Measurable Residual Disease Does Not Preclude Prolonged Progression-free Survival in CLL Treated with Ibrutinib

Blood ◽  
2021 ◽  
Author(s):  
Victoria Wang ◽  
Curtis A. Hanson ◽  
Renee Tschumper ◽  
Connie Lesnick ◽  
Esteban Braggio ◽  
...  
Keyword(s):  
Treatment Efficacy ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Surrogate Endpoint ◽  
Phase 3 ◽  
Free Survival ◽  
Hazard Ratios ◽  
Additional Support ◽  
Over Time ◽  
Measurable Residual Disease

E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus six cycles of rituximab (IR) to six cycles of fludarabine, cyclophosphamide and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (< 1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4% and 8.6% at 3, 12, 24 and 36 months for FCR, and significantly lower at 7.9%, 4.2% and 3.7% at 12, 24 and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24 and 36 months was associated with longer progression-free survival (PFS) for the FCR arm with hazard ratios (MRD detectable / MRD undetectable) of 4.29 (95% CI 1.89 - 9.71), 3.91 (95% CI 1.39 - 11.03), 14.12 (95% CI 1.78 - 111.73), and not estimable (no events among those with undetectable MRD), respectively. For the IR arm, patients with detectable MRD did not have significantly worse PFS compared to those in whom MRD was undetectable; however, PFS was longer for those with MRD levels of less than 10-1 compared to those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate endpoint for PFS in patients receiving FCR. For patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, while those with MRD less than 10-1 tend to have longer PFS, although continuation of ibrutinib is very likely required to maintain treatment efficacy.

Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia: Is It Time to Move Toward a Minimal Residual Disease-Based Definition of Complete Remission?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2571-2571
Author(s):  
Daisuke Araki ◽  
Brent L Wood ◽  
Megan Othus ◽  
Jerald P. Radich ◽  
Anna B. Halpern ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Treatment Algorithms ◽  
Free Survival ◽  
Hazard Ratios ◽  
Minimal Residual ◽  
Active Disease

Abstract Background: Treatment algorithms for allogeneic hematopoietic cell transplantation (HCT) typically consider patients with acute myeloid leukemia (AML) in morphologic complete remission (CR) separately from those with active disease (i.e. ≥5% marrow blasts by morphology), implying distinct outcomes for these two groups. However, it is well recognized that the presence of minimal residual disease (MRD) at the time of transplantation is associated with adverse post-HCT outcomes for patients in morphologic CR. This well established effect of pre-HCT MRD prompted us to compare outcomes in patients in MRDpos CR to those with active AML who underwent myeloablative allogeneic HCT at our institution. Patients and Methods: We retrospectively studied 359 consecutive adults with AML who underwent myeloablative allogeneic HCT from a peripheral blood or bone marrow donor between 2006 and 2014. Pre-HCT disease staging included 10-color multiparametric flow cytometry (MFC) on bone marrow aspirates in all patients. MRD was identified as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow. Any level of residual disease was considered MRDpos. Results: Three hundred and eleven patients (87%) were in morphologic CR at the time of transplantation, with 76 (21%) in MRDpos CR and 235 (66%) in MRDneg CR. 48 patients (13%) had active disease (7 untreated newly diagnosed AML, 16 untreated relapsed AML, and 25 refractory or relapsed AML who failed salvage therapies). Patients with MRDpos CR or active AML more often had adverse-risk cytogenetics (P=0.001) and secondary leukemias (P<0.001) than MRDneg CR patients. Patients with active AML also more often had incomplete blood count recovery before HCT than patients in morphologic CR (P<0.001). Three-year relapse estimates were 67% in MRDpos morphologic CR patients and 65% in patients with active AML, contrasted to 22% in MRDneg CR patients. Three-year overall survival estimates were 26%, 23%, and 73% in these three groups, respectively. After multivariable adjustment for age, cytogenetic risk, type of AML (de novo vs. secondary AML), pre-HCT karyotype (normalized vs. not), and pre-HCT peripheral blood counts (recovered vs. not), MRDneg CR status remained statistically significantly associated with longer overall and progression-free survival as well as lower risk of relapse compared to being in MRDpos morphologic CR or having active disease, with very similar outcomes between the latter two groups. Specifically, compared to MRDneg CR patients, the hazard ratios (95% confidence interval) for MRDpos CR patients and those with active disease were 3.68 (2.51-5.40) and 4.39 (2.56-7.53) (both P <0.001) for overall survival; for progression-free survival, corresponding hazard ratios were 4.37 (3.02-6.30) and 5.29 (3.18-8.80) (both P <0.001), whereas for risk of relapse, these estimates were 4.16 (2.68-6.44) and 4.86 (2.49-9.49) (both P <0.001), respectively. Conclusion: Outcomes for adults transplanted with morphologically detectable disease closely resemble those of MRDpos CR patients, with a cumulative relapse risk of ~65% and survival estimates of 20-25% at 3 years. This similarity held up after accounting for numerous other prognostic covariates. The resemblance in outcomes between patients with MRDpos morphologic CR and those with active disease at the time of HCT support the use of treatment algorithms that use MRD-based rather than morphology-based disease assessments. Disclosures Radich: Novartis: Consultancy, Research Funding; Incyte: Consultancy; Gilliad: Consultancy; Ariad: Consultancy. Walter:AstraZeneca, Inc.: Consultancy; Covagen AG: Consultancy; Pfizer, Inc.: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy, Research Funding.

The validity of progression-free survival (PFS) 2 as a surrogate endpoint for overall survival (OS) in randomized controlled trials (RCTs) of advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1516-1516
Author(s):  
Rachel Woodford ◽  
Deborah Zhou ◽  
Peey-Sei Kok ◽  
Sally Lord ◽  
Ian Marschner ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Surrogate Endpoint ◽  
Outcome Data ◽  
Survival Times ◽  
Free Survival ◽  
Hazard Ratios ◽  
Investigational Agents ◽  
Tumor Types

1516 Background: OS is the gold-standard endpoint for treatment efficacy in oncology RCTs. However, prolonged follow-up is required to obtain mature data, which impedes regulatory approval of potentially beneficial therapies. Furthermore, increasing therapeutic options including cross over to investigational agents at disease progression often confound OS findings. PFS-2, defined as time from randomization to progression on second-line therapy, has been proposed as a potential surrogate endpoint for OS. Using a meta-analytic approach, we aimed to assess the association between OS and PFS-2, and its validity compared with other surrogate endpoints. Methods: We performed an electronic literature search to identify RCTs of systemic therapies that reported PFS-2 as a pre-specified endpoint with defined follow up protocols. Articles were screened for eligibility and outcome data were extracted. Correlations in the relative treatment difference between treatment arms for OS vs PFS-2, PFS-1, and objective response rate (ORR) were assessed as the comparison of hazard ratios (HR) and odds ratio (OR) respectively. Results: 38 eligible RCTs comprising of 44 analysis units, with 19,031 patients across 8 unique tumor types were identified. The majority received targeted therapies (72.2%), followed by immunotherapy (IO; 26.3%). The correlations of HR-OS/HR-PFS-2, HR-OS/HR-PFS-1 and HR-OS/OR-ORR were r = 0.67 (95% CI 0.08-0.69), r = 0.12 (95% CI 0.00-0.13) and r = 0.21 (95% CI 0.00-0.33) respectively. Correlations between OS with surrogates was assessed in different subgroups according to post-progression survival times (SPP), types of treatment agents and rate of subsequent therapy after progression (table). Conclusions: Across diverse tumors and therapies, treatment effect on PFS-2 has modest to strong correlation with OS, but poor correlations were observed between OS-PFS-1 and OS-ORR respectively. Across all subgroups, PFS-2 performs consistently better than traditional surrogates of PFS-1 and ORR, validating and providing support for use in future RCTs.[Table: see text]

Sequential monitoring of PD-L1 on circulating stromal cells in blood predicts PFS in NSCLC patients undergoing immunotherapy after definitive chemoradiation.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8534-8534
Author(s):  
Daniel L Adams ◽  
Alexander Augustyn ◽  
Jianzhong He ◽  
Yawei Qiao ◽  
Ting Xu ◽  
...  
Keyword(s):  
Stromal Cells ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hazard Ratios ◽  
Fda Approval ◽  
Inflammatory State ◽  
Nsclc Patients ◽  
Tumor Biopsies ◽  
Relationship Of ◽  
The Relationship

8534 Background: Cancer Associated Macrophage-Like cells (CAMLs) are circulating stromal cells in the blood of patients (pts) with solid tumors that are phagocytic macrophages that may represent the inflammatory state of the tumor microenvironment. Previously, we demonstrated CAMLs ≥50µm after chemo-radiation therapy (CRT) in NSCLC is associated with worse progression free survival (PFS) and overall survival (OS). We also showed that PDL1 expression in CAMLs is dynamic & can change with CRT, difficult to assess with repeat biopsies, but possible with liquid biopsy. For this study we evaluated whether CAML properties can predict response to CRT with/without immunotherapy (IMT) agents in unresectable NSCLC. Methods: A single blind multi-year prospective study was undertaken to test the relationship of PDL1 expression and ≥50µm CAML size to PFS/OS in NSCLC, pre and post CRT with (n = 96) and without (n = 72) anti-PDL1/PD1 IMT. This included atezolizumab (prospective single arm NCT02525757) n = 39, durvalumab n = 52 or pembrolizumab n = 5 both after 2018 FDA approval. We recruited 168 pts with pathologically confirmed unresectable NSCLC prior to CRT. Blood samples 15 mL were taken at baseline (BL), CRT completion (T1), and ̃1 month after CRT (T2) (with n = 96 or without n = 72 IMT). Blood was filtered by CellSieve filtration and CAMLs quantified for size ( < 49 µm or ≥50 µm) and PDL1 expression to evaluate PFS and OS hazard ratios (HRs) by censored univariate and multivariate analysis at 24 months. Results: CAMLs were found in 90% of all samples, average 5.8 CAMLs/15mL. At BL, ≥50µm CAMLs did not predict PFS in CRT/IMT pts (HR 1.6, p = 0.220) nor CRT alone (HR 1.3, p = 0.593). However, after completion of CRT (T1) ≥50µm CAMLs predicted PFS in CRT/IMT pts (HR 2.7, p = 0.003) and CRT alone (HR 2.5, p = 0.015). In primary tumor biopsies, PDL1 expression > 1% did not predict CRT/IMT response (PFS HR 1.8, p = 0.262 & OS HR 2.3, p = 0.158). At BL, high CAML PDL1 did not predict PFS in CRT/IMT pts (HR 1.4, p = 0.427) nor CRT alone (HR 1.1, p = 0.982). Further, at CRT completion (T1), high CAML PDL1 only trended for better PFS in CRT/IMT pts (HR 1.7, p = 0.137), but not CRT alone (HR 1.1, p = 0.972). At T2, however, pts with continuously high CAML PDL1 had significantly better PFS with IMT (HR 3.2, p = 0.002) vs CRT alone (HR 1.4, p = 0.616). While ≥50µm CAMLs at BL did not predict 24 month progression, ≥50 µm CAMLs after CRT (with or without 1 cycle of anti-PDL1 IMT) was 84% accurate at predicting progression. Further subtyping and analysis is ongoing to evaluate OS and PDL1 in the CAML populations. Conclusions: Our data suggests that in unresectable NSCLC, ≥50 µm CAMLs after completion of CRT is prognostic regardless of IMT use. PDL1 expression in CAMLs also appears to predict for response to consolidated IMT after CRT. Additional studies are needed to validate these findings.

First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 391-391
Author(s):  
Dean F. Bajorin ◽  
Johannes Alfred Witjes ◽  
Jürgen Gschwend ◽  
Michael Schenker ◽  
Begoña P. Valderrama ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Radical Surgery ◽  
Unmet Need ◽  
Disease Free Survival ◽  
Phase 3 ◽  
Double Blind ◽  
Meaningful Improvement ◽  
Free Survival ◽  
Disease Free

391 Background: The standard of care (SOC) for patients (pts) with MIUC is radical surgery ± cisplatin-based neoadjuvant chemotherapy (chemo), but many pts are cisplatin-ineligible. There is no conclusive evidence supporting adjuvant chemo in pts who did not receive neoadjuvant chemo and in those with residual disease after neoadjuvant cisplatin. This phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in pts with MIUC after radical surgery ± neoadjuvant cisplatin (CheckMate 274) aims to address an unmet need in these pts. We report the initial results. Methods: This is a phase 3, randomized, double-blind, multicenter trial of NIVO vs PBO in pts with high-risk MIUC (bladder, ureter, or renal pelvis) after radical surgery. Pts were randomized 1:1 to NIVO 240 mg Q2W or PBO for ≤ 1 year of adjuvant treatment. Pts had radical surgery within 120 days ± neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemo, evidence of UC at high risk of recurrence per pathologic staging, were disease-free by imaging, and ECOG PS ≤ 1. Primary endpoints: disease-free survival (DFS) in all randomized pts (ITT population) and in pts with tumor PD-L1 expression ≥ 1%. DFS was stratified by nodal status, prior neoadjuvant cisplatin, and PD-L1 status. Non–urothelial tract recurrence-free survival (NUTRFS) in ITT pts and in pts with PD-L ≥ 1% is a secondary endpoint. Safety is an exploratory endpoint. Results: In total, 353 pts were randomized to NIVO (PD-L1 ≥ 1%, n = 140) and 356 pts to PBO (PD-L1 ≥ 1%, n = 142). The primary endpoint of DFS was met in ITT pts (median follow-up, 20.9 mo for NIVO; 19.5 mo for PBO) and in pts with PD-L1 ≥ 1%. DFS and NUTRFS were improved with NIVO vs PBO in both populations (Table). DFS improvement with NIVO was generally consistent across subgroups. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 17.9% and 7.2% of pts in the NIVO and PBO arms, respectively. Conclusions: NIVO demonstrated a statistically significant and clinically meaningful improvement in DFS vs PBO for MIUC after radical surgery, both in ITT pts and pts with PD-L1 ≥ 1%. AEs were manageable and consistent with previous reports. These results support adjuvant NIVO as a new SOC for pts with MIUC with high risk for recurrence despite neoadjuvant chemo or those ineligible for and/or declining cisplatin-based chemo. Clinical trial information: NCT02632409 . Research Sponsor: Bristol Myers Squibb[Table: see text]

Radiographic progression-free survival as a surrogate endpoint of overall survival in men with metastatic castrate-resistant prostate cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5057-5057
Author(s):  
Susan Halabi ◽  
Akash Roy ◽  
Qian Yang ◽  
Wanling Xie ◽  
William Kevin Kelly ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
Progression Free Survival ◽  
Surrogate Endpoint ◽  
Phase Iii ◽  
Random Assignment ◽  
Moderate Correlation ◽  
Free Survival ◽  
Castrate Resistant Prostate Cancer ◽  
Castrate Resistant

5057 Background: Radiographic progression-free survival (rPFS) is commonly used as a co-primary endpoint in randomized clinical trials in men with metastatic castrate-resistant prostate cancer (mCRPC). However, rPFS has not been established as a valid surrogate endpoint of overall survival (OS) in men with mCRPC. Here, we hypothesized that rPFS is a reliable surrogate for OS in mCRPC. We also explored whether PFS is a valid surrogate endpoint of OS at the aggregate trial level. Methods: We performed a systematic search of the literature encompassing the period January 2004-December 2020 using PubMed and clinical trials.gov to identify completed phase III trials in mCRPC post-docetaxel. Eligible trials had to be randomized phase III therapeutic trials that reported OS, PFS or rPFS. OS was measured from the date of random assignment to date of death from any cause or date of last follow-up. rPFS was defined as the time from random assignment to date of disease progression on CT and/or Tc bone scan per trial definition or death from any cause, whichever occurred first. PFS included PSA progression as a component of the composite endpoint. Trial level surrogacy was evaluated by fitting linear regression on the treatment effect of rPFS (or PFS) and OS (in other words, the weighted linear regression of the log(hazard ratio) of OS on the log(hazard ratio) of rPFS). It was pre-specified that rPFS would be considered a valid surrogate for OS if R² was 0·7 or higher. Results: We identified 33 in men with mCRPC post docetaxel approval. We assessed the association between PFS and OS in 29,456 patients from 30 trials. Overall, a moderate correlation was observed at the trial level between OS and PFS ( R2 = 0.46, 95 %CI = 0.20-0.68) in these trials. In 18 trials with 16,818 mCRPC patients where rPFS was considered as a key endpoint, a moderate correlation between the treatment effects on rPFS and OS was observed at the trial level ( R2= 0.65, 95% CI = 0.23-0.87). Conclusions: This meta-analysis demonstrates moderate correlation between treatment effects of rPFS and OS in patients with mCRPC. However, rPFS did not meet the pre-specified surrogacy threshold of 0.7. Clinical trial information: several.

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