BACKGROUND: There is a significant gap in the literature concerning the effective management of second-line therapy for patients with metastatic renal cell carcinoma (RCC) who have received immune checkpoint inhibitors (ICIs). Most of the published articles were small multicenter series or phase 2 studies. To our knowledge, a systematic review that comprehensively outlines the range of treatment options available for patients with metastatic RCC who do not respond to first-line ICIs has not yet been conducted. Our aim was to synthesize evidence on second-line therapies for patients with metastatic RCC after initial treatment with ICIs and to offer recommendations on the best treatment regimens based on the current literature.
METHODS: We conducted a search in PubMed, Embase, and the Cochrane Library on 29 February 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We selected articles that met the predetermined inclusion criteria (written in English, retrospective observational studies, prospective series, and randomized trials reporting second-line therapy for metastatic RCC after failure of ICI-based therapy). Relevant articles were identified in the reference lists. The main endpoint was the overall response rate (ORR), with the median progression-free survival (PFS) and overall survival (OS) as secondary endpoints.
RESULTS: We included 27 studies reporting the outcomes of 1970 patients. Salvage therapies were classified as targeted therapy (VEGFR TKIs) in 18 studies and ICIs in 8 studies. In studies where TKIs were the second line of choice, the pooled ORR was 34% (95% CI: 30.2-38%). In studies where ICIs, alone or in combination with TKIs, were used as second-line therapies, the ORR was 25.7% (95% CI: 15.7-39.2%). In studies where TKIs and ICIs were the second-line choices, the pooled median PFS values were 11.4 months (95% CI: 9.5-13.6 months) and 9.8 months (95% CI: 7.5-12.7 months), respectively.
CONCLUSIONS: This systematic review shows that VEGFR TKIs and ICIs are effective second-line therapies following an initial treatment with anti-PD(L)1 alone or in combination. The treatment choice should be personalized, taking into account the patient\'s response to first-line ICIs, the site of the disease, the type of first-line combination (with or without VEGFR TKIs), and the patient\'s overall condition.

Urothelial carcinoma presents significant treatment challenges, especially in advanced stages. Traditionally managed with platinum-based chemotherapy, the advent of immunotherapies, particularly immune checkpoint inhibitors, has revolutionized urothelial carcinoma treatment. This review explores the evolution of urothelial carcinoma management, focusing on the transition from immune checkpoint inhibitors monotherapy to innovative combination therapies. Pembrolizumab, following the KEYNOTE-045 trial, emerged as a pivotal ICI in pretreated metastatic urothelial carcinoma, outperforming traditional chemotherapy. However, limitations surfaced in untreated metastatic urothelial carcinoma patients, particularly in those with low PD-L1 expression, as evidenced by trials like IMvigor130 and KEYNOTE-361. These challenges led to the exploration of combination therapies, including immune checkpoint inhibitors with platinum-based chemotherapy, tyrosine kinase inhibitors, and antibody-drug conjugates. Notably, the CheckMate 901 trial demonstrated improved outcomes with a nivolumab-chemotherapy combination. A significant breakthrough was achieved with the combination of enfortumab vedotin, an antibody-drug conjugates, and pembrolizumab, setting a new standard in first-line treatment for locally advanced or metastatic urothelial carcinoma. Future directions involve further exploration of antibody-drug conjugates and immune checkpoint inhibitors, as seen in the TROPHY-U-01 and TROPiCS-4 trials. The review concludes that the locally advanced or metastatic urothelial carcinoma treatment landscape is rapidly evolving, with combination therapies offering promising avenues for improved patient outcomes, signaling a new era in urothelial carcinoma management.

BACKGROUND: Although treatment options for gastric cancer (GC) continue to advance, the overall prognosis for patients with GC remains poor. At present, the predictors of treatment efficacy remain controversial except for high microsatellite instability.
OBJECTIVE: To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1 (PD-1) inhibitor and chemotherapy.
METHODS: We acquired data from 63 patients with human epidermal growth factor receptor 2 (HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital, Chinese Academy of Medical Sciences between November 2020 and October 2022. All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.
RESULTS: As of July 1, 2023, the objective response rate was 61.9%, and the disease control rate was 96.8%. The median progression-free survival (mPFS) for all patients was 6.3 months. The median overall survival was not achieved. Survival analysis showed that patients with a combined positive score (CPS) ≥ 1 exhibited an extended trend in progression-free survival (PFS) when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment. PFS exhibited a trend for prolongation as the expression level of HER2 increased. Based on PFS, we divided patients into two groups: A treatment group with excellent efficacy and a treatment group with poor efficacy. The mPFS of the excellent efficacy group was 8 months, with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery. The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery. Using good/poor efficacy as the endpoint of our study, univariate analysis revealed that both CPS score (P = 0.004) and HER2 expression level (P = 0.015) were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC (AGC). Finally, multivariate analysis confirmed that CPS score was a significant influencing factor.
CONCLUSIONS: CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

BACKGROUND: Adherence to Helicobacter pylori (H. pylori) eradication treatment is a cornerstone for achieving adequate treatment efficacy.
OBJECTIVE: To determine which factors influence compliance with treatment.
METHODS: A systematic prospective non-interventional registry (Hp-EuReg) of the clinical practice of European gastroenterologists. Compliance was considered adequate if ≥90% drug intake. Data were collected until September 2021 using the AEG-REDCap e-CRF and were subjected to quality control. Modified intention-to-treat analyses were performed. Multivariate analysis carried out the factors associated with the effectiveness of treatment and compliance.
RESULTS: Compliance was inadequate in 646 (1.7%) of 38,698 patients. The non-compliance rate was higher in patients prescribed longer regimens (10-, 14-days) and rescue treatments, patients with uninvestigated dyspepsia/functional dyspepsia, and patients reporting adverse effects. Prevalence of non-adherence was lower for first-line treatment than for rescue treatment (1.5% vs. 2.2%; p < 0.001). Differences in non-adherence in the three most frequent first-line treatments were shown: 1.1% with proton pump inhibitor + clarithromycin + amoxicillin; 2.3% with proton pump inhibitor clarithromycin amoxicillin metronidazole; and 1.8% with bismuth quadruple therapy. These treatments were significantly more effective in compliant than in non-compliant patients: 86% versus 44%, 90% versus 71%, and 93% versus 64%, respectively (p < 0.001). In the multivariate analysis, the variable most significantly associated with higher effectiveness was adequate compliance (odds ratio, 6.3 [95%CI, 5.2-7.7]; p < 0.001).
CONCLUSIONS: Compliance with Helicobacter pylori eradication treatment is very good. Factors associated with poor compliance include uninvestigated/functional dyspepsia, rescue-treatment, prolonged treatment regimens, the presence of adverse events, and the use of non-bismuth sequential and concomitant treatment. Adequate treatment compliance was the variable most closely associated with successful eradication.

Background and aim: We conducted an equivalence trial of quadruple non-bismuth \"concomitant\" and \"hybrid\" regimens for H. pylori eradication in a high clarithromycin resistance area. Methods: There were 321 treatment-naïve H. pylori-positive individuals in this multicenter clinical trial randomized to either the hybrid (esomeprazole 40 mg/bid, amoxicillin 1 g/bid for 7 days, then 7 days esomeprazole 40 mg/bid, amoxicillin 1 g/bid, clarithromycin 500 mg/bid, and metronidazole 500 mg/bid) or the concomitant regimen (all medications given concurrently bid for 10 days). Eradication was tested using histology and/or a 13C-urea breath test. Results: The concomitant regimen had 161 patients (90F/71M, mean 54.5 years, 26.7% smokers, 30.4% ulcer) and the hybrid regimen had 160 (80F/80M, mean 52.8 years, 35.6% smokers, 31.2% ulcer). The regimens were equivalent, by intention to treat 85% and 81.8%, (p = 0.5), and per protocol analysis 91.8% and 87.8%, (p = 0.3), respectively. The eradication rate by resistance, between concomitant and hybrid regimens, was in susceptible strains (97% and 97%, p = 0.6), clarithromycin single-resistant strains (86% and 90%, p = 0.9), metronidazole single-resistant strains (96% and 81%, p = 0.1), and dual-resistant strains (70% and 53%, p = 0.5). The side effects were comparable, except for diarrhea being more frequent in the concomitant regimen. Conclusions: A 14-day hybrid regimen is equivalent to a 10-day concomitant regimen currently used in high clarithromycin and metronidazole resistance areas. Both regimens are well tolerated and safe.

UNASSIGNED: Advanced pancreatic cancer has a poor prognosis and a 5-year survival rate <5%; thus, treatment of patients with advanced unresectable or metastatic disease is challenging. Current guidelines recommend either gemcitabine plus nab-paclitaxel (GnP) or FOLFIRINOX (FOL) as first-line treatment. Data on both efficacy and toxicity of FOL versus GnP in metastatic cancer are limited. This study aimed to compare the two chemotherapy regimens in terms of efficacy and toxicity in a real-world setting.
UNASSIGNED: This retrospective propensity score matching study reviewed the medical records of 123 consecutive patients with advanced or metastatic pancreatic cancer who received either GnP or FOL between March 2013 and January 2019 in Guglielmo da Saliceto Hospital, Piacenza.
UNASSIGNED: Fifty patients (40.65%) received FOL, administered in an attenuated dose, and seventy-three patients (59.35%) received GnP. After a propensity matching score, 100 patients were retrospectively evaluated. In the final matched cohort, there was no difference in neoadjuvant therapy, radiotherapy, and surgery performed before the first-line therapy between the two groups. Progression-free survival and overall survival were comparable between the two groups and no difference was found in the percentage of toxicity.
UNASSIGNED: There was no difference in outcomes between patients who received FOL and those who received GnP. Unexpectedly, no greater FOL-related toxicity was found, probably due to the dose reduction.

There is growing evidence of prescribing sodium glucose co-transporters-2 inhibitor (SGLT-2) to patients with/at high risk of atherosclerotic cardiovascular disease as first-line (instead of metformin). This is the first meta-analysis to compare SGLT-2 inhibitors regarding the same. We aimed to compare SGLT-2 inhibitors and metformin regarding heart failure, acute coronary syndrome, and ischemic stroke. We systematically searched PubMed and Cochrane Library for relevant articles from the first article up to August 2022. The following keywords were used: Metformin, Salt glucose co-transporters inhibitors, SGLT-2 inhibitors, empagliflozin, dapagliflozin, canagliflozin, and first-line. The retrieved data were exported to an excel sheet detailing the author\'s names, the country of origin of the study, the number of patients and control subjects, the study duration, and the total number of events in the interventional and exercise groups. Out of 108 articles screened, only three studies fulfilled the inclusion criteria, a databased study, and two cohorts with 10309 events and 86487 patients. The present meta-analysis showed that SGLT-2 inhibitors had lower rates of heart failure (odd ratio, 1.51, 95% CI, 1.10-2.08) and myocardial infarction (odd ratio, 1.45, 95% CI, 1.08-1.96) than metformin with a similar rate of stroke (odd ratio, 1.03, 95% CI, 0.66-1.61). Significant heterogeneity was observed. Sodium-glucose co-transporter inhibitors-2 as first-line therapy showed a lower heart failure and myocardial infarction compared to metformin. No significant difference was found between the two drugs regarding ischemic stroke. Further larger studies comparing the adverse event are needed.

BACKGROUND: In CheckMate 227 Part 1, first-line nivolumab plus ipilimumab prolonged overall survival (OS) in patients with metastatic non-small-cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% versus chemotherapy. We report results from CheckMate 227 Part 2, which evaluated nivolumab plus chemotherapy versus chemotherapy in patients with metastatic NSCLC regardless of tumor PD-L1 expression.
METHODS: Seven hundred and fifty-five patients with systemic therapy-naive, stage IV/recurrent NSCLC without EGFR mutations or ALK alterations were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus chemotherapy or chemotherapy. Primary endpoint was OS with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC. OS in all randomized patients was a hierarchically tested secondary endpoint.
RESULTS: At 19.5 months\' minimum follow-up, no significant improvement in OS was seen with nivolumab plus chemotherapy versus chemotherapy in patients with nonsquamous NSCLC [median OS 18.8 versus 15.6 months, hazard ratio (HR) 0.86, 95.62% confidence interval (CI) 0.69-1.08, P = 0.1859]. Descriptive analyses showed OS improvement with nivolumab plus chemotherapy versus chemotherapy in all randomized patients (median OS 18.3 versus 14.7 months, HR 0.81, 95.62% CI 0.67-0.97) and in an exploratory analysis in squamous NSCLC (median OS 18.3 versus 12.0 months, HR 0.69, 95% CI 0.50-0.97). A trend toward improved OS was seen with nivolumab plus chemotherapy versus chemotherapy, regardless of the tumor mutation status of STK11 or TP53, regardless of tumor mutational burden, and in patients with intermediate/poor Lung Immune Prognostic Index scores. Safety with nivolumab plus chemotherapy was consistent with previous reports of first-line settings.
CONCLUSIONS: CheckMate 227 Part 2 did not meet the primary endpoint of OS with nivolumab plus chemotherapy versus chemotherapy in patients with metastatic nonsquamous NSCLC. Descriptive analyses showed prolonged OS with nivolumab plus chemotherapy in all-randomized and squamous NSCLC populations, suggesting that this combination may benefit patients with untreated metastatic NSCLC.

The JAVELIN Bladder 100 phase III trial led to the incorporation of avelumab first-line (1L) maintenance treatment into international guidelines as a standard of care for patients with advanced urothelial carcinoma (UC) without progression after 1L platinum-based chemotherapy. JAVELIN Bladder 100 showed that avelumab 1L maintenance significantly prolonged overall survival (OS) and progression-free survival in this population compared with a \'watch-and-wait\' approach. The aim of this manuscript is to review clinical studies of avelumab 1L maintenance in patients with advanced UC, including long-term efficacy and safety data from JAVELIN Bladder 100, subgroup analyses in clinically relevant subpopulations, and \'real-world\' data obtained outside of clinical trials, providing a comprehensive resource to support patient management. Extended follow-up from JAVELIN Bladder 100 has shown that avelumab provides a long-term efficacy benefit, with a median OS of 23.8 months measured from start of maintenance treatment, and 29.7 months measured from start of 1L chemotherapy. Longer OS was observed across subgroups, including patients who received 1L cisplatin + gemcitabine, patients who received four or six cycles of 1L chemotherapy, and patients with complete response, partial response, or stable disease as best response to 1L induction chemotherapy. No new safety signals were seen in patients who received ≥1 year of avelumab treatment, and toxicity was similar in those who had received cisplatin or carboplatin with gemcitabine. Other clinical datasets, including noninterventional studies conducted in Europe, USA, and Asia, have confirmed the efficacy of avelumab 1L maintenance. Potential subsequent treatment options after avelumab maintenance include antibody-drug conjugates (enfortumab vedotin or sacituzumab govitecan), erdafitinib in biomarker-selected patients, platinum rechallenge in suitable patients, nonplatinum chemotherapy, and clinical trial participation; however, evidence to determine optimal treatment sequences is needed. Ongoing trials of avelumab-based combination regimens as maintenance treatment have the potential to evolve the treatment landscape for patients with advanced UC.

Standard-of-care first-line treatment for metastatic urothelial carcinoma (mUC) is platinum-based chemotherapy (CTx). Maintenance immunotherapy is a treatment option for patients without progressive disease (PD) after induction CTx. IMvigor130 was a randomised, phase 3 study evaluating atezolizumab plus platinum-based CTx (arm A), atezolizumab monotherapy (arm B), or placebo plus platinum-based CTx (arm C) as first-line treatment for mUC. The primary progression-free survival (PFS) analysis showed a statistically significant PFS benefit favouring arm A versus arm C, which did not translate into overall survival (OS) benefit at the final OS analysis. We report exploratory analyses based on response to combination induction treatment (arm A vs arm C) using final OS data. Post-induction OS was analysed for patients without PD during induction (4-6 CTx cycles) who received at least one dose of single-agent atezolizumab/placebo maintenance treatment. Post-progression OS was analysed for patients with PD during induction CTx. Addition of atezolizumab to CTx did not impact OS outcomes, regardless of response to induction CTx, with hazard ratios of 0.84 (95% confidence interval [CI] 0.63-1.10) for patients without PD and 0.75 (95% CI 0.54-1.05) for those with PD during induction CTx. Treatment effects appeared to be greatest for patients treated with cisplatin and for those with PD-L1-high tumours.
UNASSIGNED: The IMvigor130 trial showed that addition of atezolizumab to chemotherapy (CTx) did not improve survival over CTx alone in patients with bladder cancer. Overall, patients whose cancer did not progress during initial treatment tended to live longer than patients whose cancer did progress, but addition of atezolizumab to CTx did not help either group live longer in comparison to CTx alone. However, the results suggest that patients who received a certain CTx drug (cisplatin) or who had high levels of a marker called PD-L1 in their tumour may get the most improvement from addition of atezolizumab to CTx.The IMvigor130 trial is registered on ClinicalTrials.gov as NCT02807636.