1L Pts Research Articles

Efficacy and safety of 1L selpercatinib in RET fusion-positive NSCLC: LIBRETTO-431 East Asian subgroup analysis.

214 Background: In prior studies, the efficacy and safety of selpercatinib, a selective RET inhibitor, was consistent in RET+ NSCLC pts across geographies. As previously reported, LIBRETTO-431 met its primary endpoint of improved PFS by blinded independent central review (BICR) at the pre-planned interim analysis. Here we report the efficacy and safety from LIBRETTO-431 in pts from East Asia, a majority of the study population. Methods: LIBRETTO-431 (NCT04194944) is a randomized, open-label phase 3 trial comparing 1L selpercatinib vs control (platinum/pemetrexed +/- pembrolizumab). Geography (East Asia vs non-East Asia) was a stratification factor. BICR-assessed PFS, ORR and DOR were examined in pts from East Asia randomized with investigator’s intent to treat with pembrolizumab (ITT-pembro) if assigned to control. AE data were collected for all pts from East Asia who received at least one dose of selpercatinib or control (n=140). Results: Of 142 randomized pts from East Asia, 116 were included in the ITT-pembro population (selpercatinib: n=75, control: n=41). Baseline characteristics were well balanced, however the selpercatinib arm had slightly more pts from East Asia vs the control arm (58% vs 49%). In ITT-pembro pts from East Asia, with a median follow up of 19.4 mo and 21.2 mo in the selpercatinib and control arms respectively, the median PFS was not yet reached with selpercatinib (95% CI: 16.4-NE) vs 11.1 mo (95% CI: 7.0-16.8) with control. At 12 mo the PFS rate was 72.8% with selpercatinib vs. 41.7% with control. The ORR was 86.7% (95% CI: 76.8-93.4) with selpercatinib vs 61.0% (95% CI: 44.5-75.8) with control. Similar results were observed in pts from East Asia in the overall ITT population. The most common AEs reported in pts from East Asia on selpercatinib included elevated AST (73.6%), elevated ALT (70.3%), hypertension (60.4%), increased blood bilirubin (52.7%) and diarrhea (44.0%) while those reported with control included anemia (61.2%), elevated AST (49.0%), leukopenia (49.0%), neutropenia (44.9%) and elevated ALT (42.9%). A summary of safety data for selpercatinib vs control in pts from East Asia is presented in the table. Conclusions: LIBRETTO-431 is the first randomized study to report efficacy and safety of a RET inhibitor in pts from East Asia. Consistent with the results in the overall population, selpercatinib demonstrated superior PFS compared to chemotherapy + pembrolizumab in 1L pts from East Asia. These data support early comprehensive genomic testing and the use of selpercatinib as the preferred 1L regimen in RET+ NSCLC pts across geographies. Clinical trial information: NCT04194944 . [Table: see text]

Effectiveness and safety analysis of serplulimab-based regimens in patients with HER2-negative advanced gastric cancer from a real-world retrospective study.

e16058 Background: Immune checkpoint inhibitors (ICIs) combined with chemotherapy are currently the preferred regimen for the treatment of HER-2 negative advanced gastric cancer. Serplulimab, an anti-PD-1 inhibitor, has been conditionally approved for the treatment of adult advanced gastric cancer. Because of the diverse nature of patients (pts), patient-centered, individualized treatment require accumulation of experience for real-world applications. Methods: We retrospectively studied 42 HER2-negative advanced gastric adenocarcinoma pts whose safety profiles of regimen containing serplulimab could be evaluated from April 2022 to October 2023 in the First Affiliated Hospital of Soochow University. Individualized treatment regimens mainly included serplulimab combined with one or two selected drug(s) from platinum, taxanes, and fluoropyrimidines. Results: Cut-off on January 30th, 2024, 30 pts (71.4%) received serplulimab based regimens as the first line (1L), 12 pts (28.6%) received the second or more line (≥2L) therapy. The characteristics were as follows: the median age, 66 years (range 35-80 years); male/female 33 (78.6%)/9(21.4%); ECOG performance status 0-1/38, ≥2/4. The median follow-up was 5.7 months (range 0.2-22.3 mos). A total of 227 cycles of treatment was administrated with a median of 4 cycles (range 1-17). Among the pts evaluable for RECIST 1.1, ORR and DCR were 42.9% and 69.0% respectively. There were 3 pts with 3 or more metastatic lesions achieved PR. Nine 1L pts and one 2L pt receiving serplulimab combined with dual chemotherapy containing platinum achieved disease control more than a year. We also tracked 11 pts who experienced grade 1-2 immune-related adverse events (irAEs) reaped over 6 months PFS. Two of four pts who stopped immunotherapy but maintained 1 or 2 cycles of original combined chemotherapy obtained PFS for more than a year. Median PFS and DoR have not reached. The most common grade 3/4 AEs was myelosuppression (7.1%), increased aminotransferases (4.7%) and elevated creatinine (2.3%). 15 (35.7%) pts experienced immune-related adverse events (irAEs) of any grade including aminotransferase elevation, increased creatinine, but no grade 3 or higher irAEs observed. Conclusions: The real-world data analysis shows that serplulimab-based flexibly combination according to patient status, achieving tumor control in diverse pts while ensuring drug safety. We successfully validated the effectiveness and safety of chemo-immunotherapy strategy in real-world practice. [Table: see text]

Assessing Adoption of Standard of Care and Comparing Clinical and Demographic Differences in First-Line (1L) Treatment (Tx) of Chronic Lymphocytic Leukemia (CLL)

Assessing Adoption of Standard of Care and Comparing Clinical and Demographic Differences in First-Line (1L) Treatment (Tx) of Chronic Lymphocytic Leukemia (CLL)

Safety and clinical activity of oleclumab (O) ± durvalumab (D) + chemotherapy (CT) in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A phase 1b/2 randomized study.

4136 Background: In a phase 1 study, the anti-CD73 monoclonal antibody (mAb) O plus the anti-PD-L1 mAb D showed antitumor activity and manageable safety in previously treated pts with advanced PDAC (Overman et al, J Clin Oncol 2018;36[suppl 15]:abs 4123). Here we report a multicenter, open-label study of O ± D + CT in pts with mPDAC. Methods: Pts were ≥18 years old with ECOG PS 0–1. Part 1 was a dose escalation phase: in Cohort A, previously untreated (1L) pts received O 1500 or 3000 mg IV Q2W for 4 doses then Q4W + D 1500 mg IV Q4W, with Q4W gemcitabine and nab-paclitaxel (GnP). In Cohort B, pts with previous G-based CT (2L) received O 1500 or 3000 mg Q2W for 4 doses then Q4W + D 1500 mg Q4W, with Q4W mFOLFOX. The primary objective for Part 1 was safety and tolerability; secondary objectives included antitumor activity and pharmacokinetics (PK). Part 2 was an expansion phase in which pts were stratified by high/low tumoral CD73 expression by IHC. In Cohort A, 1L pts were randomized 1:1:1 to GnP alone (Arm A1), O + GnP (Arm A2) or O + D + GnP (Arm A3). O was given at the recommended phase 2 dose, 3000 mg. Cohort B did not proceed to dose expansion due to emerging therapies in 2L PDAC pts. The primary endpoint for Part 2 was investigator-assessed objective response rate (ORR) by RECIST v1.1; secondary included PFS, OS, safety, PK and antidrug antibody data. Results: As of November 11, 2022, 25 pts were treated in Part 1 (Cohort A, n=14; Cohort B, n=11), and 170 pts were treated in Part 2 (Arm A1, n=62; Arm A2, n=38; Arm A3, n=70). In Part 1, dose-limiting toxicities occurred in 1 pt (Cohort B, O 3000 mg: Gr 3 nausea and Gr 3 localized edema). Safety was generally similar in Parts 1 and 2. In Part 2, Gr ≥3 treatment-emergent adverse events (TEAEs) occurred in 85.5%, 89.5% and 90.0% of pts in Arms A1, A2 and A3 respectively, most commonly neutropenia (22.6%, 34.2% and 17.1%). In Part 2, TEAEs led to discontinuation in 11.3%, 23.7% and 24.3% of pts respectively. In Part 2, ORR was similar across Arms with a trend toward longer PFS and OS in Arm 3 vs Arm 1. There was a trend toward greater clinical benefit in pts with high CD73 expression when comparing Arm A3 vs Arm A1. Conclusions: O + D + GnP had similar safety and a trend toward improved outcomes compared to GnP. Clinical trial information: NCT03611556 . [Table: see text]

Metabolic response rates of epcoritamab + R-CHOP in patients with previously untreated (1L) high-risk diffuse large B-cell lymphoma, including double-hit/triple-hit lymphoma: Updated EPCORE NHL-2 data.

7519 Background: Patients (pts) with 1L diffuse large B-cell lymphoma (DLBCL) typically receive rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); however, around 40% relapse. Complete response rates and long-term outcomes are worse for high-risk pts with International Prognostic Index (IPI) 3–5 or double-hit/triple-hit lymphoma, representing an underserved pt population requiring better curative options. Data from the pivotal study of single-agent epcoritamab, a T-cell–engaging bispecific antibody, demonstrated impressive efficacy and a manageable safety profile (Thieblemont et al, JCO 2022). Preliminary data for epcoritamab + R-CHOP in 1L DLBCL (NCT04663347) showed encouraging efficacy. Here we present results for a larger cohort with longer follow-up. Methods: Pts with 1L CD20+ DLBCL and IPI ≥3 received subcutaneous epcoritamab (cycle [C] 1–4, QW; C5–6, Q3W) + R-CHOP for 6 Cs (21 d each) followed by epcoritamab monotherapy Q4W (28-d Cs) up to a total of 1 y. Results: As of Oct 31, 2022, 47 pts (median age, 64 y) had received epcoritamab 48 mg + R-CHOP with a median follow-up of 11.5 mo (range, 0.8–15.5). All pts had IPI 3–5, 37 (79%) had stage IV disease, and of 25 pts with FISH data available, 11 (44%) had double-hit/triple-hit DLBCL. Median time from diagnosis to first dose was 28 d (range, 3–423). Median dose intensity for R-CHOP was ≥95%. The most common treatment-emergent AEs (TEAEs) of any grade (G) were neutropenia (64%), anemia (62%), CRS (60%), fatigue (40%), pyrexia (40%), injection-site reactions (38%), and nausea (38%). TEAEs led to epcoritamab discontinuation in 3 pts; 1 pt had a G5 TEAE (COVID-19, unrelated to treatment). CRS was predominantly low grade (57% G1–2, 2% G3) and occurred mostly after the first full dose (C1D15); all cases resolved. One pt experienced G2 ICANS, which resolved. All response-evaluable pts (100%) had a response, and 76% had a complete metabolic response (CMR; Table). Notably, response rates were similar for double-hit/triple-hit pts (CMR rate, 82% [9/11]). The median durations of response, progression-free survival, and overall survival were not reached. Responses were durable; at 9 mo, an estimated 96% of pts with CMR remained in CMR. Updated data will be presented. Conclusions: Subcutaneous epcoritamab + R-CHOP induces high CMR rates with a manageable safety profile in pts with 1L high-risk DLBCL, including double-hit/triple-hit pts. These results support the ongoing phase 3 study of epcoritamab + R-CHOP in 1L pts (NCT05578976). Clinical trial information: NCT04663347 . [Table: see text]

Real-world (RW) use of venetoclax (VEN) in patients (pts) with acute myeloid leukemia (AML) in a US RWE database (COTA).

7044 Background: VEN + hypomethylating agents (HMAs)/low-dose cytarabine was approved for the treatment (tx) of pts with AML who are ≥75 y or ineligible for intensive chemotherapy (CT) in 11/2018. To understand the use, safety, and efficacy of VEN in clinical practice, the COTA AML database, using pt-level curated electronic health record data from centers across the US, was analyzed. Methods: This is a retrospective, descriptive analysis of deidentified secondary data from the COTA AML database in the US. Data was abstracted for adults diagnosed with AML who initiated first-line (1L) tx on or after 01/01/2018 and received ≥1 VEN tx at any point. Pts with no diagnosis date or with concurrent primary malignancies were excluded. Follow-up was until the last recorded event (last visit or death). The study period for this analysis was 01/2018 to 09/2022. Results: Of 3836 pts with AML in the database, 1163 pts initiated 1L tx in or after 2018; of these, 636 received ≥1 VEN tx at any point. See Table for baseline demographic data. Most VEN-treated pts were seen by community healthcare providers (407/636, 64%). Genetic/molecular data were limited. Of the most frequently tested mutations, the most common were TP53 (129/461, 28%), RUNX1 (109/444, 25%), TET2 (101/414, 24%), ASLX1 (92/417, 22%), and DNMT3A (91/424, 22%). Of pts who received VEN, 47% (299/636) received 1L VEN, and the majority (269/636, 42%) received VEN + HMAs. For pts with tx prior to VEN (pretreated), 262/337 (78%) were previously treated with CT. 1L pts were more often treated in community centers than pretreated pts (73% vs 56%), had more comorbidities (56% vs 40%), and TP53 positivity (19% vs 10%) at baseline. Of 284 VEN-treated pts with available response data, 180 (63%) had a complete response (CR). Median OS (mOS) of VEN-treated pts was 14.4 mo from 1L tx initiation (de novo AML, 17 mo; secondary AML, 14 mo). mOS from diagnosis was 14 mo for newly diagnosed and 18 mo for pretreated pts. Toxicity was the main cause of dose reduction and discontinuation. Median duration of VEN tx was 78 d. Dose reduction was reported in ~30% of VEN-treated pts. Of VEN-treated pts, 53% (338/636) discontinued at least 1 VEN regimen, with a median time to discontinuation of 49.5 d. Conclusions: This study provides an overview of the RW use of VEN in pts with AML in the US since its approval in 11/2018. Despite the study period starting earlier than VEN approval, almost half of pts with AML who initiated tx after 2018 received 1L VEN. The RW CR rate in VEN-treated pts with available data was 63%, but over half of VEN-treated pts had VEN tx discontinuation. [Table: see text]

Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary phase 3 results from GLOW.

405736 Background: There is an unmet need for novel targeted therapies that improve outcomes for pts with HER2− LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 is expressed in normal gastric mucosa cells and retained in most G/GEJ adenocarcinomas. In the phase 3 SPOTLIGHT study, zolbetuximab, a CLDN18.2-targeted chimeric monoclonal antibody, significantly prolonged PFS and OS in pts with CLDN18.2+/HER2− LA unresectable or mG/GEJ adenocarcinoma when combined with mFOLFOX6. GLOW (NCT03653507) is a phase 3 global, double-blind study comparing zolbetuximab or PBO with capecitabine and oxaliplatin (CAPOX) as 1L treatment for this pt population. Methods: Pts with CLDN18.2+ (moderate-to-strong membranous CLDN18 staining in ≥75% tumor cells by IHC)/HER2− LA unresectable or mG/GEJ adenocarcinoma were randomized 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (D1 in subsequent cycles) + CAPOX (oral capecitabine 1000 mg/m2 BID on D1−14 of each cycle; oxaliplatin IV 130 mg/m2 on D1 of each cycle) for eight 21-day cycles vs PBO + CAPOX; pts continued for >8 cycles with zolbetuximab or PBO, plus capecitabine (investigator decision), until PD or a discontinuation criterium was met. The primary endpoint (EP) was PFS per RECIST v1.1 by IRC. OS was a key secondary EP; other secondary EPs included ORR and safety. Differences between treatment arms in PFS and OS were tested by stratified log-rank tests; OS was tested if PFS was significant. Results: 507 pts were randomized 1:1 to zolbetuximab + CAPOX (N = 254) or PBO + CAPOX (N = 253). Both PFS (median 8.21 vs 6.80 mo, HR 0.687, P=0.0007) and OS (median 14.39 vs 12.16 mo, HR 0.771, P=0.0118) were significantly prolonged with zolbetuximab + CAPOX (Table); in pts with measurable disease, ORR (95% CI) was 53.8% (46.58−60.99) vs 48.8% (41.76−55.84) in zolbetuximab vs PBO arm. The most common TEAEs with zolbetuximab + CAPOX were nausea (68.5% vs 50.2% in zolbetuximab vs PBO arm), vomiting (66.1% vs 30.9%), and decreased appetite (41.3% vs 33.7%); serious TEAEs (47.2% vs 49.8%), grade ≥3 TEAEs (72.8% vs 69.9%), and drug-related TEAEs leading to death (2.4% vs 2.8%) were similar in both arms. Conclusions: Targeting CLDN18.2 with zolbetuximab combined with CAPOX significantly prolonged PFS and OS in 1L pts with CLDN18.2+/HER2− LA unresectable or mG/GEJ adenocarcinoma. These results align with those observed in SPOTLIGHT and establish zolbetuximab + chemotherapy as a potential new standard-of-care option for these pts. Clinical trial information: NCT03653507 . [Table: see text]

Abstract P4-07-14: Long-term Outcomes After 1 or 2-3 Lines of Neoadjuvant Therapy in Stage III Inflammatory Breast Cancer

Abstract Background: Inflammatory breast cancer (IBC) is associated with a poor prognosis. While many stage III IBC patients (pts) experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to permit subsequent surgical therapy, the prognostic significance of requiring additional NAC to enable resectability is unknown. We sought to describe the pathologic complete response (pCR) rates, breast cancer-free survival (BCFS) and overall survival (OS) among pts requiring 1 vs >1 lines of NAC prior to surgery. Methods: Upon IRB approval, pts with stage III IBC from 2 academic institutions (Dana-Farber Cancer Institute and MD Anderson Cancer Center) who received 1L or 2-3 lines (2-3L) of NAC prior to surgery were identified. Standard NAC regimens containing different drugs, such as AC-T or TCHP, were considered as 1L. Pts with locoregional progression or metastatic disease prior to surgery were excluded. Hormone receptor (HR), HER2 status, grade, and pCR, defined as no residual invasive cancer in the breast and the axilla, were evaluated. BCFS, defined as time from surgery to locoregional and/or distant recurrence, and OS, defined as time from surgery to death, were evaluated by the Kaplan-Meier method. Multivariable Cox models stratified by institution and containing the covariates pCR and tumor subtype were utilized to estimate the HR of 2-3L vs. 1L of therapy. Results: 808 eligible pts diagnosed between 1997 and 2020 were identified. 733 (91%) had 1L and 75 (9%) had 2-3L of NAC, and the median age was 50 years. 295 (37%) had HER2+, 282 (35%) HR+HER2-, 211 (26%) had HR-HER2- disease and for 20 (2%) pts, the receptor status was unknown. The median time from diagnosis to surgery was 6 months. Grade III disease, triple-negative and HER2-positive disease were more prevalent in pts receiving 2-3L of therapy (table). pCR was achieved in 178 (24%) pts receiving 1L of NAC, and in 14 (19%) pts receiving 2-3L of NAC. At 68 months of median follow-up, 417 (52%) pts experienced a recurrence with 376 in the 1L group and 41 in the 2-3L group. The 5-year BCFS was shorter for the 2-3L group compared to the 1L group (33% v 46%, HR=1.37; 95% CI:0.99-1.91). However, in 192 pts with a pCR, BCFS was similar, regardless of the number of NAC lines. There were 38 recurrences among 178 1L pts, and 3 recurrences among 14 2-3L pts, resulting in BCFS of 76% and 83% in 1L and 2-3L pts, respectively. Overall, there were 308 deaths, 276 deaths among 1L pts and 32 among 2-3L pts. The 5-yr OS estimate in 1L versus 2-3L pts was 60% versus 53% (HR=1.32, 95% CI: 0.91-1.93). Conclusion: Among pts with stage III IBC, pCR was observed among 24% who had 1L and 19% of pts who required 2-3L of NAC. BCFS and OS were comparable among pts with pCR after 1L and 2-3L. Our results suggest the need to continue to optimize current treatment strategies in IBC to improve pCR rates across all disease subtypes regardless of the number of lines of NAC required. Citation Format: Faina Nakhlis, Samuel Niman, Naoto T. Ueno, Elizabeth Troll, Sean Ryan, Eren Yeh, Laura Warren, Jennifer Bellon, Beth Harrison, Toshiaki Iwase, H. T. Carisa Le-Petross, Sadia Saleem, Mediget Teshome, Gary J. Whitman, Wendy Woodward, Beth Overmoyer, Sara Tolaney, Meredith Regan, Filipa Lynce, Rachel M. Layman. Long-term Outcomes After 1 or 2-3 Lines of Neoadjuvant Therapy in Stage III Inflammatory Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-14.

Tagraxofusp, an Anti-CD123 Therapy, in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm and Prior or Concomitant Hematologic Malignancies: Subgroup Analysis of a Pivotal Trial

Background: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive myeloid malignancy that has a poor prognosis. BPDCN occurring concurrently with other hematologic malignancies has been observed in approximately 10-20% of patients (pts) with BPDCN having prior or concomitant hematologic malignancies (PCHM); myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are the most common. Such pts likely have a unique disease biology, which may impact the response to therapy. BPDCN derives from plasmacytoid dendritic cells that overexpress CD123 (also known as interleukin-3 receptor alpha). Tagraxofusp (TAG), a first-in-class CD123-targeted therapy, is the only FDA- and EMA-approved treatment for pts with BPDCN. The pivotal trial (NCT02113982) demonstrated that TAG 12 mcg/kg resulted in high (overall response rate [ORR] = 75%) and durable (median duration = 25 months) responses after 3 years of follow up (Pemmaraju et al. JCO 2022 doi: 10.1200/JCO.22.00034) in first-line (1L) pts; the safety profile was well characterized and manageable. Herein, we report a subgroup analysis of the pivotal trial that evaluates the safety and efficacy of TAG in 1L pts who had PCHM. Methods: This was a multicenter, 4-stage, single-arm phase 1/2 trial that enrolled 1L (n = 69) pts with BPDCN. Pts received TAG intravenous infusions once daily on days 1-5 of a 21-day cycle at 7 or 12 mcg/kg in Stage 1 (dose escalation) and 12 mcg/kg in Stages 2 (dose expansion), 3 (pivotal confirmatory), and 4 (continued access). The main endpoints were complete response (CR; defined as CR + clinical CR [CRc; CR with residual skin abnormality not indicative of active disease]), ORR, overall survival (OS), and safety. Results: In total, 65 1L pts received TAG at 12 mcg/kg. Of these, 8 (12%) had PCHM, one of whom had 2 different PCHMs; there were 4 pts with MDS, 1 pt with polycythemia vera, 1 pt with CMML, 1 pt with plasma cell myeloma, 1 pt with Hodgkin's disease, and 1 pt with lymphoma. Baseline characteristics were similar between pts with or without PCHM; respectively, median age was 69 years and 68 years, most pts were male (75% vs 81%), and the majority had ECOG PS 0/1 (100% vs 95%) (Table 1). Past medical history showed that the length of time pts had a PCHM prior to the BPDCN diagnosis varied, ranging from 4-14 years. The main efficacy outcomes are presented in Table 2. Similar rates of CR/CRc and ORR were seen across pts with and without PCHM. The most frequent (≥25%) treatment-related adverse events (TRAEs) for pts with PCHM were: increased aspartate aminotransferase (AST; 38%), increased alanine aminotransferase (ALT), weight gain, and hypoalbuminemia (25% each). No pts with PCHM experienced capillary leak syndrome (CLS). For pts with no PCHM, TRAEs occurring with an incidence ≥25% were increased ALT (56%), increased AST (53%), hypoalbuminemia (40%), thrombocytopenia (35%), pyrexia (32%), increased weight (28%), and nausea (25%); 12 (21%) pts had CLS. Conclusion: While the numbers of pts are low, there is evidence that TAG has efficacy in 1L pts with BPDCN who had PCHM. High rates of response, similar to those reported in pts with no PCHM, were observed. TAG did enable 1 of the 8 pts with PCHM to be bridged to SCT. The safety profile was manageable and predictable. PCHM did not appear to predispose pts to different TRAEs. These data also highlight how BPDCN can frequently co-occur with other hematologic malignancies. This reinforces the importance of making the correct diagnosis of BPDCN to enable treatment with disease-directed therapy, and of monitoring for cytopenia, including thrombocytopenia, in pts with BPDCN vs other hematologic malignancies, as well as the need for longer follow up. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S146: VENETOCLAX IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA WITH 17P DELETION: 6-YEAR FOLLOW-UP AND GENOMIC ANALYSES IN A PIVOTAL PHASE 2 TRIAL

Background: Patients (pts) with chronic lymphocytic leukemia (CLL) with del(17p) and/or mutated TP53 have adverse prognosis and are a population of interest for improving outcomes. In a pivotal Phase 2 study (NCT01889186) evaluating venetoclax (Ven; a selective oral BCL2 inhibitor) monotherapy in del(17p) CLL (N=158), overall response rate (ORR) was 77% (median time on study, 26.6 mo; Stilgenbauer. J Clin Oncol. 2018;17:1973). Aims: To report final analyses after 5 y from last pt enrolled, including post-hoc subgroup analyses of prognostic markers. Methods: Adults with R/R or previously untreated del(17p) CLL received Ven 400 mg (via ramp-up) orally daily until progressive disease (PD) or intolerance. Main cohort comprised pts with R/R CLL; safety expansion cohort included pts with R/R or untreated CLL. Primary endpoints were ORR (main) and safety (safety expansion). Peripheral blood (PB) and bone marrow (BM) were analyzed pre-Ven for somatic mutations via targeted next-generation sequencing (NGS). Minimal residual disease (MRD) was assessed by flow cytometry, ASO-PCR, and/or clonoSEQ NGS; undetectable MRD (uMRD) is reported at <10−4. Results: In all, 158 pts received Ven (main, n=107; safety expansion, n=51). Data cutoff was 15 December 2020. Pts had median 2 (range, 0−10) prior lines of therapy (LOT); 5 had untreated CLL (first-line [1L]). Common mutations (n/N) were TP53 (113/138 [82%]; 35/113 [31%] had >1), SF3B1 (28/137 [20%]) NOTCH1 (22/137 [16%]), ATM (11/120 [9%]), and BIRC3 (6/120 [5%]); 93/115 (81%) had unmutated IGHV and 118/158 (75%) had ≥20% del(17p). Median time on Ven was 27.4 (range, 0–79.3) mo. At study close, 77 pts were alive; 26 remained on Ven. No new safety signals were observed. With 70 mo median follow-up (f/u), investigator-assessed ORR was 77% (95% CI, 70−84); 21% achieved complete remission (CR)/CR with incomplete blood count recovery (CRi). Median duration of response was 39.3 mo (95% CI, 31.1−50.5); 28% had ongoing response at 60 mo. Of 61 evaluable pts with a PB MRD assessment, 25% had uMRD at ~2 y (24−30 mo). Median progression-free survival (mPFS) was 28.2 mo (95% CI, 23.4−37.6; Figure). Median overall survival (mOS) was 62.5 mo (95% CI, 51.7−NR; 5-y PFS and OS rates, 24% and 52%). Of 5 1L pts, 4 were alive and progression-free. In pts with CR/CRi (n=37), mPFS was 62.2 mo (95% CI, 53.1−NR); in pts with partial remission (PR)/nodular PR (n=85), mPFS was 27.6 mo (95% CI, 22.8−38.0). Overall, 98/158 (62%) pts had PD, including 24/158 (15%) with Richter transformation. Of pts with PD (n=98) or whose disease was refractory to Ven (n=11), 73 received another LOT, most commonly ibrutinib (n=41); mOS from ibrutinib initiation was 28.0 mo. In pts with both del(17p) and TP53 mutation (n=111) vs those with either (n=19), ORR was 75% vs 79%; mPFS was 27.4 vs 22.8 mo (P=.8). In pts with mutated (n=22) vs unmutated IGHV (n=93), mPFS was 40.4 vs 26.9 mo (P=.11). No significant difference in ORR, PFS, or OS was observed in pts with vs without ≥20% del(17p), >1 TP53 mutation, NOTCH1, ATM, or BIRC3 mutations; mPFS was shorter in pts with mutated SF3B1 (n=28) vs without (n=109; 16.4 vs 30.2 mo [P=.0071]). Multivariate analysis is ongoing. Image:Summary/Conclusion: At end of study (median f/u, 70 mo), 48% of pts were alive, 24% were progression-free, and 16% remained on Ven, confirming the long-term activity of Ven in this high-risk population with del(17p) CLL and median 2 prior LOT. Except SF3B1 mutation, other adverse features (eg, >1 TP53 mutation, NOTCH1 mutations, unmutated IGHV) did not influence outcomes with Ven treatment in this cohort.

Overall survival (OS) in metastatic uveal melanoma: A summary of recent prospective trials.

e21598 Background: Metastatic uveal melanoma (mUM) historically has a poor prognosis where chemotherapy and checkpoint blockade, including combination, has had no impact on OS. Tebentafusp (tebe), a TCR bispecific (gp100 x CD3), is the first therapy to demonstrate an OS benefit in a mUM randomized trial (IMCgp100-202) against pembrolizumab (pembro), ipilimumab (ipi) or dacarbazine. Here we present a summary of OS from recent prospective trials in mUM in both previously untreated (1L) and previously treated (2L+) mUM including cross trial comparison with checkpoint blockade combination. Methods: A literature review of prospective Ph2/3 clinical trials of systemic therapies in mUM published recently (2019-2021) identified 8 trials: in 1L mUM (n = 2) a randomized Ph3 of tebe (N = 252) vs investigator’s choice (IC; N = 126) of pembro, ipi or dacarbazine (IMCgp100-202) and a single arm Ph2 of nivolumab (nivo) + ipi (N = 52; Piulats, 2021) (Table); in 2L+ mUM (n = 1) a single arm Ph2 of tebe (N = 127; IMCgp100-102); and in mixed line mUM (n = 5) a randomized Ph2 of cabozantinib (N = 31) vs chemotherapy (N = 15; Luke, 2019), a single arm Ph2 of nivo + ipi (N = 35; Pelster, 2021), a single arm Ph2 of pembro + entinostat (N = 29; Ny, 2021), a single arm Ph2 of glembatumumab (N = 37; Hasanov, 2020), and a single arm Ph2 of IMC-A12 (IGF-1 receptor inhibitor; N = 18; Mattei, 2020). The PUMMA (Khoja, 2019; N = 912) and Rantala, 2019 (N = 2494; n = 510 1L pts) meta-analyses were included to provide historical benchmarks for OS. Results: In previously untreated mUM, 1-yr and median OS were 73% and 21.7 months for tebe, 59% and 15.7 months for pembro, 52% and 12.7 months for nivo + ipi and 45% and 11.3 months for conventional chemotherapy. In previously treated mUM, 1-yr and median OS were 61% and 16.8 months for tebe, 34% and 7.0 months for checkpoint inhibitors, and 43% and 10.5 months for conventional chemotherapy. In mixed line (1L+) mUM, 1-yr and median OS were 56% and 19.1 months for nivo + ipi and 59% and 13.4 months for pembro + entinostat, 13.8 months for IMC-A12, 11.9 months for glembatumumab and 6.4 months for cabozantinib. Related AEs (any grade) leading to discontinuation and death for tebe were 2% and 0% vs 5% and 0% for IC control, and 23% and 3.8% for nivo + ipi in 1L pts. Conclusions: Tebe is the only therapy demonstrated to prolong OS in mUM. The 1-yr OS for tebe in 1L and 2L+ is superior to all recent published studies, including nivo + ipi. Both tebe and checkpoint combination therapy have high rate of any grade AEs, although checkpoint combination has a higher rate of treatment related discontinuations and deaths.[Table: see text]

Prognostic testing and treatment patterns in Black patients (pts) with chronic lymphocytic leukemia (CLL) from the informCLL prospective, observational registry.

e18559 Background: Real-world data on practice patterns in Black pts with CLL are limited. We evaluated treatment (tx) patterns and prognostic biomarker testing in Black pts enrolled in the informCLL registry. Methods: Pts who initiated FDA-approved tx for CLL/SLL (index tx) were enrolled from October 2015 to June 2019. Baseline (BL) characteristics, FISH testing rates, BL factors associated with FISH testing, and patterns of index tx are summarized by line of therapy (LOT; previously untreated [1L] and relapsed/refractory [R/R]). Results: Of 1462 enrolled pts (overall registry population), 106 (7%) were Black (Table). Community-based practices enrolled 87% of Black pts, similar to the overall population (93%). Black pts were predominantly enrolled in the South (69%). Among Black pts, median age was 66 y, 65% had ECOG status ≥1, 64% had Rai stage III-IV, and median time from diagnosis to tx on registry was 40 mo (7 mo for 1L). In the overall population, median age was 71 y, 53% had ECOG status ≥1, 51% had Rai stage III-IV, and median time from diagnosis to tx was 41 mo (19 mo for 1L). FISH testing was performed in 25% of Black pts, similar to the testing rate in the overall population (28%). In a multivariate analysis, BL factors significantly associated with FISH testing were shorter time from initial diagnosis to tx, better ECOG status, earlier LOT (1L), community practice setting, and prior malignancy (p&lt;0.05 for all); race was not a predictive factor. As in the overall population, ibrutinib was the most frequent tx among Black pts in 1L (50%) and R/R (67%), followed by chemoimmunotherapy (CIT; 1L, 43%; R/R, 15%). In 1L pts, tx with ibrutinib generally increased over time (2016, 31%; 2017, 57%; 2018, 63%; 2019, 55%) while CIT use persisted (56%; 36%; 38%; 36%, respectively). In R/R pts, use of ibrutinib decreased over time while CIT remained consistent and tx with other novel agents increased. Conclusions: Black pts with CLL tended to be younger, with worse ECOG status, more advanced disease, and shorter time to 1L therapy than the overall informCLL registry population. While ibrutinib was the most common tx in Black pts, CIT use in 1L remained persistent. Similar to the overall registry population, prognostic testing rates were suboptimal in Black pts. These results highlight the importance of prognostic testing and the need to more closely monitor disease status in Black pts as they will tend to require initial CLL therapy more rapidly than other pts. Clinical trial information: NCT02582879. [Table: see text]

Rapid adoption of immunotherapy in community health systems, associated with changing treatment guidelines.

e18610 Background: In the quickly evolving landscape of developmental therapeutics, uptake of new standards of care is a critical issue. Community health systems (CHS) provide &gt; 50% of cancer care in the US. Rapidly changing immunotherapy (IO) guidelines provide a window into changing practice patterns. This analysis describes how IO use has evolved within CHS. Methods: Patients (pts) selected were ≥ 18 years, diagnosed with advanced or metastatic NSCLC 2015-2020, with 2+ EHR encounters before 4/1/2021. Two sub cohorts were analyzed. Cohort 1: pts receiving IO in any line of therapy (L); first use of IO by L was assessed over time. Cohort 2: pts receiving any first L (1L) therapy; 1L use of IO, alone or with chemotherapy (IO combo), was assessed over time. Results: In cohort 1, IO use in 1L grew from 24% of all IO pts in 2016 to 93% in 2020, increasing from 33% in Q4 2016 to 62% in Q1 2017. In cohort 2, 1L therapy shifted from 4% of all pts receiving IO in 1L in 2016 to 59% in 2020, increasing from 6% in Q4 2016 to 24% in Q1 2017. Within IO 1L pts, IO combo use grew from 29% to 68% in 2020, increasing from 35% in Q1 2018 to 53% in Q2 2018. Conclusions: We observed two rapid shifts in care patterns. First, 1L IO use grew rapidly from Q4 2016 to Q1 2017, following 1L IO approval (10/2016). Second, 1L IO use shifted rapidly toward IO combo use from Q1 2018 to Q2 2018, coinciding with pivotal trial results and FDA priority review (4/2018), but preceding label expansion (8/2018). Two RWD analyses from independent oncology practices observed less substantial shifts during similar periods of time. These results demonstrate that CHS can rapidly adjust to evolving clinical evidence and associated changes in standards of care.[Table: see text]

Tepotinib in Asian patients with advanced NSCLC with MET exon 14 (METex14) skipping.

9120 Background: Tepotinib is a highly selective, potent MET inhibitor approved in several Asian countries for the treatment of advanced METex14 skipping NSCLC. In VISION (n=275; data cut-off: Feb 1, 2021), tepotinib had an objective response rate (ORR) of 49.1% (95% CI: 43.0, 55.2) by independent review (IRC), with a median (m) DOR of 13.8 months (9.9, 19.4) across treatment lines. Here, we report outcomes in Asian pts. Methods: Pts with advanced METex14 skipping NSCLC, detected by liquid (L+) or tissue (T+) biopsy, received tepotinib 500 mg (450 mg active moiety) QD. Primary endpoint was objective response by IRC. Efficacy was assessed in 79 Asian pts with ≥3 months’ follow-up, and safety was assessed in 88 Asian pts who received tepotinib by data cut-off (Feb 1, 2021). Only pts enrolled in Asia were assessed for HRQoL. Results: In 79 Asian pts assessed for efficacy (38% female, 42% smoking history, 34% treatment-naïve [1L] and 82% adenocarcinoma), ORR was 54.4% (42.8, 65.7), mDOR was 18.5 months (8.3, ne), mPFS was 12.1 months (6.9, ne) and mOS was 20.4 months (19.1, ne). ORR was 66.7% (46.0, 83.5) in 1L pts (n=27), and 48.1% (34.0, 62.4) in previously treated pts (n=52). Meaningful activity was observed irrespective of METex14 skipping detection method (Table). In pts analyzed for HRQoL (n=73), mean change from baseline for EORTC QLQ-C30 GHS (3.94), EQ-5D-5L VAS (0.83), and EORTC QLQ-LC13 for cough (-6.59), dyspnea (-1.26), and chest pain (-6.14) symptom scores, demonstrated stability in QoL. In 88 Asian pts analyzed for safety, the most common adverse events (AEs) were peripheral edema, increased blood creatinine, and diarrhea. 29.5% of pts had Grade ≥3 treatment-related (TR) AEs. TRAEs led to dose reductions in 29.5%, temporary interruption in 43.2%, and permanent discontinuation in 14.8% of pts. Conclusions: In VISION, tepotinib showed robust and durable clinical activity in Asian pts with METex14 skipping NSCLC. TRAEs were manageable, with few leading to treatment discontinuation. Currently, VISION has enrolled 106 Asian pts with METex14 skipping NSCLC; analysis in this population is ongoing. Clinical trial information: NCT02864992. [Table: see text]

24P Tepotinib in patients with MET exon 14 skipping NSCLC: Efficacy and safety by line of therapy

We report outcomes for tepotinib – a highly selective, potent MET inhibitor – in patients (pts) with MET exon 14 (METex14) skipping in VISION Cohorts A (primary analysis) and C (confirmatory), by prior therapies. These are relevant for clinical practice, given the CHMP positive opinion (Dec 2021) for tepotinib in patients with advanced NSCLC harboring METex14 skipping, previously treated with immunotherapy (IO) and/or platinum-based chemotherapy (CT). Pts with advanced/metastatic METex14 skipping NSCLC received 500 mg (450 mg active moiety) tepotinib once daily. Safety was assessed in all pts who received tepotinib, and efficacy in pts with ≥3 months’ follow-up (data cut-off: Feb 1, 2021). Primary endpoint was objective response by IRC (RECIST 1.1). Of 275 pts evaluable for efficacy, 138 were previously treated (+2L): median age 70.9 years (range, 41–89), 51% female, 40% smoking history, 42.0% enrolled in Europe. 86% of +2L pts had prior platinum-based CT, 53% had prior IO (37% as monotherapy, 15% had IO-CT). Objective response rate (ORR) was 44.2% (95% CI: 35.8, 52.9), with median duration of response (mDOR) of 11.1 (8.4, 18.5). Disease control rate was 75.4% (67.3, 82.3), and median overall survival (mOS) was 19.9 months (15.8, 22.3). Efficacy was observed regardless of prior therapies (Table). 137 pts were treatment-naïve (1L): median age 74.6 years (range, 47–94), 50% female, 53% smoking history, 60.6% enrolled in Europe. ORR was 54.0% (45.3, 62.6) and mOS was 17.6 months (13.4, 29.7). Overall, pts with brain metastases at baseline (51/275 [18.5%]) had systemic ORR of 52.9% (38.5, 67.1), and mDOR of 9.0 months (5.6, ne). Treatment-related adverse events (TRAEs) were mostly mild-moderate across therapy lines; Grade ≥3 TRAEs occurred in 33.1% of 1L pts and 25.9% +2L pts. Safety profile was similar in pts with prior IO.Table: 24PTepotinib efficacyORR, % (95% CI)Median duration of response, months (95% CI)Median progression-free survival, months (95% CI)Line of therapy1L (n=137)54.0 (45.3, 62.6)32.7 (9.0, ne)10.4 (8.4, 15.3)+2L (n=138)44.2 (35.8, 52.9)11.1 (8.4, 18.5)11.0 (8.2, 12.4)2L (n=88)44.3 (33.7, 55.3)12.4 (8.3, ne)8.9 (6.9, 13.7)+3L (n=50)44.0 (30.0, 58.7)10.1 (6.9, 19.4)11.2 (6.9, 13.8)Prior therapiesPlatinum-based CT alone (n=98)48.0 (37.8, 58.3)12.4 (8.3, 18.5)11.0 (6.9, 13.7)IO monotherapy or IO + platinum-based CT (n=71)38.0 (26.8, 50.3)9.7 (8.3, ne)10.9 (6.9, 12.1)IO + platinum-based CT (n=21)52.4 (29.8, 74.3)9.5 (4.2, ne)10.9 (5.5, ne)CI, confidence interval; L, line; ne, not estimable. Open table in a new tab CI, confidence interval; L, line; ne, not estimable. Tepotinib demonstrated robust and durable clinical activity across treatment lines, and in pts with brain metastases. TRAEs were mostly mild-moderate.

Abstract P1-18-11: Analysis of first-line (1L) patients (pts) with de novo disease vs late relapse and all pts with vs without prior chemotherapy (CT) in the MONALEESA-3 (ML-3) trial

Abstract P1-18-11: Analysis of first-line (1L) patients (pts) with de novo disease vs late relapse and all pts with vs without prior chemotherapy (CT) in the MONALEESA-3 (ML-3) trial

Tagraxofusp, an Anti-CD123 Therapy, in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm: Subanalyses of a Pivotal Trial By Age and Baseline Disease Involvement

Tagraxofusp, an Anti-CD123 Therapy, in Patients with Blastic Plasmacytoid Dendritic Cell Neoplasm: Subanalyses of a Pivotal Trial By Age and Baseline Disease Involvement

Tagraxofusp (SL-401) in Patients with Chronic Myelomonocytic Leukemia (CMML): Updated Results of an Ongoing Phase 1/2 Trial

Tagraxofusp (SL-401) in Patients with Chronic Myelomonocytic Leukemia (CMML): Updated Results of an Ongoing Phase 1/2 Trial

SKYSCRAPER-03: A Phase III, Open-Label, Randomized Study of Atezolizumab Plus Tiragolumab Compared With Durvalumab in Patients With Locally Advanced, Unresectable, Stage III NSCLC Who Have Not Progressed After Platinum-Based Concurrent Chemoradiation

<h3>Purpose/Objective(s)</h3> Until recently, the standard of care for patients (pts) with locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC) has been platinum-based concurrent chemoradiation (cCRT); however, the 5-year OS rates are poor (13–36%; Goldstraw et al. J Thorac Oncol 2015). Durvalumab (anti-PD-L1) monotherapy was recently approved for pts without progressive disease (PD) after cCRT. However, long-term OS data are not yet available and further evaluation of novel cancer immunotherapy combinations should be explored. Targeted inhibition of a novel checkpoint TIGIT/PVR, by the anti-TIGIT antibody tiragolumab, may amplify the anti-cancer activity of anti-PD-L1/PD-1 antibodies. In the phase II CITYSCAPE study (NCT03563716), tiragolumab plus atezolizumab (anti-PD-L1) was well tolerated and improved ORR compared with atezolizumab alone (31.3 vs 16.2%) in 1L pts with PD-L1+ (TPS ≥1%) metastatic NSCLC; with greater benefit in the PD-L1-high (TPS ≥50%) subset. We hypothesize that tiragolumab plus atezolizumab may provide greater clinical benefit vs single-agent anti-PD-L1 as maintenance therapy in pts with unresectable, stage III NSCLC who have not progressed after platinum-based cCRT. SKYSCRAPER-03 (NCT04513925) will determine if tiragolumab plus atezolizumab provides superior clinical benefit to durvalumab in this setting. Current data suggests that cCRT upregulates PD-L1 expression, potentially enabling PD-L1 low or negative tumors to derive benefit, so outcomes will be evaluated in all-comer (ITT) and PD-L1+ sub-populations. <h3>Materials/Methods</h3> Eligible pts (≥18 years) must have unresectable, stage III NSCLC without PD after ≥2 cycles of platinum-based cCRT per NCCN/ESMO guidelines, and without an EGFR mutation or ALK rearrangement; known PD-L1 status; ECOG PS 0–1. Approximately 800 pts will be randomized 1:1 to receive tiragolumab 840mg IV plus atezolizumab 1680mg IV Q4W or durvalumab 10mg/kg IV Q2W / 1500mg IV Q4W. Treatment will continue for up to 13 cycles of 28 days, or until unacceptable toxicity or symptomatic deterioration due to PD; in pts with radiographic PD (per RECIST v1.1) treatment may continue if evidence of ongoing clinical benefit. Stratification factors include PD-L1 status, histology (squamous vs non-squamous), staging (IIIA vs IIIB or IIIC) and ECOG PS (0 vs 1). Primary endpoint is independent review facility-assessed PFS in the ITT and PD-L1+ (TC ≥1%) populations. Secondary endpoints include investigator-assessed PFS, OS, ORR and DoR. Safety and biomarker analyses will be performed. Recruitment is ongoing. <h3>Results</h3> forthcoming <h3>Conclusion</h3> forthcoming

1014P Characterization of cytokine release syndrome (CRS) following treatment with tebentafusp in previously untreated patients with metastatic uveal melanoma

Tebentafusp (tebe), a bispecific fusion protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T-cells to target gp100+ cells, has shown an overall survival benefit for patients (pts) with untreated metastatic uveal melanoma (mUM) in a Ph3 trial (NCT03070392). In a post-hoc analysis of a Ph2 trial of 2L+ pts with mUM, mild to moderate episodes of CRS, a cytokine-mediated adverse event (AE), were common following each of the first 3 doses of tebe (Carvajal RD et al. ASCO 2021). Here, we reviewed the incidence, kinetics, and outcome of CRS in tebe-treated pts on the IMCgp100-202 trial of 1L pts with mUM. 245 HLA-A*02:01+ 1L mUM pts were treated weekly with tebentafusp following intra-patient dose escalation: 20mcg dose 1, 30mcg dose 2 and 68mcg dose 3+. Pts were monitored overnight during escalation to allow management of hypotension and other cytokine-related AEs; prophylactic corticosteroids, antihistamines or acetaminophen were not mandated. CRS was evaluated post-hoc according to ASTCT Consensus Grading criteria (Lee, DW et al. 2019). Analysis was conducted on primary analysis snapshot (Jan 2021). The most frequent treatment-related AEs, likely cytokine-mediated, included fever (76%), chills (47%), nausea (43%), hypotension (38%). Using ASTCT criteria, 89% of tebe treated pts (n=217) had any grade CRS. Most pts had either grade (G) 1 (12%; n=29) or G2 (76%; n=186), with 2 G3 (0.8%), no G4 and no deaths. Most CRS events occurred within the first 3 doses, reducing in frequency and severity thereafter; 3 episodes of G3 CRS in 2 patients occurred following dose 1, 3 and 4. Only 2 pts discontinued tebe due to CRS (1 G2; 1 G3). Treatment of CRS included antipyretics (n=192), IV fluids (n=93), IV steroids (n=57), oxygen (n=20), and vasopressor use (n=2). Two pts received tocilizumab. CRS, a common AE observed with T-cell engaging therapies, was frequently observed within 24 hours of initial tebe treatment. Most CRS events were mild or moderate in severity, reversible with standard management strategies, decreased in frequency and severity with subsequent doses, and rarely led to treatment discontinuation.