Overall Survival Data Research Articles

Bayesian survival extrapolation for cost-effectiveness analysis: a case study of RELAY for ramucirumab in combination with erlotinib in the treatment of non-small-cell lung cancer

Aim Increasing trend for progression-free survival (PFS)-based primary endpoint in oncology has led to lack of mature overall survival (OS) data at the time of approval. To address this evidence gap in economic evaluations, we used a joint Bayesian approach to predict survival outcomes using immature OS data from the RELAY trial. Methods Patient data from RELAY and systematic literature review (SLR) of phase 3 randomized clinical trials with hazard ratio (HR) estimates of mature PFS and immature OS were considered. OS and PFS were analyzed individually using a univariate model; bivariate analysis was performed using a joint model based on modified Bayesian normal induced copula estimation model. First, a Bayesian univariate model incorporated informative priors based on predicted HR and acceleration factor for OS and PFS. Second, a Bayesian-based joint model of RELAY PFS and OS data was based on the correlation between PFS and OS established in trials of similar populations. Marginal distribution of PFS was used to estimate the same for OS. Results Publications (N = 122) of first-line treatments in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer were identified in the SLR, of which 36 trials were linked to RELAY. Twenty-six trials with HR data were used. The univariate model could predict OS with reduced uncertainty compared with the frequentist approach. In the joint model, the marginal OS distribution borrowed strength from the marginal PFS distribution through the established correlation coefficient. Limitations Bayesian approach was successfully used in RELAY analysis but may not be universally applied to oncology trials due to the different associations of OS and PFS and different trial patient populations. Conclusions We demonstrated that both the univariate and joint Bayesian models reduced uncertainty in predicting OS compared to frequentist method. The methodology introduced here will have potential applications in clinical decision-making for other oncology trials.

Clinical value of folate receptor-positive circulating tumor cells in patients with esophageal squamous cell carcinomas: a retrospective study

BackgroundThe aim of the study is to explore the role of preoperative folate receptor-positive circulating tumor cell (FR+CTC) levels in predicting disease-free survival (DFS) and overall survival (OS) in patients with esophageal squamous cell carcinomas (ESCC).MethodsThree ml blood samples were prospectively drawn from ESCC patients, and ligand-targeted polymerase chain reaction (LT-PCR) was used for the quantification of FR+CTCs. Other serum indicators were measured by traditional methods. Clinicopathological characteristics were obtained from the hospital medical record system, DFS and OS data were obtained by follow-up. The correlation between clinico-pathological characteristics, DFS, and OS and FR+CTCs were analyzed, respectively. Risk factors potentially affecting DFS and OS were explored by Cox regression analysis.Resultsthere were no significant correlations between FR+CTCs and patient age, sex, albumin, pre-albumin, C-reactive protein (CRP), ferritin and CRP/Albumin ratio, tumor size, grade of differentiation, lymph node metastasis, TNM stage, perineural invasion/vessel invasion (all P > 0.05). Nevertheless, preoperative FR+CTCs were an independent prognostic factor for DFS (HR 2.7; 95% CI 1.31-, P = 0.007) and OS (HR 3.37; 95% CI 1.06-, P = 0.04). DFS was significantly shorter for patients with post-operative FR+CTCs ≥ 17.42 FU/3ml compared with patients < 17.42 FU/3ml (P = 0.0012). For OS, it was shorter for patients with FR+CTCs ≥ 17.42 FU/3ml compared with patients < 17.42 FU/3ml, however, the difference did not reach statistical significance (P = 0.51).ConclusionsESCC patients with high FR+CTCs tend to have a worse prognosis. FR+CTCs may monitor the recurrence of cancers in time, accurately assess patient prognosis, and guide clinical decision-making.Trial registrationThe study was approved by the Sichuan Cancer Hospital & Institute Ethics Committee (No. SCCHEC-02-2022-050).

The Comparative Effectiveness of A+AVD vs PET-guided ABVD for the Management of Patients with Advanced Hodgkin Lymphoma: A Systematic Review and Matching-Adjusted Indirect Treatment Comparison

Introduction: In advanced Hodgkin lymphoma (aHL), adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) is a recommended chemotherapy regimen despite a substantial proportion of patients experiencing relapse or incomplete disease control. Per the National Comprehensive Care Network (NCCN) guidelines, positron-emission tomography (PET)-guided ABVD and brentuximab vedotin + adriamycin (doxorubicin), vinblastine and dacarbazine (A+AVD) are preferred options for the front-line treatment of aHL (NCCN Guidelines. Hodgkin lymphoma. Version 2. 2023). In the ECHELON-1 (E1) trial, superiority of A+AVD vs ABVD x6 cycles (without PET adaptation at cycle 2) was demonstrated statistically in terms of overall survival (OS) and progression-free survival (PFS). Six-year follow-up of E1 patients showed improved OS with A+AVD vs ABVD. The aim of this study was to indirectly compare the effectiveness (OS and PFS) of A+AVD vs PET-guided ABVD as front-line treatments in the management of patients aged ≤60 years with aHL (Stage III or IV). Methods: A systematic literature review was conducted using electronic databases such as MEDLINE, Embase, and the Cochrane Library (database inception to July 2022), supplementary sources and data on file for relevant materials reporting on the clinical efficacy of front-line treatments for aHL. Following the identification of relevant randomized controlled trials (RCTs), unanchored matching-adjusted indirect comparison was performed to compare the efficacy of A+AVD (the E1 trial) with PET-guided ABVD (the Risk-Adapted Therapy for aHL [RATHL] trial). As the outcomes used in the analyses were reported among the overall population in RATHL, rather than stratified by specific treatment, there was no potential anchor for the analysis. PFS and OS data from RATHL were only available for adult patients ≤60 years old with stage III/IV aHL, therefore the treatment comparison was limited to patients within this age group. Matching variables were selected based on literature review and the results of Cox regression analyses of the E1 trial data. The International Prognostic Score and Eastern Cooperative Oncology Group scores were used as matching factors as available. The weights generated from the matching procedure were incorporated in weighted Cox regression models to generate hazard ratios (HR) and corresponding 95% confidence intervals (CI). To account for the potential of violating the proportional hazards assumption, additional metrics were calculated including piecewise HRs (95% CI) using Cox regression models for specific time intervals (i.e., 0 to 24, 24 months +) and restricted mean survival times (RMST). Results : In adult patients aged ≤60 years with Stage III/IV aHL, treatment with A+AVD generally led to increased PFS and OS vs PET-guided ABVD (Table1). As the proportional hazard assumption was violated, additional metrics were calculated (RMST and piecewise HRs). HRs and RMST for survival outcomes are reported in Table1. Conclusions: The findings of this indirect treatment comparison support the improved efficacy of A+AVD relative to PET-guided ABVD with respect to OS and PFS in patients with stage III and IV aHL consistent with the results of E1 study.

Meta-Analysis of the Prognostic Significance of BCL6+/CD10+ Mantle Cell Lymphoma

Background: Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL), classically characterized by the translocation of t(11;14). MCL is typically CD10 negative, often attributed to its pre-germinal nature arising from naïve B cells. Increasing cases of CD10+ MCL suggest the possibility of germinal center-derived pathology. Moreover, a unique and rarer BCL6+/CD10+ immunophenotype has been reported in the literature and warrants investigation into its clinicopathologic significance. This meta-analysis was conducted to further investigate the relationship between MCL immunophenotypes and their clinical outcomes. Methods: A meta-analysis was conducted to investigate the relationship between MCL immunophenotypes and clinical outcomes. Endpoints collected included clinical features, overall survival (OS), morphology, immunophenotypes , Ki67%, and cytologic variants. OS data was pooled from multiple studies and assessed using the R programming package survival. A log-rank test was performed to compare OS. The mean differences in OS between BCL6+ and BCL6- MCL for individual studies were calculated and combined to minimize the batch effects. If individual Ki67 indexes were not available, the standard deviation (SD) of the mean difference was calculated based on normal distribution and the sample size of the particular study. The summary statistics across all studies was calculated by averaging all mean differences and pooling individual SDs. The correlations between CD10 &amp; BCL6, BCL6 &amp; blastoid morphology, and BCL6 &amp; SOX11 were tested using Fisher's exact test. Statistical significance was determined by setting the alpha (α) level at 0.05. Results: The meta-analysis included 537 patients (425 males and 112 females). The median age of diagnosis in CD10+ and CD10- MCL was 69 and 61.5 years old, respectively. There were 70 CD10+, 467 CD10-, and 22 BCL6+/CD10+ patients. BCL6 positivity had an odds ratio of 5.11 (95% CI [2.49, 10.46]; p=0.00002386) for CD10 positivity compared to CD10 negativity. The subgroup analysis showed a higher frequency of blastoid/pleomorphic/small morphology variants in BCL6+/CD10+ MCL. Correlation analysis between BCL6 positivity and blastoid/pleomorphic/small morphology did not demonstrate significant correlation (p=0.2423). However, positive correlation was seen between BCL6 and SOX11 (p=0.013). BCL6+ MCL was associated with an inferior median OS compared to BCL6- MCL (BCL6+: 14 months vs. BCL6-: 43 months; p=0.01). Furthermore, BCL6+/CD10+ co-expression was associated with an inferior median OS compared to BCL6-/CD10+ MCL (BCL6+/CD10+: 20 months vs. BCL6-/CD10+: 55 months; p&amp;lt;0.01). Conclusion: Based on the analysis, it was found that BCL6 expression positivity negatively impacts overall survival (OS) in MCL, regardless of CD10 expression. The higher Ki67% observed in BCL6 expression positivity compared to BCL6 negativity suggests the prognostic value of the BCL6 immunophenotype in MCL. Additionally, BCL6 expression was found to be correlated with CD10 and SOX11 expression, indicating the clinical significance of these variables when combined with BCL6 positivity. It is suggested that prognostic scoring systems adjusted for BCL6 could provide further insights into the prognostic categorization, management, classification, and future tailored treatment of MCL variants.

Molecular Measurable Residual Disease in Patients with Newly Diagnosed m IDH1 Acute Myeloid Leukemia Treated with Ivosidenib + Azacitidine

Background: Ivosidenib (IVO) + azacitidine (AZA) improved complete remission (CR) rates and overall survival (OS) relative to placebo (PBO) + AZA in patients (pts) with newly diagnosed mutant isocitrate dehydrogenase 1 (m IDH1) acute myeloid leukemia (AML) in the pivotal AGILE study (Montesinos et al. NEJM 2022). Prior analyses showed clinical responses to IVO+AZA were associated with deep clearance of m IDH1 (limit of detection [LOD]: 0.02-0.04% variant allele frequency [VAF]), as well as clearance of baseline co-mutations below the threshold of conventional next-generation sequencing (NGS) (LOD: 2.0% VAF) (Döhner et al. Blood 2022; Daigle et al. Blood 2021). Measurable residual disease (MRD), a negative prognostic marker, following chemotherapy is often detected via multiparametric flow cytometry or quantitative polymerase chain reaction although both techniques have their limitations. (Heuser et al. Blood 2021). NGS can detect a wide range of AML mutations and studies show that NGS-assessed MRD is highly predictive of both relapse and survival (Thol et al. Blood 2018; Tsai et al. Blood Adv 2021). However, a limitation of NGS is difficulty in distinguishing between somatic leukemia-associated mutations and clonal hematopoiesis of indeterminate potential (CHIP) (Bacher et al. Blood Cancer J 2018). We aimed to perform an NGS analysis of MRD responses in the AGILE study. Methods: All AGILE pts who had a best overall response (BOR) of CR, CR with incomplete count recovery, or CR with incomplete platelet recovery, and had ≥1 on-treatment bone marrow mononuclear cell (BMMC) sample available were included. Suggested timepoints for MRD testing included day 1 of treatment cycles 3, 5, 7, 9, 11, 14, 20, 26, and 32. Baseline and on-treatment BMMC DNA samples were analyzed using a diagnostic 51-gene myeloid NGS panel (LOD: 3% VAF) and a 26-gene AML MRD panel, respectively. For variants detected at baseline, the LOD was 0.1% VAF; for variants not detected at baseline (either emerging mutations or if baseline samples were unavailable), the LOD was 0.5% VAF. All variants above the applicable LOD with known or potential clinical significance were considered evidence of positive MRD, aside from DNMT3A, TET2 and ASXL1 (“DTA”) mutations to reduce the risk of false-positive MRD due to CHIP. Results: The analysis set comprised 173 samples from 33 IVO+AZA-treated pts and 10 PBO+AZA-treated pts (Fig. 1). Clinical response data were based on a March 18, 2021 primary analysis data cut; OS data were based on an updated June 30, 2022 data cut. The median number of baseline mutations was 4 (range: 1-10) per patient, median number of MRD assessments was 3 (range: 1-9) and median follow-up period was 189 days (range: 49-875). Ten (30.3%) IVO+AZA-treated pts became MRD-negative (MRD neg), compared with 2 (20.0%) PBO+AZA-treated pts. All pts attaining an MRD neg response had a BOR of CR (10 [34.5%] of 29 IVO+AZA-treated pts in CR; 2 [22.2%] of 9 PBO+AZA-treated pts in CR). Seven (70.0%) of the 10 MRD neg IVO+AZA-treated responding pts converted to an MRD neg response by day 1 of cycle 7 (C7D1). Fewer pts with an MRD neg response had an Adverse risk at baseline according to European LeukemiaNet 2022 genetic risk classification versus those pts with an MRD-positive (MRD pos) response (26.3% vs 73.7%) (Table 1). In the IVO+AZA arm, rates of event-free survival at 12 months and OS at 24 months were numerically higher in MRD neg vs MRD pos responders (80.0% vs 60.6% and 88.9% vs 72.3%, respectively) but did not reach statistical significance. All 5 (15.2%) IVO+AZA-treated pts with confirmed relapses had detectable MRD at the last completed assessment prior to relapse. One pt converted from an MRD neg to an MRD pos response (“MRD relapse”) 169 days prior to overt clinical relapse. Among the 23 IVO+AZA-treated pts without an MRD neg response, 16 were alive as of the updated data cut; OS duration ranged from 20.3-48.9 months. Conclusions: IVO+AZA induced molecular MRD negativity in approximately one third of responding pts with newly diagnosed m IDH1 AML; MRD neg responses were most often observed on or before C7D1. Interestingly, several pts had durable clinical responses and OS despite ongoing MRD positivity, potentially due to persistent CHIP rather than true MRD, illustrating the complexity of interpreting NGS MRD data. Additional analyses, including associations between specific molecular alterations, MRD response, and OS are ongoing and will be presented.

A Meta-Analysis Comparing the Relative Efficacy of Pediatric-Inspired Regimens Versus Hyper-CVAD for the Treatment of Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma in Adolescents, Young Adults, and Adults

Background: Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL)are rare aggressive hematologic malignancies. Children with ALL/LBL have an overall favorable prognosis; however, adult patients (pts) have a poorer outcome. As a result, pediatric or pediatric-inspired regimens with asparaginase (ASP) have been used in adolescents and young adult (AYA) pts with ALL/LBL with promising results. Unfortunately, there are no prospective randomized studies comparing this approach with hyper-CVAD, a commonly used adult regimen not containing ASP. A meta-analysis was conducted to assess the efficacy of pediatric-inspired ASP-containing regimens compared with hyper-CVAD in treating ALL/LBL in AYA and adult pts. Methods: We performed a systematic literature review (using databases including PubMed, Embase, and Cochrane Library) to identify relevant studies comparing ASP-containing regimens and hyper-CVAD in pts with ALL/LBL published up to April 21, 2022. The search strategy consisted of title/abstract key words and subject headings describing key concepts of “acute lymphoblastic leukemia,” “lymphoblastic lymphoma,” “asparaginase,” “hyper-CVAD,” “refractory,” and “minimal residual disease.” Abstracts were screened for inclusion to identify full texts that were assessed for eligibility. To determine the effects of intervention on complete response (CR) and overall survival (OS) (2 commonly reported outcomes across identified studies), odds ratios (OR) and hazard ratios (HR) were calculated. A meta-analysis was conducted using both random- and fixed-effects models to estimate the pooled OR and HR, 95% confidence intervals (CIs), and 95% prediction intervals (PIs). Scenario analyses identified potential sources of heterogeneity and bias. Results: The initial search identified 46 primary publications of potential relevance: 12 studies directly compared ASP-containing regimens and hyper-CVAD, but none were randomized. Based on direct comparison studies, ASP-containing regimens had statistically significant improvement in median OS (4 studies), 2-year OS (1 study), 3-year OS (3 studies), and 5-year OS (1 study) compared with hyper-CVAD. Four studies with comparable demographics were suitable for meta-analysis (n=702 total pts; n=366 ASP-containing regimens; n=336 hyper-CVAD): 2 studies in AYA (aged 13-43 yrs) and 2 in adults of any age (aged &amp;gt;16 yrs). ASP-containing regimens in the included studies were all based on Berlin-Frankfurt-Münster (BFM) or Cancer and Leukemia Group B (CALGB)-10403 protocols. Pts treated with ASP-containing regimens had a significantly higher chance of achieving CR (random- and fixed-effects model: OR, 2.04 [95% CI: 1.31, 3.18]) and improved OS (random-effects model: HR, 1.76 [95% CI: 1.36, 2.29]; fixed-effects model: HR, 1.75 [95% CI: 1.36, 2.24]) than those treated with hyper-CVAD. There was a low level of heterogeneity among studies for both CR (I 2=0%, tau^2=0.00, P=0.86) and OS (I 2=0%, tau^2=0.02, P=0.79) data. One study evaluated 2 different ASP-containing regimens vs hyper-CVAD. Two separate meta-analyses were executed: 1 pooling results from both treatment arms (base case) and 1 considering them separately (scenario 1). A further analysis was limited to just 2 studies, where the proportionality assumption for the HR was robust and the results consequently most statistically reliable (scenario 2). Compared with the base case, both scenarios yielded similar estimates of treatment effect but with greater heterogeneity and wider PIs. This analysis has limitations: the type of ASP-containing regimen varied (1 study assessed L-ASP regimens, 2 assessed pegaspargase, and 1 did not specify), the studies each took place in different countries potentially contributing to heterogeneity in cultural, genetic, and healthcare practices, and not all details of pts' clinical characteristics were reported to inform on comparability of the pt populations. Further, without head-to-head studies, there was no way to address whether treatment cost or institutional bias affected the results. Conclusion(s): Meta-analysis suggests that ASP-containing regimens are associated with improved rates of CR and OS in AYA (median age range 13-43 yrs) and adult (median age range 16-60 yrs) pts.

A Multicenter Retrospective Study to Understand the Clinical Characteristics, Treatment Patterns, and Resource Utilization for Patients with Chronic Lymphocytic Leukemia: CREEK Study

Abstract Introduction: The ever-growing array of treatments available for chronic lymphocytic leukemia (CLL) led to a significant change in CLL management over the last few years. However, information about managing CLL is scattered across various regions, resulting in significant disparities in treatment approaches and patient outcomes between countries. The CREEK study aimed to describe the disease characteristics, treatment patterns, and overall survival (OS) among CLL-treated (CLL-Tx) patients and CLL treatment-naïve (CLL-N) patients in different regions. Methods: Data from 1009 patients were collected retrospectively from June 2016 to March 2023. This observational study included 886 CLL-Tx patients from 17 countries in the Middle East and Africa (MEA), Asia Pacific (AP), and Latin America (LA); and a pilot cohort of 123 CLL-N patients from the Gulf Cooperation Council (GCC) countries. Patients' demographics, disease characteristics, laboratory assessments, comorbidities, treatment patterns, treatment-related adverse events (AEs), OS, and medical resource utilization (MRU) data were recorded. Results: The average age for both cohorts was 63 years. Most patients were males, 66.7% in CLL-Tx and 69.9% in CLL-N. The mean duration from clinical manifestation until diagnosis was 21.37 months for CLL-Tx and 1.46 months for CLL-N patients (p&amp;lt;0.0001). For CLL-Tx, almost 62% of the patients in MEA, 59.3% in AP, and 68.8% in LA had an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and similarly for CLL-N patients (56.1%). Total leucocytic count, lymphocytes, and platelets showed a significant difference (p&amp;lt;0.05) between CLL-Tx and CLL-N patients. As per the Cumulative Illness Rating Scale (CIRS), musculoskeletal (p&amp;lt;0.0008) and endocrine-metabolic (p&amp;lt;0.0001) comorbidities were more frequent in the CLL-Tx group. Regarding the CLL-Tx patients, 69.7%, 62.9%, and 41.1% had extremely severe hematological problems (CIRS score 4) in MEA, LA, and AP, respectively. At diagnosis, patients from the MEA region presented with the highest prevalence of advanced disease staging, with 44.8% and 35.3% based on Rai and Binet Staging Scores, respectively; moreover, CLL-Tx patients exhibited a more advanced staging compared to CLL-N based on the same scores (p &amp;lt;0.0001). FISH testing for disease prognosis was not performed in about 59% of the patients across all regions. The testing rates for cytogenetic abnormalities, IGHV mutation status, and TP53 aberrations were relatively low in all regions. The percentage of unmutated IGHV was considerably higher (p=0.0001) in CLL-Tx (15.6%) patients, with the highest percentage in LA (21.0%), compared to CLL-N (10.6%). Cytogenetic abnormalities did not show significant differences between CLL-Tx and CLL-N patients (p&amp;gt;0.05), while TP53 aberrations differ significantly (p&amp;lt;0.05) (Table 1). Most patients, 76.0%, 81.8%, and 69.4%, received chemo-immunotherapies as 1 st line therapy, while 18.3%, 17.1%, and 30.1% received targeted therapy in MEA, AP, and LA, respectively. The percentage of patients with AEs who received 1 st line chemo-immunotherapies was higher than those who received targeted therapy (25.6% vs. 7.3%). The mean OS was 153.89 months in the treated study population (Table 2). The mean number of inpatient hospitalizations was 1.9 times for chemo-immunotherapy and 0.8 times for targeted therapy. The mean lengths of stay of 14.9 and 13.9 days, respectively; mean emergency room visits were 0.5 and 0.7, and blood transfusions were received by 16.7% and 9.2% of patients, respectively. Conclusions: This study highlights the variable disease characteristics between CLL-Tx and CLL-N patients and provides insight into the regional variations in treatment patterns and OS for CLL-Tx patients. A considerable number of patients had advanced disease staging at diagnosis; however, the study showed relatively low genetic testing rates, indicating the need for adequate clinical watchfulness. Despite being in the era of approved targeted therapy, the utilization of chemo-immunotherapy continues to be higher than that of targeted therapy in the first line, probably due to the lower access to targeted therapies. Keywords: Chronic Lymphocytic Leukemia (CLL), Genetic Testing, Treatment Patterns, Targeted Therapy, Chemo-immunotherapy, Real World Data.

Long-Term Outcomes from the Phase 3 OCEAN (OP-103) Study: Melflufen and Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed Refractory Multiple Myeloma (RRMM)

Background/Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases resulting in rapid release of alkylating agents inside tumor cells. Based on the phase 2 HORIZON study and supported by the phase 3, randomized, controlled OCEAN study, melflufen was approved in Europe for use in patients (pts) with triple-class refractory RRMM with ≥3 prior lines of therapy (LoTs) and without prior autologous stem cell transplantation (ASCT) or with a time to progression (TTP) &amp;gt;36 mo after prior ASCT. In the OCEAN study (NCT03151811), melflufen + dex showed superior progression-free survival (PFS) compared with pom + dex (6.8 vs 4.9 mo; hazard ratio [HR]: 0.79; P=0.032); PFS benefit in the melflufen + dex group was mainly driven by pts who had not received prior ASCT. Overall survival (OS) trended in favor of melflufen + dex in pts without prior ASCT and favored pom + dex in pts with prior ASCT (Schjesvold et al. Lancet Haematol. 2022;9:e98). Post-hoc analyses of OCEAN and HORIZON demonstrated that a TTP &amp;lt;36 mo after prior ASCT was a negative prognostic factor for OS with melflufen + dex (Sonneveld et al. Clin Lymphoma Myeloma Leuk. 2023;S2152). Here, we present long-term OS and safety data from the final analysis of the OCEAN study. Methods: Pts with RRMM (2-4 prior LoTs including lenalidomide [len] and a proteasome inhibitor) refractory to len and last LoT were randomized 1:1 (stratified by age, no. of prior LoTs, and International Staging System score) to receive 28-day (d) cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to 21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, as assessed by independent review committee per IMWG Uniform Response Criteria, and key secondary endpoints were overall response rate, OS, and safety. Results: As of 3 Feb 2023, 495 pts were randomized (246 to melflufen; 249 to pom); median age was 68 y (range, 39-91) and median prior LoTs was 3. In the intent-to-treat (ITT) melflufen and pom populations, median OS was 20.2 mo vs 24.0 mo (HR, 1.09 [95% CI, 0.88-1.35]), at a median follow-up of 40.3 mo and 38.1 mo, respectively. In the target subgroup of the melflufen and pom groups (pts without a prior ASCT or TTP &amp;gt;36 mo after an ASCT), median OS was 23.6 mo vs 19.1 mo (HR, 0.88 [95% CI, 0.67-1.16]); in the non-target population (pts with TTP &amp;lt;36 mo after ASCT), median OS was 15.7 mo vs 27.5 mo (HR, 1.60 [95% CI, 1.15-2.21]), respectively. While any grade hematologic toxicities were more common with melflufen, the occurrence of non-hematologic toxicities was similar in the 2 groups. Grade 3/4 (G3/4) treatment-emergent adverse events (TEAEs) in the safety population (melflufen [n=228] and pom [n=246]) occurred in 90% vs 76% of pts, respectively; most commonly thrombocytopenia (78% vs 13%; occurring with G3/4 hemorrhage in 1% vs 0%), neutropenia (64% vs 50%; occurring with G3/4 infections in 4% vs 7%), anemia (43% vs 19%), and infection and infestations (14% vs 24%). Serious AEs occurred in 43% vs 50% of pts (including pneumonia [6% vs 9%], COVID-19 pneumonia [5% vs 6%], and anemia [4% vs 2%]), and fatal AEs in 14% vs 15% (including COVID-19 pneumonia [4% vs 2%] and pneumonia [2% vs 2%]) in the melflufen and pom groups, respectively. With melflufen and pom, TEAEs led to dose reductions in 52% vs 28% of pts (most frequently thrombocytopenia [32% vs 2%] and neutropenia [12% vs 8%]), and discontinuations in 30% vs 24% of pts, respectively. Deaths occurred in 74% vs 68% of pts in the melflufen and pom groups, with AEs being the primary cause of death ≤30 d after last dose in 8% and 11%, respectively. Conclusion: Long-term results were consistent with those of previous analyses (Schjesvold, et al. Lancet Haematol. 2022;9:e98-e110). While OS trended in favor of pom in the ITT population, OS outcomes continued to be more favorable with melflufen in pts with no prior ASCT or with TTP &amp;gt;36 mo after ASCT. No new safety signals were reported, and AEs were manageable with dose modifications, consistent with previous reports. This long-term follow-up of OCEAN confirms the favorable safety and OS outcomes of melflufen + dex in the target population and supports its continued use as an alternative treatment choice for pts with RRMM who have received ≥2 prior LoT and who have not received ASCT.

Updated Results from a Matching-Adjusted Indirect Comparison of Efficacy Outcomes for Isatuximab Plus Pomalidomide and Dexamethasone Versus Daratumumab Plus Pomalidomide and Dexamethasone in Patients with Relapsed and/or Refractory Multiple Myeloma

Introduction: Findings from a previously conducted matching-adjusted indirect comparison (MAIC) between isatuximab plus pomalidomide and dexamethasone (IsaPd) and daratumumab plus pomalidomide and dexamethasone (DaraPd) among relapsed and/or refractory multiple myeloma (RRMM) patients receiving at least two prior lines of therapy (LoT) including lenalidomide and a proteasome inhibitor (PI) demonstrated a significantly better overall survival (OS) and a positive trend for progression-free survival (PFS), overall response rate (ORR), and very good partial response or better (≥VGPR) rates with IsaPd than that with DaraPd, with a similar safety profile for both treatments [Leleu X et al, Value in Health 2022;25(1):S39]. The present study used longer follow-up data from the phase 3 ICARIA trial (NCT02990338) to update the previous MAIC, evaluating the comparative efficacy of IsaPd versus DaraPd. Methods: A MAIC was performed with the latest available individual patient-level data (IPD) from the ICARIA trial (IsaPd arm, n = 154; Pd arm, n = 153), data cutoff of March 14, 2022, and aggregate data from study publications of the phase 3 APOLLO trial (DaraPd arm, n = 151; Pd arm, n = 153, NCT03180736) [Dimopoulos MA, et al. Blood 2022;140 (Suppl 1):7272-7274; Dimopoulos MA, et al. Lancet Oncol. 2021;22(6):801-812; Dimopoulos MA, et al. Blood 2020;136(Suppl 1):5-6]. To match patients with APOLLO, patients in ICARIA who did not meet the inclusion criteria of APOLLO were excluded. In APOLLO, 11% patients received only one prior LoT. As patients with one prior LoT were not enrolled in ICARIA, it was not feasible to match on this factor; however, the treatment effect of DaraPd versus Pd on PFS among these patients was similar to patients in APOLLO with ≥2 prior LoTs. Therefore, this difference in study populations is unlikely to bias the MAIC. Remaining patients in ICARIA were then weighted using standardized MAIC weights (mean value = 1.0) generated using the method of moments, with active treatment and control arms matched separately to ensure any residual imbalances between active and control arms in APOLLO were replicated in the matched ICARIA sample. Anchored MAICs for the hazard ratio (HR) for OS and PFS, odds ratio (OR) for ORR, and ≥VGPR for IsaPd versus DaraPd were calculated using the Bucher method [Bucher HC, et al. J Clin Epidemiol. 1997;50(6):683-691]. Results: MAIC weighting was able to match all characteristics included in the matching algorithm, with standardized mean difference (SMDs) &amp;lt;0.0001 after weighting. The effective sample size after weighting was 28.1 for IsaPd and 43.1 for Pd. Based on an anchored MAIC, OS was significantly better with IsaPd versus DaraPd (HR [95% CI]: 0.49 [0.24-0.98]; p = 0.04) (Figure 1). A numerical trend in favor of IsaPd versus DaraPd was observed for PFS, ORR, and ≥VGPR, although the differences were statistically non-significant (Table 1). Conclusions: This MAIC analysis demonstrated a significant benefit in OS and a positive trend in the improvement of PFS, ORR, and ≥VGPR in favor of IsaPd compared with DaraPd. These findings were consistent with the previous MAIC with a longer follow-up data (present analysis used a maximum follow-up of 4.5 years of OS data from both trials, whereas the previous analysis used a follow-up of 3 years from ICARIA and unknown from APOLLO), which highlights the therapeutic potential of IsaPd in RRMM, particularly for patients who become refractory to lenalidomide and a PI.

Quantifying the impact of novel metastatic cancer therapies on health inequalities in survival outcomes

Background: Novel therapies in metastatic cancers have contributed to improvements in survival outcomes, yet real-world data suggest that improvements may be mainly driven by those patient groups who already had the highest survival outcomes. This study aimed to develop and apply a framework for quantifying the impact of novel metastatic cancer therapies on health inequalities in survival outcomes based on published aggregate data.Methods: Nine (N = 9) novel therapies for metastatic breast cancer (mBC), metastatic colorectal cancer (mCRC), and metastatic non–small cell lung cancer (mNSCLC) were identified, 3 for each cancer type. Individual patient data (IPD) for overall survival (OS) and progression-free survival (PFS) were replicated from published Kaplan-Meier (KM) curves. For each cancer type, data were pooled for the novel therapies and comparators separately and weighted based on sample size to ensure equal contribution of each therapy in the analyses. Parametric (mixture) distributions were fitted to the weighted data to model and extrapolate survival. The inequality in survival was defined by the absolute difference between groups with the highest and lowest survival for 2 stratifications: one for which survival was stratified into 2 groups and one using 5 groups. Additionally, a linear regression model was fitted to survival estimates for the 5 groups, with the regression coefficient or slope considered as the inequality gradient (IG). The impact of the pooled novel therapies was subsequently defined as the change in survival inequality relative to the pooled comparator therapies. A probabilistic analysis was performed to quantify parameter uncertainty.Results: The analyses found that novel therapies were associated with significant increases in inequalities in survival outcomes relative to their comparators, except in terms of OS for mNSCLC. For mBC, the inequalities in OS increased by 13.9 (95% CI: 1.4; 26.6) months, or 25.0%, if OS was stratified in 5 groups. The IG for mBC increased by 3.2 (0.3; 6.1) months, or 24.7%. For mCRC, inequalities increased by 6.7 (3.0; 10.5) months, or 40.4%, for stratification based on 5 groups; the IG increased by 1.6 (0.7; 2.4) months, or 40.2%. For mNSCLC, inequalities decreased by 14.9 (−84.5; 19.0) months, or 12.2%, for the 5-group stratification; the IG decreased by 2.0 (−16.1; 5.1) months, or 5.5%. Results for the stratification based on 2 groups demonstrated significant increases in OS inequality for all cancer types. In terms of PFS, the increases in survival inequalities were larger in a relative sense compared with OS. For mBC, PFS inequalities increased by 8.7 (5.9; 11.6) months, or 71.7%, for stratification based on 5 groups; the IG increased by 2.0 (1.3; 2.6) months, or 67.6%. For mCRC, PFS inequalities increased by 5.4 (4.2; 6.6) months, or 147.6%, for the same stratification. The IG increased by 1.3 (1.1; 1.6) months, or 172.7%. For mNSCLC, inequalities increased by 18.2 (12.5; 24.4) months, or 93.8%, for the 5-group stratification; the IG increased by 4.0 (2.8; 5.4) months, or 88.1%. Results from the stratification based on 2 groups were similar.Conclusion: Novel therapies for mBC, mCRC, and mNSCLC are generally associated with significant increases in survival inequalities relative to their comparators in randomized controlled trials, though inequalities in OS for mNSCLC decreased nonsignificantly when stratified based on 5 groups. Although further research using real-world IPD is warranted to assess how, for example, social determinants of health affect the impact of therapies on health inequalities among patient groups, the proposed framework can provide important insights in the absence of such data.

NCOG-18. CLINICAL CHARACTERISTICS OF H3.G34 DIFFUSE HEMISPHERIC GLIOMA: A CASE SERIES AND REVIEW OF THE LITERATURE

Abstract BACKGROUND Diffuse hemispheric glioma (DHG) is an uncommon infiltrating glioma, defined in the World Health Organization 2021 guidelines by a mutation in the H3F3A gene at codon 34 (H3.G34). DHG primarily affects children and young adults. Due to its rarity, there is paucity of knowledge regarding factors affecting overall survival (OS). We retrospectively assessed our institutional experience and present a review of the literature. METHODS We searched our institution’s pathology records to identify six cases of DHG. Demographic, clinical, diagnostic, treatment, and outcome data were recorded. We next searched for published articles regarding DHG cases via PubMed through May 2023. Four-hundred-fifty-four published individual cases of H3.G34 glioma were identified, 204 of which were hemispheric/supratentorial tumors with OS data reported, providing a combined 210 cases for analysis. 132 of these cases included MGMT promoter methylation status. 111 included extent of surgical resection. Kaplan-Meier and Cox regression survival analysis was performed. RESULTS Age range for DHG patients was 7-66 years (median 17). Median OS was 18.5 months (95% CI, 17-25). Greater extent of surgical resection and presence of MGMT promoter methylation were associated with better prognosis. Median OS for biopsy alone was 12 months (95% CI, 10-NA), subtotal resection was 16 months (95% CI, 14-23), and gross total resection was 27 months (95% CI 23-NA) – log-rank p&amp;lt; 0.001. OS for MGMT promoter unmethylated was 14 months (95% CI 12-22), MGMT promoter methylated was 24 months (95% CI, 17-30) – log-rank p=0.028. Contrary to previous reports, patient age was not found to impact prognosis (using 18, 21, and 40 years as cutoffs or as a continuous variable with Cox regression). CONCLUSION Extent of surgical resection and MGMT promoter methylation status are important prognostic factors for DHG. Unlike many primary brain tumors, survival does not appear to be significantly impacted by age.

Intensive Induction Chemotherapy with or without Gemtuzumab Ozogamicin Among Patients with Core-Binding Factor Acute Myeloid Leukemia

Background: Core-binding factor acute myeloid leukemia (CBF-AML) is characterized by the presence of inv(16)/t(16;16) or t(8;21), and is classified as favorable risk by the 2022 European LeukemiaNet (ELN) guidelines. High remission rates are observed in the setting of cytarabine- or anthracycline-based induction regimens. The CD33-targeted antibody-drug conjugate gemtuzumab ozogamicin (GO) is FDA-approved for use in newly-diagnosed CD33+ AML; a meta-analysis of 5 prospective randomized studies investigating intensive chemotherapy (IC) +/- GO demonstrated an improved overall survival (OS) with the addition of GO to IC for favorable-risk AML (Hills et al, Lancet Oncol 2014). The trials included in the meta-analysis did not restrict inclusion criteria to CBF-AML alone and there remains variation amongst IC regimens utilized in CBF-AML treatment. In addition, IC combined with the KIT inhibitor dasatinib has shown remission rates and promising overall survival in prospective studies (Paschka et al, Leukemia 2018; Marcucci et al, Blood Adv 2020). We set out to investigate the outcomes of patients (pts) with CBF-AML treated with IC +/- targeted agents (GO or KIT inhibitor) across 5 institutions that are part of the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Methods: Retrospective chart review was done to identify pts who were treated with IC with AML harboring inv(16)/t(16;16) or t(8;21) identified on cytogenetics, from January 2010 through April 2023, and were treated across 5 geographically-diverse academic institutions. Pt clinical characteristics, cytogenetics, molecular mutations, treatment, relapse, and OS data were collected. Relapse-free survival (RFS) and OS were both analyzed using Kaplan-Meier analysis. Results: One-hundred forty-nine consecutive pts with CBF-AML were identified, 76 (51%) with inv(16) and 73 (49%) with t(8;21). Median age of pts was 47 years (yrs) (range 18-80yrs), with 64% male pts, and 106 (71%) pts had an ECOG performance status of 0-1. One-hundred seven (72%) pts identified as non-Hispanic White, 22 (15%) identified as non-Hispanic Black, and 12 (8%) identified as Hispanic. Molecular testing via next-generation sequencing was available for 124 pts (83%); 49 (33%) pts had adverse-risk ELN cytogenetics or mutations when excluding CBF status, and 27 (18%) pts harbored KIT mutations. Other baseline pt characteristics are listed in Table 1A. All pts underwent induction with IC; 44 (30%) pts received IC + GO, 21 (14%) received IC + KIT inhibitor (14 received dasatinib, 7 received midostaurin), and the remaining 84 (56%) received IC without a targeted agent. One-hundred fourteen (77%) pts achieved a complete response (CR) to induction therapy, and 1 pt experienced induction-related mortality. Fluorescence in-situ hybridization (FISH) data was available in 82 pts at end of induction with 83% achieving FISH negativity. Measurable residual disease (MRD) testing was done by polymerase chain reaction (PCR) in 62 pts with 76% achieving MRD-negativity. One-hundred forty pts underwent consolidation with a median of 3 cycles of chemotherapy; 21 (15%) pts received GO with consolidation and 17 (12%) received a KIT inhibitor with consolidation. Forty-four (30%) pts underwent allogeneic stem cell transplantation (alloSCT), with 17 in first CR, and 27 after second-line or beyond therapy. With a median follow-up of 22.5 months, the observed 3-yr RFS was 51% (95% CI: 43-61%) and the 3-yr OS was 69% (95% CI: 61-78%). Pts treated with IC + KIT inhibitor had significantly improved 3-yr RFS of 85% (95% CI: 70-100%) compared to other pts, including those who received IC + GO who had a 3-yr RFS of 51% (95% CI: 37-70%) and those who received IC without targeted therapy who had a 3-yr RFS of 45% (95% CI: 35-58%) ( p = 0.02) ( Figure 1). Full survival statistics are shown in Table 1B and Figure 1. Conclusions: In this multi-center retrospective study of pts with CBF-AML undergoing induction with IC regimens with diverse national treatment practices, we find that the addition of GO to IC is not associated with improved outcomes. Pts treated with IC + KIT inhibitor had significantly improved RFS; of note, pts receiving a KIT inhibitor oftentimes continued on maintenance even after consolidation. These data suggest that there may be a role for targeted therapies other than GO to be explored in randomized prospective studies of intensive induction chemotherapy for CBF-AML.

Real-Life Experience of the Combination of Daratumumab, Bortezomib, Melphalan, and Prednisone (DVMP) in Patients with Newly Diagnosed Multiple Myeloma Ineligible for Autologous Stem-Cell Transplantation

INTRODUCTION The combination of daratumumab, bortezomib, melphalan, and prednisone (D-VMP) is an effective and safe alternative treatment for patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous hematopoietic stem-cell transplantation (HSCT) as described in ALCYONE clinical trial. However, real-life data is limited. This study aims to evaluate the data derived from real-life experience with this combination. METHODS This is a Spanish retrospective, multicenter study. One hundred eleven adults with NDMM ineligible for autologous HSCT who had started first-line treatment with D-VMP from 01/Jun/2019 to 01/Apr/2023 were included. The primary endpoint was to describe the progression-free survival (PFS), and the secondary endpoints were to describe overall response rate (ORR), very good partial response (VGPR), complete response (CR), overall survival (OS), and safety profile. RESULTS A total of 111 patients were included, 57 (51%) were males. The median age was 77 years (IQR 73-82), with 67% ≥ 75 years. Seven percent had an ECOG &amp;gt;2, 6% severe anemia (Hb &amp;lt;7.5g/dL), 14% creatinine &amp;gt;2mg/dL, and 7% had a first in-hospital dialysis. Twenty-one (19%) had R-ISS III disease stage, and 22 (20%) had extramedullary disease (16% bone-related plasmacytomas and 4% soft-tissue plasmacytomas). Of the 95 patients evaluable for cytogenetics, 13 (14%) had t(11;14), 36 (38%) had at least one poor-prognosis cytogenetic abnormality (del17p, t(4;14), t(14;16), gan/amp(1q) or del(1p)), and 10 (10%) had &amp;gt; 1. Of all patients, 83 (75%) had completed induction, with a median number of cycles of 9 (IQR 6-9). Among these patients, 26 (23%) received combined maintenance with daratumumab and bortezomib. The ORR was 91%, with at least VGPR in 66% of patients. The ORR and VGPR/CR rates were consistent regardless of age (ORR &amp;gt;74 years 86% vs &amp;lt;75 years 92%; VGPR/CR &amp;gt;74 years 67% vs &amp;lt;75 years 62%) and cytogenetic risk (ORR high-risk cytogenetic 86% vs standard cytogenetic 94%; VGPR/CR high risk cytogenetic 64% vs standard cytogenetic 68%). The median time to response was 35 days (IQR 24-49), and the median time to best response was 206 days (IQR 91-458). Minimal residual disease (MRD) was determined in 27 (54%) of patients in CR and 6 (26%) in VGPR. Eighteen patients in CR and 1 patient in VGPR had negative MRD (at least 10 -4). Twelve patients with negative MRD were subsequently re-evaluated, and 7 maintained MRD negativity at 4 (1), 6 (2), 9 (2), 12 (1) and 24 (1) months. Median OS was 44 months (95% confidence interval [CI], 33 to 55) and median PFS was 28 months (95% CI, 21 to 36). At a median follow-up of 22,6 months (IQR 15-30), the 36-month OS rate was 60% (95% CI, 52 to 68). Median OS was 36 months (95% CI 24 to 45) in the high cytogenetic risk group. Median PFS was 22 months(IC 95% 7 to 38) in the high cytogenetic risk group and 9 months (IC 95% 0 to 22) in the group with &amp;gt; 1 poor-prognosis cytogenetic abnormality. The dose of bortezomib was reduced in 42% of patients, mainly due to neuropathy (42%). The dose of melphalan was reduced in 28%, mainly because of myelotoxicity (29%) and kidney failure (19%). Both bortezomib and melphalan were discontinued in 6% of patients. Daratumumab did not require adjustment or early suspension. There were 13 deaths (12%), 4 due to progression, 4 due to infection, and 5 due to a cause unrelated to the MM. Among 24 (22%) of total patients who experienced relapse, 96% received subsequent therapy. The most frequent therapy was Lenalidomide-Dexamethasone (46%) followed by Carfilzomib-Lenalidomide-Dexamethasone (38%). CONCLUSIONS In real-life practice, D-VMP combination in patients with NDMM ineligible for transplant showed comparable efficacy and safety profile with those reported in ALCYONE clinical trial. Although the PFS and OS data are lower than those reported in ALCYONE, this could be due to the older age and a worse clinical involvement of the patients included in this study.

A Prospective, Multinational Study of Clinical and Biological Factors Associated with Short Overall Survival in Multiple Myeloma

Introduction: Multiple myeloma (MM) is an incurable cancer, but a subset of patients can achieve long-term remission and overall survival (OS). We aimed to study the clinical and biological factors associated with short OS defined as less than 3 years. Methods: A prospective, observational, multinational study was conducted by Australian and New Zealand (ANZ) and Asia-Pacific (APAC) Myeloma and Related Disease Registry (MRDR) from January 2013 to January 2023, across 5 countries (Australia, New Zealand, Korea, Singapore, Malaysia). Eligible patients were ≥18 years old, diagnosed with MM per International Myeloma Working Group (IMWG) criteria, received a bortezomib-containing triplet, and had at least 3 years of follow-up or had deceased within 3 years. Descriptive analysis was completed using chi-squared test for categorical variables and Wilcoxon rank-sum test for continuous variables. The Kaplan-Meier method was used for analysing OS and follow-up data. The ‘stepwise’ function in Stata was used for the forward stepwise logistic regression, with the p-value set to 0.1. All analyses were completed using Stata 16. Results: Of the 1539 patients enrolled, majority were from ANZ (1071 and 359, respectively), with male preponderance (61.0%). Half were above 65 years old. High risk cytogenetic abnormalities, a criterion of the Revised International Staging System (R-ISS), was unknown for half of the patients (49.4%). 45.3% patients presented as ISS stage 1, 21.9% stage II, and 32.8% stage III, respectively at study entry . The most frequent front-line agent used in combination with bortezomib-based triplet was cyclophosphamide [VCd, 1380 (89.7%)], followed by thalidomide [VTd, 92(6.0%)], lenalidomide [VRd, 63 (4.1%)] and daratumumab [DVd, 4 (0.3%)]. The median follow-up was 29.9 months (95%CI: 28.3-31.8) and the median OS was 87.7 months (95%CI: 80.9-93.2). Thirty percent patients had OS&amp;lt;3 years. Clinical and biological factors associated with long OS (≥3 years) were compared with those &amp;lt;3 years (Table 1). Baseline factors associated with higher odds of short OS included age≥65, Eastern Cooperative Oncology Group performance status (ECOG PS)≥2, ISS III, lower creatinine clearance and platelet count, high LDH and poor cytogenetic abnormalities (Table 1). In a multivariate analysis, age≥65 (OR:2.50; p&amp;lt;0.001), ECOG≥2 (OR:2.08; p&amp;lt;0.001), ISS III (OR:2.48; p&amp;lt;0.001), t(4;14)[OR:2.04; p=0.004], t(14;16)[OR:6.33; p=0.004] and 17p deletion (OR:2.77; p =0.001) were associated with a significantly shorter OS. Conclusion: From clinician perspective, identifying patients with an increased likelihood of shorter OS through the determination of patient- and disease-specific risk factors might be clinically relevant to facilitate better treatment decisions.

In-Class Transition ( iCT) from Parenteral Bortezomib (V) to Oral Ixazomib Therapy in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) in the Community-Based US MM-6 Study: Subanalysis of Randomized Controlled Trial (RCT)-Ineligible and RCT-Eligible Pts

Introduction Up to 72% of real-world multiple myeloma (MM) pts are considered ineligible for RCTs due to criteria such as old age, frailty, and comorbidities, limiting the generalizability of findings to the wider MM population. The US MM-6 study (NCT03173092) aimed to increase the duration of proteasome inhibitor (PI)-based therapy and improve outcomes with a tolerable safety profile in a patient (pt) cohort representative of that in routine clinical practice. Results for the fully accrued dataset have been reported previously (N=141; Yimer IMS 2022). Here we report the results of a US MM-6 subanalysis describing pt characteristics and key efficacy and safety outcomes of two groups: RCT-ineligible (RCT-i) and RCT-eligible (RCT-e). Methods Transplant-ineligible/delayed-transplant (≥24 months) NDMM pts with ≥stable disease after 3 cycles of parenteral V-based induction were enrolled at US community sites to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd) for up to 39 cycles or until progression or toxicity (Manda CLML 2020). Pts were grouped based on whether any baseline characteristic met common RCT ineligibility criteria including but not limited to hematologic/organ dysfunction, ECOG PS &amp;gt;2, renal dysfunction, prior malignancies, cardiac dysfunction, and pulmonary disease. Two-year progression-free survival (PFS; primary endpoint), overall survival (OS), overall response rate (ORR), and safety were analyzed by RCT group. Results At final data cut-off (Oct 17, 2022) 140 pts were evaluable; 57 (40.7%) met ≥1 RCT ineligibility criteria and were included in the RCT-i group; 83 (59.3%) were included in the RCT-e group. The most common ineligibility criteria in the RCT-i group were cardiac arrhythmias (14.3%), chronic pulmonary disease (8.6%), and prior malignancy (7.9%) (Table). At enrollment, in the RCT-i vs RCT-e groups, median age was 73 years (range 48-90) vs 72 years (range 49-86), 54.4% vs 60.2% were male, 77.2% vs 69.9% were white. In RCT-i vs RCT-e, 24.6% vs 27.7%, 40.4% vs 42.2%, and 33.3% vs 30.1% had ISS stage I, II, and III, respectively. A total of 98.2% vs 90.4% of pts in the RCT-i vs RCT-e group had any comorbidity; 15.8% vs 10.8% had peripheral neuropathy (PN) as a comorbidity. At data cut-off, 84.2% of pts in the RCT-i group had discontinued treatment, commonly (&amp;gt;20% of pts) due to progressive disease (27.1%), adverse events (25.0%), and pt withdrawal (20.8%). In the RCT-e group, 75.9% had discontinued treatment, commonly due to pt withdrawal (25.4%) and adverse events (23.8%). In both RCT-i and RCT-e groups, pts received a median of 11 (range 1-39) IRd and ixazomib cycles; median duration of PI therapy was 13.6 months. After a median follow-up of 29.2 vs 24.6 months for RCT-i vs RCT-e groups, 2-year PFS rates were 68% (95% confidence interval [CI] 52-80) vs 73% (95% CI 60-82); 2-year OS rates were 90% (95% CI 78-96) vs 84% (95% CI 72-91). ORR increased from 61.4% vs 66.3% at the end of V-based induction to 80.7% vs 79.5% after iCT for RCT-i vs RCT-e groups. For the respective RCT-i and RCT-e groups, treatment-emergent adverse events (TEAEs) were observed in 98.2% and 97.6% of pts (treatment-related: 82.5% and 81.9%), and serious TEAEs in 43.9% and 44.6% (treatment-related: 12.3% and 13.3%) of pts; on-study deaths occurred in 3 pts and 1 pt. The most common any-grade TEAEs (&amp;gt;30% of pts in either arm) were diarrhea (RCT-i: 49.1%; RCT-e: 51.8%), fatigue (RCT-i: 38.6%; RCT-e: 30.1%), and PN (RCT-i: 31.6%; RCT-e: 25.3%). In the RCT-i and RCT-e groups, respectively, grade ≥3 TEAEs were observed in 73.7% and 65.1% of pts. The most common grade ≥3 TEAEs in RCT-i pts were pneumonia (8.8%), cellulitis, neutropenia, and hypokalemia (all 7.0%). Among RCT-e pts the most common grade ≥3 TEAEs were diarrhea (12.0%), pneumonia, anemia, and fatigue (all 4.8%). TEAEs led to dose modification/discontinuation of any of the three study drugs in the IRd regimen in 68.4%/21.1% of RCT-i pts and 65.1%/19.3% of RCT-e pts. Conclusions This subanalysis demonstrates the feasibility of utilizing iCT to obtain similar outcomes to RCTs in the community. Although 41% of US MM-6 pts would have been ineligible for RCTs, there were no notable differences in PFS, ORR, OS, and safety data between the two groups. These data show that iCT from V-based induction to IRd permits long-term, tolerable PI-based therapy translating into improved efficacy in community-treated pts with NDMM who are more representative of the wider MM population.

Network Meta-Analysis of Randomized Trials in Relapsed/Refractory Multiple Myeloma: Relative Efficacy for Patients Who Are Lenalidomide-Refractory

Background: Continuous lenalidomide in combination with dexamethasone (Rd), with bortezomib and dexamethasone (VRd) or, more recently, with daratumumab and dexamethasone (DRd) is the standard first-line (1L) therapy for transplant-ineligible multiple myeloma (MM) patients (pts). Lenalidomide maintenance is the standard therapy after ASCT. As a result, more pts with MM become LEN-refractory at relapse, representing a difficult-to-treat population with a high unmet need for effective treatments. Selinexor is a first-in-class, oral, XPO1 inhibitor indicated for use in combination with bortezomib and dexamethasone (SVd) in adults with relapsed and refractory (RR) MM who have received at least one prior line. Efficacy and safety of SVd were evaluated in the BOSTON phase 3 randomized controlled trial (RCT) comparing SVd to bortezomib + dexamethasone (Vd). Extended follow-up of the BOSTON trial showed a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) with SVd vs Vd for the LEN-refractory subgroup (Mateos et al, EHA 2023). In the absence of head-to-head trials comparing SVd with other approved regimens in LEN-refractory subgroups, a network meta-analysis (NMA) was performed to evaluate the relative efficacy (PFS and OS) of SVd vs other treatment options in LEN-refractory pts. Methods: A systematic literature review (SLR) was conducted to identify the clinical efficacy and safety evidence of the approved treatments in Europe for RR MM. Searches were performed in Medline, Embase, Cochrane, and CRD up to February 2023. Following a feasibility assessment, the RCTs reporting PFS and/or OS hazard ratios (HRs) in the LEN-refractory subgroup were summarized in separate PFS and OS networks. Because these networks were disconnected, a two-step approach was implemented, beginning with a matching-adjusted indirect comparison (MAIC) followed by a random-effects Bayesian NMA. Based on clinical input, different prognostic factors and treatment effect modifiers were considered for the matching process in the MAIC: median age, sex, ECOG performance status, Revised-International Staging System, high-risk cytogenetics, prior ASCT, number of prior regimens, and median time since diagnosis. Results: Twelve RCTs (APOLLO, ASPIRE, BOSTON, CANDOR, CASTOR, ENDEAVOR, ELOQUENT-3, ICARIA-MM, IKEMA, MM-002, MM-003, and OPTIMISMM) were identified in the SLR reporting PFS and/or OS results for LEN-refractory pts. Three and two disconnected networks were formed for PFS and OS, respectively, which were linked through a MAIC by matching Vd pts in the BOSTON trial with the pomalidomide + dexamethasone (Pd) population of the MM-002 trial. Anti-CD38-based regimens approved in 2L+ RR MM, ie, daratumumab + Vd (DVd), daratumumab + carfilzomib + dexamethasone (DKd), and isatuximab + Kd (IKd) report the lowest PFS HRs vs Vd for LEN-refractory pts. SVd had the lowest PFS HR vs Vd (0.52, 95% CI 0.23-1.21) compared with the remaining comparators in the network. This includes SVd's direct comparators in the post-DRd population as per current ESMO MM guidelines: PFS HR of Kd vs Vd is 0.80 (95% CI 0.39-1.73) and PFS HR of pomalidomide + bortezomib + dexamethasone (PVd) vs Vd is 0.66 (95% CI 0.32-1.34), Figure 1. In the OS network, among the regimens included (with DKd, DVd and IKd excluded due to the lack of OS data on LEN-refractory pts), SVd also had the lowest OS HR vs Vd (0.53, 95% CI 0.22-1.28) compared with the other regimens, including Kd (HR vs Vd: 0.86, 95% CI 0.41-1.77), Figure 2. Conclusion: This is the first two-step approach NMA linking the disconnected networks of treatments available for LEN-refractory pts using efficacy results for this subgroup from their respective RCTs. Excluding anti-CD38-based regimens, which are unlikely to be used in a 2L+ setting with DRd increasingly prescribed in 1L, SVd is the most efficacious treatment option for LEN-refractory pts among commonly used combinations such as PVd, Kd, and pomalidomide-based regimens, with a reduction of 48% in the risk of progression vs Vd. Moreover, among the regimens included in the OS network, SVd had the largest OS improvement vs Vd. We hypothesize the substantial reduction for LEN-refractory pts in the risk of progression and death of SVd vs Vd compared to most of the regimens included in the NMA is due to the two different mechanisms of action with SVd.

Update on the Management of Stage III NSCLC: Navigating a Complex and Heterogeneous Stage of Disease.

Stage III nonsmall cell lung cancer (NSCLC) represents a heterogeneous group of patients. Many patients are treated with curative intent multimodality therapy, either surgical resection plus systemic therapy or chemoradiation plus immunotherapy. However, many patients are not suitable for curative intent therapy and are treated with palliative systemic therapy or best supportive care. This paper is a review of recent advances in the management of patients with curative intent disease. There have been significant advances in curative intent therapy for patients with stage III NSCLC in recent years. These include both adjuvant and neoadjuvant systemic therapies. For patients with resectable NSCLC, two trials have demonstrated that adjuvant atezolizumab or pembrolizumab, following chemotherapy, significantly improved disease-free survival (DFS). In patients with tumours harbouring a common mutation of the EGFR gene, adjuvant osimertinib therapy was associated with a large improvement in both DFS and overall survival (OS). Five randomized trials have evaluated chemotherapy plus nivolumab, pembrolizumab, durvalumab, or toripalimab, either as neoadjuvant or perioperative (neoadjuvant plus adjuvant) therapy. All five trials show significant improvements in the rate of pathologic complete response (pCR) and event-free survival (EFS). OS data are currently immature. This would now be considered the standard of care for resectable stage III NSCLC. The addition of durvalumab to chemoradiation has also become the standard of care in unresectable stage III NSCLC. One year of consolidation durvalumab following concurrent chemoradiation has demonstrated significant improvements in both progression-free and overall survival. Immune checkpoint inhibitor (ICI) therapy has become a standard recommendation in curative intent therapy for stage III NSCLC.

Characteristics of clinician input in Canadian funding decisions for cancer drugs: a cross-sectional study based on CADTH reimbursement recommendations

ObjectiveTo examine characteristics of clinician input to the pan-Canadian Oncology Drug Review (pCODR) for cancer drug funding recommendations from 2016 to 2020.Design, setting and participantsDescriptive, cross-sectional study including 62 reimbursement...

Timing and Reporting of Secondary Overall Survival End Points for Phase III Trials in Advanced/Metastatic Disease.

Recent therapeutic advances have led to improved patient survival in many cancer settings. Although prolongation of survival remains the ultimate goal of cancer treatment, the availability of effective salvage therapies could make definitive phase III trials with primary overall survival (OS) end points difficult to complete in a timely manner. Therefore, to accelerate development of new therapies, many phase III trials of new cancer therapies are now designed with intermediate primary end points (eg, progression-free survival in the metastatic setting) with OS designated as a secondary end point. We review recently published phase III trials and assess contemporary practices for designing and reporting OS as a secondary end point. We then provide design and reporting recommendations for trials with OS as a secondary end point to safeguard OS data integrity and optimize access to the OS data for patient, clinician, and public-health stakeholders.

Dalpiciclib and pyrotinib in women with HER2-positive advanced breast cancer: a single-arm phase II trial

CDK4/6 inhibitors have shown a synergistic effect with anti-HER2 therapy in hormone receptor (HR)-positive and HER2-positive breast cancer (BC). In this phase 2 study (NCT04293276), we aim to evaluate a dual-oral regimen of CDK4/6 inhibitor dalpiciclib combined with HER2 tyrosine kinase inhibitor pyrotinib as front-line treatment in women with HER2-positive advanced BC (n = 41) including those with HR-negative disease. The primary endpoint is the objective response rate, and secondary endpoints include progression-free survival (PFS), overall survival (OS), and safety. With a median follow-up of 25.9 months, 70% (28/40) of assessable patients have a confirmed objective response, meeting the primary endpoint. The median PFS is 11.0 months (95% CI = 7.3–19.3), and OS data are not mature. The most common grade 3 or 4 treatment-related adverse events (AEs) are decreased white blood cell count (68.3%), decreased neutrophil count (65.9%), and diarrhea (22.0%). Most AEs are manageable, and no treatment-related deaths occur. These findings suggest that this combination may have promising activity and manageable toxicity. Further investigation is needed.