 weeks using a 3+3+3 dose escalation design. Dose expansion occurred at 10 and 20 mg/kg in selected tumor types. The primary objective was to assess the safety and tolerability, and to determine the maximum tolerated dose (MTD). The secondary objectives included pharmacokinetics, pharmacodynamics and preliminary antitumor activity based on Response Evaluation Criteria in Solid Tumors V.1.1. RESULTS: Between October 2, 2019 and January 14, 2021, a total of 51 patients were enrolled and received ivonescimab. Two dose-limiting toxicities were reported at 30 mg/kg. The MTD of ivonescimab was 20 mg/kg every 2 weeks. Grade≥3 treatment-related adverse events (TRAEs) occurred in 14 patients (27.5%). The most common TRAEs of any grade were rash (29.4%), arthralgia (19.6%), hypertension (19.6%), fatigue (17.6%), diarrhea (15.7%) and pruritus (11.8%). The most common grade≥3 TRAEs were hypertension (7/51, 13.7%), alanine aminotransferase increased (3/51, 5.2%), aspartate aminotransferase increased (2/51, 3.9%) and colitis (2/51, 3.9%). Of 47 patients who had at least one postbaseline assessment, the confirmed objective response rate was 25.5% (12/47) and disease control rate was 63.8% (30/47). Among 19 patients with platinum-resistant ovarian cancer, 5 patients (26.3%) achieved partial response (PR). Efficacy signals were also observed in patients with mismatch repair proficient (pMMR) colorectal cancer, non-small cell lung cancer, and both MMR deficient and pMMR endometrial cancer. CONCLUSIONS: Ivonescimab demonstrated manageable safety profiles and promising efficacy signals in multiple solid tumors. Exploration of alternative dosing regimens of ivonescimab monotherapy and combination therapies is warranted. TRIAL REGISTRATION NUMBER: NCT04047290.

Evaluation of the efficacy and safety of a precise thymalfasin-regulated PRaG regimen for advanced refractory solid tumours: protocol for the open-label, prospective, multicentre study (PRaG5.0 study).

INTRODUCTION: The PRaG regimen, which consists of hypofractionated radiotherapy combined with a programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitor and granulocyte-macrophage colony stimulating factor (GM-CSF), has been demonstrated to have a survival benefit in patients with advanced solid tumours who have failed at least two lines of treatment. Nonetheless, lymphopenia poses an impediment to the enduring efficacy of PD-1/PD-L1 inhibitor therapy. Adequate lymphocyte reserves are essential for the efficacy of immunotherapy. Coupling the PRaG regimen with immunomodulatory agents that augment the number and functionality of lymphocytes may yield further survival benefits in this cohort of patients. OBJECTIVE: The aim of this study is to investigate the effectiveness and safety of a meticulously thymalfasin-controlled PRaG regimen in patients with advanced and chemotherapy-resistant solid tumours. METHODS AND ANALYSIS: The study has a prospective, single-arm, open-label, multicentre design and aims to recruit up to 60 patients with histologically confirmed advanced solid tumours that have relapsed or metastasised. All eligible patients will receive a minimum of two cycles of the PRaG regimen comprising thymalfasin followed by maintenance treatment with a PD-1/PD-L1 inhibitor and thymalfasin for 1 year or until disease progression. Patients will be monitored according to the predetermined protocol for a year or until disease progression after initiation of radiotherapy. ETHICS AND DISSEMINATION: The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University, on 25 November 2022 (JD-LK-2022-151-01) and all other participating hospitals. Findings will be disseminated through national and international conferences. We also plan to publish our findings in high-impact peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05790447.

Plasma Proteome-Based Test for First-Line Treatment Selection in Metastatic Non-Small Cell Lung Cancer.

PURPOSE: Current guidelines for the management of metastatic non-small cell lung cancer (NSCLC) without driver mutations recommend checkpoint immunotherapy with PD-1/PD-L1 inhibitors, either alone or in combination with chemotherapy. This approach fails to account for individual patient variability and host immune factors and often results in less-than-ideal outcomes. To address the limitations of the current guidelines, we developed and subsequently blindly validated a machine learning algorithm using pretreatment plasma proteomic profiles for personalized treatment decisions. PATIENTS AND METHODS: We conducted a multicenter observational trial (ClinicalTrials.gov identifier: NCT04056247) of patients undergoing PD-1/PD-L1 inhibitor-based therapy (n = 540) and an additional patient cohort receiving chemotherapy (n = 85) who consented to pretreatment plasma and clinical data collection. Plasma proteome profiling was performed using SomaScan Assay v4.1. RESULTS: Our test demonstrates a strong association between model output and clinical benefit (CB) from PD-1/PD-L1 inhibitor-based treatments, evidenced by high concordance between predicted and observed CB (R2 = 0.98, P < .001). The test categorizes patients as either PROphet-positive or PROphet-negative and further stratifies patient outcomes beyond PD-L1 expression levels. The test successfully differentiates between PROphet-negative patients exhibiting high tumor PD-L1 levels (≥50%) who have enhanced overall survival when treated with a combination of immunotherapy and chemotherapy compared with immunotherapy alone (hazard ratio [HR], 0.23 [95% CI, 0.1 to 0.51], P = .0003). By contrast, PROphet-positive patients show comparable outcomes when treated with immunotherapy alone or in combination with chemotherapy (HR, 0.78 [95% CI, 0.42 to 1.44], P = .424). CONCLUSION: Plasma proteome-based testing of individual patients, in combination with standard PD-L1 testing, distinguishes patient subsets with distinct differences in outcomes from PD-1/PD-L1 inhibitor-based therapies. These data suggest that this approach can improve the precision of first-line treatment for metastatic NSCLC.

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A 70-year-old man had radical surgery for colon cancer one year before the symptoms of memory loss and decreasing cognitive function. Subsequent magnetic resonance imaging revealed a brain mass, which was surgically resected and confirmed to be metastatic intestinal adenocarcinoma. Immunohistochemistry of the primary tumor and brain metastasis showed mismatch repair deficiency. The patient received adjuvant chemotherapy after surgery. However, the brain metastasis relapsed one month after the last chemotherapy. Genetic testing on the resected colon tumor samples confirmed microsatellite instability-high with a high tumor mutation burden by 77.7 muts/Mb. The patient was subsequently treated with programmed death-1 (PD-1) monoclonal antibody pembrolizumab (keytruda). The brain metastatic lesions were completely shrunk, and a complete clinical response was achieved.

Nanoparticle-mediated blockade of CXCL12/CXCR4 signaling enhances glioblastoma immunotherapy: Monitoring early responses with MRI radiomics.

The limited therapeutic efficacy of checkpoint blockade immunotherapy against glioblastoma is closely related to the blood-brain barrier (BBB) and tumor immunosuppressive microenvironment, where the latter is driven primarily by tumor-associated myeloid cells (TAMCs). Targeting the C-X-C motif chemokine ligand-12/C-X-C motif chemokine receptor-4 (CXCL12/CXCR4) signaling orchestrates the recruitment of TAMCs and has emerged as a promising approach for alleviating immunosuppression. Herein, we developed an iRGD ligand-modified polymeric nanoplatform for the co-delivery of CXCR4 antagonist AMD3100 and the small-molecule immune checkpoint inhibitor BMS-1. The iRGD peptide facilitated superior BBB crossing and tumor-targeting abilities both in vitro and in vivo. In mice bearing orthotopic GL261-Luc tumor, co-administration of AMD3100 and BMS-1 significantly inhibited tumor proliferation without adverse effects. A reprogramming of immunosuppression upon CXCL12/CXCR4 signaling blockade was observed, characterized by the reduction of TAMCs and regulatory T cells, and an increased proportion of CD8+T lymphocytes. The elevation of interferon-γ secreted from activated immune cells upregulated PD-L1 expression in tumor cells, highlighting the synergistic effect of BMS-1 in counteracting the PD-1/PD-L1 pathway. Finally, our research unveiled the ability of MRI radiomics to reveal early changes in the tumor immune microenvironment following immunotherapy, offering a powerful tool for monitoring treatment responses. STATEMENT OF SIGNIFICANCE: The insufficient BBB penetration and immunosuppressive tumor microenvironment greatly diminish the efficacy of immunotherapy for glioblastoma (GBM). In this study, we prepared iRGD-modified polymeric nanoparticles, loaded with a CXCR4 antagonist (AMD3100) and a small-molecule checkpoint inhibitor of PD-L1 (BMS-1) to overcome physical barriers and reprogram the immunosuppressive microenvironment in orthotopic GBM models. In this nanoplatform, AMD3100 converted the "cold" immune microenvironment into a "hot" one, while BMS-1 synergistically counteracted PD-L1 inhibition, enhancing GBM immunotherapy. Our findings underscore the potential of dual-blockade of CXCL12/CXCR4 and PD-1/PD-L1 pathways as a complementary approach to maximize therapeutic efficacy for GBM. Moreover, our study revealed that MRI radiomics provided a clinically translatable means to assess immunotherapeutic efficacy.

The prognostic significance of programmed cell death protein 1 and its ligand on lymphoma cells and tumor-immune cells in diffuse large B-cell lymphoma, not otherwise specified.

BACKGROUND: Diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS) is the most common type non-Hodgkin's lymphoma, where the treatment of relapsed/refractory cases is the major challenge. Programmed cell death protein 1 (PD-1) and its ligand PD-L1 play a crucial role in the negative regulation of the immune response against the disease. The aim of the study was to analyze the expression of PD-1 and PD-L1 on lymphoma cells (LCs) and tumor-immune cells (TICs) and to investigate their correlation with outcome. PATIENTS AND METHODS: Samples from 283 patients diagnosed with DLBCL, NOS (both germinal center B cell like [GCB] and non-GCB subtypes) were included in the study. Expression of PD-1 and PD-L1 was determined using double immunohistochemical staining (D-IHC) for PD-1/PAX5 and PD-L1/PAX5 on tissue microarrays. LCs were highlighted by D-IHC to obtain more accurate results. Clinical data and histologic diagnoses were obtained from electronic data records. We correlated clinical characteristics, and PD-1 and PD-L1 expression on LCs and TICs with progression-free survival (PFS) and overall survival (OS). RESULTS: Expression of PD-1 on TICs was observed in 38.4% and on LCs in 8.8% of cases, while PD-L1 was expressed on TICs in 46.8% and on LCs in 6.5% of cases. PD-L1 expression on LCs was more frequent in non-GCB subtype (p = 0.047). In addition, patients with PD-L1 expression on LCs had significantly shorter PFS (p = 0.015), and the expression retained significant in the multivariate model (p = 0.034). CONCLUSIONS: PD-L1 was more frequently expressed in LCs of the non-GCB subtype. Additionally, PD-L1 in LCs may predict shorter PFS time. D-IHC staining for PD-L1/PAX5 is a feasible method to assess PD-L1 expression on LCs of DLBCL, NOS patients and can be used to identify patients who may benefit from targeted immunotherapy with checkpoint inhibitors.

Survival analysis of comprehensive treatment in Chinese patients with metastatic melanoma: A retrospective analysis.

BACKGROUND: Most of the current progression of immune checkpoint inhibitors for malignant melanoma is based on data from Caucasians in Western countries, but the benefit of Chinese patients is limited, mainly due to different pathological subtypes. The patients in western countries are mainly skin melanoma (about 90%), while the acral and mucosal types are dominant in China, accounting for 41.8% and 22.6% respectively. Acral and mucosal melanoma have lower response rates to immunotherapy and chemotherapy. OBJECTIVE: Whether immune checkpoint inhibitors can improve the survival of Chinese patients with malignant melanoma, therefore, we conducted a retrospective analysis. METHODS: We analyzed 53 patients with metastatic melanoma treated in our hospital to evaluate the efficacy and safety of PD-1 mAb in Chinese patients with metastatic melanoma, and performed univariate and multivariate analyses of prognostic factors that may affect overall survival (OS). RESULTS: In a study of 125 patients with advanced malignant melanoma, 53 patients participated, with a median follow-up of 16 months. Among these, 69.8% died, and 30.2% remained on treatment. Median progression-free survival (PFS) was 6 months, and median OS was 19 months. Patients treated with immune checkpoint inhibitors had improved outcomes, with a median PFS of 7 months and a median OS of 24 months. Patients with bone metastasis and aberrant Lactate dehydrogenase (LDH) post-treatment had worse prognoses, while immunotherapy was a protective factor. Subgroup analysis showed the benefits of immunotherapy across various patient characteristics. No unexpected toxicities were observed. CONCLUSION: The study highlights the efficacy of immune checkpoint inhibitors, particularly PD-1 mAb, in improving survival outcomes for Chinese patients with metastatic melanoma.

Integrative score based on CDK6, PD-L1 and TMB predicts response to platinum-based chemotherapy and PD-1/PD-L1 blockade in muscle-invasive bladder cancer.

BACKGROUND: Cyclin-dependent kinase 6 (CDK6) was proved to be an important regulator in the progression of cell cycle and has been a promising therapeutic target in cancer treatment. However, the clinical significance of CDK6 in muscle-invasive bladder cancer (MIBC) remains obscure. Herein, we attempt to explore the clinical relevance of CDK6 and assess the feasibility of the integrative model to predict immune checkpoint blockade (ICB) response. METHODS: This study enrolled 933 patients with muscle-invasive bladder cancer (MIBC) from Zhongshan Hospital (ZSHS), The Cancer Genome Atlas (TCGA), Chemo, IMvigor210 and UC-GENOME cohorts. Kaplan-Meier survival and Cox regression analyses were performed to assess clinical outcomes based on CDK6 expression. RESULTS: High CDK6 expression conferred poor prognosis and superior response to platinum-based chemotherapy but inferior response to ICB in MIBC. Furthermore, the integrative model named response score based on CDK6, PD-L1 and TMB could better predict the response to ICB and chemotherapy. Patients with higher response scores were characterised by inflamed immune microenvironment and genomic instability. CONCLUSIONS: CDK6 expression was correlated with prognosis and therapy response in MIBC. Integration of CDK6, PD-L1 and TMB could better identify patients who were most likely to benefit from ICB and chemotherapy.

Relationship between immune checkpoint proteins and neoadjuvant chemotherapy response in breast cancer.

INTRODUCTION: Following major developments in cancer immunotherapy, treatments targeting immune checkpoint proteins (ICP) gained interest in breast cancer, though studies mostly focus on patients with metastatic disease as well as patients nonresponsive to the conventional treatments. Herein, we aimed to investigate the levels of ICP in tumor stroma and tumor infiltrating lymphocytes, and tumor tissue prior to neoadjuvant chemotherapy administration to evaluate the relationship between ICP levels, clinicopathological parameters, and NAC response. MATERIALS AND METHODS: This study was conducted with 51 patients where PD-1, PD-L1, CTLA-4, TIM-3, CD24 and CD44 levels were investigated in CD45+ cells while CD326, CD24, CD44 and PD-L1 protein expression levels were investigated in CD45- population. In addition, CD44 and CD24 levels were evaluated in the tumor stroma. TIL levels were investigated according to the TILS Working Group. Treatment responses after NAC were evaluated according to the MD Anderson RCB score. RESULTS: Our results revealed positive correlation between CTLA-4 and CD44 expression in cases with high TIL levels as well as TIL levels and CTLA-4 expression in cases with partial response. Similarly, positive correlation was detected between TIM3 and PD-L1 levels in cases with good response. In addition, a negative correlation between TILs after NAC and PD-1/PD-L1 expression in lymphocytes in cases with partial complete response. CONCLUSIONS: Our study provides preliminary data about the correlation between ICP and clinicopathological status and NAC response in breast cancer, in addition to underlining the requirement for further research to determine their potential as therapeutic targets.

Combination of vitamin D and photodynamic therapy enhances immune responses in murine models of squamous cell skin cancer.

Improved treatment outcomes for non-melanoma skin cancers can be achieved if Vitamin D (Vit D) is used as a neoadjuvant prior to photodynamic therapy (PDT). However, the mechanisms for this effect are unclear. Vit D elevates protoporphyrin (PpIX) levels within tumor cells, but also exerts immune-modulatory effects. Here, two murine models, UVB-induced actinic keratoses (AK) and human squamous cell carcinoma (A431) xenografts, were used to analyze the time course of local and systemic immune responses after PDT ± Vit D. Fluorescence immunohistochemistry of tissues and flow analysis (FACS) of blood were employed. In tissue, damage-associated molecular patterns (DAMPs) were increased, and infiltration of neutrophils (Ly6G+), macrophages (F4/80+), and dendritic cells (CD11c+) were observed. In most cases, Vit D alone or PDT alone increased cell recruitment, but Vit D + PDT showed even greater recruitment effects. Similarly for T cells, increased infiltration of total (CD3+), cytotoxic (CD8+) and regulatory (FoxP3+) T-cells was observed after Vit D or PDT, but the increase was even greater with the combination. FACS analysis revealed a variety of interesting changes in circulating immune cell levels. In particular, neutrophils decreased in the blood after Vit D, consistent with migration of neutrophils into AK lesions. Levels of cells expressing the PD-1+ checkpoint receptor were reduced in AKs following Vit D, potentially counteracting PD-1+ elevations seen after PDT alone. In summary, Vit D and ALA-PDT, two treatments with individual immunogenic effects, may be advantageous in combination to improve treatment efficacy and management of AK in the dermatology clinic.

Efficacy and safety of 'Second Adjuvant' therapy with BRAF/MEK inhibitors after local therapy for recurrent melanoma following adjuvant PD-1 based immunotherapy.

BACKGROUND: Anti-PD-1 antibodies and BRAK/MEK inhibitors (BRAF/MEKi) reduce the risk of recurrence for patients with resected stage III melanoma. BRAFV600-mutated (BRAFmut) melanoma patients who recur with isolated disease following adjuvant therapy may be suitable for 'second adjuvant' treatment after local therapy. We sought to examine the efficacy and safety of 'second adjuvant' BRAF/MEKi. PATIENTS AND METHODS: Patients with BRAFmut melanoma treated with adjuvant PD-1 based immunotherapy who recurred, underwent definitive local therapy and were then treated with adjuvant BRAF/MEKi were identified retrospectively from 13 centres (second adjuvant group). Demographics, disease and treatment characteristics and outcome data were examined. Outcomes were compared to BRAFmut patients who did not receive 'second adjuvant' therapy (no second adjuvant group). RESULTS: 73 patients were included; 61 who received 'second adjuvant' therapy and 12 who did not. Most initially recurred on PD-1 therapy (66%). There were no differences in characteristics between groups. 92% of second adjuvant group received dabrafenib and trametinib and median duration of therapy was 11.8 months (0.4, 34.5). 72% required dose adjustments, 23% had grade 3 + toxicity and 38% permanently discontinued drug due to toxicity. After median 26.1 months (1.9, 56.3) follow-up, recurrence-free survival (RFS) was improved in second adjuvant group versus no second adjuvant group (median 30.8 vs 4 months, HR 0.35; p = 0.014), largely driven by a delay in early recurrence, with no difference in overall survival (p = 0.59). CONCLUSION: This is the first study examining outcomes of 'second adjuvant' targeted therapy for melanoma, after failure of adjuvant PD-1 based immunotherapy. Data suggest a short-term improvement in RFS, but at the cost of toxicity. Alternative strategies and more data on sequencing adjuvant therapies are required to improve outcomes.

Lipid alterations play a role in the integration of PD-1/PD-L1 inhibitors and anlotinib for the treatment of advanced non-small-cell lung cancer.

BACKGROUND: Studies have shown that integrating anlotinib with programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors enhances survival rates among progressive non-small-cell lung cancer (NSCLC) patients lacking driver mutations. However, not all individuals experience clinical benefits from this therapy. As a result, it is critical to investigate the factors that contribute to the inconsistent response of patients. Recent investigations have emphasized the importance of lipid metabolic reprogramming in the development and progression of NSCLC. METHODS: The objective of this investigation was to examine the correlation between lipid variations and observed treatment outcomes in advanced NSCLC patients who were administered PD-1/PD-L1 inhibitors alongside anlotinib. A cohort composed of 30 individuals diagnosed with advanced NSCLC without any driver mutations was divided into three distinct groups based on the clinical response to the combination treatment, namely, a group exhibiting partial responses, a group manifesting progressive disease, and a group demonstrating stable disease. The lipid composition of patients in these groups was assessed both before and after treatment. RESULTS: Significant differences in lipid composition among the three groups were observed. Further analysis revealed 19 differential lipids, including 2 phosphatidylglycerols and 17 phosphoinositides. CONCLUSION: This preliminary study aimed to explore the specific impact of anlotinib in combination with PD-1/PD-L1 inhibitors on lipid metabolism in patients with advanced NSCLC. By investigating the effects of using both anlotinib and PD-1/PD-L1 inhibitors, this study enhances our understanding of lipid metabolism in lung cancer treatment. The findings from this research provide valuable insights into potential therapeutic approaches and the identification of new therapeutic biomarkers.

Paclitaxel liposome (Lipusu) based chemotherapy combined with immunotherapy for advanced non-small cell lung cancer: a multicenter, retrospective real-world study.

BACKGROUND: Paclitaxel liposome (Lipusu) is known to be effective in non-small cell lung cancer (NSCLC) as first-line treatment. This study aimed to evaluate the effectiveness and safety of paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor in patients with advanced NSCLC. METHODS: In this multicenter, retrospective, real-world study, patients with advanced NSCLC who were administered paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor in three centers (Peking University People's Hospital as the lead center) in China between 2016 and 2022 were included. Progression-free survival (PFS), overall survival (OS), objective response rate, disease control rate, and adverse events (AEs) were evaluated. RESULTS: A total of 49 patients were included, with 33 (67.3%) receiving paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor as first-line treatment. There were 34 patients (69.4%) diagnosed with squamous cell carcinoma and 15 (30.6%) with adenocarcinoma. The median follow-up was 20.5 (range: 3.1-41.1) months. The median PFS and OS of all patients were 9.7 months (95% confidence interval [CI], 7.0-12.4) and 30.5 months (95% CI, not evaluable-not evaluable), respectively. Patients with squamous cell carcinoma and adenocarcinoma had median PFS of 11 months (95%CI, 6.5-15.5) and 9.3 months (95%CI, 7.0-12.4), respectively. The median PFS was 9.9 months (95%CI, 7.1-12.7) in patients who received the combined regimen as first-line treatment. Treatment-related AEs of any grade were observed in 25 (51.0%) patients, and AEs of grade 3 or worse were observed in nine patients (18.4%). The most common treatment-related AEs were myelosuppression (14.3%) and fever (10.2%). CONCLUSIONS: Paclitaxel liposome based chemotherapy plus PD-1/PD-L1 inhibitor prolonged the PFS in advanced NSCLC with acceptable safety, which was worthy of clinical application.

Atezolizumab and Platinum Plus Pemetrexed With or Without Bevacizumab for Metastatic Nonsquamous Non-Small Cell Lung Cancer: A Phase 3 Randomized Clinical Trial.

Importance: The combination of an antibody to programmed cell death-1 (PD-1) or to its ligand (PD-L1) with chemotherapy is the standard first-line treatment for metastatic non-small cell lung cancer (NSCLC). Bevacizumab is expected to enhance the efficacy not only of chemotherapy but also of PD-1/PD-L1 antibodies through blockade of vascular endothelial growth factor-mediated immunosuppression, but further data are needed to support this. Objective: To evaluate the efficacy and safety of bevacizumab administered with platinum combination therapy and atezolizumab in patients with advanced nonsquamous NSCLC. Design, Setting, and Participants: An open-label phase 3 randomized clinical trial was conducted at 37 hospitals in Japan. Patients with advanced nonsquamous NSCLC without genetic driver alterations or those with genetic driver alterations who had received treatment with at least 1 approved tyrosine kinase inhibitor were enrolled between January 20, 2019, and August 12, 2020. Interventions: Patients were randomly assigned to receive either atezolizumab plus carboplatin with pemetrexed (APP) or atezolizumab, carboplatin plus pemetrexed, and bevacizumab (APPB). After 4 cycles of induction therapy, maintenance therapy with atezolizumab plus pemetrexed or with atezolizumab, pemetrexed, and bevacizumab was administered until evidence of disease progression, development of unacceptable toxic effects, or the elapse of 2 years from the initiation of protocol treatment. Main Outcomes and Measures: The primary end point was progression-free survival (PFS) as assessed by blinded independent central review (BICR) in the intention-to-treat (ITT) population. Results: A total of 412 patients were enrolled (273 men [66%]; median age, 67.0 [range, 24-89] years) and randomly assigned, with 205 in the APPB group and 206 in the APP group of the ITT population after exclusion of 1 patient for good clinical practice violation. The median BICR-assessed PFS was 9.6 months with APPB vs 7.7 months with APP (stratified hazard ratio [HR], 0.86; 95% CI, 0.70-1.07; 1-sided stratified log-rank test; P = .92). According to prespecified subgroup analysis of BICR-assessed PFS, an improved PFS with APPB vs APP was apparent specifically in driver oncogene-positive patients (median, 9.7 vs 5.8 months; stratified HR, 0.67; 95% CI, 0.46-0.98). Toxic effects related to bevacizumab were increased in the APPB group. Conclusions and Relevance: The findings of this trial did not show superiority of APPB over APP for patients with nonsquamous NSCLC; however, this regimen showed a similar tolerability and improved survival relative to APP in patients with driver oncogenes. Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080224500.

A phase Ib/II study of cadonilimab (PD-1/CTLA-4 bispecific antibody) plus anlotinib as first-line treatment in patients with advanced non-small cell lung cancer.

BACKGROUND: Cadonilimab is a bispecific antibody that simultaneously targets programmed cell death receptor-1 and cytotoxic T lymphocyte-associated antigen-4. This study aimed to assess the safety and efficacy of cadonilimab plus anlotinib for the first-line treatment of advanced non-small cell lung cancer (NSCLC) without sensitizing EGFR/ALK/ROS1 mutations. METHODS: Patients received cadonilimab 15 mg/kg and 10 mg/kg every three weeks (Q3W) plus anlotinib at doses of 10 or 12 mg once daily for two weeks on a one-week-off schedule. The primary endpoints included safety and objective response rate (ORR). RESULTS: Sixty-nine treatment-naïve patients received cadonilimab 15 mg/kg Q3W combination (n = 49) and 10 mg/kg Q3W combination (n = 20). Treatment-related adverse events (TRAEs) were reported in 48 (98.0%) and 19 (95.0%) patients, with grade ≥3 TRAEs occurring in 29 (59.2%) and five (25.0%) patients, respectively. TRAEs leading to cadonilimab discontinuation occurred in eight (16.3%) and one (5.0%) patients in the cadonilimab 15 mg/kg Q3W and 10 mg/kg Q3W dosing groups. The confirmed ORRs were 51.0% (25/49) and 60.0% (12/20) accordingly. CONCLUSIONS: Cadonilimab 10 mg/kg Q3W plus anlotinib showed manageable safety and promising efficacy as a first-line chemo-free treatment for advanced NSCLC. GOV IDENTIFIER: NCT04646330.

Combination of Itacitinib or Parsaclisib with Pembrolizumab in Patients with Advanced Solid Tumors: A Phase I Study.

PURPOSE: This phase Ib open-label, multicenter, platform study (NCT02646748) explored safety, tolerability, and preliminary activity of itacitinib (Janus kinase 1 inhibitor) or parsaclisib (phosphatidylinositol 3-kinase δ inhibitor) in combination with pembrolizumab [programmed death-1 (PD-1) inhibitor]. EXPERIMENTAL DESIGN: Patients with advanced or metastatic solid tumors with disease progression following all available therapies were enrolled and received itacitinib (Part 1 initially 300 mg once daily) or parsaclisib (Part 1 initially 10 mg once daily; Part 2 all patients 0.3 mg once daily) plus pembrolizumab (200 mg every 3 weeks). RESULTS: A total of 159 patients were enrolled in the study and treated with itacitinib (Part 1, n = 49) or parsaclisib (Part 1, n = 83; Part 2, n = 27) plus pembrolizumab. The maximum tolerated/pharmacologically active doses were itacitinib 300 mg once daily and parsaclisib 30 mg once daily. Most common itacitinib treatment-related adverse events (TRAE) were fatigue, nausea, and anemia. Most common parsaclisib TRAEs were fatigue, nausea, diarrhea, and pyrexia in Part 1, and fatigue, maculopapular rash, diarrhea, nausea, and pruritus in Part 2. In patients receiving itacitinib plus pembrolizumab, four (8.2%) achieved a partial response (PR) in Part 1. Among patients receiving parsaclisib plus pembrolizumab, 5 (6.0%) achieved a complete response and 9 (10.8%) a PR in Part 1; 5 of 27 (18.5%) patients in Part 2 achieved a PR. CONCLUSIONS: Although combination of itacitinib or parsaclisib with pembrolizumab showed modest clinical activity in this study, the overall response rates observed did not support continued development in patients with solid tumors. SIGNIFICANCE: PD-1 blockade combined with targeted therapies have demonstrated encouraging preclinical activity. In this phase I study, patients with advanced solid tumors treated with pembrolizumab (PD-1 inhibitor) and either itacitinib (JAK1 inhibitor) or parsaclisib (PI3Kδ inhibitor) experienced limited clinical activity beyond that expected with checkpoint inhibition alone and showed little effect on T-cell infiltration in the tumor. These results do not support continued development of these combinations.

Eficacia y seguridad de pembrolizumab en pacientes menores de 18 años con linfoma de Hodgkin clásico, refractario / recaída a dos o más líneas de quimioterapia / Efficacy and safety of pembrolizumab in patients under 18 years of age with classic hodgkin's lymphoma, refractory/relapse to two or more lines of chemotherapy

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Instituto de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021, se ha elaborado el presente dictamen, el cual expone la evaluación de la eficacia y seguridad de pembrolizumab en pacientes menores de 18 años con linfoma Hodgkin clásico, refractario/recaída a dos o más líneas de quimioterapia. Así, el Dr. José Aparicio Hernández Briceño, médico especialista en oncología del Hospital Nacional Guillermo Almenara Irigoyen, siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de uso por fuera del petitorio del producto farmacéutico pembrolizumab. ASPECTOS GENERALES: El linfoma de Hodgkin (LH) es una neoplasia maligna poco frecuente que afecta los ganglios y el sistema linfático. Representa, aproximadamente, el 7 % de los cánceres infantiles y el 1 % de las muertes por cáncer infantil en los Estados Unidos (McClain y Kamdar 2022). En el Perú al 2020, el LH fue la quinta causa de cáncer en niños y jóvenes de O - 19 años, con una tasa de incidencia estandarizada por edad de 0.44 casos por cada 100 000 habitantes. Asimismo, fue la sexta causa de muerte por cáncer con una tasa estandarizada por edad de 0.06 muertes por cada 100 000 habitantes (GLOBOCAN [Internet] 2020). El LH, según la Organización Mundial de la Salud (OMS), se divide en linfoma de Hodgkin clásico (LHC) y linfoma de Hodgkin con predominio linfocitario nodular (LHPLN). En los países occidentales, el LHC representa el 95 % y LHPLN representa el 5 % de todos los LH (Eichenauer et al. 2018; NCCN 2022). El LHC se caracteriza por la presencia de las células de Reed-Sternberg, cuya superficie expresa el antígeno CD30. Las células de ReedSternberg y las células infiltrantes del microambiente celular expresan fuertemente las proteínas PD-L1 y PD-L2 que se unen al receptor PD-1 de los linfocitos T (una proteína que ayuda a controlar la respuesta inmune del cuerpo) (Ansell 2021; Carey et al. 2017). METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad de pembrolizumab en pacientes menores de 18 años con linfoma Hodgkin clásico, refractario/recaída a dos o más líneas de quimioterapia. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC) incluyendo el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), el Scottish Medicines Consortium (SMC), el Scottish Intercollegiate Guidelines Network (SIGN), el Institute for Quality and Efficiency in Healthcare (IQWiG por sus siglas en alemán), la International Database of GRADE Guideline, el Centro Nacional de Excelencia Tecnológica en Salud (CENETEC), la Guidelines International Network (GIN), National Health and Medical Research Council (NHMRC), la Cancer Guidelines Database, el New Zealand Guidelines Group (NZGG), el Instituto de Evaluación Tecnológica en Salud (IETS), el Instituto de Efectividad Clínica y Sanitaria (IECS), la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la OMS, el Ministerio de Salud del Perú (MINSA) y el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Además, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en oncología o hematología, tales como: National Comprehensive Cancer Network (NCCN), la Society for Immunotherapy of Cancer (SITC), la European Society for Medical Oncology (ESMO), la American Society of Clinical Oncology (ASCO), la British Society for Haematology (BSH) y la American Society of Hematology (ASH). Finalmente, se realizó una búsqueda en la página web www.clinicaltrials.gov, para identificar ensayos clínicos (EC) en curso o que no hayan sido publicados aún. RESULTADOS: Luego de la búsqueda bibliográfica hasta febrero de 2022, se identificaron dos GPC elaboradas por la NCCN (NCCN 2021) y la ESMO (Eichenauer et al. 2018); 2 ETS elaboradas por la CADTH (CADTH 2021) y la SMC (SMC 2021) y un ensayo clínico denominado KEYNOTE-051 (Geoerger et al. 2020). CONCLUSIÓN Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación no aprueba el uso de pembrolizumab para pacientes pacientes menores de 18 años con LHC, refractario/recaída a dos o más líneas de quimioterapia, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud. CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación no aprueba el uso de pembrolizumab para pacientes pacientes menores de 18 años con LHC, refractario/recaída a dos o más líneas de quimioterapia, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud.

La inhibición de los puntos de control inmunológico, una terapia en evolución: remembranza del Premio Nobel de Medicina 2018 / Immune checkpoint inhibitors: a breakthrough in cancer therapy

Professors James P. Allison and Tasuku Honjo were awarded with the 2018 Nobel Prize in Medicine for their contributions in cancer immunotherapy. The latter is a breakthrough in cancer therapy, aimed to overcome tumor-induced immunosuppression, leading to the reactivation of the immune system against cancer cells. Under physiological conditions, the CTLA-4 and PD-1 proteins expressed on T-cells and discovered by the awarded scientists, lead to immune tolerance. Cancer cells exploit these control points to enhance the inhibition of T-cells. The expression of PD ligands (PD-L1) in tumor cells and CTLA-4 ligands in antigen presenting cells, which bind the PD-1 receptor and CTLA-4 respectively, block anti-tumor immunity. This situation led to a biotechnological race focused on the development of effective antibodies able to "turn-on" the immune system cheated by the tumor. Anti-CTLA-4 and anti-PD-1 antibodies improve life-expectancy in cancer patients. In this review, we perform an historical overview of Professors Allison and Honjo contribution, as well as the immunological basis of this new and powerful therapeutic strategy, highlighting the clinical benefits of such intervention.

Monitoramento do horizonte tecnológico: Medicamentos para tratamento de primeira linha do câncer colorretal metastático / Monitoring the technological horizon: Drugs for first-line treatment of metastatic colorectal cancer

A DOENÇA Os cânceres de cólon e reto, ou câncer colorretal, abrangem os tumores que acometem o intestino grosso (cólon) e o reto, sendo que cerca de 50% localizam-se no reto e sigmoide e 30% no ceco. Estima-se que, no mundo, no ano de 2020, o câncer colorretal (CCR) tenha sido, entre os tipos de neoplasias malignas, o terceiro mais diagnosticado e o segundo mais letal, com 1,9 milhões de casos novos e 935.000 óbitos. No Brasil, o CCR é considerado a segunda neoplasia maligna mais incidente entre homens e mulheres, desconsiderando os tumores de pele não melanoma. Para cada ano do triênio de 2020-2022, são estimados 20.520 casos em homens e 20.470 em mulheres. O risco estimado de novos casos é de 19,63 para cada 100 mil homens e 19,03 para cada 100 mil mulheres. Em 2019, foram registradas aproximadamente 20 mil mortes por câncer colorretal no Brasil. TRATAMENTOS SISTÊMICOS DE PRIMEIRA LINHA DISPONÍVEIS: Na Agência Nacional de Vigilância Sanitária (Anvisa) estão registrados dez medicamentos com indicação em bula para o CCRm, que podem compor diferentes esquemas terapêuticos. São eles: aflibercepte, bevacizumabe, capecitabina, cetuximabe, fluorouracil (5- FU), irinotecano, oxaliplatina, panitumumabe, pembrolizumabe, regorafenibe e trifluridina + tipiracila. As Diretrizes Diagnósticas e Terapêuticas (DDT) do Câncer de Cólon e Reto, publicada em 2014, estão em processo de atualização no momento22,23 . O CCRm irressecável não é alvo da versão atual em curso da diretriz supracitada, sendo seu tratamento apresentado de forma geral. Para os doentes com metástases hepáticas irressecáveis e ausência ou mínima invasão extra-hepática é recomendada a quimioterapia paliativa sistêmica baseada em fluoropirimidina contendo ou não oxaliplatina ou irinotecano, com o objetivo de reduzir o volume tumoral e permitir, assim, a ressecção cirúrgica. De acordo com a DDT, existe evidência de que o uso de esquema terapêutico associado ao cetuximabe ou bevacizumabe promove uma taxa de ressecabilidade maior que controles históricos, entretanto, na época da sua elaboração (busca realizada em 2012) ainda existia incerteza quanto ao significado clínico em termos de benefícios clínicos duradouros ou ganho de sobrevida. ESTRATÉGIA DE BUSCA: Os medicamentos em fase de desenvolvimento para o tratamento de primeira linha de pacientes com CCRm foram identificados, inicialmente, na base de pesquisa clínica Clinicatrials.gov em 01 de julho de 2021 e atualizado em 15 de outubro de 2021, com filtro para estudo de intervenção, na fase 3 de ensaio clínico e em andamento (situação do recrutamento: ativo, não recrutando ainda, ativo sem recrutamento, inscrição por convite). TECNOLOGIAS EM DESENVOLVIMENTO: A busca inicial no Clinicaltrials.gov retornou 52 registros de ensaios clínicos, dentre os quais onze ensaios foram selecionados a partir dos critérios de elegibilidade definidos. A partir desses ensaios clínicos foram identificados oito medicamentos potenciais em desenvolvimento nas classes: inibidores checkpoint imunológico PD-1, inibidor do receptor do fator de crescimento epidérmico, inibidor multi-tirosina quinase e inibidor da proteína quinase BRAF. CONSIDERAÇÕES FINAIS: Em 2020, o câncer colorretal (CCR) foi o terceiro tipo de câncer mais incidente e a segunda causa mais comum de mortes relacionadas ao câncer no mundo2 . Quando detectado precocemente e sem a presença de metástase em outros órgãos o CCR pode ser tratado e curado. Entretanto, quando há a presença de metástases não ressecáveis, o quadro clínico é de pior prognóstico. Nas últimas duas décadas, o tratamento de câncer colorretal metastático (CCRm) teve avanços com a aprovação de novos medicamentos citotóxicos e de terapia-alvo. As classes de inibidores do receptor do fator de crescimento endotelial vascular (cetuximabe e panitumumabe) e do receptor do fator de crescimento epidérmico (bevacizumabe) representaram um aumento na sobrevida dos pacientes com CCR. Apesar dos ganhos em sobrevida global e sobrevida livre de progressão da doença com as diferentes combinações de esquemas terapêuticos entre quimioterápicos e biológicos, o componente genético característico do CCR tem importante influência sobre o desempenho dos tratamentos entre os pacientes. Este informe de Monitoramento do Horizonte Tecnológico identificou oito tecnologias que se encontram em fase 3 de ensaio clínico para o tratamento de primeira linha do CCRm, inclusive pela via oral para maior comodidade posológica dos pacientes. Entre as classes dos medicamentos estão os inibidores de pontos de verificação imunológico PD-1 (checkpoint), inibidores do receptor do fator de crescimento epidérmico, inibidores multi-tirosina quinase e inibidores da proteína quinase BRAF. Na classe de inibidores checkpoint imunológico PD-1 foram identificadas cinco tecnologias (atezolizumabe, nivolumabe, serplulimabe, sintilimabe e imunoterapia com células autólogas). O atezolizumabe, nivolumabe, serplulimabe e o sintilimabe são anticorpos monoclonais humanizados direcionados ao receptor de morte programada. O nivolumabe é registrado no FDA e EMA para pacientes com CCRm com a presença confirmada de instabilidade de microssatélites elevada (MSI-H ­ microsatellite instability-high) ou deficiência de reparação por incompatibilidade (dMMR ­ mismatch repair deficient). O atezolizumabe também está sendo estudado para os pacientes com CCRm e presença de MSI-H e dMMR. O serplulimabe e sintilimabe iniciaram seus ensaios clínicos de fase 3 recentemente, em 2020 e 2021, respectivamente e não apresentam resultados parciais publicados. Os resultados da fase anterior (fase 2) em outras linhas de tratamento demostraram que o serplulimabe apresentou uma taxa de resposta objetiva em torno de 38% para os tumores com MSI-H e dMMR, incluindo o CCR. A imunoterapia de células autólogas é uma terapia avançada na qual os linfócitos T autólogos são retirados e ativados para ter como alvo o receptor de morte programada-1 e assim retornam ao mesmo paciente para desempenhar melhor seu papel imunológico de modo direcionado ao tumor. Os resultados de fase 3 também não foram publicados até o momento da busca. Após a expiração da patente do medicamento cetuximabe de referência, algumas empresas começaram a desenvolver biossimilares. Atualmente, existem alguns ensaios clínicos em andamento em diversas fases com o cetuximabe biossimilar para a indicação de CCR metastático. Não foram identificados resultados publicados para a fase 3 em andamento para o tratamento de primeira linha, entretanto resultados para a segunda linha de tratamento de CCR metastático indicaram que o CMAB009 (um dos códigos de biossimilares sendo estudado) aumentou a taxa de resposta global em relação ao irinotecano em monoterapia. Outro medicamento, o anlotinibe foi identificado na classe de inibidores multitirosina quinase, que possui ação em vários receptores que implicam no crescimento tumoral, na angiogênese e na progressão metastática do câncer. Os ensaios clínicos de fase 3 ainda estão em andamento com previsão de finalização em 2024. Resultados preliminares de fase 2 com o anlotinibe indicaram melhora em alguns desfechos. Por fim, foi identificado o medicamento encorafenibe, pertencente à classe de inibidor da proteína quinase BRAF, que possui resultados promissores em estudos de fase 2, tendo sido registrado, recentemente, nas agências EMA e FDA para os pacientes com CCR metastático com gene BRAF V600E mutado que apresentaram progressão com tratamentos anteriores. Motivados por esses resultados promissores em linhas posteriores de tratamento o esquema terapêutico com o encorafenibe associado a outros medicamentos vem sendo testado na população de pacientes com CCRm BRAF V600 mutado sem tratamento prévio. Os ensaios clínicos de todos os medicamentos identificados específicos para tratamento de primeira linha estão em andamento com previsão de finalização até 2025. De modo que é preciso continuar seu monitoramento a fim de observar os resultados e os impactos que as tecnologias estudadas possam apresentar no tratamento inicial dos pacientes com CCR metastático.

PD-1 blockade as a future treatment for colorectal cancer with microsatellite instability / Bloqueio do PD-1 como futuro tratamento do cancro colorretal com instabilidade de microssatélites

ABSTRACT Introduction: Colorectal cancer is the third most common cancer worldwide, with about 15% of these tumours related with microsatellite instability, which confers distinct characteristics to these tumours, both clinicopathological and in the response to treatments. In fact, the poor response to chemotherapy in these tumours has led to the investigation for new treatments, with immunotherapy being the most successful one to date. The focus of this review is to assess the response of microsatellite unstable colorectal cancer to PD-1 blockade, and the mechanisms behind that response. Methods: A PubMed research was conducted, resulting in the inclusion of 47 articles in this review. Results: Microsatellite instability results in a high neoantigen load, leading to a highly active immune microenvironment of the tumour, mainly due to T-cells. To counteract this, there is an upregulation of PD-1, acting as a "brake" for immune cells, facilitating tumour growth and metastasis. This upregulation makes these tumours great candidates for treatment with PD-1 blockade, as seen in many clinical trials, where the overall responses and progression free survival rates were higher than those observed in microsatellite stable tumours. Conclusion: With the importance of colorectal cancer with microsatellite instability new treatments are necessary. Therefore, PD-1 blockade is a promising treatment for colorectal cancer with microsatellite instability, with improvement in survival rates and a better prognosis for these patients.

RESUMO Introdução: O câncer colorretal é o terceiro mais comum em todo o mundo, com cerca de 15% desses tumores relacionados com instabilidade dos microssatélites, o que confere características distintas a esses tumores, tanto clínico patológicas quanto na resposta aos tratamentos. De fato, a fraca resposta à quimioterapia nesses tumores levou à investigação de novos tratamentos, sendo a imunoterapia a mais bem sucedida até o momento. O foco desta revisão é avaliar a resposta do câncer colorretal com microssatélites instáveis ao bloqueio do PD-1 e os mecanismos por trás dessa resposta. Métodos: Foi realizada uma pesquisa na base de dados PubMed, resultando na inclusão de 47 artigos nesta revisão. Resultados: A instabilidade de microssatélites resulta em uma alta carga de neoantígenos, levando a um microambiente imunológico altamente ativo do tumor, principalmente devido às células T. Para neutralizar isso, há uma maior expressão do PD-1, atuando como um "freio" para as células imunes, facilitando o crescimento do tumor e suas metástases. Essa expressão faz desses tumores grandes candidatos ao tratamento com bloqueio PD-1, como demonstrado em vários ensaios clínicos, onde as respostas globais e as taxas de sobrevivência livres de progressão foram maiores do que as observadas em tumores com microssatélites estáveis. Conclusão: Com a importância do câncer colorretal com instabilidade de microssatélites, novos tratamentos são necessários. Portanto, o bloqueio do PD-1 é um tratamento promissor para o câncer colorretal com instabilidade de microssatélites, com melhora nas taxas de sobrevivência e melhor prognóstico para esses pacientes.