Clinical Outcomes In Pts Research Articles

Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of cisplatin (cis)-eligible population from EV-302/KEYNOTE-A39.

4562 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemo (PBC) for first-line (1L) treatment (tx) of patients (pts) with la/mUC regardless of cis eligibility. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with PBC for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P<0.00001) and overall survival (OS) (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023), reducing the risk of progression and/or death by more than 50%. EV+P was FDA-approved in Dec 2023 for tx of adults with la/mUC. As cis eligibility status has long defined 1L tx, here we present results for pts who were eligible for cis at randomization. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and P (200 mg IV; Day 1) or PBC (gemcitabine with cis or carboplatin). Select secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and safety. Pts were deemed eligible/ineligible for cis by protocol-defined criteria and were stratified accordingly. Results: 478 pts (EV+P: 244, PBC: 234) were cis-eligible at randomization. 220 (94.0%) pts in the PBC arm received cis at Cycle 1. mPFS was 14.6 mo for EV+P; 6.5 mo for PBC (HR: 0.48, 95% CI, 0.38, 0.62). mOS was 31.5 mo for EV+P; 18.4 mo for PBC (HR: 0.53, 95% CI, 0.39, 0.72). ORR for EV+P was 70.8% with 32.5% complete response (CR) rate; mDOR (95% CI) was not reached (18.2 mo, NR). ORR for PBC was 53.0% with 15.5% CR rate; mDOR (95% CI) was 8.3 mo (5.9, 10.9). In EV+P arm, 82 pts (33.6%) remained on tx at data cutoff (DCO). 85 pts (34.8%) received subsequent therapy. 72 pts (29.5%) received any platinum-based therapy as first subsequent therapy; 43 pts (17.6%) received cis. In PBC arm, all pts were off study tx at DCO. 146 pts (62.4%) received any PD-1/L1 therapy following PBC. 83 pts received maintenance avelumab; 59 pts received PD-1/L1 therapy as 2L tx. Grade ≥3 TRAEs occurred in 53.9% of pts with EV+P and 62.7% of pts with PBC. Most common grade ≥3 TRAEs of special interest for EV were skin reactions (14.8%), hyperglycemia (7.8%), and peripheral neuropathy (5.8%). Most common grade ≥3 tx-emergent AEs of special interest for P were severe skin reactions (9.5%), pneumonitis (4.9%), and colitis (2.9%). Conclusions: EV+P improved clinical outcomes in pts who were eligible for cis with previously untreated la/mUC, reducing the risk of death by 47% compared with PBC. Results were consistent with the overall population. The AE profile of EV+P was generally manageable with no new safety signals. The results of EV-302 support EV+P as a new SOC for la/mUC, including pts who are eligible for cis. Clinical trial information: NCT04223856 .

A prospective study to evaluate the prevelance of chemobrain (CB) in patients (pts) receiving adjuvant treatment.

e23174 Background: Although adjuvant chemotherapy (CT) significantly improves the clinical outcome of pts with early-stage (ES) cancer, it is also known to cause side-effects. CT-induced cognitive impairment or CB refers to a clinical condition characterized by lack of mental sharpness, memory and concentration impairment and difficulty in processing information and executing simple tasks. Prospective data regarding the emergence of CB are limited. We aimed to explore the prevalence and predictors for CB among pts receiving adjuvant CT and to evaluate its impact on their quality of life (QoL). Methods: This was a prospective cohort study conducted at the University Hospital of Larissa. Pts who were recently diagnosed with ES breast (BC) or colorectal (CRC) cancer and were about to receive adjuvant CT containing doxorubicin (D) or oxaliplatin (O), respectively, were eligible for this study (C1). The first control group (C2) consisted of ES cancer pts that were not eligible for adjuvant CT and the second group (C3) was recruited from a pool of healthy controls (HCs). All participants (pcs) met the following inclusion criteria: age > 50 years old, ability to speak and write in Greek. Pts with pre-existing dementia/anxiety disorder and severe anemia were excluded from the study. Pts in C1 were assessed before receiving CT and 3 months after CT initiation. All subjects in C2 and C3 were assessed in 3 months intervals as well. After completion of the informed consent process, all pts and age-matched noncancer controls completed the Greek Version of Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) to specifically assess CB. QoL was measured using the EORTC QLQ-C30. Results: Overall, 82 pts (53 with BC and 29 with CRC) were included in C1, 36 pts (24 with BC and 12 with CRC) in C2 and 15 pcs in C3. At baseline, pts in C1 and C2 had significantly lower FACT-Cog scores than healthy controls in C3 (p: 0.028 and p:0.038, respectively), indicating a higher prevalence of self-reported cognitive impairment among pts with cancer after a curative surgery compared to age-matched HCs. However, after 3 months of CT the majority of pts in C1 (59/82, 72%) demonstrated a decline in their cognitive performance (35/53, 66% in BC pts receiving D and 24/29, 82% in CRC pts receiving O). Pts with CRC receiving O experienced more severe cognitive deficits. On the contrary, 55% of the pts in C2 (20/36, 16 with BC and 4 with CRC) demonstrated an improvement. The presence of CB (decline in cognitive functioning in the absence of severe anemia) was associated with decreased QoL (p = 0.004). Pts were mostly frustrated by the difficulty in executing simple tasks. Conclusions: As demonstrated in one of the largest cohorts of pts with ES cancer, CB is a common problem among pts receiving adjuvant CT and is associated with detrimental impact on daily life. Creating awareness is crucial to offer cancer survivors the best care directed at improving QoL.

Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of the cisplatin (cis)-ineligible population from EV-302/KEYNOTE-A39.

4563 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemo (PBC) for first-line (1L) treatment (tx) of patients (pts) with la/mUC regardless of cis eligibility. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with PBC for the dual primary endpoints of PFS (hazard ratio [HR]: 0.45; P<0.00001) and OS (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023), reducing the risk of progression and/or death by more than 50%. EV+P was FDA-approved in Dec 2023 for tx of adults with la/mUC. As cis eligibility status has long defined 1L tx, here we present results of an analysis for pts who were ineligible for cis at randomization. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and P (200 mg IV; Day 1) or PBC (gemcitabine with cis or carboplatin [carbo]). Select secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and safety. Pts were deemed eligible/ineligible for cis following protocol-defined criteria and stratified accordingly. Results: 408 pts (EV+P: 198, PBC: 210) were cis-ineligible at randomization. 205 (97.6%) pts in the PBC arm received carbo at Cyle 1. mPFS was 10.6 months for EV+P; 6.1 months for PBC (HR: 0.43, 95% CI, 0.33, 0.55). mOS was not reached for EV+P and was 12.7 months for PBC (HR: 0.43, 95% CI, 0.31, 0.59). ORR for EV+P was 63.9% with 24.7% complete response (CR) rate; mDOR (95% CI) was not reached (16.3 months, NR). ORR for PBC was 34.9% with 9.1% CR rate; mDOR (95% CI) was 6.6 months (5.6, 10.2). In EV+P arm, 62 pts (31.3%) remained on tx at data cutoff (DCO). 55 pts (27.8%) received subsequent therapy. 10 pts received cis and 27 pts received carbo as first subsequent therapy. In PBC arm, all were off study tx at DCO. 114 pts (54.3%) received any PD-1/L1 therapy following PBC. 52 pts received maintenance avelumab; 58 pts received PD-1/L1 therapy as second-line tx. Grade ≥3 TRAEs occurred in 58.4% of pts with EV+P and 77.1% of pts with PBC. Most common grade ≥3 TRAEs of special interest for EV were skin reactions (16.2%), peripheral neuropathy (8.1%), and hyperglycemia (4.1%). Most common grade ≥3 tx-emergent AEs of special interest for P were severe skin reaction (14.7%), hepatitis (2.0%), and pneumonitis (2.0%). Conclusions: In this pt population with historically poor prognosis, EV+P improved clinical outcomes in pts who were ineligible for cis; results were consistent with the overall population. The risk of death was reduced by more than 50%. The AE profile of EV+P was generally manageable with no new safety signals. The results of EV-302 support EV+P as a new SOC for la/mUC, including pts who are ineligible for cis. Clinical trial information: NCT04223856 .

FGFR3 alterations (FGFRalt) in patients (pts) who develop locally advanced or metastatic urothelial cancer (mUC), and their association with tumor subtype and clinical outcomes in pts treated with erdafitinib (erda) vs. pembrolizumab (pembro).

4578 Background: Erda, an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor is approved to treat adult pts with locally advanced or mUC with susceptible FGFR3alt, whose disease progressed on or after at least one line of prior systemic therapy. In superficial and surgically resectable UC, FGFRalt has been shown to be highly associated with luminal subtype characterized by expression of luminal markers, low expression of basal markers and with immune cold / poor immune infiltration. In a randomized open-label phase III THOR study (Cohort 2), erda showed improvement in objective response and progression-free survival (PFS) compared to pembro, with no significant improvement in overall survival (OS). Exploration of subtypes in a large cohort of mUC pts has not been done and so a molecular analysis was undertaken to further understand the clinical findings. Methods: All available tumors from pts enrolled in Cohort 2 ( FGFRalt positive; N = 201) and a subset of FGFR wildtype (N = 116) were used to perform whole transcriptome RNA sequencing, where 152 and 84, respectively, passed quality control. The consensus single-sample classifier was applied to the RNAseq data to determine molecular subtypes. Tumor subtypes was correlated with treatment response to erda or pembro, PFS and OS. Results: Molecular classification of tumors identified a significant proportion of luminal-papillary (LumP) subtype in the tumors harboring FGFRalt compared to FGFR WT (78.3% vs. 36.9%, p < 0.001) vs. other subtypes: basal/squamous (Ba/Sq; 11.2% vs. 31.0%), stroma-rich (6.6% vs. 10.7%), neuroendocrine-like (0% vs. 2.4%), luminal-unstable (3.3% vs. 17.9%) and luminal-unspecified (0.7% vs. 1.2%), respectively. Consistently, FGFRalt type showed differential association with subtypes: 3.2% of fusions and 14.1% of mutations were detected in Ba/Sq subtype while 74.2% and 79.3%, respectively, were detected in LumP. Clinical outcomes evaluated within LumP subset showed a significant improvement in ORR of erda-treated vs. pembro-treated pts (41.7 vs. 19.7%; p = 0.01), which was consistent with the intent to treat (ITT) population (40.0% vs. 21.6%). Numerical improvement were observed in PFS in the LumP subtype between erda vs. pembro (5.5 vs 2.7 months) compared with the ITT population (4.4 vs 2.7). However, the benefit of erda over pembro in the LumP subtype did not translate to OS (10.9 vs. 12.9 months), similar to the ITT population (10.9 vs. 11.1 months). Conclusions: A significant overlap was identified between genomic selection of FGFRalt and the LumP subtype. Clinical outcomes based on transcriptomic analyses were consistent with those observed in the ITT population. These findings warrant further understanding of LumP tumors and association to treatment response. Clinical trial information: NCT03390504 .

Abstract PS04-02: BRCA testing and PARP inhibitor utilization in real-world HER2-negative metastatic breast cancer

Abstract Background: PARP inhibitors (PARPi) have demonstrated progression-free survival benefits vs. chemotherapy in patients (pts) with metastatic breast cancer (mBC) and germline BRCA mutations (gBRCAm). NCCN guidelines recommend that all pts with mBC are offered gBRCAm testing to aid in systemic treatment decisions with PARPi. Understanding real-world gBRCAm testing patterns and PARPi use would be beneficial for improving clinical outcomes of pts with gBRCAm mBC. Methods: This retrospective cohort study identified pts ≥ 18 years old with HER2-negative mBC, diagnosed from 2014 to 2022 (US Flatiron Electronic Health Record database). gBRCAm testing patterns in mBC over time were examined by BC subtype (hormone receptor-positive [HR+] or triple-negative breast cancer [TNBC]) and disease stage at diagnosis [de novo or recurrent]). Timing of gBRCAm testing and subsequent initiation of first-line or later PARPi in pts with gBRCAm HR+ and TNBC mBC was assessed in pts diagnosed after 2018 when PARPi were approved in mBC. Prevalence of gBRCAm was calculated overall and by mBC subtype. Demographic and clinical characteristics were described by gBRCAm testing and PARPi initiation (yes/no). Real-world overall survival (OS) by PARPi use since mBC diagnosis was estimated using the Kaplan-Meier method and a log-rank test. Results: Of 15,006 total pts, 4654 (31.0%) had a gBRCAm test. Compared with pts who were not tested, gBRCAm-tested pts were younger at initial mBC diagnosis (median age: 53.5 vs. 62.0 years), had a shorter median disease-free interval before mBC diagnosis (821 vs. 959 days), and were less likely to have de novo mBC (28.0% vs. 31.2%). gBRCAm testing prevalence was 6.1% in the HR+ group (n=11,945) and 8.9% in the TNBC group (n=2430). gBRCAm testing rates mostly increased from 2014 to 2022 and were lowest in HR+ tumor subtypes; < 2/3 of all pts had a gBRCAm test from 2020 onwards (Table). Most pts with recurrent mBC (HR+: 68.3%; TNBC: 76.1%) were gBRCAm tested before diagnosis, whereas pts with de novo mBC were tested at a later timepoint ( > 60 days after mBC diagnosis – HR+: 48.3%; TNBC: 38.4%). Of all pts with gBRCAm diagnosed from 2018 onwards (n=187), 44.4% initiated PARPi. A higher proportion of pts with gBRCAm in the TNBC group initiated PARPi (52.9%) than in the HR+ group (42.4%). Pts with gBRCAm in the TNBC group received PARPi earlier than pts with gBRCAm in the HR+ group (mean days from mBC diagnosis to first PARPi use: 173 and 411 days, respectively). Fewer pts with de novo mBC (35.7%) initiated PARPi than pts with recurrent mBC (50.8%). With a median follow-up of 15.3 months, pts with gBRCAm initiated on PARPi had numerically longer median OS (32.3 months [95% CI: 24.2–47.4]) than PARPi non-initiators (21.4 months [95% CI:18.4–43.5]). OS results should be regarded with caution due to the small sample size (n=187). Conclusions: Despite NCCN guideline gBRCAm-testing recommendations, < 2/3 of pts with HER2-negative mBC in our study were gBRCAm tested from 2020 onwards. gBRCAm testing was lower in pts with HR+ disease and was performed at a later timepoint for pts with de novo disease. Wider and timelier implementation of gBRCAm testing to identify pts that could benefit from PARPi is warranted. Fewer pts with gBRCAm who had HR+ tumors or de novo disease received PARPi than pts with TNBC. Our data suggest that pts who initiated PARPi had numerically longer OS than PARPi non-initiators; further research into OS trends and PARPi use in gBRCAm mBC would be of interest. Editorial acknowledgment: Medical writing assistance was provided by Leigh-Ann Booth, Ph.D. from BOLDSCIENCE Inc., funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US Legal entity responsible for the study: AstraZeneca. Funding: This study was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US, who are codeveloping olaparib. Table. gBRCAm testing rates over time in pts with HER2-negative mBC HER2-negative mBC is defined as IHC 0, or 1-positive, or IHC2-positive/ISH-negative. *Olaparib approved in mBC; †Olaparib approved in eBC. eBC, early breast cancer; gBRCAm, germline breast cancer gene mutation; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; pt, patient; TNBC, triple-negative breast cancer. Citation Format: Siddhartha Yadav, Sam Hillman, Linlin Luo, Weiyan Li, Jagadeswara Earla, Xiaoqing Xu. BRCA testing and PARP inhibitor utilization in real-world HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS04-02.

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.

Update results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in patients with hepatocellular carcinoma (HCC) at high risk of recurrence after surgery: A single arm, multi-center, phase II clinical trial.

513 Background: High recurrence rate after curative resection significantly compromised the long-term survival of patients with HCC patients (pts). TACE as adjuvant therapy was proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy. However, the prognosis of TACE reminded unsatisfactory and controversial. Therefore, this study aimed to identify the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. The update results were reported here with longer follow-up duration. Methods: HCC pts with one of the following high risk factors after hepatectomy: ≥5 cm and <10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II) were recruited. Eligible pts received cTACE treatment within 1-2 months after hepatectomy, on the 3-5th day after cTACE, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The predefined sample size was 30. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: The data cut-off date was March 2023, 29 pts were enrolled and 27 pts received at least once tumor assessment. The median follow-up was 21.8 (IQR, 17.3-26.3) months. Of 27 with assessable efficacy, mDFS was 24.2 (95% CI, not applicable-not applicable) months, with 12-, and 24-month DFS rates of 72.2% (95% CI, 50.4%-85.7), and 61.8% (95% CI, 38.8%-78.3%), respectively. 18 of 27 pts (66.7%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 4 pts (14.8%) included hypertension (7.4%), leukocytopenia (7.4%) and ascites (3.7%). No grade 4 or 5 TRAEs occurred. Conclusions: Anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in large scale clinical trials subsequently. Clinical trial information: NCT04213118 .

Impact of Type of Hypomethylating Agent (HMA) Used on Outcomes of Patients (Pts) with Higher-Risk Myelodysplastic Syndromes/Neoplasms (HR-MDS) - a Large, Multicenter, Retrospective Analysis

JPB and TK Co-first; RK and AMZ are Co-senior authors Introduction HMAs remain the mainstay for frontline treatment of HR-MDS. Azacitidine (AZA) and decitabine (DEC; including oral cedazuridine/decitabine) are the only FDA-approved HMAs. However, AZA and DEC have not been compared directly in randomized trials. In this study, we aimed to assess the clinical outcomes of pts with HR-MDS treated with different HMA regimens, focusing on overall survival (OS) and treatment responses. Methods The VALIDATE database includes pts with HR-MDS treated with HMA-based therapies in the frontline setting from 14 specialized MDS centers. HR-MDS pts treated with HMA-based therapies in the frontline setting were included. HR-MDS was defined as having an IPSS ≥1.5 or IPSS-R >3.5 (n=213 pts excluded). Pts were excluded from the survival analysis if age at diagnosis was <18 years (n=1), bone marrow (BM) blasts ≥20% or unknown at HMA initiation (n=61), or if survival status, follow-up time, date of HMA initiation, or HMA type was unknown (n=28). To be included in the analysis of response based on IWG 2023 criteria (Zeidan A et al, Blood 2023), pts had to have a BM response assessment within 180 days after HMA initiation to allow determination of response (n=290 pts excluded). Time to event analyses were estimated using the Kaplan-Meier method and treatment groups (AZA vs DEC monotherapy) were compared by log-rank test and assessed from the time of HMA initiation. Multivariable Cox regression models were performed among pts treated with AZA and DEC monotherapy to identify predictors of response and OS. This study was supported by an independent research grant from AbbVie. Results 1,223 pts were screened of whom 919 were included in the survival analysis. Median age was 68 years (Range [R]: 19-95) with 66% males. Our cohort was enriched for pts with adverse genetic features including complex karyotype (38%) and TP53 mutations (36%). Overall, 76% of pts were treated with HMA monotherapy (56% AZA, 20% DEC) and 24% received HMA-based combination therapy (HMA/VEN: 15%, other HMA combinations: 9%). 38.2% underwent allogeneic hematopoietic cell transplant (allo-HCT). The median HMA duration was 5 cycles (R: 1 - 94). Due to the small number and the heterogeneity of pts receiving HMA combinations, as well the multiple partner drugs used in these pts ( Table), we compared OS and responses only between pts treated with AZA (n = 512 pts) or DEC monotherapy (n = 186 pts). In unadjusted analyses, median OS differed by treatment type (p = 0.002) and was 19.8 months (mo) with AZA (95% CI: 17.0 - 23.1 mo) and 14.3 mo with DEC (95% CI: 11.2 - 18.5 mo). Among 629 pts evaluable for response, rates of complete remission (CR) and overall response (ORR) were 14.8% and 48.6% for AZA monotherapy and 5.6% and 50.4% for DEC monotherapy, respectively. In a Cox multivariable regression model ( Figure) adjusted for age, sex, TP53 mutation status, complex karyotype, IPSS-M category (compared to very high risk), and receipt of allo-HCT, there was no difference in OS when comparing AZA and DEC monotherapy (Hazard ratio [HR]: 0.95, 95% CI: 0.72 - 1.26; p = 0.740). Variables associated with adverse OS were male sex (HR: 1.52; 95% CI: 1.16 - 2.00; p = 0.002) and presence of TP53 mutation (HR: 1.50, 95% CI: 1.05 - 2.14; p = 0.027). Conversely, receipt of allo-HCT (HR: 0.26, 95% CI: 0.19 - 0.37; p<0.001) and IPSS-M moderate-high (HR: 0.57, 95% CI: 0.37 - 0.87; p=0.009) and moderate-low (HR: 0.58, 95% CI: 0.36 - 0.95; p = 0.031; both compared to IPSS-M very high risk) were associated with improved OS. Similarly, there were no statistically significant differences in ORR between AZA and DEC (OR: 1.05, 95% CI: 0.66 - 1.68; p = 0.832) in a Cox multivariable regression model adjusted for age, sex, TP53 mutation, complex karyotype, IPSS-M category, and treatment type. Conclusions: Among pts included in the real-world VALIDATE database, there were no significant difference in OS or ORR (IWG 2023) between AZA- and DEC-treated pts in adjusted analyses. Other factors (e.g., TP53 mutations, complex karyotype) are substantially more relevant to outcomes than the specific HMA used. The small number of pts and heterogeneity of partner drugs in HMA-based combinations precluded robust analyses or conclusions regarding differences in efficacy. Additional analyses evaluating the impact of combinations and molecular subtypes on response and survival will be presented during the meeting as more pts are added to the database.

Outcomes Multiple Myeloma Patients Progressing after BCMA-Directed Chimeric Antigen Receptor T Cell (CART) Therapy

Background: Chimeric Antigen Receptor T Cell Therapy (CART) targeting B-cell Maturation Antigen (BCMA) has gained approval for Relapsed/Refractory Multiple Myeloma (RRMM) following a minimum of four prior lines of therapy (LOT). Despite the significant improvement in outcomes with a remarkable progression-free survival (PFS) reported in pivotal trials, a substantial proportion of patients (pts) eventually experience disease progression. The available treatment options thereafter are currently limited, and the outcomes in this specific cohort of pts have not been extensively characterized. This study aimed to investigate the clinical outcomes of pts with RRMM who failed BCMA CART therapy, either as standard of care (SOC) or as part of a clinical trial. Methods: We conducted a retrospective analysis as of 7/10/2023 of RRMM pts progressing after BCMA CART and receiving the next LOT at the University of Kansas Medical Center in collaboration with US Myeloma Research Innovations Research Collaborative (USMIRC). Those who received therapy on clinical trial as the next LOT were included. Baseline demographic data were described, and outcomes were evaluated for two subgroups: “early” relapse pts (progression ≤ 6 months) and “later relapse”, those progressing after 6 months. Baseline pt characteristics were outlined by descriptive analyses. Responses including overall response rate (ORR), and complete response or better (>CR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Statistical analysis was done with the use of Fisher's exact test and the Kaplan-Meier method for progression-free (PFS) and overall survival (OS) calculations. OS was calculated from relapse after CAR-T till the last office visit/death. Regression models for univariate and multivariate analysis were performed. Results: Thirty pts were included in the analysis. Baseline demographics is summarized in Table 1. The majority (57%) had extramedullary disease (EMD) and 90% had an ECOG performance status of 0-1. The mean age of the pts was 61.3 years (SD=9.6), with 73% male and 80% White. Pts had 5 median prior LOT. All pts were refractory to PI, IMid, Daratumumab, double-refractory and-triple refractory. 63% were penta-refractory. Sixteen (53%) pts relapsed ≤ 6 mo after CART infusion and 14 (47%) relapsed after 6 months, with median follow-up of 21.73 Months (25-75 IQR: 13.87-40.17 mo). Baseline demographics were similar. The presence of 1p genetic mutation was significantly associated with lower incidence of early progression (early: 0% vs later: 36%, p=0.014). Also, pts with 2 autologous stem cell transplants (ASCT) had later relapses (early: 0% vs later: 43%, p=0.009). Outcomes with next LOT: Of these 30 pts, 10 received BCMA-directed therapies (3 got belantamab mefodotin and 7 received bispecifics (BCMA on Harpoon trial and teclistamab, 2 received GPRC5D targeting bispecific, talquetamab. The rest 18 (60%) got chemo immunotherapies including 1 ASCT and 5 VD-PACE/KD-PACE. 70% of pts progressed on the next LOT. Overall response rate (ORR) was 30%. (Figure 2a). There were 14 deaths, all related to myeloma progression. The median OS was 8.53 months (4.9-NR). Figure 2b summarizes the LOT and OS outcomes. In univariate analysis (UVA), EMD was associated with a significantly higher risk of death (HR=4.15, 95% CI=1.12-15.3, p=0.019), but this was not significant after adjusting in the multivariate analysis (MVA) (HR=2.74, 95% CI=0.63-11.8, p=0.2). Male gender was associated with worse survival in UVA. However, no factors were associated with a higher risk of death in a multivariate analysis. Conclusion: This study describes outcomes for post-CART relapse in RRMM. Most pts do not respond to the first LOT post-BCMA CART relapse. The survival was less than a year, suggesting need for further studies with a longer follow-up and larger sample size to establish the best regimen for CART failure and characterize prognostic factors associated with poor outcomes for CART relapses.

Clinical Outcomes with Prophylactic Corticosteroid Use for Axicabtagene Ciloleucel (axi-cel) in Patients with Relapsed/Refractory Large B-Cell Lymphoma (R/R LBCL): A Multicenter Analysis

Introduction: In Cohorts 1+2 of the ZUMA-1 Phase 1/2 study of axi-cel in R/R LBCL, 11% and 31% of patients (pts) experienced Grade ≥3 cytokine release syndrome (CRS) or neurologic evenets), respectively. To minimize the toxicities seen with axi-cel, a safety management cohort, Cohort 6 (N=40), was added to evaluate whether prophylactic (ppx) corticosteroids (CS) could decrease grade ≥ 3 CRS or ICANS. The 2-year update of ZUMA-1 Cohort 6 showed no grade ≥3 CRS and 15% grade ≥3 ICANS without any difference in objective response rate (ORR) or complete response rate (CR) when compared to cohorts 1+2 (Oluwole Blood 2022). The FDA had previously approved an update to the prescribing information for axi-cel to include use of ppx CS across all approved indications in January 2022. However, ppx CS is not a mandatory standard treatment and we sought to establish the clinical outcomes in the real-world practice. Methods: To assess the clinical outcomes of pts receiving ppx CS, we conducted a multicenter retrospective analysis of pts with R/R LBCL who were treated with axi-cel since the FDA approval of ppx CS in January 2022. Baseline characteristics, toxicities, and efficacy were compared between the no ppx and ppx CS groups. CRS and ICANS were graded based on ASTCT 2019 guidelines. Event-free survival (EFS) was defined as time from axi-cel infusion to progression, re-treatment, or death. Overall survival (OS) was defined as time from axi-cel infusion to death due to any cause. Results: A total of 66 pts at 5 centers received axi-cel between Jan 31, 2022, and June 20, 2023. Thirty-five (52%) pts received ppx CS, with a median age of 63 years (26-85 years). By histology, 75% (n=50) of the pts had DLBCL, 13.6% (n=9) had high grade B-cell lymphoma (HGBL), 9.1% (n=6) had transformed follicular lymphoma (TFL) and 1.5% (n=1) primary mediastinal LBCL (PMBCL). 59% of the pts (n=37) had IPI >2 and 66% (n=43) had stage III/IV disease. The baseline characteristics at the time of apheresis are shown in Table 1 and were comparable between the 2 groups, except for more HGBL, fewer prior lines of therapy and longer median time from apheresis to axi-cel infusion in the ppx CS group. Among the entire cohort, only 37% (n=25) met ZUMA-1 eligibility criteria at the time of lymphodepletion, and 67% (n=44) needed bridging therapy. Any grade CRS occurred in 88% (n=58) of the pts, with grade ≥2 CRS in 38% (n=25). Any grade ICANS occurred in 55% (n=37) of the pts, with grade ≥2 ICANS in 41% (n=27). Any grade ICANS was significantly lower in the ppx CS group than the no ppx group (45.7% vs 65.5%). The rates of any grade CRS, grade ≥2 CRS, grade ≥2 ICANS, the median time to CRS onset, ICANS onset, CRS duration, and ICANS duration were comparable between the 2 groups. Tocilizumab and steroids use was similar between two groups with a trend towards less ICU admission in patients in the ppx CS group. Overall, 14 (21%) pts developed infectious complications within 30 days of axi-cel infusion. The day 30 ORR was 84% and was comparable between the 2 groups (77% in the ppx group vs 93% in the no ppx group). The CR was 45.7% in ppx CS group compared to 65.5% in no ppx group. At a median follow up of 219 days (27-1178), 37 (56.1%) pts had progressed and 25 (37.9%) pts had died. The number of days to progress was significantly lower in the ppx CS arm. The median EFS and OS were not significant between the 2 groups. Conclusions: This multicenter retrospective study showed that the efficacy of treatment with axi-cel in R/R LBCL did not decrease with the use of ppx CS. No significant differences in efficacy or CAR-T-associated toxicities were noted in the 2 groups, potentially due to selective use with patients at presumed higher risk of severe CRS and ICANS. A larger dataset and longer follow-up is needed for risk-stratified analysis and the study is ongoing.

TP53 Mutations Detected By Clinical Laboratory Mutation Analysis Predict for Inferior Clinical Outcomes in Patients with Newly-Diagnosed Aggressive B Cell Lymphomas, Including Those with High-Risk Features

Introduction While comprehensive genomic analyses have identified genetic subgroups of diffuse large B cell lymphoma (DLBCL) when retrospectively performed on tumor biopsies (bx) from patients (pts) subsequently treated with R-CHOP (PMID 29713087, 29641966), it is unclear if these or similar assays can be applied in clinical practice. We aimed to determine if mutations (mut) detected in bx from newly-diagnosed DLBCL/high grade B cell lymphoma (HGBL) pts by clinical laboratory mutation analysis (CLMA) could predict for clinical outcomes following receipt of first-line therapy. Methods Pts with newly-diagnosed DLBCL/HGBL from January 2018-June 2022 whose bx underwent CLMA at the Penn Center for Personalized Diagnostics and received standard-dose R-CHOP or R-EPOCH as first-line therapy were included. Exclusion criteria were death due to non-lymphoma causes during first-line therapy and follow-up <1y after diagnosis if in remission. Pathologic workup of bx was performed as per institutional standard. Therapy was given at the discretion of the treating physician. Data were censored on July 1, 2023. Results One hundred thirty-seven pts met inclusion criteria, 15 were subsequently excluded and 117/122 pt bx underwent successful performance of CLMA (96%) with a median turnaround time of 17 days. Baseline characteristics, including mut occurring in ≥10% of cases tested, as well as genetic subgroup classification by LymphGen 2.0 based on available molecular data, are listed in the Table. R-CHOP was received by 72% of pts and R-EPOCH 38% of pts. The overall response rate (ORR) was 84% (complete response rate [CRR] 69%), and with a median follow-up of 31.3 months, estimated (est) 2 year (y) progression free survival (PFS), est 2y overall survival (OS) and est median OS post-relapse were 70%, 83% and 21.4 months (mo), respectively. Univariate analysis (UVA) identified HGBL classification, MYC rearrangement (R) and TP53 mut as significantly predictive of progression at 2y; however, only TP53 mut remained predictive on multivariate analysis (MVA) (HR 2.3, 95% CI 1.1-4.8, P=0.03). Additionally, UVA identified International Prognostic Index (IPI) score ≥3, HGBL classification, MYC-R, MYC-BCL2 double hit lymphoma, TP53 mut and TNFRSF14 mut as significantly predictive of death at 2y; however, only HGBL classification (HR 5.0, 95% CI 1.1-22.7, P=0.04) and MYC-R (HR 4.4, 95% CI 1.0-18.0, P=0.04) remained predictive on MVA. Given that TP53 mut predicted for both progression and death at 2y, we further analyzed bx with this mut. Forty-seven TP53 mut were detected in 42 pt bx, and were characterized as missense (mis) in 34, frameshift (fs) in 5, nonsense (non) in 5 splice site (ss) in 2 and other in 1. Thirty-eight (81%) TP53 mut were deemed loss of function (LOF), either as a mis/non mut designated as non-functional and/or LOF through The TP53 Database (https://tp53.isb-cgc.org/) or a fs/ss mut (PMID 22955915). Characteristics of pts with and without TP53 mut are listed in the Table. Significantly lower rates of ORR (71% vs 90%, P=0.009), CRR (55% vs 77%, P=0.01), est 2y PFS (57% vs 77%, P=0.006), est 2y OS (70% vs 91%, P=0.001) and est median OS post-relapse (6.1 mo vs not yet reached, P=0.001) were achieved by pts with vs without any TP53 mut. Est 2y PFS was 70% vs 33% ( P=0.01) and 2y OS was 85% vs 43% ( P=0.001) for pts with any TP53 mut treated with R-CHOP vs R-EPOCH. Additional analysis incorporating LOF status for TP53 mut revealed that for pts with at least one TP53 LOF mut vs only TP53 non-LOF mut vs no TP53 mut, 2y PFS was 51% vs 86% vs 77% ( P=0.002) as depicted in the Figure and 2y OS was 64% vs 100% vs 91% ( P=0.0004), respectively. Finally, stratified log-rank demonstrated either inferior or a trend towards inferior 2y PFS for pts with vs without TP53 LOF mut harboring high-risk features, including IPI score ≥3 (42% vs 80%, P=0.009), HGBL histology (25% vs 70%, P=0.046), non-GCB cell of origin by Hans algorithm (52% vs 81%, P=0.01), MYC rearrangement (33% vs 48%, P=0.17), MYC-BCL2 double hit lymphoma (40% vs 67%, P=0.34) and EZB genetic subgroup (30% vs 81%, P=0.04). Conclusions TP53 mut identified through CLMA, specifically those resulting in LOF, predict for inferior clinical outcomes in pts with newly-diagnosed DLBCL/HGBL. Results of CLMA can be practically used to inform prognosis and/or identify pts for clinical trials investigating therapies targeting derangements caused by specificmut.

Real-world overall survival (OS) of patients (pts) with metastatic urothelial carcinoma (mUC) receiving first-line (1L) systemic therapy (tx): Results from IMPACT UC II.

529 Background: Urothelial cancer (UC) is the most common urinary system cancer. The IMPACT UC II study aimed to assess tx patterns and clinical outcomes in pts with mUC treated with platinum-based chemotherapy or immuno-oncology monotherapy (IO-mono) in 1L. Methods: This was a retrospective claims analysis of pts diagnosed with mUC from July 2015 to June 2020 and continuously enrolled for 6 mo before and ≥6 mo after index date (ie, date of first claim) using Optum Research Database, which represents ≈8% of commercially insured and 18% of Medicare Advantage (MAPD) populations. Pts were followed up until disenrollment, study end in August 2021, or death. Analyses examined OS and time to 2L tx (TT2L) in three tx cohorts: cisplatin (cis)-based, carboplatin (carbo)-based, or IO-mono. Results: Of 3,006 pts diagnosed with mUC, 1,037 received 1L tx: 365 (35.2%) with cis-based tx; 337 (32.5%) with carbo-based tx, and 335 (32.3%) with IO-mono. Among treated pts, mean age was 72.5 years (SD, 9.9 years), 72.3% were male, and 77.4% were MAPD insured. At baseline, pts receiving cis-based tx had a lower percentage of ≥3 comorbidities (defined by National Cancer Institute criteria): cis-based, 22.2%; carbo-based, 39.5%; and IO-mono, 45.1%. Among 290 pts (27.9%) receiving 2L tx, carbo-based tx had the shortest median TT2L (5.7 mo). Pts receiving cis-based tx had the longest median OS (27.4 mo). Relative to cis-based tx, multivariable–adjusted mortality risk was 2 times higher with IO-mono (hazard ratio [HR], 2.0; 95% CI, 1.6-2.5) and 1.5 times higher with carbo-based tx (HR, 1.5; 95% CI, 1.3-1.9) (Table). Conclusions: This study shows that, before avelumab 1L maintenance approval, the majority of pts did not receive any systemic anticancer tx. following mUC diagnosis. In 1L, after multivariable adjustment (including for baseline comorbidities), real-world OS was lower in pts receiving carbo-based tx and IO-mono compared with cis-based tx. Future research should examine outcomes with newer standard of care.[Table: see text]

SDPS-10 DISPARITIES IN THE RISK OF CNS METASTASIS AND CLINICAL OUTCOMES IN PATIENTS WITH HER2- MUTATION POSITIVE (HER2+) NON-BREAST VERSUS HER2+ BREAST CANCERS

Abstract BACKGROUND Risk of CNS metastases is well characterized for patients (pts) with HER2+ breast cancer (BC), however, poorly defined for pts with HER2+ non-breast solid tumors (ST). METHODS We performed a retrospective cohort analysis to characterize the frequency of CNS metastasis and clinical outcomes in pts with Her2+ ST treated at the University of Virginia Emily Couric Cancer Center between 01/2010- 01/2022. Risk of CNS metastasis, time to CNS metastasis, progression free survival (PFS) and overall survival (OS) were analyzed for each cohort and stage IV subgroups. The outcomes were further compared between HER2+ ST vs BC cohorts. RESULTS 50 pts had HER2+ ST and 383 had HER2+ BC. In the ST group, median age was 66.0 years (y), 37 (74.0%) were male, 43 (86.0%) were white and 2(4.0%) were African American. Majority (74%) of patients had gastro-esophageal tumors. Median time to CNS metastasis was 5.8 y and median PFS was 0.7 y (95% CI 0.55-0.98, p<0.05). In those with CNS metastasis 5 (50%) received CNS directed plus HER2 targeted therapy and 3(30%) received CNS directed therapy alone. 24 (48%) pts had baseline CNS imaging in ST group, compared to 11 (2.9%) in the BC group. Rate of CNS metastasis was 20% (n=10) vs 6.8% (n=26) in the ST and BC cohorts (p<0.0001). OS differs in ST vs BC cohorts overall (p<0.0001; median OS 1.7 vs 18.5y) and in patients with metastatic disease at diagnosis (p<0.0001; median OS 1 vs 6.3y). Advanced N (p=0.0445) and smoking (p=0.0868) were associated with early CNS metastasis CONCLUSIONS Pts with HER2+ ST have higher risk of CNS metastasis and shorter OS compared to BC pts. Improved understanding of disease characteristics and standardized management approaches are imminently needed to improve outcomes.

Effect of CBM588 in combination with cabozantinib plus nivolumab for patients (pts) with metastatic renal cell carcinoma (mRCC): A randomized clinical trial.

LBA104 Background: We have previously demonstrated that the live bacterial product CBM588 may augment clinical outcomes in pts with mRCC receiving 1st-line (1L) therapy with dual immune checkpoint inhibitors (ICIs; Dizman et al Nature Medicine 2022). As tyrosine kinase inhibitors (TKIs) in combination with ICIs also represent a 1L standard of care in mRCC, we sought to determine if CBM588 would augment clinical outcome with the TKI cabozantinib (cabo) with nivo. Methods: Eligible pts were ≥18 yrs old (Karnofsky performance status ≥70%) with histologically verified (clear-cell, papillary or sarcomatoid component) mRCC and no prior systemic therapy for metastatic disease. Patients were randomized 1:2 to receive either cabo/nivo at the standard dose/schedule (40mg PO QD and 480mg IV monthly, respectively) alone or with CBM588 dosed at 80mg PO BID. The primary endpoint was the relative abundance of Bifidobacterium spp. in stool specimens at baseline and after 12 weeks of treatment. Secondary endpoints included assessment of response rate, overall survival, progression-free survival (PFS), systemic immunomodulation, and toxicity. A two-group t-test with a one-sided type I error of 0.05 was used to assess the study's primary endpoint, hypothesizing an increase in Bifidobacterium spp. with CBM588 therapy. Results: A total of 30 (20:10 M:F) pts were recruited; median age was 65 (36-84) and 5 pts (17%) had sarcomatoid features and 2 pts (7%) had predominant papillary histology. 12 (40%), 12 (40%) and 6 pts (20%) had good, intermediate and poor risk, respectively. Metagenomic sequencing of paired stool specimens showed a significant decrease in diversity from baseline to week 12 in patients receiving cabo/nivo (P=0.02); no significant difference was observed in those treated with cabo/nivo+CBM588. No significant change in Bifidobacterium spp. was observed. RR was 63% in pts receiving cabo/nivo+CBM588 vs 33% in pts receiving cabo/nivo alone. Median PFS was not reached in pts receiving CBM588 vs 5.8 mos in pts receiving cabo/nivo along (P=0.03). Grade 3/4 toxicities were observed in 44% and 42% of patients on control and experimental arms, respectively. Conclusions: In the second prospective trial assessing the addition of CBM588 to ICI-based therapy in mRCC, a consistent result with improved PFS and RR was observed. Further translational efforts are underway to characterize the mechanism through which CBM588 augments clinical activity. Clinical trial information: NCT05122546 .

Clinical efficacy analysis of patients (pts) with HER-2 expressing metastatic urothelial carcinoma (mUC) treated with enfortumab vedotin (EV).

e16618 Background: EV, an antibody drug conjugate (ADC) targeting NECTIN-4, is an approved salvage treatment for unselected pts with mUC. ADCs targeting the human epidermal growth factor receptor-2 (HER-2) have also shown robust activity in clinical trials for mUC with tumor HER-2 expression. We investigated the interaction between HER-2 expression and clinical outcomes of pts treated with EV, which are currently unknown. Methods: We conducted a retrospective, single institution study analyzing pts with mUC who received EV. Immunohistochemistry (IHC) staining for HER-2 was completed with PATHWAY anti-HER2 (4B5) Antibody (Ventana Medical Systems, Tucson, AZ) using established breast cancer scoring algorithm. Wilcoxon rank sum and Fisher exact tests were used to compare continuous and categorical variables, respectively. Cox proportional hazards regression model was used to evaluate a variable’s ability to predict overall survival (OS). Variables with p-value ≤0.1 were included in the multivariate analysis (MVA). Results: We identified 158 pts with mUC who received EV. Median age at EV start was 70 (IQR 66-76), most pts were Caucasian (144, 91%), male (108, 68%), primary bladder tumors (113, 72%), and pure urothelial histology (95, 60%). 96 pts (61%) received prior platinum therapy and 117 pts (74%) had prior immunotherapy. ECOG scores ≥2 was seen in 54 pts (39%) while 75 pts (54%) had Bellmunt scores ≥2 (54%). Median follow up time was 12.5 months and median OS from EV start was 13 months. 94 pts (60%) had HER2 IHC staining. There was no association between HER2 intensity and any of the clinical variables. On univariate analysis (UVA): HER2 3 vs HER2 ≤2 HR was 0.38 (0.14, 0.98), male vs female HR=1.56 (0.94, 2.58), ECOG ≤1 vs ≥2 HR=0.6 (0.38,0.95), Bellmunt score 0-1 vs 2-3 HR=0.49 (0.3, 0.78), and hemoglobin (Hgb) HR=0.75 (0.67, 0.85). MVA showed HER2 3 vs HER2 ≤2 HR was 0.42 (0.16, 1.12), male vs female HR=2.3 (1.17, 4.42), ECOG ≤1 vs ≥2 HR=0.56 (0.30, 1.05), and Hgb HR=0.77 (0.65, 0.92). Conclusions: MVA of this single-site retrospective cohort did not show any association between HER2 expression and survival outcomes in pts with mUC who received EV. Further studies are needed to continue assessing the role of HER2 as a potential prognostic and predictive biomarker in UC, especially if HER-2 directed therapies become incorporated in the mUC treatment paradigm. [Table: see text]

Impact of smoking status (SS) on the clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with first line (1L) immuno-oncology (IO)-combination regimens: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

4555 Background: Active smoking is associated with decreased overall survival (OS) in patients (pts) with mRCC treated with VEGF targeted therapy (VEGF-TT) (Kroeger N. et al. 2019, IMDC investigators). Conversely, smoking history has been linked to improved OS in pts with advanced non-small cell lung carcinoma (NSCLC) receiving 1L pembrolizumab monotherapy (Popat S. et al., 2022). Herein, we assess the association between SS and outcomes in pts with mRCC treated with 1L standard of care (SOC) IO-based regimens. Methods: Real-world data from the IMDC were collected retrospectively. We included mRCC pts who received either dual IO therapy or IO + VEGF-TT in the 1L setting and known SS at disease diagnosis. Pts were categorized as current, former and non-smokers. The primary outcomes were OS, time to treatment failure (TTF) and objective response rate (ORR) on 1L IO-based regimens. OS and TTF were evaluated using Cox regression, adjusting for age at 1L treatment, IMDC risk groups, BMI, histological type and time from diagnosis to 1L treatment initiation. ORR was compared between the SS groups using a logistic regression, adjusting for the same confounders. Results: 989 pts were eligible and included. 438 (44.3%), 415 (42%), and 136 (13.7%) pts were non-smokers, former, and current smokers at diagnosis, respectively. Median time from diagnosis to initiation of 1L IO-based treatment was 0.47 years (IQR 0.13-2.15). At baseline, there were no significant differences in age at 1L, IMDC risk groups, KPS status, BMI, and presence of sarcomatoid features across the 3 groups (p>0.05). Median follow up was 21.2 months from 1L IO-based treatment initiation. On multivariable analysis, no significant differences in OS, TTF or ORR were seen between the SS groups (p>0.05). Conclusions: To our knowledge, this represents the first and largest effort to evaluate the impact of smoking on clinical outcomes in pts with mRCC treated with IO-based regimens. There was no association between SS at diagnosis and the clinical outcomes of patients with mRCC receiving current 1L SOC IO-based regimens. As opposed to other cancer types (i.e., NSCLC), current or past smoking history did not appear to be predictive of benefit from IO-based therapy. [Table: see text]

Clinical outcomes with neoadjuvant nivolumab (N) + chemotherapy (C) vs C by definitive surgery in patients (pts) with resectable NSCLC: 3-y results from the phase 3 CheckMate 816 trial.

8521 Background: In CheckMate 816, neoadjuvant N + C demonstrated statistically significant and clinically meaningful improvements in event-free survival (EFS) and pathologic complete response (pCR) vs C in pts with resectable NSCLC. Here, we report clinical outcomes in pts with or without definitive surgery following neoadjuvant treatment (tx). Methods: Adults with stage IB (tumors ≥ 4 cm) to IIIA (per AJCC 7th ed) resectable NSCLC, ECOG PS ≤ 1, and no known EGFR/ ALK mutations were randomized 1:1 to 3 cycles of N 360 mg + C Q3W or C Q3W, followed by definitive surgery within 6 wk of tx. Primary endpoints were EFS and pCR, both per blinded independent review. Exploratory analyses included EFS (secondary definition; no censoring for subsequent tx), time to death or distant metastasis (TTDM), and EFS2 (EFS on next-line tx) in pts with or without surgery. Results: Among 358 randomized pts, 149 (83%; N + C) and 135 (75%; C) had definitive surgery. Baseline characteristics were similar in pts with or without surgery (N + C, 30; C, 44) and between tx arms, except that a higher proportion of pts who did not have surgery had ECOG PS 1 (both arms) or were from Europe (N + C arm). Surgery was canceled due to progressive disease (PD) in 11 (N + C) and 17 (C) pts; PD was locoregional in 4 and 15 pts and distant in 3 and 2 pts, while 4 pts in the N + C arm had both locoregional and distant PD. At database lock (October 14, 2022; median f/u: 41.4 mo), EFS, TTDM, and EFS2 were numerically improved in pts with vs without surgery, regardless of tx arm. In pts with surgery, median TTDM was not reached (NR) vs 46.8 mo (HR, 0.55) with N + C vs C, respectively; 3-y TTDM rates were 77% vs 59%. In pts without surgery, median TTDM was 24.8 vs 15.6 mo (HR, 0.63) with N + C vs C; 3-y rates were 36% vs 13%. Among pts without surgery, 17 (57%) vs 28 (64%) pts in the N + C vs C arms, respectively, received subsequent tx: radiotherapy 37% vs 41%; surgery 3% vs 2%; systemic tx 50% vs 52%. Grade 3/4 tx-related AEs occurred in 38% (N + C) and 36% (C) in pts with surgery, and 26% and 46% in pts without surgery. Conclusions: In CheckMate 816, neoadjuvant N + C demonstrated long-term clinical benefit vs C in pts with resectable NSCLC who received definitive surgery. In pts who did not receive definitive surgery, these exploratory analyses showed that neoadjuvant N + C was associated with numerically improved TTDM. Clinical trial information: NCT02998528 . [Table: see text]

Clinical outcomes of patients with multiple myeloma following disease progression after BCMA-targeted CAR T-cell therapy.

e20002 Background: While BCMA-targeted CAR T therapies have yielded unprecedented efficacy in patients with multiple myeloma, most patients (pts) experience disease relapse. Treatment after progression on CAR T has become an unmet need given the limited novel treatment options available. We evaluated clinical outcomes for pts relapsing after BCMA CAR T. Methods: This was a single-center retrospective analysis including pts who had been treated with a BCMA-targeted CAR T therapy prior to 12/31/22 and then had disease progression. Data for all subsequent lines of therapy were collected, and best response to therapy was graded as per IMWG criteria. Statistics were descriptive in nature. Results: Thirty pts treated with BCMA CAR T (14 trial, 16 commercial) relapsed. The cohort of median age 61 had notable disease characteristics of 40% with high-risk FISH and 30% with extramedullary disease (EMD). The median number of prior lines of therapy (LOT) was 5, with 80% triple-class refractory and 47% penta-refractory. Patients treated with late BCMA CAR T (≥ 4 prior LOT; n=20) had higher rates of EMD (40% v 10%), triple-class refractory (90% v 60%), and penta-refractory disease (55% v 30%) compared to pts who received early CAR T (< 4 prior LOT; n=10). At data cutoff, 4 pts died without receiving subsequent therapy and 1 pt was pending start of their first regimen. The remaining 25 pts received 58 salvage therapies, of which 54 regimens were evaluable for response. The overall response rate (ORR) for all regimens was 46%. Median overall survival (OS) was not reached, and the 6 and 12-month OS rates were 83% and 77% respectively. ORR and median progression free survival (PFS) stratified by the specific type of salvage therapy are shown in the table. Patients who received a regimen consisting only of agents they had received in a prior LOT had an ORR of 57% and median PFS of 3.6 months. Patients who received early CAR T had a higher ORR to all subsequent salvage therapies (59% v 33%), longer median PFS (4.6 months v 1.6 months), and higher 12-month OS (90% v 70%). Conclusions: For pts with progression after BCMA CAR T, treatment with another BCMA CAR T or transplant had more favorable outcomes. Retreatment with prior therapies resulted in disease control for a fair number of patients, which can serve as a bridge to another novel therapy. The pts treated with early CAR T had more favorable post-progression outcomes than late CAR T, yet 70% of pts who received late CAR T were alive at 1 year post-progression. [Table: see text]

Mass cytometry immune profiling to detect signatures of clinical activity of bintrafusp alfa (BA) in patients with advanced non-small cell lung cancer (NSCLC).

e21016 Background: BA, a bifunctional fusion protein targeting programed death-ligand 1 and transforming growth factor-β, is clinically active in a subset of patients (pts) with advanced NSCLC. In this study, mass cytometry was used to identify immune features associated with response and survival in pts with NSCLC treated with BA. Methods: Peripheral blood mononuclear cells were collected at baseline and after 1 and 3 doses of BA from 12 NSCLC pts treated every 2 weeks in a dose expansion biomarker cohort of a phase I clinical trial (NCT02517398). Samples were analyzed using a 44-marker mass cytometry panel designed to detect immune cell subsets and functional states of the innate and adaptive immune system. Manually gated immune cell subpopulations and unsupervised clusters were analyzed with Kruskal Wallis and Wilcoxon Rank Sum testing for multigroup comparison; and with linear correlation, univariate Cox regression and Kaplan Meier methods for progression free survival (PFS) analysis. Results: Among 12 pts, 3 had an objective response (OR), 6 had stable disease (SD) and 3 developed progressive disease (PD). Immune cell subsets associated with clinical activity by multigroup analyses included memory B cells, CD16+ natural killer (NK) cells, and double negative T cells (DNT). Pts with OR had a 2-fold higher frequency of memory B cells at baseline compared to pts who developed SD or PD. After 1 dose of BA, pts who subsequently developed an OR or SD had a 5-fold increase of CD16+ NK cells compared to pts with PD. After 3 doses of BA, pts who subsequently developed an OR had 4-fold more memory B cells and 3-fold more T-bet+ DNTs compared to pts with PD or SD. Immune cell subpopulations associated with survival included 3 unsupervised clusters annotated by the clustering algorithm as CD16+ NK cells, DNTs and classical monocytes. Fewer CD16+ NK cells at baseline were associated with longer PFS (p = 0.0053). Longer PFS was also associated with higher CD161+ CD127+ DNT cells after 1 dose of BA relative to baseline (p = 0.029), while an expansion of IgG4+ PD-1+ classical monocytes after 3 doses of BA was associated with shorter PFS (p = 0.015). Linear correlation analysis did not find strong associations between any one immune state and survival. Conclusions: Our study demonstrates the ability of mass cytometry immune profiling to detect potential immunological markers of response and survival in NSCLC pts treated with BA. The association between CD16+ NK cell frequencies and clinical benefit could reflect the ability of BA to facilitate antibody-dependent cellular cytotoxicity by NK cells in NSCLC. A high fraction of memory B cells at baseline and after 3 doses identifies pts likely to respond to BA. If validated in larger studies, these novel immune signatures can be used to improve clinical outcomes in pts with NSCLC considering immunotherapy.

Clinical outcomes in patients with post-chemotherapy residual non-retroperitoneal (RP) disease in non-seminomatous germ-cell tumors (NSGCT).

e17027 Background: In patients (pts) with metastatic NSGCT, the presence of teratoma in the primary tumor specimen or in the post-chemo RP lymph node dissection (RPLND) has previously been shown to have no impact on prognosis. We report clinical outcomes of pts based on pathology in primary tumor and from post-chemotherapy non-RP disease surgical resection. Methods: The prospectively maintained Indiana University testicular cancer database was queried for pts with metastatic NSGCT treated between 1990-2021 who completed first-line chemotherapy and had residual extra-RP disease in the absence of residual RP disease. Pts who had post-chemo non-RP surgical resection were included. Kaplan-meier methods were used to analyze progression-free survival (PFS) and overall survival (OS). Results: 131 pts met eligibility. Median age at diagnosis was 28.6 (range, 16.2-51.5). Primary site was testis in 130 pts (99%). Primary tumor predominant histology was embryonal (34.4%), mixed (26%), choriocarcinoma (14.5%), teratoma (11.5%), yolk sac (10.7%), seminoma (1.5%). Metastatic sites at diagnosis were lung (27.5%), brain (19.8%), RP (14.5%), liver (8.4%), mediastinal LN (7.6%), bone (7.6%). All pts with RP mets at diagnosis had normalization of RP nodes after chemo. All pts had surgical resection of non-RP disease. None had RPLND. IGCCCG risk was good in 56, intermediate in 23, and poor in 52 pts. Median pre-chemo AFP was 66.7 (0.9-467,000). hCG was 692 (0.5-500,000). First-line chemo was BEPX4 in 68, BEPX3 in 29, EPX4 in 10, VIPX4 in 8, and other in 16 pts. 76 pts (58%) had teratoma in the primary tumor. Median follow-up was 3.16yrs. 2-yr PFS for pts with teratoma in primary was 59% (95% CI 45-71) vs. 54% for pts without (95% CI 38-67); p = 0.42. 2-yr OS for pts with teratoma in primary was 85% (95% CI 73-92) vs. 70% for pts without (95% CI 54-81); p = 0.18. 2-yr PFS and OS based on pathology and location of non-RP site are listed in Table 1. Conclusions: The presence of teratoma in primary tumor and post-chemotherapy non-RP resections is not associated with worse PFS or OS in pts with metastatic NSGCT. [Table: see text]