Overall Survival Data Research Articles

Evidence of clinical benefit of cancer medicines considered for funding in Australia.

To describe the type of evidence and the clinical benefit of cancer medicines assessed for funding in Australia by the Pharmaceutical Benefits Advisory Committee (PBAC) and to assess it with the European Society of Medical Oncology Magnitude of Clinical Benefit Scale version 1.1 (ESMO-MCBS). All data on applications submitted to PBAC between 2010 and 2020 were extracted from PBAC Public Summary Documents available online. ESMO-MCBS ratings were retrieved from the ESMO-MCBS website. Then, 182 cancer indications for 100 cancer medicines were examined by PBAC, including 124 (68.1 percent) for solid tumors and 58 (31.9 percent) for hematological cancers. A total of 137 (75.3 percent) indications were recommended for PBS funding and 40 (21.9 percent) were rejected. Randomized clinical trials (RCTs) were the main source of evidence in 154 indications (84.6 percent), single-arm studies in 28 (15.4 percent) indications. Statistically significant improvement in overall survival (OS) was reported in 80 (44 percent) of the indications, with a median OS gain of 3.0months (range 0.9-17.0) for solid tumors and 8.2months (range 1-49.1) for hematological cancers when mature OS data were available. The ESMO-MCBS score was available for 99 solid tumor indications, of which 51 (51.5 percent) showed substantial clinical benefit according to ESMO-MCBS, including 40 (54.1 percent) of PBAC-recommended indications and 9 (42.9 percent) of PBAC-rejected indications. There was no association between the ESMO scoring and PBAC decision. Most cancer medicines indications considered by PBAC were supported by RCTs. A minority showed a substantial improvement in OS.

Beta-2-Microglobulin Maintains Overall Survival Prediction in Binet A Stage Chronic Lymphocytic Leukemia Patients with Compromised Kidney Function in Both Treatment Eras of Chemoimmunotherapy and Targeted Agents

Background: Elevated beta-2-microglobulin (B2M) plasma levels commonly imply a higher CLL-IPI risk category for short overall survival (OS), but the risk model was not adjusted for compromised kidney function and not validated in Binet A stage CLL patients. Methods: CLL patients were identified from 2000 to 2022 at Innsbruck University Hospital, Austria. B2M levels, CLL-IPI risk stratification, and kidney function were assessed. Treatment modalities in case of disease progression and OS data during follow-up were evaluated. Results: A total of 259 Binet A stage CLL patients were identified; 16.9% (n = 44/259) presented with concurrent chronic kidney disease (CKD, GFR < 60 mL/min). Median OS was 170 months and was similar in CKD and non-CKD patients (p = 0.25). The CLL-IPI facilitated prognostic segregation in both CKD (p = 0.02) and non-CKD patients (p = 0.008). Although more frequently elevated in CKD patients (44.1% versus 10.6%, p < 0.001), B2M > 3.5 mg/L remained associated with inferior OS in this subgroup (p = 0.03). Contrary to the CLL-IPI, the prognostic value of B2M alone was also maintained in CLL patients diagnosed and potentially treated frontline in the era of targeted agents (2014–2022, p = 0.03). Conclusions: B2M retains its prognostic value for OS in early-stage CLL patients with concurrent CKD and still represents a promising covariate for up-coming prognostic models to identify patients at high risk for inferior OS in the era of targeted agents.

The role of PD-L1 in patients with non-small cell lung cancer receiving neoadjuvant immune checkpoint inhibitor plus chemotherapy: a meta-analysis

Background: The use of immune checkpoint inhibitors (ICIs) as neoadjuvant therapy is a promising novel approach in resectable non-small-cell lung cancer (NSCLC). This study aimed to investigate the prognostic value of PD-L1 in patients with NSCLC receiving neoadjuvant immune checkpoint inhibitor plus chemotherapy (CT). Materials and methods: Several databases (PubMed, Embase, and cochrane central register of controlled trials [CENTRAL]) were systematically searched. Randomized controlled trials (RCTs) investigating pathological and survival outcomes with neoadjuvant ICI + CT versus CT alone in NSCLC were analyzed. Results: Overall, eight RCTs (n = 3,404) were included. The analyses showed neoadjuvant ICI + CT significantly improved complete pathological response (pCR) and event-free survival (EFS) in either tumor PD-L1 < 1%, ≥ 1%, 1-49%, or ≥ 50% population (both p < 0.0001) compared with neoadjuvant CT alone. The overall survival (OS) data are not yet mature among all included RCTs, and only three RCTs presented OS data by PD-L1 status of patients. The pooled OS favored neoadjuvant ICI + CT in the PD-L1 ≥ 1% population (hazard ratio [HR], 0.45; 95% CI, 0.31–0.65; p < 0.0001), but not in the PD-L1 < 1% population (HR, 0.89; 95% CI, 0.66–1.19; p = 0.43). Conclusions: Compared with neoadjuvant CT alone, neoadjuvant ICI + CT significantly enhanced pCR and EFS for patients with resectable NSCLC regardless of the expression of PD-L1. It seems that only patients with PD-L1 positive tumors may achieve a better OS, but it’s currently inconclusive due to immature data, so future research with long-term follow-up is still needed.

A 14-year retrospective of HER2 + metastatic breast cancer treatment at one comprehensive cancer center: Impact of the trastuzumab/pertuzumab and trastuzumab-emtansine sequence versus trastuzumab on overall survival.

Introduction: Monoclonal antibodies represent a significant improvement in the treatment of the HER2 + metastatic cancer, which is associated with a worse prognosis. The objective of this study was to compare overall survival (OS) data in patients treated with trastuzumab + pertuzumab followed by trastuzumab-emtansine (T-DM1) in the second line of metastatic treatment (Arm A) versus patients treated with trastuzumab alone (Arm B). Progression-free survival (PFS) in first-line metastatic patients was also compared in both arms. Methods: This single-center retrospective study included patients from February 2008 to August 2022. OS and PFS of both arms were described and estimated using the Kaplan-Meier method. Data were extracted from electronic medical records and CHIMIO prescribing software. Results: The total duration of metastatic treatment of the 82 patients was significantly longer in the arm A (43.2 ± 28 months vs 33.6 ± 28.9 months), as was the median time to death (59 vs 52 months). The OS data showed a significant reduction in the risk of death in the arm A (Hazard Ratio = 0.59; 95% Confidence Interval [0.37-0.94]; p = 0.02). No difference was shown for PFS. Conclusion: The trastuzumab/pertuzumab/T-DM1 combination showed a significant improvement in OS. Our results are in line with the CLEOPATRA and EMILIA studies, but long-term responders in the arm A may have impacted our results. The absence of difference in term of PFS in first metastatic line may be explained by a selection bias, as patients in the arm A potentially have more aggressive forms.

Brazilian Real-Life Experience of Multiple Myeloma (MMyBRAve): Improvement in Outcomes, But Remaining Diagnostic and Therapeutic Gaps

BackgroundThis study aimed at describing the demographic and clinical characteristics, treatment patterns and overall survival of patients with MM in Brazil to identify gaps in the disease diagnosis and treatment. MethodsMMyBRAve (NCT03506386) was a multicenter, observational study of patients diagnosed with MM in Brazil between January 2008 and December 2016, with data collection between August 2018 and September 2019 at 17 participating centers. ResultsOf 943 patients included, 914 had complete data for overall survival (OS) analysis. The most used frontline regimens were cyclophosphamide, thalidomide and dexamethasone; bortezomib, cyclophosphamide and dexamethasone; and thalidomide and dexamethasone. After a median follow-up of 63 months, the median OS from diagnosis was 70 months. These results indicate continuous improvements in comparison with previous observational studies from Brazil. The median OS in transplantation-ineligible (N = 491) and eligible (N = 452) patients were 49 and 93 months, respectively (hazard ratio [HR] = 0.52; 95% confidence interval [CI], 0.43 to 0.63; P < .001). The median OS also differed between patients with and without known prognostic factors. ConclusionDespite the improvements, our results suggest that access to novel agents and transplantation continue to hinder further progress in patient outcomes in Brazil and countries with similar health-care constraints.

A phase III trial of adjuvant ribociclib plus endocrine therapy versus endocrine therapy alone in patients with HR-positive/HER2-negative early breast cancer: final invasive disease-free survival results from the NATALEE trial

NATALEE assessed efficacy and tolerability of 3 years of adjuvant ribociclib plus NSAI compared with a nonsteroidal aromatase inhibitor (NSAI) alone in a broad population of patients with HR+/HER2- early breast cancer, including a select group without nodal involvement. This is the final preplanned analysis of invasive disease-free survival (iDFS). Premenopausal/postmenopausal women and men were randomized 1:1 to ribociclib (n=2549; 400 mg/day, 3 weeks on/1 week off for 36 months) plus NSAI (letrozole 2.5 mg/day or anastrozole 1 mg/day for 60 months) or NSAI alone (n=2552). Men and premenopausal women also received goserelin (3.6 mg once every 28 days). Patients had anatomical stage IIA (N0 with additional risk factors or N1), IIB, or III disease. The primary endpoint was iDFS. Secondary efficacy endpoints were recurrence-free survival (RFS), distant DFS (DDFS), and overall survival (OS). This final iDFS analysis was planned after ≈500 events. At data cutoff (21 July 2023), ribociclib was stopped for 1996 patients (78.3%); 1091 (42.8%) completed 3 years of ribociclib, and ribociclib treatment was ongoing for 528 (20.7%). Median follow-up for iDFS was 33.3 months. Overall, 226 and 283 iDFS events occurred with ribociclib plus NSAI vs NSAI alone, respectively. Ribociclib plus NSAI demonstrated significant iDFS benefit over NSAI alone (Hazard Ratio 0.749, 95% Confidence Interval [CI] 0.628-0.892; P=0.0012). The 3-year iDFS rates were 90.7% (95% CI 89.3%-91.8%) vs 87.6% (95% CI 86.1%-88.9%). A consistent benefit was observed across prespecified subgroups, including stage (II/III) and nodal status (+/-). DDFS and RFS favored ribociclib plus NSAI. OS data were immature. No new safety signals were observed. With longer follow-up and most patients off ribociclib, NATALEE continues to demonstrate iDFS benefit with ribociclib plus NSAI over NSAI alone in the overall population and across key subgroups. Observed adverse events remained stable.

Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer.

Outcomes in patients with hormone receptor-positive metastatic breast cancer worsen after one or more lines of endocrine-based therapy. Trastuzumab deruxtecan has shown efficacy in patients with metastatic breast cancer with low expression of human epidermal growth factor receptor 2 (HER2) after previous chemotherapy. We conducted a phase 3, multicenter, open-label trial involving patients with hormone receptor-positive metastatic breast cancer with low HER2 expression (a score of 1+ or 2+ on immunohistochemical [IHC] analysis and negative results on in situ hybridization) or ultralow HER2 expression (IHC 0 with membrane staining) who had received one or more lines of endocrine-based therapy and no previous chemotherapy for metastatic breast cancer. Patients were randomly assigned in a 1:1 ratio to receive trastuzumab deruxtecan or the physician's choice of chemotherapy. The primary end point was progression-free survival (according to blinded independent central review) among the patients with HER2-low disease. Secondary end points included progression-free survival among all the patients who had undergone randomization, overall survival, and safety. Of the 866 patients who underwent randomization, 713 had HER2-low disease, and 153 had HER2-ultralow disease. Among the patients with HER2-low disease, the median progression-free survival was 13.2 months (95% confidence interval [CI], 11.4 to 15.2) in the trastuzumab deruxtecan group and 8.1 months (95% CI, 7.0 to 9.0) in the chemotherapy group (hazard ratio for disease progression or death, 0.62; 95% CI, 0.51 to 0.74; P<0.001); the results were consistent in the exploratory HER2-ultralow population. Data for overall survival were immature. Adverse events of grade 3 or higher occurred in 52.8% of the patients in the trastuzumab deruxtecan group and in 44.4% of those in the chemotherapy group. Adjudicated interstitial lung disease or pneumonitis occurred in 49 patients (11.3%; three events were grade 5 in severity) and in 1 patient (0.2%; grade 2), respectively. Among patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy, treatment with trastuzumab deruxtecan resulted in longer progression-free survival than chemotherapy. No new safety signals were identified. (Funded by AstraZeneca and Daiichi Sankyo; DESTINY-Breast06 ClinicalTrials.gov number, NCT04494425.).

Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01.

The global, phase 3, open-label, randomized TROPION-Breast01 study assessed the trophoblast cell surface antigen 2-directed antibody-drug conjugate datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer. Adult patients with inoperable/metastatic HR+/HER2‒ breast cancer, who had disease progression on endocrine therapy, for whom endocrine therapy was unsuitable, and had received one to two previous lines of chemotherapy in the inoperable/metastatic setting, were randomly assigned 1:1 to Dato-DXd (6 mg/kg once every 3 weeks) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine). Dual primary end points were progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Patients were randomly assigned to Dato-DXd (n = 365) or ICC (n = 367). Dato-DXd significantly reduced the risk of progression or death versus ICC (PFS by BICR hazard ratio [HR], 0.63 [95% CI, 0.52 to 0.76]; P < .0001). Consistent PFS benefit was observed across subgroups. Although OS data were not mature, a trend favoring Dato-DXd was observed (HR, 0.84 [95% CI, 0.62 to 1.14]). The rate of grade ≥3 treatment-related adverse events (TRAEs) with Dato-DXd was lower than ICC (20.8% v 44.7%). The most common TRAEs (any grade; grade ≥3) were nausea (51.1%; 1.4%) and stomatitis (50%; 6.4%) with Dato-DXd and neutropenia (grouped term, 42.5%; 30.8%) with ICC. Patients receiving Dato-DXd had statistically significant and clinically meaningful improvement in PFS and a favorable and manageable safety profile, compared with ICC. Results support Dato-DXd as a novel treatment option for patients with inoperable/metastatic HR+/HER2‒ breast cancer who have received one to two previous lines of chemotherapy in this setting.

A phase 3 study (PATHWAY) of palbociclib plus tamoxifen in patients with HR-positive/HER2-negative advanced breast cancer

Palbociclib combined with endocrine therapy is approved for treating patients with hormone-receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) advanced breast cancer; however, data on palbociclib combined with tamoxifen are limited. We investigated the efficacy and safety of palbociclib–tamoxifen in patients with HR+/HER2− advanced breast cancer. This double-blind phase 3 study included 184 women who were randomly assigned 1:1 to receive palbociclib–tamoxifen or placebo–tamoxifen. Pre/perimenopausal women also received goserelin. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Median PFS was 24.4 months (95% confidence interval [CI], 13.1–32.4) with palbociclib–tamoxifen and 11.1 months (95% CI, 7.4–14.6) with placebo–tamoxifen (hazard ratio [HR], 0.60; 95% CI, 0.43–0.85; P = 0.002). Palbociclib–tamoxifen improved PFS in patients who were treated with first-line or second-line endocrine therapy and pre-, peri-, and postmenopausal patients. Though OS data are still immature (median not reached in both groups), an overall risk reduction of 27% (HR, 0.73; 95% CI, 0.44–1.21) with palbociclib–tamoxifen was observed at the time of PFS analysis. The most common grade 3/4 adverse event with palbociclib–tamoxifen was neutropenia (89.0% [none were febrile] versus 1.1% with placebo–tamoxifen). There were no deaths owing to adverse events in either group. Among patients with HR+/HER2− advanced breast cancer, palbociclib–tamoxifen resulted in significantly longer PFS than tamoxifen alone. Early OS data showed a trend favoring palbociclib–tamoxifen. Trial registration: ClinicalTrials.gov number, NCT03423199. Study registration date: February 06, 2018.

Initial ribociclib plus endocrine therapy for HR+/HER2- advanced breast cancer in pre- and postmenopausal Chinese women: Primary results from a phase 2 randomized study.

AbstractBackgroundThe MONALEESA‐7 and ‐2 phase 3 randomized trials demonstrated a statistically significant progression‐free survival (PFS) and overall survival (OS) benefit with initial ribociclib + endocrine therapy (ET) versus placebo + ET in pre‐ and postmenopausal patients with hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2−) advanced breast cancer (ABC), respectively. Similar trends were observed in Asian subgroup analyses. This phase 2 bridging study of initial ET + ribociclib enrolled pre‐ and postmenopausal patients with HR+/HER2– ABC from China and was conducted to demonstrate consistency of PFS results in a Chinese population relative to the global MONALEESA‐7 and ‐2 studies.MethodsPatients were randomized (1:1) to ET (nonsteroidal aromatase inhibitor + goserelin for premenopausal patients; letrozole for postmenopausal patients) + either ribociclib or placebo. The primary endpoint was investigator‐assessed PFS.ResultsAs of April 25, 2022, the median follow‐up was 34.7 months in both cohorts. In the premenopausal cohort, median PFS was 27.6 months in the ribociclib arm (n = 79) versus 14.7 months in the placebo arm (n = 77) (hazard ratio 0.67 [95% CI: 0.45, 1.01]). In the postmenopausal cohort, median PFS was not reached in the ribociclib arm versus 18.5 months in the placebo arm (n = 77 in each arm) (hazard ratio 0.40 [95% CI: 0.26, 0.62]). Data also suggested improvements in secondary efficacy endpoints, although OS data were not mature. The safety profile in this population was consistent with that in global studies.ConclusionsThese data demonstrate a favorable benefit–risk profile for ribociclib + ET in Chinese patients.

Evaluating the role of sarcopenia and [18F]FDG PET/CT parameters in prognosis of pancreatic ductal adenocarcinoma

This study investigates the relationship between 18F-fluorodeoxyglucose ([18F]FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters, clinicopathological characteristics, and sarcopenia in patients with pancreatic ductal adenocarcinoma (PDAC) and evaluates their prognostic roles. Material and methodsThe primary tumor's maximum standard uptake (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) values, as well as clinicopathological factors, were evaluated retrospectively. Computed tomography (CT) was used to assess the skeletal muscle index (SMI). Sarcopenia was defined based on SMI calculated at the third lumbar vertebra (L3). SMI cut-off values ​​for sarcopenia were accepted as 44.77 cm2/m2 for men and 32.50 cm2/m2 for women. The primary endpoint was the overall survival (OS). OS data were analyzed by the Kaplan-Meier method and compared using the log-rank test. To identify predictive factors for sarcopenia, multivariable logistic regression was used following univariable logistic regression. Cox proportional hazards regression analyses were used to find predictors of OS. ResultsOf the 86 patients included in the study, 37 (43%) were diagnosed with sarcopenia. Compared with non-sarcopenic patients, sarcopenia was observed in older patients (P=0,028) and patients with lower body mass index (BMI) (p=0,001). Age and BMI independently predicted sarcopenia. Univariate analysis identified sarcopenia, advanced stage, and higher primary tumor TLG as significant predictors of overall survival. Multivariate Cox regression analysis revealed that the advanced tumor stage (p=0.017) and higher TLG (p=0,042) independently predicted OS. The median OS was 9.4 months in non-sarcopenic patients and 5.0 months in sarcopenic patients (p=0,021). ConclusionIn this study cohort, advanced-stage disease and higher primary tumor TLG were identified as independent predictors of OS in patients with PDAC. Additionally, we emphasize the importance of incorporating [18F]FDG PET/CT-derived sarcopenia assessments into the prognostic evaluation and clinical management of PDAC patients. While sarcopenia was associated with shorter OS in univariate analysis, it was not an independent predictor in multivariate analysis.

Combining PSMA-PET and PROMISE to re-define disease stage and risk in patients with prostate cancer: a multicentre retrospective study

Prostate-specific membrane antigen (PSMA)-PET was introduced into clinical practice in 2012 and has since transformed the staging of prostate cancer. Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria were proposed to standardise PSMA-PET reporting. We aimed to compare the prognostic value of PSMA-PET by PROMISE (PPP) stage with established clinical nomograms in a large prostate cancer dataset with follow-up data for overall survival. In this multicentre retrospective study, we used data from patients of any age with histologically proven prostate cancer who underwent PSMA-PET at the University Hospitals in Essen, Münster, Freiburg, and Dresden, Germany, between Oct 30, 2014, and Dec 27, 2021. We linked a subset of patient hospital records with patient data, including mortality data, from the Cancer Registry North-Rhine Westphalia, Germany. Patients from Essen University Hospital were randomly assigned to the development or internal validation cohorts (2:1). Patients from Münster, Freiburg, and Dresden University Hospitals were included in an external validation cohort. Using the development cohort, we created quantitative and visual PPP nomograms based on Cox regression models, assessing potential PPP predictors for overall survival, with least absolute shrinkage and selection operator penalty for overall survival as the primary endpoint. Performance was measured using Harrell's C-index in the internal and external validation cohorts and compared with established clinical risk scores (International Staging Collaboration for Cancer of the Prostate [STARCAP], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN] risk scores) and a previous nomogram defined by Gafita et al (hereafter referred to as GAFITA) using receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) estimates. We analysed 2414 male patients (1110 included in the development cohort, 502 in the internal cohort, and 802 in the external validation cohort), among whom 901 (37%) had died as of data cutoff (June 30, 2023; median follow-up of 52·9 months [IQR 33·9-79·0]). Predictors in the quantitative PPP nomogram were locoregional lymph node metastases (molecular imaging N2), distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases), tumour volume (in L), and tumour mean standardised uptake value. Predictors in the visual PPP nomogram were distant metastases (extrapelvic nodal metastases, bone metastases [disseminated or diffuse marrow involvement], and organ metastases) and total tumour lesion count. In the internal and external validation cohorts, C-indices were 0·80 (95% CI 0·77-0·84) and 0·77 (0·75-0·78) for the quantitative nomogram, respectively, and 0·78 (0·75-0·82) and 0·77 (0·75-0·78) for the visual nomogram, respectively. In the combined development and internal validation cohort, the quantitative PPP nomogram was superior to STARCAP risk score for patients at initial staging (n=139 with available staging data; AUC 0·73 vs 0·54; p=0·018), EAU risk score at biochemical recurrence (n=412; 0·69 vs 0·52; p<0·0001), and NCCN pan-stage risk score (n=1534; 0·81 vs 0·74; p<0·0001) for the prediction of overall survival, but was similar to GAFITA nomogram for metastatic hormone-sensitive prostate cancer (mHSPC; n=122; 0·76 vs 0·72; p=0·49) and metastatic castration-resistant prostate cancer (mCRPC; n=270; 0·67 vs 0·75; p=0·20). The visual PPP nomogram was superior to EAU at biochemical recurrence (n=414; 0·64 vs 0·52; p=0·0004) and NCCN across all stages (n=1544; 0·79 vs 0·73; p<0·0001), but similar to STARCAP for initial staging (n=140; 0·56 vs 0·53; p=0·74) and GAFITA for mHSPC (n=122; 0·74 vs 0·72; p=0·66) and mCRPC (n=270; 0·71 vs 0·75; p=0·23). Our PPP nomograms accurately stratify high-risk and low-risk groups for overall survival in early and late stages of prostate cancer and yield equal or superior prediction accuracy compared with established clinical risk tools. Validation and improvement of the nomograms with long-term follow-up is ongoing (NCT06320223). Cancer Registry North-Rhine Westphalia.

Improving Collection and Analysis of Overall Survival Data.

Advances in anticancer therapies have provided crucial benefits for millions of patients who are living long and fulfilling lives. Although these successes should be celebrated, there is certainly room to continue improving cancer care. Increased long-term survival presents additional challenges for determining whether new therapies further extend patients' lives through clinical trials, commonly known as the gold standard endpoint of overall survival (OS). As a result, an increasing reliance is observed on earlier efficacy endpoints, which may or may not correlate with OS, to continue the timely pace of translating innovation into novel therapies available for patients. Even when not powered as an efficacy endpoint, OS remains a critical indication of safety for regulatory decisions and is a key aspect of the FDA's Project Endpoint. Unfortunately, in the pursuit of earlier endpoints, many registrational clinical trials lack adequate planning, collection, and analysis of OS data, which complicates interpretation of a net clinical benefit or harm. This article shares best practices, proposes novel statistical methodologies, and provides detailed recommendations to improve the rigor of using OS data to inform benefit-risk assessments, including incorporating the following in clinical trials intending to demonstrate the safety and effectiveness of cancer therapy: prospective collection of OS data, establishment of fit-for-purpose definitions of OS detriment, and prespecification of analysis plans for using OS data to evaluate for potential harm. These improvements hold promise to help regulators, patients, and providers better understand the benefits and risks of novel therapies.

Survival benefits of propofol-based versus inhalational anesthesia in non-metastatic breast cancer patients: a comprehensive meta-analysis

Whether the anesthesia technique, inhalational general anesthesia (IGA) or propofol-based anesthesia (PBA), influences the long-term survival of non-metastatic breast cancer (eBC) remain unclear and controversial. We carried out a literature search on 16thJuly, 2022 for studies comparing IGA and PBA in eBC undergoing standard surgery, according to PRISMA 2020. The major endpoint in our study was overall survival (OS). Seventeen studies including four randomized clinical trials and thirteen retrospective cohort studies were included in the meta-analysis. Ten studies provided data for crude OS in unweighted eBC patients (imbalance in baseline characteristics). The summarized estimate HRs of the PBA group versus the IGA group (ten studies, N = 127,774, IGA group: 92,592, PBA group: 35,182.) was 0.83 (95%CI: 0.78–0.89). Compared with IGA, PBA was associated with both better 1-year OS (two studies, N = 104,083, IGA group: 84,074, PBA group: 20,009. Pooled HR = 0.80, 0.73–0.89) and 5-year OS (six studies, N = 121,580, IGA group: 89,472, PBA group: 32,108. HR = 0.80, 0.74–0.87). Ten studies applied PSM method to balance the baseline characteristics. In these weighted patients, PBA still showed a better OS (ten studies, N = 105,459, IGA group: 79,095, PBA group: 26,364. HR = 0.93, 0.87–1.00), a better 1-year OS (two studies, N = 83,007, IGA group: 67,609, PBA group: 15,398. HR = 0.88, 0.78–0.98) and a trend towards a better 5-year OS (nine studies, N = 121,580, IGA group: 76,797, PBA group: 24,066. HR = 0.95, 0.88–1.03). Loco-regional recurrence-free survival (LRRFS) was also better in PBA group (HR = 0.73, 0.61–0.86). The present study is the first comprehensive meta-analysis to demonstrate that propofol-based anesthesia could significantly improve OS and LRRFS in non-metastatic breast cancer patients, compared with inhalational anesthesia.

Treatment-Switching Adjustment of Overall Survival in CheckMate 227 Part 1 Evaluating First-Line Nivolumab Plus Ipilimumab Versus Chemotherapy for Metastatic Nonsmall Cell Lung Cancer

ObjectivesCheckMate 227 (NCT02477826) evaluated first-line nivolumab-plus-ipilimumab versus chemotherapy in patients with metastatic nonsmall cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) expression ≥ 1% or < 1% and no EGFR/ALK alterations. However, many patients randomized to chemotherapy received subsequent immunotherapy. Here, overall survival (OS) and relative OS benefit of nivolumab-plus-ipilimumab were adjusted for potential bias introduced by treatment switching. Materials and methodsTreatment-switching adjustment analyses were conducted following the NICE Decision Support Unit Technical Support Document 16, for CheckMate 227 Part 1 OS data from treated patients (database lock, July 2, 2019). Inverse probability of censoring weighting (IPCW) was used in the base-case analysis; other methods were explored as sensitivity analyses. ResultsOf 1166 randomized patients, 391 (PD-L1 ≥ 1%) and 185 (PD-L1 < 1%) patients received nivolumab-plus-ipilimumab; 387 (PD-L1 ≥ 1%) and 183 (PD-L1 < 1%) patients received chemotherapy, with 29.3-month minimum follow-up. Among chemotherapy-treated patients, 169/387 (43.7%; PD-L1 ≥ 1%) and 66/183 (36.1%; PD-L1 < 1%) switched to immunotherapy poststudy. Among treated patients, median OS was 17.4 months with nivolumab-plus-ipilimumab versus 14.9 months with chemotherapy (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.68-0.95) in the PD-L1 ≥ 1% subgroup and 17.1 versus 12.4 months (HR, 0.62; 95% CI, 0.49-0.80) in the PD-L1 < 1% subgroup. After treatment-switching adjustment using IPCW, the HR (95% CI) for OS for nivolumab-plus-ipilimumab versus chemotherapy was reduced to 0.68 (0.56-0.83; PD-L1 ≥ 1%) and 0.53 (0.40-0.69; PD-L1 < 1%). Sensitivity analyses supported the robustness of the results. ConclusionTreatment-switching adjustments resulted in a greater estimated relative OS benefit with first-line nivolumab-plus-ipilimumab versus chemotherapy in patients with metastatic NSCLC.

MDB-94. RADIOMICS-BASED DECISION SUPPORT FOR PEDIATRIC MEDULLOBLASTOMA RISK STRATIFICATION ON MULTI-PARAMETRIC MRI

Abstract BACKGROUND Medulloblastoma (MB) is the most common pediatric brain malignancy. Accurate risk stratification is crucial for prescribing appropriate therapy. However, current risk stratification into standard or high-risk groups is limited in scope and does not accurately address the unique biological behavior of each specific tumor, with approximately 30% of children diagnosed with MB suffering from treatment failure. We developed a radiomic tool to more accurately risk stratify children with MB. METHODS We collected 1.5T/3T MRI (Siemens, Philips, or GE scanners) and clinical data from 80 patients with MB treated at Children’s Healthcare of Atlanta. Radiomic features that quantify textural heterogeneity including first and second order statistics, Haralick’s features from Gray Level Co-occurrence Matrices, and CoLIAge were extracted from tumor volumes segmented by a board-certified radiologist from multi-parametric MRI data including Apparent Diffusion Coefficient (ADC), T2, and post-contrast T1 sequences. Continuous survival models were built using the Cox proportional hazard method with 70% of the data for progression free survival (PFS) and overall survival (OS) using the 5 most predictive features obtained by univariate analysis after removing correlated features within the training data. RESULTS We developed three models with T1, T2, and ADC separately to evaluate predictive power of radiomic signatures. Three models for predicting MB OS delivered Harrel’s concordance indices (C-index) of 0.72 and 0.61 (T1); 0.70 and 0.65 (T2); and 0.80 and 0.76 (ADC) for training and test, respectively. C-indices for PFS were 0.70 and 0.69 (T1); 0.73 and 0.67 (T2); and 0.63 and 0.61 (ADC). CONCLUSIONS Our preliminary results show the feasibility and efficacy of our approach for predicting MB OS and PFS. Future studies will build an integrated model combining T1,T2, ADC, and other clinical information for predicting MB OS and PFS using a large multi-center validation cohort.

Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial.

We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer (BTC). This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included treatment-naïve adults with locally advanced/metastatic BTC. Patients (N=297) were randomized to receive an intravenous infusion of BA (2400mg once/3wk) plus GemCis (gemcitabine 1000mg/m2+cisplatin 25mg/m2 on days 1 and 8/3wk; 8 cycles) (BA group, n=148) or placebo+GemCis (placebo group, n=149). The primary endpoint was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cut-off: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naïve, when 80 progression-free survival events had occurred and ≥19 weeks of follow-up had been completed (BA, n=73; placebo, n=77). Median OS (95% CI) for the BA (11.5mo [9.3-not estimable, NE]) and placebo (11.5mo [10.0-NE]) groups was comparable (hazard ratio 1.23 [95% CI 0.66-2.28]; p=0.7394); OS data maturity was 27.2% (41 events/151 patients). The most common grade ≥3 treatment-related adverse event was anemia (BA, 26.0%; placebo, 22.8%). Bleeding adverse events were reported more frequently in the BA group (28.8%) versus the placebo group (7.4%). Deaths within 60 days of the first dose were reported in 7.5% and 1.3% of patients in the BA and placebo groups, respectively. BA+GemCis did not provide a clinically meaningful benefit compared to GemCis alone as first-line treatment for BTC and the study was discontinued early (terminated: August 20, 2021).

Circulating Tumor DNA-Guided De-Escalation Targeted Therapy for Advanced Non−Small Cell Lung Cancer

Uninterrupted targeted therapy until disease progression or intolerable toxic effects is currently the routine therapy for advanced non-small cell lung cancer (NSCLC) involving driver gene variations. However, drug resistance is inevitable. To assess the clinical feasibility of adaptive de-escalation tyrosine kinase inhibitor (TKI) treatment guided by circulating tumor DNA (ctDNA) for achieving complete remission after local consolidative therapy (LCT) in patients with advanced NSCLC. This prospective nonrandomized controlled trial was conducted at a single center from June 3, 2020, to July 19, 2022, and included 60 patients with advanced NSCLC with driver variations without radiologically detectable disease after TKI and LCT. The median (range) follow-up time was 19.2 (3.8-29.7) months. Data analysis was conducted from December 15, 2022, to May 10, 2023. Cessation of TKI treatment and follow-up every 3 months. Treatment was restarted in patients with progressive disease (defined by the Response Evaluation Criteria in Solid Tumors 1.1 criteria), detectable ctDNA, or elevated carcinoembryonic antigen (CEA) levels, whichever manifested first, and treatment ceased if all indicators were negative during follow-up surveillance. Progression-free survival (PFS). Secondary end points were objective response rate, time to next treatment, and overall survival. Among the total study sample of 60 participants (median [range] age, 55 [21-75] years; 33 [55%] were female), the median PFS was 18.4 (95% CI, 12.6-24.2) months and the median (range) total treatment break duration was 9.1 (1.5-28.1) months. Fourteen patients (group A) remained in TKI cessation with a median (range) treatment break duration of 20.3 (6.8-28.1) months; 31 patients (group B) received retreatment owing to detectable ctDNA and/or CEA and had a median PFS of 20.2 (95% CI, 12.9-27.4) months with a median (range) total treatment break duration of 8.8 (1.5-20.6) months; and 15 patients (group C) who underwent retreatment with TKIs due to progressive disease had a median PFS of 5.5 (95% CI, 1.5-7.2) months. For all participants, the TKI retreatment response rate was 96%, the median time to next treatment was 29.3 (95% CI, 25.3-35.2) months, and the data for overall survival were immature. The findings of this nonrandomized controlled trial suggest that this adaptive de-escalation TKI strategy for patients with NSCLC is feasible in those with no lesions after LCT and a negative ctDNA test result. This might provide a de-escalation treatment strategy guided by ctDNA for the subset of patients with advanced NSCLC. ClinicalTrials.gov Identifier: NCT03046316.

Interim results of the randomized phase 2 cohort of study FW-2020-01 assessing the efficacy, safety and pharmacodynamics of CM24 in combination with nivolumab and chemotherapy in advanced/metastatic pancreatic cancer.

LBA4143 Background: The novel monoclonal antibody CM24 blocks the activity of Carcinoembryonic Antigen Cell Adhesion Molecule 1 (CEACAM1), known to have key roles in cancer progression, immune evasion, and metastasis. We present the interim efficacy and safety data from the global multi-center, open label, randomized Phase 2 study (NCT 04731467) in patients (pts) with advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) who progressed after 1st line therapy, treated with CM24, nivolumab (nivo) and chemotherapy vs. chemotherapy (CH). Methods: Patients with advanced/metastatic PDAC progressing after 1 prior line of systemic therapy including fluoropyrimidine/irinotecan or gemcitabine/nab-paclitaxel, having ≥1 measurable lesion, ≥18-year-old, ECOG ≤1 and adequate organ function were randomized 1:1 based on the class of prior CH received. Randomization was either to the experimental groups (EX) receiving CM24 (20mg/kg, q2wk), nivo (240mg/kg, q2wk) with one of the following CH regimens, liposomal irinotecan, 5 fluorouracil and leucovorin (Nal-IRI; q2wk) or gemcitabine/nab-paclitaxel (gem/nab; q1wk x3) or the control groups (C) with one of the CH regimens alone. This is a Bayesian design with an overall planned sample size of 60 pts with Overall Survival (OS) as the primary endpoint. Secondary endpoints include progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR). An interim estimate of PFS HR, ORR and DCR based on data cut-off date of 21 Feb 2024 is reported. The analysis compares the EX vs. the respective C arm using log-rank test stratified by CH regimen. Results: A total of 63 PDAC pts were evenly randomized across the study arms. At data cut-off date, a total of 18 pts, 9 per treatment regimen remain on treatment. The median follow-up time for the Nal-IRI regimen is 6.3 months (95% CI: 5.5-8.4) and 5.2 months (95% CI: 4.0-6.7) for the gem/nab regimen. Median PFS ORR and DCR for the Nal-IRI EX arm were 3.8m (1.9-5.1; HR 0.70; p=0.213), 18.8% and 62.6%, and for the Nal-IRI C arm 1.9m (1.8-5.6), 6.3% and 40%, respectively (Table). Data for the gem/nab regimen and OS data for both regimens are not mature. Overall Grade ≥3 AE rate was 50% in the Nal-IRI EX arm and 13% in the C arm. The most common treatment-emergent grade ≥3 AEs EX vs. C were diarrhea (18.8% vs 6.7%), fatigue (18.8% vs 6.7%) and anemia (6.3% vs 0%). Conclusions: The interim analysis suggests that the combination of CM24/nivo/Nal-IRI/5FU/LV has a manageable safety profile with a longer PFS supported by higher ORR and DCR. OS Data continues to mature and will be reported once available. Clinical trial information: NCT04731467 . [Table: see text]

A phase III randomized, double-blinded, placebo-controlled study of suvemcitug combined with chemotherapy for platinum-resistant ovarian cancer (SCORES).

LBA5516 Background: Suvemcitug is a new-generation recombinant humanized anti-VEGF rabbit monoclonal antibody. In the previous P1b study, Suvemcitug demonstrated its favorable safety profile and efficacy signals when combo with chemotherapy in platinum-resistant ovarian cancer (PROC). SCORES is the first randomized, double-blind, placebo-controlled phase III clinical trial to confirm the efficacy of Suvemcitug combo with chemo in PROC, whether or not previously received antiangiogenic agents or PARP inhibitors. Methods: Eligible patients had progressed during platinum-based therapy or within 6 months after ≥4 cycles of platinum-based therapy with at least one measurable lesion. After the investigators chose chemotherapy (CT) (weekly paclitaxel 80 mg/ m2 d1, 8, 15 &amp; 22 q4w, pegylated liposomal doxorubicin 40 mg/m2 d1 q4w or topotecan 4 mg/m2 d1, 8 &amp; 15 q4w), patients were randomly assigned (2:1) to either Suvemcitug (1.5 mg/kg q2w) or placebo combine with CT until progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by blinded independent review committee (BIRC) according to the RECIST 1.1. Key secondary end point is the overall survival (OS). Results: A total of 421 patients were enrolled between June 2021 and June 2023 in China. As the data cut off of the primary efficacy analysis (8 December 2023), 197 PFS events (70.1%) in Suvemcitug arm and 111 PFS events (79.3%) in placebo arm had occurred with the median follow-up of 14.36 and 14.26 months, respectively. The median PFS by BIRC was 5.49 months in Suvemcitug arm versus 2.73 months in placebo arm (hazard ratio[HR] 0.46, p&lt;0.0001). OS data are immature. 42.7% and 50.7% of patients are deceased in Suvemcitug arm or placebo arm respectively, and there is a trend of OS benefit trend: median OS 16.07 months vs. 14.88 months, HR 0.79, p=0.1244. Efficacy results are summarized below. Treatment-emergent adverse events (TRAEs) occurred in all patients in Suvemcitug arm, with the most common being neutrophil count decreased, white blood cell count decreased and platelet count decreased. No Suvemcitug-related grade 5 TEAE occurred. Conclusions: To the best of our knowledge, this is the first double-blinded phase III study demonstrated promising antitumor activity of anti-angiogenic agent in patients with PROC. The improvement in PFS, ORR and DCR gained by adding Suvemcitug to single-agent CT was observed with no new safety concern. Clinical trial information: NCT04908787 . [Table: see text]