Efficacy of consolidation of immune checkpoint inhibitor after chemoradiation for unresectable, locally advanced PD‐L1 negative non‐small cell lung cancer: A systematic review and meta‐analysis
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ABSTRACT:
SUBMITTER: Rao S
PROVIDER: S-EPMC11008101 | biostudies-literature | 2024 Apr
REPOSITORIES: biostudies-literature
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Project description:For local advanced rectal cancer (LARC), total neoadjuvant treatment (TNT) has shown more complete response (CR), reduced risk of distant metastasis (DM) and increase of the sphincter preservation rate. Now it is the one and only recommendation for high-risk group of LARC according to National Comprehensive Cancer Network (NCCN) rectal cancer guideline, while it is also preferentially recommended for low-risk group of LARC. TNT is also beneficial for distant rectal cancer patients who have need for organ preservation. Even though the prognostic value of programmed cell death-ligand 1 (PD-L1) in the neoadjuvant chemoradiotherapy (NACRT) of LARC patients is undetermined yet, the combination of NACRT and programmed cell death-1 (PD-1)/PD-L1 antibodies seem bring new hope for mismatch repair proficient (pMMR)/microsatellite stable (MSS) LARC patients. Accumulating small sample sized studies have shown that combining NACRT with PD-1/PD-L1 antibody yield better short-term outcomes for pMMR/MSS LARC patients than historic data. However, ideal total dose and fractionation of radiotherapy remains one of unresolved issues in this combination setting. Thorough understanding the impact of radiotherapy on the tumor microenvironment and their interaction is needed for in-depth understanding and exquisite design of treatments combination model.
| S-EPMC10079866 | biostudies-literature
Project description:BackgroundTriple negative breast cancer (TNBC) represents a particularly aggressive and clinically challenging subtype of breast cancer, characterized by its invasive nature and generally poor prognosis. Treatment options for unresectable TNBC are limited. In recent years, the advent of PD-1/PD-L1 immune checkpoint inhibitors has offered a promising new treatment option for unresectable TNBC. The role of PD-1/PD-L1 immune checkpoint inhibitors (ICIs) in unresectable TNBC management remains a subject of debate. This article aims to synthesize evidence from randomized controlled trials (RCTs) through a meta-analysis (MA) to provide a comprehensive evaluation of the efficacy and safety profile of ICIs in the treatment of unresectable TNBC.MethodWe searched PubMed, Embase, Cochrane library, Web of Science, and ClinicalTrials.gov for the eligible RCTs which compared the efficacy and safety of PD-1/PD-L1 ICIs and chemotherapy alone. The outcomes analyzed included overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and treatment-related adverse effects (AEs).ResultsThis meta-analysis included 11 trials. Therapy with PD-L1 inhibitors was superior to chemotherapy in terms of OS in both the intention-to-treat (ITT) population and the PD-L1-positive population. (ITT: HR: = 0.90 [0.81, 0.99], P = 0.04, I2 = 48%; PD-L1 + : HR = 0.82 [0.70, 0.95], P = 0.01, I2 = 64%); In terms of PFS, treatment with PD-L1 inhibitors prolonged PFS in both the ITT and PD-L1-positive populations compared with chemotherapy (ITT: HR: = 0.85 [0.77, 0.93], P = 0.0006, I2 = 46%; PD-L1 + : HR = 0.72 [0.62, 0.83], P < 0.00001, I2 = 70%, Fig. 5); Compared with chemotherapy alone, treatment with PD-1 inhibitors prolonged OS in both the PD-L1-positive and ITT populations. (ITT: HR = 0.87 [0.78, 0.96], P = 0.007, I2 = 71%; CPS ≥ 1: HR = 0.81 [0.71, 0.92], P = 0.001, I2 = 39%); In terms of PFS, therapy with PD-1 inhibitors improved PFS in both the ITT population and the PD-L1-positive population compared with chemotherapy. (ITT: HR = 0.79 [0.70, 0.90], P = 0.0004, I2 = 0%; CPS ≥ 1: HR = 0.71 [0.61, 0.83], P < 0.0001, I2 = 0%; CPS ≥ 10: HR = 0.67 [0.53, 0.84], P = 0.0008, I2 = 0%).ConclusionBoth PD-1 and PD-L1 inhibitors can offer survival benefits to TNBC patients, with the primary beneficiaries being those who are PD-L1-positive. However, immunotherapy can also lead to an increase in treatment-related adverse events. Therefore, it is essential to conduct a risk assessment for each patient before starting treatment to prevent the occurrence of serious adverse reactions.Trial registrationThis systematic review study has been filed with PROSPERO (Registration number: CRD42024571775).
| S-EPMC11526542 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is a subtype of breast cancer that is negative for oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression. Locally advanced and metastatic TNBC not only have a worse prognosis and are more invasive than TNBC, but are also the most immunogenic subtypes of breast cancer. There is still a lack of clarity regarding the optimal treatment of locally advanced or metastatic TNBC. The present study aimed to assess the efficacy and safety of programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitor-based immunotherapy [i.e., immune checkpoint inhibitors (ICIs)] alone or in combination with other therapies for the treatment of locally advanced or metastatic TNBC. The PubMed, Cochrane Library, Embase and MEDLINE databases were searched up to July 19, 2023 to identify studies that examined the efficacy and safety of ICIs for treating TNBC. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The secondary outcomes were safety and adverse events. The data were analysed using Review Manager 5.4. A total of 8 studies (3,338 patients) were included in the present meta-analysis. Compared with other therapies, ICIs had a significantly different effect on OS [hazard ratio (HR)=0.83; 95% confidence interval (CI)=0.69-1.00; P<0.05; I2=59%] in patients with locally advanced or metastatic TNBC. In addition, ICIs significantly prolonged PFS compared with other therapies (intent-to-treat: HR=0.81; 95% CI=0.75-0.88; P<0.00001; I2=0%). Immunotherapy based on PD-1/PD-L1 inhibitors showed variable efficacy on OS and PFS in TNBC, while a significant improvement was observed for PD-L1(+). Future studies should focus on PD-L1 subgroup status, which may help optimize personalized treatment regimens for TNBC.
| S-EPMC11600704 | biostudies-literature
Project description:IntroductionThe introduction of consolidation immunotherapy after chemoradiotherapy has improved outcome for patients with locally advanced non-small cell lung cancer. However, not all patients receive this treatment. This study identifies factors associated with failure to start durvalumab as consolidation therapy with the aim of optimizing treatment, supportive care and prehabilitation to ensure that more patients complete the planned treatment.Materials and methodsPatients from two clinical trials and a named patient use program, were included in this study. All patients received platinum-doublet chemotherapy concomitant with radiotherapy to a total dose of 60-66 gray. Patient characteristics, cancer treatment, toxicity, performance status and laboratory data before and after chemoradiotherapy were recorded and patients who never started durvalumab were compared with those who did.ResultsA total of 101 patients were included, of which 83 started treatments with durvalumab after chemoradiotherapy. The 18 patients who did not start durvalumab had significantly higher lactate dehydrogenase at baseline and a worse performance status, cumulative toxicity and higher c-reactive protein after completed chemoradiotherapy. Data also suggest that pre-treatment diabetes and reduced hemoglobin and/or diffusion capacity of the lungs for carbon monoxide contribute to the risk of treatment abruption.ConclusionTreatment plan disruption rate was 18%. Systemic inflammation and performance status were associated with failure to receive durvalumab after chemoradiation. Further studies are needed to confirm findings and prospective trials should investigate whether prehabilitation and supportive treatment could help more patients finishing the planned treatment.Clinical trial registrationclinicaltrials.gov, identifier NCT03798535; NCT04392505.
| S-EPMC10354813 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) has a high prevalence and mortality rate worldwide. Sorafenib monotherapy has been the standard of first-line treatment for advanced HCC for a long time, but there are still many shortcomings. In recent years, with the deepening of research on tumor immune microenvironment, researchers have begun to explore new approaches in immunotherapy, and the introduction of immune checkpoint inhibitors has brought fundamental changes to the treatment of HCC. Programmed cell death protein 1 (PD-1) is an immune checkpoint molecule that plays an important role in down-regulating immune system function and promoting tolerance. Programmed cell death ligand 1 (PDL-1) is involved in tumor immune evasion by binding to PD-1, resulting in failure of treatment. Currently, immunotherapy targeting the PD-1/PD-L1 axis has achieved unprecedented success in HCC, but it also faces great challenges, with its low remission rate still to be solved. For most patients with HCC, the PD-1/PD-L1 pathway is not the only rate limiting factor of antitumor immunity, and blocking only the PD-1/PD-L1 axis is not enough to stimulate an effective antitumor immune response; thus, combination therapy may be a better option. In this study, changes in the immune microenvironment of HCC patients were reviewed to clarify the feasibility of anti-PD-1/PD-L1 therapy, and a series of monotherapy and combination therapy clinical trials were summarized to verify the safety and efficacy of this newly developed treatment in patients with advanced HCC. Furthermore, we focused on hyperprogressive disease and drug resistance to gain a better understanding of PD-1/PD-L1 blockade as a promising treatment.
| S-EPMC9806143 | biostudies-literature
Project description:Despite declining smoking rates, lung cancer remains the second most common malignancy in the United States and the leading cause of cancer-related mortality. Non-small cell lung cancer (NSCLC) comprises roughly 85% of cases, and patients tend to present with advanced disease. Historically, concurrent chemoradiotherapy (CRT) has been the standard of care for stage III unresectable NSCLC but outcomes even with multimodal therapy have remained relatively poor. Efforts to improve outcomes through radiation dose escalation with conventional dose fractionation were unsuccessful with RTOG 0617, demonstrating significantly decreased overall survival (OS) with high dose radiation with respect to standard therapy. The recent PACIFIC trial established a new role for consolidative immune checkpoint blockade therapy after CRT using the programmed death ligand 1 (PD-L1) inhibitor durvalumab, by demonstrating significantly improved progression free survival and OS. Although promising, the addition of immunotherapy to multimodal therapy has generated debate regarding the most effective immune pathways to target, appropriate sequencing of therapy, most effective radiation techniques, and toxicity-related concerns. This review will highlight recent and ongoing trials in unresectable, locally advanced NSCLC that incorporate chemotherapy, radiation, and immunotherapy with an emphasis on analysis of treatment-related toxicities and implications for future study design.
| S-EPMC7653152 | biostudies-literature
Project description: Not available
| S-EPMC11912038 | biostudies-literature
Project description:In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0-17) and 0.5 (range, 0-27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups (p = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation.
| S-EPMC7563314 | biostudies-literature
Project description:BackgroundThe PACIFIC study has defined a new standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) in the form of immune checkpoint inhibitor (ICI) consolidation therapy. However, there is little specific data pertaining to the safety and efficacy of this approach in Chinese NSCLC patients.MethodsThis was a prospective multicenter cohort study. Between September 2018 and January 2020, patients with unresectable stage III NSCLC that had undergone chemoradiation therapy (CRT) and ICI consolidation treatment were enrolled in this study. The short-term safety, tolerability, and efficacy of ICI combination with CRT were evaluated in these patients.ResultsOf the 20 Chinese patients eligible for inclusion, 17 (85.0%) underwent concurrent CRT treatment. In these patients, a median period of 40.5 days (range: 1-85 days) passed between the end of CRT and initiation of consolidation therapy. Pneumonitis occurred in 80.0% of patients, with seven (35.0%) being diagnosed with grade 1 pneumonitis and nine (45.0%) with grade 2 pneumonitis. No patients experienced grade 3 or higher pneumonitis or other ICI-related toxicities. Lung V20 ≥ 20% was associated with higher grade 2 pneumonitis (77.8%; ≥20% vs. 18.2%; <20%, P = 0.027). The overall response rate (ORR) in these patients was 95.0%. Over a median follow-up period of 11.3 months (range: 6.2-21.8 months), 12-month PFS of these patients were 89.5% (95% CI: 76.7-100.0%), and 12 months OS was 100.0%.ConclusionsThese data indicate that ICI consolidation therapy can achieve favorable short-term efficacy, while exhibiting good safety and acceptable toxicity profiles in Chinese patients with unresectable stage III NSCLC.Key pointsSignificant findings of the study This is the first report evaluating the safety and efficacy of ICI consolidation therapy after chemoradiotherapy in China. Our results indicate that ICI consolidation is associated with favorable efficacy and no severe pneumonitis incidence in Chinese patients undergoing both anti-PD-1 and anti-PD-L1 monoclonal antibody consolidation. What this study adds Post-hoc analysis of the Japanese subgroup in the PACIFIC study suggested that consolidation therapy may be associated with increased pneumonitis incidence in Asian patients. However, our findings indicate that consolidation therapy is safe and tolerable in Chinese patients with unresectable stage III NSCLC.
| S-EPMC7529561 | biostudies-literature
Project description:Despite therapeutic advancements, the prognosis of locally advanced non-small cell lung cancer (LANSCLC), which has invaded multiple lobes or the other lung and intrapulmonary lymph nodes, remains poor. The emergence of immunotherapy with immune checkpoint blockade (ICB) is transforming cancer treatment. However, only a fraction of lung cancer patients benefit from ICB. Significant clinical evidence suggests that the proinflammatory tumor microenvironment (TME) and programmed death-ligand 1 (PD-L1) expression correlate positively with response to the PD-1/PD-L1 blockade. We report here a liposomal nanoparticle loaded with cyclic dinucleotide and aerosolized (AeroNP-CDN) for inhalation delivery to deep-seated lung tumors and target CDN to activate stimulators of interferon (IFN) genes in macrophages and dendritic cells (DCs). Using a mouse model that recapitulates the clinical LANSCLC, we show that AeroNP-CDN efficiently mitigates the immunosuppressive TME by reprogramming tumor-associated macrophage from the M2 to M1 phenotype, activating DCs for effective tumor antigen presentation and increasing tumor-infiltrating CD8+ T cells for adaptive anticancer immunity. Intriguingly, activation of interferons by AeroNP-CDN also led to increased PD-L1 expression in lung tumors, which, however, set a stage for response to anti-PD-L1 treatment. Indeed, anti-PD-L1 antibody-mediated blockade of IFNs-induced immune inhibitory PD-1/PD-L1 signaling further prolonged the survival of the LANSCLC-bearing mice. Importantly, AeroNP-CDN alone or combination immunotherapy was safe without local or systemic immunotoxicity. In conclusion, this study demonstrates a potential nano-immunotherapy strategy for LANSCLC, and mechanistic insights into the evolution of adaptive immune resistance provide a rational combination immunotherapy to overcome it.
| S-EPMC10208391 | biostudies-literature