Median TTNT Research Articles

Real-world (rw) treatment (tx) patterns and clinical outcomes among patients (pts) with metastatic urothelial carcinoma (mUC) receiving first-line (1L) systemic tx and avelumab 1L maintenance (1LM): Results from the IMPACT UC-III study.

390 Background: Avelumab 1LM is a standard of care for pts with mUC that has not progressed after 1L platinum-based chemotherapy (PBC). Immuno-oncology (IO) monotherapy is considered in pts with mUC who are ineligible to receive PBC. Recently approved 1L tx options include enfortumab vedotin + pembrolizumab and nivolumab + gemcitabine/cisplatin. This US retrospective study examined pt characteristics, tx patterns, and clinical outcomes among pts with mUC receiving 1L tx, including avelumab 1LM. Methods: Pts with mUC (bladder cancer; stage IIIB or IV, or ≥2 claims with ICD-10 diagnoses for metastatic cancer) aged ≥18 years, who initiated 1L tx (index date) from Jan 1, 2020 to Jul 31, 2023, were identified from the Healthcare Integrated Research Database (HIRD®; claims and clinical data from the health plan’s Cancer Care Quality Program). Clinical outcomes, including time to next tx (TTNT; time from 1L tx initiation to second-line tx) and overall survival (OS), were evaluated post index date. Pt characteristics and tx patterns were summarized using descriptive statistics. Avelumab 1LM use was identified on/after June 30, 2020 and ≤90 d after 1L PBC discontinuation. OS from the start of 1L tx or 1LM was analyzed using Kaplan-Meier methodology. Results: Of 2,820 pts with mUC, 1L tx was PBC in 37.0% (n=1,044), IO monotherapy in 39.0% (n=1,099), and other tx in 24.0% (n=677; antibody-drug conjugates and non-PBC). Among pts who received 1L PBC, 15.0% (n=157) initiated avelumab 1LM within 90 days of completing 1L PBC. Avelumab uptake in 2020-2023 by year was 10.8% (Jun-Dec 2020), 29.9%, 34.4%, and 24.8% (Jan-Aug 2023), respectively; 38.9% of pts were still receiving avelumab at the end of the study period. In the 1L PBC and IO cohorts, mean age (SD) was 65.5 (11.1) and 74.6 (10.7) years, respectively. 60% of pts were male. In the 1L PBC and 1L IO monotherapy cohorts, respectively, median follow-up (IQR) was 11.2 (5.6-20.3) and 8.6 (4.0-17.7) months (mo); median TTNT (IQR) was 4.8 (2.8-8.3) and 5.5 (2.8-11.0) mo; and median OS (95% CI) was 29.7 (25.1-37.2) and 20.0 (17.1-25.6) mo. In pts who received avelumab 1LM, median follow-up (IQR) from start of 1L PBC was 14.6 (9.2-21.3) mo; median TTNT (IQR) was 7.6 (6.2-12.3) mo; median time on avelumab tx was 5.0 (1.8-10.2) mo; and 1- and 2-year OS rates, respectively, from start of avelumab 1LM were 78% and 65%, and from start of 1L PBC were 84% and 68% (median OS was not estimable because >50% of pts remained alive at the end of the study period). Conclusions: Despite advances in 1L tx for mUC, IO monotherapy remains a prevailing option for older, commercially insured patients in the US. In this descriptive rw study, pts treated with 1L PBC had longer OS than pts treated with 1L IO monotherapy. Future studies with longer follow-up are needed to further evaluate pt outcomes.

Baseline 18F-FDG PET/CT may contribute to the determination of initial treatment strategy for newly diagnosed follicular lymphoma

Background“Watch-and-wait” approach is an important management option in asymptomatic follicular lymphoma (FL) patients with low tumor burden. Since most FL lesions are FDG-avid, we wonder if 18F-FDG PET/CT at baseline can help to better choose the patients who can benefit from early chemotherapy. This study aimed to investigate the prognostic value of baseline 18F-FDG PET/CT in newly diagnosed FL patients treated with either watch-and-wait approach or chemotherapy. ResultsPatients received chemotherapy as initial treatment had higher Ann Arbor stage, higher incidence of extranodal involvement and bulky disease, more involved lymph nodes larger than 3 cm, and higher SUVmax, MTV, and TLG than those managed with watch-and-wait approach (p < 0.05). The median PFS and TTNT in patients received chemotherapy and under watch-and-wait did not show significant difference, however patients with MTV<111.66 mL or TLG<141.50 SUVbw*mL had significantly longer PFS and TTNT than those patients with MTV≥111.66 mL or TLG≥141.50 SUVbw*mL (p < 0.05). Further analysis revealed that for patients with TLG≥141.50 SUVbw*mL or MTV≥111.66 mL, those who received chemotherapy as initial treatment had a significantly longer PFS and TTNT than those managed with initial watch-and-wait approach (p < 0.05). However, for patients with MTV<111.66 mL or TLG<141.50 SUVbw*mL in baseline PET/CT, there was no significant difference in PFS or TTNT between patients who received chemotherapy and those under watch-and-wait. ConclusionBaseline 18F-FDG PET/CT may provide prognostic value and help to improve the decision-making of initial treatment plans for newly diagnosed FL patients.

Real-world data comparison of time to next treatment for patients with HER2 low metastatic treated with either chemotherapy or fam-trastuzumab deruxtecan-nxki following chemotherapy in the metastatic setting.

e13169 Background: In the Destiny-04 trial, pts who received TDxd following chemo in the metastatic setting experienced 10.1 months of progression-free survival compared to 5.4 months for pts who received chemo. We sought to evaluate the TTNT, a surrogate for progression-free survival, and OS using real-world data to assess whether such pts see similar benefits beyond the clinical trial setting. Methods: We used the Integra Connect PrecisionQ real-world de-identified database of over 3 million cancer pts across 500 sites of care to identify 252 breast cancer pts for the analysis. Pts were identified as HER2 low (IHC of 1+ or an IHC of 2+ with an ISH/FISH negative result) at the time of treatment initiation following the chemo in the metastatic setting, and each started treatment on or after June 1, 2022, through December 31, 2023. The first treatment following chemo in the metastatic setting was used for comparison. TTNT was measured from the treatment start to either the initiation of a subsequent line of therapy or death. Descriptive analyses were used, proportions were compared using a chi-squared test, and TTNT and OS were analyzed using a Kaplan-Meier analysis. Results: Median (IQR) age was 56 (47.5, 66). 100% of the pts were female; 108 (42.9%) received TDxd with a median (IQR) age of 65.5 at treatment start, and 144 (57.1%) received chemo (most commonly paclitaxel, capecitabine, carboplatin, gemcitabine) with a median (IQR) age of 64 (54, 74) at treatment. TDxd pts had higher ECOG scores (p&lt;0.05) and higher rates of lung (p&lt;0.05) and bone (p&lt;0.05) metastases. Median TTNT was 9.0 months (95% confidence interval [CI], 7.9 to 11.1) for pts who received TDxd compared to 5.4 months (95% CI, 4.6 to 6.0) for pts who received chemo ( p&lt;0.01). Median OS was not reached (NR) in TDxd pts (95% CI, 13.0 to NR) whereas it was 13.1 months (95% CI, 10.8 to NR) in the pts treated with chemo ( p&lt;0.01). The percent of TDxd pts who were deceased was 22.2% compared to 34.7% for chemo treated pts. The probability of pts on therapy after 6 months was 72.8% (95% CI, 62.3% to 80.8%) for those who received TDxd compared to 38.0% (95% CI, 28.9% to 17.1%) for those who received chemo ( p&lt;0.01). The probability of pts on therapy after 12 months was 31.4% (95% CI, 19.7% to 43.8%) for those who received TDxd compared to 17.1% (95% CI, 9.7% to 26.3%) for those who received chemo ( p&lt;0.05). Conclusions: The real-world comparison of TDxd to chemo in the metastatic setting for pts with HER2low breast cancer demonstrated a statistically significant difference in both OS and TTNT, reaffirming the results of the Destiny-04 trial. However, 57% of pts were found to not have received TDxd, suggestingan opportunity to improve outcomes in HER2low breast cancer pts.

Extraction of Unstructured Electronic Health Records to Evaluate Glioblastoma Treatment Patterns.

Data on lines of therapy (LOTs) for cancer treatment are important for clinical oncology research, but LOTs are not explicitly recorded in electronic health records (EHRs). We present an efficient approach for clinical data abstraction and a flexible algorithm to derive LOTs from EHR-based medication data on patients with glioblastoma multiforme (GBM). Nonclinicians were trained to abstract the diagnosis of GBM from EHRs, and their accuracy was compared with abstraction performed by clinicians. The resulting data were used to build a cohort of patients with confirmed GBM diagnosis. An algorithm was developed to derive LOTs using structured medication data, accounting for the addition and discontinuation of therapies and drug class. Descriptive statistics were calculated and time-to-next-treatment (TTNT) analysis was performed using the Kaplan-Meier method. Treating clinicians as the gold standard, nonclinicians abstracted GBM diagnosis with a sensitivity of 0.98, specificity 1.00, positive predictive value 1.00, and negative predictive value 0.90, suggesting that nonclinician abstraction of GBM diagnosis was comparable with clinician abstraction. Of 693 patients with a confirmed diagnosis of GBM, 246 patients contained structured information about the types of medications received. Of them, 165 (67.1%) received a first-line therapy (1L) of temozolomide, and the median TTNT from the start of 1L was 179 days. We described a workflow for extracting diagnosis of GBM and LOT from EHR data that combines nonclinician abstraction with algorithmic processing, demonstrating comparable accuracy with clinician abstraction and highlighting the potential for scalable and efficient EHR-based oncology research.

Daratumumab-based regimens for patients with multiple myeloma plus extramedullary plasmacytomas or paraskeletal plasmacytomas: initial follow-up of an Italian multicenter observational clinical experience.

Myeloma with extramedullary plasmacytomas not adjacent to bone (EMP) is associated with an extremely poor outcome compared with paraosseous plasmacytomas (PP) as current therapeutic approaches are unsatisfactory. The role of new molecules and in particular of monoclonal antibodies is under investigation. To determine whether daratumumab-based regimens are effective for myeloma with EMP, we report herein an initial multicenter observational analysis of 102 myeloma patients with EMP (n = 10) and PP (n = 25) at diagnosis and EMP (n = 28) and PP (n = 39) at relapse, treated with daratumumab-based regimens at 11 Haematological Centers in Italy.EMP and PP at diagnosis were associated with higher biochemical (90% vs. 96%, respectively) and instrumental ORR (86% vs. 83.3%, respectively), while at relapse, biochemical (74% vs. 73%) and instrumental (53% vs. 59%) ORR were lower. Median OS was inferior in EMP patients compared with patients with PP both at diagnosis (21.0 months vs. NR) (p = 0.005) and at relapse (32.0 vs. 40.0 months) (p = 0.428), although, during relapse, there was no statistically significant difference between the two groups. Surprisingly, at diagnosis, median TTP and median TTNT were not reached either in EMP patients or PP patients and during relapse there were no statistically significant differences in terms of median TTP (20 months for two groups), and median TTNT (24 months for PP patients vs. 22 months for EMP patients) between the two groups. Median TTR was 1 month in all populations.These promising results were documented even in the absence of local radiotherapy and in transplant-ineligible patients.

Abstract 3817: Real-world clinical outcomes in patients with advanced ROS1+non-small cell lung cancer in the US

Abstract Introduction: ROS1 rearrangements define a rare molecular subtype of non-small cell lung cancer (NSCLC), occurring in 1-2% of patients (pts) with advanced NSCLC (aNSCLC). Crizotinib and entrectinib received US approval for ROS1+ aNSCLC in March 2016 and August 2019, respectively. Few studies have addressed temporal trends in first-line (1L) utilization since these drugs’ approval. This study describes treatment patterns and clinical outcomes in pts with ROS1+ aNSCLC in the US. Methods: This retrospective study used the nationwide Flatiron Health (FH) electronic health record-derived de-identified database and included adult pts with ROS1+ aNSCLC who received 1L (index) therapy between March 2015 and December 2022. Pts were followed until March 31, 2023, and had ≥ 3 months of follow-up post-index date. Treatment-related (sequence, time to treatment discontinuation [TTD], time to next treatment [TTNT]) and clinical (real-world progression-free survival [rwPFS], overall survival [OS]) outcomes of 1L therapy were assessed using descriptive statistics and Kaplan-Meier methods. Results: In the FH database, 87,784 pts had aNSCLC, and 242 were ROS1+. The median age was 65 years; most were female (64%), White (67%), non-squamous (91%) and had a history of smoking (52%), with most pts having ECOG performance status 0 (31%) or 1 (35%). 19% had brain metastases prior to or up to 30 days post-index. Median follow-up time was 14.2 months. In 1L treatment, only 59% received ROS1-sensitive TKI monotherapy (i.e. crizotinib, entrectinib, ceritinib), with 97 (40%) and 40 (17%) treated with crizotinib and entrectinib monotherapy, respectively. Median TTD and TTNT for 1L was 6.4 (95% CI: 5.0, 7.6) and 7.6 (95% CI: 6.5, 9.4) months, respectively. Among 1L crizotinib pts, 51% had 2L treatments and 57% of those initiated another ROS1-sensitive TKI (16% entrectinib). Among 1L entrectinib pts, 43% had 2L therapy; of these, 82% initiated another ROS1-sensitive TKI. Median rwPFS was 7.5 (95% CI: 6.2, 9.3) months (1L crizotinib, 8.6 [95% CI: 5.3, 13.0] months; 1L entrectinib, 8.0 [95% CI: 5.3, 13.6] months). Median OS was 29.0 (95% CI: 19.4, 35.9) months (1L crizotinib, 31 [95% CI: 19.4, not estimable [NE]] months; 1L entrectinib, NE). Patients initiated ROS1-sensitive TKIs (crizotinib, entrectinib or ceritinib) in 1L across each year of the study (2015: 67%, 2016: 58%, 2017: 51%, 2018: 47%, 2019: 63%, 2020: 81%, 2021: 52%, 2022: 68%). Overall, 5% received checkpoint-inhibitor (CPI) only, 17% chemotherapy alone, and 7% a chemotherapy/CPI combination. Conclusion: Compared to relevant clinical trials, ROS1+ aNSCLC pts in this real-world study were older, had greater smoking exposure, and worse overall survival. Only 59% of pts initiated 1L ROS1-sensitive TKI monotherapy. These results highlight potential disparities in the diagnosis and treatment of ROS1+ NSCLC and opportunities for improving clinical outcomes. Citation Format: Reginald Villacorta, Saurabh Ray, Yong Yuan, Sushupta Vijapur, Sonia Kim, Haiyan Sun, Sky Myers, Vincent Lam. Real-world clinical outcomes in patients with advanced ROS1+non-small cell lung cancer in the US [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3817.

Abstract A081: Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada

Abstract Background: Real-world data on treatment patterns and prevalence of brain metastases in patients with HER2+ metastatic breast cancer (mBC) are limited. This study described treatment patterns and clinical outcomes among patients with HER2+ mBC in Canada. Methods: This was a retrospective chart review of adult patients diagnosed with de-novo or recurrent HER2+ mBC between Jan 1, 2014 and Mar 1, 2021 (prior to wide availability of new treatments) at Sunnybrook Research Institute and Sinai Health, two large BC treatment centres in Canada. Data on patient characteristics and treatment regimens were extracted. Treatment patterns, time to next treatment (TTNT; as a proxy for progression-free survival), and presence of brain metastases were assessed in the first-line (1L), second-line (2L), and third-line (3L) settings. TTNT analyses used Kaplan-Meier methodology to account for censoring. Results: Of 121 patients with HER2+ mBC, the median (IQR) age was 54.0 (17.0) years. 38.0% of patients had de-novo disease and 62.0% had recurrent mBC; 12 (9.9%) had brain metastases at the time of mBC diagnosis. Systemic therapies generally aligned with Canadian funded regimens for 1L (101 of 121 patients [83.5%] received trastuzumab + pertuzumab ± chemotherapy ± subsequent endocrine therapy; 8/121 [6.6%] received endocrine therapy only) and 2L (50/68 [73.5%] received T-DM1 ± endocrine therapy; 9/68 [13.2%] received endocrine therapy only). However, treatment patterns were heterogeneous in the 3L setting (14/46 [30.4%] received anti-HER2 TKI + chemotherapy ± trastuzumab; 10/46 [21.7%] received endocrine therapy only; 10/46 [21.7%] received chemotherapy). Median (95% CI) TTNT in months was 21.4 (16.1, 27.2) in 1L, 11.0 (8.5, 16.5) in 2L, and 8.7 (5.4, 15.6) in 3L. Median (IQR) follow-up was 29.9 (25.2) months. In total, 57 patients (47.1%) were diagnosed with brain metastases during the study period (17 pre-1L, 24 post-1L/pre-2L, 6 post-2L/pre-3L) and of these, 73.7% received radiation therapy. Conclusions: In patients with HER2+ mBC in Canada, 3L treatment patterns are heterogeneous, median TTNT is &amp;lt;1 year, and almost half develop brain metastases. These data from two large treating centres in Ontario suggest a high unmet need for more effective treatment regimens in later lines of therapy, particularly 3L, for patients with HER2+ mBC. Citation Format: Katarzyna J Jerzak, Ruth Moulson, Ling-I Hsu, Chris Lenhu, Dhivo Krishnathasan, Jessica Weiss, Christine Brezden-Masley. Real-world treatment patterns and clinical outcomes in patients with HER2+ metastatic breast cancer receiving systemic therapy in Ontario, Canada [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A081.

Development and validation of a tumor tissue based multivariate biomarker for predicting angiogenesis inhibitor clinical benefit in renal cell carcinoma (RCC).

467 Background: Angiogenesis inhibitors, including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs), are standard of care therapy (alone and in combination) for several advanced cancers, including RCC. There is an unmet need for a biomarker to identify patients with RCC most likely to benefit from VEGFR TKIs to guide individualized treatment decision making. Hence, we sought to develop and validate a biomarker for predicting single-agent systemic VEGFR TKI benefit in patients with RCC. Methods: Candidate biomarkers were selected by co-expression patterns in VEGFR TKI sensitive/resistant tumor types from pan-solid tumor TCGA expression profiling data and the literature. The angiogenesis inhibitor treatment response score (Angio TRS) was developed as a multivariate expression-based algorithm from RNA-based quantitative transcriptional profiling (qTP) performed in parallel with clinical FFPE tumor based comprehensive genomic profiling, with the Angio TRS High/Low threshold set at the median of clear cell RCC samples. The locked Angio TRS (and High/Low status) was then validated in a cohort of adult RCC patients treated with a systemic line of single agent VEGFR TKI therapy within a prospective observational trial; group outcomes (by time to next therapy [TTNT]) were compared by univariate analysis, Cox proportional hazards modeling (adjusting for age, biologic sex, histology, nuclear grade [incorporating sarcomatoid features], therapy line, and TKI type), and unadjusted Kaplan Meier analysis. Laboratory information for IMDC risk group status was not available. Results: Across 3,721 solid tumor tissue samples, median Angio TRS was highest in known VEGFR TKI sensitive tumors (RCC, thyroid carcinoma, sarcoma). Angio TRS was then validated in a separate cohort of 86 patients with RCC treated with single agent systemic VEGFR TKI (median follow-up 29.2 months; 76% male, 77% clear cell, 14% with sarcomatoid features, 84% 1st line, and 71% treated with sunitinib, pazopanib or axitinib); 52% of patients were Angio TRS High. By univariate analysis, Angio TRS status (p=0.008) and nuclear grade 4 (with or without sarcomatoid features; p=0.06 &amp; 0.07) were most significantly associated with VEGFR TKI TTNT; by multivariate analysis, only Angio TRS status was significantly associated with TTNT (High vs. Low median TTNT 15.8 vs. 5.6 months, adjusted hazard ratio 0.46, p=0.012). Conclusions: Angio TRS is a multivariate expression-based algorithm performed on FFPE tumor tissue, validated to be prognostic of clinical outcome for patients with RCC treated with single agent VEGFR TKI when controlling for clinical factors. Angio TRS may support individualized treatment decision making in patients with advanced RCC. Additional independent validation in a cohort of Kaiser Permanente patients will be presented. Clinical trial information: NCT03061305 .

Real-world overall survival and time to next treatment in patients with metastatic pancreatic ductal adenocarcinoma who received FOLFIRINOX and modified FOLFIRINOX in the first line.

629 Background: FOLFIRINOX (FFX) is a recommended first line (1L) treatment option for patients (pts) with mPDAC but is known for its high toxicity. Efforts to balance pts’ quality of life (QoL) during treatment with treatment effectiveness have led to the use of modified FOLFIRNOX (mFFX) regimens that employ decreased doses of FFX components. Further evidence is needed to assess OS and progression-free survival (PFS) among pts who receive FFX or mFFX treatment in the real world compared to the trial setting. We identified a real-world (RW) sample of pts with mPDAC treated with FFX and mFFX in 1L and assessed their OS, and, as a RW proxy for PFS, TTNT. Methods: This retrospective observational study utilized the Flatiron Metastatic Pancreatic Cancer Enhanced Data Mart. Adult pts diagnosed with mPDAC between January 2014 and May 2022 who initiated treatment with FFX or mFFX in 1L within 90 days of their diagnosis for metastatic disease were included in the study. mFFX was defined as administration of &lt;150mg/m2 of irinotecan or &lt;2,720mg/m2 5-FU total (bolus+infusion) during cycle 1; doses greater than these were considered FFX. TTNT was defined as duration between 1L treatment initiation and the start of second line therapy or death. Kaplan-Meier analyses were used to assess median OS and TTNT from the start of 1L FFX or mFFX treatment and log-rank tests for the statistical significance of differences in OS and TTNT. Results: 2,212 mPDAC pts met the study inclusion criteria, with 507 pts (23%) receiving FFX and 1,705 pts (77%) receiving mFFX in 1L. For FFX vs. mFFX, the median age at 1L initiation was 63yr vs. 65yr, 72% vs. 56% were male, 67% vs. 63% were white, 36% vs. 30% had an ECOG score of 0, 31% vs. 32% had an ECOG score of 1, and 83% vs. 81% received treatment at community oncology centers. For FFX vs. mFFX, median OS was 9.5 (95% CI: 8.9–10.7) vs. 9.0 months (95% CI: 8.4–9.7) (p=.452) and median TTNT was 4.8 (95% CI: 4.5–5.5) vs. 4.8 months (95% CI: 4.5–5.2) (p=.256). Conclusions: In a RW sample of 2,212 pts receiving 1L FFX and mFFX at primarily community oncology practices in the United States from 2014–2022, more than three-quarters received mFFX. Pts experienced similar median OS and TTNT across the two regimens, indicating that full-strength FFX may provide little benefit to OS in exchange for its increased toxicity. In the PRODIGE 4/ACCORD 11 trial of unmodified FFX, conducted earlier (2005–2009) among a group of 342 French pts, median OS was 11.1 months (95% CI: 9.0–13.1) and median PFS was 6.4 months (95% CI: 5.5–7.2). The median RW OS of FFX and mFFX pts in our study was numerically lower than the trial, as was RW TTNT compared with trial PFS. Future research should seek to understand the factors driving differences in RW and clinical trial outcomes as well as to assess the tradeoff between regimen toxicity and survival benefit.

Real-World Outcomes Among 2L+ Patients with Chronic Lymphocytic Leukemia (CLL) By Line of Therapy (LOT)

Introduction: The chronic lymphocytic leukemia (CLL) treatment landscape is rapidly evolving, and real-world (rw) outcomes of patients receiving 2L+ therapy in the current treatment paradigm are incompletely understood. This study examined the rw outcomes of patients with CLL/ small lymphocytic lymphoma (SLL) receiving 2 or more lines of therapy (LOTs) using a large, contemporary rw dataset. Methods: Patients meeting the study criteria were identified in the COTA real-world, clinical database: Aged ≥ 18 years at diagnosis with CLL/SLL who initiated 2L therapy between January 1, 2014 and June 30, 2021. The initial index date for the study was the date of 2L initiation and was updated to the start of each subsequent LOT for LOT-specific analyses. The following time to event outcomes were evaluated for the study population and by LOT using the Kaplan-Meier method: time to next treatment (TTNT: time from index to the initiation of the next LOT or death), time to treatment discontinuation (TTD: time from index to treatment discontinuation for any reason, including end of therapy as prescribed/indicated), rw duration of response (rwDOR: time from the first clinician-documented CR or PR to the first assessment of progressive disease or the initiation of next LOT among responders), rw progression-free survival (rwPFS), and rw overall survival (rwOS). For all time-to-event endpoints, patients were censored at the date of last visit. Rw overall response rate (rwORR) was the proportion of patients who had a clinician-documented PR or CR as the best response to a LOT among all patients who received that LOT. Results: A population of 1,102 patients was identified from the COTA database meeting the study criteria. Key patient and clinical characteristics included: median age at diagnosis of 64 years, 60.9% male, 88.1% treated in a community setting, 74.1% diagnosed in 2014 or earlier, 9.3% positive for TP53 mutation (55.0% unknown), and 7.8% with del(17p) mutation (66.2% unknown). Median TTNT among patients who received 2L (n=1102) was 29.3 months (95% CI: 27.3, 32.6), and median DOR to 2L (n=863) was 31.9 months (95% CI: 27.5, 36.4). Generally, median TTNT and DOR decreased across LOT 2-4. Median TTNT from 3L (n=468) and 4L (n=201) initiation were 21.4 (95% CI: 18.2, 25.1) and 15.1 months (95% CI: 11.5, 20.2), respectively, and median DOR among 3L (n=333) and 4L (n=130) responders were 22.6 (95% CI: 18.3, 26.2) and 15.1 months (95% CI: 11.7, 22.9), respectively. More than three-quarters (78.3%) of 2L patients experienced a physician-documented CR or PR, and rwORR decreased over subsequent LOTs (71.2% in 3L and 64.7% in 4L). Median TTD varied by treatment type. Patients who received continuous therapy with Bruton's Tyrosine Kinase inhibitors (BTKis) experienced longer median TTD, while patients who received fixed-duration therapies experienced shorter median TTD. Median TTD among patients who received ibrutinib (n=391), acalabrutinib (n=54), or venetoclax + rituximab (n=48) in 2L was 24.8, 32.6, or 23.5 months, respectively, while median TTD among patients who received BR (n=194) or rituximab monotherapy (n=67) was 4.0 or 0.9 months, respectively. Finally, median rwPFS and rwOS decreased by LOT for patients who received 2L-4L. Median rwPFS for 2L, 3L, and 4L were 31.4 (95% CI: 28.6, 35.5), 22.8 (95% CI: 19.1, 26.4), and 16.5 (95% CI: 13.6, 22.6) months, respectively, and median rwOS were 79.0 (95% CI: 68.9, 85.3), 56.3 (95% CI: 51.6, 64.5), and 51.9 months (95% CI: 33.8, Not Reached), respectively. Conclusions: In this real-world, contemporary database analysis, median TTNT and DOR exceeded 2 years among 2L patients. Although the adoption of novel therapies has changed the CLL/SLL treatment paradigm and patients who received 2L BTKi therapy experienced numerically greater TTD relative to those who received other treatment types, patients with relapsed/refractory (R/R) disease continue to experience poor rwPFS and rwOS relative to patients in clinical trials. This study demonstrates the continued unmet need for this rw patient population and highlights the need for continued innovation, namely new therapeutic agents leveraging novel mechanisms of action, to improve rw outcomes for patients with R/R CLL/SLL.

Age-Based Comparison of Dara-Rvd, Krd and Rvd Induction Therapies during the First Line of Therapy for Multiple Myeloma Patients

Background Since the development of proteasome inhibitors, the combination of lenalidomide (R), bortezomib (V), and dexamethasone (d) for induction has been the standard of care when treating patients with multiple myeloma. This combination has been shown to improve the clinical outcomes and quality of life of multiple myeloma patients. More recently, new generations of proteasome inhibitors, such as carfilzomib (K), and the development of monoclonal antibodies have created new opportunities for treatment that provide better outcomes with fewer side effects. The addition of daratumumab (Dara) to the RVd induction therapy has shown more potent results, increasing response rates and outcomes. However, there is a lack of evidence about the influence that age may have on the efficacy of these therapies. Methodology Using HealthTree Cure Hub for Multiple Myeloma (PMID: 35271305), we analyzed real-world data from 1100 patients with multiple myeloma. Patients were categorized into two groups based on age (&amp;lt;65 and ≥65). We compared ‘Time to Next Treatment’ (TTNT) among patients who received DaraRVd, KRd, or RVd as induction therapy. The analysis was conducted using Kaplan-Meier curves in R. Age groups were also subclassified by high-risk cytogenetics according to mSMART staging by fluorescence in situ hybridization (FISH), and the Revised International Staging System (R-ISS) stage. Chi-square tests were used to assess the association with R-ISS and mSMART stages. Results We analyzed the data of 1100 patients with MM, of which 718 patients (65.3%) were age &amp;lt;65 and 382 patients (34.7%) were age ≥65. The &amp;lt;65 group had a median age of 55±7, and the ≥65 group had a median age of 70±5. The majority of patients were female (n=586, 53.3%). The median year of diagnosis was 2018 (2009-2022). In the &amp;lt;65 group, the majority of patients were White (88%), and other big groups were Blacks (5.8%), and Hispanics or Latinos (2.6%). Similarly, in the ≥65 group, the majority of patients were White (93.0%), and other big groups were Blacks (3.3%), and Hispanics or Latinos (2%). In the &amp;lt;65 group, 55 patients had DRVd as induction therapy, 77 KRd, and 586 RVd. In the ≥65 group, 38 patients received DRVd as induction therapy, 39 KRd, and 305 RVd. R-ISS staging was available for 588 patients. In the &amp;lt;65 group, 139 patients (36.7%) were classified as R-ISS stage I, 170 patients (44.8%) stage II, and 70 patients (18.5%) stage III. In the ≥65 group, 75 patients (35.9%) were stage I, 104 patients (49.8%) were stage II, and 30 patients (14.3%) were stage III ( p=0.37). mSMART staging was available for 1035 patients, of whom patients with high-risk, double, and triple hit represented 16.2%, 5.0%, and 0.3%, respectively ( p = 0.35). Regarding stem cell transplant (SCT), 571 patients (51.9%) underwent SCT. In the &amp;lt;65 group, 404 patients (56.3%) received SCT; of those, 18 (32.7%) received DRVd, 21 (53.3%) KRd, and 345 (58.9%) RVd. In the ≥65 group, 167 patients (43.7%) received SCT; of those, 12 (31.6%) received DRVd, 23 (59%) KRd, and 132 (43.3%) RVd as induction therapy. For patients aged &amp;lt;65, the median TTNT was not yet reached for the DRVd group, 33 mo for the KRd group, and the RVd group was longer at 48 mo ( p=0.049). For patients aged ≥65, the median TTNT was not yet reached for the DRVd group, and 54 mo for the KRd group, which did not significantly differ from the RVd group, which had a median TTNT of 47 mo (p=0.52). Conclusion This study found that in the &amp;lt;65 age group, RVd induction therapy led to a longer TTNT compared to KRd, while in the ≥65 age group, KRd showed a longer TTNT than RVd. When considering the SCT usage rate, which increases TTNT by at least 12 months on average, KRd did not significantly improve outcomes over RVd in both age groups. However, when evaluating KRd induction, it's worth noting that KRd showed an improved outcome with a longer TTNT in the ≥65 age group compared to the &amp;lt;65 age group, despite toxicity concerns. These results align with the ENDURANCE trial, which also indicated that KRd did not significantly improve outcomes in standard-risk patients compared to VRd. Though the TTNT for the DRVd group is yet to be reached, the current trend suggests promising results for DRVd as a first-line therapy over KRd and RVd in both age groups. Nevertheless, further research is needed to validate and gain better insight into these observed trends.

Response to Subsequent Novel Therapies and Time to Second Progression-Free Survival Event in the MURANO Trial in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Previously Treated with Fixed-Dose Venetoclax Plus Rituximab

Background: The randomized Phase III MURANO trial (NCT02005471) assessed fixed-duration treatment with venetoclax (Ven) plus rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Despite improved clinical outcomes (progression-free survival [PFS], overall survival [OS] and time-to-next-treatment [TTNT], as well as minimal residual disease conversion and progressive disease [PD] association [Seymour et al. Blood 2022]) for pts randomized to VenR compared with bendamustine-R (BR), most pts will ultimately require subsequent therapies. However, the efficacy of subsequent treatment after relapse remains largely unexplored. This study was conducted prior to the widespread availability of other targeted therapies, so pts were not previously exposed to targeted therapies prior to MURANO treatment allocation. Here we report response rates to follow-up therapy with Ven-based regimens, or Bruton tyrosine kinase inhibitor (BTKi) therapy, as well as time to the second PFS events from the final analysis of the MURANO trial. Methods: Overall, 389 pts were randomized to VenR (2 years of Ven, with R for the first 6 months) or 6 months of BR. Pts in either arm with PD were followed for disease response to any subsequent anti-CLL therapeutic regimens, PFS and OS. A sub-study, introduced in 2018, allowed pts who developed PD following treatment with VenR or BR to receive the MURANO VenR regimen. Pts who initiated new anti-CLL therapy without a response assessment reported by the investigator, were considered unevaluable. Results : At the final clinical cutoff date of August 3, 2022, all pts had ceased study-specified treatment and the median follow-up of the main study was 85.7 (range: 0-99.2) months. PFS and OS benefits were maintained at the 7-year follow-up (Kater et al. EHA 2023). Overall, 73/194 (37.6%) pts in the VenR arm had not received a next-line therapy at the final cutoff, and 26 pts had died without subsequent therapy. Median TTNT or death with VenR was 63.0 months vs 24.0 months with BR (hazard ratio: 0.30). Following PD, 95/194 (49.0%) pts randomized to VenR and 131/195 (67.2%) pts randomized to BR had received subsequent anti-CLL therapy; the median (range) time off therapy in these pts was 28.3 months (-0.1-68.6) and 17.9 months (0.7-82.4), respectively. Of the 95 VenR pts receiving subsequent anti-CLL therapy, 30 (32.3%) received BTKi therapy (ibrutinib [n=25], acalabrutinib [n=4] and zanubrutinib [n=1]), with 18 ongoing at the time of the final cutoff; 47 (51.6%) received Ven-based therapy, with 12 ongoing at the time of the final cutoff; and 16 (17.2%) received chemoimmunotherapy (CIT). Two pts received a non-CLL therapy for another malignancy so were excluded from the subsequent analysis. Of the 131 BR pts receiving subsequent therapy, 79 (60.3%) received BTKi therapy (ibrutinib [n=69], acalabrutinib [n=6] and zanubrutinib [n=4]), with 20 ongoing at the time of the final cutoff; 17 (13.0%) received Ven-based therapy, with 3 ongoing at the time of the final cutoff; 24 (18.3%) received CIT; and 11 (8.4%) received other novel agents. Median time from randomization to second PFS event was 85.9 months (95% confidence interval [CI]: 81.8-88.2) in pts randomized to VenR and 48.4 months (95% CI: 44.5-56.6) in pts randomized to BR; p&amp;lt;0.0001 ( Figure). Best overall response (BOR; defined as complete remission [CR], CR with incomplete count recovery, partial remission [PR] and nodular PR) rates to first subsequent anti-CLL therapy for pts with evaluable responses were 75/93 (80.6%) for VenR and 85/107 (79.4%) for BR. Among evaluable pts previously treated with VenR and BR, the BOR rate to subsequent BTKi therapy was 19/22 (86.4%) and 51/65 (78.5%), respectively, while BOR rate to subsequent Ven-based therapies was 32/42 (76.2%) and 15/17 (88.2%), respectively. Conclusions: Final data from MURANO demonstrate that, despite the majority of BR pts receiving novel therapies after relapse on MURANO, there was a significantly prolonged time to second PFS event observed in favor of the VenR arm. Pts who had relapsed and received retreatment or crossed over to Ven-based regimens or subsequent BTKi therapy also demonstrated high response rates. These results indicate that early intervention with fixed-duration VenR in R/R CLL is an effective approach and does not compromise subsequent therapy response.

Deletion 1p at Time of Diagnosis of Multiple Myeloma Portends Inferior Outcomes

Background: Multiple myeloma (MM) is associated with several cytogenetic abnormalities (CA) that influence the disease course, response to treatment and survival. Trisomies and immunoglobulin H chain translocations are primary CA while del(17p), gain(1q), del(1p) and others are secondary CA. Gain (3 copies) and amplification (&amp;gt;3 copies) 1q have been recognized as adverse prognostic markers and incorporated into the second revision of the International Staging System (R2-ISS). However, the role of del(1p) is less well defined, especially in the era of modern myeloma therapeutics. We aimed to analyze the outcomes of newly diagnosed MM (NDMM) patients (pts) with chromosome 1 abnormalities, mainly del 1p, treated with autologous hematopoietic cell transplant (AHCT) consolidation at The Ohio State University. Methods: We identified and reviewed the medical records of all NDMM pts who were treated with AHCT from 1/1/2015-2/13/2019 (n=511). High-risk cytogenetics (HRC) was defined by the presence of del(17p), t(4;14), or t(14;16) similar to R-ISS; standard-risk cytogenetics (SRC) were defined as the absence of HRC. Modified HR cytogenetics (mHRC) included gain/amp 1q and/or t(14;20) in addition to HRC, while ultra high-risk (uHRC) included 2 or more mHRC risk factors. Results: The baseline pt characteristics are presented in Table 1. Of 511 pts transplanted, 453 had cytogenetic data from diagnosis. SRC were seen in 353 pts (77.9%), while 100 (22.1%) had HRC, 156 (34.4%) had mHRC, and 43 (9.5%) had uHRC. Thirty-two (7.1%) pts had del(1p) while 105 (23.2%) had gain 1q and 30 (6.6%) had amp 1q. As expected, compared to SRC pts, pts with HRC, mHRC and uHRC had higher risk of relapse or death. Patients with gain and amp 1q had inferior outcomes in terms of PFS (HR 1.35; 95% CI 1.06-1.73, p=0.016), TTNT (HR 1.84; 95% CI 1.40-2.42, p&amp;lt;0.001) and OS (HR 1.47; 95% CI 1.06-2.02, p=0.02), consistent with published literature. The median PFS, TTNT and OS from AHCT in pts with gain/amp 1q was 3.17 years (y), 3.95y and 7.13y, respectively, compared to 4.01y, 7.60y and 8.21y in pts without gain/amp 1q. Pts with del(1p) had inferior PFS (median 2.43y versus 3.98y; HR 1.75; 95% CI 1.16-2.64, p=0.008), TTNT (median 2.72y versus 6.17y; HR 1.96; 95% CI 1.22-3.14, p=0.005) and OS (median 4.11y versus 8.38y; HR 2.19; 95% CI 1.34-3.58, p=0.002) from AHCT compared to those without del(1p). (Figure 1). Conclusions: In this cohort of NDMM pts that underwent AHCT, del(1p) at diagnosis was an independent predictor of shorter PFS, TTNT and OS. Despite advances in induction regimens, AHCT consolidation and maintenance therapy, del(1p) continues to portend inferior outcomes. Larger analyses are needed to validate the prognostic value of del(1p) and investigate its role in predicting outcomes in MM.

Sterotactic Ablative Radiotherapy in a Multicentric Series of Oligometastatic SCLC: The SAMOS Cohort

AimsSCLC is the most aggressive lung cancer histology with a 5-year OS <10%. At the diagnosis, almost two-thirds of the SCLC an Extended Disease presentation. Two randomized studies (CASPIAN and ImPower133) demonstrated an OS improvement, when immunotherapy was prescribed as maintenance therapy after standard chemotherapy. To date, SABR has had a limited indication in managing metastatic SCLC, although recent reports proposed it as a valid treatment option in selected patients. We propose a retrospective multicentric analysis of patients treated with SABR for oligometastatic SCLC. MethodData of patients affected by oligometastatic-SCLC treated with SABR between 2017 and 2022 in 11 Italian centers were collected. Clinical and therapeutic variables together with OS and time to next treatment were analyzed. Univariate analysis with Kaplan–Meier curve were calculated, and log-rank test were applied. Cox proportional hazard model was used for multivariate analysis. ResultsData from 93 patients and 132 metastatic lesions were analyzed. The median age was 64 years (36-86) and all but 1 had Performance Status 0 or 1. Fifty-two patients presented ED at diagnosis. The first line treatment was radiochemotherapy in 42%, CHT alone in 24% and CHT-IO in 28%, others treatment accounts for 4% and only 2% of patients underwent best supportive care. Of the 132 lesions treated with SBRT 55 were in brain, 27 in lung, 11 in liver, 10 in lymph nodes, 8 in bones and 20 in adrenal gland. Median OS was 14 months, 1 year-OS and 2 years OS were 53% and 27%, respectively. The median TtNT was 14 months for the entire population. Of all the analyzed variables only, the anatomical site of the metastases and their number showed statistical significance in the univariate analysist, confirmed in the subsequent multivariate. ConclusionSABR seems to play a role in delaying further systemic lines in oligometastatic disease and to extend the use of ongoing treatment in oligoprogressive state. Prospective studies are needed to confirm these findings.

Idecabtagene Vicleucel (ide-cel) Versus Standard (std) Regimens in Patients (pts) with Triple-Class-Exposed (TCE) Relapsed and Refractory Multiple Myeloma (RRMM): Updated Analysis from KarMMa-3

Introduction A single ide-cel infusion showed significantly longer median progression-free survival (PFS) vs std regimens (13.3 vs 4.4 months [mo], HR 0.49, 95% CI 0.38-0.65, P &amp;lt; 0.001) with deep, durable responses in heavily pretreated TCE RRMM at an interim analysis (IA) of KarMMa-3 (NCT03651128); safety data were consistent with prior studies (Rodríguez-Otero et al. NEJM 2023). Ide-cel benefits were consistent across pts in high-risk subgroups and across 2-4 prior lines of therapy (Tx). Results of the preplanned final PFS analysis of KarMMa-3 with 12.3 mo additional follow-up are reported. Methods In the phase 3 KarMMa-3 trial, pts with RRMM who received 2-4 prior regimens, including an immunomodulatory agent, proteasome inhibitor, and daratumumab, and were refractory to last regimen were randomized 2:1 to ide-cel or a std regimen (DPd, DVd, IRd, Kd, or EPd). In the ide-cel arm, pts could receive ≤ 1 cycle of optional bridging Tx for disease control. Pts in the std regimens arm could receive ide-cel after confirmed disease progression (PD). The primary endpoint was IRC-assessed PFS in the ITT population; final PFS was planned to be analyzed with ~289 events. Key secondary endpoints were IRC-assessed overall response rate (ORR) and overall survival (OS); other secondary endpoints included complete response rate (CRR), duration of response (DOR), minimal residual disease (MRD) status, time to next anti-myeloma Tx (TTNT; time from randomization to next anti-myeloma Tx [MTx]), event-free survival (EFS; time from randomization to first PD, next MTx or any-cause death, whichever is first), PFS2 (time from randomization to second objective PD or any-cause death, whichever is first), safety, and health-related quality of life (QOL). Results Of 386 randomized pts (ide-cel, n = 254; std regimens, n = 132), 225 received ide-cel and 126 received a std regimen. Baseline characteristics were generally balanced. Median follow-up from randomization to data cutoff (April 28, 2023) was 30.9 mo (range 12.7-47.8). Ide-cel significantly improved median PFS (95% CI) vs std regimens (13.8 [11.8-16.1] vs 4.4 [3.4-5.8] mo), representing a 51% reduced risk of PD or death (HR 0.49, 95% CI 0.38-0.63; Figure); 18 mo PFS rates were 41% vs 19%, respectively. Ide-cel significantly improved ORR vs std regimens (71% vs 42%) with deeper (CRR 44% vs 5%; ≥CR and MRD negative status [sensitivity level 10 -5], 22% vs 1%), more durable responses (median DOR 16.6 vs 9.7 mo; Table). PFS and ORR benefits of ide-cel vs std regimens were consistent with the IA. Interim OS will be included in the presentation. In pts who received ide-cel (n = 225) or a std regimen (n = 126), median PFS (95% CI) was 15.7 (12.5-18.9) vs 4.4 (3.4-5.8) mo, respectively. In the ITT population, median TTNT, EFS, and PFS2 were numerically longer with ide-cel vs std regimens. Median (range) TTNT was 20.9 (16.6-24.2) vs 7.0 (5.3-8.5) mo. Median (95% CI) EFS was 13.3 (11.3-15.7) vs 3.9 (3.0-5.3) mo. Median PFS2 (95% CI) was 23.5 (18.4-27.9) vs 16.7 (12.2-20.3) mo; ide-cel was next MTx in 70 (53%) pts in the std regimens arm. In the treated population, grade (gr) 3/4 infections occurred in 66/249 (27%) pts in the ide-cel arm vs 25/126 (20%) in the std regimens arm. In the ide-cel safety population, any gr cytokine release syndrome occurred in 197/225 (88%) pts, gr ≥ 3 in 11 (5%); median time to first onset was 1 d (1-14), median duration was 4 d (1-51). Any gr investigator-identified neurotoxicity occurred in 34/225 (15%) pts, gr ≥ 3 in 7 (3%); median time to onset was 3 d (range 1-317); median duration was 2.5 d (range 1-252). Ide-cel continued to demonstrate durable, clinically meaningful improvements in pt-reported outcomes, including symptoms, functioning, and QOL vs std regimens. Conclusions In this final PFS analysis of KarMMa-3, significantly longer PFS was maintained with ide-cel; PD or death risk reduced by 51%; responses were deeper and more durable vs std regimens. CRR with ide-cel increased since the IA, indicating a deepening response, but were unchanged with std regimens. A single ide-cel infusion vs continuous treatment with std regimens resulted in longer median TTNT and PFS2, indicating improved long-term disease control. The ide-cel safety profile was consistent with previous reports, with no parkinsonism or Guillain-Barré syndrome reported. These data continue to support use of ide-cel in pts with TCE RRMM. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Outcomes of Venetoclax-Based Therapy in Patients with Daratumumab-Refractory t(11;14) Positive Light Chain Amyloidosis

Background: Light chain (AL) amyloidosis is a rare plasma cell disorder (PCD) characterized by misfolded light chains produced by clonal plasma cells leading to organ dysfunction. Over the past few years, the introduction of daratumumab (dara), a CD38 monoclonal antibody, into clinical practice has markedly improved outcomes, however, relapses still occur with limited available options. Venetoclax (VEN) is a BCL-2 inhibitor that has shown encouraging clinical efficacy in PCDs harboring the translocation between the chromosomes 11 and 14 (t[11;14]). The aim of this study was to evaluate the efficacy of VEN-based therapy (VBT) in patients with dara-refractory AL who were positive for t(11;14). Methods:Of all adult patients with systemic AL amyloidosis evaluated at our center between 1/2016 and 7/2023, we focused on those who had prior refractoriness to dara (dara was given at any time during the disease course, as frontline or salvage treatment) and received VBT (at any time after dara refractoriness). Data was obtained via retrospective chart review. Hematologic responses including complete response (CR), very good partial response (VGPR) and partial response (PR) were according to the AL consensus criteria. No patients had concomitant multiple myeloma. Baseline characteristics were outlined by descriptive analysis. Kaplan-Meier method was used for progression free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS) calculations. Results: A total of 21 patients who met the above criteria, were included in this analysis. The median age of patients was 65 (range 48-80) years, median number of prior lines of therapy (LOT) was 2 (range 1-5) and median percentage of bone marrow plasma cells prior to VBT initiation was 15 (range 5-40). Fifteen (71%) patients had cardiac involvement, 11 (52%) renal involvement, and 7 (33%) in addition to other organs had bone marrow involvement; 67% of patients had &amp;gt;2 organs involved. Of the entire cohort, 24% had undergone autologous hematopoietic cell transplant (AHCT) as frontline therapy. All patients had t(11;14) and one patient had an additional 1q gain. The baseline characteristics are summarized in Table 1. VEN was given in combination with: dexamethasone (VEN-dex) in 9 patients (43%), daratumumab-dex (VEN-dara-dex) in 6 patients (28.5%) and proteasome inhibitor-dex (VEN-PI-dex) in 6 patients (28.5%). The median duration on VBT was 9 (range 1.5-24.1) months. At data cut-off, 5 patients had discontinued therapy because of ongoing CR/VGPR, 1 due to ongoing fatigue and 6 due to disease progression or death. The hematologic overall response rate (ORR) was 95% with 11 (53%) patients achieving CR or better and 7 achieving (33%) VGPR. Patients responded rapidly, with a median time to best hematologic response being 2 (range1-5) months. Among the 18 (86%) patients who achieved &amp;gt;VGPR, 15 also achieved difference of free light chains (dFLC) &amp;lt;10 mg/l. Of the 15 patients with cardiac involvement, 6 (40%) achieved response to VBT, while 4 (27%) were non-evaluable (3 had maintained response from previous LOT and 1 had undergone heart transplant); the remaining 5 (33%) had stable disease without response. Of the 11 patients with renal involvement, 4 (36%) achieved organ response to VBT, while 2 (18%) were non-evaluable (1 had maintained response from previous LOT and 1 had undergone kidney transplant); the remaining 5 (46%) had stable disease without response. Eventually, 4/21 patients experienced disease progression. The median PFS for the entire cohort was not-reached (NR); the 6 and 12-month PFS rates were 83% and 68% respectively. Median TTNT was also NR. At data cut-off, 3 patients had died (2 from cardiac complications [cardiac arrest and heart failure], and 1 from dialysis complications). The median OS was NR; the 6- and 12-month OS rates were 89% and 83%, respectively. Conclusion: Our findings suggest that VEN is effective in t(11;14) positive relapsed-refractory AL amyloidosis in combination with dexamethasone alone or with other established plasma-cell directed agents. VBT led to deep and rapid overall response rates with more than 80% of patients achieving VGPR after exposure to only 2 cycles of therapy. This is critical in the setting of dara-refractoriness where therapeutic options are very limited. A clinical trial is ongoing to further evaluate the role of VEN in relapsed-refractory AL amyloidosis.

International study of treatment efficacy in SS shows superiority of combination therapy and heterogeneity of treatment strategies

AbstractDespite increasing availability of therapies, patients with Sezary syndrome (SS) commonly endure multi-line treatment journeys, mostly with partial responses of short duration. Measuring clinical benefit is challenging; time-to-next-treatment (TTNT) provides a robust, objective measurement of efficacy. This international observational study examines patterns of clinical care and therapeutic benefit as measured by TTNT. TTNT was calculated for monotherapies and combination therapies, with consideration to treatment line. 178 patients with SS (73% de novo, 27% secondary) were included, receiving 721 lines of systemic therapy, with median follow-up of 56.9 months. Across all lines, 58 different therapeutic regimens were prescribed (54 were systemic therapies) and classified into 17 treatment groups. The most common first-line treatments were extracorporeal photopheresis (ECP)–containing combination therapy (20%) and retinoid monotherapy (19%). Median TTNT for all first-line therapies was short (5.4 months). First-line, combination therapies had longer median TTNT than monotherapies, 10.0 vs 5.0 months (P = .004), respectively. Later delivery of combination therapies was associated with shorter clinical benefit, with median TTNT reduced to 6.2 and 2.2 months for mid-line (2nd-4th line) and late-line (≥5th line), respectively (P < .001). First-line ECP-containing treatments were associated with longer median TTNT than non-ECP–containing treatments, 9.0 vs 4.9 months (P = .007). For both ECP-monotherapy and ECP–containing combination therapy, significant reductions in TTNT were seen in later lines. These data suggest therapeutic benefit from first-line delivery of combination therapy for SS and favor early inclusion of ECP in the treatment algorithm for those who can access it.

PARPi monotherapy as first-line maintenance following chemotherapy + bevacizumab in advanced ovarian cancer.

e17601 Background: Chemotherapy (CT) + bevacizumab is a standard-of-care option for first-line (1L) treatment for patients with advanced ovarian cancer (AOC). Real-world approaches to 1L maintenance (1LM) treatment include, among others, bevacizumab monotherapy or switching to poly(ADP-ribose) polymerase inhibitor (PARPi) monotherapy after completing 6–9 cycles of induction CT + bevacizumab. Methods: We identified 61 patients with AOC from the US-based, deidentified Integra PrecisionQ database who received 1LM bevacizumab monotherapy (n=27) or PARPi monotherapy (n=34) after 1L CT + bevacizumab initiated between July 1, 2019, and March 31, 2021, and followed them until the data cut-off of March 31, 2022. Using the start of 1LM therapy as the index date, we examined patient characteristics, time to next treatment or death (TTNT; often used as a real-world proxy for progression-free survival), and overall survival (OS) for these two treatment groups. Results: For patients who received 1LM bevacizumab, the median age was 69 years, 89% had Eastern Cooperative Oncology Group (ECOG) performance status 0–1, 63% had Stage III disease at index, and only 1 (4%) had a recorded/documented homologous recombination deficiency (HRd)-positive tumor. Of the 34 patients who switched to 1LM PARPi monotherapy, 21 (62%) received olaparib, 12 (35%) niraparib, and 1 (3%) rucaparib. The median age of these patients was 63.5 years, 94% had ECOG performance status 0–1, 62% had Stage III disease at index date, and 47% had HRD+ tumors. For patients who switched to 1LM PARPi monotherapy, the median TTNT was 10.8 months (mo) and 97% were still alive at the 12-month mark. For patients who continued with 1LM bevacizumab, the median TTNT was 4.9 mo and 81% remained alive at the 12-month mark. Conclusions: This study suggests that switching to maintenance with PARPi monotherapy following induction CT + bevacizumab is a viable option for the treatment of AOC. A higher prevalence of HRd patients switching to PARPi monotherapy may indicate clinician preference for PARPi monotherapy in biomarker-selected subgroups, and further analysis is needed to examine which patients are most likely to benefit from switch maintenance. Funding: GSK215281. [Table: see text]

Fixed-duration ibrutinib + venetoclax for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 4-y follow-up from the FD cohort of the phase 2 CAPTIVATE study.

7535 Background: CAPTIVATE (PCYC-1142) is a multicenter phase 2 study of first-line ibrutinib (I) + venetoclax (V) in CLL/SLL. Follow-up results from the fixed duration (FD) cohort showed 3-y PFS rate of 88% overall and rates ≥80% in patients (pts) with high-risk features (Wierda, ASCO 2022). Here we present updated results from the FD cohort with 4-y follow-up. Methods: Pts aged ≤70 y with previously untreated CLL/SLL received 3 cycles of I then 12 cycles of I+V (I 420 mg/d orally; V ramp-up to 400 mg/d orally). Responses were investigator assessed per iwCLL 2008 criteria. Undetectable minimal residual disease (uMRD; &lt;10‒4) was assessed by 8-color flow cytometry. Results: 159 pts were enrolled, including pts with high-risk features of unmutated IGHV (uIGHV) (56%) or del(17p) and/or TP53 mutation (17%). Median time on study was 50 mo (range 1‒53). At 4 y of follow-up, the best CR rate was 58% and ORR was unchanged at 96%. At 4 y, PFS rate was 79% (95% CI 71‒84) and OS rate was 98% (95% CI 94–99). 4 y PFS rates were numerically lower in pts with uIGHV (73%) or del(17p) and/or TP53 mutation (63%), while OS rates remained consistently high (Table). 4 y PFS rates by MRD status 3 mo after stopping treatment (EOT+3) were significantly higher overall in pts with uMRD vs detectable MRD (dMRD) in PB (90% vs. 66%, Table); this difference was minimal at 24 mo (100% vs 91%). Median TTNT was not reached overall (range 1–53 mo); the 4 y rate of freedom from next treatment was 84% (95% CI 77–89). Second malignancies continue to be collected off treatment; 1 AE of prostate cancer occurred during this y of follow-up. To date, 19 pts with PD after completing fixed duration I+V in either the FD cohort or MRD cohort placebo arm initiated retreatment with I. Responses in 17 pts with available data were 1 CR, 13 PR, and 1 each PR with lymphocytosis, SD, and PD. Median time on retreatment was 11 mo (range 0–39). The most common AEs (≥10%) with retreatment were diarrhea (n=3), COVID-19 (n=3), and anemia (n=2). In addition, 4 pts have started I+V retreatment to date. Conclusions: Results of the CAPTIVATE study support I+V as an all-oral, once-daily fixed-duration regimen for previously untreated pts with CLL/SLL. With 4 y follow-up, fixed-duration I+V continues to provide deep, durable remissions with clinically meaningful PFS and time off treatment, including in pts with high-risk disease features. New safety findings off-treatment were expectedly negligible, highlighting the benefits of a fixed duration regimen. Promising responses were observed upon retreatment with I in progressing pts. Clinical trial information: NCT02910583 . [Table: see text]

A study of frontline therapy in adults &gt;80 years with chronic lymphocytic leukemia (CLL).

12057 Background: AlthoughCLL primarily affects older adults (median age 71 years), limited data exists about the outcomes of adults who are ≥80 years old because they are under-enrolled on clinical trials. Methods: The Mayo Clinic CLL Database was used to conduct a retrospective cohort study of adults ≥80 years at the time of frontline CLL treatment. Kaplan-Meier analysis was used to plot OS, and cumulative incidence was used to plot TTNT, accounting for competing risk of death. The Mayo Clinic IRB approved the study. Results: Our study included 216 patients with CLL who were age ≥80 years at the time of frontline CLL therapy between 1/1995 and 11/2022 (Table). The median time from CLL diagnosis to initiation of frontline therapy was 3.1 years. The median OS after start of frontline therapy was 3.9 years. The median OS was 3.3 years (95% CI 2.6–4.2) for patients who received alkylating agents (e.g., chlorambucil, n=96), 3.8 years (95% CI 2.8–not reached [NR]) for purine analogues (e.g., fludarabine, n=11), 3.9 years (95% CI 3.2–4.9) for anti-CD20 monoclonal antibody monotherapy (e.g., obinutuzumab, n=64), and not reached (95% CI 3.3-NR) for novel agents (n=43) (P=0.02). The types of novel agents included ibrutinib (n=19), acalabrutinib (n=16), venetoclax (n=7), and orelabrutinib (n=1). There was no difference in OS between 36 patients who received a BTKi compared to the 7 patients who received venetoclax-based therapy. At a median follow-up time of 6.7 years from the first visit, 143 patients died from the following: progressive CLL (n=63), infections (n=12), other cancer (n=11), non-CLL reasons (n=21). Cause of death was unavailable for 36 patients. On multivariable analyses, older age (i.e., any 5-year increase in age) was associated with a 50% increased risk of death (HR 1.5, 95% CI 1.2-1.9, p=0.001), and treatment with non-novel agents was associated with 3.2 times increased risk of death (HR 3.2, 95% CI 1.2-8.9, p=0.02). Of the 216 patients, 76 patients required second-line therapy; the median TTNT was 4.2 years (95% CI 2.9-NE). The most used second-line agents were monoclonal antibodies alone (20/76, 26%) and single-agent alkylators (18/76, 24%). Conclusions: When compared to all other CLL treatments, novel agents such as BTKi and venetoclax-based treatments are associated with significantly improved OS in patients with CLL ≥80 years old when used in the frontline setting. [Table: see text]