Ratio For Progression-free Survival Research Articles

Prospective Randomized Study of Prophylactic Ciprofloxacin Versus Levofloxacin in Hematopoietic Stem Cell Transplant Patients: An Interim Report

Infection is a serious complication of hematopoietic stem cell transplantation (SCT). However, the optimum oral agent for antibacterial prophylaxis in SCT recipients remains uncertain. Different antibiotics might affect incidence of blood stream infections, resistance, Clostridium difficile, gut microbiome, GVHD and relapse. To explore this we started this first clinical trial of levofloxacin (Levo) versus ciprofloxacin (Cipro) at our center. Methods: This is a single center prospective randomized study. Patients who meet the SCT program criteria to undergo autologous or allogeneic hematopoietic stem cell transplantation are eligible. Results: We present interim results. 111 consecutive patients were randomized since June 2018. At the time of the present report 102 of these patients have follow up for 60 days or more. There were 62 males and 40 females. Median age at time of SCT was 61. Fifty received Cipro and 52 received Levo. Fifty-six patients had autologous (27 Cipro and 29 Levo) while 46 patients had allogeneic SCT (23 Cipro and 23 Levo). For allogeneic SCT, 12 patients in each group had ATG. Time to engraftment and length of stay were similar in both groups. In the Cipro group 6 patients (12%) had bacteremia while in the Levo group 7 (13%) had bacteremia. Of patients with bacteremia, in the Cipro group none had Gram negative bacteremia while in the Levo group 4 had gram negative bacteremia (OR 9.37, p = 0.137). In the Cipro group 6 patients had gram positive bacteremia while in the Levo group 3 patients had gram positive bacteremia (OR 2.22, p = 0.277). In the Cipro group, 6 (12%) had clostridium difficile while in the Levo group only 1 (1.9%) had Clostridium difficile (OR 6.95, p = 0.078). Acute GVHD of all grades accrued in 17 patients (34%) in Cipro group and in 16 patients (30.7%) in the Levo group. Grade III-IV aGVHD occurred in 6 patients (12%) in Cipro group and in 3 patients (5.8%) in the Levo group (OR 2.23, p = 0.277). The hazard ratio for progression free survival was 0.67 (95% CI: 0.27, 1.67), p=0.395 for Levo vs. Cipro. The hazard ratio for overall survival, adjusted for auto/allo and age at transplant was 0.29 (95% CI: 0.09, 0.95), p = 0.041, for Levo vs. Cipro. However, 3 of deaths in the Cipro group were not related to type of antibacterial prophylaxis (listeriosis from contaminated food, fungal pneumonia in a wooden-house builder and stroke from intraventricular thrombus). So, unadjusted hazard ratio for overall survival (Levo vs. Cipro): 0.41 (95% CI: 0.13, 1.34), p = 0.142. Hazard ratio for overall survival (Levo vs. Cipro), adjusting for allo/auto and age at transplant: 0.39 (95% CI: 0.11, 1.33), p = 0.132. Conclusion: At this point, in this interim analysis, there seems to be a trend for Cipro to protect patients from gram negative bacteremia compared to levo. As a trade-off, there is higher trend for Clostridium difficile in the Cipro group compared to Levo group, but none is statistically significant so far.

The Moore Criteria: Applicability in a diverse, non-trial, recurrent cervical cancer population

ObjectiveThe Moore Criteria is a prognostic index for recurrent or metastatic cervical cancer based on five factors. The criteria were developed retrospectively and validated prospectively in clinical trial populations receiving systemic chemotherapy (C). Our objective was to evaluate the prognostic value of the Moore Criteria in a largely minority, non-trial population at first recurrence. MethodsPatients treated for recurrent cervical cancer diagnosed between 2012 and 2017 were analyzed retrospectively. Progression free survival (PFS) was defined from the date of recurrence to date of second recurrence. Overall survival (OS) was defined from the date of recurrence to date of death. ResultsOf 274 patients identified, 78 were treated in the second line. 48 (61.5%) were Hispanic, 22 (28.2%) were black, and 7 (9%) were white non-Hispanic. By Moore criteria, 9 patients (11.5%) were classified as low-risk, 48 (61.5%) as moderate risk, and 21 (26.9%) as high-risk. 53 patients (67.9%) received C, and 25 (32.1%) received other treatment modalities without C. The high-risk category carried a significantly higher hazard ratio for both PFS (5.24, p < .001) and OS (3.15, p = .002) compared with the low- and intermediate-risk combined group. The low- and intermediate-risk groups demonstrated 78.9% response rate, compared with 33.3% in the high-risk category (p = .001). Black race did not affect survival or response rate. ConclusionThe Moore Criteria carries prognostic value across a diverse recurrent cervical cancer population outside of the clinical trial setting. Our data suggest that in a non-trial population, black race is not predictive of worse OS or PFS.

Cyclin-dependent kinase 4 and 6 inhibitors in hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer: a meta-analysis of randomized clinical trials.

Breakthrough progress has been made in Cyclin-Dependent kinase 4 and 6 (CDK4/6) inhibitors when combined with endocrine therapy (ET) for hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Though significant improvements of progression-free survival(PFS) for CDK4/6 inhibitors were demonstrated, however, the results of overall survival (OS) profile were not consistent. This study is conducted to further evaluate the efficacy and safety of CDK4/6 inhibitors for HR+ /HER2- ABC, and explore the prefer population through subgroup analysis. We identified relevantrandomized controlled trials that compared CDK4/6 inhibitors plus ET to ET alone in HR+ /HER2- ABC. We calculated the hazard ratios (HRs) for PFS and OS, and risk ratios (RRs) for objective response rate (ORR), clinical benefit rate (CBR), adverse events (AEs). Statistical analysis was performed with the random-effects model. Eight trials and 4580 patients were included in this meta-analysis. Compared to ET alone, CDK4/6 inhibitors plus ET not only produced a significantly longer PFS (HR = 0.55, 95% confidence interval [CI] 0.50-0.59, p < 0.00001), but also manifested an extension of OS (HR = 0.79, 95% CI 0.67-0.93, p = 0.004) for HR+ /HER2- ABC. Similarly, the benefit was also manifested in ORR (RR = 1.47, 95% CI 1.30-1.67, p < 0.00001) and CBR (RR = 1.20, 95% CI 1.12-1.30, p < 0.00001). The improvements of PFS were observed in the combined treatment group as both the first-line (HR = 0.56) and the second-line therapy (HR = 0.53), and irrespective of menopausal status, the presence of visceral metastasis, previous treatment with chemotherapy, their race or age. Nevertheless, more hematologic and gastrointestinal adverse events were observed with CDK4/6 inhibitors. The most common Grade 3-4 AEs is neutropenia (RR 31.95). Significant advantages of PFS and OS were observed for CDK4/6 inhibitors in HR+/HER2- ABC. Furthermore, the benefit of PFS was across all subgroups. Though associated with an increased occurrence of AEs, most of which are reversible, manageable, and acceptable. Therefore, CDK4/6 inhibitors could be recommended as a preferred options for patients with HR+ /HER2- ABC.

Magnitude of advantage in tumor response contributes to a better correlation between treatment effects on overall survival and progression-free survival: a literature-based meta-analysis of clinical trials in patients with metastatic colorectal cancer.

Although it is suggested that the endpoints originated from the concept of tumor shrinkage dynamics, such as early tumor shrinkage and depth of response, are strongly associated with overall survival (OS) in patients with metastatic colorectal cancer (mCRC), they are yet to be validated as a single surrogate endpoint of OS by themselves. This study aimed to investigate the impact of advantage in tumor response on the correlation between treatment effects on progression-free survival (PFS) and OS in mCRC patients. Based on an electronic search, we identified randomized controlled trials of first-line therapy for mCRC. The impact of advantage in objective response rate (ORR) on the correlation between treatment effects on PFS and OS was evaluated based on Spearman correlation coefficients (rs). Forty-seven trials with a total of 24,018 patients were identified. The hazard ratio for PFS showed a relatively higher correlation with that for OS (rs = 0.63) when the trials were limited to those that demonstrated a larger difference in ORR, compared to the case for trials that demonstrated a smaller difference (rs = 0.32). This tendency was also observed in the subgroup analysis stratified by the types of treatment agents (targeted or non-targeted). The magnitude of advantage in tumor response was suggested to contribute to a better prediction of OS benefit based on PFS in patients with mCRC. The accuracy of OS estimation in mCRC is expected to be improved by considering the degree of tumor shrinkage in conjunction with PFS.

AJCC 8th edition prognostic staging provides no better discriminatory ability in prognosis than anatomical staging in triple negative breast cancer

BackgroundWe retrospectively compared the prognostic value between the AJCC 8th edition anatomic (AS) and prognostic staging (PS) system for triple negative breast cancer (TNBC) in a cohort from two involved institutions and a large population database.MethodsClinicopathological data of TNBCs were identified in two involved institutions (SYSUCC-PWH cohort). Data from SEER database during 2010–2015 was also accessed. We restaged all cases into AS and PS group according to the AJCC 8th staging system.ResultsA total of 611 and 31,941 TNBCs were identified in two cohorts, with a median follow-up of 53.5 and 27 months respectively. PS upstaged 46.1% of patients in SYSUCC-PWH cohort, and 62.4% in SEER cohort. No significant difference was observed in C index between AS and PS models for disease-specific survival (DSS), progression-free survival (PFS) or overall survival (OS) in either cohort. χ2 statistic and Hazard Ratio for PFS, DSS and OS showed better discrimination between IA and IB, IIB and IIIA, IIIA and IIIB in AS model than PS model. Besides, patients with IIIC unchanged stage showed worse PFS compared to those with AS IIIA or IIIB upstaged to PS IIIC in both cohorts(p = 0.049, p < 0.001).ConclusionsOur findings demonstrated that prognostic staging system did not provide better discriminatory ability in predicting TNBCs prognosis than anatomic staging system.

A meta-analysis comparing responses of Asian versus non-Asian cancer patients to PD-1 and PD-L1 inhibitor-based therapy

ABSTRACT Background Subgroup analysis of clinical trials of PD-1/PD-L1 inhibitors have reported ethnic differences in outcomes. We systematically collected published data and performed a meta-analysis to compare therapeutic efficacy in Asian and non-Asian patients receiving PD-1/PD-L1 inhibitors. Methods Eligible studies included phase II and III prospective clinical trials with available subgroup data on Asian versus non-Asian populations. Overall survival (OS) and progression-free survival (PFS) were used to evaluate differences in outcome between Asian versus non-Asian cancer patients. Results A total of 11,020 cancer patients from 19 prospective randomized controlled clinical trials were included. The overall estimated HR for OS was 0.69 with 95% CI of 0.61–0.77 in Asian versus 0.82 with 95% CI of 0.77–0.88 in non-Asian patients. The estimated hazard ratio (HR) for PFS measured 0.54 (95% CI, 0.32–0.76) and 0.69 (95% CI, 0.54–0.85) in Asian and non-Asian patients, respectively. Pooled ratios of OS HRs and PFS HRs reported in Asian versus non-Asian cancer patients were 0.84 (95% CI, 0.75–0.94) and 0.78 (95% CI, 0.59–0.97), respectively. Conclusions This meta-analysis shows for the first time that Asian cancer patients have a significantly improved survival benefit than non-Asian patients receiving PD-1/PD-L1 inhibitor-based therapy.

Moving Molecular Profiling to Routine Clinical Practice: A Way Forward?

Molecular profiling of a patient's tumor to guide targeted treatment selection offers the potential to advance patient care by improving outcomes and minimizing toxicity (by avoiding ineffective treatments). However, current development of molecular profile (MP) panels is often based on applying institution-specific or subjective algorithms to nonrandomized patient cohorts. Consequently, obtaining reliable evidence that molecular profiling is offering clinical benefit and is ready for routine clinical practice is challenging. In particular, we discuss here the problems with interpreting for clinical utility nonrandomized studies that compare outcomes in patients treated based on their MP vs those treated with standard of care, studies that compare the progression-free survival (PFS) seen on a MP-directed treatment to the PFS seen for the same patient on a previous standard treatment (PFS ratio), and multibasket trials that evaluate the response rates of targeted therapies in specific molecularly defined subpopulations (regardless of histology). We also consider some limitations of randomized trial designs. A two-step strategy is proposed in which multiple mutation-agent pairs are tested for activity in one or more multibasket trials in the first step. The results of the first step are then used to identify promising mutation-agent pairs that are combined in a molecular panel that is then tested in the step-two strategy-design randomized clinical trial (the molecular panel-guided treatment for the selected mutations vs standard of care). This two-step strategy should allow rigorous evidence-driven identification of mutation-agent pairs that can be moved into routine clinical practice.

The effect of antibiotics on clinical outcomes in immune-checkpoint blockade: a systematic review and meta-analysis of observational studies.

Pre-clinical and early clinical data suggests the microbiome plays an important role in oncogenesis and influences response to immune checkpoint blockade (ICB). The objective of this systematic review and meta-analysis was to determine whether antibiotics affect overall survival (OS) and progression free survival (PFS) in patients with solid malignancies treated with ICB. A systematic search of EMBASE, MEDLINE and conference proceedings was conducted for observational studies examining the effect of antibiotics on ICB. A random effects study-level meta-analysis was performed with pooling of the hazards ratio (HR) for OS and PFS. Meta-regression was used to determine the impact of the timing of antibiotic exposure on OS. 766 studies were identified, and 18 studies met the inclusion criteria. Of the 2889 patients included, 826 (28.6%) were exposed to antibiotics. The most common malignancies were lung (59%), renal cell carcinoma (RCC) or urothelial carcinoma (16.3%) and melanoma (18.7%). OS was prolonged in those without antibiotic exposure (pooled HR 1.92, 95% CI 1.37-2.68, p < 0.001). The effect of antibiotics on OS was greater in studies defining antibiotic exposure as 42days prior to initiation of ICB (HR 3.43, 95% CI 2.29-5.14, p < 0.0001). PFS was also longer in patients who did not receive antibiotics (pooled HR 1.65, 95% CI 1.3-2.1, p < 0.0001). In patients receiving ICB, OS and PFS are longer in patients who are not exposed to antibiotics. Antibiotic use in the 42days before starting ICB appears to be most detrimental to outcome.

Comparison of Oncologic Outcomes Between Two Alternative Sequences with Abiraterone Acetate and Enzalutamide in Patients with Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

Sequential treatment of androgen receptor axis targeted agents (ARAT), abiraterone acetate (ABI) and enzalutamide (ENZA), in metastatic castration-resistant prostate cancer (mCRPC) demonstrated some positive effects, but cross-resistances between ABI and ENZA that reduce activity have been suggested. Therefore, we conducted a meta-analysis to compare oncologic outcomes between the treatment sequences of ABI-ENZA and ENZA-ABI in patients with mCRPC. The primary endpoint was a combined progression-free survival (PFS), and the secondary endpoint was overall survival (OS). A total of five trials on 553 patients were included in this study. Each of the included studies was retrospective. In two studies including both chemo-naïve and post-chemotherapy mCRPC patients, for ABI-ENZA compared with ENZA-ABI, pooled hazard ratios (HRs) for PFS and OS were 0.37 (p < 0.0001; 95% confidence intervals (CIs), 0.23–0.60) and 0.64 (p = 0.10; 95% CIs, 0.37–1.10), respectively. In three studies with chemo-naïve mCRPC patients only, for ABI-ENZA compared with ENZA-ABI, pooled HRs for PFS and OS were 0.57 (p = 0.02; 95% CIs, 0.35–0.92) and 0.86 (p = 0.39; 95% CIs, 0.61–1.21), respectively. The current meta-analysis revealed that ABI-ENZA had a significantly more favorable oncological outcome, but the level of evidence was low. Therefore, large-scale randomized trials may be needed.

When compared to plasma‐based detection, osimertinib‐treated non‐small cell lung cancer (NSCLC) with tissue rebiopsy‐confirmed acquired T790M mutation is associated with better survival

Osimertinib has been approved by the Food and Drug Administration (FDA) of the United States (US) for the treatment of progressive non-small cell lung cancer (NSCLC) that has acquired T790M mutation during treatment with first-line epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI). We compared the progression-free survival (PFS) of patients whose T790M mutation was identified by tissue rebiopsy with those by plasma-based biopsy. This is a retrospective single-center cohort study conducted in Queen Mary Hospital, Hong Kong S.A.R. that included 118 Chinese patients with advanced NSCLC who had disease progression after treatment with a first-line EGFR tyrosine kinase inhibitor and received osimertinib upon detection of T790M mutation, either by tissue rebiopsy or plasma-based biopsy (by identification of circulating tumor DNA in the peripheral circulation). The primary endpoint is PFS. Patients with T790M mutation detected by tissue rebiopsy (n=22) had significantly better PFS than those by plasma-based biopsy (n=96) (median PFS: 415vs 224 days, P=.018) Hazard ratio for PFS, in favor of the tissue rebiopsy group, was 0.496 (95% confidence interval [CI]: 0.277-0.889). For patients who have NSCLC that progressed after first-line EGFR-TKI, rebiopsy by peripheral blood liquid biopsy and tissue rebiopsy for T790M mutation may have prognostic implication in terms of differences in PFS.

Alliance A041702: A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (≥ 70 Years of Age) with Chronic Lymphocytic Leukemia (CLL)

Alliance A041702: A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (≥ 70 Years of Age) with Chronic Lymphocytic Leukemia (CLL)

Progression-Free but No Overall Survival Benefit for Adult Patients with Bevacizumab Therapy for the Treatment of Newly Diagnosed Glioblastoma: A Systematic Review and Meta-Analysis.

Glioblastoma (GBM) is the most common high-grade primary brain tumor in adults. Standard multi-modality treatment of glioblastoma with surgery, temozolomide chemotherapy, and radiation results in transient tumor control but inevitably gives way to disease progression. The need for additional therapeutic avenues for patients with GBM led to interest in anti-angiogenic therapies, and in particular, bevacizumab. We sought to determine the efficacy of bevacizumab as a treatment for newly diagnosed GBM. We conducted a literature search using the PubMed database and Google Scholar to identify randomized controlled trials (RCTs) since 2014 investigating the safety and efficacy of bevacizumab in the treatment of adult patients (18 years and older) with newly diagnosed GBM. Only Level Ι data that reported progression-free survival (PFS) and overall survival (OS) were included for analysis. Random effects meta-analyses on studies with newly diagnosed glioblastoma were conducted in R to estimate the pooled hazard ratio (HR) for PFS and OS. Six RCTs met requirements for meta-analysis, revealing a pooled estimate of PFS HR suggesting a 33% decreased risk of disease progression (HR 0.67, 95% CI, 0.58–0.78; p < 0.001) with bevacizumab therapy, but no effect on OS (HR = 1, 95% CI, 0.85–1.18; p = 0.97). A pooled estimate of the mean difference in OS months of −0.13 predicts little difference in time of survival between treatment groups (95% CI, −1.87–1.61). The pooled estimate for the mean difference in PFS months was 2.70 (95% CI, 1.89–3.50; p < 0.001). Meta-analysis shows that bevacizumab therapy is associated with a longer PFS in adult patients with newly diagnosed glioblastoma, but had an inconsistent effect on OS in this patient population.

Community-driven development of a modified progression-free survival ratio for precision oncology trials

Abstract Background The success of a cancer therapy in an individual patient can be estimated by calculating the progression-free survival (PFS) ratio. First conceived by Daniel Von Hoff more than two decades ago, it is now increasingly being used in precision oncology trials. Here, the PFS ratio is defined as the PFS under a molecularly guided therapy (PFS2) divided by the PFS under the last systemic therapy before molecular tumour profiling (PFS1). A significant therapy response is usually defined as a PFS ratio above 1.3 or 1.5. Methods To investigate if current PFS ratio cut-offs are in line with the response evaluation by physicians, we conducted a survey among investigators of the MASTER (Molecularly Aided Stratification for Tumor Eradication Research) Program of the German Cancer Consortium. Physicians were asked to classify the success of molecularly guided therapies in 194 patients enrolled in the MOSCATO 01 trial based on PFS1 and PFS2 times. We received 100 complete replies. Results A comparison of classification profiles revealed three clusters of response assessments. Only one cluster (29% of physicians) was consistent with a PFS ratio cut-off of 1.3, whereas the remaining 71% of participants applied a different classification scheme that did not rely on the relation between PFS times alone, but also took into account absolute PFS1 intervals. Based on these community-driven insights, we developed a modified PFS ratio that factors in the influence of the absolute PFS1 interval. Applying the modified PFS ratio to two recent precision oncology trials, MOSCATO 01 and WINTHER, revealed significantly improved concordance with the physician-perceived clinical benefit, while the proportions of responders to molecularly guided therapies remained largely unchanged. Conclusions The modified PFS ratio may represent a meaningful clinical endpoint that could aid in the design and interpretation of future precision oncology trials. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

PNS26 USING SURROGATES FOR PREDICTION OVERALL SURVIVAL IN ONCOLOGY: CONSIDERATIONS FOR NEW TREATMENTS AND EARLIER STAGES OF CANCER

Overall survival (OS) is required to assess the cost-effectiveness of new oncology treatments. Trials often prioritize immediate outcomes like progression-free survival (PFS) and response to treatment and have incomplete data on OS. This is relevant for early-stage disease or treatments inducing sustained response where patients may have extended survival, limiting the number of deaths observed in the study. Modelers will sometimes rely on surrogacy analyses using aggregate data to correlate the benefits of treatment on surrogate outcomes, like progression or response, and longer-term outcomes like OS. For example, using an equation relating the magnitude of hazard ratios (HRs) for PFS to those of OS from past trials in the same type of cancer and at similar stage of disease to estimate for OS HR based on the observed HR for PFS in a new study. We caution that this approach may be problematic in two specific situations: in early stages of cancer and for treatments with a novel mechanisms of action (MOA). With early-stage cancer, where mortality isn’t yet aggressive, survival observed in trials may be highly affected by treatments assigned following discontinuation of the study treatments. Depending on the timing and location of the trials, these can vary considerably between the trials included in the surrogacy analyses and specifically from the trial for which a prediction is needed. In particular, patients in more recent trials may have access to newer, more effective later-line treatments. Thus, correlations between surrogate and OS may not be applicable to the current study. Similar issues arise with treatments with novel MOAs such as immunotherapies; these treatments can produce long sustained response, and hence prolonged survival. While limited mortality events during a trial can require relying on surrogate date, using surrogacy analyses from historical trials risks underestimating the benefits on OS in these cases.

480P - Safety and efficacy of dacomitinib for EGFR+ NSCLC in the subgroup of Asian patients from ARCHER 1050

480P - Safety and efficacy of dacomitinib for EGFR+ NSCLC in the subgroup of Asian patients from ARCHER 1050

A Systematic Review and Meta-Analysis of Bevacizumab in First-Line Metastatic Breast Cancer: Lessons for Research and Regulatory Enterprises.

The US Food and Drug Administration's accelerated approval and later withdrawal of bevacizumab in patients with metastatic breast cancer (mBC) is a seminal case for ongoing debates about the validity of using progression-free survival (PFS) as a surrogate measure for overall survival (OS) in cancer drug approvals. We systematically reviewed and meta-analyzed the evidence around bevacizumab's regulatory approval and withdrawal in mBC. We searched for all published phase II or III clinical trials testing bevacizumab as a first-line therapy for patients with mBC. Data were extracted on trial demographics, interventions, and outcomes. Descriptive analysis was stratified by whether the trial was initiated before, during, or after the accelerated approval. We used a cumulative random-effects meta-analysis to assess the evolution of evidence of the effect of bevacizumab on PFS and OS. We estimated the association between the trial-level PFS and OS effect using a nonlinear mixed-regression model. Fifty-two studies were included. Trial activity dramatically dropped after the accelerated approval was withdrawn. Eight clinical trials reported hazard ratios (hazard ratios) and were meta-analyzed. The cumulative hazard ratio for PFS was 0.72 (95% CI = 0.65 to 0.79), and the cumulative hazard ratio for OS was 0.90 (95% CI = 0.80 to 1.01). The regression model showed a statistically nonsignificant association between PFS benefit and OS benefit (β = 0.43, SE = 0.81). The US Food and Drug Administration's decision-making in this case was consistent with the evolving state of evidence. However, the fact that seven clinical trials are insufficient to conclude validity (or lack thereof) for a trial-level surrogate suggests that it would be more efficient to conduct trials using the more clinically meaningful endpoints.

Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis

BackgroundTherapeutic advances have greatly extended survival times in patients with multiple myeloma, necessitating increasingly lengthy trials when using survival outcomes as primary endpoints. A surrogate endpoint that can more rapidly predict survival could accelerate drug development. We conducted a meta-analysis to evaluate minimal residual disease (MRD) status as a valid progression-free survival (PFS) surrogate in patients with newly diagnosed multiple myeloma (NDMM). Materials and MethodsWe searched abstracts in PubMed, The American Society of Hematology, and the European Hematology Association for “myeloma,” “minimal residual disease,” and “clinical trial.” Because of the need to evaluate the treatment effect on MRD response, only randomized studies for subjects with NDMM were included. Details on the MRD-tested populations were required. The meta-analysis was performed by principles outlined at the 2013 United States Food and Drug Administration workshop on MRD in acute myeloid leukemia.42 For samples that were not measured for MRD and within the subset specified for MRD assessment, their MRD status was imputed from the samples that had known MRD status. Patients that were excluded from planned MRD assessment were considered MRD-positive. ResultsSix randomized studies, representing 3283 patients and 2208 MRD samples, met analysis inclusion criteria. MRD negativity rates ranged from 0.06 to 0.70. The treatment effect on the odds ratio for MRD-negative response strongly correlated with the hazard ratio for PFS with a coefficient of determination for the weighted regression line of 0.97. Our meta-analysis suggested that MRD status met both the Prentice criteria for PFS surrogacy. ConclusionsThese results support the claim that MRD status can be used as a surrogate for PFS in NDMM.

323P - Endocrine therapy alone versus targeted combination strategy as first line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials

BackgroundCombined endocrine/targeted approaches have been investigated as first-line treatment in hormone receptors positive metastatic breast cancer (BC). Randomized trials showed that the addiction of CDK (cyclin-dependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged >65 years) are under represented in most of the trials. Due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present meta-analysis aimed to understand the role of the new endocrine approaches in elderly women. MethodsThis meta-analysis included first line phase II/III randomized published trials comparing ET to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged > 65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Prospero registration number: CRD42019120215. Results8 studies were included: 4 (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found. ConclusionsThe novel experimental strategies showed an improvement in PFS in elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone, the magnitude of PFS benefit is age-independent. To define the role of novel agents, future trials should be designed taking in account not only the age, but also adequate geriatric assessment and comorbidity status. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureL. Cortesi: Speaker Bureau / Expert testimony: Astazeneca; Speaker Bureau / Expert testimony: Pierre Fabre Pharma. F. Piacentini: Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: Pfizer. S. Cascinu: Advisory / Consultancy, Speaker Bureau / Expert testimony: Bayer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Lilly. L. Moscetti: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Roche; Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis. All other authors have declared no conflicts of interest.

1278P - Validation of progression-free survival (PFS) as surrogate endpoint in randomised trials of immune checkpoint inhibitors in advanced solid cancers

BackgroundCombination of ICIs and chemotherapy (ICI-C) has become a more favourable design in recent trials. We have previously reported 6-month PFS rate (PFS6) is a good surrogate for 12-month overall survival rate (OS12) within treatment (ICI) arms, but had limited data to examine surrogate endpoints for treatment comparisons. We extend our work to validate prior findings by updating with data from more recent randomized controlled trials (RCTs), especially studies testing combination ICI-C. MethodsWe performed a literature search to identify eligible Phase (Ph) 2 and 3 RCTs of ICI. We excluded studies with sample size of<100 or control arms without active treatment. Efficacy data including objective response rate (ORR), PFS, OS, PFS6 and OS12 were extracted. We examined the associations of relative treatment comparisons between ORR risk ratio (RR) with hazard ratios (HRs) for PFS and OS. We also studied the correlations between ORR, PFS6 and OS12 within ICI arm. A correlation coefficient (r) of 0 indicates lack of association whereas 1 implies perfect surrogacy. ResultsForty-six RCTs (5 Ph2; 41 Ph3) with 51 treatment comparisons were identified. Associations between ORR RR with PFS HR, ORR RR with OS HR, and PFS HR with OS HR were r=0.67, r=0.42 and r=0.52 respectively. For the 16 RCTs of ICI-C, these associations were r=0.79, r=0.58 and r=0.64 respectively. For the 35 RCTs of ICI monotherapy, these associations were r=0.71, r=0.40 and r=0.54. Within the ICI arms, associations between ORR and PFS6, ORR and OS12, and PFS6 and OS12 were r=0.67, r=0.54 and r=0.79. Within ICI-C trials, these associations were r=0.60, r=0.56 and r=0.60 respectively. Within ICI monotherapy trials, these associations were r=0.51, r=0.46 and r=0.80 respectively. ConclusionsIn treatment comparison, the correlation between PFS and OS was modest, but stronger in ICI-C trials. Within ICI arms, PFS6 had stronger correlation with OS12 than ORR. PFS is recommended as a surrogate endpoint for ICI trials over ORR. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureM. Friedlander: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Lecturer fees: AstraZeneca; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Takeda. All other authors have declared no conflicts of interest.

926P - Erdafitinib (erda) versus available therapies in advanced urothelial cancer: A matching adjusted indirect comparison

BackgroundErda, a pan-fibroblast growth factor receptor (FGFR) inhibitor recently received accelerated US FDA approval for locally advanced or metastatic urothelial cancer (mUC) in adult patients (pts) with FGFR2/3 alterations who progressed on≥1 prior platinum-containing chemotherapy, based on a single-arm phase 2 study. In the absence of head-to-head studies, a matching-adjusted indirect comparison (MAIC) was used to compare the efficacy of erda relative to available therapies in mUC pts. MethodsSystematic literature review was performed to identify published randomized controlled trials (RCTs) of 2nd-line treatments (from 1990-on) in mUC pts with unknown FGFR status. Individual patient-level data (IPD) were used from the phase 2 study (NCT02365597) in mUC pts treated with erda (8mg/day). ORR (primary endpoint), overall survival (OS) and progression-free survival (PFS) were compared using an unanchored MAIC. The IPD were weighted to match the aggregated data from comparator studies. ResultsNine relevant RCTs of 6 comparators (docetaxel [D], vinflunine [V], pembrolizumab [Pb], atezolizumab [A], paclitaxel [P], and mixed-chemotherapy [D, V or P]) that were identified could be matched with. The matching-adjusted odds ratios (OR) for ORR were consistently >1 vs all comparators, suggesting higher ORR with erda treatment over all comparator 2nd-line therapies. The matching-adjusted hazard ratios (HRs) for OS and PFS vs all comparators were <1, suggesting better outcomes (PFS/OS) with erda. Results from the sensitivity analyses showed varied statistical significance, however, the overall trends were relatively similar. Study limitations: availability of comparable endpoints and baseline characteristics; small sample size of the erda study.Table926P MAIC results for base case scenario: Erda (in FGFR+ pts) vs available 2nd-line therapies in pts with unknown FGFR statusTableComparatorStudyN (Neff)ORR (OR [95% CI])OS (HR [95% CI])PFS (HR [95% CI])PembrolizumabNCT0225643679 (40)2.26 [1.11; 4.59]*0.61 [0.37; 0.99]*0.77 [0.58; 1.03]AtezolizumabNCT0230280774 (45)6.80 [3.55; 13.02]***0.58 [0.37; 0.92]*Mixed-chemotherapyNCT0225643679 (45)4.15 [2.04; 8.46]***0.54 [0.35; 0.85]**0.77 [0.56; 1.07]Mixed-chemotherapyNCT0230280774 (51)6.26 [3.37; 11.63]***0.54 [0.34; 0.84]**DocetaxelaNCT0128246368 (45)3.71 [1.11; 12.35]*0.72 [0.41; 1.25]0.51 [0.32; 0.80]*DocetaxelNCT0088033478 (42)3.98 [1.48; 10.74]**0.52 [0.31; 0.87]*0.84 [0.56; 1.26]DocetaxelNCT0178054584 (47)6.02 [2.48; 14.63]***0.37 [0.23; 0.61]***DocetaxelNCT0242612578 (63)3.46 [1.80; 6.66]**0.63 [0.47; 0.84]*VinflunineaNCT0031523778 (53)4.74 [2.21; 10.18]***0.57 [0.39; 0.84]**VinflunineNCT0183023161 (32)1.51 [0.45; 5.10]0.49 [0.24; 0.99]*0.96 [0.51; 1.81]PaclitaxelaNCT0094945568 (44)2.63 [1.03; 6.73]*0.59 [0.37; 0.95]*0.95 [0.64; 1.41]For most comparators, only the main characteristics (according to clinical experts; number of risk factors, ECOG, liver metastases, hemoglobin<10g/dl, visceral disease, liver/bone metastasis, metastatic disease, primary tumor site, smoking status, and time since prior therapy) were included in the base case matching process to maintain a reasonable effective sample size (Neff). aAll available characteristics were included. When type of ORR (assessment by independent review committees [IRR] or assessment by investigators) is not specified for the comparator study, IRR was used for erda as this leads to conservative results.*p≤0.05;**p≤0.01;***p≤0.0001 ConclusionsTreatment of FGFR+ mUC pts with erda may be associated with improved overall response, PFS and OS as compared to available therapies in pts with unknown FGFR status. Clinical trial identificationNCT02365597. Editorial acknowledgementPriya Ganpathy, MPharm, ISMPP CMPP™ (SIRO Clinpharm Pvt. Ltd, India) provided writing assistance and Harry Ma, PhD (Janssen Global Services) provided additional editorial support. Legal entity responsible for the studyJanssen Research & Development, LLC. FundingJanssen Research & Development, LLC. DisclosureY. Loriot: Honoraria (self), Consultancy / Advisory Role- Astellas Pharma, AstraZeneca, Janssen, Merck Sharp & Dohme, Pfizer, Roche, Ipsen, Seattle Genetics, Sanofi; Research Funding- Sanofi (Inst) S. Van Sanden: Shareholder / Stockholder / Stock options, Employee and stockholder: Janssen Research & Development. J. Diels: Shareholder / Stockholder / Stock options, Employee and Share holder: Janssen Reserach & Development. N. Rahhali: Shareholder / Stockholder / Stock options, Employee and stockholder: Janssen Research & Development. D. Seshagiri: Shareholder / Stockholder / Stock options, Employee & stockholder: Janssen Reserach & Development. B. Kowalski: Shareholder / Stockholder / Stock options, Employee & stockholder: Janssen Research & Development. S. Fleming: Shareholder / Stockholder / Stock options, Employee & stockholder: Janssen Research & Development. P. De Porre: Shareholder / Stockholder / Stock options, Employee & stockholder: Janssen Research & Development. A.O. Siefker-Radtke: Consulting / Advisory Role: AstraZeneca, Bristol-Myers Squibb, Eisai, EMD Serono, Genentech, Inovio Pharmaceuticals, Janssen, Lilly, Merck, NCCN; Speakers’ Bureau: Genentech; Research funding: Bristol-Myers Squibb, Janssen, Michael, Sherry Sutton; Fund for Urothelial Cancer: NIH, Takeda; Patents / Royalties / Other Intellectual Property: Methods of characterizing and treating molecular subsets of muscle-invasive bladder cancer.