Estimation of Overall Survival with Subsequent Treatment Effect by Applying Inverse Probability of Censoring Weighting in the LATITUDE Study

e18727 Background: Treatment for multiple myeloma (MM) over the past decade has significantly improved survival. In particular, 3 drug classes have altered the treatment paradigm for MM patients: proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and CD38 monoclonal antibodies (anti-CD38s). Despite these advances, the majority of patients with MM will become refractory to PIs, IMiDs, and anti-CD38s, and limited evidence indicates these patients have poor outcomes. A retrospective study in the US showed that 275 patients treated at 14 academic institutions with prior exposure to a PI, IMiD, and anti-CD38 had median overall survival of 9.2 months. The aim of this study was to evaluate real-world treatment patterns and outcomes (duration of therapy and overall survival) of patients who had been treated with a PI, IMiD, and anti-CD38 in community practices in the US. Methods: This retrospective observational study was conducted using the Integra Connect (IC) database. The IC database includes electronic health data from structured and unstructured fields from 12 community practices on the East and West Coast of the US. Adult patients with ≥2 ICD-9/ICD-10 codes for MM on at least 2 separate dates, who received MM treatment between Jan 1, 2016, and Dec 31, 2019, with treatment history that included at least one PI, one IMiD, and one anti-CD38 (triple exposed), and initiated a subsequent line of therapy (s-LOT) after becoming triple exposed, were included. Duration of length of s-LOT was defined as number of days from start of s-LOT to last-day supply of s-LOT. Overall survival was defined as the length of time from start of s-LOT through death or the date of the last office visit. Results: A total of 501 patients were included in this analysis. The median age of patients was 64.9 years; 50% were male; 50% had commercial insurance. 82.8% of patients had ECOG 0 or 1 at diagnosis and had received a median of 3 prior lines of therapy (LOTs) before initiating s-LOT. Prior to initiating s-LOT, 91% had been exposed to bortezomib, 81% to carfilzomib, 94% to lenalidomide, 82% to pomalidomide, and 100% to daratumumab. In s-LOT, 95% received treatment that included same drug or same drug class (30% received bortezomib, 48% carfilzomib, 31% lenalidomide, 47% pomalidomide, and 31% daratumumab). The median duration of s-LOT was 78 days and median survival was 10.3 months (308 days) from initiation of s-LOT. Conclusions: For triple-class exposed patients, there is a lack of consensus on the most efficacious approach to subsequent treatment. The present study shows a significant amount of retreatment with previously used agents or classes among these patients with short duration of therapy and poor survival. As has been previously noted, new strategies and agents targeting novel aspects of MM are needed to improve outcomes for these patients. Disclosures: This study (213286) was sponsored by GlaxoSmithKline.

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Efficacy of Subsequent Therapies in Multiple Myeloma Patients after Progression on a BCMA Targeting Therapy: A Single-Center Experience

Blood ◽

10.1182/blood-2020-141637 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 11-13

Author(s):

Barry Paul ◽

Myra Robinson ◽

Kristen Cassetta ◽

Daniel Slaughter ◽

Jordan Robinson ◽

...

Keyword(s):

Clinical Trial ◽

Multiple Myeloma ◽

Overall Survival ◽

Research Funding ◽

Subsequent Treatment ◽

Single Center ◽

Targeting Therapy ◽

Single Center Experience ◽

Best Response ◽

Car T

Background: Targeting B-cell maturation antigen (BCMA) with antibody-drug conjugates (ADCs), bispecific antibodies, or chimeric antigen receptor t-cells (CAR-Ts) has proven safe and effective in recent clinical trials, but relapses remain common. As most patients treated with BCMA targeting therapies are refractory to conventional anti-myeloma therapies, management of these patients poses unique challenges once they progress, with no data available to guide subsequent therapies. Methods: We performed a retrospective chart review of all relapsed refractory multiple myeloma (RRMM) patients at our institution who progressed while on or after a BCMA targeting therapy and were treated with subsequent therapies. We evaluated the best response achieved and overall survival (OS) measured from progression on BCMA targeting therapies. Kaplan Meier methods were used to estimate OS curves and landmarks between classes of BCMA targeting therapy received (ADC, bispecific antibody or CAR-T), and by type of subsequent therapy. Results: At a median follow up of 6 months, a total of 47 patients were treated with a BMCA targeting therapy. Of those, a total of 21 (44.7%) patients have progressed, with 18 (38.3%) receiving another therapy. Twelve-month overall survival of the patients who received a subsequent treatment was 51.1% (figure 1a), but varied considerably based on the class of BCMA therapy they received (figure 1b). Patients who progressed after a BCMA CAR-T had the best OS (N =2, 6 mo OS: 100%, 12 mo OS: Of the 18 patients who progressed and were treated with subsequent therapies, 7 (38.9%) received 2 lines of therapy, 5 (27.8%) received 3 lines of therapy, and 1 patient (5.6%) received 5 lines of therapy. In the first relapse, 4 (22.2%) patients received infusional chemotherapy with CAR-D PACE or CAR-DCEP, 4 (22.2%) received the combination of elotuzumab, pomalidomide, and dexamethasone (Elo-Pd; one of which was first treated with CAR-DCEP), 3 (16.7%) received selinexor based regimens. The best response seen after first-line post BCMA treatment was a partial response (PR) in 5 (27.8% of patients), whereas 8 (61.5%) patients who received second-line treatment post-BCMA therapy had a PR or better, including 3 (23.1%) who had a very good partial response (VGPR). In the third line post-BCMA, 1 (16.7%) had a VGPR, while 1 (16.7%) had stable disease as their best response. The use of Elo or Dara after anti-BCMA progression seemed to correlate with improved OS (see figure 1c below). While all these patients were Elo naïve, the majority (94.4%) were previously Dara exposed. Conclusions: Our data demonstrate that many RRMM patients who progress on BCMA targeting therapies still derive benefit from subsequent treatment. Early evidence from our experience suggests a survival advantage with monoclonal antibody-based therapies even in patients who had previously been exposed to these agents-suggesting a possible resensitization with BCMA directed therapy. Although our dataset is a single-center experience, to our knowledge it represents the first report of post-BCMA exposed management of RRMM and provides valuable insight into the treatment of this challenging and ever-expanding population. Disclosures Paul: Bristol-Myers Squibb: Other: Stock Ownership (prior employee); Amgen: Consultancy, Speakers Bureau; Regeneron: Membership on an entity's Board of Directors or advisory committees. Bhutani:BMS: Other: Clinical trial funding to institute, Speakers Bureau; Takeda: Other: Clinical trial funding to institute, Speakers Bureau; Prothena: Other: Clinical Trial Funding to Institute; Amgen: Speakers Bureau; MedImmune: Other: Clinical Trial Funding to Institute; Sanofi Genzyme: Consultancy; Janssen: Other: Clinical Trial Funding to Institute. Voorhees:Adaptive Biotechnologies: Other: Personal fees; Bristol-Myers Squibb: Other: Personal fees; Celgene: Other: Personal fees; Janssen: Other: Personal fees; Novartis: Other: Personal fees; Oncopeptides: Other: Personal fees; TeneoBio: Other: Personal fees; Levine Cancer Institute, Atrium Health: Current Employment. Usmani:Celgene: Other; Janssen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; SkylineDX: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Array Biopharma: Research Funding; GSK: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; BMS, Celgene: Consultancy, Honoraria, Other: Speaking Fees, Research Funding; Amgen: Consultancy, Honoraria, Other: Speaking Fees, Research Funding. Atrash:BMS, Jansen oncology, Sanofi: Speakers Bureau; Takeda, Amgen, Karyopharm, BMS, Sanofi, Cellactar, Janssen and Celgene: Honoraria; Amgen, GSK, Karyopharm.: Research Funding.

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Optimal subsequent treatments for patients with hepatocellular carcinoma resistant to anti-PD-1 treatment

Immunotherapy ◽

10.2217/imt-2021-0057 ◽

2021 ◽

Author(s):

Xuqi Sun ◽

Ziliang Yang ◽

Yuhao Tang ◽

Sihan Mao ◽

Peiyao Xiong ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Overall Survival ◽

Progressive Disease ◽

Subsequent Treatment ◽

Locoregional Therapy ◽

Resistant Group

Aim: The subsequent treatments for patients with hepatocellular carcinoma (HCC) resistant to immunotherapy remain unclear. This study aimed to identify optimal treatments for HCC patients with progression after anti-PD-1 therapy. Methods: The authors retrospectively analyzed 197 HCC patients with progressive disease after anti-PD-1 treatment. These patients were classified into initial resistant and secondary resistant groups. Results: In the initial resistant group, subsequent treatment with PD-1 antibody plus locoregional therapy prolonged post-progression survival and overall survival (p = 0.025 and 0.029, respectively). In the secondary resistant group, subsequent treatment did not improve the prognosis of patients. Conclusion: Subsequent PD-1 antibody plus locoregional therapy could achieve survival benefits in HCC patients initially resistant to anti-PD-1 immunotherapy.

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Comparing Performance of Methods to Deal With Differential Attrition in Randomized Experimental Evaluations

Evaluation Review ◽

10.1177/0193841x211034363 ◽

2021 ◽

Vol 45 (1-2) ◽

pp. 70-104

Author(s):

Kaitlin Anderson ◽

Gema Zamarro ◽

Jennifer Steele ◽

Trey Miller

Keyword(s):

Randomized Controlled Trials ◽

Research Design ◽

Treatment Effect ◽

Controlled Trials ◽

Probability Weighting ◽

Attrition Rates ◽

Inverse Probability ◽

Randomized Controlled ◽

Two Samples ◽

Weighting Methods

Background: In randomized controlled trials, attrition rates often differ by treatment status, jeopardizing causal inference. Inverse probability weighting methods and estimation of treatment effect bounds have been used to adjust for this bias. Objectives: We compare the performance of various methods within two samples, both generated through lottery-based randomization: one with considerable differential attrition and an augmented dataset with less problematic attrition. Research Design: We assess the performance of various correction methods within the dataset with problematic attrition. In addition, we conduct simulation analyses. Results: Within the more problematic dataset, we find the correction methods often performed poorly. Simulation analyses indicate that deviations from the underlying assumptions for bounding approaches damage the performance of estimated bounds. Conclusions: We recommend the verification of the underlying assumptions in attrition correction methods whenever possible and, when verification is not possible, using these methods with caution.

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Surgery for pathological T3a, T3b and lymph node positive, prostate cancer: surgical, functional and oncological outcomes

Journal of Clinical Urology ◽

10.1177/2051415820958207 ◽

2020 ◽

pp. 205141582095820

Author(s):

Niall Gilliland ◽

Sarath Vennam ◽

Robert Geraghty ◽

Julian Peacock ◽

Matthew Crockett ◽

...

Keyword(s):

Prostate Cancer ◽

Overall Survival ◽

Biochemical Recurrence ◽

Subsequent Treatment ◽

Pathological Stage ◽

Level Of Evidence ◽

Cancer Specific Survival ◽

Durable Response ◽

Oncological Outcomes

Objective: To investigate and document the surgical, functional and oncological outcomes following surgery for high-risk prostate cancer patients. Patients and methods: Patients with pathological T3a, T3b and N1 disease were extracted from our prospectively updated institutional database. Data include demographics, preoperative cancer parameters, short and long-term complications and functional results. Details of biochemical recurrence, type and oncological outcome of salvage treatments, cancer-specific and overall survival were also obtained. Results: A total of 669 patients were included; 58.9% had T3a disease, 35.9% had pT3b and 11.4% N1 disease. With a median follow-up of 66 months (8–129), overall survival was 94.3%, cancer-specific survival was 98.7% and biochemical recurrence was 45.6%. Average inpatient stay was 1 day and the overall complication rate was 9.1%; 54.2% experienced a biochemical recurrence and 90.3% went on to have one or more salvage treatments, which were varied. Significant predictors of biochemical recurrence included pathological stage, any positive margin and patient age ( P<0.005). A total of 44.9% had an immediate biochemical recurrence, with 90% receiving subsequent treatment and 20.5% having a durable response. None of the patients receiving prostate bed radiotherapy alone had a durable response. 54% had a delayed biochemical recurrence, with 63.5% receiving subsequent treatment and 44% having a durable response. Conclusions: Surgery is associated with encouraging surgical and functional outcomes, cancer-specific survival and overall survival rates in these patients. Pathological stage is a significant predictor of biochemical recurrence. The present analysis shows that long-term observation for certain patients with biochemical recurrence is appropriate and questions the effectiveness of further local salvage treatments in patients with an immediate biochemical recurrence postoperatively. Level of evidence: II

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Immortal Time Bias in Observational Studies of Time-to-Event Outcomes

Cancer Control ◽

10.1177/1073274818789355 ◽

2018 ◽

Vol 25 (1) ◽

pp. 107327481878935 ◽

Cited By ~ 14

Author(s):

Parul Agarwal ◽

Erin Moshier ◽

Meng Ru ◽

Nisha Ohri ◽

Ronald Ennis ◽

...

Keyword(s):

Overall Survival ◽

Treatment Effect ◽

Cox Regression ◽

Analytical Techniques ◽

Time Dependent ◽

Simulation Studies ◽

Significant Treatment ◽

Immortal Time Bias ◽

Postmastectomy Radiation Therapy ◽

Landmark Model

The objectives of this study are to illustrate the effects of immortal time bias (ITB) using an oncology outcomes database and quantify through simulations the magnitude and direction of ITB when different analytical techniques are used. A cohort of 11 626 women who received neoadjuvant chemotherapy and underwent mastectomy with pathologically positive lymph nodes were accrued from the National Cancer Database (2004-2008). Standard Cox regression, time-dependent (TD), and landmark models were used to compare overall survival in patients who did or did not receive postmastectomy radiation therapy (PMRT). Simulation studies showing ways to reduce the effect of ITB indicate that TD exposures should be included as variables in hazard-based analyses. Standard Cox regression models comparing overall survival in patients who did and did not receive PMRT showed a significant treatment effect (hazard ratio [HR]: 0.93, 95% confidence interval [CI]: 0.88-0.99). Time-dependent and landmark methods estimated no treatment effect with HR: 0.97, 95% CI: 0.92 to 1.03 and HR: 0.98, 95% CI, 0.92 to 1.04, respectively. In our simulation studies, the standard Cox regression model significantly overestimated treatment effects when no effect was present. Estimates of TD models were closest to the true treatment effect. Landmark model results were highly dependent on landmark timing. Appropriate statistical approaches that account for ITB are critical to minimize bias when examining relationships between receipt of PMRT and survival.

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Presentations in suspected cancer

10.1093/med/9780199568741.003.0323 ◽

2018 ◽

Author(s):

David Cutter ◽

Martin Scott-Brown

Keyword(s):

Overall Survival ◽

Subsequent Treatment ◽

Clinical Suspicion ◽

Organ System ◽

The Body ◽

Neoplastic Disease ◽

Early Diagnosis Of Cancer ◽

Underlying Malignancy ◽

Diagnosis Of Cancer ◽

Vast Range

Malignant neoplastic disease includes a vast range of conditions that can originate from and can directly or indirectly affect virtually every organ system of the body. As a consequence of this, the presentation of malignancy can be similarly varied. While a diagnosis of malignancy may be clinically obvious in some cases, in others diagnosis and investigation may be delayed due to non-specific presentations and the attribution of symptoms to non-malignant conditions. Early diagnosis of cancer has an impact on the success of subsequent treatment and overall survival. It is therefore vital to maintain an appropriate level of clinical suspicion when deciding whether and how much to investigate patients with symptoms that could be secondary to an underlying malignancy.

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The Treatment of Relapsed Refractory Chronic Lymphocytic Leukemia

Hematology ◽

10.1182/asheducation-2011.1.110 ◽

2011 ◽

Vol 2011 (1) ◽

pp. 110-118 ◽

Cited By ~ 26

Author(s):

Jennifer R. Brown

Keyword(s):

Overall Survival ◽

Clinical Trials ◽

Stem Cell ◽

Chronic Lymphocytic Leukemia ◽

Clinical Problem ◽

Subsequent Treatment ◽

Lymphocytic Leukemia ◽

Targeted Therapeutics ◽

Poor Overall Survival ◽

Traditional Definition

Abstract Despite the widespread use of highly effective chemoimmunotherapy (CIT), fludarabine-refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical problem associated with poor overall survival (OS). The traditional definition, which includes those patients with no response or relapse within 6 months of fludarabine, is evolving with the recognition that even patients with longer remissions of up to several years after CIT have poor subsequent treatment response and survival. Approved therapeutic options for these patients remain limited, and the goal of therapy for physically fit patients is often to achieve adequate cytoreduction to proceed to allogeneic stem cell transplantation (alloSCT). Fortunately, several novel targeted therapeutics in clinical trials hold promise of significant benefit for this patient population. This review discusses the activity of available and novel therapeutics in fludarabine-refractory or fludarabine-resistant CLL as well as recently updated data on alloSCT in CLL.

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