Data from Personalized Antibodies for Gastroesophageal Adenocarcinoma (PANGEA): A Phase II Study Evaluating an Individualized Treatment Strategy for Metastatic Disease
Daniel V.T. CatenacciStephanie MoyaSamantha LomnickiLeah M. ChaseBryan PetersonNatalie ReizineLindsay AlpertNamrata SetiaShu-Yuan XiaoJohn HartUzma D. SiddiquiD. Kyle HogarthOliver S. EngKiran K. TuragaKevin K. RogginMitchell C. PosnerPaul J. ChangSunil NarulaMurtuza RampurwalaYuan JiTheodore KarrisonChih‐Yi LiaoBlasé N. PoliteHedy L. Kindler
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<div>Abstract<p>The one-year and median overall survival (mOS) rates of advanced gastroesophageal adenocarcinomas (GEA) are ∼50% and <12 months, respectively. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion-platform type II design with a survival primary endpoint. Of 68 patients by intention-to-treat, the one-year survival rate was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided <i>P</i> = 0.0024). First-line response rate (74%), disease control rate (99%), and median progression-free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study.</p>Significance:<p>This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial.</p><p><i>This article is highlighted in the In This Issue feature, p. 211</i></p></div>Keywords:
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The use of auxiliary endpoints may provide efficiencies for clinical trial design, but such endpoints may not have intrinsic clinical relevance or clear linkage to more meaningful endpoints. The purpose of this study was to generate a novel endpoint that considers both overall survival (OS) and earlier events such as progression-free survival (PFS) and determine whether such an endpoint could increase efficiency in the design of glioblastoma clinical trials.Recognizing that the association between PFS and OS varies depending on therapy and tumor type, we developed a statistical model to predict OS based on PFS as the trial progresses. We then evaluated the efficiency of our model using simulations of adaptively randomized trials incorporating PFS and OS distributions from prior published trials in neuro-oncology.When treatment effects on PFS and OS are concordant, our proposed approach results in efficiency gains compared with randomization based on OS alone while sacrificing minimal efficiency compared with using PFS as the primary endpoint. When treatment effects are limited to PFS, our approach provides randomization probabilities that are close to those based on OS alone.Use of OS as the primary endpoint, combined with statistical modeling of the relationship between OS and PFS during the course of the trial, results in more robust and efficient trial designs than using either endpoint alone.
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FigureThough overall survival has traditionally been considered the benchmark endpoint in determining efficacy of a treatment in large randomized controlled trials, new data analyzing outcomes of trials in soft tissue sarcomas where progression-free survival and response rate were the primary endpoints found those endpoints to be appropriate surrogates in trials. The findings were published online ahead of print in the Journal of Clinical Oncology (doi: 10.1200/JCO.2015.64.3437). “Soft tissue sarcomas are a cluster of rare and heterogenic tumors, making trial design and interpretation particularly challenging,” the study's lead author, Alona Zer, MD, of the Division of Medical Oncology at Princess Margaret Cancer Center in Toronto, explained in an email. “Many sarcoma randomized controlled trials used progression-free survival as a primary endpoint. We found that overall survival—the most definitive endpoint in oncology—was used as primary endpoint in only four percent of randomized controlled trials. “It was reassuring to discover that progression-free survival is a good surrogate for overall survival,” she said. The data also showed that other endpoints increasingly being used in clinical trials—three-month progression-free survival and six-month progression-free survival—have no correlation with overall survival. Study Details For the study, the researchers analyzed data from 52 randomized controlled trials in locally advanced/metastatic soft tissue sarcoma. The studies included 9,762 patients and 45 of the studies evaluated cytotoxic agents—and 11 studies included three arms (two experimental arms and one control arm), bringing the total number of comparisons in the analysis to 63. Some of the key findings and trends about the soft tissue sarcoma randomized controlled trials that the researchers reported were the following: The number of trials in soft tissue sarcoma has increased substantially over time with 19 studies being published between 1974 and 1994 and 33 from 1994 to 2014. Overall survival was the primary endpoint in two studies, whereas 23 studies used other time-to-event primary endpoints. Over time, there was an increase in the frequency of progression-free survival as a primary endpoint, as well as a reduction in the use of response rate as an endpoint. Secondary endpoints included overall survival in 39 studies, toxicity/safety in 35 studies, other time-based events in 24 studies, and response rate in 23 studies. Three studies included quality of life as a secondary endpoint. Sponsorship was reported in 42 studies, with 10 studies being sponsored by industry, 23 being sponsored by a cooperative group or an institution, and nine receiving combined funding. Compared with studies published between 1974 and 1994, the studies published in the past two decades were more likely to be supported by industry. Toxicity was reported comprehensively in 20 studies and reported poorly in six studies—with no observed changes in toxicity reporting over time. Surrogacy Analysis The researchers analyzed the surrogacy of the progression-free survival and response rate endpoints for overall survival using weighted linear regression (including only those studies reporting the hazard ratio for overall survival and the hazard ratio for either progression-free survival or data allowing the calculation of overall response for response rate, three-month progression-free survival, or six-month progression-free survival). The data showed a highly significant correlation between overall survival and progression-free survival, a substantially significant correlation between response rate and overall survival, and no significant correlation between three-month progression-free survival and overall survival or between six-month progression-free survival and overall survival. The eligible trials included in this study were found by a search of the MEDLINE, MEDLINE in-process, and EMBASE clinical trial databases, as well as meeting abstracts from the American Society of Clinical Oncology, the European Society for Medical Oncology, and the European Cancer Congress. The search included studies conducted between 1974 and December 2014. Because of their distinct biologic characteristics, trials involving bone sarcoma or gastrointestinal stromal tumors were excluded. The researchers also excluded review articles, meta-analyses, systematic reviews, phase I and II nonrandomized clinical trials, observational studies, and case reports. Key Messages “The main message from this study is that the new emerging endpoints—three- and six-month progression-free survival—should be used with caution, and probably not as the primary endpoint in randomized controlled trials for soft tissue sarcomas,” Zer said. “And overall survival is still the ultimate primary endpoint, even though it requires larger, longer, and more expensive studies. “And if a surrogate endpoint is chosen in place of overall survival, our data support the use of progression-free survival.” Additionally, Zer noted that a practical message from the study is that when reading a phase III randomized controlled trial abstract clinicians should pay attention to what primary endpoint was chosen for the study, she said. “Is it legitimate? Does it represent effectiveness of the treatment? Was it validated?” In an accompanying editorial also published online ahead of print in JCO, Fengmin Zhao, MHS, PhD, of the Department of Biostatistics & Computational Biology at Dana-Farber Cancer Institute, discusses a few limitations of the study by Zer et al., including cautions about properly validating surrogate endpoints (doi: 10.1200/JCO.2016.66.4581). But, he notes in the editorial: “Continuous efforts to improve the validation of surrogate endpoints are important in several ways. “In this era of personalized medicine and rapid development of oncology drugs, many drugs are in the pipeline, waiting for testing in phase III clinical trials. It is difficult, if not impossible, to conduct a phase III trial with overall survival as the primary endpoint for a rare disease. Surrogate endpoints usually allow for smaller trials and shorter completion times and, once validated, could help resolve these issues.” Sarah DiGiulio is a contributing writer.
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4072 Background: Pts with advanced or metastatic cholangiocarcinoma (CCA) have limited response to current chemotherapy regimens and poor overall survival (OS). Nab-Paclitaxel (nabPAC) can increase the intra-cellular concentration of gemcitabine (GEM) through depletion of its metabolizing enzyme, cytidine deaminase (CDA). We investigated the nabPAC+GEM combination in a ph II single arm trial in advanced or metastatic CCA pts with exploratory biomarker evaluation, including CDA, hENT1, SPARC and circulating tumor cells (CTCs). Methods: Key eligibility criteria: advanced or metastatic CCA with no prior systemic chemotherapy, age > 18, ECOG PS 0-1 and Child-Pugh < 8. Pts received nabPAC (125 mg/m2 IV) and GEM (1000 mg/m2 IV) days 1, 8 and 15 Q4 weeks until progression. Primary endpoint: progression-free survival (PFS) rate at 6 months. Secondary endpoints: safety, time to progression (TTP), objective response (ORR) and disease control rates (DCR), median PFS and OS, as well as correlation of change in CA 19-9 to clinical efficacy. The study required > 43 of 67 evaluable patients alive and progression-free at 6 months to conclude the 6-month PFS rate is at least 70% against a null hypothesis of 55% based on historical data. Results: 73 eligible patients (41.1% male, 91.8% Caucasian, 45.2% ECOG PS 0) were enrolled across 22 sites with a median age of 62 (range 36-87) years and received a median of 6 (range 1-18) cycles. The primary endpoint of PFS rate at 6 months was 54.7% on intention to treat analysis. Response evaluation is underway and will be reported at the meeting. The median PFS and OS were 6.5 (95% CI, 5.1-7.7) and 10.3 (95% CI, 9.1-14.6) months, respectively. The safety profile of nabPAC+GEM was similar to that reported in ph III MPACT trial. The most common treatment-related G3/4 toxicities were neutropenia (24.3%), fatigue (13.5%) and anemia (12.2%). Five patients remain on the trial. Exploratory analyses are pending. Conclusions: The observed PFS rate at 6 months with nabPAC+GEM in CCA is insufficient to reject the null hypothesis of 55% PFS at 6 months, and appears to be as effective as the historical control. Clinical trial information: NCT02181634.
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Current therapies for Alzheimer's disease improve symptoms, but do not have disease modifying effects. Disease modifying therapies are urgently needed to address the considerable burden on patients, caregivers and society. The EMA's 2016 guideline on AD stated that a therapy can be considered disease modifying if the slowing of the rate of decline in clinical signs and symptoms is linked to a significant effect on adequately validated biomarkers that reflect key pathophysiological aspects of the disease. However, it is unclear on how to establish the link between the clinical endpoints and the biomarker data. We propose a set of analyses to explore the link between clinical endpoints and biomarkers: correlation analysis, mediation analysis and meta-analysis. Each analysis evaluates different forms of relationship between the biomarker and clinical endpoint. The correlation analysis quantifies the association between the clinical endpoint and biomarker. The mediation analysis, which appraises the biomarker as an intermediate endpoint, determines to what extent the treatment effect on the clinical endpoint can be attributed to the treatment effect on the biomarker at the individual patient level. The meta-analysis assesses the association between the treatment effect on the biomarker and its effect on the clinical endpoint at the trial/dose level. Using simulations, we examined the roles of these three approaches to assess the link between the clinical endpoints and biomarkers. The simulations demonstrated that a biomarker that is strongly correlated with the clinical endpoint yet may not fully explain the treatment effect on the clinical endpoint. In contrast, a biomarker that mediates all the treatment effect on the clinical endpoint may not necessarily have strong correlation with the clinical endpoint. The mediation analysis approach serves as a capable tool to quantify the treatment effect on the clinical endpoint that can be attributed to the biomarker, even in the absence of strong correlation. Correlation, mediation, and meta analyses are a useful set of tools to explore the link between clinical endpoints and biomarkers as support for disease modifying therapies.
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384950 Background: Tislelizumab is a humanized immunoglobulin G4 anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb). At the interim analysis (median follow-up, 10.0 months), RATIONALE-309 met its primary endpoint, as first-line tislelizumab + chemotherapy significantly improved PFS, as assessed by an independent review committee (IRC), in patients with recurrent/metastatic nasopharyngeal cancer (RM NPC) compared with placebo + chemotherapy. Tislelizumab + chemotherapy had an acceptable safety profile, comparable to placebo + chemotherapy (Yang Y, et al. ESMO-IO Virtual Congress, 2021. Oral presentation 121O). Here, we report an updated analysis of PFS, PFS after next line of treatment (PFS2), and overall survival (OS) with an extended median follow-up of 15.5 months. Methods: A total of 263 eligible patients with RM NPC were randomly assigned 1:1 to receive tislelizumab 200 mg intravenously (IV) or placebo on day 1, plus gemcitabine (1 g/m 2 IV day 1, day 8), plus cisplatin (80 mg/m 2 day 1) every 3 weeks for 4–6 cycles, followed by tislelizumab or placebo every 3 weeks until disease progression, unacceptable toxicity, or withdrawal. After IRC-confirmed disease progression, patients in the placebo arm could crossover to receive tislelizumab monotherapy. The primary endpoint was IRC-assessed PFS. Secondary endpoints included IRC-assessed objective response rate and duration of response, investigator-assessed PFS and PFS2, and OS. Biomarker analysis was an exploratory endpoint. Results: At an updated data cut-off (September 30, 2021), IRC-assessed PFS was consistent with the interim data analysis and demonstrated significant improvement for tislelizumab + chemotherapy versus placebo + chemotherapy (median PFS, 9.6 vs. 7.4 months, respectively; hazard ratio [HR], 0.50; 95% CI, 0.37, 0.68). Median PFS2 and OS were not reached for the tislelizumab + chemotherapy arm and were 13.9 months and 23.0 months for the placebo + chemotherapy arm, respectively. The HRs were 0.38 (95% CI, 0.25, 0.58) for PFS2 and 0.60 (95% CI, 0.35, 1.01) for OS. The association of tumor microenvironment features by gene-expression analysis with clinical benefit will be presented. Conclusions: Tislelizumab + chemotherapy showed consistent, clinically meaningful improvement in PFS compared with placebo + chemotherapy in this updated analysis. Clinically meaningful improvements in PFS2 and OS were also observed for the tislelizumab + chemotherapy arm. This is the first report of PFS2 benefit for an anti–PD-1 mAb in combination with chemotherapy in the first-line treatment setting of RM NPC. These results support the use of tislelizumab + chemotherapy as first-line therapy for RM NPC. Clinical trial information: NCT03924986.
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Selection of clinical trial endpoints is a critical decision for investigators. Choosing a poor endpoint can result in false discovery or thwart regulatory approval. Overall survival (OS) is the most objective clinical trial endpoint; however, use of this endpoint is impractical in some tumors. A prime example is in epithelial ovarian cancer where the case for a surrogate endpoint such as progression-free survival (PFS) is best exemplified in the front-line setting where post-progression survival (PPS) intervals are long and even exceed the primary PFS. Furthermore, when a pivotal trial leads to regulatory approval of a new agent, in later lines of therapy, extensive cross-over to the experimental agent and/or to other active agents may obscure any OS effect. OS proponents will cite the subjective nature of the assessment of PFS; nevertheless, PFS correlates well with OS and with true patient benefit when assessed in a rigorous manner. In a therapeutically responsive disease such as ovarian cancer, OS improvements are frequently derived from a cobbling together of PFS gains from multiple interventions. In fact, insisting upon OS as the primary endpoint would have denied patients the 12 new regulatory approvals in the past six-plus years in ovarian cancer, many of which have demonstrated PFS hazard ratios <0.50, a remarkable clinical benefit for patients.
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Abstract Progression-free survival (PFS) is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Although in its simplest form, PFS is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease progression is recorded. In this overview, we review the circumstances that can devalue the use of PFS as a primary endpoint and attempt to provide a pathway for a future desired state when PFS will become not just a secondary alternative to overall survival but rather an endpoint of choice. Clin Cancer Res; 19(10); 2607–12. ©2013 AACR.
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The main objective of this project was to estimate progression-free survival rates at different fixed time points in order to design future phase-II trials targeting the progression-free survival rate as primary endpoint in mesothelioma. Response rate has traditionally been used as an endpoint in many phase-II trials of oncology therapies. However, progression-free survival could be a more appropriate endpoint in rapidly progressing disease, at least in three situations: (1) when testing cytostatic agents, (2) when the response to a regimen is difficult to assess, (3) when the response is expected to be low. The use of progression-free survival as an endpoint instead of the response rate is relevant in mesothelioma for two primary reasons. Firstly, the global incidence of mesothelioma is increasing and current treatments yield disappointingly poor results. The development of more active treatments is thus highly desirable and new targeted therapies, including cytostatic agents, are currently the main focus of mesothelioma research. Secondly, in mesothelioma the assessment of response is difficult and not reproducible, and the response rate is usually low. In order to evaluate a novel therapy using progression-free survival rate as the primary endpoint, we need data about the progression of patients and especially about the progression-free survival rate at fixed time point. Data on 523 patients included in 10 mesothelioma trials conducted by the European Organisation for Research and Treatment of Cancer were analysed. Values of progression-free survival rate at 3, 4, 5 and 6 months in groups of different levels of therapeutic activity and in different risk groups were calculated. Our work also provides a prognostic index which allows the definition of more homogeneous groups of patients that avoids dilution of results between groups. Based on these results, the size of future mesothelioma trials can be calculated and designs can be adapted to improve the assessment of the activity of a new therapy. Furthermore the use of progression-free survival rate rather than response rate as a primary endpoint would not require much more time to assess the endpoint. It would also decrease the probability to reject a potentially interesting therapy by considering non-progressive diseases as successes.
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