Time To Next Treatment Research Articles

Sirolimus is effective for refractory/relapsed idiopathic multicentric Castleman disease: A single-center, retrospective study.

Refractory/relapsed idiopathic multicentric Castleman disease (R/R iMCD) has limited treatment options. With studies showing increased mTOR activation in iMCD patients, sirolimus becomes an attractive and promising therapy for R/R iMCD. Here we report the results of a retrospective study involving 26 R/R iMCD patients treated with sirolimus-containing regimen. The median age at sirolimus initiation was 40.5 years (23-60), with a median prior treatment line of 2 (1-5). 18 patients (69.2%) achieved symptomatic and biochemical response, with a median time to at least overall partial remission of 1.9 months (0.5-14.6). The median follow-up time from sirolimus initiation was 11.7 months (1.6-50.7) and the median time to next treatment (TTNT) was 46.2 months. No patients died at the end of follow-up. Most of the patients in the cohort are in ongoing responses and continue sirolimus therapy. Sirolimus is well tolerated with minor adverse effects. In conclusion, sirolimus is effective for R/R iMCD patients with good tolerance.

Improved Survival of Patients With Chronic Lymphocytic Leukemia Between 1998-2022, Including the Era of Target Therapies With BCL2 and BTK Inhibitors.

The treatment for chronic lymphocytic leukemia (CLL) has changed dramatically over the last two decades. The current study aimed to investigate the impact on overall survival (OS) and time to next treatment (TTT) among CLL patients from 1998 to 2022. The cohort was based on data obtained from electronic medical records of Maccabi, the second largest healthcare organization in Israel. All included patients were diagnosed with CLL based on the IWCLL criteria and complete clinical, laboratory, and treatment data were available. The study encompassed 3,964 patients diagnosed with CLL during the specified study period. Patients with CLL who required therapy were divided into three eras based on the dominant treatment approach: chemotherapy alone before 2010, therapy with chemotherapy and anti-CD20 between 2010 and 2017, and therapy with targeted agents between 2017 and 2022. Median OS was 4.1 years, 7.5 years, and not reached, respectively. The six-year OS rates were 40%, 55%, and 69%, respectively, (p=0.0001). The median time to the next treatment improved from 5.5 years before 2010, to 8.3 between 2010-2017, to not reached after 2017 (p=0.0021). Marked improvements in survival subsequent to fundamental changes in first-line therapy were found in patients with CLL from before 2010 to after 2017.

Real-world study of pegylated interferon α-2a to treat mycosis fungoides/Sézary syndrome using time to next treatment as a measure of clinical benefit: an EORTC CLTGstudy.

Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon (IFN)-α (subtypes 2a and 2b) has been used to treat MF/SS since 1984; however, its production was recently stopped. The recombinant pegylated (PEG) form of IFN-α-2a remains the only alternative IFN treatment, although it has not been approved for use in MF/SS. To assess the effectiveness and safety of PEG-IFN-α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in a real-world setting. We conducted an international, multicentre retrospective study of patients with MF and SS (of any stage) treated with PEG-IFN-α-2a from July 2012 to February 2022. Patients were included across 11 centres in 10 countries. The primary endpoints were to determine the TTNT of PEG-IFN-α-2a and adverse events (AEs) in MF/SS. In total, 105 patients were included [mean (SD) age 61 (13.1) years]; 42 (40.0%) had stage IA-IIA and 63 (60.0%) had stage IIB-IVB disease. PEG-IFN-α-2a was combined with other therapies in 67 (63.8%) patients, most commonly with extracorporeal photopheresis (36%) and bexarotene (22%). Patients with stage I-IIA disease achieved an overall response rate (ORR) of 57%; the ORR in those with stage IIB-IVB disease was 51%. Combination treatment resulted in a median TTNT of 10.4 months (range 0.6-50.7) vs. 7.0 months (range 0.7-52.4) for those who received monotherapy (P < 0.01). Overall, the mean (SD) TTNT was 9.2 (10.6) months and the ORR was 53.3% (n = 56). A complete response was seen in 13% of patients and a partial response in 40%. AEs were described in 68.6% (n = 72) of patients. Flu-like symptoms (n = 28; 26.7%), lymphopenia (n = 24; 22.9%) and elevated liver function (n = 10; 9.5%) were the most frequently reported. Grade 3-4 AEs were reported in 23 (21.9%) patients, mostly related to myelosuppression. PEG-IFN-α-2a for MF/SS resulted in an ORR of 53.3% and a mean (SD) TTNT of 9.2 (10.6) months. Combination regimens were superior to monotherapy and doses of 180 µg PEG-IFN-α-2a weekly were related to a higher ORR.

Abstract CT223: Dormancy reprograming therapy of 5-azacitidine (AZA) and all-trans retinoic acid (ATRA) in biochemically recurrent prostate cancer

Abstract Microenvironmental signals and epigenetic changes can instruct proliferative disseminated tumor cells to enter dormancy. The combination of Azacitidine (AZA) and All-trans retinoid acid (ATRA) can reprogram active prostate cancer (PCa) cells into a dormant state. Herein, we evaluated the safety and clinical activity of AZA + ATRA in patients (pts) with biochemically recurrent PCa. Eligible pts were those with diagnosis of PCa post-local therapy with rising PSA (PSADT &amp;lt; 10 mo). Pts were excluded if they had radiographic evidence of disease or if they were a candidate for salvage radiation therapy (RT). Eligible pts were randomized 1:1 to arm A vs. B. All pts received Lupron 7.5 mg IM at the start of study. Four weeks later, pts entered a 24-week treatment (tx) phase. Pts in arm A received AZA 40 mg/m2 SQ x 5 days and ATRA 45 mg/m2 PO x 5 days Q4W for 12 weeks (w), followed by 12w of observation. Pts in arm B underwent 12w of observation, followed by 12w of AZA and ATRA at same dosing as arm A. All pts underwent follow up until initiation of next tx. The primary endpoint was safety and tolerability as assessed by CTCAE v5.0. Key secondary endpoints included % of pts with prolongation of PSADT pre- and post-tx and time to next treatment (TTNT). Levels of dormancy biomarkers, BMP4 and BMP7, were quantified using ELISA. Circulating tumor cells (CTCs) were analyzed for positive expression of NR2F1 using immunofluorescence. Wilcoxon signed rank test was used for comparing the PSADT. All statistical analysis was performed in R. Fourteen pts were enrolled (A: N=6, B: N=8) with a median age of 66 (range 54-77). At baseline, mean PSA was 4.75 ng/ml (A: 7.11, B: 2.99) and mean PSADT was 2.89 months (A: 3.51, B: 2.43). Eight (57.1%) pts had a Gleason score &amp;gt; 8 at initial diagnosis (A: 83.3%, B: 37.5%). There were no reported Grade &amp;gt; 3 treatment-related adverse events (TRAEs) and no treatment discontinuations. The most common TRAEs included hot flashes, white blood cell decreased and lymphocyte count decreased (all 8.3% each), and anemia (5.6%). There was prolongation of PSADT pre- and post-tx in 6 (46%) pts, however, overall difference in PSADT was non-significant [p&amp;gt;0.1]. 13 out of 14 (93%) pts had TTNT of &amp;gt; 6 months. One pt developed radiographic progression prior to completion of tx phase and a total of 6 pts (42.8%) within 3 months of tx phase. Out of 8 pts, 37.5% and 75% of pts showed increased levels of BMP4 and BMP7 respectively. Upon tx, CTC count decreased in 3 out of 5 pts analyzed, while CTCs were undetectable in two pts. Upon tx, NR2F1 expression could not be detected due to non-detection of CTCs, except for one pt who showed 100% NR2F1 positive CTCs in follow up. AZA + ATRA appears safe and well tolerated, and there was clinical activity in a small subset of pts potentially correlated with dormancy. Additional prospective clinical studies are needed to elucidate dormancy mechanisms further and optimize dosing strategy. Citation Format: Vaibhav G. Patel, Deepak Singh, Himanshu Joshi, Bobby Liaw, Che-Kai Tsao, Matthew Galsky, Lindsay Diamond, Julio Agguire-Ghiso, William Oh. Dormancy reprograming therapy of 5-azacitidine (AZA) and all-trans retinoic acid (ATRA) in biochemically recurrent prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT223.

Tucatinib Combination Treatment After Trastuzumab-Deruxtecan in Patients With ERBB2-Positive Metastatic Breast Cancer

Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC). To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan. This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022. Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose. Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR). A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months. In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.

Efficacy of elotuzumab for multiple myeloma deteriorates after daratumumab: a multicenter retrospective study.

Elotuzumab-based regimens are sometimes selected for multiple myeloma treatment after daratumumab-based regimens. However, there has been insufficient discussion on the efficacy of elotuzumab after daratumumab. We used Kansai Myeloma Forum registration data in a multicenter retrospective evaluation of the efficacy of elotuzumab after daratumumab. Overall survival (OS) rate and time to next treatment (TTNT) were significantly worse in the cohort given elotuzumab after daratumumab (Dara cohort, n = 47) than in the cohort with no history of daratumumab administration before elotuzumab (No-Dara cohort, n = 80, OS: P = 0.03; TTNT: P = 0.02; best response: P < 0.01). In the Dara cohort, OS and TTNT rates were worse with sequential elotuzumab use after daratumumab than with non-sequential (OS: P = 0.02; TTNT: P = 0.03). In patients given elotuzumab < 180 days after daratumumab, OS (P = 0.08) and best response (P = 0.21) tended to be worse, and TTNT was significantly worse (P = 0.01), than in those given elotuzumab after ≥ 180 days. These findings were confirmed by subgroup analyses and multivariate analyses. Monoclonal-antibody-free treatment might be preferable after daratumumab-based regimens. If possible, elotuzumab-based regimens should be considered only ≥ 180 days after daratumumab use.

NK and T-lymphocyte Kinetics Predict Outcome in Myeloma Patients Treated With Elotuzumab, Lenalidomide Plus Dexamethasone.

Elotuzumab, an anti-SLAMF7 monoclonal antibody, can enhance immune activity via elevated antibody-dependent cellular cytotoxicity and reduced SLAMF7+CD8+CD57+ regulatory T-cells (Tregs). This multicenter observational study investigated the kinetics of lymphocytes in myeloma patients treated with elotuzumab, lenalidomide, and dexamethasone (ERd) by two-color flow cytometry using peripheral blood samples. Twenty-one patients were included in this study. The median duration of ERd was 22.6 months, and the cutoff time for long-duration ERd was two years. The CD2+CD16+ and CD16+CD57- NK cells were significantly increased over time in the long-duration ERd group compared to those in the short-duration ERd group (p=0.035 and p<0.001). The CD8+ and CD16-CD57+ lymphocytes, identified as low-activity NK cells or SLAMF7+ Tregs, were significantly increased in the patients whose ERd outcome was progressive disease (PD) compared to those in the non-PD group (p=0.023 and p<0.001). The mean CD4/CD8 ratio and CD19+ lymphocyte counts in the long-duration ERd group were significantly lower than those in the short-duration ERd group, although the kinetics of them did not change over time (p=0.016 and p=0.011). When the cutoff value of CD4/CD8 ratio was 0.792 according to ROC curves, the two-year time to next treatment (TTNT) in the low CD4/CD8 group was significantly longer than that in the high CD4/CD8 group (80.0% vs. 15.0%, p=0.024). The change in NK cells and CD8+ Tregs predicted long-duration ERd and PD, and maintaining low CD4/8 ratio predicted long TTNT, suggesting that these lymphocyte fractions might be biomarkers for a durable therapeutic effect of ERd in myeloma patients.

Clinical outcomes and safety of immune checkpoint inhibitors in patients with solid tumors and paraneoplastic syndromes

BackgroundPatients with paraneoplastic syndromes (PNS) are excluded from clinical trials involving immune checkpoint inhibitors (ICIs) due to safety concerns. Moreover, real-world data on efficacy and safety is scarce.MethodsIn this retrospective...

Comparative Efficacy of Talquetamab vs. Current Treatments in the LocoMMotion and MoMMent Studies in Patients with Triple-Class-Exposed Relapsed/Refractory Multiple Myeloma.

Talquetamab, a bispecific antibody targeting GPRC5D × CD3, is approved for the treatment of patients with triple-class -exposed (TCE) relapsed/refractory multiple myeloma (RRMM) on the basis of the results from the phaseI/II MonumenTAL-1 trial. The relative effectiveness of talquetamab vs. real-world physician's choice of therapy (RWPC) was assessed using adjusted comparisons. An external control arm for MonumenTAL-1 (subcutaneously administered talquetamab 0.4mg/kg weekly [QW] and 0.8mg/kg every other week [Q2W]) was created from two observational real-world studies: LocoMMotion and MoMMent. Imbalances in baseline covariates were adjusted using inverse probability weighting. The relative effectiveness of talquetamab vs. RWPC was estimated for overall response rate (ORR), ≥ very good partial response (VGPR), and ≥ complete response (CR); odds ratios and relative response ratios (RRs) were derived from weighted logistic regression. Hazard ratios (HRs) for duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), and overall survival (OS) were estimated using a weighted Cox proportional hazards model. After reweighting, baseline characteristics were balanced across cohorts. In adjusted comparisons, patients treated with talquetamab QW (n = 143) had significantly improved outcomes vs. RWPC; RRs were ORR 2.67, p < 0.0001; ≥ VGPR 4.70, p < 0.0001; ≥ CR 78.05, p = 0.0002; and HRs were PFS 0.52, p < 0.0001; TTNT 0.48, p < 0.0001; OS 0.36, p < 0.0001. Patients treated with talquetamab Q2W (n = 145) also had significantly improved outcomes vs. RWPC; RRs were ORR 2.62, p < 0.0001; ≥ VGPR 5.04, p < 0.0001; ≥ CR 101.14, p = 0.0002; and HRs were PFS 0.40, p < 0.0001; TTNT 0.39, p < 0.0001; OS 0.37, p < 0.0001. Effectiveness of talquetamab for both schedules was significantly better than RWPC for ORR, ≥ VGPR, ≥ CR, PFS, OS, and TTNT, highlighting its clinical benefit for patients with TCE RRMM. MonumenTAL-1, ClinicalTrials.gov identifier NCT03399799/NCT04634552; LocoMMotion, ClinicalTrials.gov identifier NCT04035226; MoMMent, ClinicalTrials.gov identifier NCT05160584.

Treatment Pattern, Healthcare Resource Utilization and Symptom Burden Among Patients with Triple Class Exposed Multiple Myeloma: A Population-Based Cohort Study

PurposeThis study aims to describe the treatment patterns, outcomes, health care utilization and symptom burden of triple class exposed (TCE) relapsed/refractory patents with multiple myeloma (MM) receiving a subsequent line of treatment (LOT). MethodsThis is a retrospective observational cohort study using administrative databases in Ontario, Canada. Outcomes were captured for TCE patients receiving a subsequent LOT and included: treatment regimen details, time to next treatment (TTNT), overall survival (OS), health care utilization, palliative care referral, and patient reported symptoms. ResultsOf the 16,777 patients diagnosed with MM between 2007-2021 in Ontario, 1358 (8%) patients were classified as TCE. Among the TCE MM patients, 489 (36%) received a subsequent LOT. The two most commonly administered therapies post TCE were carfilzomib/dexamethasone (n = 111, 22%) and pomalidomide/dexamethasone(n = 95, 19%). Median TTNT was 1.7 months (95%CI 1.2-2.4 months) and median OS 12.8 months (95%CI 10.8-16.5). Healthcare utilization was high with 276 (56%) of patients evaluated in an emergency department (ED) or admitted to hospital. There was high symptom burden as reported by patients with moderate-severe impairment in well-being, fatigue, pain and drowsiness noted in greater than 25% of the cohort. Palliative care referrals rates were low with only 10% (n = 48) patients referred to palliative care. Among the patients that died during study follow up, the majority died in hospital (n = 147,44%). ConclusionOur study reports one of the largest series of real-world TCE patients published and demonstrates the poor outcomes of TCE patients receiving a subsequent LOT.

Clinical characteristics of patients treated with immune checkpoint inhibitors in EGFR-mutant non-small cell lung cancer: CS-Lung-003 prospective observational registry study

PurposeImmune checkpoint inhibitors (ICIs) are ineffective against epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). This study aimed to investigate the clinical characteristics of patients who were treated or not treated with ICIs, and of those who benefit from immunotherapy in EGFR-mutant NSCLC.MethodsWe analyzed patients with unresectable stage III/IV or recurrent NSCLC harboring EGFR mutations using a prospective umbrella-type lung cancer registry (CS-Lung-003).ResultsA total of 303 patients who met the eligibility criteria were analyzed. The median age was 69 years; 116 patients were male, 289 had adenocarcinoma, 273 had major mutations, and 67 were treated with ICIs. The duration of EGFR-TKI treatment was longer in the Non-ICI group than in the ICI group (17.1 vs. 12.7 months, p < 0.001). Patients who received ICIs for more than 6 months were categorized into the durable clinical benefit (DCB) group (24 patients), and those who received ICIs for less than 6 months into the Non-DCB group (43 patients). The overall survival in the DCB group exhibited longer than the Non-DCB group (69.3 vs. 47.1 months), and an equivalent compared to that in the Non-ICI group (69.3 vs. 68.9 months). Multivariate analysis for time to next treatment (TTNT) of ICIs showed that a poor PS was associated with a shorter TTNT [hazard ratio (HR) 3.309; p < 0.001]. Patients who were treated with ICIs and chemotherapy combination were associated with a longer TTNT (HR 0.389; p = 0.003). In addition, minor EGFR mutation was associated with a long TTNT (HR 0.450; p = 0.046).ConclusionICIs were administered to only 22% of patients with EGFR-mutated lung cancer, and they had shorter TTNT of EGFR-TKI compared to other patients. ICI treatment should be avoided in EGFR mutated lung cancer with poor PS but can be considered for lung cancer with EGFR minor mutations. Pathological biomarker to predict long-term responders to ICI are needed.

Evolving metastatic renal cell carcinoma (mRCC) treatment landscape in the post vascular endothelial growth factor (VEGF) and immune checkpoint inhibitor (IO) setting.

406 Background: IO and VEGF based therapies have transformed the front-line treatment paradigm for patients with mRCC. This study's objective is to describe treatment patterns and clinical outcomes among mRCC patients in the post IO and VEGF setting. Methods: Adult patients diagnosed with mRCC between Jan 2015 - Dec 2022 and received IO and VEGF (in combination or sequence) in the first three lines of therapy after mRCC diagnosis were identified from Optum’s de-identified Clinformatics® Data Mart Database, a large retrospective claims database. Index date was defined as the date of the first (index) treatment in the post IO and VEGF setting. Patients were required to have continuous enrollment of 6 months prior to index date. Patients were categorized into 3 cohorts based on lines of index treatment (2L, 3L, 4L). Treatment patterns were described and real world (rw) time on treatment (ToT), time to next treatment (TTNT), and overall survival (OS) were estimated by Kaplan Meier analysis. Results: A total of 664 patients were included (2L:186, 3L:429, 4L:49). 37% received IO and VEGF in combination prior to index line of therapy. Median age at mRCC diagnosis was 67.0 years, with 72.7% male and 68.1% White; 11.6% died and 7.4% disenrolled during index treatment. Post IO and VEGF, cabozantinib was the most used therapy across 3 cohorts (2L: 43.5%, 3L: 35.2%, 4L: 30.6%) (Table). Median rwToT and rwTTNT for 2L, 3L, and 4L cohorts were 4.4, 5.0, and 5.6 months and 10.7, 11.7, and 9.5 months, respectively. Median OS from mRCC diagnosis was similar across the 3 cohorts (2L: 41.6, 3L: 38.7, 4L: 40.6 months); median OS from index date decreased with advancement in LOT (2L: 20.6, 3L: 14.1, 4L: 10.3 months). Conclusions: Our study is one of the largest and comprehensive study giving a unique perspective into evolving treatment patterns and outcomes for mRCC patients in the post IO and VEGF setting. Post IO+VEGF, the most common treatments were tyrosine kinase inhibitor-based treatments, and the median ToT was less than 6 months. Hence, novel treatments are needed to improve clinical outcomes for mRCC patients in the post IO and VEGF setting. [Table: see text]

Real-world (rw) treatment patterns, sequencing, and outcomes in patients (pts) with locally advanced or metastatic urothelial carcinoma (la/mUC) receiving avelumab first-line maintenance (1LM) in the US.

605 Background: Avelumab 1LM is recommended in international guidelines for pts with la/mUC and disease control after 1L platinum-based chemotherapy (PBC). This study describes the treatment landscape after FDA approval of avelumab in June 2020 by examining pt characteristics, treatment patterns and sequencing, and rw outcomes in pts treated with avelumab 1LM. Methods: This noninterventional retrospective study identified pts with la/mUC who received avelumab 1LM in the US using data from Flatiron Health’s electronic health record database. Pts aged ≥18 y with ≥2 visits on/after Jan 1, 2011, diagnosed with la/mUC from Jan 1, 2019 - Dec 31, 2022, treated with 1L PBC followed by avelumab 1LM on/after Jul 1, 2020, ≤90 d after 1L PBC discontinuation, and with no disease progression ≤14 wk after 1L PBC were included. Treatment patterns in 1LM, second line (2L), and third line (3L) were assessed. Clinical outcomes, including rw progression-free survival (rwPFS), rw overall survival (rwOS), time to treatment discontinuation (TTD), and time to next treatment (TTNT) from 1LM or 2L initiation, were assessed using Kaplan-Meier methods. Results: 214 avelumab 1LM-treated pts met eligibility criteria. Median age was 70 y; most pts were male (77%), White (66%), and had an ECOG of 0-1 (77%). Median follow-up from 1LM was 8.7 mo. Of 96 (45%) pts who received 2L treatment post avelumab 1LM, enfortumab vedotin (EV) monotherapy (55%) was most common, followed by carboplatin-based therapy (11%). Of 40 (42%) pts who received 3L treatment, EV monotherapy was most common (25%), followed by sacituzumab govitecan (20%). Median PFS and OS from start of avelumab 1LM was 5.1 (95% CI 4.1-7.0) and 23.8 (95% CI 18.2-NE) mo. Median TTNT from avelumab 1LM initiation was 7.0 (95% CI 5.6-8.6) mo. Of pts who received 2L EV, median rwPFS and rwOS from 2L initiation were 4.9 (95% CI 3.9-8.8) and 11.2 (95% CI 6.8-NE) mo. Further rw outcomes are presented in the Table. Conclusions: Clinical outcomes in this study are aligned with those of the JAVELIN Bladder 100 trial (NCT02603432), further supporting avelumab 1LM as a standard of care. With each additional line of therapy, substantial treatment attrition and less favorable clinical outcomes were observed. This study provides insights into the sequencing of treatments and management of pts with la/mUC after disease progression with avelumab 1LM in this rapidly evolving therapeutic landscape. The use of more effective upfront therapies may decrease the attrition rates. [Table: see text]

P1037 Treatment sequences and time on specific treatments in patients with inflammatory bowel disease under advanced treatment – a German claims data analysis

Abstract Background The number of advanced therapies (ADT) approved for the treatment (Tx) of inflammatory bowel disease (IBD) in is increasing, however, yet no guidance on optimal sequencing of treatments is available in Germany (and elsewhere). This study aims to investigate applied Tx sequences of ADT in claims data based on real-world setting across Germany in patients (pts) with IBD. Methods A retrospective healthcare claims data analysis was conducted using claims data from approx. 4.5 Mio pts within German statutory health insurance, including pts diagnosed with Crohn’s disease (CD) and ulcerative colitis (UC) from 2014 to 2021. Pts were followed up for at least 6 months after the first prescription of ADT (index date) if not deceased. A pre-index period of at least 12 months was applied to only include pts naïve to ADT. The study assessed Tx sequences and time to next treatment (TTNT) among other parameters. Data was not adjusted to disease severity and only descriptively reflects real world Tx patterns within the database. Results The database included 15.041/18.361 pts with CD/UC. Pts with CD/UC starting ADT between 2014 to 2021 received either Adalimumab (ADA: 923/337), Infliximab (IFX: 616/419), Ustekinumab (UST: 113/25) or Vedolizumab (VDZ: 139/248). In an analysis of ADT sequences and TTNT defined as start of first line (1L) Tx to start of second line (2L) Tx we found that during the observation period the majority of pts (71.4%) have not switched to 2L Tx yet. In 1L, ADA was observed as the preferred Tx in CD pts (51.5%) followed by IFX (34.4%), VDZ (7.8%) and UST (6.3%), in UC pts IFX (40.7%) was mostly prescribed as 1L followed by ADA (32.8%), VDZ (24.1%) and UST (2.4%). The proportion (%) of pts not switched to 2L Tx within one year for CD/UC were: ADA (83.6/70.3), IFX (79.0/73.1), UST (93.5/96.0) and VDZ (85.4/86.6). Within three years proportions of pts not switched to 2L Tx changed for CD/UC: ADA (68.1/54.5), IFX (57.8/56.8), UST (82.5/72.0) and VDZ (72.7/73.0) (table1). For pts who had a switch to a different ADT, the switch occurred within one year in over 50% of all pts. Most Tx switches (45.8%) were observed in pts who received IFX as 1L Tx, both in the UC and CD population. The majority of CD pts that received 2L Tx were switched to UST (35.7%), while in UC, a high proportion of pts were switched to VDZ (44.3%). Further Tx pathways and proportions of switches are summarized in Figure 1. Conclusion The study found that most IBD pts started ADT with ADA or IFX, but unadjusted time on 1L data may suggest a trend towards superior TTNT of VDZ and UST in UC and CD. Data should be interpreted carefully, as pts for &amp;gt;1L are limited and UST and VDZ were approved during the study period.

Clinical impact of KRAS mutations in metastatic pancreatic ductal adenocarcinoma (PDAC).

619 Background: Mutations in the KRAS oncogene occur in most PDAC and lead to the activation of the KRAS protein. Little is known about the differential impact of KRAS mutations on the outcomes of patients receiving standard of care cytotoxic treatments for metastatic disease. KRAS inhibitors are emerging as promising options for this disease and understanding the impact of distinct KRAS mutations in patient outcomes is needed. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database from 5,369 patients. Adult patients with diagnosis of metastatic PDAC who received at least one line of systemic therapy and had sufficient data available were included in this analysis. Median time to next treatment (TTNT) and overall survival (OS) time were calculated for three common first-line treatments and KRAS mutations. TTNT and OS were calculated for each permutation of treatment and each KRAS mutation. Hazard ratios (HR) were generated for each KRAS mutation and treatment, accounting for potentially confounding variables. Results: Of the 5,369 patients, 2,472 met the inclusion/exclusion criteria. G12C had the shortest median OS (7.5 mo) and G12R had the longest (9.1 mo). Overall, KRAS mutation-positive patients had a median OS of 8.6 mo, compared to 11.7 mo for KRAS Wild Type (WT) patients. A Cox Proportional Hazard analysis of OS across KRAS mutation status found that G12C, G12V, G12D, and Other Non G12/13 KRAS had significantly higher HR than KRAS WT. A comparison of the three common first-line interventions for metastatic PDAC showed that FOLFIRINOX had the longest median TTNT (5.3 mo) and the longest OS (10.2 mo), while Gemcitabine had the shortest TTNT (2.6 mo) and OS (5.9 mo). A Cox Proportional Hazard analysis of OS across all patients found that Gemcitabine and Gemcitabine with Nabpaclitaxel had significantly higher HR than FOLFIRINOX. FOLFIRINOX had the longest TTNT in the G12C, G12V, G12D, G12R, and other non-G12/G13 KRAS groups (see table). Conclusions: Our data suggest that FOLFIRINOX has a longer TTNT than other first-line regimens for KRAS G12C, G12V, G12D, and G12R. KRAS G12C was associated with the shortest OS among common KRAS mutations.[Table: see text]

Real-world analysis of irinotecan (iri) with or without fluorouracil (5FU) in the second line treatment (2L) of metastatic colorectal cancer (mCRC).

102 Background: The most used 1st line (1L) chemotherapy backbone for mCRC is fluoropyrimidine (FP) + oxaliplatin. In the 2L, iri alone or with 5FU (FOLFIRI), ± a biologic agent (biologic), are options. It is unclear whether adding 5FU to iri is beneficial following disease progression on prior FP. Methods: This study used the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database to identify patients diagnosed with mCRC from 01-01-2013 to 02-13-2023, who received 1L with FP + oxaliplatin ± biologic, and 2L with irinotecan ± 5FU ± biologic. Baseline patient/tumor characteristics were obtained. The number of major comorbidities was computed using ICD-9-CM/10 codes within 1 year prior to 2L (Quan, 2005). Time to next treatment (TTNT) was defined from the start of 2L to the start of next line treatment (excluding maintenance). For survival outcomes, the median survival time and 95% confidence interval (CI) were estimated using the Kaplan-Meier method. Uni- and multi-variable analyses (UVA and MVA) were performed with the cox proportional hazard model. All covariates were evaluated in UVA, and those significant were included in MVA with adjusted hazard ratio (HR) and 95% CI. Results: 3,215 patients met criteria; most previously received a biologic with 1L (70.5% prior anti-angiogenesis and 5.9% prior anti-EGFR) and had 0 structured major comorbidity diagnoses (82.1%). In the 2L, FOLFIRI was the most used chemotherapy backbone (90.6%, vs iri 9.4%), 79% of patients also received a biologic, and patients who received FOLFIRI were younger (median age 61 vs 65 years) and had better ECOG performance status (87.8% vs 81.8% ECOG 0-1). Overall survival (OS) was longer with FOLFIRI than iri (median 14.4 vs 9.8 months, p&lt;0.001), as was TTNT (median 7.6 vs 5.3 months, p&lt;0.001). In MVA, when controlling for age, comorbidities, CEA, ECOG performance status, and 1L, iri was associated with shorter OS than FOLFIRI (HR 1.38, 95% CI 1.21-1.57, p&lt;0.001). In MVA, the addition of a biologic to FOLFIRI and iri prolonged OS and TTNT in some subgroups (Table). Conclusions: In this retrospective real-world analysis of 3,215 patients with mCRC who received 1L with FP + oxaliplatin ± biologic, 2L FOLFIRI was associated with longer OS compared to iri alone (both ± biologic). [Table: see text]

Real-world treatment patterns and outcomes in patients with mCRC by MMR/MSI status.

52 Background: There are limited data on real-world (RW) treatment patterns and outcomes in patients (pts) with metastatic colorectal cancer (mCRC), especially those with deficient mismatch repair (dMMR)/high microsatellite instability (MSI-H) disease, as they progress through lines of therapy. Methods: Data were extracted from the Flatiron Health electronic health record-derived database. Pts aged ≥18 years diagnosed with mCRC and with ≥2 clinical visits between January 01, 2013 and October 31, 2022 were included. Treatment patterns by therapeutic category and specific agent/regimens were explored across 3 time periods anchored to the start date of first line (1L): years &lt;2017, 2017–2019 and ≥2020 for pts both with dMMR/MSI-H and proficient mismatch repair (pMMR)/microsatellite stability (MSS) disease. Analyzed outcomes, by treatment category, included overall survival (OS), time to treatment discontinuation (TTD) and time to next treatment (TTNT). Descriptive statistics and Kaplan–Meier analyses were conducted. Results: A total of 34,853 pts with mCRC were identified; 24,622 pts (70.6%) were tested for MMR or MSI status, of whom 1,594 (6.5%) were dMMR or MSI-H. After applying key eligibility criteria, 938 dMMR/MSI-H and 12,305 pMMR/MSS pts were included. Overall, chemotherapy-based treatment was the most common treatment category given to pts, but the use of immuno-oncology (IO) agents increased over time. In the dMRR/MSI-H cohort, IO was the most commonly used treatment in 1L and 2L after 2020, driven largely by the use of pembrolizumab. The median OS (mOS) from start of 1L, irrespective of treatment type, was 30.30 months (95% confidence interval [CI]: 24.47, 34.41) in the dMMR/MSI-H cohort and 23.78 months (95% CI: 23.32, 24.34) in the pMMR/MSS cohort. For pts with dMMR/MSI-H, those receiving 1L IO had a mOS of 57.60 months (95% CI: 42.43, not reached [NR]). In pts who had IO after 1L-chemotherapy alone or chemotherapy + targeted treatment, mOS was 52.63 months (95% CI: 38.06, NR) and 59.61 months (95% CI: 34.41, NR), respectively. In pMMR/MSS pts, chemotherapy alone or chemotherapy + targeted treatment had the longest OS when received as 1L-therapy, at 23.88 months (95% CI: 22.89, 25.10) and 24.28 months (95% CI: 23.55, 25.10), respectively. The median TTD and TTNT from start date of 1L, irrespective of treatment type, were 4.90 months (95% CI: 4.28, 5.20) and 7.96 months (95% CI: 7.04, 8.78), respectively, in the dMRR/MSI-H cohort, and 5.79 months (95% CI: 5.72, 5.95) and 10.33 months (95% CI: 10.07, 10.59) in the pMMR/MSS cohort. Conclusions: These real-world data from over 10,000 pts with mCRC supplement findings from clinical trials and limited reported RW evidence. While IO demonstrates significant improvement for pts with dMMR/MSI-H, and mOS is similar regardless of whether IO is given in the 1L or later setting, there remains a high unmet need in pMMR/MSS for additional effective treatment options.

Assessment of circulating tumor DNA (ctDNA) burden and association with outcomes in metastatic gastric cancer (mGC) patients using real-world data (RWD).

276 Background: CtDNA burden has been shown to have potential uses in early cancer detection, guiding treatment decisions, residual disease and drug resistance detection, and treatment response monitoring. While published literature suggested that ctDNA may be prognostic of clinical outcomes for various tumor types, there is limited RWD assessing its use in mGC. This study uses RWD to evaluate the association of pre-treatment ctDNA burden with clinical outcomes in mGC. Methods: Patients were identified from the Guardant INFORM real-world clinical-genomic database, which links ctDNA results via plasma-based next-generation sequencing Guardant360 assay (G360) to de-identified claims data. Adult mGC patients in the US, who received NCCN guideline treatments post-diagnosis and underwent testing with G360 from June 2014 to March 2022 were included. For those who received first line (1L) therapy within 60 days after a G360 test result, median of the maximum variant allele fraction (mVAF) was used to classify them into high or low ctDNA burden groups, with undetectable ctDNA burden considered low. Associations with time to next treatment (TTNT) and overall survival (OS) were assessed using log rank tests and multivariable Cox proportion hazards models adjusting for age, sex, Elixhauser comorbidity score, and anatomical location. Results: 2,200 mGC patients were identified, of which 824 (37%) initiated 1L therapy within 60 days after a G360 test. Among the 824 patients, mean age was 63 years, 70% were male and 47% had gastric adenocarcinoma and 53% gastroesophageal junction cancer. Median mVAF among these patients was 2.9%, with 91% having detectable ctDNA. Patients with high ctDNA burden treated with 1L chemotherapy (Chemo) showed significantly worse TTNT and OS than low ctDNA burden patients (Median TTNT= 4.7 months vs 7.5 months, p&lt;0.001; Median OS=12.4 months vs 19.1 months, p&lt;0.001). Multivariable Cox analyses showed similar results for 1L Chemo group. Treatment group outcomes based on adjusted Cox models were reported (Table). Conclusions: We used RWD to demonstrate that high pre-treatment ctDNA burden was associated with worse clinical outcomes in a mGC population treated with 1L Chemo. Our analysis adds to the body of evidence that suggest ctDNA burden could be used as a prognostic biomarker for mGC. The small sample size of the other 1L treatment groups warrants further investigation because the use of IO-based therapy is expected to increase with recent approvals. [Table: see text]

Treatment patterns of patients with HR+/HER2- metastatic breast cancer receiving CDK4/6 inhibitor-based regimens: a cohort study in the French nationwide healthcare database

PurposeTo assess real-world treatment patterns in patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (mBC) who received cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant at first line.MethodsPatient characteristics, treatment history, and outcomes data were extracted from the French ‘Système National des Données de Santé’ (SNDS) database for patients diagnosed with HR+/HER2- mBC between January 2014 and June 2019 and who received combination therapy with a CDK4/6 inhibitor and endocrine therapy. Kaplan-Meier methodology was used to assess time to next treatment (TTNT) and time to treatment discontinuation (TTTD).ResultsThe cohort comprised 6061 patients including 4032 patients who received CDK4/6 inhibitors + AIs and 2029 patients who received CDK4/6 inhibitors + fulvestrant. Median follow-up was 13.5 months (IQR 9.5–18.1). The median TTTD of first line treatment with CDK4/6 inhibitors + AIs and CDK4/6 inhibitors + fulvestrant was 17.3 months (95% CI 16.8–17.9) and 9.7 months (95% CI 9.0–10.2), respectively. Chemotherapy was the most common second line therapy. Median TTTD of subsequent treatment lines was progressively shorter following first line treatment with CDK4/6 inhibitors + AIs (2nd line: 4.6 months (95% CI 4.4–4.9) and with CDK4/6 inhibitors + fulvestrant (2nd line: 4.7 months (95% CI 4.3–5.1). TTNT was longer than TTTD across lines of therapy.ConclusionThis real-world analysis confirms the effectiveness of CDK4/6 inhibitor-based regimens in French patients and highlights the frequent use of chemotherapy as second line therapy.

INSURE: a pooled analysis of ixazomib-lenalidomide-dexamethasone for relapsed/refractory myeloma in routine practice.

Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXAand REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asiaand North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5months). Median TTNT and PFS were 18.4 and 19.9months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.