Objective Response and Progression-Free Survival Contribute to Prolong Overall Survival in Atezolizumab plus Bevacizumab Treatment for Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Atezolizumab plus bevacizumab (Atez/Bev) is a standard treatment for unresectable hepatocellular carcinoma (HCC) due to its good antitumor and survival prolongation effects. Post-progression survival (PPS) has been reported to be a great contributor in the treatment with tyrosine kinase inhibitors for unresectable HCC. This study aimed to clarify the significance of progression-free survival (PFS) or PPS of Atez/Bev treatment for HCC. METHODS: We analyzed the correlations of PFS and PPS with overall survival (OS) in studies of HCC patients treated with Atez/Bev and evaluated the contribution to OS in Atez/Bev treatment with patients at our institutions as clinical practice. RESULTS: Analysis of 18 studies involving 3,752 patients treated with Atez/Bev found that PPS had a stronger correlation with OS (R2 = 0.872, p < 0.001) than did PFS (R2 = 0.605, p = 0.001). Analysis of 80 patients with unresectable HCC treated with Atez/Bev found that presence of antitumor responses during Atez/Bev was the most significant contributor to OS, and post-progression treatment after Atez/Bev also significantly contribute to OS. CONCLUSION: The presence of antitumor response with tumor shrinkage during Atez/Bev treatment contributes to good OS through its durable response. Atez/Bev treatment could be considered as first-line treatment for unresectable HCC. However, there is a need for optimal biomarkers for good antitumor response.

Progression pattern and post-progression survival following atezolizumab and bevacizumab treatment in advanced hepatocellular carcinoma.

BACKGROUND: Although the combination of atezolizumab and bevacizumab (ATZ + BEV) is a standard treatment for advanced hepatocellular carcinoma (HCC), strategies for addressing treatment failure and prognostic factors of post-progression survival (PPS) remain unestablished. METHODS: We conducted a multicentre retrospective study to evaluate PPS following ATZ + BEV treatment in patients with advanced HCC. We classified the patients into three groups: BCLC stage B and BCLC stage C without or with new extrahepatic lesions (BCLCp-C1 and BCLCp-C2, respectively) at the time of progression. RESULTS: Of the 204 patients who started ATZ + BEV treatment between October 2020 and September 2022, 110 showed disease progression, with 33, 55 and 22 showing the BCLCp-B, BCLCp-C1 and BCLCp-C2 stages of the disease, respectively. Specifically, patients with the BCLCp-B stage of the disease showed better overall survival than those with the BCLCp-C1 and BCLCp-C2 stages (hazard ratios: 1.93 [95% confidence interval, CI, 1.06-3.51] and 2.64 [95% CI, 1.32-5.30] for HCC stages BCLCp-C1 and BCLCp-C2, respectively). Via multivariable analysis, we identified the BCLCp-C1 and BCLCp-C2 stages, as well as performance status, Child-Pugh class and alpha-fetoprotein as poor prognostic factors for PPS. CONCLUSIONS: BCLCp-B1 stage was identified as a better prognostic factor for PPS following ATZ + BEV treatment compared with BCLCp-C1 and BCLCp-C2 stages. This may help in making decisions regarding subsequent treatment after ATZ + BEV.

Impact of post-progression survival in second-line treatment with molecular target agents for unresectable hepatocellular carcinoma.

AIM: Sequential therapies are essential to extend overall survival (OS) in patients with unresectable hepatocellular carcinoma (HCC). Several second-line treatments with molecular target agents have shown survival benefits. However, the significance of post-progression survival (PPS) in extending OS in patients with HCC given such treatments remains uncertain. METHODS: Through a systematic review of the literature in the PubMed database, this study investigated the correlation between PPS and OS and that between progression-free survival (PFS) and OS in patients with HCC given second-line treatments. RESULTS: In total, 3935 patients who had received second-line treatment with regorafenib, ramucirumab, or cabozantinib, which are approved molecular target agents, were identified. In the patients treated with regorafenib, PPS showed a strong correlation with OS (R2 = 0.729, R = 0.854, p < 0.001) whereas PFS showed a weak correlation (R2 = 0.218, R = 0.467, p = 0.021). In the patients treated with ramucirumab, PPS showed a strong correlation with OS (R2 = 0.800, R = 0.894, p = 0.016) whereas PFS showed a negligible correlation (R2 = 0.020, R = 0.140, p = 0.791). In the patients treated with cabozantinib, PPS showed a strong correlation with OS (R2 = 0.856, R = 0.925, p = 0.003) as did PFS (R2 = 0.946, R = 0.973, p < 0.001). CONCLUSIONS: PPS plays a more significant role than PFS in extending OS in patients given second-line treatment for unresectable HCC. Sequential therapies after disease progression in second-line treatment are essential to acquire good OS. Maintenance of hepatic reserve function and the patient's general condition is essential during systemic treatments for unresectable HCC.

Post-progression treatment in cancer randomized trials: a cross-sectional study of trials leading to FDA approval and published trials between 2018 and 2020.

BACKGROUND: Suboptimal treatment upon progression may affect overall survival (OS) results in oncology randomized controlled trials (RCTs). We aim to assess the proportion of trials reporting post-progression treatment. METHODS: This cross-sectional analysis included two concurrent analyses. The first one examined all published RCTs of anti-cancer drugs in six high impact medical/oncology journals between January 2018 and December 2020. The second studied all US Food and Drug Administration (FDA) approved anti-cancer drugs during the same period. Included trials needed to study an anti-cancer drug in the advanced or metastatic setting. Data abstracted included the tumor type, characteristics of trials, and reporting and assessment of post-progression treatment. RESULTS: There were 275 published trials and 77 US FDA registration trials meeting inclusion criteria. Assessable post-progression data were reported in 100/275 publications (36.4%) and 37/77 approvals (48.1%). Treatment was considered substandard in 55 publications (n = 55/100, 55.0%) and 28 approvals (n = 28/37, 75.7%). Among trials with assessable post-progression data and positive OS results, a subgroup analysis identified substandard post-progression treatment in 29 publications (n = 29/42, 69.0%) and 20 approvals (n = 20/26, 76.9%). Overall, 16.4% of publications (45/275) and 11.7% of registration trials (9/77) had available post-progression data assessed as appropriate. CONCLUSION: We found that most anti-cancer RCTs do not report assessable post-progression treatment. When reported, post-progression treatment was substandard in most trials. In trials reporting positive OS results and with assessable post-progression data, the proportion of trials with subpar post-progression treatment was even higher. Discrepancies between post-progression therapy in trials and the standard of care can limit RCT results' applicability. Regulatory rules should enforce higher requirements regarding post-progression treatment access and reporting.

Post-Progression Survival Highly Influences Overall Survival in Driver Gene Mutation/Translocation Negative or Unknown Type of Non-Small Cell Lung Cancer.

INTRODUCTION: In stage I-III non-small cell lung cancer (NSCLC), which is considered operable, surgical resection is the most efficacious treatment and is considered to provide a cure. However, after complete surgical resection, approximately 50% of patients with stage I-IIIA NSCLC experience recurrence and death. Once postoperative recurrence of NSCLC occurs, the prognosis is significantly poor, and the course of treatment after recurrence may influence overall survival (OS). Consequently, we investigated the relationship between relapse-free survival (RFS), post-progression survival (PPS), and OS in patients with postoperative recurrence of NSCLC with driver gene mutation/translocation negative or unknown status. METHODS: Between January 2007 and September 2019, 101 patients with driver gene mutation/translocation negative or unknown status of NSCLC who underwent complete resection and in whom recurrence occurred were analyzed. The associations between RFS, PPS, and OS were analyzed at the individual patient level. RESULTS: Linear regression and Spearman rank correlation analyses revealed that PPS was strongly associated with OS (r = 0.83, p < 0.0001, R2 = 0.71), whereas RFS was moderately correlated with OS (r = 0.65, p < 0.0001, R2 = 0.48). In the multivariate analysis, performance status at relapse, administration of immune checkpoint inhibitors, and radiotherapy for oligo-recurrences were significantly associated with PPS (p < 0.001). CONCLUSION: Current analysis of individual-level data of patients who underwent complete resection implied that PPS had a higher impact on OS than RFS in patients with postoperative recurrence of driver gene mutation/translocation negative or unknown status of NSCLC. Additionally, current perceptions indicate that treatment beyond progression after complete surgical resection might strongly affect OS.

Impacts of genotypic variants on survival following reoperation for recurrent glioblastoma.

INTRODUCTION: Recurrent glioblastoma (rGBM) prognosis is dismal. In the absence of effective adjuvant treatments for rGBM, re-resections remain prominent in our arsenal. This study evaluates the impact of reoperation on post-progression survival (PPS) considering rGBM genetic makeup. METHODS: To assess the genetic heterogeneity and treatment-related changes (TRC) roles in re-operated or medically managed rGBMs, we compiled demographic, clinical, histopathological, and next-generation genetic sequencing (NGS) characteristics of these tumors from 01/2005 to 10/2019. Survival data and reoperation were analyzed using conventional and random survival forest analysis (RSF). RESULTS: Patients harboring CDKN2A/B loss (p = 0.017) and KDR mutations (p = 0.031) had notably shorter survival. Reoperation or bevacizumab were associated with longer PPS (11.2 vs. 7.4-months, p = 0.006; 13.1 vs 6.2, p < 0.001). Reoperated patients were younger, had better performance status and greater initial resection. In 136/273 (49%) rGBMs undergoing re-operation, CDKN2A/B loss (p = 0.03) and KDR mutations (p = 0.02) were associated with shorter survival. In IDH-WT rGBMs with NGS data (n = 166), reoperation resulted in 7.0-month longer survival (p = 0.004) than those managed medically. This reoperation benefit was independently identified by RSF analysis. Stratification analysis revealed that EGFR-mutant, CDKN2A/B-mutant, NF1-WT, and TP53-WT rGBM IDH-WT subgroups benefit most from reoperation (p = 0.03). Lastly, whether or not TRC was prominent at re-operation does not have any significant impact on PPS (10.5 vs. 11.5-months, p = 0.77). CONCLUSIONS: Maximal safe re-resection significantly lengthens PPS regardless of genetic makeup, but reoperations are especially beneficial for IDH-WT rGBMs with EGFR and CDKN2A/B mutations with TP53-WT, and NF1-WT. Histopathology at recurrence may be an imperfect gauge of disease severity at progression and the imaging progression may be more reflective of the prognosis.

Estimation of time to progression and post progression survival using joint modeling of summary level OS and PFS data with an ordinary differential equation model.

measures such as progression-free survival (PFS) and overall survival (OS) are commonly reported in literature for oncology trials, while time to progression (TTP) and post progression survival (PPS) are not usually reported. A time-variant transition hazard model was developed using an ordinary differential equation (ODE) model to estimate TTP and PPS from summary level PFS and OS. The model was applied to published data from immune checkpoint inhibitor trials for non-small cell lung cancer (NSCLC) in a meta-analysis framework. This model-based method was able to robustly estimate TTP and PPS from summary level OS and PFS data, provided a quantitative approach for understanding the patterns of disease progression across different treatments through the time-variant disease progression rate function, and provided a summary of how different treatments affect TTP and PPS. The proposed method can be generalized to characterize and quantify multiple time-to-event endpoints jointly in oncology trials and improve our understanding of disease prognostics for different treatments.

Post-Progression Survival Influences Overall Survival among Patients with Advanced Non-Small Cell Lung Cancer Undergoing First-Line Pembrolizumab Monotherapy.

BACKGROUND: Among patients with non-small cell lung cancer (NSCLC), the impact of first-line treatment on overall survival (OS) may be influenced by subsequent therapies. Thus, using patient-level data, we assessed the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS among patients with high-programmed death-ligand 1 (PD-L1) expression undergoing first-line pembrolizumab monotherapy for NSCLC. METHODS: We reviewed data from 133 patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC at 6 Japanese centers between February 2017 and December 2018. The correlations of PFS and PPS with OS were evaluated at the patient level. RESULTS: Linear regression analyses and Spearman's rank correlation coefficient revealed that PPS was strongly correlated with OS (r = 0.76, p < 0.05, R2 = 0.65), while PFS was only moderately correlated with OS (r = 0.71, p < 0.05, and R2 = 0.4). Furthermore, PPS was significantly associated with performance status at the end of pembrolizumab monotherapy, as well as the use of platinum-based combination chemotherapy after pembrolizumab monotherapy (both p < 0.05). CONCLUSIONS: Among patients with high PD-L1 expression undergoing first-line pembrolizumab monotherapy for NSCLC, PPS was more strongly correlated with OS, relative to the relationship between PFS and OS. Therefore, subsequent treatment appears to significantly influence OS in patients with disease progression following first-line pembrolizumab monotherapy.

Pattern of progression in advanced hepatocellular carcinoma treated with ramucirumab.

BACKGROUND & AIMS: Radiological progression patterns to first-line sorafenib have been associated with post-progression and overall survival in advanced hepatocellular carcinoma, but these associations remain unknown for therapies in second- and later-line settings. This post hoc analysis of REACH and REACH-2 examined outcomes by radiological progression patterns in the second-line setting of patients with advanced hepatocellular carcinoma treated with ramucirumab or placebo. METHODS: Patients with advanced hepatocellular carcinoma, Child-Pugh A and Eastern Cooperative Oncology Group Performance Status 0 or 1 with prior sorafenib were randomized to receive ramucirumab 8mg/kg or placebo every 2 weeks. Among 625 patients with ≥1 progression pattern (new extrahepatic lesion [including new macrovascular invasion], new intrahepatic lesion, extrahepatic growth or intrahepatic growth), data were analysed by trial and for pooled individual patient data for REACH-2 and REACH (alpha-fetoprotein ≥400 ng/mL). Cox models evaluated prognostic implications of progression patterns on overall and post-progression survival. RESULTS: Post-progression survival was worse among those with new extrahepatic lesions in REACH (HR 2.33, 95% CI 1.51-3.60), REACH-2 (HR 1.49, 95% CI 0.72-3.08) and the pooled population (HR 1.75, 95% CI 1.12-2.74) compared to other progression patterns. Overall survival was also significantly reduced in those with new extrahepatic lesions across studies. Ramucirumab provided an overall survival benefit across progression patterns, including patients with new extrahepatic lesions (HR 0.56, 95% CI 0.39-0.80) in the pooled population. CONCLUSIONS: The emergence of new extrahepatic lesions in the second-line setting is a poor prognostic factor for post-progression survival. The benefit of ramucirumab for overall survival was consistent across progression patterns.

The use of bevacizumab is correlated with improved post-progression survival in advanced recurrent ovarian cancer.

BACKGROUND: The recent improvements in anti-cancer therapy following first-line treatment can potentially impact post-progression survival. We evaluated the factors that influence post-progression survival in advanced recurrent ovarian cancer. METHODS: Eighty-nine patients who underwent first-line treatment between June 2005 and December 2017 were included. The post-progression survival was defined as the difference between overall survival and initial progression-free survival. The effects of age, histology, stage, optimal surgery, secondary debulking surgery, bevacizumab administration, platinum sensitivity, and olaparib maintenance in recurrence were compared and independent risk factors were determined. RESULTS: The median follow-up duration was 60.0 months (range: 2-181). Platinum-sensitive recurrence had longer post-progression survival than platinum-resistant (P < 0.001). Inclusion of bevacizumab in first-line treatment did not produce a significant difference in post-progression survival (P = 0.462). Secondary debulking surgery (P = 0.013), bevacizumab administration (P < 0.001), and olaparib maintenance (P = 0.001) during recurrence increased post-progression survival. In multivariate analysis, histologies other than serous or endometrioid (hazard ratio = 2.389; 95% confidence interval = 1.200-4.754; P = 0.013) and non-bevacizumab usage in recurrence (hazard ratio = 4.484; 95% confidence interval = 1.939-10.370; P < 0.001) were independently correlated with poorer prognosis. Bevacizumab administration beyond progressive disease elicited improved post-progression survival (P < 0.001). In patients receiving bevacizumab in first-line treatment, exclusion of bevacizumab in the recurrent therapy (hazard ratio = 5.507; 95% confidence interval = 2.301-12.124; P < 0.001) was independently correlated with poorer prognosis. CONCLUSIONS: The continuous use of bevacizumab beyond progressive disease improves post-progression survival suggesting its important role in first-line and recurrence treatment for ovarian cancer.

Post-Progression Survival Is Strongly Associated with Overall Survival in Patients Exhibiting Postoperative Relapse of Non-Small-Cell Lung Cancer Harboring Sensitizing EGFR Mutations.

Background and Objective: Patients with advanced non-small-cell lung cancer (NSCLC) harboring sensitizing epidermal growth factor receptor (EGFR) mutations show a good response to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). The subsequent treatments influence the evaluability of the efficacy of front-line therapy on overall survival (OS). Consequently, we evaluated the associations of relapse-free survival (RFS) and post-progression survival (PPS) with OS in patients who exhibited postoperative relapse of EGFR-mutated NSCLC. Materials and Methods: We analyzed the data of 35 patients with EGFR-mutated NSCLC who underwent complete resection between January 2007 and June 2019. The correlations of RFS and PPS with OS were evaluated at the individual patient level. Results: Linear regression and Spearman's rank correlation analyses demonstrated that the PPS highly correlated with OS (r = 0.91, p < 0.05, R2 = 0.85), whereas the RFS weakly associated with OS (r = 0.36, p < 0.05, R2 = 0.25). Age and performance status at relapse were significantly associated with PPS. Conclusion: Overall, PPS was more strongly and significantly associated with OS than RFS. These results suggest that the OS of our cohort may be affected by treatments, besides postoperative relapse. However, larger-scale prospective studies are needed to confirm these results.

Olaparib as maintenance therapy in patients with BRCA 1-2 mutated recurrent platinum sensitive ovarian cancer: Real world data and post progression outcome.

OBJECTIVES: Olaparib is approved as maintenance therapy in patients with BRCA mutated platinum sensitive (PS) recurrent ovarian cancer (OC) after response to last platinum based therapy. Few data are available regarding the use out of the registration trials and on response to further treatments after progression. MATERIALS AD METHODS: In this non interventional, retrospective study, patients treated with olaparib in 13 centers, according to the label, have been collected and analyzed. Primary objectives of the study are to describe effectiveness and safety of olaparib in a real world setting with a focus on post progression treatments and response. RESULTS: 234 patients were analyzed. All patients were BRCA mutated and most of them had germline mutations. Around 50% of the patients received olaparib after 3 or more lines of platinum based chemotherapy achieving a radiologic complete (CR) or partial response. 12.4% patients with stable disease were also included. Median PFS was 14.7 months (95% CI:12.6-18), with statistically longer PFS in patients with normal serum Ca125 at baseline, a CR after last platinum based therapy and that received olaparib after second platinum based therapy. Median OS was not reached. Most frequent G3-G4 toxicity was anaemia (6%) with dose discontinuation and dose reduction in 11 (4.7%) and 49 (20.9%) of cases, respectively. Among 66 patients receiving further treatment after olaparib progression and evaluable for response, ORR was 22.2, 11.1% and 9.5% in patients with Platinum Free interval (PFI) of more than 12 months, between 6 and 12 months and less than 6 months, respectively. CONCLUSIONS: Olaparib is effective and safe in real world setting. Data on post-progression treatments seem to suggest cross resistance with chemotherapy and need to be confirmed in larger studies because of the potential importance in clinical practice decisions.

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 2.78 months, p < 0.001 and 6.29 versus 5.02 months, 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.

Clinical Impact of Post-Progression Survival on Overall Survival in Elderly Patients with Non-Small-Cell Lung Cancer Harboring Sensitive EGFR Mutations Treated with First-Line EGFR Tyrosine Kinase Inhibitors.

BACKGROUND/AIMS: More than 50% of patients with lung cancer are aged > 65 years, and non-small-cell lung cancer (NSCLC) accounts for 85% of all cases of lung cancer among both elderly and adult patients. Subsequent therapies confound the capability to discern the effect of first-line chemotherapy on overall survival (OS). Therefore, using individual-level data, our study aimed to determine the relationships of progression-free survival (PFS) and post-progression survival (PPS) with OS after first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment in elderly patients with NSCLC harboring sensitive EGFR mutations. METHODS: Between April 2008 and December 2015, we analyzed 68 elderly patients with NSCLC harboring sensitive EGFR mutations and treated with first-line EGFR-TKI. The relationships of PFS and PPS with OS were analyzed at an individual level. RESULTS: Linear regression analysis showed that PPS was more closely associated with OS (R2 = 0.54) than PFS was (R2 = 0.48). Best response at first-line treatment, performance status at the end of first-line treatment, and administration of EGFR-TKI rechallenge were significantly correlated with PPS. CONCLUSIONS: PPS has a stronger impact on OS than PFS does in elderly patients with NSCLC harboring sensitive EGFR mutations and treated with first-line EGFR-TKI. These results indicate that OS in this patient population may be influenced by treatments subsequent to first-line chemotherapy; however, this remains to be verified in prospective studies.

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

BACKGROUND: Conventional 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 METHODS: Patients 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. RESULTS: In 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. CONCLUSION: In 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 ID: NCT02108652.

Outcomes in patients with advanced urothelial carcinoma after discontinuation of programmed death (PD)-1 or PD ligand 1 inhibitor therapy.

OBJECTIVE: To study the subsequent therapy and disease outcomes of patients with advanced urothelial carcinoma (UC) after discontinuation of programmed death-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors. PATIENTS AND METHODS: We performed a retrospective analysis to examine outcomes and systemic therapy administration after PD-1/PD-L1 inhibitor therapy in patients with advanced UC. Data on demographics and therapy administered were collected from the institutions involved in the study. Univariable Cox regression analyses were performed to examine the clinical factors potentially associated with overall survival (OS) after PD-1/PD-L1 inhibitor therapy. RESULTS: Data from 62 patients were available from four institutions, with capture of subsequent therapy and outcomes after checkpoint inhibitor immunotherapy. The median patient age was 65.5 years and 51 patients (82.3%) were male. The median (range) duration of PD-1/PD-L1 inhibitor therapy in 55 patients for whom these data were available was 64 (7-669) days. Of these, 22 patients (35.5%) received post-PD-1/PD-L1 inhibitor therapy through a variety of different chemotherapy regimens (n = 16), chemobiological combination (n = 1), biological agents (n = 4) and immunotherapy (n = 1). The median (range) time from last PD-1/PD-L1 inhibitor therapy to subsequent therapy was 58 (14-242) days. The median OS of all patients after completion of PD-1/PD-L1 inhibitor therapy was 149 days (95% confidence interval [CI]: 75-359). Among those who received some post-PD-1/PD-L1 inhibitor therapy, the median OS was 182 days (95% CI: 121-372), and the median time to progression was 124 days (95% CI: 61-273) from the start of post-PD-1/PD-L1 therapy. Among these 22 patients, the only significant baseline prognostic factor associated with OS was performance status. CONCLUSIONS: In this dataset, 35.5% of patients with advanced UC received systemic therapy after salvage therapy with PD-1/PD-L1 inhibitors. Outcomes after subsequent therapy appear similar to those historically observed in patients who had not received prior PD-1/PD-L1 inhibitor therapy. Further study of patients receiving post-PD-1/PD-L1 inhibitor therapy is warranted to identify factors associated with outcomes and potentially synergistic sequences.

Survival after failure of first-line chemotherapy in advanced gastric cancer patients: differences between Japan and the rest of the world.

In this review, we focus on post-progression survival after first-line chemotherapy of advanced gastric cancer, and particularly the differences between Japan and the rest of the world. We reviewed 15 recent phase III trials of which 4 were solely recruited from Japanese and 11 from rest of the world. The patient characteristics age, performance status, previous gastrectomy and the number of metastatic sites were similar in Japan and rest of the world. However, the diffuse histological type was more common in Japan. While overall survival was longer in Japan (10.5-14.1 vs. 7.9-12.2 months), progression-free survival tended to be shorter in Japan (3.6-6.0 vs. 3.1-7.4 months). Post-progression survival calculated as the difference between median overall survival and progression-free survival was clearly longer in Japan (6.9-8.6 vs. 2.4-6.2 months). The proportion of patients receiving second-line chemotherapy (%2nd-CX) was quite different in Japan and rest of the world (69-85% vs. 11-59%). Correlations between %2nd-CX and post-progression survival were strong (Spearman's rank correlation coefficient; ρ = 0.86, P < 0.001). Correlations between %2nd-CX and ratio of post-progression survival to total overall survival were also strong (ρ = 0.84, P < 0.001). Because a survival benefit of second-CX was documented in several phase III trials, it can be concluded that higher %2nd-CX partly contributed to extended post-progression survival. However, considering that second-CX increased survival only by ~1.5 months at median, other factors such as third-line chemotherapy may have some influences to prolonged post-progression survival.

Post-Progression Survival Associated with Overall Survival in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Docetaxel Monotherapy as Second-Line Chemotherapy.

BACKGROUND: In patients with non-small-cell lung cancer (NSCLC), the effects of second-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies. Therefore, using individual-level data, we aimed to determine the relationships between progression-free survival (PFS) and post-progression survival (PPS) with OS in patients with advanced NSCLC treated with docetaxel monotherapy as second-line chemotherapy. METHODS: Between April 2002 and December 2014, data from 86 patients with advanced NSCLC who underwent second-line docetaxel monotherapy following first-line treatment with platinum combination chemotherapy were analyzed. The relationships of PFS and PPS with OS were analyzed at the individual level. RESULTS: Spearman rank correlation and linear regression analyses showed that PPS was strongly associated with OS (r = 0.86, p < 0.05, R2 = 0.93), whereas PFS was moderately correlated with OS (r = 0.50, p < 0.05, R2 = 0.21). Performance status at the end of second-line treatment and the number of regimens after progression beyond second-line chemotherapy were significantly associated with PPS (p < 0.05). CONCLUSIONS: In patients with advanced NSCLC with unknown oncogenic driver mutations undergoing docetaxel monotherapy as second-line chemotherapy, when compared with PFS, PPS had a stronger association with OS. This finding suggests that subsequent treatment after disease progression following second-line docetaxel monotherapy has a significant influence on OS.

Interim decision-making strategies in adaptive designs for population selection using time-to-event endpoints.

Adaptive designs in oncology clinical trials with interim analyses for population selection could be used in the development of targeted therapies if a predefined biomarker hypothesis exists. In this article, we consider an interim analysis using overall survival (OS), progression-free survival (PFS), and both OS and PFS, to determine whether the whole population or only the biomarker-positive population should continue into the subsequent stage of the trial, whereas the final decision is made based on OS data only. In order to increase the probability of selecting the most appropriate population at the interim analysis, we propose an interim decision-making strategy in adaptive designs with correlated endpoints considering the post-progression survival (PPS) magnitudes. In our approach, the interim decision is made on the basis of predictive power by incorporating information on OS as well as PFS to supplement the incomplete OS data. Simulation studies assuming a targeted therapy demonstrated that our interim decision-making procedure performs well in terms of selecting the proper population, especially under a scenario in which PPS affects the correlation between OS and PFS.