Median Post-progression Survival Research Articles

Surrogacy of Time to Progression for Overall Survival in Advanced Hepatocellular Carcinoma Treated with Systemic Therapy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Time to progression (TTP) is widely used as the endpoint in early-phase trials of advanced hepatocellular carcinoma (HCC). However, the relevance of using TTP as a surrogate marker for overall survival (OS) in pivotal trials remains uncertain. The PubMed database and ASCO Meeting Library were searched for reports of randomized controlled trials that investigated patients with advanced HCC, included data for both OS and TTP, and were launched between 2009 and 2016. The correlation between hazard ratios (HRs) for TTP and OS was determined using weighted linear regression. Correlations between median OS and TTP, and between median OS and postprogression survival (PPS), defined as the period obtained by subtracting the median TTP from the median OS, were also evaluated. The database search yielded 24 trials with 50 arms. Overall, TTP HR correlated with OS HR (R = 0.73); however, the coefficient in the regression equation was 0.48. The correlation between median OS and median TTP was not so strong (R = 0.50), whereas the correlation between median OS and median PPS was strong (R = 0.78). In advanced HCC, the OS HR can be predicted from the TTP HR, which is useful when considering whether to proceed to a pivotal trial based on the results of early-phase trials. TTP may be a better endpoint than OS for evaluating a novel agent in a pivotal trial, because an improvement in antitumor effect cannot fully reflect an improvement in OS due to the strong impact of PPS on OS.

Clinical outcomes of sorafenib treatment failure for advanced hepatocellular carcinoma and candidates for regorafenib treatment in real-world practice.

As second-line therapy, regorafenib has been shown to provide a survival benefit for patients with hepatocellular carcinoma (HCC) who progress on sorafenib. In this retrospective study, we assessed the clinical outcomes of sorafenib treatment failure with regard to second-line chemotherapy. Patients (n = 160) with advanced HCC, Child-Pugh A liver function and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 treated with sorafenib between June 2009 and September 2016 were enrolled. Among 147 patients with progressive disease (PD), we defined those with Child-Pugh A liver function and ECOG PS 0-1 at progression as candidates for second-line chemotherapy and those who had tolerated sorafenib (≥400mg/day for ≥20 of the last 28days of treatment) as candidates eligible for regorafenib treatment. Among all 160 patients, median overall survival was 10months, and median progression-free survival was 3.5months. Among the 147 patients with PD, 74 (50.3%) were candidates for second-line chemotherapy, and 45 (30.6%) were eligible for regorafenib treatment. The median post progression survival of the candidates for second-line chemotherapy (8.8months) was statistically longer (P = 0.0002) than that of the non-candidates (3.6months). Predictive factors for candidates were absence of macroscopic vascular invasion (MVI) (odds ratio [OR], 0.39; P = 0.009) and serum albumin >3.5g/dL (OR, 3.3; P = 0.005) at sorafenib initiation. Among patients with PD on sorafenib, approximately 30% were eligible for regorafenib treatment, whereas few patients with MVI or hypoalbuminemia at sorafenib initiation were eligible for regorafenib treatment.

Prognostic Factors Associated with Postprogression Survival in Advanced Hepatocellular Carcinoma Patients Treated with Sorafenib Not Eligible for Second-Line Regorafenib Treatment

Objectives: The aim of this study was to investigate the prognostic factors associated with postprogression survival (PPS) in advanced hepatocellular carcinoma (HCC) patients treated with sorafenib, who were not eligible for second-line treatment with regorafenib. Methods: A total of 103 patients with radiological confirmation of progressive disease (PD) were enrolled. Results: The median PPS (n = 67) was 6.1 months. Significant and independent prognostic factors at initial radiological PD associated with good PPS were an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0, the absence of macrovascular invasion (MVI), and time to progression (TTP) ≥4 months. Upon scoring these three variables as good PPS factors, the median PPS in the good PPS score of 3 or 2 group (n = 38) was significantly longer than that in the good PPS score of 1 or 0 group (n = 29) (16.6 vs. 2.9 months; p < 0.0001, respectively). Conclusions: An ECOG-PS score of 0, the absence of MVI, and TTP ≥4 months at first radiological confirmation of PD may be useful for predicting good PPS in patients with advanced HCC who do not meet the eligibility criteria for the RESORCE trial.

Survival impact of post-progression chemotherapy in advanced gastric cancer: systematic review and meta-analysis.

We conducted a systematic review and meta-analysis on survival impact of post-progression chemotherapy (post-Cx) after first-line chemotherapy (1st-Cx) and after second-line chemotherapy (2nd-Cx), and survival benefit of third-line chemotherapy (3rd-Cx) for advanced gastric cancer (AGC). Phase III trials of systemic chemotherapy for AGC published in English between 2005 and 2015 or presented at annual meetings of ASCO or ESMO between 2013 and 2015 were searched. Numbers of patients, types of chemotherapy, patient baseline, proportion of patients receiving post-Cx (post-Cx%), median progression-free survival (mPFS), and median overall survival (mOS) of each treatment arm were surveyed; trials not reporting these parameters were excluded. Median post-progression survival (mPPS) was calculated as the difference between mOS and mPFS. Weighted Spearman's correlation coefficients between post-Cx% and survival outcomes (mOS and mPPS) were calculated. The effect of post-Cx% on survival outcomes adjusted for the types of chemotherapy and patient characteristics was evaluated by meta-regression. Overall, 25 phase III trials of AGC were selected: 15 trials with 31 arms for 1st-Cx, and 10 trials with 16 arms for 2nd-Cx. Weighted Spearman's correlation coefficients for post-Cx% and mOS/mPPS were 0.520/0.739 for 1st-Cx, and 0.767/0.823 for 2nd-Cx. Meta-regression analyses adjusting for types of chemotherapy, age, and PS showed that a 10% increase in post-Cx% was associated with prolongation of mOS by 1.033months for 1st-Cx and 0.344 months for 2nd-Cx. Post-Cx% both after 1st-Cx and 2nd-Cx were correlated with mOS/mPPS, suggesting a survival benefit of 3rd-Cx in addition to that of 2nd-Cx for AGC.

Post-progression survival following second-line chemotherapy in patients with advanced pancreatic cancer previously treated with gemcitabine: a meta-analysis.

Background Post-progression survival (PPS) could be a confounding element in interpreting data from clinical trials of second-line chemotherapy in patients with advanced pancreatic cancer (PC) previously treated with gemcitabine (GEM) because a recent meta-analysis of oxaliplatin combination therapy showed statistical heterogeneity for overall survival (OS) but not for progression-free survival (PFS). This study aimed to improve the understanding of the impact of PPS on OS in this setting. Methods Databases were searched to identify randomized controlled trials (RCTs) in the salvage setting. We evaluated relationships between OS and PFS, PPS, and other variables. Results Totally, 17 RCTs with 3253 patients were identified. Median OS was strongly and moderately associated with median PPS and PFS, respectively (r = 0.913; p < 0.001 and 0.780; p < 0.001, respectively). The proportion of patients with good performance status was significantly associated with both PPS and PFS (r = 0.574, p < 0.001 and 0.492, p < 0.001, respectively). The induction rate of subsequent chemotherapy was related to the duration of PPS and OS (r = 0.640, p < 0.001 and 0.647, p < 0.001, respectively). Median PPS and OS were significantly longer in recent trials than those in older trials (3.55 versus 2.78months, p < 0.001 and 6.29 versus 5.02months, p < 0.001). Conclusions Median PPS was strongly correlated with median OS. Given the recently increased opportunity for subsequent chemotherapy and supportive care, PPS may serve as an important element to clarify problems in this setting.

A multicenter, observational study of metastatic breast cancer patients who were treated with eribulin mesylate or taxane-based regimens.

This multicenter, observational study aimed to investigate the survival benefit of eribulin as well as that of taxane-based regimens in Japanese patients with metastatic breast cancer (MBC) in a real-world setting. This study enrolled women with MBC who received eribulin or taxane-based regimens with or without bevacizumab in routine clinical practice from July 2011 to March 2014. Patients were followed until September 2015. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), post-progression survival (PPS) and adverse events. Efficacy findings were adjusted according to demographics. In total, 216 patients receiving eribulin monotherapy (n=101), taxane monotherapy (n=73) or taxane plus bevacizumab (n=42) were followed for a median time of 15.4 months. Median OS, PFS and PPS were 22.3, 8.1 and 14 months in the eribulin monotherapy group; 13.2, 3.6 and 7.6 months in the taxane monotherapy group; and 12.9, 5.7 and 6.3 months, in the taxane plus bevacizumab group, respectively. The incidence of neutropenia was 67.3, 41.1 and 16.7%, and the incidence of grade 4 neutropenia was 1.0, 8.2 and 7.1% in the eribulin monotherapy, taxane monotherapy and taxane plus bevacizumab groups, respectively. One patient (1.0%) discontinued eribulin and 18 patients (15.7%) discontinued taxane-based regimens because of adverse events. In Japanese MBC patients in a real-world setting, eribulin showed a survival benefit and tolerability similar to that in previous reports.

Surrogacy of time to prgression for overall survival in advanced hepatocellular carcinoma treated with systemic therapy: A systematic review and meta-analysis of randomized controlled trials.

403 Background: Time to progression (TTP) is widely used as the endpoint in early-phase trials for advanced hepatocellular carcinoma (HCC). However, the relevance of using TTP as a surrogate marker for overall survival (OS) in pivotal trials remains uncertain. Methods: The PubMed database and ASCO meeting library were searched for reports of randomized controlled trials that investigated patients with advanced HCC, included data for both OS and TTP, and were launched between 2009 and 2016. Correlation between hazard ratios (HRs) for TTP and OS was determined using weighted linear regression. Correlations between median OS and TTP, and between median OS and post-progression survival (PPS), defined as the period obtained by subtracting median TTP from median OS, were also evaluated. Results: The database search yielded 24 trials with 50 arms. Overall, TTP HR correlated with OS HR (R = 0.73); however, the coefficient in the regression equation was 0.48. When trials were stratified by treatment line, TTP HR was more strongly correlated with OS HR in second-line (R = 0.91) than in first-line (R = 0.77) settings. Correlation between median OS and median TTP was weak (R = 0.50), whereas the correlation between median OS and median PPS was strong (R = 0.78). Conclusions: In advanced HCC, the OS HR can be predicted from the TTP HR, especially in second-line trials, which is useful when considering whether to proceed to a pivotal trial based on the results of early-phase trials. However, TTP may not be appropriate as a primary endpoint in a pivotal trial if the trial aims to evaluate the survival benefit of novel agents because improvement of TTP cannot fully reflect improvement of OS because of the impact of PPS on OS.

Survival impact of post-progression chemotherapy (post-Cx) in advanced gastric cancer (AGC): Systematic review and meta-analysis.

130 Background: We conducted a systematic review and meta-analysis to assess the survival impact of post-Cx after first-line chemotherapy (1st-line Cx) and second-line chemotherapy (2nd-line Cx) for AGC. Methods: Phase III trials published in English between 2005 and 2015 or presented at annual meetings of ASCO or ESMO between 2013 and 2015 were searched. No. of patients, types of chemotherapy, and patient characteristics, proportion of post-Cx use (post-Cx%), median progression free survival (mPFS), and median overall survival (mOS) of each treatment arm were surveyed; trials not reporting these were excluded from the study. Median post-progression survival (mPPS) was calculated as difference between mOS and mPFS. Weighted Spearman's correlation coefficients between post-Cx% and survival outcomes (mOS and mPPS) were calculated. The effect of post-Cx% on survival outcomes adjusted for the types of chemotherapy and patient characteristics was evaluated by meta-regressions. Results: Overall, 25 trials were selected: 15 with 31 arms for 1st-line Cx, and 10 with 16 arms for 2nd-line Cx. Weighted Spearman's correlation coefficients between post-Cx% and mOS/mPPS were 0.520/0.739 for 1st-line Cx, and 0.767/0.823 for 2nd-line Cx, respectively. Meta-regression analysis adjusting for types of chemotherapy, age and PS, showed that 10% increase in post-Cx% was associated with prolongation of mOS by 1.033 months for 1st-line Cx and 0.34 months for 2nd-line Cx. Conclusions: Post-Cx% after 2nd-line Cx are correlated with mPPS and mOS as well as 1st-line Cx, suggesting a survival benefit of 3rd-line Cx. [Table: see text]

Progression-free survival as a surrogate endpoint for overall survival in modern ovarian cancer trials: a meta-analysis.

Background:Progression-free survival (PFS) has been adopted as the primary endpoint in many randomized controlled trials, and can be determined much earlier than overall survival (OS). We investigated whether PFS is a good surrogate endpoint for OS in trials of first-line treatment for epithelial ovarian cancer (EOC), and whether this relationship has changed with the introduction of new treatment types.Methods:In a meta-analysis, we identified summary data [hazard ratio (HR) and median time] from published randomized controlled trials. Linear regression was used to assess the association between treatment effects on PFS and OS overall, and for subgroups defined by treatment type, postprogression survival (PPS) and established prognostic factors.Results:Correlation between HRs for PFS and OS, in 26 trials with 30 treatment comparisons comprising 24,870 patients, was modest (r2 = 0.52, weighted by trial sample size). The correlation diminished with recency: preplatinum/paclitaxel era, r2 = 0.66; platinum/paclitaxel, r2 = 0.44; triplet combinations, r2 = 0.22; biologicals, r2 = 0.30. The median PPS increased over time for the experimental (Ptrend = 0.03) and control arms (Ptrend = 0.003). The difference in median PPS between treatment arms strongly correlated with the difference in median OS (r2 = 0.83). In trials where the control therapy had median PPS of less than 18 months, correlation between PFS and OS was stronger (r2 = 0.64) than where the median PPS was longer (r2 = 0.48).Conclusions:In EOC, correlation in the relative treatment effect between PFS and OS in first-line platinum-based chemotherapy randomized controlled trials is moderate and has weakened with increasing availability of effective salvage therapies.

Overall survival and post-progression survival are potent endpoint in phase III trials of second/third-line chemotherapy for advanced or recurrent epithelial ovarian cancer.

Purpose: A growing number of treatment options and active compounds in treatments have led to better outcomes for patients with advanced or recurrent epithelial ovarian cancer. We examined the association between progression-free survival (PFS), post-progression survival (PPS) and overall survival (OS) in phase III trials of second- and third-line chemotherapy for advanced or recurrent epithelial ovarian cancer. We aim to determine whether PFS or PPS is a surrogate of OS so that we can decide progress of disease is optimal endpoint for ovarian cancer.Methods: We identified 22 trials conducted between January 1, 2000 through December 31, 2014 by literature search. We divided OS into PFS and PPS, and assessed the association between OS and PFS/PPS. We also examined whether the year of trial enrollment completion was associated with any variables.Results: The median PPS was slightly longer in recent trials compared to older trials (10.0 vs. 8.8 months). While PPS was strongly associated with OS (r = 0.88) in all trials, PFS was moderately correlated with OS (r = 0.72). The correlation between OS and PPS in recent trials (r = 0.93) was stronger than in older trials (r = 0.84).Conclusions: Our findings indicate that PPS is highly associated with OS in second/third-line chemotherapy for advanced or recurrent epithelial ovarian cancer, while the association between PFS and OS is moderate. We recommend using OS as primary endpoint for clinical trial of ovarian cancer, however PFS is still an optional endpoint.

Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study

BackgroundConventional criteria for tumor progression may not fully reflect the clinical benefit of immunotherapy or appropriately guide treatment decisions. The phase II IMvigor210 study demonstrated the efficacy and safety of atezolizumab, a programmed death-ligand 1-directed antibody, in patients with platinum-treated locally advanced or metastatic urothelial carcinoma. Patients could continue atezolizumab beyond Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 progression at the investigator’s discretion: this analysis assessed post-progression outcomes in these patients. Patients and methodsPatients were treated with atezolizumab 1200 mg i.v. every 3 weeks until loss of clinical benefit. Efficacy and safety outcomes in patients who experienced RECIST v1.1 progression and did, or did not, continue atezolizumab were analyzed descriptively. ResultsIn total, 220 patients who experienced progression from the overall cohort (n = 310) were analyzed: 137 continued atezolizumab for ≥ 1 dose after progression, 19 received other systemic therapy, and 64 received no further systemic therapy. Compared with those who discontinued, patients continuing atezolizumab beyond progression were more likely to have had a baseline Eastern Cooperative Oncology Group performance status of 0 (43.1% versus 31.3%), less likely to have had baseline liver metastases (27.0% versus 41.0%), and more likely to have had an initial response to atezolizumab (responses in 11.7% versus 1.2%). Five patients (3.6%) continuing atezolizumab after progression had subsequent responses compared with baseline measurements. Median post-progression overall survival was 8.6 months in patients continuing atezolizumab, 6.8 months in those receiving another treatment, and 1.2 months in those receiving no further treatment. Atezolizumab exposure-adjusted adverse event frequencies were generally similar before and following progression. ConclusionIn this single-arm study, patients who continued atezolizumab beyond RECIST v1.1 progression derived prolonged clinical benefit without additional safety signals. Identification of patients most likely to benefit from atezolizumab beyond progression remains an important challenge in the management of metastatic urothelial carcinoma. ClinicalTrials.gov IDNCT02108652.

Postprogression survival in patients with glioblastoma treated with concurrent chemoradiotherapy: a routine care cohort study.

Glioblastoma is the commonest malignant brain tumor in adults. Most patients develop progressive disease before they die. However, survival after developing progressive disease is infrequently reported. We identified patients with histologically proven disease who were treated with concurrent chemoradiotherapy during 2006-2013. We analyzed overall survival (OS), progression-free survival and postprogression survival (PPS) in relation to age, O6-methylguanine-DNA methyltransferase promoter methylation and extent of surgical resection. We identified 166 patients. Median survival was 13.5months; 2-year OS was 21.7%. Median progression-free survival and PPS were 7.03 and 4.53months, respectively. Age and extent of surgical resection were correlated with OS. Only the extent of surgical resection was associated with PPS. Our work suggests that the established prognostic factors for glioblastoma do not appear to help predict PPS.

Validation of the albumin-bilirubin grade-based integrated model as a predictor for sorafenib-failed hepatocellular carcinoma.

Sorafenib is the standard treatment for advanced hepatocellular carcinoma (HCC) but is challenging after treatment failure. Appropriate criteria for enrolling patients into second-line trials are still limited. In this study, we aimed to establish more objective criteria based on Albumin-Bilirubin (ALBI) grade to select patients with better post-progression survival (PPS) for second-line treatment. Consecutive 404 advanced HCC patients receiving sorafenib were retrospectively enrolled. All patients were in Child-Pugh class A and BCLC stage C with either portal vein invasion or extrahepatic metastasis at the beginning of sorafenib treatment. Radiological evaluation based on mRECIST criteria and clinical assessments with compliance were performed on schedule. During the median follow-up period of 5.8months, 310 patients developed progressive disease (PD) and 350 deaths occurred. The PD patients were randomized into derivation and validation cohorts by a 1:1 ratio. The independent predictors of poor PPS in derivation cohort were ALBI grade 3 at PD (hazard ratio [HR]=3.24, P=.002), new extrahepatic lesions (NEH) (HR=1.75, P=.011), and early PD within 4months (HR=1.88, P=.037). ALBI-PD criteria were proposed by incorporating these three risk factors. In the validation cohort, PPS could be independently predicted by presence of early PD, NEH as well as ALBI grade 3 at PD. Patients within ALBI-PD criteria had significant longer median PPS than those beyond it even in Child-Pugh A (9.7 vs 4.9months, P=.005) subpopulations. The ALBI-PD criteria can differentiate PPS and stratify the patients with advanced HCC for the second-line trials or salvage therapy.

Clinicopathological features and outcomes of progression of CLL on the BCL2 inhibitor venetoclax

AbstractThe BCL2 inhibitor venetoclax achieves responses in ∼79% of patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (RR-CLL/SLL), irrespective of risk factors associated with poor response to chemoimmunotherapy. A limitation of this targeted therapy is progressive disease (PD) in some patients. To define the risk factors for progression, the clinicopathological features of PD, and the outcomes for patients after venetoclax failure, we analyzed 67 heavily pretreated patients on 3 early phase clinical trials. Investigations at progression included positron emission tomography scan and biopsy. Twenty-five (37%) patients manifested PD on therapy: 17 with Richter transformation (RT) and 8 with progressive CLL/SLL. RT occurred significantly earlier (median 7.9 months) than progressive CLL (median 23.4 months) (P = .003). Among patients who received the recommended phase 2 dose of venetoclax or higher (≥400 mg/d), fludarabine refractoriness and complex karyotype were associated with progression (hazard ratio 7.01 [95% confidence interval 1.7-28.5]; P = .002 and 6.6 [1.5-29.8]; P = .005, respectively), whereas del(17p) and/or TP53 mutation were not (P = .75). Median postprogression survival was 13 (<1-49.9) months. Bruton tyrosine kinase inhibitors were active in progressive CLL, but outcomes were mixed. Patients with disease that is fludarabine refractory or who have complex cytogenetics should have occult RT excluded before initiating venetoclax therapy.

A systemic review and meta-analysis to evaluate the efficacy and postprogression survival of second-line chemotherapy for gemcitabine-refractory pancreatic cancer.

e15768 Background: We previously reported positive relationship between overall survival (OS) and both of postprogression survival (PPS) and post-trial anti-cancer therapies in first-line pancreatic cancer patients. We conducted a meta-analysis to gain a better understanding of the impact of PPS and post-trial anti-cancer therapies on OS and to determine the efficacy of second-line systemic therapy. Methods: We searched randomized trials of second-line systemic therapy for pancreatic cancer patients. We evaluated the relation between OS and either progression-free survival (PFS) or PPS and calculated the pooled effect size by using random effects models. Results: Eleven randomized trials with 23 treatment arms that involved examining 2267 patients were analyzed. Median OS was strongly associated with median PPS and PFS (r = 0.908 and 0.754, respectively), but no correlation between rate of post-trial anti-cancer therapies and OS was detected (r = 0.050). Average OS, PFS and PPS were significantly longer in recent trials than in older trials, (6.08 versus 4.17 months, p &lt; 0.001), (2.65 versus 1.95 months, p &lt; 0.001) and (3.43 versus 2.25 months, p &lt; 0.001), respectively. Overall, experimental therapies compared to control did not significantly improve PFS (HR, 0.83; 95% CI, 0.67-1.03; I2 = 73%) or OS (HR, 0.89; 95% CI, 0.72-1.11; I2 = 69%). When the analysis was restricted to fluoropyrimidine compared to irinotecan or oxaliplatin in combination with fluoropyrimidine, each therapy produced advantage in a term of PFS (HR, 0.65; 95% CI, 0.47-0.88; I2 = 39% for irinotecan, HR, 0.81; 95% CI, 0.67-0.98; I2 = 13% for oxaliplatin) but only irinotecan produced advantage in a term of OS (HR, 0.70; 95% CI, 0.55-0.89; I2 = 0% for irinotecan, HR, 1.04; 95% CI, 0.65-1.65; I2 = 82% for oxaliplatin). Conclusions: Although second-line treatment benefit for OS can be skewed by PPS in patients with gemcitabine-refractory pancreatic cancer, the effects of subsequent therapies are weak in the salvage setting.

Clinical Features of Acquired Resistance to Anti-PD-1 Therapy in Advanced Melanoma.

Anti-PD-1 therapy has improved clinical outcomes in advanced melanoma, but most patients experience intrinsic resistance. Responding patients can develop acquired resistance to anti-PD-1. We retrospectively reviewed 488 patients treated with anti-PD-1 from three academic centers and identified 36 patients with acquired resistance, defined as disease progression following objective response. The incidence, timing, disease sites, post-progression survival (PPS), and outcomes were evaluated descriptively. The acquired resistance cohort consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial and complete responses were achieved in 89% (n = 32) and 11% (n = 4) of patients, respectively, and median time to resistance (progression-free survival; PFS) was 11.1 months (range 4.3-32.8 months). Most progression was isolated (78% of patients, n = 28) and occurred while receiving therapy (78%, n = 28). The median PPS was 12.8 months (range 0.1-51.8 months), and the median overall survival was 33.7 months. Among isolated progressors, 15 received localized therapy (12 with surgery, 3 with radiation). Patients with isolated versus systemic progression exhibited a trend for improved PPS (P = 0.081), and patients with an initial PFS ≥ 15 months showed significant PPS improvement (P = 0.036). Two patients experienced subsequent responses to anti-PD-1 resumption. In conclusion, acquired resistance to anti-PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption. Cancer Immunol Res; 5(5); 357-62. ©2017 AACR.

Positive relationship between subsequent chemotherapy and overall survival in pancreatic cancer: meta-analysis of postprogression survival for first-line chemotherapy.

To gain a better understanding of the impact of postprogression survival (PPS) and post-trial anticancer therapy on overall survival (OS) in first-line pancreatic cancer patients. A literature search identified 54 randomized trials, focusing on gemcitabine monotherapy to eliminate effects of heterogeneity of first-line regimens. We evaluated the relation between OS and either progression-free survival (PFS) or PPS. We also examined whether any association might be affected by the year of completion of trial enrollment. For all 54 trials, PPS was strongly associated with OS (r = 0.844), whereas PFS was moderately associated with OS (r = 0.623). Average OS and PPS were significantly longer in recent trials than in older trials, (7.29 versus 6.15 months, p < 0.001) and (3.64 versus 2.86 months, p < 0.001), respectively. The correlation between OS and PPS in recent trials was much stronger than that in older trials (r = 0.846 versus 0.729). The relation between OS and PFS in recent and older trials did not differ (r = 0.595 versus 0.563). The percentage of patients with post-trial treatment was significantly higher in recent trials than in older trials (52.7 versus 39.7%, p < 0.001). The rate of post-trial anticancer therapy was significantly associated with OS (r = 0.910). We found an increase in median PPS in accordance with an increase in median OS in recent trials compared with older trials and that rate of post-trial anticancer therapy was strongly associated with median OS. It is important that researchers be aware of these findings in designing clinical trials of first-line chemotherapy for pancreatic cancer patients.

Treatment of Advanced Hepatocellular Carcinoma after Failure of Sorafenib Treatment: Subsequent or Additional Treatment Interventions Contribute to Prolonged Survival Postprogression.

Background Sorafenib is a first-line treatment option for advanced hepatocellular carcinoma (HCC) patients; however, survival predictors upon progression have not been well characterized. In the present study, we aimed to show the efficacy of multidisciplinary therapy for patients who had failed to respond to sorafenib treatment. Methods Among 146 BCLC stage B or C HCC patients treated with sorafenib monotherapy between July 2009 and August 2014, the first radiological progression according to the modified RECIST was identified in 71 patients; factors predicting overall survival (OS) and survival postprogression (SPP) were analyzed in these patients. Results The median OS and SPP for patients who failed to respond to sorafenib treatment were 10.5 and 6.2 months, respectively, and the SPP was strongly correlated with the OS (r = 0.982, P < 0.01, and R2 = 0.965). The independent predictors of OS and SPP were identical. The predictors of SPP were des-gamma-carboxy prothrombin, progression of portal vein thrombosis, and subsequent second-line or additional treatment. Conclusions SPP is closely associated with OS and might be notable in patients who have failed to respond to initial sorafenib treatment. Furthermore, interventions consisting of other treatment options upon the appearance of progression might prolong OS.

135P A multicenter retrospective observation study about overall survival benefit of eribulin mesylate in comparison with taxane regimens for metastatic cancer patients

Background Eribulin (Eri) has been reported to prolong overall survival (OS) in several studies with metastatic breast cancer (MBC) patients (pts). Recently, some reports have showed OS benefit in Eri comparison with taxane regimens for the early line MBC pts. Here we presented an analysis about the OS extension effect of Eri in a retrospective multicenter observation study for MBC pts. Methods MBC pts who received eribulin or taxanes in the early line treatment from August 2011 to March 2014 in our institutes were analyzed. Taxane regimens included monotherapy of paclitaxel, docetaxel, nab-paclitaxel and the taxane combination with bevacituzumab. The efficacy including complete response (CR) and objective response rate (ORR) and adverse events were determined. Kaplan-Meier method was utilized to estimate median OS and survival post progression (SPP). And subgroup analysis of OS was by tumor subtypes and treatment-line. Results A total 221 patients were analyzed included in this study and 101 pts received eribulin and 120 pts received taxanes. ORR was higher in eribulin than taxanes (49.5% vs 21.7%) and CR rate was 11% in eribulin and 0.4% in taxanes. The median OS and SPP were longer in eribulin than taxanes (OS: 22.3 months vs 13.6 months, SPP: 14.0 months vs 7.7 months). Subgroup analysis showed tendency of longer OS in MBC pts who had ER positive and visceral metastases, and who received in early line treatment. The major reason for discontinuing Eri treatment was due to increase of primary tumor size. Adverse events had been observed lower in Eri (1.0%) than in taxanes (16.0%). The study also found that the incidence of distant metastases at the time of PD was lower in patients receiving eribulin (11.3%) compared with those receiving taxanes (28.3%). Mean number of treatment regimens after the study therapy were 2.4 in eribulin and 1.5 in taxanes. Conclusions From those analysis, the higher efficacy and acceptable safety profile of eribulin might contribute to prolonged survival. Legal entity responsible for the study N/A Funding N/A Disclosure All authors have declared no conflicts of interest.

ALBI Grade Determines Post-progression Survivals after Sorafenib Treatment Failure in Advanced HCC Patients: A Model for Second-Line Trial Selection

Introduction: Sorafenib can improve the overall survival (OS) and progression-free survival (PFS) of advanced hepatocellular carcinoma (HCC). Appropriate criteria for selection patients who can be enrolled in second-line trials are in unmet need. In this study, we aimed to evaluate the post-progression survival (PPS) in patients undergoing sorafenib for advanced HCC based on Albumin-Bilirubin (ALBI) grade, a new model with good performance in predicting OS of HCC. Methods: Consecutive 276 advanced HCC patients receiving sorafenib were retrospectively enrolled. All patients were in Child-Pugh A status and BCLC stage C with either portal vein invasion or extrahepatic metastasis. Radiologic evaluation was based on mRECIST criteria, clinical and compliance assessments were performed every two months, and two to four weeks, respectively. Results: During the median follow-up period of 5.6 months (interquartile range [IQR], 3.0-13.5), 220 (79.7%) patients developed progressive disease (PD) and 245 (88.8%) deaths occurred. The mean sorafenib dosage was 613.3mg (standard deviation, 189.7mg) per day; and the medium treatment duration was 64 days (IQR, 50-125). The median PFS, OS, and PPS were 2.1 (IQR, 1.4-5.9), 5.7 (IQR, 3.1-13.6), and 4.0 (IQR, 1.9-9.1) months, respectively. The ALBI grade could independently predict the OS (hazard ratio [HR], 1.505 for grade 2 vs 1; and 4.354 for grade 3 vs 1) but did not have a role in predicting PFS. Independent predictors of PPS included ALBI grade at progression (HR, 1.654 for grade 2 vs 1; and 2.655 for grade 3 vs 1), new extrahepatic lesions (NEH) (HR, 2.026), high alpha-fetoprotein level (HR, 1.801), and early progression within 4 months (HR, 1.591). In the subgroup analysis according to the alpha-fetoprotein level at PD and time to progression interval, better PPS was only presented while NEH(-), ALBI grade 1 in early PD, high AFP group as well as NEH(-), ALBI grade 1-2 in late PD, low AFP group. Conclusion: Liver function and progression pattern are important determinants of survival after sorafenib failure. The presence of NEH is contraindicated for second-line trials as a poor PPS can be expected. Patients with early PD and high AFP level, ALBI grade 1; or patients without early PD or high AFP level, ALBI grade 1 & 2 can be a new inclusion criteria of second-line trials for advanced HCC.