Progression-free Survival Benefit Research Articles

TMOD-33. DOES PRE-CLINICAL DRUG ACTIVITY PREDICT PHASE II CLINICAL EFFICACY IN GLIOBLASTOMA? A DETAILED ANALYSIS

Abstract Despite decades of research, there are fewer than six FDA-approved therapies for glioblastoma (GBM). The drug approval process relies on studies establishing pre-clinical activity, most commonly using murine models, followed by in human studies establishing safety and then efficacy. Although murine models for GBM have allowed for insights into tumor biology, their utility in assessing the efficacy of novel anti-cancer therapies remains highly debated. Here, we sought to establish whether there was any relationship between drug activity in preclinical models and phase 2 clinical trial outcomes. Using ClinicalTrials.gov (NIH), all phase 2 trials in glioblastoma up to December 2023 were queried and downloaded. Trials that were never started, had not yet started, were withdrawn, not completed, or contained indications beyond glioblastoma were excluded. Studies examining anti-tumor effects of an investigational agent with or without bevacizumab, temozolomide, or radiation therapy in glioblastoma were included, and studies examining alternative dosing strategies, various medical devices, or drug combinations, were excluded. The corresponding preclinical studies were identified via literature review for each clinical trial. Data including the progression free and overall survival benefit, mouse models used, and sample sizes were extracted from each study. 659 trials between 1994 and 2023 were included for analysis. Of these, 272 (41%) were for monotherapies, examining 90 unique small molecules. Preclinical endpoints included murine survival and tumor weight. In comparing mouse survival and tumor size to progression free and overall survival in humans, our preliminary analysis did not reveal any clear correlation. The correlation between preclinical and clinical drug response in GBM remains uncertain. Future work will examine whether mouse genotype, immune status, or GBM cell line used affected the degree of concordance with human clinical trial data. Our analysis suggests that further investigation into preclinical models of GBM, and standardized reporting of preclinical models, are needed.

RADT-44. EARLY CLINICAL EXPERIENCE WITH PROTON CRANIOSPINAL IRRADIATION FOR THE TREATMENT OF LEPTOMENINGEAL DISEASE

Abstract BACKGROUND Leptomeningeal disease (LMD) is a uniformly terminal event of advanced cancer with limited therapeutic options, with survival ranging from weeks to a few months. Recently, proton craniospinal irradiation (pCSI) has been demonstrated to confer a progression-free and overall survival benefit in select patients with LMD as compared to more limited site radiotherapy. Early results from an institutional experience of pCSI for patients with LMD from solid tumor malignancies are reviewed. METHODS All patients with LMD and treated with pCSI at our institution were reviewed, specifically with regards to baseline patient characteristics, radiation dosimetry parameters and clinical outcomes. RESULTS Between February 2023-April 2024, nine patients were treated with pCSI for a range of primary tumor histologies, including two with triple-negative breast cancer and one each with ER+/PR+/HER2- breast cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, esophageal cancer, pancreatic cancer and ovarian cancer. All patients received 30Gy(RBE) in 10 fractions to the craniospinal axis, with one patient receiving an intracranial boost (6Gy(RBE)). Median age and performance status was 58 years and KPS 80, respectively. Five (56%) patients underwent CSF diversion prior to pCSI, 22% of patients had undergone prior CNS-directed radiotherapy, and all patients received at least one line of systemic therapy in the metastatic setting prior to pCSI. Median survival from the first day of pCSI was 4.3 months (range 1.3-10.7mo). Median survival among patients undergoing CSF diversion prior to pCSI (n=5) was 5.3 months (vs. 2.9mo with no CSF diversion). Median survival among patients who received systemic treatment after pCSI (n=5) was 9.1 months (vs. 2.9mo for patients who did not). CONCLUSIONS Careful patient selection is imperative to identify those who will best benefit from pCSI with suggestion of patients undergoing pre-pCSI CSF diversion and receiving post-pCSI systemic therapy achieving superior survival.

CTNI-47. A PHASE 1, RANDOMIZED, PERIOPERATIVE TRIAL OF VORASIDENIB AND IVOSIDENIB IN IDH1-MUTANT DIFFUSE GLIOMA: UPDATED RESULTS

Abstract BACKGROUND Vorasidenib (VOR) and ivosidenib (IVO) showed clinical activity in subjects with isocitrate dehydrogenase mutant (mIDH) gliomas. We evaluated both agents in a phase 1, randomized, open-label perioperative trial (NCT03343197). Pharmacodynamics, pharmacokinetics, and preliminary objective response rate (ORR) data as of 29-April-2020 were previously reported (Mellinghoff et al. Nat Med. 2023). Progression-free survival (PFS) data were not mature at publication time. We report here longer-term follow-up results, including mature PFS. METHODS Participants with grade 2/3 non-enhancing mIDH1 R132H mutant gliomas were randomized to VOR (50 or 10 mg QD), IVO (500 or 250 mg BID), or no treatment (control) for 4 weeks prior to planned surgery, with the option to continue treatment with VOR or IVO post-surgery. Secondary objectives included PFS, ORR assessed by Investigator in the post-surgery period, and safety profile of VOR and IVO. RESULTS Enrollment completed in April-2019. 49 participants were randomized, of which 46 participants (24 oligodendroglioma, 20 astrocytoma, 1 anaplastic oligodendroglioma, 1 anaplastic oligoastrocytoma) received treatment with either VOR (N=24) or IVO (N=22) after surgery. As of 23-September-2023 data cutoff, 11 (46%) and 5 (20%) participants remain on treatment for VOR and IVO, respectively. Median (range) post-operative treatment duration was 44.7 months (0.9–62.7) for VOR, 23.9 months (0–62.7) for IVO. Median (95% CI) PFS was 41.4 months (9.3, NE) for VOR and 38.6 months (18.3, NE) for IVO. ORR per Response Assessment in Neuro-Oncology in low-grade gliomas (RANO-LGG) was 46% for VOR and 27% for IVO. Longer safety follow up will also be presented. CONCLUSION These results provide further evidence of prolonged response using IVO and VOR immediately following surgery in predominantly non-enhancing gliomas. This longer-term follow-up is consistent with Phase 3 INDIGO study results where VOR demonstrated PFS benefit with manageable safety compared with placebo in participants with non-enhancing mIDH gliomas.

Soluble and EV-bound CD27 act as antagonistic biomarkers in patients with solid tumors undergoing immunotherapy

BackgroundThe major breakthrough in cancer therapy with immune checkpoint inhibitors (ICIs) has highlighted the important role of immune checkpoints in antitumoral immunity. However, most patients do not achieve durable responses, making biomarker research in this setting essential. CD27 is a well known costimulatory molecule, however the impact of its soluble form in ICI is poorly investigated. Therefore, we aimed at testing circulating concentrations of soluble CD27 (sCD27) and CD27 bound to extracellular vesicles (EVs) as potential biomarkers to predict response and overall survival (OS) in patients undergoing ICI.MethodsSerum and plasma levels of sCD27 were assessed by immunoassay in three patient cohorts (n = 187) with advanced solid malignancies including longitudinal samples (n = 126): a training (n = 84, 210 specimens, Aachen ICI) and validation cohort (n = 70, 70 specimens, Hamburg ICI), both treated with ICI therapy, and a second independent validation cohort (n = 33, 33 specimens, Hamburg non-ICI) undergoing systemic therapy without any ICI. In a subset (n = 36, 36 baseline and 108 longitudinal specimens), EV-bound CD27 from serum was measured, while EV characterization studies were conducted on a fourth cohort (n = 45).ResultsIn the Aachen and Hamburg ICI cohorts, patients with lower circulating sCD27 levels before and during ICI therapy had a significantly longer progression-free survival (PFS) and OS compared to patients with higher levels, a finding that was confirmed by multivariate analysis (MVA) (Aachen ICI: pPFS = 0.012, pOS = 0.001; Hamburg ICI: pPFS = 0.040, pOS = 0.004) and after randomly splitting both cohorts into training and validation. This phenomenon was not observed in the Hamburg non-ICI cohort, providing a rationale for the predictive biomarker role of sCD27 in immune checkpoint blockade. Remarkably, EV-bound CD27 baseline levels and dynamics during ICI therapy also emerged as potent predictive biomarkers, acting however antagonistically to soluble sCD27, i.e. higher levels were associated with PFS and OS benefit. Combining both molecules (“multi-CD27” score) enhanced the predictive ability (HRPFS: 17.21 with p < 0.001, HROS: 6.47 with p = 0.011).ConclusionSoluble and EV-bound CD27 appear to have opposing immunomodulatory functions and may represent easily measurable, non-invasive prognostic markers to predict response and survival in patients undergoing ICI therapy.

RCHOP plus BTK Inhibitor Improves Clinical Outcomes in Double Expressor Diffuse Large B-Cell Lymphoma, Unlike RCHOP plus Lenalidomide

BackgroundDouble-expressor diffuse large B-cell lymphoma (DE-DLBCL) has a poor prognosis, and optimal treatment strategies remain unclear. This study evaluates the efficacy and safety of RCHOP, R2-CHOP (RCHOP plus lenalidomide), and RCHOP plus Bruton's Tyrosine Kinase inhibitors (BTKi) in DE-DLBCL treatment. MethodsData from 213 DE-DLBCL patients treated from January 2019 and February 2024. Among them, 112 received R-CHOP, 65 received R2-CHOP, and 36 received R-CHOP plus BTKi. We evaluated clinical characteristics, overall response rate (ORR), complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) for each groups. ResultsBaseline characteristics were comparable across groups. ORRs were 95.5% for R-CHOP, 96.9% for R2-CHOP, and 97.2% for R-CHOP plus BTKi, with CR rates of 76.5%, 80%, and 75%, respectively. BTKi significantly improved PFS (p=0.033) but not affect OS (p=0.165). Lenalidomide showed no benefit in PFS (p=0.153) or OS (p=0.351). With median follow-up times of 20.6 months for R-CHOP, 23.5 months for R2-CHOP, and 17.6 months for R-CHOP plus BTKi, the 1-year PFS rates were 73.6%, 82.2%, and 93.3%, and the 1-year OS rates were 96.2%, 93.2%, and 100%, respectively. Grade 3-4 adverse events included leukopenia, neutropenia, and anemia, and thrombocytopenia, with no significant differences among groups. ConclusionThe addition of BTK inhibitor enhances progression-free survival in DE-DLBCL, especially in advanced-stage patients, without introducing new severe adverse reactions. In contract, adding lenalidomide dose not does not offer additional efficacy or survival benefits.

Camizestrant, a next-generation oral SERD, versus fulvestrant in post-menopausal women with oestrogen receptor-positive, HER2-negative advanced breast cancer (SERENA-2): a multi-dose, open-label, randomised, phase 2 trial

Resistance to endocrine therapies in hormone receptor-positive breast cancer is challenging. We aimed to assess the next-generation oral selective oestrogen receptor degrader (SERD) and complete oestrogen receptor antagonist, camizestrant, versus the first-approved SERD, fulvestrant, in post-menopausal women with oestrogen receptor-positive, HER2-negative, advanced breast cancer. SERENA-2 is an open-label, randomised, phase 2 trial that is being conducted at 74 study centres across Asia, Europe, the Middle East, and North America. Female patients aged 18 years or older who were post-menopausal with histologically or cytologically confirmed metastastic or locoregional oestrogen receptor-positive, HER2-negative breast cancer, an Eastern Cooperative Oncology Group or WHO performance status of 0 or 1, and disease recurrence or progression on at least one line of endocrine therapy, and no more than one previous endocrine therapy in the advanced setting. Patients were initially randomly assigned (1:1:1:1) to receive oral camizestrant once daily at 75 mg, 150 mg, or 300 mg (until the 300 mg group was closed), or fulvestrant intramuscularly at 500 mg (per label). Randomisation was managed through an interactive web-based system and stratified by previous treatment with CDK4/6 inhibitors and presence of liver and/or lung metastases. The primary objective was to determine clinical efficacy of camizestrant versus fulvestrant at each dose level using the primary endpoint of investigator-assessed progression-free survival, per Response Evaluation Criteria in Solid Tumours (version 1.1), assessed by intention to treat in all randomly assigned patients (full analysis set). No formal statistical comparison for the efficacy analysis of the camizestrant 300 mg dose versus fulvestrant was to be performed. Safety analyses included all randomly assigned patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04214288, and is ongoing. Between May 11, 2020, and Aug 10, 2021, 240 patients were randomly assigned to receive camizestrant 75 mg (n=74), 150 mg (n=73), 300 mg (n=20), or fulvestrant (n=73), and were included in the full analysis set. All patients received at least one dose of study drug. Median follow-up was 16·6 months (IQR 12·9-19·4) for the camizestrant 75 mg group, 16·3 months (12·9-18·3) for the camizestrant 150 mg group, and 14·7 months (12·7-20·1) for the fulvestrant 500 mg group. Median progression-free survival was 7·2 months (90% CI 3·7-10·9) with camizestrant 75 mg, 7·7 months (5·5-12·9) with camizestrant 150 mg, and 3·7 months (2·0-6·0) with fulvestrant. The hazard ratio for camizestrant 75 mg versus fulvestrant was 0·59 (90% CI 0·42-0·82; p=0·017), and the hazard ratio for camizestrant 150 mg versus fulvestrant was 0·64 (0·46-0·89; p=0·0090). Treatment-related adverse events occurred in 39 (53%) of 74 patients in the camizestrant 75 mg group, 49 (67%) of 73 patients in the camizestrant 150 mg group, 14 (70%) of 20 patients in the camizestrant 300 mg group, and 13 (18%) of 73 patients in the fulvestrant group. No single grade 3 or worse treatment-emergent adverse event occurred in more than two (3%) patients in any group. Serious treatment-emergent adverse events occurred in six (8%) patients in the camizestrant 75 mg group, seven (10%) patients in the camizestrant 150 mg group, two (10%) patients in the camizestrant 300 mg group, and four (5%) patients in the fulvestrant group. No treatment-related deaths occurred. Camizestrant at 75 and 150 mg showed a significant benefit in progression-free survival versus fulvestrant. These results support further development of camizestrant for the treatment of oestrogen receptor-positive, HER2-negative breast cancer. AstraZeneca.

Optimum radiation dose for palliation in head and neck squamous cell carcinoma (OpRAH) – A phase 3 randomized controlled trial

PurposeRadiotherapy is frequently employed for palliative treatment in locally advanced head and neck squamous cell carcinoma (HNSCC) but radiation dose fractionation regimens are not well-defined. We designed this phase 3 randomized controlled trial to compare two weekly hypo fractionated regimes and study the effect on progression-free survival (PFS) in this subset of patients. Materials and MethodsNon-metastatic locally advanced HNSCC patients (n = 305) who were not suitable for curative treatment were randomized to Arm A (20 Gy/5#/5 days) and Arm B (30 Gy/5#/5 days). PFS and OS were recorded along with acute toxicity using patient-reported quality of life HN QLQ 43. ResultsFrom April 2020 to August 2023, 390 patients were randomized, of which 305 were eligible for final analysis. At a median follow-up of 13.9 months, PFS and median overall survival (OS) for the entire cohort was 7.4 and 10.03 months, respectively. PFS (p-0.553) and OS (p-0.203) did not differ significantly between the two groups. Toxicity rates were similar between the two arms and dose escalation was well tolerated. Patients with a better PS were found to have significantly better OS. No significant benefit in OS or PFS was observed in patients who received neoadjuvant chemotherapy (NACT), underwent definitive conversion, or received palliative chemotherapy at progression. ConclusionThis is the largest phase 3 RCT to analyze the safety and efficacy of weekly palliative radiotherapy regimens and has not demonstrated further improvement with dose escalation

Beyond hazard ratios: appropriate statistical methods for quantifying the clinical effectiveness of immune-oncology therapies – the example of the Netherlands

BackgroundThe Dutch Committee for the Evaluation of Oncological Drugs evaluates the effectiveness of new oncological treatments. The committee compares survival endpoints to the so-called PASKWIL-2023 criteria for palliative treatments, which define if treatment effects are considered clinically relevant. A positive recommendation depends on whether the median overall survival (OS) is below or above 12 months in the comparator arm. If the former applies, an OS benefit of at least 12 weeks, and a hazard ratio (HR) smaller than 0.7 are required. If the latter applies, an OS or progression free survival (PFS) benefit of at least 16 weeks, and an HR smaller than 0.7 are required. Nonetheless, the median survival time may not be reached and the proportional hazards (PH) assumption, quantified by the HR, is likely violated for immuno-oncology (IO) therapies, deeming these criteria inappropriate.MethodsWe conducted a systematic literature review to identify statistical methods used to represent the clinical effectiveness of IO therapies based on trial data. We searched MEDLINE and EMBASE databases from inception to August 31, 2022, limited to English papers. Methodological studies, randomized controlled trials, and discussion papers recognising key issues of survival data analysis of IO therapies were eligible for inclusion.ResultsA total of 1,035 unique references were identified. After full paper screening, 17 publications were included in the review. Additionally, 43 papers were identified through ‘snowballing’. We conclude that the current PASKWIL-2023 criteria are methodologically incorrect under non-PH. In that case, single summary statistics fail to capture the treatment effect and any measure should be interpreted in combination with the Kaplan-Meier curves. We recommend ’parameter-free’ measures, such as the difference in restricted mean survival time, avoiding assumptions on the underlying survival.ConclusionsThe HR is commonly used to assess treatment effectiveness, without investigating the validity of the PH assumption. This happens with the application of the PASKWIL-2023 criteria for palliative oncology treatments, which can only be valid under a PH setting. Under non-PH, alternative treatment effect measures are suggested. We propose a step-by-step approach supporting the choice of the most appropriate methods to quantify treatment effectiveness that can be used to redefine the PASKWIL-2023 criteria, or similar criteria in other clinical areas.

Adding Metastasis-Directed Therapy to Standard-of-Care Systemic Therapy for Oligometastatic Breast Cancer (EXTEND): a Multicenter, Randomized Phase II Trial

PurposePrior evidence suggests a progression-free survival (PFS) benefit from adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy for patients with some oligometastatic solid tumors. Randomized trials testing this hypothesis in breast cancer have yet to be published. We sought to determine whether adding MDT to SOC systemic therapy improves PFS in oligometastatic breast cancer. MethodsEXTEND is a multicenter phase II randomized basket trial testing the addition of MDT to SOC systemic therapy in patients with ≤5 metastases (NCT03599765). Patients were randomized 1:1 to MDT (definitive local treatment to all sites of disease, plus SOC systemic therapy) or to SOC systemic therapy only. Primary endpoint was PFS, and secondary endpoints included overall survival (OS), time to subsequent line of systemic therapy, and time to the appearance of new metastases. Exploratory analyses included quality of life (QOL) and systemic immune response measures. ResultsFrom September 2018 through July 2022, 22 and 21 patients were randomized to the MDT and no-MDT arms, respectively. At a median follow-up of 24.8 months, PFS was not improved with the addition of MDT to SOC systemic therapy (median PFS 15.6 months MDT vs 24.9 months no-MDT [hazard ratio {HR} 0.91; 95% CI 0.34–2.48, p=0.86]). Similarly, MDT did not improve OS, time to subsequent line of systemic therapy, or time to the appearance of new metastases (all p>0.05). No significant differences were found in QOL measures, systemic T-cell activation, or T-cell stimulatory cytokine concentration. ConclusionAmong patients with oligometastatic breast cancer, the addition of MDT to SOC systemic therapy did not improve PFS. These findings suggest that MDT may have no systemic benefit in otherwise unselected oligometastatic breast cancer patients, although this trial was limited by a heterogenous and small sample size and overperformance of both treatment arms.

Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP).

Human epidermal growth factor receptor 2 (HER2)-targeted therapy is standard of care for HER2-positive (HER2+) breast cancer, but most patients develop progressive disease with persistent HER2 expression. No definitive treatment guidance currently exists beyond second line. Trastuzumab duocarmazine (T-Duo) is a third-generation, HER2-targeted antibody-drug conjugate that demonstrated efficacy and acceptable safety in phase I studies of heavily pretreated patients with HER2+/HER2-low breast cancer. In this open-label, randomized, phase III trial, T-Duo was compared with physician's choice (PC) in patients with unresectable locally advanced/metastatic HER2+ breast cancer with progression during/after ≥2 HER2-targeted therapies or after trastuzumab emtansine (T-DM1). The primary endpoint was progression-free survival (PFS) by blinded independent central review. In total, 437 patients were randomly assigned 2:1 to T-Duo (n = 291) or PC (n = 146). The median age was 56.0 years (range, 24-86); most patients (93.6%) had metastatic disease. The median time from diagnosis of metastatic disease to trial entry was 3.5 years; the median number of prior HER2-targeted therapies in metastatic setting was three. The median PFS was 7.0 months (95% CI, 5.4 to 7.2) with T-Duo versus 4.9 months (95% CI, 4.0 to 5.5; hazard ratio [HR], 0.64 [95% CI, 0.49 to 0.84]; P = .002) with PC. PFS benefit was maintained across most predefined subgroups. The median overall survival (first analysis) was 20.4 (T-Duo) versus 16.3 months (PC; HR, 0.83 [95% CI, 0.62 to 1.09]; P = .153). Objective response rate was 27.8% (T-Duo) versus 29.5% (PC); other efficacy end points-clinical benefit rate, duration of response, and reduction in target lesion measurement-tended to favor T-Duo. Grade ≥3 treatment-emergent adverse events occurred in 52.8% (T-Duo) versus 48.2% (PC). Treatment with T-Duo was manageable, but tolerability was affected by prevalent ocular toxicity, leading to a higher discontinuation rate in the T-Duo arm. T-Duo significantly reduced the risk of progression in patients with advanced HER2+ breast cancer who have progressed during/after ≥2 HER2-targeted therapies or after T-DM1.

The efficacy of Veliparib in combination with chemotherapy in the treatment of lung cancer: systematic review and meta-analysis.

This meta-analysis aims to examine the effectiveness of veliparib, a poly ADP-ribose polymerase inhibitor, in combination with chemotherapy in treating bronchogenic carcinoma. PubMed, Cochrane, Scopus, and Web of Science were searched for eligible randomized controlled trials comparing veliparib plus chemotherapy to standard chemotherapy in adult lung cancer patients, until July 2023. The main outcomes were overall survival (OS) and progression-free survival (PFS). This meta-analysis included six studies encompassing 2,136 patients. Veliparib has a slight OS improvement over placebo, HR = 0.91, 95% CI [0.83 to 1.0], p = 0.05. Veliparib offers more OS benefit in the subpopulation of non-small cell lung cancer (NSCLC) than small-cell lung cancer (SCLC), HR = 0.89, 95% CI [0.81,0.99], p = 0.03 and HR = 1.00, 95% CI [0.79, 1.28], p = 0.97, respectively. There was no significant PFS benefit between the two groups, HR = 0.92, 95% CI [0.81-1.01], p = 0.08). Veliparib has a marginal inclination for overall survival improvement, more so in NSCLC, with an acceptable safety profile. Our results merit the pursuit of better-powered trials to support further the extent of veliparib's effectiveness in lung cancer patients. PROSPERO (CRD42023453705).

The repeated treatment of targeted therapy in the treatment of skin melanoma

Currently, patients with disseminated forms of skin melanoma have limited treatment options. The most effective treatments, according to research, are targeted drugs BRAF/MEK inhibitors when a mutation in exon 15 of the BRAF gene is detected in tumor biopsy tissue and immune synapse modulators, specifically anti-CTLA-4 and anti-PD-1 drugs. Both classes of drugs show a significant benefit in overall and progression-free survival, but convincing data on their effectiveness in second and subsequent lines of therapy are still lacking. Most often, with the progression of disseminated skin melanoma during tyrosine kinase inhibitor therapy, a dual immunotherapy combination is used. In the event of further progression, due to the limited treatment options, clinical oncologists face questions about the possibility of returning to targeted therapy, changing tyrosine kinase inhibitor drugs, or using the initial combination, and their impact on progression-free survival in choosing treatment strategies for such patients, as well as the potential use of BRAF/MEK inhibitors. Assessing the reuse of tyrosine kinase inhibitor drugs is a highly relevant issue in clinical oncology.

FDA Approval Summary: Polatuzumab Vedotin in the First-Line Treatment of Select Large B-cell Lymphomas.

In April 2023, the U.S. Food and Drug Administration granted regular approval to polatuzumab vedotin-piiq in combination with a rituximab product, cyclophosphamide, doxorubicin, and prednisone (pola+R-CHP) for adult patients who have previously untreated diffuse large B-cell lymphoma, not otherwise specified or high-grade B-cell lymphoma and who have an International Prognostic Index score of 2 or greater. Approval was based on POLARIX, a randomized, double-blinded, placebo-controlled trial evaluating the superiority of substituting vincristine with polatuzumab vedotin in the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen as first-line therapy for patients with large B-cell lymphoma (LBCL). Efficacy was based on investigator-assessed progression-free survival (PFS) in 879 patients who were randomized to receive pola+R-CHP or R-CHOP, followed by two cycles of rituximab alone. PFS was statistically significantly longer with pola+R-CHP with a HR of 0.73 [95% CI: 0.57, 0.95] and log-rank p-value of 0.0177 (two-sided α=0.05). There was no improvement demonstrated in the key secondary endpoints of CR rate at the end of therapy or overall survival (OS). Several issues raised uncertainty about the benefit-risk of polatuzumab vedotin in this curative-intent setting including the modest PFS benefit of pola+R-CHP and lack of OS benefit. The application was therefore presented at an Oncology Drug Advisory Committee. This article summarizes key aspects of the regulatory review, including perspectives on PFS and OS results and other endpoints.

Efficacy and safety of immunotherapy combined with chemotherapy in patients with ES-SCLC: A systematic review and network meta-analysis of RCTs and RWSs.

To evaluate the efficacy and safety of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors in the treatment of extensive-stage small-cell lung cancer (ES-SCLC), we conducted a systematic review and meta-analysis that included randomized controlled trials (RCTs) and real-world studies (RWS). By scanning PubMed, Web of science, Embase, and other relevant clinical information public databases, nine RCTs and eight RWSs involving 5205 patients were included in the study. We directly compared the differences between chemotherapy and PD-1/PD-L1 inhibitors plus chemotherapy, and determined the optimal treatment strategy through network meta-analysis (NMA). Compared to chemotherapy, the addition of PD-1/PD-L1 inhibitors significantly improves the overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) in SCLC patients. Regarding safety, both RCTs and RWSs indicated no significant difference in grade 3-4 adverse events between chemotherapy and chemoimmunotherapy. NMA showed serplulimab plus chemotherapy (Serp_Chemo) appears to provide the best OS, PFS, and ORR benefit, while nivolumab plus chemotherapy shows higher toxicity than other regimens. In subgroup analysis, for elderly patients (age ≥65) and non-elderly (age <65) patients, the most promising quality regimens for achieving better OS extension are atezolizumab plus chemotherapy (Atez_Chemo) and Serp_Chemo, respectively. For patients with PD-L1 ≥ 1% and lactate dehydrogenase (LDH) > upper limit of normal (ULN), there is no apparent OS benefit from immune therapy. In ES-SCLC treatment, adding PD-1/PD-L1 inhibitors to standard chemotherapy improves OS, PFS, and ORR, with Serp_Chemo shows the most promise. Atez_Chemo and Serp_Chemo provided better survival for elderly and non-elderly patients, respectively.

Comparing the Efficacy and Safety of First-Line Treatments for Chronic Lymphocytic Leukemia: A Network Meta-Analysis.

The Chronic Lymphocytic Leukemia (CLL) treatment strategies have transitioned from chemotherapy and chemoimmunotherapy to chemo-free regimens. Frequentist network meta-analysis allows for both direct and indirect comparisons between different treatments. Randomized controlled trials assessing first-line treatments were included. Outcomes were progression-free survival (PFS), overall survival, undetectable minimal residual disease (MRD), objective response rate, and adverse events. Studies with comparable characteristics also underwent subgroup analysis, stratifying by age, comorbidities, IGHV status, and cytogenetic abnormalities. 30 eligible trials involved 12,818 patients and 30 treatments were included. Acalabrutinib demonstrated a PFS advantage over ibrutinib and obinutuzumab-venetoclax (OV) in patients over 65 years old or with unmutated IGHV. In younger patients with comorbidities, Acalabrutinib-Obinutuzumab (AO) had superior PFS compared to Ibrutinib-Obinutuzumab (IO), Ibrutinib-Venetoclax (IV), and OV. For older patients with comorbidities, Acalabrutinib and AO both outperformed OV without significant difference between them. MRD-guided IV surpassed OV in patients without comorbidities. IO exhibited extended PFS benefits compared to OV in patients with mutated IGHV or with del(17p) and/or TP53 mutations. IV and IO have lower neutropenia rates than OV. IV have fewer infections than Acalabrutinib and AO. AO causes less diarrhea than IV but more headaches than IO and OV. OV has lower hypertension rates than IO. IV has fewer arthralgia than AO. For any grade secondary primary neoplasms, IV and OV is less than AO. Tailored chemo-free regimens can be selected based on age, comorbidities, IGHV status, and cytogenetic abnormalities to optimize treatment outcomes while considering different response spectra.

Clinicopathological characteristics, treatment patterns and outcomes in patients with HER2-positive breast cancer based on hormone receptor status: a retrospective study

BackgroundDifferent hormone receptor (HR) expression patterns have significant biological and therapeutic implications in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, the distinction between HR-positive /HER2-positive (HR+/HER2+) and HR-negative/HER2-positive (HR-/HER2+) subtypes remains unclear.MethodsThis retrospective study analyzed 828 patients with HER2-positive breast cancer at the First Affiliated Hospital of Xi’an Jiaotong University from 2012 to 2022. Baseline characteristics were compared by chi-square test. Survival outcomes were estimated by Kaplan-Meier method.ResultsIn total, 56.3% (n = 466) had HR-positive and 43.7% (n = 362) had HR-negative disease. Comparatively, HR+/HER2 + breast cancers presented favorable clinicopathological features. At a median follow-up of 49 months, 199 disease-free survival (DFS) events and 99 deaths were observed. HR+/HER2 + patients had significantly better survival outcomes than HR-/HER2 + patients. HR-positive status was an independent protective factor for overall survival (OS) [P = 0.032; hazard ratio, 0.61; 95% confidence interval (CI), 0.39–0.96] and DFS (P = 0.001; hazard ratio, 0.61; 95% CI, 0.46–0.81). HR+/HER2 + patients were significantly less sensitive to neoadjuvant therapy than HR-/HER2 + patients. In the first-line treatment for HR+/HER2 + advanced breast cancer, receiving endocrine therapy significantly improved advanced-OS (P < 0.001; hazard ratio, 0.33; 95% CI, 0.18–0.59) and progression-free survival (PFS) (P < 0.001; hazard ratio, 0.38; 95% CI, 0.25–0.58) compared with not receiving endocrine therapy. Moreover, maintenance endocrine therapy after HER2-targeted therapy and chemotherapy is associated with significant advanced-OS and PFS benefits compared with no maintenance endocrine therapy (advanced-OS: P < 0.001; hazard ratio, 0.05; 95% CI, 0.03–0.12; PFS: P < 0.001; hazard ratio, 0.35; 95% CI, 0.21–0.57).ConclusionsThis study reveals the high heterogeneity of HER2-positive breast cancer related to HR status in clinicopathological features, metastasis patterns, and outcomes. Large randomized controlled trials are warranted to optimize treatment strategies for the HER2-positive breast cancer population.

A new proposal of simplified classification of non-small cell lung cancer oligometastases for easy applicability through systematic literature analysis and meta-analysis validation

IntroductionOligometastasis (OM) exhibits wide range of prognosis, which necessitates appropriate classification for optimal therapeutic decision-making. Complementing the ESTRO-EORTC classification which lacked prognostic differentiation and was rather complex, we propose a new and simpler classification based on systematic literature analysis and meta-analysis validation. MethodThe databases were searched up to April 2024. Inclusion criteria were (1) ≥ 10 Non-small cell lung cancer OM patients, (2) local ablative treatment (LAT) versus control (systemic/supportive treatment), (3) reporting progression free survival (PFS) or overall survival (OS), respectively. A simpler classification was proposed through systematic reviews evaluating outcomes based on OM characteristics. According to this new classification, the LAT benefit and pooled 2-year OS and 1-year PFS percentiles were validated through meta-analysis. ResultsIn overall meta-analysis, LAT was correlated with enhanced 1-year PFS (odds ratio (OR):3.487, p < 0.001) and 2-year OS (OR:2.984, p < 0.001), respectively. According to simplified classification, LAT benefit of 1-year PFS was differentiated with ORs of 5.631 (p < 0.001), 3.484 (p < 0.001), and 1.702 (p = 0.067) for Synchronous (Syn), OPS (Oligopersistence), and OPR (Oligoprogression/recurrence) subgroups, respectively. Inter-subgroup comparisons showed significant differences as well. For 2-year OS, ORs of LAT benefit were 3.366 (p < 0.001), 3.355 (p < 0.001), and 1.821 (p = 0.127) in Syn, OPS, and OPR subgroups, respectively; LAT benefit was significant in Syn and OPS, but not significant in OPR. In pooled percentile comparison, 1-year pooled PFS was significantly lower in the OPR group than others, both in the LAT and control arms. ConclusionBased on a systematic literature analysis and meta-analysis validation, we developed a simpler three-step OM classification: Syn, OPS, and OPR. We would propose this new classification that is simpler and more applicable to clinical decisions than the currently available classification.

Sustained benefit of zanubrutinib vs ibrutinib in patients with R/R CLL/SLL: final comparative analysis of ALPINE

AbstractThe ALPINE trial established the superiority of zanubrutinib over ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma; here, we present data from the final comparative analysis with extended follow-up. Overall, 652 patients received zanubrutinib (n = 327) or ibrutinib (n = 325). At an overall median follow-up of 42.5 months, progression-free survival benefit with zanubrutinib vs ibrutinib was sustained (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.54-0.84), including in patients with del(17p)/TP53 mutation (HR, 0.51; 95% CI, 0.33-0.78) and across multiple sensitivity analyses. Overall response rate remained higher with zanubrutinib compared with ibrutinib (85.6% vs 75.4%); responses deepened over time with complete response/complete response with incomplete bone marrow recovery rates of 11.6% (zanubrutinib) and 7.7% (ibrutinib). Although median overall survival has not been reached in either treatment group, fewer zanubrutinib patients have died than ibrutinib patients (HR, 0.77 [95% CI, 0.55-1.06]). With median exposure time of 41.2 and 37.8 months in zanubrutinib and ibrutinib arms, respectively, the most common nonhematologic adverse events included COVID-19–related infection (46.0% vs 33.3%), diarrhea (18.8% vs 25.6%), upper respiratory tract infection (29.3% vs 19.8%), and hypertension (27.2% vs 25.3%). Cardiac events were lower with zanubrutinib (25.9% vs 35.5%) despite similar rates of hypertension. Incidence of atrial fibrillation/flutter was lower with zanubrutinib vs ibrutinib (7.1% vs 17.0%); no cardiac deaths were reported with zanubrutinib vs 6 cardiac deaths with ibrutinib. This analysis, at 42.5 months median follow-up, demonstrates that zanubrutinib remains more efficacious than ibrutinib with an improved overall safety/tolerability profile. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.

Fulvestrant en la práctica clínica: análisis de efectividad en pacientes uruguayas con cáncer de mama HR+/HER2.

Fulvestrant demonstrated benefits in overall survival and progression-free survival in patients with advanced breast cancer, who are hormone receptor-positive and human epidermal growth factor receptor 2 negative. The characteristics, evolution, and survival of patients with hormone receptor-positive, HER2-negative breast cancer treated with fulvestrant were evaluated according to the national treatment coverage protocols of the National Resources Fund, with the aim of understanding the efficacy of fulvestrant in patients treated in usual clinical practice and comparing our results with those from pivotal studies. A database from the National Resources Fund covering the period from 2009 to 2022 was used. Survival curves were assessed using the Kaplan-Meier method, and differences were analyzed using the Log-Rank test. A total of 1085 patients with an average age of 63,66 years were included. Following a follow-up of 14 months, the median overall survival was 16 months, and the median progression-free survival was 6 months. The presence of liver and bone metastases was associated with a shorter overall survival. Patients from the public sector and those with a better performance status experienced longer overall survival. Our findings provide a valuable perspective for treatment management in a context of limited resources. Overall survival and progression-free survival were somewhat lower than those reported in pivotal clinical trials. The presence of liver and bone metastases was associated with worse prognosis and survival; additionally, patients with worse performance status had shorter overall survival. These findings underscore the need for personalized therapies, opening new lines of future research.

Doxycycline Plus Bortezomib-Containing Regimens for the Treatment of Light-Chain Amyloidosis in the Frontline Setting: Experience from the Amyloidosis Program of Calgary.

Background: Pre-clinical and retrospective data suggest that doxycycline added to treatment regimens has benefit in AL amyloidosis. However, a recent multicenter, open-label, randomized controlled trial in AL amyloidosis patients treated with CyBorD did not demonstrate a progression-free survival (PFS) or cardiac PFS benefit with added doxycycline. Objective: The main objective of this study was to explore the role of doxycycline combined with bortezomib-containing regimens (BCRs) for newly diagnosed AL amyloidosis patients with cardiac involvement and to compare them with a cohort of concurrent patients treated with BCR only. Material and Methods: AL amyloidosis patients, newly diagnosed between January 2012 and March 2022, who were treated with BCR at the Amyloidosis Program of Calgary (APC) were evaluated. Results: Sixty-four concurrent patients were identified. Thirty-nine patients received doxycycline in addition to BCR (BCR-D) for a median of 8 months. The overall response rate was similar among the groups. No significant differences in VGPR/CR, dFLC at 1 month, time to first response, time to best response, or organ responses were noted between the BCR alone and BCR-D groups. Summary and Conclusions: Our retrospective study demonstrated that doxycycline combined with BCR failed to prolong OS, PFS, or cardiac responses compared with BCR alone in patients with cardiac AL amyloidosis.