Efficacy and safety of PD-1/PD-L1 and CTLA-4 immune checkpoint inhibitors in colorectal cancer: a meta-analysis

Chunhui Jin ◽  
Xiaodan Zhu ◽  
Xiaona Huang ◽  
Tingjie Gong ◽  
Zhipeng Wei ◽  

Aims: To evaluate the efficacy and safety of PD-1/PD-L1 and/or CTLA-4 inhibitors in the treatment of colorectal cancer (CRC) by meta-analysis. Methods: Electronic databases were searched. Eligible studies included investigations of efficacy and safety of anti-PD-1/PD-L1 or anti-CTLA-4 agents in patients with CRC. Corresponding indicators were calculated. Results: A total of 15 articles were included. The pooled objective response rate, overall survival rate, progression-free survival rate and adverse event rate were 33, 56, 46 and 59%, respectively. The objective response rates for CRC with deficient mismatch repair and CRC with proficient mismatch repair were 43 and 3%, respectively, in patients treated with PD-1 inhibitors. Conclusion: The authors' study indicates that PD-1/PD-L1 inhibitors manifest promising clinical responses in the treatment of CRC with deficient mismatch repair with acceptable treatment-related adverse events.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 115-115
Xiaoyu Xie ◽  
Jianwei Zhang ◽  
Huabin Hu ◽  
Yue Cai ◽  
Zehua Wu ◽  

115 Background: Recent studies have shown efficacy of chemotherapy (CTX) in combination with different biological agents including regorafenib (REG) in second-line treatment of metastatic colorectal cancer (mCRC). As there is no evidence on the relative efficacy and safety of REG as compared to other biological agents in combination with CTX, we evaluated the same in this network meta-analysis (NMA). Methods: Randomized controlled trials (RCTs) comparing efficacy and safety of biological agents + CTX against CTX alone as second-line treatment of mCRC were retrieved from PubMed, EMBASE and Cochrane databases. Progression free survival (PFS) was the primary outcome, while objective response rate (ORR), overall survival (OS) and safety were secondary outcomes. Outcomes were compared by random/mixed-effects NMA using Bayesian (R software, Gemtc package) and frequentist (R software, netmeta package) approaches. Results: Twelve RCTs comparing 9 different treatment regimens with a total of 6805 patients were included for analysis. Hazard ratios (HR)/ odds ratio (OR)/ relative risk (RR) and 95% confidence intervals (CI) for PFS, ORR and grade> 3 adverse events (AE) of selected comparisons from the results of the NMA are shown in table. Conclusions: REG combined with CTX might be a potential alternative to conventional therapeutic options and could be considered as the best option for treating KRAS and BRAF mutated mCRC patients. Future RCTs are needed to confirm our results. [Table: see text]

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14073-e14073
Amit Rauthan ◽  
Poonam Patil ◽  
Tanvi Sood ◽  
Shriniwas Subhash Kulkarni ◽  
Nitin Yashas ◽  

e14073 Background: Pembrolizumab is approved for deficient mismatch repair (dMMR) or high microsatellite instability (MSI-H) metastatic solid tumors with objective response rate (ORR) of 39.6% and response lasting for more than 6 months in 78% patients. Nivolumab is also approved in dMMR metastatic colorectal cancers (mCRC) with ORR of 28% and response lasting greater than 6 months in 67% patients. But finding these patients is difficult as only about 5% of metastatic cancers have dMMR. There is limited data from India in this population. We report our experience with testing and treatment in these patients. Methods: This is a single centre, retrospective study of metastatic solid tumors which had progressed on standard treatment. 137 patients were tested between May 2017 and Dec 2018. MMR testing was done by immunohistochemistry (IHC). The aim was to identify patients with dMMR; and to see their ORR, progression free survival (PFS) at 1 year, and adverse events on treatment with Nivolumab. Results: 137 metastatic cancer patients were tested. 75 had colorectal cancer (mCRC), 30 gastric, 10 hepatobiliary, 10 pancreatic, 8 endometrial, 2 small bowel cancer and 2 had breast cancer. 15 (11%) patients had dMMR. 3 (37%) of endometrium, 5 (16.6%) of stomach, 6 (8%) of mCRC and 1(10%) of hepatobiliary tree cancer had dMMR. 5 of the 15 dMMR patients received immunotherapy with Nivolumab - 2 in mCRC, 2 in stomach and 1 in endometrium. ORR was 60% with 3 partial responses, stable disease was seen in 1 (20%) and progression in 1 (20%). PFS at 1 year was 80%. Treatment was well tolerated.1 patient had hypothyroidism and 1 patient had grade 1 skin toxicity. Conclusions: Testing for dMMR is important in metastatic solid tumors as these patients are ideal for treatment with immunotherapy. But finding dMMR is difficult due to its infrequent presentation, and has been seen in 11% of our unselected patients. We recommend testing for dMMR by IHC in our Indian patients, as this is fast and cost effective. Finding dMMR cancers, and then treating with immunotherapy is rewarding irrespective of the site of origin. High ORR of 60% and 1 year PFS of 80% is very heartening to see in this relapsed metastatic patient group. Treating more dMMR patients and longer followup, will further elucidate the benefit of immunotherapy in our patients.

2020 ◽  
Vol 9 (18) ◽  
pp. 1285-1292
Shengqi He ◽  
Dongqing Hu ◽  
Haixia Feng ◽  
Ye Xue ◽  
Jin Jin ◽  

Aim: PD-1 inhibitors have a leading role among immunotherapy while its efficacy on colorectal cancer (CRC) patients did not reach consensus and the small sample size remains as a limitation. Therefore, we undertook a meta-analysis on the effects of the monotherapy anti-PD-1 inhibitors in treating metastatic colorectal cancer (mCRC). Materials & methods: We searched databases to identify studies on efficacy of anti-PD-1 inhibitor on CRC. Objectives were objective response rate, progression-free survival rate, disease control rate and overall survival rate with their 95% CI. Results: The overall survival rate at 1-year was 64.2% (95% CI: 0.46–0.83). Disease control rate was 56.5% (CI: 0.27–0.86) and the objective response rate as 19.7% (CI: 0.08–0.32). The 1-year-progression-free survival rate was 38.4% (CI: 0.12–0.66). Sensitivity analysis and subgroup analysis were also conducted. Conclusion: The monotherapy anti-PD-1 inhibitors are effective in treating mCRC and could be a new option for dMMR mCRC patient in first-line treatment.

2021 ◽  
Robin Park ◽  
Laercio Lopes ◽  
Sunggon Lee ◽  
Ivy Riano ◽  
Anwaar Saeed

Aims: The authors present a systematic review/meta-analysis of the impact of BRAF mutations on prognosis and immune checkpoint inhibitor (ICI) response in deficient mismatch repair/microsatellite instability-high colorectal cancer. Methods: Hazard ratios for overall survival and odds ratios for objective response rate to ICIs were calculated in BRAF-mutated versus BRAF wild-type patients. Results: After screening, nine and three studies, respectively, were included for analysis of prognosis (analysis A) and ICI response (analysis B). Analysis A showed worse overall survival in BRAF-mutated compared with BRAF wild-type stage I–IV patients (hazard ratio: 1.57; 95% CI: 1.23–1.99), and analysis B showed no difference in objective response rate (odds ratio: 1.04; 95% CI: 0.48–2.25). Conclusion: BRAF mutations are associated with worse overall survival but not differential response to ICIs in deficient mismatch repair/microsatellite instability-high colorectal cancer.

Immunotherapy ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 541-555
Lingrong Tang ◽  
Tingting Liu ◽  
Jun Chen ◽  
Jun Dang ◽  
Guang Li

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.

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2663
Tung Hoang ◽  
Jeongseon Kim

This study aimed to investigate the efficacy and safety of systemic therapies in the treatment of unresectable advanced or metastatic colorectal cancer. Predicted hazard ratios (HRs) and their 95% credible intervals (CrIs) for overall survival (OS) were calculated from the odds ratio (OR) for the overall response rate and/or HR for progression-free survival using multivariate random effects (MVRE) models. We performed a network meta-analysis (NMA) of 49 articles to compare the efficacy and safety of FOLFOX/FOLFIRI±bevacizumab (Bmab)/cetuximab (Cmab)/panitumumab (Pmab), and FOLFOXIRI/CAPEOX±Bmab. The NMA showed significant OS improvement with FOLFOX, FOLFOX+Cmab, and FOLFIRI+Cmab compared with that of FOLFIRI (HR = 0.84, 95% CrI = 0.73–0.98; HR = 0.76, 95% CrI = 0.62–0.94; HR = 0.80, 95% CrI = 0.66–0.96, respectively), as well as with FOLFOX+Cmab and FOLFIRI+Cmab compared with that of FOLFOXIRI (HR = 0.69, 95% CrI = 0.51–0.94 and HR = 0.73, 95% CrI = 0.54–0.97, respectively). The odds of adverse events grade ≥3 were significantly higher for FOLFOX+Cmab vs. FOLFIRI+Bmab (OR = 2.34, 95% CrI = 1.01–4.66). Higher odds of events were observed for FOLFIRI+Pmab in comparison with FOLFIRI (OR = 2.16, 95% CrI = 1.09–3.84) and FOLFIRI+Bmab (OR = 3.14, 95% CrI = 1.51–5.89). FOLFOX+Cmab and FOLFIRI+Bmab showed high probabilities of being first- and second-line treatments in terms of the efficacy and safety, respectively. The findings of the efficacy and safety comparisons may support the selection of appropriate treatments in clinical practice. PROSPERO registration: CRD42020153640.

2020 ◽  
Vol 12 ◽  
pp. 175883592094093
Yinying Wu ◽  
Yangwei Fan ◽  
Danfeng Dong ◽  
Xuyuan Dong ◽  
Yuan Hu ◽  

Background: The evidence base for optimum third-line therapy for metastatic colorectal cancer (mCRC) is not conclusive. Recent studies have demonstrated the efficacy of regorafenib as third-line therapy in mCRC. This indirect meta-analysis compared the efficacy and safety of regorafenib with other available third-line therapies for mCRC. Methods: A literature search for randomized controlled trials (RCTs) was conducted in PubMed, Embase, and Cochrane Library for studies evaluating the efficacy and safety of fruquintinib, regorafenib, TAS-102, and nintedanib as third-line therapies in patients with mCRC. Overall survival (OS) and progression-free survival (PFS) were the primary outcomes, while objective response rate (ORR) and safety were the secondary outcomes. Hazard ratio (HR) and relative risk (RR) with their respective 95% confidence interval (CI) were used for analysis of survival, clinical response, and safety data. An adjusted indirect meta-analysis with placebo as the common comparator was performed. Results: We identified eight RCTs comparing regorafenib (two studies), fruquintinib (two studies), TAS-102 (three studies), and nintedanib (one study) against placebo. The OS with regorafenib was significantly better when compared with nintedanib (HR = 0.66; 95% CI: 0.45, 0.95, p = 0.02) but was similar to that of fruquintinib (HR = 1.01; 95% CI: 0.67, 1.52, p = 0.94) and TAS-102 (HR = 0.97; 95% CI: 0.68, 1.38, p = 0.88). The PFS and ORR for regorafenib were slightly better than those of TAS-102 (PFS: HR = 0.86, 95% CI: 0.54, 1.37, p = 0.5; ORR: RR = 1.13, 95% CI: 0.11, 11.05, p = 0.92) and nintedanib (PFS: HR = 0.68, 95% CI: 0.42, 1.10, p = 0.12; ORR: not reported) but were lower than those for fruquintinib (PFS: HR = 1.53, 95% CI: 0.93, 2.52, p = 0.08; ORR: RR = 0.68269, 95% CI: 0.045, 10.32, p = 0.79). Safety analysis showed that the RR of adverse events (AEs) was lesser in patients treated with regorafenib in comparison with that in patients treated with fruquintinib, but was similar to that in patients treated with nintedanib and TAS-102. Conclusion: Regorafenib has efficacy similar to that of TAS-102 and better safety when compared with fruquintinib. Considering the mechanism of action of regorafenib, which targets multiple factors in the angiogenic pathway, it could be an ideal option for treatment in the beyond second-line setting.

2020 ◽  
Vol 48 (7) ◽  
pp. 030006052092640
Guan-Li Su ◽  
Yuan-Yuan Wang ◽  
Jin-Cheng Wang ◽  
Hao Liu

Objective We performed this meta-analysis to compare the efficacy and toxicity of regorafenib and TAS-102. Methods Electronic databases were searched to identify studies comparing the efficacy and safety of regorafenib and TAS-102 in patients with chemotherapy-refractory metastatic colorectal cancer using pooled analyses. Results Three clinical trials were included in this analysis. Regarding the reasons for treatment discontinuation, regorafenib was significantly associated with disease progression (odds ratio [OR] = 0.33, 95% confidence interval [CI] = 0.21–0.50) and adverse events (OR = 4.38, 95% CI = 2.69–7.13). However, overall (OR = 0.97, 95% CI = 0.81–1.17) and progression-free survival (OR = 1.01, 95% CI = 0.86–1.18) did not significantly differ between the groups. The most common treatment-related adverse events in the regorafenib group were neutropenia (OR = 0.06, 95% CI = 0.03–0.11), hand–foot syndrome (OR = 50.34, 95% CI = 10.44–242.84), and liver dysfunction (OR = 34.51, 95% CI = 8.30–143.43). Conversely, the incidence of thrombocytopenia did not differ between the two groups. Conclusions Regorafenib and TAS-102 have similar efficacy but different adverse event profiles. Differences in the toxicity profiles of the two drugs will help guide treatment selection.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 795-795
Yuuki Sunakawa ◽  
Goro Nakayama ◽  
Kiyoshi Ishigure ◽  
Hiroyuki Yokoyama ◽  
Keisuke Uehara ◽  

795 Background: The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC). Methods: Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety. Results: The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0–14.8) and 30.6 months (95% CI, 27.6–33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy. Conclusions: CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC. Clinical trial information: UMIN000006478.

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3206
Susanne Deininger ◽  
Peter Törzsök ◽  
David Oswald ◽  
Lukas Lusuardi

Background: In the first and second-line therapy of metastatic urothelial carcinoma (mUC), checkpoint inhibitors (CPI) such as Pembrolizumab and Atezolizumab have been widely implemented. Little is currently known about what therapeutic options are effective after therapy with CPI. This article presents a systemic review of current treatment options in this setting. Methods: From August 2020 to 15 April 2021, a literature search was performed through the PubMed/Medline. Subsequently, a single-group meta-analysis of three studies testing Enfortumab vedotin (EV) was conducted. Results: Five therapy regimens tested in the post-CPI setting with adequate data were identified: Chemotherapy (CT), Ramucirumab plus Docetaxel, Erdafitinib (Erd), EV, and Sacituzumab govitecan (SG). In n = 74 + 125 + 288 patients, the single-group meta-analysis showed an objective response rate of 42.1% for EV compared to 17.9% for CT in a similar setting. EV was also ahead in progression free survival (5.9 months with EV vs. 3.7 months with CT) and overall survival (12.8 months with EV vs. 9.0 months with CT). Conclusion: Most data are currently available for EV. Further research is needed on the question of which patients’ subcollectives particularly benefit from which therapeutic approach.

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