Progression-free Survival Status Research Articles

Impact of Progression-Free Survival at 24 Months on Subsequent Survival in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP Therapy: A Supplementary Analysis of JCOG0601

Introduction The impact of progression-free survival status at 24 months (PFS24) or event-free survival status at 24 months (EFS24) on subsequent survival has been evaluated in patients with various lymphoma subtypes. Patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) who achieve PFS24 or EFS24 generally have excellent outcomes. It has been observed that the overall survival (OS) after achieving EFS24 was not significantly different from that of the general population (M.J. Maurer. J Clin Oncol, 2014). However, the OS after achieving PFS24 was significantly worse than that of the general population (M.J. Maurer. Ann Oncol, 2018). Consequently, the impact of achieving PFS24 for DLBCL patients remains controversial. In this supplementary analysis, we evaluated the impact of achieving PFS24 on the subsequent survival of untreated DLBCL patients by using data from JCOG0601, a randomized phase2/3 study assessing the schedule of rituximab administration in combination with tri-weekly CHOP (Ohmachi K. Blood Adv, 2021). Methods Among 422 patients enrolled between Dec 2007 and Dec 2014 in JCOG0601, 409 patients were eligible for this analysis (Data cutoff date: Dec 19, 2017). PFS24 was defined as being alive without progression or relapse for 24 months from randomization. The protocol treatment was initiated within 7 days after randomization. OS from PFS24 was defined as the time from achieving PFS24 or the date of progression or relapse to death from any cause. We compared OS from PFS24 with that of age-, sex-, and calendar period-matched Japanese general population using standardized mortality ratios (SMRs). Similarly, PFS12 and PFS60, as well as OS from PFS12 and PFS60, were defined in the same manner as PFS24 and OS from PFS24. The log-rank P-values for OS were calculated. Results The baseline characteristics of the 409 patients were as follows: a median age of 62 years (range, 20-79), with males accounting for 56% (n=227) of the patients. At diagnosis, 46% (n=188) of the patients were Ann Arbor stage III or IV. The majority of patients (82%; n=335) were classified as international prognostic index low or low-intermediate risk. Based on the Hans algorithm for cell-of-origin, 51% (n=210) of the patients were categorized as non-germinal center B-cell type (non-GCB). At a median follow-up of 5.3 years among all patients, a total of 334 patients (82%) achieved PFS24, while 66 patients (16%) failed to achieve PFS24. Five patients died without progression within 24 months, and four patients were lost to follow-up within 24 months. Multivariable analysis revealed that risk factors for failing to achieve PFS24 included serum LDH levels higher than the upper normal limit and two or more extranodal lesions. Patients who achieved PFS24 had a significantly better OS than those who failed to achieve PFS24 (median OS, not reached vs. 1.3 years; P < 0.001). Similar results were observed when using PFS12 and PFS60, regardless of the cell-of-origin. Among the patients who failed to achieve PFS24, non-GCB type patients more frequently had relapsed or refractory diseases in extranodal sites (72%: n=26/36) compared to GCB type patients (43%; n=6/14). The OS after achieving PFS24 or PFS60 was not remarkably different from that of the general population (PFS24: SMR 1.29, 95% confidence interval [CI] 0.72-2.12, P = 0.39; PFS60: SMR 1.43, 95% CI 0.47-3.33, P = 0.55). However, the OS after achieving PFS12 was significantly worse than that of the general population (SMR 2.30, 95%CI 1.59-3.22, P < 0.001). The primary cause of death for patients achieving PFS12 was DLBCL with the cumulative incidence of more than 5% at 5 years, while the incidence of death due to DLBCL was less than 5% for those achieving PFS24. The primary cause of death for the patients achieving PFS24 was other diseases except for DLBCL and treatment-related toxicity, including secondary malignancies (n=4/7) and pneumonia (n=3/7). Conclusion Newly diagnosed DLBCL patients treated with R-CHOP who achieved PFS24 exhibited an excellent subsequent outcome, which did not differ from those of age-, sex-, calendar-period matched individuals in the general population. Our findings suggest that PFS24 achievement could serve as a surrogate endpoint for OS in DLBCL patients. Further research is warranted to establish the utility of PFS24 achievement as a reliable milestone in clinical practice.

A single-arm, phase 2 clinical trial of abemaciclib in adult patients with recurrent grade 3 oligodendroglioma.

2045 Background: Oligodendroglioma is a malignant glial neoplasm arising primarily in young adults. Although radiotherapy (RT) and chemotherapy result in durable disease control, tumor recurrence is inevitable and life-limiting. The cyclin D1-CDK4 axis is frequently dysregulated in recurrent oligodendroglioma. Abemaciclib is a selective CDK4/6 inhibitor that has been shown to achieve pharmacologically-relevant concentrations in brain tumor tissue. Methods: We conducted a single-center, single-arm, phase 2 trial evaluating the efficacy of abemaciclib in patients with recurrent oligodendroglioma, IDH-mutant and 1p/19q-codeleted, WHO Grade 3, following prior RT and ≥ 1 line of alkylating chemotherapy. Patients received abemaciclib 200mg twice daily. Primary endpoint was progression-free survival status at 6 months (PFS-6). Ten patients were needed for 80% power to detect the difference between the null (PFS-6 = 50%) and alternative (PFS-6 = 85%) hypotheses; one-sided α = 0.05. Modified RANO criteria were used for patients with enhancing tumors and RANO low-grade glioma criteria for patients with nonenhancing tumors. Results: Between November 2019 - August 2022, 10 patients were enrolled (Baseline Characteristics). Most common treatment-related adverse event (trAE) was grade 1-2 diarrhea, occurring in all 10 patients. Grade 3-4 trAEs included grade 4 thrombocytopenia (n=2), grade 3 neutropenia (n=1), grade 3 fatigue (n=2), and grade 3 ALT increase (n=1). In patients with enhancing tumor (n=9), best response was partial response in 2 patients (ORR=22.2%; DOR 13.1 and 7.7 months, respectively), stable disease (SD) in 3 patients (33.3%; duration of SD 17.0, 6.7, and 2.5 months, respectively), progressive disease in 3 patients (33.3%), and not evaluable in 1 patient (11.1%). In the patient with nonenhancing tumor, best response was SD (duration 10.2 months). Median PFS was 7.7 months (95% CI, 1.7 – 13.1 months); median overall survival was not reached (median follow-up 17 months). The study’s primary endpoint was not met; 5/10 patients (50%) were alive and progression-free at 6 months, below the minimum required (8/10) to consider abemaciclib worthy of further investigation. Conclusions: Despite objective responses and durable disease control in a small subset of patients, the efficacy of abemaciclib in recurrent grade 3 oligodendroglioma was not adequate to warrant further clinical evaluation of abemaciclib monotherapy in unselected patients. Correlative studies are ongoing to identify which patients with oligodendroglioma may benefit from abemaciclib. Clinical trial information: NCT03969706 . [Table: see text]

Abstract OT2-28-01: A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704

Abstract Background:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer, disproportionally affecting African American and Hispanic patients, and germline BRCA1/2 mutation carriers. Prognosis of relapsed, metastatic disease is extremely poor and effective well-tolerated therapies are urgently needed. Our collaborators have discovered that TNBCs often lose feedback control of receptor tyrosine kinases (RTKs) including PDGFR and MET, locking these receptors in a chronically active state. These receptors share a common negative regulator called Protein Tyrosine Phosphatase, Non-Receptor Type 12 (PTPN12). Baylor investigators have shown that PTPN12- deficient TNBCs may be responsive to combined RTK inhibition. Sitravatinib is a spectrum selective RTK inhibitor that has shown strong antitumor activity in patient derived xenografts (PDXs) of TNBC with low levels of PTPN12. We have therefore designed a phase II, multi-institution, two cohort trials to evaluate the efficacy of sitravatinib in patients with metastatic TNBC (mTNBC). Methods: Patients with diagnosis of mTNBC who have received at least one line of chemotherapy +/- atezolizumab for advanced disease would be considered for enrollment. Patients would need to have tissue from metastatic site available for evaluation or agree to undergo biopsy if banked tumor tissue is not available. Sitravatinib at 100 mg daily, the recommended phase 2 dose for sitravatinib monotherapy, will be started at the initiation of the study and continued until progression or unacceptable toxicity. The study will employ a modified optimal Simon’s two stage design. Patients will be recruited into two cohorts: PTPN12 low or PTPN12 high/normal cohorts simultaneously and independently. Seven patients will be enrolled to each arm during the first stage. After the first stage, depending on the observed number of responses, the study will proceed to the 2nd stage. The primary endpoint is progression-free survival status at 24 weeks (PFS24). Current Trial status: The trial is funded by Mirati Therapeutics and opened to enrollment at Dan L Duncan Comprehensive Cancer Center (DLDCCC) clinics as of 6/8/21. Trial is due to open at UT Southwestern Dallas by 11/2021. The correlative science is funded by an institutional SPORE grant. Conclusion: This trial aims to show that sitravatinib is safe and to investigate whether it could be a treatment option in mTNBC. Citation Format: Maryam Nemati Shafaee, Kristen Otte, Nicholas J Neill, Kent C Osborne, Thomas F Westbrook, Susan Hilseneck, Matthew J Ellis. A phase 2 study of sitravatinib in metastatic, pre-treated, triple negative breast cancer, NCT # 04123704 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-28-01.

DOCK8 Serves as a Prognostic Biomarker and Is Related to Immune Infiltration in Patients With HPV Positive Head and Neck Squamous Cell Carcinoma.

Purpose:Dedicator of cytokinesis 8 (DOCK8) was reported to have a vital link to immunoregulation. However, the mechanisms by which it drives immune infiltration in cancer remain uncertain. We tried to assess the role of DOCK8 in patients with cancer, especially human papillomavirus (HPV)-positive head and neck squamous cell carcinoma (HNSCC).Methods:Data on the expression and survival of DOCK8 in patients with various cancers were analyzed using the Oncomine and TIMER databases. The TIMER database assessed the relationship of DOCK8 with immune infiltration levels and various markers of multiple immune cells. Gene set enrichment analysis revealed tumor-associated biological processes related to DOCK8. ENCODE database was used to explore relevant transcription factors of DOCK8, and a PPI network was constructed using GENEMINIA. The expression and survival role of DOCK8 was confirmed in patients from independent GEO datasets.Results:We determined that DOCK8 expression was upregulated or downregulated in various cancers unlike in healthy tissues. A high expression of DOCK8 was significantly correlated with a favorable prognosis in HPV-positive HNSCC and lung adenocarcinoma (LUAD). Furthermore, multivariate Cox regression analysis revealed that DOCK8 was an independent prognostic factor of HPV-positive HNSCC. Additionally, elevated DOCK8 expression was positively correlated with multiple immune cell infiltration levels and immune marker expression associated with particular immune cell subsets. Also, 14 pathways involved in immune activities and carcinogenesis, 22 potential TFs, and co-expression proteins of DOCK8 indicated DOCK8 to be related to tumor-associated biological processes. Ultimately, we verified that DOCK8 is upregulated and confers a favorable overall survival and progression-free survival status in patients with HPV-positive HNSCC.Conclusion:These results elucidate that high expression of DOCK8 indicates a favorable prognosis in patients with HPV-positive HNSCC as well as increased microenvironmental immune infiltration levels. It would provide new insights into the prognosis predicting and clinical regimen decision making in patients with HPV-positive HNSCC.

Biomarkers for Risk Stratification in Patients With Previously Untreated Follicular Lymphoma Receiving Anti-CD20-based Biological Therapy.

Follicular lymphoma (FL) is an indolent B-cell neoplasm of germinal center origin. Standard treatment regimens consist of anti-CD20 therapy with or without chemotherapy. While high response rates to initial therapy are common, patients ultimately relapse or have progressive disease. Clinical risk factors such as the Follicular Lymphoma International Prognostic Index (FLIPI) have been identified, but there is a need for prognostic and predictive biomarkers. We studied markers of lymphoma cells and tumor microenvironment by immunohistochemistry in tissue samples from patients enrolled in 1 of 4 phase 2 trials of anti-CD20-based biological therapy for previously untreated grades 1 to 2 or 3A FL. Results were correlated with progression-free survival (PFS) and PFS status at 24 months. The 4 trials included 238 patients (51.1% male, median age: 55 y) with stage III, IV, or bulky stage II disease. By FLIPI, 24.6% had low-risk, 56.8% had intermediate-risk, and 18.6% had high-risk disease. The outcome differed significantly for patients treated with lenalidomide and rituximab (CALGB 50803) compared with the other 3 trials (median: PFS not reached vs. 3.0 y, hazard ratio=3.47, 95% confidence interval: 2.11-5.72); therefore, data were stratified by clinical trial (CALGB 50803 vs. all others) and adjusted for FLIPI risk group. Among 154 patients with available tissue, interfollicular BCL6 positivity, interfollicular CD10 positivity, and elevated Ki67 proliferation index ≥30% within neoplastic follicles were each associated with inferior PFS and a high risk of the early event by PFS status at 24 months. We identify promising biomarkers for FL risk stratification that warrant further validation in phase 3 trials.

PD-(L)1 Inhibitors in Combination with Chemotherapy as First-Line Treatment for Non-Small-Cell Lung Cancer: A Pairwise Meta-Analysis.

The combination of programmed cell death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors with chemotherapy has emerged as a promising therapeutic option for advanced non-small-cell lung cancer (NSCLC). The aim of this meta-analysis was to evaluate the efficacy of the combined strategy in this setting. For this purpose, we performed a literature search of randomized controlled trials comparing PD-(L)1 inhibitors plus platinum-based chemotherapy versus chemotherapy alone in stage IV NSCLC patients. Seven clinical trials with 4562 patients were included. In the intention-to-treat wildtype population, PD-(L)1 inhibitor plus chemotherapy was significantly associated with improved progression-free survival (PFS) (Hazard ratio (HR) = 0.61, 95% confidence interval (CI): 0.57–0.65, p < 0.001) and overall survival (OS) (HR = 0.76, 95% CI: 0.67–0.86; p < 0.001) compared to chemotherapy. A significantly higher overall response rate (ORR) was also observed with the combined strategy (Odds ratio (OR) = 2.12, 95% CI: 1.70–2.63, p < 0.001). Furthermore, in all the analyzed subgroups, addition of PD-(L)1 inhibitors to chemotherapy significantly improved efficacy endpoints. Specifically, stratification according to PD-L1 expression revealed a benefit across all patients, regardless of their PFS status. In conclusion, PD-(L)1 blockade added to standard platinum-based chemotherapy significantly improved PFS, OS, and ORR in the up-front treatment of advanced NSCLC.

A prospective validation cohort study of baseline plasma cell-free DNA (cfDNA) as a prognostic biomarker in newly diagnosed glioblastoma (GBM).

2508 Background: Due to significant interpatient heterogeneity, survival outcomes vary widely in patients with GBM. Novel prognostic biomarkers are needed. We aimed to determine the prognostic impact of baseline plasma cfDNA concentration in patients with GBM. Methods: We analyzed 84 patients with newly diagnosed GBM and at least 7 months of follow-up time. The first 41 patients comprised a previously published derivation cohort (Bagley, Clin Cancer Res 2020). The subsequent 43 patients served as an independent validation cohort. cfDNA was extracted from plasma collected prior to initial surgical resection and quantified by qPCR for a 115 bp amplicon of the human ALU repeat element. Receiver operating characteristic (ROC) curve analysis was used in the derivation cohort to (1) assess the accuracy of plasma cfDNA concentration for predicting progression-free survival status at 7 months (PFS-7), a landmark based on the median PFS for newly diagnosed GBM (Stupp, N Engl J Med 2005), and (2) derive the optimal cutoff for dichotomizing patients into high- and low-cfDNA groups. In the validation cohort, logistic regression was used to measure the association of plasma cfDNA concentration (high vs. low) with PFS-7, adjusted for age, isocitrate dehydrogenase ( IDH) 1/2 mutational status, 0-6-methylguanine-methyltransferase ( MGMT) methylation, extent of resection, and performance status. Multivariate Cox regression was used for overall survival (OS) analysis. Results: In the derivation cohort, the optimal cutoff for plasma cfDNA was 25.0 ng/mL (area under the curve [AUC] = 0.663), with inferior PFS and OS in patients with cfDNA above this cutoff (PFS, median 4.9 vs. 9.5 months, log-rank p = 0.001; OS, median 8.5 vs. 15.5 months, log-rank p = 0.03). In the validation cohort, baseline plasma cfDNA concentration over the cutoff was independently associated with a lower likelihood of being alive and progression-free at 7 months (adjusted OR 0.13, 95% CI 0.02 – 0.75, p = 0.02). OS was also worse in in the validation cohort in patients with high plasma cfDNA (adjusted HR 3.0, 95% CI 1.1 – 8.0, p = 0.03). Conclusions: In patients with newly diagnosed GBM, high baseline plasma cfDNA concentration is associated with worse survival outcomes independent of other prognostic factors. Further validation in a larger, multicenter study is warranted.

Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

Four-Year Analysis of Murano Study Confirms Sustained Benefit of Time-Limited Venetoclax-Rituximab (VenR) in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL)

RBTT-05. A SINGLE-ARM, OPEN-LABEL, PHASE II STUDY EVALUATING THE EFFICACY AND SAFETY OF ABEMACICLIB IN PATIENTS WITH RECURRENT OLIGODENDROGLIOMA: TRIALS IN PROGRESS

Abstract BACKGROUND Oligodendroglioma is a rare primary brain tumor characterized by mutation in the IDH1/IDH2 genes and codeletion of chromosomes 1p and 19q. Although median overall survival extends beyond 10 years for patients with oligodendroglioma who receive adjuvant radiation and alkylating chemotherapy, the disease uniformly relapses and has no other effective treatments. The CIC gene, which encodes a high-mobility group box transcriptional repressor, is mutated in about 70% of oligodendrogliomas and is associated with worse prognosis and overexpression of cyclin D1 (CCND1). Cyclin D1 assembles with the cyclin-dependent kinases CDK4 and CDK6 to cause phosphorylation of Rb protein and subsequent cell cycle progression from the G1 to S phase. Therapeutic inhibition of CDK4/6 activity, which leads to Rb dephosphorylation and cell cycle arrest, has revolutionized the care of breast cancer. The current phase 2 study will investigate the efficacy and safety of abemaciclib, a selective and potent small molecule inhibitor of CDK4 and CDK6 with significant brain-brain barrier penetration, in patients with 1p/19q codeleted oligodendroglioma that has recurred after standard radiation and alkylating chemotherapy. METHODS This protocol (NCT03969706) has a single-arm, open-label, single-stage phase 2 design. Subjects will be treated with abemaciclib 200mg tablet twice daily on 28-day cycles until disease progression or unacceptable toxicity. Tumor response will be assessed according to modified Response Assessment in Neuro-Oncology (mRANO) criteria. The primary objective of the study is to determine the efficacy of abemaciclib for recurrent oligodendroglioma. The primary endpoint is the progression-free survival status of the subject at 6 months after enrollment (PFS-6). The alternative hypothesis is that the proportion of subjects without an event at 6 months will be ³85%. We will test this hypothesis against a null hypothesis of PFS-6 = 50%. With enrollment of 10 planned subjects, the power to detect this difference is 82% (one-sided alpha = 0.05).

Downstaging Disease in Patients with Hepatocellular Carcinoma Outside of Milan Criteria: Strategies Using Drug-eluting Bead Chemoembolization

PurposeTo assess downstaging rates in patients with United Network for Organ Sharing stage T3N0M0 hepatocellular carcinoma (HCC) treated with doxorubicin-eluting bead transarterial chemoembolization to meet Milan criteria for transplantation. Materials and MethodsA single-center retrospective review of 239 patients treated with doxorubicin-eluting bead (DEB) chemoembolization between September 2008 and December 2011 was undertaken. Baseline and follow-up computed tomography or magnetic resonance imaging was assessed for response based on the longest enhancing axial dimension of each tumor (ie, modified Response Evaluation Criteria In Solid Tumors measurements), and medical records were reviewed. Fisher exact tests and exact logistic regression were used to test the association of patient and disease characteristics with downstaging. ResultsAfter exclusions, 22 patients remained in the analysis, 17 of whom (77%) had their HCC downstaged to meet Milan criteria. Among those whose disease was downstaged, seven underwent transplantation, one remained listed for transplantation, six had disease progression beyond Milan criteria, two underwent conventional transarterial chemoembolization, and one underwent radiofrequency ablation. The seven patients who received transplants were still living, but recurrent HCC developed in two. Baseline age (P = .25), Model for End-stage Liver Disease score (P = .77), and α-fetoprotein (AFP) level (P = 1.00) were similar between patients with and without downstaged HCC. No associations were observed between the odds of downstaging and sex (P = .21), Child–Pugh class (P = .14), Child–Pugh class controlling for baseline tumor multiplicity (P = .15), Eastern Cooperative Oncology Group performance status (P = 1.00), tumor burden (P = .31), multiple tumors (P = .31), or hepatitis C virus infection (P = 1.00). Fifteen patients who did not receive transplants were alive at 1 year, with two progression-free. Baseline AFP levels differed between those who survived 1 year and those who did not (P = .02), but did not differ by progression-free survival status (P = .62). ConclusionsT3N0M0 HCC treatment with DEB chemoembolization has a high likelihood (77%) of downstaging the disease to meet Milan criteria.

Independent validation of progression-free survival rate at 9 and 18 weeks (PFSR-18, PFSR-9) as predictor for overall survival (OS) in patients with malignant pleural mesothelioma (MPM): EORTC 08052 study.

7584 Background: The increasing incidence and the plateau of current treatment outcomes in MPM necessitates development of new therapeutic approaches. Reliable and meaningful response assessment is difficult in phase II trials thus a primary endpoint based on progression free survival (PFS) rate at certain time point has been proposed (Greillier et al, 2011). EORTC 08052 was a phase II study in MPM where independent validation of PFSR-18 weeks was foreseen. We extend this to PFSR-9. Methods: Association of PFS and response with OS was assessed at two distinct time points; 9 and 18 weeks after registration. Landmarks method was used, PFS status (CR/PR/SD vs. PD) and response status (CR/PR vs. PD/SD) were determined at those time points. Cox regression and logrank test were performed and the corresponding c-indexes were calculated. Results: Of 82 registered patients, 28.4% achieved CR/PR and 77.8% had disease control (CR/PR/SD) as their best overall response. PFSR-18 and PFSR-9 were both strongly correlated with OS. Patients with no progression at 18 weeks had median OS of 16.9 months compared to 11.9 months in those who progressed at 18 weeks. Hazard ratio [HR] (95 confidence interval [CI]) was 0.46 (0.32-0.67), logrank test was 0.007 and C-index = 0.60. Adjusting for 3 important baseline prognosis factors, histology, performance status and disease stage resulted in PFS-18 as the only significant factor. When 9 weeks landmark was chosen, patients with no progression had median OS of 16.9 months vs. 6.8 months in those who progressed with HR (CI), logrank test and C-index 0.35(0.25-0.49), &lt; 0.0001 and 0.66 respectively. When adjusted by 3 important baseline prognosis factors PFS-9 remained the only significant factor. The results also confirmed that response at 18 weeks and 9 weeks was correlated with OS. Conclusions: PFSR-18 was strongly correlated and discriminated patients with better OS from the poorer prognosis patients. An earlier endpoint, PFSR-9 was also strongly correlated to OS and had a better discriminating capacity. Previous results on correlation between PFSR-9 and PFSR-18 and OS were independently validated.

Changes in peripheral blood immune cells: their prognostic significance in metastatic renal cell carcinoma patients treated with molecular targeted therapy

Recently, novel molecular targeted agents markedly changed the treatment of renal cell carcinoma (RCC), with promising results. However, there is little understanding of how these agents affect immune cell populations in RCC, an immunogenic tumor. Therefore, we investigated the changes in the peripheral blood immune cells in 58 RCC patients during the first 4 weeks of treatment with sorafenib, sunitinib, everolimus, or temsirolimus and evaluated whether these changes were associated with clinical outcomes. The immunological parameters were the proportion of type-1 (Th1) and type-2 (Th2) T cells, regulatory T cells (Treg), mature dendritic cells, and the neutrophil-to-lymphocyte ratio (NLR). The changes in these immune cells varied with the agents and the clinical response, dichotomized by the median progression-free survival (PFS) time (PFS-short or PFS-long). A significant decrease in the Th1/Th2 ratio was seen after sunitinib treatment only in the PFS-short group, suggesting a shift toward Th2 that down-regulates host immunity. The NLRs indicative of the balance between host immunity and cancer-related inflammation were consistently lower in the PFS-long group than in the PFS-short group, suggesting that lower NLR is associated with better clinical response. Only sunitinib decreased NLR remarkably regardless of PFS status, which may favor anti-tumor immunity. When patients were dichotomized by the cutoff values, Th1/Th2 ratio was not associated with PFS in any targeted therapy, while lower pre-treatment NLR was associated with longer PFS in each targeted therapy. In addition, in RCC patients given sequential targeted therapy, those with a lower baseline NLR survived significantly longer compared with the counterparts. Moreover, those whose baseline NLR was sustained low during the initial therapy survived the longest. Our results suggest the diverse changes in host immune cells in RCC patients during targeted therapy. The changes in NLR during the early phase of targeted therapy may be a powerful discriminator of who will benefit from the subsequent treatment.

Correlation between CA-125 serum level and response by RECIST in a phase III recurrent ovarian cancer study

Objectives To evaluate in a large phase III recurrent ovarian cancer trial (OVA-301): 1) the concordance between CA-125 level vs. best overall response (OR) and progression-free survival (PFS) determined by radiological assessment 2) the impact of early CA-125 changes over the subsequent radiological response, and 3) the prognostic value of CA-125 response and CA-125 PFS to predict radiological response and PFS. Methods Assessment of response in the entire randomized population was performed by the Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) and modified Rustin criteria for CA-125 determination. Results Most CA-125 decreases were observed in RECIST responders (82% of patients treated with the combination and 74% in the PLD alone). CA-125 progression preceded RECIST progression in 35% of patients with a median lead time of 8.4 weeks. A high concordance rate between CA-125 PFS status at 4 months (PFS4) and CA-125 response as a predictor of PFS4 (87%) and radiological response (79%) was found in the combination, with high positive predictive value for radiological PFS4 (92%) and high negative predictive value for OR (90%). An early CA-125 decrease was predictive for the ultimate response since it was found in a high rate of RECIST responders. Conclusion Radiological response was preceded by a favorable predictive CA-125 decrease in a high proportion of patients, suggesting that CA-125 evaluation may be an appropriate tool for tumor assessment in patients with ovarian cancer.

Tumor response and progression‐free survival as potential surrogate endpoints for overall survival in extensive stage small‐cell lung cancer

AbstractBACKGROUND:The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression‐free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.METHODS:Individual patient data from 870 untreated extensive stage small‐cell lung cancer patients participating in 6 single‐arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient‐level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial‐level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial‐level surrogacy measures included: R2 from weighted least squares regression model, Spearman correlation coefficient, and R2 from bivariate survival model (Copula R2).RESULTS:Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1‐10.0) and 5.5 (95% CI, 5.2‐5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient‐level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35‐0.51; concordance index 0.63; P &lt; .01), with 6‐month PFS being the strongest (HR, 0.41; 95% CI, 0.35‐0.49; concordance index, 0.66, P &lt; .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R2 = 0.79; Copula R2 = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R2≤0.48).CONCLUSIONS:PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials. Cancer 2011. © 2010 American Cancer Society.

Tumor response and progression-free survival (PFS) as potential surrogate endpoints for overall survival (OS) in extensive-stage small cell lung cancer (ES-SCLC): Findings based on North Central Cancer Treatment Group (NCCTG) trials.

7637 Background: We investigated the putative surrogate endpoints (PSEs) of best response (BR), confirmed response (CoR), and PFS for association with OS, and as possible surrogate endpoints for OS. Methods: Individual patient (pt) data for 870 untreated ES-SCLC pts from 6 single-arm (274 pts) and 3 randomized trials (596 pts from 32 participating centers) containing platinum or paclitaxel-based regimens were pooled. Patient-level associations between the PSEs and OS were assessed by Cox models using a landmark analyses at 2, 4, and 6 months post-study entry. Model discrimination was evaluated using the concordance (c) index. Trial-level surrogacy of PSEs was assessed by the association of the treatment effects on OS and individual PSEs. Treatment effects were estimated through log hazard ratios and log odds ratios. Trial-level surrogacy measures included: R2 from a weighted least squares regression model (R2 WLS), Spearman rank correlation coefficient (Spearman), and R2 from a bivariate survival model (R2 Copula). Results: The median OS and PFS were 9.6 and 5.5 months, respectively; the BR and CoR rates were 44% and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (HR=0.42 [95% CI: 0.35, 0.51]; c-index = 0.63; p < 0.01), with 6-month PFS being the strongest (HR=0.41 [95% CI: 0.35, 0.49]; c-index = 0.66; p < 0.01). At the trial level, PFS showed the highest level of surrogacy for OS (R2 WLS = 0.79; R2 Copula = 0.80), which indicates that PFS explained 79% of the variance in OS and is a good surrogacy measure (see Table). Conclusions: PFS was strongly associated with OS, where PFS status as early as 4 months was a strong predictor of subsequent survival. PFS also shows promise as a potential surrogate for OS, and needs further validation using data from a larger number of randomized phase III trials. This data, if substantiated, will allow faster yet valid evaluation of drugs for ES- SCLC. Trial-level surrogacy measures Endpoint R2 WLS R2 Copula Spearman PFS 0.79 0.80 (95% CI: 0.67, 0.93) 0.75 BR 0.21 NA 0.52 CoR 0.40 NA 0.60 No significant financial relationships to disclose.

N0539 Phase II Trial of Fulvstrant and Bevacizumab in Patients with Metastatic Breast Cancer Previously Treated with an Aromatase Inhibitor: A North Central Cancer Treatment Group Trial.

Abstract Background: Treatment of aromatase refractory metastatic breast cancer (MBC) is difficult and challenging. Estrogen receptor (ER) resistance causes enhanced expression of the vascular endothelial growth factor (VEGF).Several studies have shown that the ER interacts with the VEGF pathway and is an important mechanism of resistance. Therefore we embarked on a phase II study of fulvestrant, a complete ER suppressor and bevacizumab, a well studied VEGF monoclonal antibody in aromatase refractory MBC patients. Methods: A single stage phase II study with an interim analysis of fulvestrant and bevacizumab was conducted with these objectives: 6 month progression-free survival rate (PFS), tumor response, toxicity, and overall survival. Regimen: fulvestrant 250 mg day1 and 15 (cycle 1) then day 1 (cycle 2 and beyond) and bevacizumab 10mg/kg days 1 and 15 of each 4 weeks is a cycle. Results: At the time of interim analysis, 11/20 evaluable patients achieved 3-month progression-free survival status while remaining on treatment for at least 3 months, not meeting the protocol specified efficacy requirements and thus halting accrual. 36 patients were enrolled from September 2007-December 2008; 33 patients were evaluable. Number of prior metastatic chemotherapy regimens: 0 in 26 patients and 1 in 7 patients. 22 (67%) patients received prior hormonal therapy in the metastatic setting. 18 (55%) had measurable disease. A median of 6 cycles (range 1-19) were administered. 12/33 evaluable patients (95% CI:20-55%) achieved 6-month progression-free survival status while remaining on treatment for a least 6 months. Among 18 patients with measurable disease, 2 (11%) patients CI:1.4-35%) had a confirmed tumor reponse (both PR). Additionally, 2 patients had stable disease for greater than 6 months, for a clinical benefit rate of 22%. Median follow up was 8.5 months (range 1.7-17.5 months). Median progression-free survival was 6.2 months (95% CI:5.4-10.1 months). The 6 -month overall survival rate was 84.8% (95% CI 73.5-98%). The median dose level administered was 250 mg for fulvestrant and 10 mg/kg for bevacizumab for cycles 1-19. The most common grade 3/4 adverse events (AEs) were hypertension 2 (6%), headache pain 2 (6%), and confusion 2 (6%). There was 1 grade 5 central nervous system hemorrhage. 13 (39%) patients experienced a grade 3 non-hematologic AE and 4 (12%) experience a grade 4+ non-hematologic AE. Conclusion: Fulvestrant/bevacizumab is safe and tolerable. Although this regimen did not meet its statistical endpoint, 22% of evaluable patients with aromatase refractory diesease achieved clinical benefit with minimal toxicity. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4096.