Real-world outcomes of regorafenib combined with immune checkpoint inhibitors in patients with advanced or metastatic microsatellite stable colorectal cancer: A multicenter study

Abstract Background Treatment strategies are limited for patients with chemotherapy refractory microsatellite stable (MSS) colorectal cancer. We aim to evaluate the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with regorafenib in this population in routine clinical practice. Methods We retrospectively analyzed patients with advanced or metastatic colorectal cancer who received at least one dose of ICIs combined with regorafenib in 14 Chinese medical centers. The primary outcome was objective response rate (ORR). This study was registered at ClinicalTrials.gov on February 2020 (NCT04771715). Results Eighty-four patients received ICIs combined with regorafenib from January 2019 to January 2021. Most patients (91%) received two or more systemic treatment lines before the study treatment. Seventy-six patients (90%) had confirmed MSS status. At a median follow-up of 5.5 months, four patients achieved partial response (5%) and 37 patients achieved stable disease (45%) as the best response. The median progression-free survival (PFS) was 3.1 months, and the median overall survival was 17.3 months. Eleven patients (13%) remained progression-free for more than 6 months. Baseline liver metastasis (HR 1.98, 95%CI 1.07–3.69, P = 0.03) and neutrophil–lymphocyte ratio (NLR) of ≥ 1.5 (HR 2.83, 95%CI 1.00–7.98, P = 0.05) were associated with shorter PFS in multivariate analysis. Grade 3 or higher treatment-related adverse events (TRAEs) occurred in 16 patients (19%). Conclusion The combination of ICIs with regorafenib can be a valuable treatment option for a proportion of patients with chemotherapy refractory MSS colorectal cancer. Patients with no liver metastasis and a low NLR at baseline may derive most benefit from this strategy.

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Treatment Strategies and Metabolic Pathway Regulation in Urothelial Cell Carcinoma: A Comprehensive Review

International Journal of Molecular Sciences ◽

10.3390/ijms21238993 ◽

2020 ◽

Vol 21 (23) ◽

pp. 8993

Author(s):

Huang-Yu Yang ◽

Chao-Yi Wu ◽

Jia-Jin Chen ◽

Tao-Han Lee

Keyword(s):

Immune Checkpoint ◽

Metabolic Pathways ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Treatment Strategies ◽

Progression Free Survival ◽

Line Treatment ◽

First Line ◽

Comprehensive Review

For a long time, cisplatin-based chemotherapy had been viewed as first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC had been classified as cisplatin-ineligible who can only receive alternative chemotherapy with poor treatment response, and the vast majority of the cisplatin-eligible patients eventually progressed, even those with objective response with cisplatin-based chemotherapy initially. By understanding tumor immunology in UC, immune checkpoint inhibitors, targeting on programmed death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) pathways, had been proven as first-line treatment for cisplatin-ineligible metastatic UC and as second-line treatment for patients with platinum-refractory metastatic UC by the U.S Food and Drug Administration (FDA). In 2020, JAVEIN bladder 100 further reported that PD-L1 inhibitors showed benefits on prolonged survival and progression-free survival as maintenance therapy. Besides targeting on immune checkpoint, manipulation of the tumor microenvironment by metabolic pathways intervention, including inhibition on tumor glycolysis, lactate accumulation and exogenous glutamine uptake, had been investigated in the past few years. In this comprehensive review, we start by introducing traditional chemotherapy of UC, and then we summarize current evidences supporting the use of immune checkpoint inhibitors and highlight ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting on metabolic pathways.

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Immune-checkpoint inhibitors versus other systemic therapies in advanced head and neck cancer: a network meta-analysis

Immunotherapy ◽

10.2217/imt-2020-0070 ◽

2021 ◽

Vol 13 (6) ◽

pp. 541-555

Author(s):

Lingrong Tang ◽

Tingting Liu ◽

Jun Chen ◽

Jun Dang ◽

Guang Li

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Progression Free Survival ◽

Systemic Therapies

Aim: We assessed the efficiency of immune checkpoint inhibitors relative to other systemic therapies in previously treated recurrent/metastatic head and neck cancer. Materials & methods: Relative treatment effects were assessed from eligible randomized controlled trials using Bayesian network meta-analyses. Results: Among 15 trials evaluating 14 treatments, nivolumab achieved the best overall survival (OS) benefit; zalutumumab and buparlisib + paclitaxel provided the best progression-free survival benefit and objective response rate. Buparlisib + paclitaxel and zalutumumab were associated with the best OS rate at 6 and 12 months, respectively; nivolumab yielded the best OS rate at 18–24 months. Conclusion: Nivolumab was the most favorable treatment. Zalutumumab and buparlisib + paclitaxel had better efficiency, and might be a better selection for patients with programmed death-ligand 1-low/negative tumors than other treatments.

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Salvage Ipilimumab and Nivolumab in Patients With Metastatic Renal Cell Carcinoma After Prior Immune Checkpoint Inhibitors

Journal of Clinical Oncology ◽

10.1200/jco.19.03315 ◽

2020 ◽

Vol 38 (27) ◽

pp. 3088-3094 ◽

Cited By ~ 4

Author(s):

Anita Gul ◽

Tyler F. Stewart ◽

Charlene M. Mantia ◽

Neil J. Shah ◽

Emily Stern Gatof ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Targeted Therapy ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Free Survival ◽

Metastatic Rcc

PURPOSE Immune checkpoint inhibitors (ICIs) are standard therapy in metastatic renal cell carcinoma (RCC). The safety and activity of the combination of ipilimumab and nivolumab in patients who have received prior ICI targeting the programmed death 1 (PD-1) pathway remains unknown. We evaluated ipilimumab and nivolumab in patients with metastatic RCC after prior treatment with anti–PD-1 pathway–targeted therapy. PATIENTS AND METHODS Patients with metastatic RCC who received prior anti–PD-1 pathway-targeted therapy and subsequently received ipilimumab and nivolumab were reviewed. Objective response rate and progression-free survival per investigator assessment were recorded. Toxicity of ipilimumab and nivolumab was also assessed. RESULTS Forty-five patients with metastatic RCC were included. All patients (100%) received prior ICIs targeting the PD-1 pathway. The median age was 62 years (range, 21-82 years). At a median follow-up of 12 months, the objective response rate to ipilimumab and nivolumab was 20%. The median progression-free survival while on ipilimumab and nivolumab was 4 months (range, 0.8-19 months). Immune-related adverse events (irAEs) of any grade with ipilimumab and nivolumab were recorded in 29 (64%) of the 45 patients; grade 3 irAEs were recorded in 6 (13%) of the 45 patients. CONCLUSION Ipilimumab and nivolumab demonstrated antitumor activity with acceptable toxicity in patients with metastatic RCC who had prior treatment with checkpoint inhibition.

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Immune-Checkpoint Inhibitors for Metastatic Colorectal Cancer: A Systematic Review of Clinical Outcomes

Cancers ◽

10.3390/cancers13174345 ◽

2021 ◽

Vol 13 (17) ◽

pp. 4345

Author(s):

Dmitrii Shek ◽

Liia Akhuba ◽

Matteo S. Carlino ◽

Adnan Nagrial ◽

Tania Moujaber ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Response ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Response Rate ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Response Rates ◽

Durable Response ◽

Surgical Options

Background. Colorectal cancer (CRC) is the fourth most deadly cancer worldwide. Unfortunately, a quarter of the patients are diagnosed at late stages, when surgical options are limited. Targeted therapies, particularly immune-checkpoint inhibitors (ICIs), are the latest addition and have been studied herein regarding their efficacy outcomes. Methods. Clinical studies were identified through the PubMed, Scopus and Cochrane databases. Any trial that evaluated ICIs in patients with metastatic CRC (mCRC) and reported the objective response rate was deemed eligible. Data analysis was performed by employing the random-effects model in STATA v.17. Results. A total of 461 articles were identified; 13 clinical trials were included, encompassing a total cohort of 1209 patients. Our study determined that a single PD-1/PD-L1 checkpoint blockade provides durable clinical response in mCRC patients with high microsatellite instability (MSI-H). The combinatorial therapy of CTLA-4 + PD-1 inhibitors also showed high response rates in pre-treated MSI-H patients. The single-arm REGONIVO trial reported durable clinical response in patients with microsatellite stable (MSS) status. Conclusions. Our study surmises that PD-1/PD-L1 inhibitors as well as combination therapy with CTLA-4 and PD-1 inhibitors show encouraging response rates in mCRC patients, albeit exclusively in patients with cancer that are of MSI-H status. A single study suggests that nivolumab + regorafenib can reach a durable response rate in MSS patients; however, further studies in larger randomized settings are required.

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Lenvatinib Plus Immune Checkpoint Inhibitors Improve Survival in Advanced Hepatocellular Carcinoma: A Retrospective Study

Frontiers in Oncology ◽

10.3389/fonc.2021.751159 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiaozhun Huang ◽

Lin Xu ◽

Teng Ma ◽

Xin Yin ◽

Zhangkan Huang ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Complete Response ◽

Advanced Hepatocellular Carcinoma ◽

Advanced Hcc ◽

New Strategy

BackgroundNivolumab and pembrolizumab disrupt the programmed cell death-1 immune checkpoint and display promising efficacy and safety results in advanced hepatocellular carcinoma (HCC). However, the benefits remain limited. The preliminary results of lenvatinib (LEN) combined with immune checkpoint inhibitors (ICIs) reveal that the combinations were well-tolerated and encouraging. This study aimed to analyze the safety and efficacy of LEN plus ICIs in a real-world cohort of patients with advanced HCC.MethodBetween June 4, 2017, and June 30, 2019, 16 patients received LEN plus nivolumab, and 13 patients were treated with LEN plus pembrolizumab, with the confirmed advanced HCC retrospectively analyzed. The clinical parameters, as well as the outcomes, were assessed.ResultsAll the patients had Barcelona Clinical Liver Cancer Stage C. LEN with ICIs was used as systemic second-, third-, and fourth-line treatments in seven (24.1%), 14 (48.3%), and eight (27.6%) patients, respectively. At the time of data cutoff, six patients (37.5%) were still receiving LEN with nivolumab, while another six patients (46.2%) were still receiving LEN with pembrolizumab. An objective response was recorded in seven patients (25.9%), while the best overall responses were from one complete response and six partial responses. The 6- and 12-month over survival (OS) rates were 62.6% and 53.7%, respectively. Furthermore, the 6- and 12-month progression-free survival (PFS) rates were 43.5% and 31.8%, respectively. In the subgroup analyses, the 6- and 12-month OS and PFS rates for patients treated with LEN plus nivolumab were 62.5% and 52.1%, respectively, and 43.8% and 30.0%, respectively. The 6- and 12-month OS and PFS rates for patients treated with LEN plus pembrolizumab were 51.3% and 51.3%, respectively, and 49.2% and 49.2%, respectively. A total of 11 (31%) deaths were reported in this study, four of which were attributed to grade 5 adverse events presented as fatal treatment-related hepatitis.ConclusionThe combination of LEN and ICIs is a promising new strategy for the treatment of HCC patients. However, high-grade hepatic toxicity was observed and further evaluation of this combination is still required.

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Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919861905 ◽

2019 ◽

Vol 11 ◽

pp. 175883591986190 ◽

Cited By ~ 9

Author(s):

Giandomenico Roviello ◽

Silvia Paola Corona ◽

Gabriella Nesi ◽

Enrico Mini

Keyword(s):

Overall Survival ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Progression Free Survival ◽

Pooled Analysis ◽

First Line

Background: The aim of this study was to perform a literature-based meta-analysis to assess the efficacy of the novel immune checkpoint inhibitors (ICIs) in first-line metastatic renal cell carcinoma (RCC), focusing on the predictive role of PD-L1 expression. Methods: The primary outcome was overall survival, and secondary outcomes were progression-free survival (PFS) and objective response. We planned a subgroup analysis for overall survival according to PD-L1 status. Results: Five studies were included in the analysis for a total of 4063 cases. Overall survival was greater in PD-L1 positive tumours (HR = 0.49, 95% CI: 0.36–0.67; p < 0.001). The pooled analysis of the unselected cases showed a statistically significative improvement in PFS with the use of ICIs (HR = 0.85, 95% CI: 0.72–0.99; p = 0.04) and we found a greater PFS benefit (HR = 0.65, 95% CI: 0.57–0.74; p < 0.001) in patients with PD-L1 positive tumours. Conclusions: This study supports the efficacy of ICIs and, although a significant clinical benefit has been reported in PD-L1 negative patients, a greater efficacy of ICIs was observed in PD-L1 positive patients. More prospective randomized studies are needed to clarify the role of PDL-1 status in metastatic RCC treated with ICIs.

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The Lung Immune Prognostic Index Discriminates Survival Outcomes in Patients with Solid Tumors Treated with Immune Checkpoint Inhibitors

Cancers ◽

10.3390/cancers11111713 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1713 ◽

Cited By ~ 11

Author(s):

Meyers ◽

Stukalin ◽

Vallerand ◽

Lewinson ◽

Suo ◽

...

Keyword(s):

Solid Tumors ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Prognostic Index ◽

Progression Free Survival ◽

Clinical Tools ◽

Tumor Types

Immune checkpoint inhibitors (ICI) have revolutionized the treatment landscape of several solid tumor types. However, as patient outcomes are heterogeneous, clinical tools to aid in prognostication are needed. The Lung Immune Prognostic Index (LIPI) correlates with outcomes in patients with non-small cell lung cancer (NSCLC) treated with ICI, but its applicability beyond NSCLC is poorly defined. We sought to determine whether LIPI is associated with overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in a pooled, real-world, retrospective cohort of patients with solid tumors treated with ICI. Of the total pooled cohort (N = 578), 47.2%, 38.2% and 14.5% of patients were stratified into good, intermediate and poor LIPI group, respectively. Median OS were 22.8 (95% CI 17.4–29.5), 7.8 (95% CI 6.6–9.6), and 2.5 months (95% CI 1.4–3.4) (p < 0.0001). Median PFS were 9.9 (95% CI 7.2–11.5), 3.6 (95% CI 2.7–4.3), and 1.4 months (95% CI 1.2–2.2) (p < 0.0001). ORR was also associated with LIPI group (p < 0.001). Intermediate and poor LIPI were independently prognostic of OS compared to good LIPI, with hazard ratios (HR) of 1.8 (95% CI 1.4–2.3, p < 0.001) and 3.6 (95% CI 2.5–5.1, p < 0.001), respectively. These data are the first to suggest that in a real-world setting, the prognostic value of LIPI may be tumor agnostic.

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Results from a Meta-analysis of Combination of PD-1/PD-L1 and CTLA-4 Inhibitors in Malignant Cancer Patients: Does PD-L1 Matter?

Frontiers in Pharmacology ◽

10.3389/fphar.2021.572845 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yuqian Feng ◽

Huimin Jin ◽

Kaibo Guo ◽

Yuying Xiang ◽

Yiting Zhang ◽

...

Keyword(s):

Combination Therapy ◽

Cancer Patients ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Malignant Tumors ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Progression Free Survival ◽

Combination Immunotherapy

Background: Combination therapy with immune checkpoint inhibitors (ICIs) has been widely used for clinical treatment in recent years, which has a better survival benefit. However, not all patients can derive clinical benefit from combination immunotherapy. Therefore, it is necessary to explore the biomarkers of combination immunotherapy.Methods: We retrieved articles from electronic databases including PubMed, EMBASE and Cochrane. The statistical analysis was performed using RevMan software. Progression free survival (PFS), overall survival (OS) and objective response rate (ORR) were the outcome indicators. In the unselect population, we compared combination therapy with other treatments. In addition, we also conducted subgroup analysis on PFS, OS and ORR according to PD-L1 status.Results: Seven studies were included in the analysis for a total of 3,515 cases. In the unselected population, we found that combination therapy has longer PFS, OS, and better ORR than other treatments for cancer patients. The longer PFS was showed in PD-L1 ≥ 5% cases (HR = 0.64, 95% CI: 0.56–0.76; p < 0.001) than PD-L1 ≥ 1% cases (HR = 0.72, 95% CI: 0.66–0.79; p < 0.001), while ORR and OS have not related to the status of PD-L1.Conclusion: This study supported the efficacy of combination therapy with immune checkpoint inhibitors (ICIs), and also showed that PFS in patients with malignant tumors is positively correlated with PD-L1 expression. Due to the limited number of trials included, more high-quality clinical randomized controlled trials should be conducted to confirm the review findings.

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Parameters associated with outcomes in pretreated MSI/dMMR metastatic colorectal cancer (mCRC) treated with immune checkpoint inhibitors (ICI): Subgroup analysis of a prospective cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3580 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3580-3580

Author(s):

Raphael Colle ◽

Marine Cachanado ◽

Alexandra Rousseau ◽

Magali Svrcek ◽

Yves Menu ◽

...

Keyword(s):

Lynch Syndrome ◽

Immune Checkpoint ◽

Prospective Cohort ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Methylation Status ◽

Objective Response ◽

Progression Free Survival ◽

Treatment Type ◽

The Impact

3580 Background: Immune checkpoint inhibitors (ICI) have demonstrated efficacy in patients (pts) with MSI/dMMR mCRC. We aimed to evaluate clinical, pathological and molecular factors associated with progression-free survival (PFS) and overall survival (OS) in ICI-treated pretreated mCRC patients (pts). Methods: Pts are drawn from a prospective cohort of all patients treated with ICI for MSI/dMMR mCRC at Saint-Antoine Hospital, Paris, France. All MSI/dMMR mCRC pts with disease progression after ≥ 1 prior systemic treatment (fluoropyrimidine and oxaliplatin or irinotecan ± targeted therapy) were included. MSI/dMMR status was centrally reviewed. Lynch syndrome or sporadic status was determined according to MMR gene germline mutational testing, MLH1 methylation status and BRAFV600E mutation. PFS and objective response rate (ORR) were assessed using iRECIST criteria. The impact of Lynch syndrome on PFS was analyzed apart from the multivariate analysis due to the interaction with the BRAFV600E mutation status. Results: Of 130 included pts, 66 received anti-PD1 alone, 1 anti-PDL1 alone and 63 anti-PD1 plus anti-CTLA4. 71% have had at least 2 prior lines of treatment. 33 patients (25%) have BRAFV600Emutation (mt) and 49 (38%) RASmt. The ORR for the whole population was 62.8 % IC95% [53.8; 71.1]. Median follow-up was 21.0 months, median PFS and OS were not reached. Results of PFS unadjusted and adjusted analysis are displayed in the table. BRAFV600E and RAS mutation were not associated with PFS and OS in multivariate analyses. After adjustment for the treatment type, Hazard Ratio (HR) for PFS between patients with proven Lynch syndrome (N=44) and patients with proven sporadic tumors (n= 44) was 0.57 (95%IC 0.26 -1.26). Conclusions: In this cohort, main known clinical, pathological and molecular factors do not influence the efficacy of ICI in pre-treated MSI/dMMR mCRC.[Table: see text]

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Treatment Strategies and Metabolic Pathway Regulation in Urothelial Cell Carcinoma: A Comprehensive Review

10.20944/preprints202010.0338.v1 ◽

2020 ◽

Author(s):

Huang-Yu Yang ◽

Chao-Yi Wu ◽

Jia-Jin Chen ◽

Tao-Ha Lee

Keyword(s):

Immune Checkpoint ◽

Metabolic Pathways ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Strategies ◽

Progression Free Survival ◽

Comprehensive Review ◽

Tumor Glycolysis ◽

Platinum Refractory ◽

Pathway Regulation

Cisplatin-based chemotherapy has long been viewed as the first-line chemotherapy for advanced and metastatic urothelial carcinoma (UC). However, many patients with UC have been classified as “cisplatin-ineligible patient”, which requires alternative chemotherapy due to their poor responses. In fact, vast majority of those who initially responded to cisplatin-based chemotherapy eventually progressed. Understanding of UC tumor immunology provided an immunopathogenic bases for immune checkpoint inhibitors, targeting PD-1 and CTLA-4, to treat cisplatin ineligible metastatic UC and patients with platinum-refractory metastatic UC. In 2020, data from the trail further showed that PD-L1 inhibitors benefit prolonged survival and progression-free survival as maintenance therapy. Besides immune-targeting therapies, manipulation of tumor microenvironment via metabolic pathways alternation, such as inhibiting tumor glycolysis, lactate accumulation and exogenous glutamine uptake, has been investigated in the past few years. In this comprehensive review, we started by introducing traditional chemotherapy of UC, and summarized current evidences supporting the use of immune checkpoint inhibitors and highlighted ongoing clinical trials. Lastly, we reviewed the tumor metabolic characteristic and the anti-tumor treatments targeting metabolic pathways.

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