Objective Response Research Articles

A meta-analysis and systematic review of randomized controlled trials in combination gemcitabine with erlotinib in the pancreatic cancer.

Previous studies have demonstrated the efficacy and safety of combining gemcitabine and erlotinib (Gem-Erlo) for the treatment of pancreatic cancer (PaC). However, there is a limited number of clinical studies and multiple prospective randomized controlled trials (RCTs) have yielded inconsistent conclusions. The question of whether Gem-Erlo has significant advantages over conventional chemotherapy in the treatment of PaC has been controversial. In order to provide valuable insights for PaC treatment, this study conducted a meta-analysis based on the current evidence from RCTs. We searched several databases including PubMed/Medline, Web of Science, Cochrane Library, and Embase, as well as relevant conference abstracts from the beginning of their inception to July 2023. We used the patient/population, intervention, comparison, outcomes and study design (PICOS) principle to screen the literature. After title, abstract and full text filtering, we extract the data from each study to assess the risk of bias by examining the quality of the literature. We used a meta-analysis with random effects model to synthesize and summarize the results regarding objective response rate (ORR), disease control rate (DCR), median progression-free survival (median PFS), median overall survival (median OS) and 1-year survival rate. Seven RCTs were included, involving 2,152 PaC patients treated with either Gem-Erlo or gemcitabine alone. The results showed that Gem-Erlo significantly improved DCR [odds ratio (OR) =1.74; 95% confidence interval (CI): 1.03 to 2.92; P=0.04]; but did not significantly improve median OS [standardized mean difference (SMD) =-0.20; 95% CI: -1.46 to 1.06; P=0.75], median PFS (SMD =-0.97; 95% CI: -4.01 to 2.07; P=0.53), ORR (OR =1.29; 95% CI: 0.84 to 1.97), or 1-year survival rate (OR =1.18; 95% CI: 0.88 to 1.57). In addition, sensitivity analysis of the median OS showed the Gem-Erlo group significantly prolonged the median OS compared to the gemcitabine alone group [weighted mean difference (WMD) =-1.74; 95% CI: -1.87 to -1.62; P<0.001]. The most common adverse events (AEs) were rash, diarrhea, fatigue, neutropenia and thrombocytopenia in both groups, but the Gem-Erlo group is more often than the gemcitabine alone (OR =1.40, 95% CI: 1.19 to 1.65; P<0.001), and all AEs were within the acceptable range for patients. Gem-Erlo can improve DCR when compared to gemcitabine. There was no statistically significant improvement in median PFS, median OS, ORR and 1-year survival rate. However, sensitivity analysis showed a statistical difference in the median OS. Our study indicated that Gem-Erlo had better efficacy than gemcitabine alone in PaC therapy. The occurrence of AEs is under the acceptable range for patients.

Palbociclib in Patients With Head and Neck Cancer and Other Tumors With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study.

Targeted Agent and Profiling Utilization Registry is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and targetable genomic alterations. Two cohorts of patients with cyclin-dependent kinase inhibitor 2A (CDKN2A)-mutated tumors treated with palbociclib are reported: one with head and neck cancer (HNC) with both squamous and nonsquamous cell histologies, and one with histology-pooled (HP) cancers. Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16+ weeks duration. For the HNC cohort, Simon's two-stage design with a null DC rate of 15% versus 35% (power = 0.85; α = .10) was used. For the HP cohort, the null hypothesis of a DC rate of 15% was rejected if the lower limit of a one-sided 90% CI was >15%. Secondary end points included OR, safety, progression-free survival, overall survival, duration of response, and duration of SD. Seventy patients with HNC (N = 28) or HP cancers (N = 42) were treated with palbociclib. For the HNC cohort, DC and OR rates were 40% (one-sided 90% CI, 27 to 100) and 4% (95% CI, <1 to 18), respectively. The null hypothesis was rejected (P = .002). For the HP cohort, DC and OR rates were 13% (one-sided 90% CI, 6 to 100) and 5% (95% CI, <1 to 17), respectively. The null hypothesis was not rejected. Thirty-one of 70 patients experienced treatment-related grade 3 to 4 adverse events (AEs) or serious AEs, the most common including neutropenia, thrombocytopenia, and leukopenia. Palbociclib met prespecified criteria to declare a signal of activity in patients with HNC with CDKN2A alterations, but not in the HP cohort.

Long-Term Survival Outcomes With First-Line Nivolumab Plus Ipilimumab–Based Treatment in Patients With Metastatic NSCLC and Tumor Programmed Death-Ligand 1 Lower Than 1%: A Pooled Analysis

IntroductionNivolumab plus ipilimumab–based treatment regimens have shown long-term, durable efficacy benefits in patients with metastatic NSCLC. Here we report clinical outcomes from a pooled analysis of patients with metastatic NSCLC and tumor programmed death-ligand 1 (PD-L1) lower than 1% treated with first-line nivolumab plus ipilimumab with or without two cycles of chemotherapy versus up to four cycles of chemotherapy in the randomized phase 3 CheckMate 227 and CheckMate 9LA studies. MethodsPatients were aged 18 years or older and had stage IV/recurrent NSCLC with no sensitizing EGFR/ALK alterations. Assessments included overall survival (OS), progression-free survival (PFS), objective response rate, duration of response, and safety. ResultsIn patients with tumor PD-L1 lower than 1% in the nivolumab plus ipilimumab with or without chemotherapy (n = 322) versus chemotherapy (n = 315) arms, median OS was 17.4 versus 11.3 months, respectively, (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.54–0.76; 5-y OS rate, 20% versus 7%) at a median follow-up of 73.7 months. The OS benefit was observed across key subgroups, including difficult-to-treat populations such as those with baseline brain metastases (HR = 0.44, 95% CI: 0.26–0.75) or squamous NSCLC (HR = 0.51, 95% CI: 0.36–0.72). In the overall pooled population, the median PFS was 5.4 versus 4.9 months (HR = 0.72, 95% CI: 0.60–0.87; 5-y PFS rate, 9% versus 2%), the objective response rate was 29% versus 22%, and the median duration of response was 18.0 versus 4.6 months. No new safety signals were observed. ConclusionNivolumab plus ipilimumab with or without chemotherapy provides a long-term, durable clinical benefit in patients with metastatic NSCLC and tumor PD-L1 lower than 1%, supporting the use of this strategy as a first-line treatment option in this population with high unmet need. Clinical Trial Registrations: NCT02477826, NCT03215706

Clinical Management in NSCLC Patients With EGFR Mutation After Osimertinib Progression With Unknown Resistance Mechanisms.

Osimertinib is approved as a standard treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation by FDA. However, the mechanisms of resistance for nearly half of patients after osimertinib progression are still unknown, and the optimal therapies for these patients are still controversial. In this retrospective study, we compared efficacy and safety between immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab in NSCLC patients after osimertinib progression with unknown resistance mechanisms. Advanced NSCLC patients with unknown resistance mechanisms after osimertinib progression were retrospectively reviewed and divided into immunotherapy + chemotherapy, chemotherapy alone, and osimertinib + bevacizumab treatment groups according to the treatment they received after osimertinib progression. Clinicopathological features, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were compared between groups. A total of 121 patients were enrolled in this study, 22 in the immunotherapy + chemotherapy group, 72 in the chemotherapy group, and 27 in the osimertinib + bevacizumab group. The ORR was much higher in the immunotherapy + chemotherapy group compared with chemotherapy or osimertinib + bevacizumab group (55.56% vs. 14.81% vs. 0% in patients after progression on 1st line osimertinib treatment; 30.77% vs. 6.67% vs. 13.33% in patients after progression on 2nd/3rd line osimertinib treatment). Median PFS was also significantly longer in the immunotherapy + chemotherapy group compared with other groups (8.2 months vs. 4.0 months vs. 6.0 months in all patients, p = 0.0066). The median OS did not reach remarkable difference among groups, although osimertinib + bevacizumab group had a numerically longer median OS (37.0 months vs. 37.0 months vs. 47.6 months in all patients, p = 0.6357). Compared with immunotherapy + chemotherapy and chemotherapy, treatment-related adverse events (AEs) of osimertinib + bevacizumab were milder, especially in AEs related to gastrointestinal and bone marrow suppression. Our study provides clinical evidence that NSCLC patients after osimertinib progression with unknown resistance mechanisms may benefit from immunotherapy + chemotherapy, with higher ORR and longer PFS compared with osimertinib + bevacizumab or chemotherapy groups. Osimertinib + bevacizumab treatment was also an optional option for patients because OS was numerically longer and safer in this group.

Brief report: Ivonescimab combined with etoposide plus carboplatin as first-line treatment for extensive-stage small-cell lung cancer: results of a phase Ib clinical trial

INTRODUCTIONIvonescimab is a humanized IgG1 bispecific anti-PD-1/VEGF antibody. This study aimed to evaluate the safety and tolerance of ivonescimab combined with etoposide and carboplatin as first-line treatment in patients with extensive-stage small cell lung cancer (ES-SCLC) and explore the primary efficacy of this regimen. METHODSEligible patients received intravenous ivonescimab 3 mg/kg, 10 mg/kg, or 20 mg/kg every 3 weeks combined with etoposide and carboplatin for up to 4 cycles, followed by ivonescimab as maintenance. The primary endpoints were safety and objective response rate (ORR). RESULTSBetween April 23, 2021 and December 2, 2021, 35 patients were enrolled. At data cutoff (October 25, 2023), the median follow-up was 13.3 months (range, 0.3-28.5). For all patients, the confirmed ORR and disease control rate were 80% and 91.4%, respectively. The ORR was 66.7%, 90.9%, and 76.2% at the dose of 3 mg/kg, 10 mg/kg, and 20 mg/kg, respectively. Grade ≥3 treatment-related adverse events (TRAEs) were observed in 21 patients (60%), and the most frequent toxicities were decreased neutrophil count (n=8, 22.9%), decreased white blood cell count (n=5, 14.3%), and anemia (n=5, 14.3%). Grade ≥3 TRAEs occurred in 66.7%, 54.5%, and 61.9% of patients in 3, 10, and 20 mg/kg groups, respectively. TRAEs leading to death were reported in 2 patients (5.7%). Adverse events with potential immunologic etiology, most of them grade 1 or 2, occurred in 14 patients (40.0%). CONCLUSIONSIvonescimab in combination with etoposide and carboplatin was well-tolerated and showed promising antitumor activity in ES-SCLC.

The efficacy of first and second immunotherapy exposure in patients with recurrent or metastatic cervical cancer.

Immunotherapy has led to changes in cervical cancer guidelines. Therefore, additional biomarkers to identify the ideal patient who would experience the most benefit may be important. We retrospectively collected 208 patients with R/M CC and recorded clinicopathologic information, peripheral blood markers and treatments to analyze the prognostic factors of clinical outcomes. Response rate comparison, univariate, and multivariate analyses were performed to assess the efficacy of different factors. A total of 43.27% patients achieved objective responses, including 18 with complete response and 72 with partial response. Patients receiving first-line immunotherapy had much higher objective response rate (ORR) than the remaining patients (53.8% vs. 34.8%, p = 0.006). CRP >3 ECOG ≥1 and recurrence in 6 months predicted shorter progression free survival (PFS). CRP >3, GLU >6.1 independently predicted unfavorable overall survival (OS). Compared with no antiangiogenic therapy, previous antiangiogenic therapy reduced the median OS by nearly 14 months. Immunotherapy rechallenge was still effective after first immunotherapy failure, and combined with dual-immunotherapy or bevacizumab combined with chemoradiotherapy resulted in a 60.00% or 62.50% ORR, respectively. Patients with squamous cell carcinoma, with stable disease or objective response in the first immunotherapy or without chemotherapy in second immunotherapy had favorable clinical outcome. The baseline CRP levels in serum was an independent factor for PFS and OS of R/M CC patients treated with immunotherapy, and previous antiangiogenic therapy was associated with poor OS. Patients still show response to immunotherapy rechallenge and combined treatment with bevacizumab or candonilimab showed higher response rate than anti-PD-1 after immunotherapy failure.

A phase 2 trial of gemcitabine plus toripalimab for cisplatin-ineligible patients with recurrent or metastatic nasopharyngeal carcinoma

Cisplatin is a cornerstone chemotherapy for nasopharyngeal carcinoma (NPC); however, certain patients are ineligible for cisplatin-based regimens. This phase 2 trial (NCT04405622) evaluated the efficacy and safety of gemcitabine and toripalimab in previously untreated patients with recurrent or metastatic NPC who were either ineligible for cisplatin or had experienced severe adverse events from prior cisplatin-based treatments. Patients received gemcitabine (1,000mg/m2) and toripalimab (240mg) every three weeks for six cycles, followed by toripalimab monotherapy for up to two years. The primary endpoint was the incidence of grade ≥3 adverse events, while secondary endpoints included objective response rate (ORR) and overall survival (OS). Of 30 screened patients, 21 were enrolled. No treatment-related fatalities occurred, with the most frequent adverse events being headache and nausea. The ORR was 61.9%, coupled with a disease control rate of 100%. Overall, gemcitabine plus toripalimab demonstrated low toxicity and promising efficacy for this specific patient cohort.

Safety and Efficacy of Rechallenge With Immune Checkpoint Inhibitors in Advanced Solid Tumor: A Systematic Review and Meta-Analysis.

Immune checkpoint inhibitors (ICIs) have drastically shifted the current landscape toward a wide variety of malignancies. However, ICIs are interrupted owing immune-related adverse events (irAEs), therapy completion, and disease progression. The risk-benefit of rechallenged ICIs remains inconclusive. Herein, a systematic review and meta-analysis were conducted to evaluate the safety and efficacy of ICI rechallenge in the treatment of advanced solid tumor. PubMed, Web of Science, Embase, and Cochrane Library were searched to analyze the efficacy and safety of ICI rechallenge. The study protocol was approved by the PROSPERO International Register of Systematic Reviews (CRD42022372222). The last updated search date was March 2, 2024. Objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence rates of all- and high-grade irAEs were evaluated. A total of 41 retrospective studies comprising 2343 patients were ultimately enrolled for qualitative and quantitative assessments. A total of 1200 (51.2%) individuals were male and the median age was 66 years (range 18-97 years). The majority of the tumors was lung cancer (n = 898, 38.3%). The occurrence rates of all-grade and high-grade (grade 3 or 4) irAEs between initial and readministration ICIs were not significantly different (all-grade: OR, 0.75, 95% CI: 0.39-1.45, p = 0.40; I2 = 87%; high-grade: OR, 0.96, 95% CI: 0.62-1.49, p = 0.87, I2 = 65%). ICIs restart presented a decreased ORR and DCR compared to initial ICI administration (ORR: OR, 0.36, 95% CI: 0.23-0.56, p < 0.00001; I2 = 67%; DCR: OR, 0.62, 95% CI: 0.43-0.89, p = 0.010; I2 = 53%). Seven studies with 513 patients for survival analysis revealed a nonsignificant difference in OS between the ICIs rechallenge and discontinuation cohorts (hazard ratio [HR]: 0.68, 95% confidence interval (CI): 0.35 to 1.35, p = 0.27). Rechallenging immunotherapy is feasible, and patients should be carefully evaluated by a multidisciplinary team prior to initial therapy for close monitoring and assessment of the risk-benefit ratio. Therefore, prospective trials are essential to guide clinicians in the decision-making process. PROSPERO Registration: CRD42022372222.

The Innate Immune Landscape of dMMR/MSI Cancers Predicts the Outcome of Nivolumab Treatment: Results from the Drug Rediscovery Protocol.

The treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid mismatch repair deficiency/microsatellite-instable (dMMR/MSI) tumors, and in-depth biomarker analyses were performed to inform precision immunotherapy approaches. Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Rediscovery Protocol, a pan-cancer clinical trial that treats patients with cancer based on their tumor molecular profile with off-label anticancer drugs (NCT02925234). Patients received nivolumab (four cycles of 240 mg every 2 weeks, thereafter 480 mg every 4 weeks). The primary endpoint was clinical benefit (CB: objective response or stable disease ≥16 weeks). Whole-genome sequencing and RNA sequencing were performed on pretreatment tumor biopsies. A total of 130 evaluable patients were enrolled with 16 different cancer types. CB was observed in 62% [95% confidence interval (CI), 53-70], with an objective response in 45% (95% CI, 36-54). After a median follow-up of 14.5 months (95% CI, 13-19), the median progression-free survival was 18 months (95% CI, 9-not reached), and the median overall survival was not reached. Whereas CB was not, or only weakly, associated with markers of adaptive immune cell infiltration, CB was strongly associated with expression of a broad set of innate immune receptors/ligands. This clearly contrasted findings in melanoma, in which markers of adaptive immunity dominated the biomarker landscape. Nivolumab proved highly effective in advanced dMMR/MSI tumors. Expression of key innate immune receptors/ligands was the main predictor of a good treatment outcome, contrasting findings in melanoma and strengthening the rationale for tumor type-specific biomarkers for guiding immunotherapy.

Randomized Phase II Trial of Amrubicin Plus Irinotecan Versus Cisplatin Plus Irinotecan in Chemo-naïve Patients With Extensive-Disease Small-Cell Lung Cancer: Results of the Japan Multinational Trial Organization (JMTO) LC 08-01

BackgroundWe conducted a randomize phase II study to evaluate the efficacy and safety of topoisomerase II inhibitor amrubicin plus topoisomerase I inhibitor irinotecan (AI) compared with cisplatin plus irinotecan (PI) as first-line therapy in patients with extensive-disease (ED) small-cell lung cancer (SCLC). Patients and MethodsChemo-naïve patients with pathologically proven ED-SCLC (including limited disease (LD) SCLC with malignant effusion) were enrolled. Patients were randomized 1:1 to receive either AI (amrubicin 90mg/m2 on day 1 and irinotecan 50mg/m2 on days 1 and 8 of a 21-day cycle) or PI (cisplatin 60mg/m2 on day 1 and irinotecan 60mg/m2 on days 1, 8 and 15 of a 28-day cycle). The primary endpoint was overall survival proportion at 1 year. ResultsA total of 100 patients were randomly assigned to AI (n = 50) or to PI (n = 50). The 1-year overall survival proportions were 68.0% (95% confidence interval (CI): 56.2-82.2%) for AI and 59.2% (46.9-74.7%) for PI (1-sided P = .18). Median survival time was 14.8 months for AI and 13.5 months for PI with a hazard ratio (HR) of 0.618 (0.398-0.961, stratified log-rank test P = .031). Median progression-free survival time was 4.8 months for AI and 5.4 months for PI (stratified log-rank test, P = .54). Objective response rate was 70.0% (55.4-82.1%) for AI and 55.1% (40.2-69.3%) for PI (Fisher exact test, P = .15). There was no significant difference in hematological toxicity, whereas rates of vomiting, loss of appetite, diarrhea, and elevated serum creatinine are more frequent in PI. Interstitial lung disease (Grade 2 or 3) developed in 5 patients in AI and in 1 patient in PI. There was no treatment-related death. ConclusionAlthough the study did not meet its primary endpoint, AI showed promising efficacy and good tolerability in chemo-naïve patients with ED-SCLC.

Bi-weekly irinotecan is an effective and convenient regimen in the treatment of relapsed or refractory small cell lung cancer

BackgroundDespite initial dramatic responses, metastatic small cell lung cancer (SCLC) invariably recurs. Irinotecan is one of the active agents for patients with recurrent SCLC. In the second line, weekly or three-weekly irinotecan regimens have been adopted, however, the optimal dose and schedule is not defined. In our institution, we use a bi-weekly regimen of irinotecan. In this study, we aimed to investigate the safety and efficacy of the bi-weekly irinotecan in the second- or third-line treatment of SCLC patients.MethodsThe study population consisted of advanced stage SCLC patients who were followed at Hacettepe University Cancer Institute between January 2007 and March 2021 and received salvage irinotecan 180 mg/m2 every two weeks, following progression after platinum-etoposide treatment.ResultsOne hundred patients were included. At diagnosis, nineteen patients (19%) had limited stage and 81 patients (81%) had extensive stage SCLC. Objective response rates (ORR) were 44.6% and 46.2% for patients who received irinotecan treatment in second line, and in third line, respectively. Seventeen percent of all the patients had grade 3 and above adverse events during irinotecan treatment. In our study, 45.8% of patients were able to complete at least 6 cycles of irinotecan treatment and 69.8% were able to receive at least 3 cycles of irinotecan treatment without any dose interruption or reduction.ConclusionsIrinotecan 180 mg/m2 every two weeks appears to be safe and effective in the 2nd- and 3rd-line treatment of advanced stage SCLC. Bi-weekly administration allows G-CSF prophylaxis in between doses, leading to an uninterrupted administration.

Real-World Clinical Outcomes With Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG) is approved for the treatment of metastatic triple-negative breast cancer (mTNBC). We report the real-world clinical effectiveness and toxicity data of SG in patients with mTNBC. A multi-institution retrospective study of patients with mTNBC treated with SG from January 2021 to May 2023 was conducted. Demographic and clinicopathologic variables were collected. Univariate and multivariate Cox regression models were used for survival analysis. A total of 115 patients were included. The median age at SG initiation was 60 years (range, 31-85). All patients were female; 73 (63.5%) were White and 31 (27.0%) were Black. The median number of previous therapies in the metastatic setting was two (range, 0-8). Sixty-one (56.0%) patients had primary refractory disease. Median relative dose intensity was 92% (range, 33%-100%). Grade 3 or higher adverse events (AEs) were seen in 50.9% of patients, which included neutropenia (35.7%), anemia (27.0%), vomiting (16.5%), fatigue (8.7%), and diarrhea (7.0%). Dose reductions and treatment discontinuation due to AEs were required in 51.3% and 13.2%, respectively. The objective response rate (ORR) was 27.8%. Median overall survival was 9.6 months (95% CI, 7.8 to 12.9) and median progression-free survival (PFS) was 4.8 months (95% CI, 3.6 to 5.9). In patients with human epidermal growth factor receptor 2 (HER2)-low mTNBC who received trastuzumab deruxtecan (T-DXd) after SG, the ORR to T-DXd was 34.8% and median PFS was 7 months (95% CI, 4.6 to 10.1). In a real-world cohort of heavily pretreated patients with mTNBC, SG retains its clinical activity. In a subgroup with HER2-low disease, T-DXd continues to demonstrate promising clinical activity after SG, supporting the use of sequential antibody-drug conjugates in this population.

Pembrolizumab in combination with lenvatinib in participants with hepatocellular carcinoma (HCC) before liver transplant as neoadjuvant therapY-PLENTY pilot study.

The high recurrent rate after liver transplantation (LT) remains a clinical challenge, especially for those exceeding the Milan criteria (MC) and with high RETREAT scores. Therefore, the authors aim to investigate whether neoadjuvant systemic therapy allows safely administered and effectively reduces post-LT recurrence for those patients. In this prospective, randomized, open-label, pilot study, patients with HCC exceeding the MC were randomly assigned to PLENTY or control group before LT. The primary endpoint of the study was the recurrence-free survival after LT. Twenty-two patients were enrolled and randomly assigned: 11 to the PLENYT group and 11 to the control group. The 30-month tumor-specific RFS was 37.5% in the PLENTY group and 12.5% in the control group. The 12-month tumor-specific RFS after LT was significantly improved in the PLENTY group (87.5%) compared to the control group (37.5%) (P=0·0022). The objective response rate in the PLENTY group was 30 and 60% when determined by RECIST 1.1 and mRECIST, respectively. Six patients (60%) had significant tumor necrosis, including three (30%) who had complete tumor necrosis at histopathology. No acute allograft rejection after LT occurred in the PLENTY and Control group. Neoadjuvant pembrolizumab plus lenvatinib before LT appears to be safe and feasible, associated with significantly better RFS for patients exceeding the MC. Despite the limitations of small sample size, this is the first RCT to evaluate neoadjuvant PD-1 blockade combined with tyrosine kinase inhibitors in LT recipients, the results of this study will inform future research.

Systemic therapy in the management of metastatic or locally recurrent adenoid cystic carcinoma of the salivary glands: a systematic review of the last decade.

Recurrent/metastatic adenoid cystic carcinoma (R/M AdCC) presents a clinical challenge with limited treatment options, particularly in the face of unsatisfactory efficacy from current therapeutic approaches. This review underscores the unmet clinical needs in managing R/M AdCC, emphasising the imperative for novel therapeutic strategies to address this critical gap. The primary objective of this review is to comprehensively analyse and assess trials investigating therapeutic approaches for R/M AdCC. Emphasis is placed on endpoints such as tumour response rates and progression-free survival. The specific interventions, populations, and outcomes examined in these trials will be detailed to provide a focused and informative systematic review. The systematic search spanned databases, including PubMed, EMBASE, and the Cochrane database of systematic reviews. Employing terms like "Carcinoma, Adenoid Cystic" and "trial," the search focused on English full-text articles from April 1, 2010, to August 9, 2023. Inclusion criteria encompassed studies with patients having R/M AdCC, involving drug interventions. Study quality was assessed using the Newcastle-Ottawa Scale for retrospective studies, Cochrane ROBINS-I tool for non-randomised trials, and the ROB-2 tool for randomised controlled trials. A total of 46 trials involving 1244 patients are included in this review, encompassing a variety of therapeutic approaches for R/M AdCC. Targeted therapies, particularly Apatinib at 500 mg, exhibit efficacy with a 47.1% objective response rate (ORR). Conversely, immunotherapeutic agents demonstrate suboptimal performance, with an overall ORR ranging from 0 to 18%. While Apatinib shows promise, the review underscores the imperative for a thorough exploration of drugs targeting unique mechanisms in the immunologically cold nature of R/M AdCC. Substantial progress in systemic therapy for R/M AdCC is evident, driven by early-phase clinical trials, particularly with promising outcomes in VEGF-2 inhibitors. However, challenges persist, notably in immunotherapy due to the cancer's immunologically cold nature. Ongoing research, prioritising early-stage trials, is crucial, emphasising exploration of emerging therapies like cell therapy and antibody-drug conjugates. Transitioning to Phase III trials is essential for more precise therapeutic insights. Collaborative efforts and a focus on personalised precision medicine are vital for overcoming challenges and advancing our understanding of treatment efficacy in this rare cancer.

Treatment strategies with electrochemotherapy for limb in-transit melanoma: Real-world outcomes from a European, retrospective, cohort study

BackgroundThis study analysed treatment strategies with electrochemotherapy (ECT) in melanoma with limb in-transit metastases (ITM). MethodsWe audited AJCC v.8 stage IIIB-IIID patients treated across 22 centres (2006–2020) within the International Network for Sharing Practices of ECT (InspECT). Results452 patients were included, 58 % pre-treated (93 % had lower limb ITM, 44 % had ≤10 metastases [median size 1.5 cm]. Treatment strategies included first-line ECT (n = 145, 32 %), ECT with concurrent locoregional/systemic treatment (n = 163, 36 %), and salvage ECT (n = 144, 32 %). The objective response rate was 63 % (complete response [CR], 24 %), increasing to 74 % (CR, 39 %) following retreatment (median two ECT, range 1–8). CR rate in treatment-naïve and pre-treated patients was 50 % vs 32 % (p < 0.001). Bleomycin de-escalation was associated with lower CR (p = 0.004). Small tumour number and size, hexagonal electrode, retreatment, and post-ECT skin ulceration predicted response in multivariable analysis. At a median follow-up of 61 months, local and locoregional recurrence occurred in 55 % and 81 % of patients. Median local progression-free, new lesions-free, and regional recurrence-free survival were 32.9, 6.9, and 7.7 months. Grade-3 toxicity was 15 %. Concurrent treatment and CR correlated with improved regional control and survival. Concomitant checkpoint inhibition did not impact toxicity or survival outcomes. The median overall survival was 5.7 years. ConclusionsAmong patients with low-burden limb-only ITM, standard-dose bleomycin ECT results in durable local response. Treatment naivety, low tumour volume, hexagonal electrode application, retreatment, and post-ECT ulceration predict response. CR and concurrent treatment correlate with improved regional control and survival outcomes. Combination with checkpoint inhibitors is safe but lacks conclusive support.

Real-World Outcomes of Pralsetinib in RET Fusion-Positive NSCLC

IntroductionPralsetinib is a RET inhibitor found to have antitumor activity in advanced, metastatic, RET fusion-positive NSCLC. ObjectiveTo assess real-world efficacy of pralsetinib and treatment sequences in patients with RET fusion-positive NSCLC. DesignRetrospective study of consecutive patients enrolled in the French expanded-access program for pralsetinib from December 1, 2019, to December 31, 2021. ParticipantsA total of 41 patients with advanced, refractory, RET fusion-positive NSCLC were included. Pralsetinib was administered at a daily dose of 400 mg based on safety and pharmacokinetic outcomes from previous phase 1/2 study. ResultsPralsetinib was administered as second line in 23 patients (56%) and as third line and beyond in 15 patients (37%). After a median follow-up of 26.3 months, pralsetinib was ongoing in 13 patients. Median real-world progression-free survival was 11.8 (95% confidence interval [CI]: 9.3–15.5) months. Objective response rate was 68% (95% CI: 50%–82%), and disease control rate was 89% (95% CI: 75%–97%). Subsequent line of systemic therapy was initiated in 11 patients. Median overall survival from pralsetinib initiation was 23.8 (95% CI: 16.5–not reached) months. ConclusionIn this extensive real-world cohort of patients with advanced or metastatic NSCLC harboring RET fusions, we highlight the antitumor efficacy of pralsetinib, particularly when administered in later treatment lines. We also observe the aggressive nature of disease progression, frequent utilization of chemotherapy and antiangiogenic agents as initial subsequent therapies, and limited insight into resistance mechanisms due to infrequent rebiopsy and genomic profiling at progression.

Real-World Outcomes of Patients With Malignant Pleural Mesothelioma Receiving a Combination of Ipilimumab and Nivolumab as First- or Later-Line Treatment

ObjectivesOn the basis of the positive results of CheckMate-743, first-line (1L) treatment of malignant pleural mesothelioma (MPM) with the combination of ipilimumab and nivolumab (ipi/nivo) has become a standard-of-care. Furthermore, patients who received 1L platinum/pemetrexed chemotherapy are often considered for second or further-line (2L+) ipi/nivo on the basis of MAPS2 results. Here we report on real-world survival and safety outcomes of ipi/nivo for patients with MPM in Switzerland. MethodsTwelve cancer centers contributed data to this retrospective cohort. Baseline characteristics including age, sex, histology, programmed death-ligand 1 expression, Eastern Cooperative Oncology Group performance status (ECOG PS), and previous/subsequent therapies were collected. The efficacy and safety outcomes were assessed by local investigators. ResultsOf the 109 patients with MPM treated with ipi/nivo between November 2017 and March 2023 (median follow-up of 16.6 months) 75% had epithelioid, 9% biphasic, and 16% sarcomatoid histology. The median age was 72 years; 91% were males, and 83% had an ECOG PS of 0 to 1. Ipilimumab in combination with nivolumab was given as 1L in 43% and as 2L+ treatment in 57% of patients. The objective response rate was 21% in 1L and 15% in 2L+. Median progression-free survival was 6.5 and 2.8 months, respectively. Median overall survival (OS) from the start of ipi/nivo was 12.6 months for 1L and 6.9 months for 2L+. No differences in OS were observed depending on age and programmed death-ligand 1 expression. Nevertheless, the median OS was significantly worse in patients with an ECOG PS of 2 or higher than those with an ECOG PS of 0 to 1 (2.4 versus 11.9 months, p < 0.001). Treatment-related adverse events (TRAEs) of any grade related to ipi/nivo treatment occurred in 65 patients (62%). The highest-grade TRAE was 1 to 2 in 58% of these patients and 3 or higher in 42% Treatment discontinuation due to a TRAE occurred in 22% of patients. ConclusionIn this real-world cohort of patients with MPM treated with ipi/nivo survival outcomes were inferior to those reported in the CheckMate-743 and MAPS2 trials, whereas safety outcomes were similar.

Is atezolizumab plus bevacizumab as first-line therapy for unresectable hepatocellular carcinoma superior to lenvatinib? a systematic review and meta‑analysis.

This meta-analysis was dedicated to evaluating the effectiveness and safety of Atezolizumab plus Bevacizumab (Atez/Bev) and Lenvatinib (LEN) as first-line systematic therapy for unresectable hepatocellular carcinoma (u-HCC). The prospective protocol for this study was registered with the PROSPERO (Registration number: CRD42022356874). Literature searches were conducted in PubMed, EMBASE database Cochrane Library, and Web Science to determine all clinical controlled studies that reported Atez/Bev and LEN for treating u-HCC. We. evaluated as primary end-point overall survival (OS) and progression-free survival (PFS), as well as other outcomes such as tumor response and adverse events (AEs).Quality assessment and data extraction of studies were conducted independently by three reviewers. Mean difference (MD) and odds ratio (OR) with 95% confidence interval (CI) were calculated using a fixed-effects or random-effects model. The meta-analysis was performed with RevMan 5.3 software. 12 retrospective cohort studies (RCSs) involving a total of 4948 patients were finally included. The results showed that compared with LEN, Atez/Bev can improve the patient's PFS (HR = 0.80, 95% CI: 0.72 ~ 0.88; p < 0.0001) and reduce the rate of overall AEs (OR = 0.46 95% CI: 0.38 ~ 0.55, p < 0.00001) and grade ≥ 3 AEs (OR = 0.43; 95% CI: 0.36 ~ 0.51, p < 0.00001), while there is no difference between OS and treatment responses rate (objective response rate, disease control rate, complete response, partial response, progressive disease, and stable disease) between two groups. In addition, the subgroup analysis shows that Atez/Bev can promote the OS of patients with viral hepatitis. (HR = 0.79, 95% CI: 0.67 ~ 0.95; p = 0.01), while LEN has an advantage in improving OS in patients with Child-Pugh grade B liver function (HR = 1.98, 95% CI: 1.50 ~ 2.63; p < 0.00001). Current evidence shows that compared with LEN, Atez/Bev has more advantages in PFS and safety in treating u-HCC and can improve the OS of patients with viral. LEN has advantages in improving the OS of patients with grade B liver function. However, more multicenter randomized controlled experiments are needed in the future to verify our results.

A Randomised, Multicentre, Phase II Trial of Camrelizumab with or without Metastasis-directed Stereotactic Body Radiotherapy in Recurrent or Metastatic Nasopharyngeal Carcinoma

PurposeTo investigate the efficacy of metastasis-directed therapy (MDT) when added to camrelizumab (Cam) in patients with recurrent or metastatic nasopharyngeal carcinoma (R/M-NPC). MethodsWe conducted a randomised, controlled, multicentre, phase II trial in 3 centres from China (NCT04830267). Patients with R/M-NPC, without prior exposure to immunotherapy, who presented with ≥2 lesions, and at least 1 measurable lesion were randomised 1:1 to either Cam alone or Cam plus MDT (Cam+MDT). Patients randomised to the MDT group must have 1 lesion that is amendable to stereotactic body radiotherapy (SBRT) prescribed to 27Gy in 3 fractions every other day. Primary endpoint was objective response rate (ORR) of unirradiated lesions by RECIST v1.1. ResultsBetween April 2021 and August 2023, 39 patients were randomly assigned to receive either Cam (n=20) or Cam+MDT (n=19). 17/39 (43.6%) patients had oligometastatic disease (≤3 lesions); 18/39 (46.2%) had liver involvement; 3/39 (7.7%) had locoregional recurrent disease. ORR of unirradiated lesions did not differ between the treatment groups (26.3% [Cam+MDT] vs 30.0% [Cam], P=1.0). DCR of unirradiated lesions was 73.7% in the Cam+MDT group compared with 60.0% in the Cam group (P=0.571). After a median follow-up of 25.8 months, median progression-free survival was 9.3 (95% CI: 6.2-NR) months in the Cam+MDT group and 8.8 (95% CI: 3.3-NR) months in the Cam group (P=0.750). Exploratory analyses suggested a longer overall survival (OS) with Cam+MDT for patients with >3 lesions (HR 0.23 [95% CI: 0.07-0.77], P=0.009). G3 and above adverse events were comparable between the treatment groups (15.8% [Cam+MDT] vs 20.0% [Cam]). Overall rate of capillary proliferation was 17.9% (7/39) on the trial. ConclusionsOur study did not meet its primary endpoint of superior ORR of unirradiated lesions with the addition of MDT to Cam in patients with R/M-NPC.

CRYO-VATE: A Pilot Study of Lung Cancer Cryoactivation in Combination With Immunotherapy in Advanced NSCLC

IntroductionNSCLC is the leading cause of cancer-related mortality. Although immune-checkpoint inhibitors (ICIs) have improved survival in patients with advanced NSCLC, treatment resistance remains a challenge. Cryoactivation, a technique inducing cell death by cycles of freezing/thawing, has the potential to augment tumor responses when combined with ICIs. MethodsThis single-arm phase 1 clinical trial enrolled patients with previously untreated advanced NSCLC and 50% or higher programmed cell death ligand 1. Patients underwent cryoactivation followed by ICI monotherapy initiated 5 days later. The primary end point was the objective response rate. Co-secondary end points included the safety and feasibility of the procedure and overall survival. Immune cell infiltration by immunohistochemistry was performed on paired pre- and post-treatment samples, with patients dichotomized according to clinical benefit (CB) rate (CB versus no CB [NCB]). ResultsEight patients were enrolled. Two patients achieved a partial response, yielding an objective response rate of 25%. Median progression-free survival and overall survival were 3.8 and 13.0 months, respectively. The cryoactivation procedure was well tolerated, without grade 3 to 4 adverse events. Post-hoc analysis reported a CB rate of 50%. Immunohistochemistry analysis reported a numerical difference in the cluster of differentiation 8–positive (CD8+) T cell infiltration in CB versus NCB in the pre- and post-treatment biopsies (p = 0.09) and an increase in CD8+ T cells in the post-treatment biopsies of CB versus NCB (p = 0.03). ConclusionsAlthough cryoactivation combined with pembrolizumab was safe and well tolerated in patients with NSCLC, therapeutic benefits were not evident compared with historical cohorts of ICI monotherapy. Correlative analyses validated CD8+ T cell recruitment in patients deriving CB.