Impact of subsequent therapy on survival in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as first-line therapy for advanced urothelial carcinoma (UC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 439-439
Author(s):  
Ajjai Shivaram Alva ◽  
Tibor Csőszi ◽  
Mustafa Ozguroglu ◽  
Nobuaki Matsubara ◽  
Lajos Geczi ◽  
...  
Keyword(s):  
Progressive Disease ◽  
Statistical Significance ◽  
Exploratory Analysis ◽  
Phase Iii ◽  
Survival Outcomes ◽  
First Line ◽  
First Line Therapy ◽  
Research Sponsor ◽  
Advanced Urothelial Carcinoma ◽  
Clinical Trial Information

439 Background: The phase III KEYNOTE-361 study examined the efficacy and safety of 1L pembro + chemo or pembro alone vs chemo for pts with advanced UC. The PFS and OS benefit of pembro + chemo vs chemo did not reach statistical significance; no further formal tesing was done. We present an exploratory analysis of OS by subsequent therapy in KEYNOTE-361 (NCT02853305) to assess how 1L and 2L therapy selection affected survival outcomes; no formal comparisons were conducted. Methods: OS was estimated for pts by whether they received subsequent therapy, and by whether subsequent therapy included an anti–PD-(L)1 agent. Results: 351 pts were randomized to pembro + chemo, 307 pts to pembro, and 352 pts to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. 124/351 pts (35%) in the pembro + chemo arm, 126/307 pts (41%) in the pembro arm, and 215/352 pts (61%) in the chemo arm received any subsequent therapy. Similar rates of subsequent therapy (pembro + chemo: 32%; pembro: 43%; chemo: 59%) were observed for pts who experienced progressive disease (PD) by blinded independent central review (BICR). A higher rate of pts (169/352 [48%]) in the chemo arm received subsequent anti–PD-(L)1 therapy than in either the pembro + chemo arm (23/351 [7%]) or pembro arm (14/307 [5%]). Due to the small pt numbers, pts in the pembro + chemo or pembro arms who received subsequent anti−PD-(L)1 were not considered further. This analysis included all pts who received 2L therapy (465/1010 pts [46%]); the rate of 2L therapy was similar in pts with PD by BICR (274/615 [45%]). Chemo agents alone or in combination, specifically carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, and paclitaxel, were the most commonly received subsequent therapies for pts who did not receive anti–PD-(L)1 in 2L. Pts who received 1L chemo followed by subsequent anti–PD-(L)1 had longer mOS (19.1 mo [95% CI 16.2-22.2]) than pts with 1L pembro followed by 2L therapy not including an anti−PD-(L)1 agent (16.0 mo [95% CI 11.8-19.2]) (Table). Conclusions: In this exploratory analysis, favorable survival outcomes were observed for pts who received 1L chemo followed by anti–PD-(L)1 compared with pts who received 1L pembro followed by 2L therapy not including an anti–PD-(L)1 agent. These data underline the continued importance of immunotherapy as 2L therapy for advanced UC. Clinical trial information: NCT02853305 . Research Sponsor: Merck & Co., Inc[Table: see text]

Analysis of PFS2 by subsequent therapy in KEYNOTE-361: Pembrolizumab (pembro) plus chemotherapy (chemo) or pembro alone versus chemo as 1L therapy for advanced urothelial carcinoma (UC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 448-448
Author(s):  
Mustafa Ozguroglu ◽  
Ajjai Shivaram Alva ◽  
Tibor Csőszi ◽  
Nobuaki Matsubara ◽  
Lajos Geczi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Urothelial Carcinoma ◽  
Progressive Disease ◽  
Exploratory Analysis ◽  
Phase Iii ◽  
Treatment Sequence ◽  
Advanced Urothelial Carcinoma ◽  
To Receive ◽  
Clinical Trial Information

448 Background: 1L pembro + chemo did not show statistically superior PFS and OS vs chemo for pts with advanced UC in the phase III KEYNOTE-361 study; OS for pembro vs chemo was not formally tested. We analyzed PFS2 (time from randomization to progressive disease [PD] on first subsequent therapy, or death from any cause, whichever occurs first) by study treatment and subsequent therapy in KEYNOTE-361 (NCT02853305) to determine the effects, if any, of therapy sequence on PFS2. Methods: PFS2 was estimated for pts in each treatment arm, who received any subsequent therapy including any anti–PD-(L)1, any therapy other than anti–PD-(L)1, or no therapy. These were exploratory analyses; no formal comparisons were done. Results: 1010 pts were randomized: 351 pts to receive pembro + chemo, 307 to pembro, and 352 to chemo. As of Apr 29, 2020, the median (range) time from randomization to data cutoff was 31.7 (22.0-42.3) mo. Subsequent therapy was received by 124/351 (35%), 126/307 (41%), and 215/352 (61%) pts in the pembro + chemo, pembro, and chemo arms, respectively. Subsequent anti–PD-(L)1 therapy was received by 169/352 (48%) pts in the chemo arm vs 23/351 (7%) in the pembro + chemo arm and 14/307 (5%) in the pembro arm. Of pts in the pembro arm who received subsequent therapy, >90% received 2L cisplatin-based or carboplatin-based treatment. Median (m) PFS2 (95% CI) for all pts by treatment arm was 14.1 mo (12.6-16.2) with pembro + chemo, 10.9 mo (9.5-12.9) with pembro, and 10.4 mo (9.8-11.2) with chemo. Across treatment arms, pts in the pembro + chemo arm had the longest mPFS2 with any subsequent therapy (14.5 mo [95% CI 13.1-16.6]) (Table). Pts in the pembro arm who received no subsequent therapy had a longer mPFS2 (12.9 mo [95% CI 8.1-17.9]) vs pts in the chemo arm who received no subsequent therapy (9.4 mo [95% CI 7.6-10.6]). Finally, pts treated with 1L pembro in the trial followed by 2L therapy other than anti−PD-(L)1 had comparable mPFS2 (10.2 mo [95% CI 8.6-12.1]) to pts treated with 1L chemo in the trial followed by 2L anti−PD-(L)1 (11.1 mo [95% CI 10.2-12.9]). Conclusions: In this exploratory analysis, treatment sequence of chemo followed by anti−PD-(L)1 upon PD vs anti–PD-(L)1 followed by chemo upon PD did not appear to impact mPFS2. Among pts who did not receive 2L therapy, 1L pembro appeared to be associated with longer mPFS2 than chemo, potentially driven by long-term responders to pembro. Clinical trial information: NCT02853305 . [Table: see text]

Post-progression survival (PPS) and improvements in progression-free survival (PFS) in randomized controlled trials (RCTs) in advanced gastric cancer (AGC).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 93-93
Author(s):  
Kohei Shitara ◽  
Marc E. Buyse ◽  
Everardo D. Saad
Keyword(s):  
Statistical Significance ◽  
Progression Free Survival ◽  
Phase Iii ◽  
First Line ◽  
Free Survival ◽  
World Region ◽  
Randomized Controlled ◽  
First Line Therapy ◽  
Kaplan Meier ◽  
Randomized Phase Ii

93 Background: Since PPS may influence overall survival (OS), studying PPS may help in understanding why gains in PFS do not always translate into gains in OS. Methods: We searched PubMed for RCTs on first-line therapy for AGC published between 01/82 and 01/12. We estimated mean PFS and OS (in months) using the area under the published Kaplan-Meier curves, computing mean PPS as mean OS minus mean PFS for each trial arm. We compared PPS between trial arms grouped according to PFS duration (longer versus shorter PFS, regardless of statistical significance) and world region (using t tests). Results: We retrieved 53 trials (25 were phase III, 24 were randomized phase II, and 4 had no explicit phase) enrolling 12,050 patients in 121 arms. We could estimate mean endpoints for 33 trials (26/6/1 with 2/3/4 arms), which were more likely to be phase III than the 20 trials with no Kaplan-Meier curves for both endpoints. The average mean PPS was almost identical between trial arms with longer or shorter PFS. Use of PPS assessed as median OS minus median PFS yielded qualitatively similar results. Conclusions: Treatments that improve PFS do not seem to influence PPS. Asian trials appear to have longer OS due to longer PPS, not PFS. Work with individual patient data collected worldwide by the GASTRIC group is under way to confirm our findings. [Table: see text]

ZAP-70 Versus CD38 Expression as the Prognostic Factors in B-Cell Chronic Lymphocytic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4780-4780
Author(s):  
Iwona Hus ◽  
Agnieszka Bojarska-Junak ◽  
Monika Podhorecka ◽  
Ewa Wasik-Szczepanek ◽  
Malgorzata Sieklucka ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Progressive Disease ◽  
Clinical Course ◽  
Statistical Significance ◽  
First Line ◽  
Stage Of Disease ◽  
First Line Therapy ◽  
Cd38 Expression ◽  
Line Therapy ◽  
Mutational Status

Abstract B-CLL is a heterogeneous disease with a highly variable clinical course. The mutational status of immunoglobulin heavy-chain variable region (IgVH) genes in the leukemic cells seems to be of great importance in assessing the prognosis in B-CLL. Recent studies have shown that both CD38 and ZAP-70 might be surrogate markers for IgVH mutation identifying patients with a more aggressive clinical course. The aim of our study was to estimate the clinical value of both ZAP-70 and CD38 as B-CLL prognostic factors. The analysis with use of flow cytometry technique was performed at diagnosis in the group of 100 B-CLL patients. 39/100 persons were defined as ZAP-70 positive and 61/100 persons as ZAP-70 negative (based on 20% cut off value in the CD19+/CD5+ population). ZAP-70+ patients had significantly higher lymphocytosis (p=0.003) and LDH level (p=0.009), while hemoglobin (p=0.049) and platelet levels (p=0.002) were significantly lower than in ZAP-70− patients. The proportion of CD19+/CD5+ cells expressing ZAP-70 correlated significantly with stage of disease (p=0.035). Patients with Rai stage III–IV (32/100 patients) had higher percentage of CD19+/CD5+/ZAP-70+ cells than patients with stage 0-II (68/100 patients) (24.81±17.40% and 14.89±13.54%, respectively, p=0.008). The mean treatment-free interval was longer in the ZAP-70 negative (8.46±4.63 months) than in the ZAP-70 positive patients (1.16±0.28 months). Furthermore, patients requiring treatment (57/100) had significantly higher percentage of CD19+/CD5+ cells expressing ZAP-70 protein than untreated patients (20.18±15.09 and 13.44±11.84, respectively, p=0.034). In the midst of patients requiring treatment, percentage of CD19+/CD5+/ZAP-70+ cells was significantly lower in patients achieving remission after first line therapy (26/57) than in patients with progressive disease (31/57) (p=0.004). According to CD38 analysis the patients with ≥ 20% of CD38 expression were considered positive (CD38+) and those < 20% were considered negative (CD38−). Patients CD38 positive, like the ZAP-70 positive patients, had more advanced Rai stage of disease, significantly higher lymphocytosis and LDH serum level. Patients requiring treatment had higher percentage of CD19+/CD5+CD38+ cells than untreated patients, however no statistical significance was detected. Percentage of CD19+/CD5+CD38+ was not a dicriminating factor between patients with good response to the first line therapy and those with progressive disease. The obtained results indicate that both ZAP-70 and CD38 expression may be prognostic markers identifying a subgroup of B-CLL patients with aggressive clinical presentation. However, the ZAP-70 expression seems to have more prognostic power, especially in predicting response to the first line therapy.

266 Tumour mutation burden (TMB) and efficacy outcomes in the phase III DANUBE study of advanced urothelial carcinoma (UC)

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A292-A292
Author(s):  
Sophie Wildsmith ◽  
Jill Walker ◽  
Anne L’Hernault ◽  
Weimin Li ◽  
Hannah Bye ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Stage Iv ◽  
Small Cell ◽  
Phase Iii ◽  
Survival Outcomes ◽  
Line Treatment ◽  
Small Cell Lung ◽  
First Line ◽  
Unresectable Stage ◽  
First Line Treatment

BackgroundThe phase III DANUBE study assessed the efficacy of the PD-L1 inhibitor durvalumab (D), alone or in combination with the CTLA-4 inhibitor tremelimumab (T), versus standard of care chemotherapy (SoC) for the first-line treatment of unresectable, locally advanced or metastatic UC. The study did not meet its co-primary endpoints of improving overall survival (OS) for D monotherapy vs SoC in patients with high tumor PD-L1 expression or for D+T vs SoC in the intention-to-treat population.1 TMB measurement in blood (bTMB) or tumour (tTMB) has been linked to improved efficacy with PD-1/PD-L1 inhibitors in UC and with D+T in non-small cell lung cancer,2 thus providing a rationale to explore TMB in the DANUBE trial.MethodsBaseline plasma samples from DANUBE were assessed for bTMB using the Guardant OMNI platform, while baseline tTMB was measured in formalin-fixed paraffin-embedded (FFPE) tumour samples using the FoundationOne CDx gene panel. Associations between progression-free survival (PFS) and median and landmark OS with bTMB and tTMB levels at various cutoffs were assessed as part of a pre-specified exploratory analysis. The data cutoff occurred on January 27, 2020.ResultsAmong 1032 patients randomised in DANUBE, 536 (51.9%) were evaluable for bTMB and 623 (60.4%) were evaluable for tTMB. For D vs SoC, bTMB and tTMB were not associated with OS or PFS at any cutoff. For D+T, stronger associations between bTMB and OS as well as PFS were observed with increasing bTMB cutoffs (table 1). At the bTMB cutoff ≥ 24 mut/Mb, 12-month OS rates were 76.7% for D+T and 54.3% for SoC, whereas for bTMB < 24 mut/Mb, 12-month OS rates were 53.4% for D+T and 51.2% for SoC. Similar trends for both OS and PFS were observed with tTMB (table 1).Abstract 266 Table 1Association between TMB and survival outcomes with D+TAssociation between TMB and survival outcomes with D+TConclusionsBoth bTMB and tTMB are potentially useful biomarkers for enriching responses to D+T in previously untreated, advanced UC. Neither bTMB nor tTMB was associated with better outcomes for D monotherapy. Cutoffs of 24 mut/Mb for bTMB and 10 mut/Mb for tTMB appear optimal for D+T in the setting of previously untreated, advanced UC.Trial RegistrationThe trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.ReferencesAstraZeneca. Update on phase III DANUBE trial for IMFINZI and tremelimumab in unresectable, stage IV bladder cancer [press release] March 6, 2020. [https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-danube-trial-for-imfinzi-and-tremelimumab-in-unresectable-stage-iv-bladder-cancer-06032020.html]Rizvi NA, Cho BC, Reinmuth N, et al. Durvalumab with or without tremelimumab vs standard chemotherapy in first-line treatment of metastatic non-small cell lung cancer: The MYSTIC phase 3 randomized clinical trial. JAMA Oncol. 2020:6:661–674.Ethics ApprovalThe study protocol was approved by the Ethics Board at each investigator’s institution.

Survival of Patients With Advanced Colorectal Cancer Improves With the Availability of Fluorouracil-Leucovorin, Irinotecan, and Oxaliplatin in the Course of Treatment

2004 ◽  
Vol 22 (7) ◽  
pp. 1209-1214 ◽  
Author(s):  
Axel Grothey ◽  
Daniel Sargent ◽  
Richard M. Goldberg ◽  
Hans-Joachim Schmoll
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Phase Iii Trials

Purpose Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV, irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated. Materials and Methods We analyzed data from seven recently published phase III trials in advanced CRC to correlate the percentage of patients receiving second-line therapy and the percentage of patients receiving all three agents with the reported median OS, using a weighted analysis. Results The reported median OS is significantly correlated with the percentage of patients who received all three drugs in the course of their disease (P = .0008) but not with the percentage of patients who received any second-line therapy (P = .19). In addition, the use of combination protocols as first-line therapy was associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73 months; P = .0083). Conclusion Our results support the strategy of making these three active drugs available to all patients with advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, OS should no longer be regarded as the most appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.

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