Mature Overall Survival Data Research Articles

Trilaciclib combined with sacituzumab govitecan (SG) in metastatic triple-negative breast cancer (mTNBC): Updated phase 2 safety and efficacy results.

1091 Background: Trilaciclib, a reversible cyclin-dependent kinase 4/6 inhibitor, protects hematopoietic stem and progenitor cells during chemotherapy (myeloprotection). In a phase 2 trial in mTNBC (NCT02978716), administering trilaciclib prior to chemotherapy enhanced T-cell activity and modulated antitumor immunity. In a phase 3 trial (ASCENT; NCT02574455), the antibody–drug conjugate SG significantly extended overall survival (OS) versus single-agent chemotherapy (12.1 vs 6.7 months) but was associated with increased neutropenia (any grade, 63% vs 43%; grade 3/4, 51% vs 33%) and diarrhea (any grade, 59% vs 12%; grade 3/4, 10% vs < 1%). This phase 2 single-arm trial was designed to assess safety and efficacy of trilaciclib prior to SG in mTNBC (NCT05113966). Methods: Eligible patients (≥ 2 prior systemic therapies [≥ 1 in the metastatic setting]; measurable disease; confirmed hormone receptor- and human epidermal growth factor receptor 2-negative status; Eastern Cooperative Oncology Group performance status 0 or 1) received intravenous trilaciclib 240 mg/m2 prior to SG 10 mg/kg on days 1 and 8 of each 21-day cycle until disease progression or toxicity. Tumor assessments occurred at screening, every 6 weeks through week 26, then every 9 weeks until disease progression or subsequent anticancer therapy. Endpoints included antitumor efficacy, myeloprotection, and safety and tolerability. Results: As of January 2, 2024, 30 female patients had been enrolled (median age, 56 years) and completed a median 6 (range, 2–29) cycles. Median follow-up was 11.2 months. Safety is summarized in the Table. The confirmed overall response rate (95% CI) was 23.3% (9.9–42.3), the clinical benefit rate was 46.7% (28.3–65.7), and the median duration of response was 9.1 (4.0–not estimable) months. Median progression-free survival was 4.1 (2.2–7.3) months. OS data are not yet mature; currently, median OS among patients receiving trilaciclib prior to SG is 17.9 (9.9–not estimable) months. Conclusions: Adding trilaciclib prior to SG reduces the rate and severity of multiple adverse events, notably neutropenia and diarrhea, compared with results from trials of SG alone. Preliminary data suggest clinically meaningful OS outcomes among patients receiving trilaciclib prior to SG compared with historical data for SG alone; however, caution should be exercised when interpreting results from cross-trial comparisons. Mature OS data will be presented. Clinical trial information: NCT05113966 . [Table: see text]

Camrelizumab plus apatinib and temozolomide as first-line therapy for advanced acral melanoma: 2-year survival results from CAP 03.

9547 Background: Acral melanoma is the predominant subtype in Asia, which presents with aggressive biological behavior. First-line immunotherapy yields modest efficacy in advanced acral melanoma, suggesting the need of combination therapy. Our CAP 03 study investigated the combination of anti-PD-1 antibody plus antiangiogenic agent and chemotherapy for the first-line treatment of advanced acral melanoma, and the primary analysis has been published on JAMA Oncology in June 2023 (objective response rate [ORR], 64%; median progression-free survival [PFS], 18.4 months). Here we updated the efficacy results with a median follow-up of 30.3 months (95% CI, 28.9-32.5; reverse Kaplan-Meier method) at data cutoff date on January 8, 2024. Methods: In this single-center phase 2 trial (NCT04397770), patients with pathologically confirmed unresectable stage III or IV acral melanoma and without prior systemic therapy for advanced disease were recruited. Patients received first-line intravenous camrelizumab (200 mg once every 2 weeks) plus oral apatinib (250 mg once a day) and intravenous temozolomide (200 mg/m2 once a day on days 1-5 every 4 weeks) until disease progression or intolerable toxicity. The primary endpoint was ORR per Response Evaluation Criteria In Solid Tumors, version 1.1. Imaging assessment was performed after 4 weeks, then every 8 weeks until one year, and every 3 months thereafter. Overall survival (OS) was followed every 3 months. Results: Between May 2020 and August 2021, a total of 50 patients were enrolled. The confirmed ORR was 66.0% (33 of 50; 95% CI, 51.2%-78.8%). The median PFS was 21.2 months (95% CI, 10.1-27.1). The median OS was not reached, and the 1-year and 2-year OS rates were 88.0% (95% CI, 75.2%-94.4%) and 64.8% (95% CI, 49.5%-76.5%), respectively. Further analyses indicated comparable PFS benefit in subgroups by age (<65 years vs ≥65 years), sex (male vs female), Eastern Cooperative Oncology Group performance status (0 vs 1), NRAS status (variant vs wild-type), stage, lactic dehydrogenase (LDH) level, and PD-L1 combined positive score (<5 vs ≥5). Regarding OS, similar trends were observed in these subgroups, except that patients with normal LDH had better median OS than those with elevated LDH (not reached vs 22.6 months, log-rank nominal P=0.033). Conclusions: This first-line triplet combination shows encouraging survival benefits in patients with advanced acral melanoma, regardless of NRAS status or PD-L1 expression level. Follow-up is still ongoing to obtain mature OS data. Clinical trial information: NCT04397770 .

An updated cost-effectiveness analysis of axicabtagene ciloleucel in second-line large B-cell lymphoma patients in the United States

Aims This economic evaluation of axicabtagene ciloleucel (axi-cel) versus previous standard of care (SOC; salvage chemotherapy followed by high-dose therapy with autologous stem cell rescue) in the second line (2L) large B-cell lymphoma population is an update of previous economic models that contained immature survival data. Methods This analysis is based on primary overall survival (OS) ZUMA-7 clinical trial data (median follow-up of 47.2 months), from a United States (US) payer perspective, with a model time horizon of 50 years. Mixture cure models were used to extrapolate updated survival data; subsequent treatment data and costs were updated. Patients who remained in the event-free survival state by 5 years were assumed to have achieved long-term remission and not require subsequent treatment. Results Substantial survival and quality of life benefits were observed despite 57% of patients in the SOC arm receiving subsequent cellular therapy: median model-projected (ZUMA-7 trial Kaplan–Meier estimated) OS was 78 months (median not reached) for axi-cel versus 25 months (31 months) for SOC, resulting in incremental quality-adjusted life year (QALY) difference of 1.63 in favor of axi-cel. Incrementally higher subsequent treatment costs were observed in the SOC arm due to substantial crossover to cellular therapies, thus, when considering the generally accepted willingness to pay threshold of $150,000 per QALY in the US, axi-cel was cost-effective with an incremental cost-effectiveness ratio of $98,040 per QALY. Conclusions Results remained consistent across a wide range of sensitivity and scenario analysis, including a crossover adjusted analysis, suggesting that the mature OS data has significantly reduced the uncertainty of axi-cel’s cost-effectiveness in the 2L setting in the US. Deferring treatment with CAR T therapies after attempting a path to transplant may result in excess mortality, lower quality of life and would be an inefficient use of resources relative to 2L axi-cel.

The evolving value assessment of cancer therapies: Principles from the cancer community.

e13647 Background: Oncology-relevant measures of disease and treatment support earlier detection, accelerated drug development, and inform treatment pathways. To advance access to transformative treatments for people with cancer, especially those for early-stage cancers where medical intervention has the greatest opportunity to impact the course of the disease, the cancer community identified seven principles that support the evolution of value assessment frameworks. Here we summarize the five key principles. Methods: A group of 24 cancer community experts (9 oncologists, 6 patient advocacy leaders, 1 former regulator, 6 former payers, and 4 health economists) from 14 countries came together to discuss and build consensus on oncology-relevant value principles. Over five months, the expert group engaged via surveys, virtual discussion panels, and interviews. Results: The expert group developed seven consensus principles covering two areas: oncology-relevant endpoints to assess the value of treatments; and additional important value components and how they can be integrated into value assessments. The key 5 principles were oncology-relevant endpoints assessing clinical effectiveness, including the following three items. 1) Consider oncology-relevant endpoints, other than Overall Survival (OS), with intrinsic value for decision-making e.g., Event-, Disease-, or Relapse-Free Survival. 2) Continue to build evidence for endpoints that indicate treatment efficacy earlier e.g., pathologic Complete Response. 3) Develop evidence for the next generation of predictive measures that detect and monitor disease, e.g., circulating tumor DNA and Minimal Residual Disease. Additional value components supporting patient access include the following two items. 1) Use managed entry (type of access) agreements supported by ongoing real world evidence collection to help address decision-maker (regulator and Health Technology Assessment body) evidence needs. 2) Routinely use Patient Reported Outcomes (PROs) in value assessments. Conclusions: To achieve the common goal of all cancer community stakeholders—improved outcomes for people with cancer—collaboration across the cancer community is essential to define how value is assessed, especially for early-stage cancer treatments. This is particularly important since mature OS data is not always available during initial decision-making, and decision-makers need to evolve which are the most appropriate endpoints. This supports measuring clinical impact, but also broader social, financial and ethical impact for patients, caregivers, healthcare systems, society, and the economy (not considered in this abstract). To achieve these goals, the expert group recommends: 1) increasing awareness and systematically engaging people with cancer in value assessments, 2) leveraging PROs in those assessments, and 3) further validation in clinical trials of oncology-relevant endpoints that could provide an earlier indication of clinical outcomes.

Shifting perspectives on the value of non-OS endpoints and PROs: Considerations across stakeholder groups to support oncology HTA decision-making.

e13646 Background: The ability of novel cancer drugs to extend patients’ overall survival (OS) has been key to determining their approval and access conditions. However, in some disease settings, OS can have limitations: delayed access due to the time required to collect mature OS data; confounding from subsequent treatment lines; and poor ability to reflect value beyond survival. Stakeholders such as regulators and physicians increasingly recognise the value of non-OS endpoints as surrogates for OS. In addition, non-OS endpoints and patient reported outcomes (PROs) may have stand-alone value, e.g., in capturing disease burden. However, stakeholders are misaligned on the benefits of non-OS endpoints and PROs due to differences in underlying value drivers. Methods: This study investigates stakeholder perceptions of non-OS endpoints and PROs, based on 76 semi-structured interviews with physicians, patients, patient advocacy groups (PAGs), regulators and health economists in 7 key markets (U.S., Canada, Japan, UK, France, Germany and Italy), 3 roundtable discussions and a literature review. Results: Non-OS endpoints address some concerns with OS as they can be captured earlier in trials and may act as surrogates of OS; show reduced susceptibility to confounding; and better reflect the value to patients beyond survival. However, the value perception of non-OS endpoints and PROs varies across stakeholders: 1) Patients / PAGs value non-OS endpoints as they capture outcomes beyond mortality, e.g., the avoidance of surgery and PROs such as pain. 2) Physicians acknowledge the scientific and clinical trial limitations of relying primarily on OS, but note that OS limitations vary by cancer type / stage. 3) Regulators are accepting of non-OS endpoints, providing accelerated / conditional approvals when they are used as surrogates for OS or when they have standalone value, and increasingly expect PROs in submission dossiers. 4) Payers are uncertain, as without appropriate validation, drugs approved based on non-OS endpoints risk additional treatment burden and cost to healthcare systems without patient benefit. The limited alignment in value perception among stakeholders is further complicated as this may shift during the course of the disease – e.g., patients at early stages may value treatments which prolong survival but may place more emphasis on quality of life and freedom from progression as the disease advances. Conclusions: The value of non-OS endpoints and PROs is increasingly recognised, particularly by physicians and regulators; payers, however, can be less accepting, driven largely by uncertainties around their value, as surrogates or as stand-alone measures of benefit. Stakeholders must align on the value of non-OS endpoints and PROs, ensuring they are fit for purpose for each cancer type / stage, to improve their acceptance and advance patient access to novel therapies.

128P Long-term outcomes of neoadjuvant immunotherapy plus chemotherapy in early-stage triple-negative breast cancer: An extracted individual patient data and trial-level meta-analysis

Neoadjuvant therapy combining immunotherapy (IO) and chemotherapy (CT) is the standard of care in early-stage triple-negative breast cancer (ESTNBC), following the results of the KEYNOTE-522. However, overall survival (OS) gain is uncertain so far. This study aims to evaluate long-term outcomes of neoadjuvant IO plus CT for ESTNBC. We conducted a systematic review using PubMed, Embase, and Cochrane databases until February 13th, 2023. Randomized phase II or III trials evaluating neoadjuvant IO plus CT versus CT alone for ESTNBC were selected. A meta-analysis of extracted individual patient (pt) data (eIPD) was performed to evaluate event-free survival (EFS) and OS outcomes. Individual pt data was reconstructed from reported Kaplan-Meier plots through WebPlotDigitizer and the R package IPDfromKM and further combined. In addition, we conducted a trial-level meta-analysis using fixed and random effects models. Comparisons were made with Cox regression. The literature search resulted in 107 items, and 4 trials with EFS or OS data available were included (Keynote 522, IMpassion 031, I-SPY 2 and GeparNuevo). 1456 patients were included in EFS analysis (900 in IO arm versus 556 in control arm) and 1348 patients in OS analysis (872 versus 476 patients, respectively). The addition of neoadjuvant IO to CT was associated with better EFS and OS in eIPD analysis (Table). Median OS and EFS were not achieved. The trial-level meta-analysis yielded similar results (fixed effects model: HR 0.66, 95%CI 0.48-0.90; random effects model: 0.57, 95% CI 0.33-1.01). Table: 128PeIPD meta-analysisIO armControl armHR95% CIP4-year EFS84%73%0.600.47 - 0.76< 0.0014-year OS90%84%0.670.49 - 0.930.015 Open table in a new tab This meta-analysis suggests that the addition of IO to neoadjuvant CT in ESTNBC provides a significant improvement in EFS (absolut gain of 11% in 4 years) and a possible OS benefit (significant in the eIPD and in the trial-level fixed effects model meta-analysis). Longer follow-up with mature OS data are awaited to confirm these results.

Efficacy and Toxicity of Combined Inhibition of EGFR and VEGF in Patients With Advanced Non-small Cell Lung Cancer Harboring Activating EGFR Mutations: A Systematic Review and Meta-analysis.

Dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways have demonstrated promising results for treatment of advanced non-small cell lung cancer. We conducted a systematic review and meta-analysis to assess the efficacy and toxicity of the combined treatment with EGFR tyrosine kinase inhibitors (TKIs) and VEGF blockade for patients with advanced non-small cell lung cancer harboring activating EGFR mutations, in comparison to EGFR TKIs alone. The electronic databases were searched for relevant randomized trials between 2000 and 2022. The primary endpoints were overall survival (OS) and progression-free survival. Secondary endpoints included objective response rate (ORR), disease control rate, and grade ≥3 adverse events (AEs). The pooled hazard ratios (HR) and odds ratios were meta-analyzed using the generic inverse variance and the Mantel-Haenszel methods. A total of 1528 patients from 8 trials were evaluated for analyses. The combination treatment decreased the risk of disease progression by 37% (HR=0.63; 95% CI, 0.56 to 0.72) but had no added benefit on OS compared with EGFR inhibition alone (HR=0.90; 95% CI, 0.76 to 1.05). There was no significant difference in objective response rate or disease control rate between treatments. There was a significantly increased number of AEs reported in the dual treatment arm (odds ratio=3.02; 95% CI, 1.71 to 5.31), with proteinuria and hypertension being the most significantly increased AEs. This meta-analysis suggests combined inhibition of EGFR and VEGF pathways significantly improves progression-free survival, with no OS benefit, and increases AEs. Mature OS data are needed along with results from more trials exploring this strategy with third-generation EGFR TKIs to strengthen these results.

816P Investigating surrogate endpoints (SE) for overall survival (OS) in first-line (1L) advanced melanoma: A pooled-analysis of immune checkpoint inhibitor (ICI) trials

ICIs transformed the treatment of advanced melanoma with substantial improvements in OS. Establishing valid SEs for OS enables earlier assessment of randomized controlled trials (RCTs) of ICIs due to lengthy follow-up required to observe mature OS data. We examined progression-free survival (PFS), time-to-next treatment (TNT) and objective response rate (ORR) as potential SEs for OS in 1L advanced melanoma by pooling patient-level data from 4 RCTs (CheckMate [CM] 066, 067, 069 & 511) of nivolumab, ipilimumab, and their combinations. Individual-level (IL)-correlation measures - Spearman’s (ρ) & Kendall’s (τ) rank correlation coefficients for PFS and TNT, and an odds ratio (OR) for survival due to presence of objective response - were derived from copula models. For the trial-level (TL)-correlation, surrogacy equations and coefficients of determination (R2) between the treatment effects on SEs and OS were estimated via regression. Primary analyses used all patients (n=1865) from all RCTs. Sensitivity of the results were tested with respect to BRAF-status and removal of CM 069 due to imbalances in subsequent systemic therapy and ICI use between the arms of this study. At the IL, ORR was strongly correlated with OS, whereas both PFS & TNT showed moderate correlation with OS. All SEs were moderately correlated with OS at the TL (Table). Removing CM 069 from the analyses only marginally affected IL-correlations (≤ 0.01 change in ρ and τ, 4.5% change in the OR) but greatly strengthened TL-correlations for all SEs (R2 ≥ 0.87 with significantly narrower 95% CIs for all SEs). IL-correlations were insensitive to BRAF status, whereas TL-correlations were slightly stronger for the BRAF wild-type.Table: 816PCorrelationρ [95% CI]τ [95% CI]R2 [95% CI]PFS - OS0.72 [0.71, 0.73]0.53 [0.49, 0.57]0.71 [0.23, 1.00]TNT - OS0.77 [0.76, 0.78]0.58 [0.55, 0.62]0.75 [0.32, 1.00]ORR - OSOR12.29 [9.78-14.80]0.62 [0, 1.00] Open table in a new tab With moderate-to-strong correlation to OS on both levels, all candidate SEs can assist predictions for OS benefits of ICIs with a range of uncertainty depending on BRAF-status and subsequent treatment patterns.

External control cohorts for the single-arm LIBRETTO-001 trial of selpercatinib in RET+ non-small-cell lung cancer

BackgroundData for selpercatinib [a selective REarranged during Transfection (RET) inhibitor] from a single-arm trial (LIBRETTO-001, NCT03157128) in RET-fusion-positive advanced/metastatic non-small-cell lung cancer (NSCLC) were used in combination with external data sources to estimate comparative efficacy [objective response rate (ORR), progression-free survival, and overall survival (OS)] in first- and second-line treatment settings.MethodsPatient-level data were obtained from a de-identified real-world database. Patients diagnosed with advanced/metastatic NSCLC with no prior exposure to a RET inhibitor and one or more prior line of therapy were eligible. Additionally, individual patient-level data (IPD) were obtained from the pemetrexed + platinum arm of KEYNOTE-189 (NCT03950674, first line) and the docetaxel arm of REVEL (NCT01168973, post-progression). Patients were matched using entropy balancing, doubly robust method, and propensity score approaches. For patients with unknown/negative RET status, adjustment was made using a model fitted to IPD from a real-world database.ResultsIn first-line unadjusted analyses of the real-world control, ORR was 87.2% for LIBRETTO-001 versus 66.7% for those with RET-positive NSCLC (P = 0.06). After adjustment for unknown RET status and other patient characteristics, selpercatinib remained significantly superior versus the real-world control for all outcomes (all P < 0.001 except unadjusted RET-fusion-positive cohort). Similarly, outcomes were significantly improved versus clinical trial controls (all P < 0.05).ConclusionsFindings suggest improvement in outcomes associated with selpercatinib treatment versus the multiple external control cohorts, but should be interpreted with caution. Data were limited by the rarity of RET, lack of mature OS data, and uncertainty from assumptions to create control arms from external data.

Osimertinib: A Review in Completely Resected, Early-Stage, EGFR Mutation-Positive NSCLC.

Osimertinib (TAGRISSO®) is an orally administered, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that is approved for the adjuvant treatment of adults with completely resected, stage IB-IIIA, EGFR sensitizing mutation (exon 19 deletion or exon 21 [L858R] substitution)-positive non-small cell lung cancer (NSCLC). In the pivotal ADAURA trial in adults with completely resected, early-stage, EGFR mutation-positive (EGFRm+) NSCLC, osimertinib adjuvant therapy significantly prolonged disease-free survival (DFS) compared with placebo in the overall population of patients with stage IB-IIIA disease, as well as in the primary population of patients with stage II-IIIA disease. A DFS benefit of osimertinib was seen irrespective of whether or not patients received prior adjuvant chemotherapy. Overall survival (OS) data were very immature at the time of the analysis of DFS, and more mature OS data are awaited with interest. Osimertinib adjuvant therapy did not adversely affect health-related quality of life and was generally well tolerated, with a manageable safety profile and no new safety signals identified. Based on the available evidence, osimertinib is thus an appropriate targeted option for the adjuvant treatment of adults with completely resected, stage IB-IIIA, EGFRm+ NSCLC.

Updated overall survival (OS) analysis for ProCAID: A randomized, double-blind, placebo-controlled phase II trial of capivasertib with docetaxel versus docetaxel alone in metastatic castration-sensitive prostate cancer (mCRPC).

108 Background: The AKT pathway is frequently deregulated in mCRPC. ProCAID tested addition of capivasertib, a potent selective inhibitor of all three AKT isoforms (AKT1/2/3) to docetaxel chemotherapy vs. placebo plus docetaxel for mCRPC. The primary analysis showed no difference between treatment arms for the primary endpoint of composite progression free survival (cPFS). However, OS, which was a secondary endpoint, was extended in the capivasertib plus docetaxel arm. cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway biomarker status (Crabb et al, J Clin Oncol 2021;39(3):190-201). Methods: An updated analysis of mature OS data was undertaken once events reached ≥65% by Cox proportional hazards model, adjusted for minimisation factors, within the intent to treat (ITT) population (n = 150). Patients (pts) and investigators remained blinded to treatment allocation. We also investigated OS outcomes within subsets based on prior androgen receptor targeted agent (ARTA) exposure to abiraterone and/or enzalutamide (abi/enza) and the balance of post-trial life extending treatment use by treatment arm. Funding: Cancer Research UK (C9317/A16029, CRUK/12/042) and AstraZeneca. Results: At this OS update, 99 pts (66.0%) had died, with 88 of these deaths (88.9%) due to prostate cancer. 5 pts (3.3%) remained on capivasertib or placebo. Median OS was 25.3 months for the capivasertib plus docetaxel arm vs. 20.3 months for placebo plus docetaxel (hazard ratio (HR) 0.70, 95% confidence interval (CI) 0.47 to 1.05; nominal p = 0.09). One, or more, subsequent life extending treatment options, including abiraterone, enzalutamide, radium-223 and cabazitaxel, were received by 99 pts (66.0%) and were balanced between treatment arms (68% capivasertib, 64% placebo). 101 pts (67.3%; 51 capivasertib, 50 placebo) had received abi/enza prior to entering ProCAID. Within this subgroup, OS benefit for capivasertib plus docetaxel (median OS 31.1 months) was maintained vs. placebo plus docetaxel (median OS 19.3 months; HR 0.57, 95% CI 0.36 to 0.91), but not in the remaining 49 pts who were naive to prior abi/enza (median OS 31.1 vs. not reached respectively; HR 1.43, 95% CI 0.63 to 3.23). These updated OS results remained consistent irrespective of biomarker status for PI3K/AKT/PTEN pathway activation. No clinically significant differences from the previously reported safety outcomes were seen with extended follow up of this trial. Conclusions: OS remains longer within the ProCAID ITT population with the addition of capivasertib to docetaxel for mCRPC. This does not appear to be explained by subsequent treatment choices. Exploratory analysis found prolonged OS with capivasertib within a subset of pts previously exposed to an ARTA which should be evaluated in prospective trials. Clinical trial information: NCT02121639.

POSB11 Correlation and Prognostic Value of Surrogate Endpoints and Overall Survival (OS) in Multiple Myeloma (MM): A Systematic Literature Review (SLR)

Emerging therapies in MM increase OS but also prolong time to mature OS data. This research aims to critically review and evaluate potential surrogate endpoints for OS in MM and to explore if these could be used to support health technology assessments (HTAs) for new therapies when mature OS data are unavailable.

Oncology drugs and added benefit: insights from 3 European health technology assessment agencies on the role of efficacy endpoints

Objective This study aimed to understand the impact of different efficacy endpoints on reimbursement decisions made by health technology assessment (HTA) bodies. Materials and methods European Medicines Agency (EMA) oncology product marketing authorizations were screened to identify products that completed review by 3 HTA bodies during 2016–2019: United Kingdom’s National Institute for Health and Care Excellence, Germany’s Gemeinsamer Bundesausschuss, and France’s Haute Autorité de Santé. Each decision’s endpoint information, including overall survival (OS) and progression-free survival (PFS), was extracted. Each endpoint’s influence on added benefits rating (the degree of added benefit as judged by the HTA agency) and full reimbursement (i.e. reimbursed population to label) decisions was tested using bivariate analyses. Results An increasing trend was observed toward HTA submissions with immature OS data (36.8% and 71.4% in 2016 and 2019, respectively), which was a predictor of limited added benefit (p < .001). Regarding data availability, 63% of submissions provided OS, 2% provided PFS without OS; and 35% provided neither. OS availability significantly influenced added benefit (p < .001) but not full reimbursement (p > .05) decisions, whereas PFS without OS had no significant impact compared with either OS or PFS data for either outcome (p = .99). Conclusions The trend toward fewer products filing mature OS data over time suggests sponsors may be increasingly confident achieving reimbursement with surrogate endpoint data, although mature OS data provided the strongest correlation to positive reimbursement decisions. Notably, in some locally advanced settings, OS data maturity will take a long time to obtain. To expedite patient access to new medicines, payers should consider the acceptance of surrogate endpoints predictive of clinical benefit.

The Impasse on Overall Survival in Oncology Reimbursement Decision-Making: How Can We Resolve This?

Mature overall survival (OS) data are often unavailable at the time of regulatory and reimbursement decisions for a new cancer treatment. For patients with early-stage cancers treated with potentially curative treatments, demonstrating an OS benefit may take years and may be confounded by subsequent lines of therapy or crossover to the investigational treatment. For patients with advanced-stage cancers, mature OS data may be available but difficult to interpret for similar reasons. There are strong opinions about approval and reimbursement in the absence of mature OS data, with concerns over delay in patient access set against concerns about uncertainty in long-term benefit. This position paper reflects our individual views as patient advocate, clinician or health economist on one aspect of this debate. We look at payer decisions in the absence of mature OS data, considering when and how non-OS trial outcomes could inform decision-making and how uncertainty can be addressed beyond the trial, supporting these views with evidence from the literature. We consider when it is reasonable for payers to expect or not expect mature OS data at the initial reimbursement decision (based on criteria such as cancer stage and treatment efficacy) acknowledging that there are settings in which mature OS data are expected. We propose flexible strategies for generating and appraising patient-relevant evidence, including context-relevant endpoints and quality of life measures, when survival rates are good and mature OS data are not expected. We note that fair reimbursement is important; this means valuing patient benefit as shown through prespecified endpoints and reappraising if there is ongoing uncertainty or failure to show a sustained benefit. We suggest that reimbursement systems continue to evolve to align with scientific advances, because innovation is only meaningful if readily accessible to patients. The proposed strategies have the potential to promote thorough assessment of potential benefit to patients and lead to timely access to effective medicines.

Real-World Conditional Survival Analysis of Patients with Relapsed/Refractory Classical Hodgkin's Lymphoma in the US

Introduction:While the majority of patients (pts) with newly diagnosed classical Hodgkin's lymphoma (cHL) achieve remission following first-line therapy, approximately 30-40% will relapse or become refractory (R/R). Despite R/R status, the 5-year relative survival rate in this population is high (ranging from 78% to 92%) (American Cancer Society 2020). While overall survival (OS) is an unambiguous measure of efficacy in clinical trials, using it as a primary end point requires a long duration of follow-up and may prolong the process of identifying novel and potentially beneficial therapy. Surrogate outcomes, such as progression-free survival (PFS) and time to progression (TTP) are sometimes regarded as valid alternatives when assessing efficacy of a treatment in the absence of mature OS data. The objectives of this study were to assess the conditional survival (CS) given prior PFS among R/R cHL pts treated in the real-world setting. Methods:This retrospective cohort study used electronic medical record (EMR) data of US pts from a network of oncology practices, including practices affiliated with CancerLinQ, maintained in the Definitive Oncology Dataset. Eligible adult (≥18 years) pts who had a confirmed diagnosis of cHL and ≥1 R/R event that occurred between 2000 to 2019 were included. Refractory disease was defined as not achieving a complete or partial response (CR or PR) during a line of therapy. Relapsed disease was defined as the reappearance of cHL at any time after the end of treatment after having achieved a CR or PR. PFS and OS were measured from the start of second-line [2L] therapy to the earlier or disease progression or death; pts without evidence of disease progression or death were censored at the last observed visit. The association between PFS and OS was quantified through the nonparametric Kendall tau rank correlation for bivariate censored data. CS was defined as the Kaplan-Meier probability of surviving an additionalymonths (from the start of 2L), given no OS or PFS event in the previousx(&amp;lt; y) months. Results:A total of 286 R/R cHL pts were included. Most pts were Caucasian (77.3%, n=221) with a median age of 35 years (range: 19-86) at the first R/R event. Median length of follow-up was 12 months from the first R/R event. The most common B symptoms reported were night sweats (38.8%, n=111), weight loss (36.4%, n=104), and fatigue (27.3%, n=78). More than half of pts (54.9%, n=157) received autologous stem-cell transplant (SCT) and 6.6% (n=19) received allogenic SCT. Two-hundred twenty-six pts (79.0%) had documented 2L therapy (first R/R event). From the first R/R event, among these 226 pts, median PFS was 21.0 months (95% confidence interval [CI]: 15.1, 52.5) and median OS was 146.7 months (95% CI: 119.9, not achieved [NA]). CS rates among pts alive without disease progression increased with time: 1-year and 6-year survival rates were 95.7% (95% CI: 91.5, 97.8) and 79.3% (95% CI: 70.5, 85.7), respectively, in pts alive without progression at 3 months, but increased to 100.0% (95% CI: 100, 100) and 94.6% (95% CI: 79.9, 98.6) in pts alive without progression at 3-years (Table). The calculated Kendall tau correlation was 0.42 (p&amp;lt;0.0001), which suggested a statistically significant dependence between PFS and OS. Conclusion:In the real-world setting, R/R cHL pts with longer time without disease progression had lower rates of death and better prognosis. Results from this study support a relationship between PFS and OS; however, further validation and acceptance of PFS as a surrogate endpoint in cHL is required. Establishing these relationships may inform future clinical trial design and interpretation of interim trial data. Disclosures Desai: Merck &amp; Co., Inc:Current Employment, Current equity holder in publicly-traded company.Yang:Merck &amp; Co, Inc.:Current Employment.Gilligan:ConcertAI:Current Employment;Merck &amp; Co., Inc.:Research Funding.Li:Merck &amp; Co., Inc.:Current Employment, Current equity holder in publicly-traded company.Raut:Merck &amp; Co., Inc.:Current Employment.Nahar:Merck Sharp &amp; Dohme, Corp., a subsididary of Merck &amp; Co., Inc., Kenlworth, NJ, USA:Current Employment.

Apalutamide: A Review in Metastatic Castration-Sensitive Prostate Cancer.

Apalutamide (Erleada®) is an oral selective androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. It is approved in the EU and the USA for the treatment of adult men with metastatic castration-sensitive prostate cancer (mCSPC). In a multinational, phase III study (TITAN) in this patient population, the addition of apalutamide (240mg once daily) to androgen deprivation therapy (ADT) significantly improved median radiographic progression-free survival (rPFS), median overall survival (OS) and the median time to cytotoxic chemotherapy, while maintaining health-related quality of life (HR-QOL) and not substantially differing from placebo plus ADT in safety. Although mature OS data are awaited with interest, the addition of apalutamide to ADT extends the treatment options available for standard of care in adult men with mCSPC.

PCN413 A BAYESIAN MIXTURE CURE MODEL USING INFORMATIVE PRIORS

The use of mixture cure models (MCMs) is becoming more relevant within health technology assessment (HTA) of curative cancer treatments to extrapolate overall survival (OS). At HTA submission, survival data may not be mature enough to reliably estimate cure and extrapolate survival for both treatment arms. To improve the accuracy in MCMs, progression-free survival (PFS) cure rates or published mature OS data can be used as priors to inform OS. In this study, a Bayesian MCM with priors is introduced to predict immature OS rates in previously untreated advanced melanoma. The MCM with priors was tested on immature data from an RCT assessing nivolumab versus dacarbazine. The PFS curve in this trial showed a cure rate of 40% for nivolumab. Mature trial data assessing ipilimumab+dacarbazine versus dacarbazine showed a cure rate of 10% for dacarbazine. The cure rates were incorporated as prior information using a logit model. of the MCM with priors were compared to the MCM without priors and standard Weibull distribution. The predicted cure rates and survival extrapolations for the three approaches were validated with mature OS data from the long-term follow-up study of nivolumab versus dacarbazine. The MCM with priors estimated cure rates of 37.48% and 9.75% for nivolumab and dacarbazine, respectively compared to 19.99% and 0.65% without priors. The mean OS was 8.1 and 2.6 years with priors, 4.4 and 1.1 years without priors, and 4.3 and 1.0 years with standard Weibull for nivolumab and dacarbazine, respectively. The validation data closest resembled the survival predictions of the MCM with priors, followed by Weibull and MCM without priors. The use of informative prior distributions produced the most accurate results compared to standard Weibull extrapolation and MCM without priors. Prior derivation based on literature and expert opinion can improve the fit of mixture cure models considerably.

475O - Overall survival (OS) from the AURA3 phase III study: Osimertinib vs platinum-pemetrexed (plt-pem) in patients (pts) with EGFR T790M advanced non-small cell lung cancer (NSCLC) and progression on a prior EGFR-tyrosine kinase inhibitor (TKI)

475O - Overall survival (OS) from the AURA3 phase III study: Osimertinib vs platinum-pemetrexed (plt-pem) in patients (pts) with EGFR T790M advanced non-small cell lung cancer (NSCLC) and progression on a prior EGFR-tyrosine kinase inhibitor (TKI)

New Hormonal Agents in Patients With Nonmetastatic Castration-Resistant ProstateCancer: Meta-Analysis of Efficacy and Safety Outcomes.

In the past few years several hormonal agents have been tested in patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) leading to an impressive improvement in terms of metastases-free survival (MFS). We performed a meta-analysis aimed to: (1) estimate the pooled effect of new hormonal compounds in terms of MFS, overall survival (OS) in overall and specific subpopulations; and (2) estimate the effect of high-grade toxicities of these drugs. We identified 881 studies published between January 1, 2010 and February 16, 2018 on PubMed/Medline, Cochrane Library, and Scopus. Three randomized placebo controlled clinical trials were selected (PROSPER, SPARTAN, and ARAMIS). Because of the absence of individual data, all of the analyses performed were made on aggregated data provided in selected studies. We used the inverse variance technique for the meta-analysis of the hazard ratios collected for MFS and OS analysis. Fixed and randomized models were used. Relative risk and 95% confidence intervals and risk difference were estimated considering the number of Grade 3 adverse events in treatment and control arms. Administration of new hormonal compounds in nmCRPC patients led to a significant benefit in MFS in the overall population and in all subgroups analyzed. These agents might also improve OS but longer follow-up is needed to confirm this hypothesis. Indeed results of OS analysis should be carefully evaluated because none of the studies selected provided mature OS data. Administration of these agents resulted in a significant increased risk of treatment-related death, high cardiovascular toxicity, hypertension, fractures, and falls. Administration of new hormonal compounds prolongs the time of metastases occurrence and might prolong also survival in patients with nmCRPC. Treatment-related toxicity is an important issue because these agents increase the risk of death, cardiovascular toxicity, hypertension, fractures, and risk of falls.

Estimating Lifetime Benefits Associated with Immuno-Oncology Therapies: Challenges and Approaches for Overall Survival Extrapolations.

BackgroundStandard parametric survival models are commonly used to estimate long-term survival in oncology health technology assessments; however, they can inadequately represent the complex pattern of hazard functions or underlying mechanism of action (MoA) of immuno-oncology (IO) treatments.ObjectiveThe aim of this study was to explore methods for extrapolating overall survival (OS) and provide insights on model selection in the context of the underlying MoA of IO treatments.MethodsStandard parametric, flexible parametric, cure, parametric mixture and landmark models were applied to data from ATLANTIC (NCT02087423; data cut-off [DCO] 3 June 2016). The goodness of fit of each model was compared using the observed survival and hazard functions, together with the plausibility of corresponding model extrapolation beyond the trial period. Extrapolations were compared with updated data from ATLANTIC (DCO 7 November 2017) for validation.ResultsA close fit to the observed OS was seen with all models; however, projections beyond the trial period differed. Estimated mean OS differed substantially across models. The cure models provided the best fit for the new DCO.ConclusionsStandard parametric models fitted to the initial ATLANTIC DCO generally underestimated longer-term OS, compared with the later DCO. Cure, parametric mixture and response-based landmark models predicted that larger proportions of patients with metastatic non-small cell lung cancer receiving IO treatments may experience long-term survival, which was more in keeping with the observed data. Further research using more mature OS data for IO treatments is needed.Electronic supplementary materialThe online version of this article (10.1007/s40273-019-00806-4) contains supplementary material, which is available to authorized users.