Chinese Pts Research Articles

CHAPTER-GIST-101: A phase I study of pimitespib combined with imatinib in patients with imatinib-refractory gastrointestinal stromal tumor.

TPS97 Background: Gastrointestinal stromal tumor (GIST) is soft-tissue sarcoma of the gastrointestinal tract. Most GISTs harbor mutations in KIT or PDGFRA, recognized as key drivers of GIST development and progression. Imatinib (IM), which inhibits KIT/PDGFRA tyrosine kinase, exerts significant clinical activity in GIST, but most GISTs develop resistance to IM, mainly due to secondary kinase-domain mutations in KIT. Therefore, standard therapies for patients (pts) with IM-refractory GIST have room for improvement. Heat shock protein 90 (HSP90) is one of the molecular chaperones. Many of HSP90's client proteins, such as KIT, PDGFRA, and BRAF, have been identified as cancer-related proteins required for tumor development, and their activation, especially in mutant forms, is dependent on HSP90.Therefore, HSP90 inhibitors have a potential to overcome IM-resistance. Pimitespib (PIMI) is a novel HSP90 inhibitor, approved in Japan for pts with fourth line GIST based on the results of the phase 3 study (CHAPTER-GIST-301). We reported at ESMO 2023 (1917MO) that PIMI effectively inhibited tumor growth in an IM-resistant xenograft model, and further enhanced the anti-tumor activity when given with IM, and that PIMI + IM was well tolerated with no dose-limiting toxicity and suggested preliminary efficacy in pts resistant to IM in a dose-escalation part (DEP) of CHAPTER-GIST-101 study. Methods: The CHAPTER-GIST-101 study (NCT05245968) is a global phase 1 study in pts with IM-refractory advanced GIST in the second-line setting, consisting of three parts: the DEP, its expansion part (ExP), and another DEP for Chinese pts. The DEP used a 3+3 design to determine the maximum tolerated dose of PIMI (120 mg/day or 160 mg/day, orally, on 5 days on/2 days off) in combination with IM (400 mg/day once daily) and the ExP is for the efficacy and safety with determined dose of 120 mg/day PIMI + IM. The ExP is a global, open-label, randomized, part evaluating the efficacy and safety of PIMI in combination with IM, PIMI monotherapy, and standard therapy sunitinib (SU) in each arm of 20 pts. Pts are randomized 1:1:1 to receive either PIMI 120 mg on 5 days on/2 days off with IM 400 mg once daily, PIMI 160 mg on 5 days on/2 days off followed by IM 400 mg once daily after discontinuation of PIMI, or SU 50 mg on 4 weeks on/2 weeks off. The primary endpoint is progression-free survival (PFS) by the independent radiological review. The secondary endpoints include investigator-assessed PFS, overall survival, objective response rate, disease control rate, duration of response, PK and safety. Exploratory pharmacogenomics analysis is also planned. After the DLT evaluation for the DEP, enrollment for the ExP began in March 2023 in Japan, Singapore, Taiwan and Australia, and for the DEP for Chinese pts is also ongoing in China to evaluate tolerability and efficacy of this combination. Clinical trial information: NCT05245968 .

Datopotamab deruxtecan (Dato-DXd) in Chinese patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Results from the phase 1/2 TROPION-PanTumor02 study.

8548 Background: Dato-DXd consists of a humanized anti-TROP2 IgG1 mAb conjugated to a potent topoisomerase I inhibitor via a stable cleavable linker. In the Phase 3 TROPION-Lung01 study, Dato-DXd demonstrated a statistically significant improvement in progression-free survival (PFS) over docetaxel in pts with previously treated, locally advanced or metastatic NSCLC (Ahn et al, ESMO 2023). The Phase 1/2, multicenter, open-label, multiple cohort TROPION-PanTumor02 study (NCT05460273) was designed to assess Dato-DXd in Chinese pts with advanced or metastatic solid tumors. Here we present results from the NSCLC cohort. Methods: Chinese pts (aged ≥18 years) with locally advanced or metastatic NSCLC with or without actionable genomic alterations (AGAs), who had been previously treated with immunotherapy and platinum-based chemotherapy (pts without AGAs) or targeted therapy and platinum-based chemotherapy (pts with AGAs), were enrolled. Pts received Dato-DXd (6 mg/kg IV Q3W). The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR) per RECIST v1.1. Analyses presented are based on the primary analysis data cut-off (DCO; Oct 9, 2023) with 6 months (mos) follow-up post the last pt’s first dose. Results: In the NSCLC cohort, 40 pts from 11 sites in China were enrolled. Median age was 59 years (range 33–74); 29 pts (72.5%) were male, and 18 (45.0%) were current or former smokers. 23 (57.5%)/17 (42.5%) pts had tumors with non-squamous/squamous histology. 5 pts (12.5%) had NSCLC with AGAs; 4 of these pts had sensitizing EGFR mutations. At DCO, 8 pts were ongoing treatment; median study follow-up was 8.1 mos (range 1.1–11.9). Overall, confirmed ORR by ICR was 45.0% (all partial responses), disease control rate by ICR was 85.0%, median duration of confirmed response was 8.3 mos, and median time to onset of response from first dose was 1.4 mos. ORR by ICR was 56.5% (13/23) in the non-squamous subgroup, 29.4% (5/17) in the squamous subgroup, and 75.0% (3/4) in pts with EGFR mutations. Median PFS by ICR (95% CI) was 7.4 mos (5.7–not calculable [NC]) overall, 9.6 mos (7.1–NC) in the non-squamous subgroup, and 5.5 mos (1.4–NC) in the squamous subgroup. Median treatment duration was 5.6 mos (range 0.7–10.6). Treatment-emergent adverse events (TEAEs) occurred in 95.0% of pts; grade ≥3 TEAEs occurred in 57.5%, and there were no fatal TEAEs. The most common TEAEs were nausea (62.5%), stomatitis (57.5%) and anemia (57.5%). TEAEs led to dose reduction/discontinuation in 20.0%/10.0% of pts. No adjudicated drug-related interstitial lung disease was reported. Conclusions: Dato-DXd showed encouraging efficacy in Chinese pts with advanced or metastatic NSCLC; the non-squamous subgroup appeared to derive the most benefit. The efficacy/safety profile was consistent with previous studies, with no new safety signals observed. Clinical trial information: NCT05460273 .

Belzutifan plus lenvatinib (len) for Chinese patients (pts) with previously treated advanced clear cell renal cell carcinoma (ccRCC): Preliminary results of cohort 1 of the phase 1 LITESPARK-010 study.

4537 Background: Belzutifan, a first-in-class HIF-2α inhibitor, alone or in combination with a VEGFR-TKI, has shown durable antitumor activity in first- and subsequent-line settings of advanced ccRCC. LITESPARK-010 (NCT05030506) is a phase 1, 2-cohort, open-label study of belzutifan + len, with or without pembrolizumab, in Chinese pts with advanced ccRCC. We present preliminary results cohort 1. Methods: Chinese adults with histologically confirmed ccRCC who had 1-3 prior treatment regimens received belzutifan 120 mg PO QD for 3 wk followed by belzutifan 120 mg + len 20 mg PO QD until intolerable toxicity, disease progression, or pt withdrawal. The study included a dose-limiting toxicity (DLT) phase of 21 days after the start of combination treatment. Dual primary end points were safety and PK. Secondary end points included ORR, DOR, and PFS per RECIST v1.1 by investigator assessment and OS. Results: As of August 29, 2023, 24 pts were enrolled in cohort 1 and 23 received combination treatment; 1 pt discontinued in the monotherapy period because of treatment with non-study anti-cancer therapy. Median age was 61 years, 17 pts (71%) were male, and 14 (58%) had intermediate/poor IMDC risk. 14 pts (58%) received 1 prior line of therapy and 10 (42%) received ≥2 prior lines. Five pts (21%) received prior therapy with a PD-(L)1 inhibitor. As of the data cutoff date, 11 pts (46%) remained on treatment. Median follow up was 14.4 mo (range, 1.6-22.1). Ten pts were evaluated in the DLT phase, and 1 experienced a DLT (grade 2 treatment-related transient ischemic attack). All 24 pts (100%) experienced a treatment-related AE (TRAE) of any grade, most commonly anemia (100%) and proteinuria (88%). Grade 3 or 4 TRAEs occurred in 17 pts (71%), most commonly anemia (29%) and hypertension (29%). One pt (4%) experienced grade 3 hypoxia. No pts died (grade 5) due to a TRAE. After a single dose of belzutifan monotherapy, median Tmax was 1.8 h (range, 0.6-8.0), geometric mean AUC0-24 was 22,400 h·ng/mL (90% CI, 19,600-25,500), and geometric mean Cmax was 1640 ng/mL (90% CI, 1490-1820). Steady-state concentration was reached after 14 days of belzutifan monotherapy treatment; the accumulation ratio of AUC0-24 was 1.7 (90% CI, 1.5-1.9). Belzutifan + len treatment had similar PK to belzutifan monotherapy. In all 24 pts, confirmed ORR was 50% (95% CI, 29-71; all PRs). Median DOR was not reached (NR; range, 3.5-20.4+ months); 50% of responders remained in response for ≥12 mo per Kaplan-Meir estimate. Median PFS was 13.7 mo (95% CI, 8-NR) and median OS was NR (95% CI, NR-NR). The 12-mo PFS and OS rates were 57% and 75%, respectively. Conclusions: Preliminary data from the belzutifan + len showed promising antitumor activity in Chinese pts with previously treated ccRCC. The safety of belzutifan 120 mg + len 20 mg was consistent with the safety profiles of the individual drugs. Clinical trial information: NCT05030506 .

A phase II study of tunlametinib in combination with vemurafenib in patients with BRAF V600-mutant advanced melanoma.

e21519 Background: The new MEK inhibitor tunlametinib combined with the BRAF inhibitor vemurafenib showed promising clinical activity in patients (pts) with BRAF V600-mutant solid tumors in a previous Phase I study (NCT03976050). Based on the result, we designed a phase IIa study to evaluate the efficacy and safety of tunlametinib plus vemurafenib in Chinese pts with BRAF V600 mutant melanoma. Methods: This open-label, single arm, multiple-center phase IIa study enrolled Chinese pts with BRAF V600E-mutant advanced melanoma, without restriction on the disease subtype (e.g., acral, mucosal, or cutaneous melanoma). Prior treatment was permitted, excluding BRAF/MEK inhibitors. Pts received oral tunlametinib at a dose of 9 mg twice daily and vemurafenib 720 mg twice daily. The primary endpoint was the objective response rate (ORR) per RECIST v1.1. Results: Between October 15, 2021, and June 22nd, 2022, 17 pts were enrolled and included in the analysis. Thirteen (76.5%) pts had received previous systemic antitumor therapy, with 12 (70.6%) receiving immunotherapy. Seven (41.2%) pts had acral melanoma, 8 (47.1%) pts had skin melanoma (non-acral) and 2 (11.8%) pts had mucosal melanoma. All pts had metastatic disease. With a median follow-up of 15.3 months (95%CI: 6.8; NE), 12 (70.6%) pts achieved confirmed partial response (PR), resulting in a confirmed ORR of 70.6% (95% CI: 44.0%-89.7%). The disease control rate was 100% (95% CI: 80.5%, 100.0%). The median progression-free survival (PFS) was 10.0 months (95% CI: 5. 5, NE). the duration of response (DOR) was 20.1 (95% CI: 4.2, NE). The overall survival (OS) was 21.6 months (95% CI: 14.5, NE), with a 12-months OS rate of 87.4% (95% CI: 58.1%, 96.7%). Subgroup analysis revealed that in pre-treated pts, the confirmed ORR was 76.9% (95% CI: 46.2%, 95.0%), the median PFS was 10.0 months (95% CI: 5.5, NE), while in previous untreated pts, the mPFS was 14.0 months (95% CI: 9.9, NE). In pts with skin melanoma, the confirmed ORR was 87.5% (47.3%, 99.7%), the mPFS was 10.0 months (95% CI: 5.5, NE), the mOS was 21.6 months (95% CI: 5.7, NE). In pts with acral melanoma, the ORR was 57.1% (95% CI: 18.4%,90.1%), the mPFS was 18.1 months (95% CI: 2.8, NE), the mOS not reached (12.3, NE). The most common adverse events included rash, pyrexia, and elevated blood creatin phosphokinase, most of which were of grade 1-2 severity. Grade 3 or higher TRAEs occurred in 12 (70.6%) pts, of which 41.2% were rash. Most AEs were manageable with supportive therapy or dose interruption. No treatment-related deaths were reported. Conclusions: The addition of a MEK inhibitor tunlametinib to vemurafenibexhibited promising clinical efficacy in Chinese patients with BRAF V600-mutant advanced melanoma, with a manageable safety profile. Additionally, notable effects were observed in pts with acral melanoma. The efficacy in pre-treated patients was comparable to that of similar agents in previous untreated patients. Clinical trial information: NCT05263453 .

Optimal neoadjuvant treatment and prognostic factors in patients with HR-positive/HER2-positive early or locally advanced breast cancer: A national real-world study in China.

e12514 Background: Few data have been reported regarding breast cancer (BC) population characterized by HR+/HER2+ especially in a real-world setting in China. This analysis aimed at identifying differences in short-term treatment outcomes of different neoadjuvant therapy (NAT) regimens, effects of the demographics and clinical features on short-term outcomes of NAT, and further understanding the prognostic factors related to those outcomes in HR+/HER2+ early (EBC) or locally advanced BC (LABC) pts by using dataset from National Cancer Information Database (NCID) in China. Methods: This retrospective, multicenter, real-world study used electronic medical record data from NCID. We analyzed HR+/HER2+ EBC or LABC Chinese pts who were initially diagnosed between Jan 1, 2019 and May 31, 2022 and received NAT followed by surgery during study period. Primary endpoints included total pathological complete response (tpCR) and breast pCR (bpCR). Secondary endpoints included disease-free survival (DFS) and event-free survival (EFS). Results: 3792 pts from NCID covering 51 hospitals, 26 provinces met inclusion criteria and were included. After controlling for age and post-surgery N staging, 1-, 2- and 3-yr DFS was similar between trastuzumab (T) and T+pertuzumab (P) NAT subgroup (92.79%, 87.20% and 83.32% vs 94.83%, 88.82% and 87.88%; p=0.1120). 1-, 2- and 3-yr EFS was higher in T+P subgroup (T vs T+P: 85.24%, 82.35%, 77.01% vs 90.86%, 89.65%, 82.78%; p = 0.0003). Logistic regression multivariate analysis showed improved tpCR and bpCR was independently positively associated with receiving T+P NAT (vs T: both p < 0.0001), platinum NAT (vs anthracycline: p = 0.0071 and 0.0122, resp.), while negatively associated with receiving no targeted therapy (vs T: p = 0.0002 and < 0.0001, resp.), ≥ 65 yrs (vs > 40 yrs, < 64 yrs: p = 0.0116 and 0.0290, resp.), or post-surgery ER positive (vs negative: both p < 0.0001). Conclusions: HR+/HER2+ EBC or LABC gained short- and long-term benefit from HER2 dual-blockade therapy in clinical practice. Prognostic factors for improved tpCR and bpCR included T+P and platinum NAT, whereas ≥ 65 yrs and post-surgery ER+ were predictive of decreased tpCR and bpCR. [Table: see text]

Correlation between imatinib trough concentration and efficacy in patients with advanced GIST with different genotypes.

e23515 Background: Imatinib (IM) has significantly enhanced the prognosis of patients (pts) with advanced gastrointestinal stromal tumors (GISTs). The clinical outcomes may correlate with IM exposure. However, the efficacy threshold, particularly based on different primary KIT mutant, remains undefined. This study aimed to establish the efficacy threshold of IM plasma trough concentration (Cmin) at steady-state in Chinese pts with advanced GIST, additionally to define subgroup thresholds based on various primary KIT mutations. Methods: This was a single-center, prospective, observational cohort study. Pts with histologically confirmed recurrent/metastatic GIST who received regular IM treatment and had undergone at least two measurements of steady-state IM Cmin were enrolled from Jul 2017 to Jun 2022. Clinical outcomes including objective response rate (ORR), survival, and IM Cmin were assessed. Results: A total of 168 pts with a median age of 52y were enrolled. The primary lesion locations comprised stomach, small intestine, rectum and others. Metastatic lesions were found in the liver, peritoneum, both liver and peritoneum and others. Median sum of longest diameter of target lesions was 10.7cm. Of 168 pts, 117 (69.6%) harbored KIT 11, 27 (16.1%) harbored KIT 9, 5 (3.0%) harbored PDGFRA, and 9 (5.4%) were KIT/PDGFRA wild type. During IM response period, 104 pts combined with surgical treatment (surgery or interventional therapy). After a median follow-up duration was 50.6m (range, 16.3–189.8), 72 pts had disease progression and 20 died. Estimated median progression-free survival (mPFS) for all patients was 79.4m (95%CI 55.7–103.1). The median overall survival was not reached. A Cmin threshold of ≥738ng/ml defined by log-rank test was associated with longer PFS for the whole population (P = 0.002) irrespective of other clinical characteristics. Pts with an IM Cmin below 738ng/ml exhibited a shorter mPFS (25.3m, 95%CI 41.9–97.1) compared to those surpassing this threshold (96.7m, 95%CI 65.8–127.6). The ORR for the whole population was 73.0% (CR 2.2%, PR 70.8%), with no significant difference observed between pts with IM Cmin below and above 738ng/ml. For pts with KIT 11 and KIT 9 mutations, the efficacy thresholds for IM Cmin were ≥680ng/ml and ≥1877ng/ml, respectively. Multivariate Cox regression analysis revealed that IM Cmin ≥738ng/ml, primary gastric origin, liver-only metastasis, sum of target lesions diameter ≤5cm, KIT 11 mutation, and combined with surgical treatment were favorable prognostic factors. Conclusions: IM exposure significantly correlates with clinical benefits in advanced GISTs, with an IM Cmin above 738ng/ml associated with a longer PFS in Chinese population. Considering different primary KIT mutant, a threshold of 680 ng/ml could be considered for efficacy in KIT 11 mutations, while a higher Cmin of 1877 ng/ml was necessary for KIT 9 mutation.

Amivantamab plus chemotherapy vs chemotherapy as first-line treatment among patients with EGFR exon 20 insertion–mutated advanced non-small cell lung cancer (NSCLC): PAPILLON Chinese subgroup analysis.

8606 Background: Amivantamab (Ami) is a bispecific antibody targeting EGFR and MET tyrosine kinase receptors with immune cell-directing activity. The phase 3 PAPILLON study (NCT04538664) investigated the combination of Ami and carboplatin/pemetrexed (ACP) vs. carboplatin/pemetrexed (CP) as first-line treatment in patients (pts) with advanced EGFR Exon20ins-mutated NSCLC. ACP improved progression free survival (PFS) in both the overall population and Asian subgroup. Methods: Pts were randomized 1:1 to ACP or CP. The primary endpoint was PFS by blinded independent central review (BICR) and key secondary endpoints included objective response rate (ORR), PFS after first subsequent therapy (PFS2), overall survival (OS), and safety. Crossover to Ami monotherapy was allowed for pts in CP arm following disease progression. Results: Among the 308 pts enrolled, 87 were Chinese, with 39 receiving ACP and 48 receiving CP. Median age was 57/57 years, 46%/63% were female, and 15%/25% history of brain metastases for pts in ACP/CP arms. Baseline characteristics were generally balanced between arms. After a median follow-up of 16.4 months (mo), median PFS was 12.3 mo (95% CI: 7.00, NE) in ACP arm compared with 6.7 mo (95% CI: 4.21, 8.57) in CP arm (hazard ratio [HR], 0.47; 95% CI, 0.26-0.85; P = 0.011) (Table). ORR was 71.8% (95% CI, 55.1%-85.0%) for ACP, and 48.9% (95% CI, 34.1%–63.9%) for CP (odds ratio, 2.46; 95% CI, 1.01-5.98; P = 0.048). Median PFS2 was not estimable (NE) for ACP vs 18.8 mo for CP (HR, 0.32; 95% CI, 0.11-0.88; P = 0.021). Interim OS showed a favorable trend for ACP vs CP (HR, 0.58; 95% CI: 0.17-2.02; P = 0.387) despite crossover among CP-randomized pts (n = 24, 50%) who had progressed. Most common AEs (all grades) ( > 50%) in ACP arm were rash, paronychia, hypoalbuminemia, neutropenia, anemia, leukopenia and thrombocytopenia which were consistent with the known safety profile of the individual agents. Notably, no pts had discontinuation of Ami due to an AE. Conclusions: ACP demonstrated superior PFS compared to CP in Chinese pts. The safety profile was manageable and tolerable. These findings in Chinese subgroup were consistent with those of overall population and Asian subgroup. Clinical trial information: NCT04538664 . [Table: see text]

Abstract PO1-06-10: Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer

Abstract Background Breast cancer is the most frequently diagnosed cancer and the 5th most common cause of cancer-related death in Chinese women with over 416,000 new cases and over 117,000 deaths estimated in 2020. Triple-negative breast cancer (TNBC) represents 10%-20% of cases in women with breast cancer. Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate and is approved for second-line or later (2L+) treatment of metastatic (m)TNBC in multiple countries, including the US and China. In the pivotal phase 3 study ASCENT, which enrolled predominantly non-Asian patients (pts), SG demonstrated improved efficacy outcomes vs treatment of physician’s choice (TPC) in pts with mTNBC treated in 2L+, with a manageable safety profile. For pts treated with SG, median progression-free survival (PFS), overall survival (OS), and objective response rate (ORR) were improved vs TPC (Bardia A et al, 2021). The single-arm phase 2b EVER-132-001 study was conducted to assess the efficacy and safety of 2L+ SG in Chinese pts with mTNBC. In preliminary findings from EVER-132-001, SG demonstrated substantial clinical activity and a manageable safety profile (Xu B et al, 2023). Here, we present additional efficacy and safety results from EVER-132-001, including the first report of median OS. Methods Pts with mTNBC who had received at least 2 prior lines of chemotherapy for mTNBC received SG (10 mg/kg IV on days 1 and 8, Q3W). The primary end point was ORR per independent review committee (IRC). Secondary end points included duration of response (DoR) per IRC, clinical benefit rate (CBR) per IRC, PFS per IRC, OS, and safety. Results Eighty pts were enrolled, with a median age of 48 years (range 24-70). Pts had received a median of 4 prior treatment regimens (range 2-8), and 59% of pts had ECOG performance status of 1. At the data cutoff, September 19, 2022, with a median follow-up of 14.7 mo (range 1.2-25.3), median OS was 14.7 mo (95% CI 10.3-18.3) and the OS rate at 12 months was 54% (95% CI 42-64) (Table). ORR was 40% (95% CI 29-52) with median DoR of 11.6 mo (95% CI 7.0-13.8), and CBR was 46% (95% CI 35-58) (Table). Median PFS was 5.6 mo (95% CI 4.1-8.3) (Table). Grade ≥ 3 treatment-emergent adverse events (TEAEs) occurred in 79% of pts, and TEAEs leading to dose reduction, treatment interruption, and treatment discontinuation occurred in 20%, 48%, and 8% of patients, respectively (Table). The most common TEAEs of any grade were decreased neutrophil count (85%), anemia (84%), and decreased white blood cell count (83%). The most common grade ≥ 3 TEAEs were decreased neutrophil count (64%), decreased white blood cell count (50%), and anemia (23%). Conclusions SG continued to demonstrate substantial clinical activity, with OS, ORR, DoR, CBR, and PFS results in the EVER-132-001 trial, consistent with the phase 3 ASCENT trial of SG in mTNBC. TEAEs were manageable and no new safety signals were identified. These results support the use of SG as a new standard of care for Chinese pts with pretreated mTNBC. Table Citation Format: Fei Ma, Shusen Wang, Zhongsheng Tong, Wei Li, Xinhong Wu, Xiaojia Wang, Tao Sun, Yueyin Pan, Herui Yao, Xian Wang, Ting Luo, Jin Yang, Xiaohua Zeng, Weihong Zhao, Kimberly Komatsubara, Rachel Nakamura, Catherine Lai, Bo Zhang, Xiuyu Cong, Binghe Xu. Overall survival results from EVER-132-001, a phase 2b single-arm study of sacituzumab govitecan in Chinese patients with metastatic triple-negative 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 PO1-06-10.

Abstract CT248: Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2 mutant non-small cell lung cancer (NSCLC): primary analysis from the Phase 2 DESTINY-Lung05 (DL-05) trial

Abstract Background: In China, non-approved therapies are used for pts with HER2 (ERBB2) mutant (HER2m) NSCLC. In DESTINY-Lung02 (DL-02), T-DXd 5.4 mg/kg showed clinical benefit with an acceptable and manageable safety profile in pts with pretreated HER2m metastatic NSCLC. DL-02 did not include any Chinese pts. We report the primary analysis of T-DXd in Chinese pts with pretreated HER2m metastatic NSCLC. Methods: In this open-label, single-arm, Phase 2 trial (NCT05246514), Chinese pts with HER2m (locally or centrally confirmed activating HER2 exon 19 or 20 mutation) metastatic non-squamous NSCLC with disease progression on or after ≥1 prior anticancer therapy (no prior HER2-directed) received T-DXd 5.4 mg/kg IV once every 3 weeks. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included investigator-assessed (INV) confirmed ORR; ICR and INV duration of response, disease control rate, progression-free survival, and safety. Results: At data cutoff (September 23, 2023), 72 pts with HER2m NSCLC received T-DXd 5.4 mg/kg (full analysis set). Median T-DXd exposure was 7.9 (0.7-13.5) months. Pt characteristics and efficacy data are in the table. 71 pts had drug-related adverse events (AEs), of which 51.4% were grade (G) ≥3. Most common G≥3 AEs by grouped term: neutropenia (26.4%), thrombocytopenia (18.1%), and leukopenia (11.1%). Drug-related AEs leading to discontinuations occurred in 2 (2.8%) pts. 17 (23.6%) pts had serious AEs, with no INV-adjudicated G5. Centrally adjudicated drug-related ILD/pneumonitis occurred in 7 (9.7%) pts (n=6 G2; n=1 G5). Conclusion: T-DXd 5.4 mg/kg demonstrated clinically meaningful and durable responses and a manageable safety profile in Chinese pts with HER2m metastatic NSCLC. Results were consistent with DL-02 and the known safety profile of T-DXd, supporting its use in this pt population. TABLE 1. NAND Pt characteristics and efficacy data Full analysis set* N=72 Median age, years (min, max) 57.0 (34, 76) Female, n (%) 41 (56.9) Former smoker, n (%) 22 (30.6) Prior lines of therapy, n (%) 1 30 (41.7) ≥2 42 (58.3) Most common prior treatment modalities, n (%) Cytotoxic chemotherapy 67 (93.1) Platinum chemotherapy 65 (90.3) Immunotherapy 49 (68.1) Antiangiogenic therapy 49 (68.1) Median duration of follow up, months (range) 9.8 (1.0–14.0) Efficacy ICR INV Confirmed ORR, % (95% CI) 58.3 (46.1, 69.8) 58.3 (46.1, 69.8) Median DOR, months (95% CI) NE (6.1, NE) 9.0 (7.2, NE) DCR, % (95% CI) 91.7 (82.7, 96.9) 93.1 (84.5, 97.7) Median PFS, months (95% CI) NE (7.2, NE) 10.8 (7.2, NE) 12-month PFS rate, % (95% CI) 55.1 (41.4, 66.8) 39.7 (19.5, 59.4) *Pts with HERm assessed by central testing. CI, confidence interval; DCR, disease control rate; DOR, duration of response; HER2m, HER2 mutant; ICR, independent central review; INV, investigator assessed; NE, not estimable; ORR, objective response rate; PFS, progression-free survival; pts, patients Citation Format: Ying Cheng, Lin Wu, Yong Fang, Yun Fan, Xingya Li, Mingjun Zhang, Yan Yu, Yu Yao, Ruilian Xu, Jun Guo, Huaping Yang, Jian Fang, Feng Luo, Xuhong Min, Ke-jing Tang, Jie Hu, Yunru Chen, Rui Mao, Victor Zhang, Dairong Li. Trastuzumab deruxtecan (T-DXd) in Chinese patients (pts) with previously treated HER2 mutant non-small cell lung cancer (NSCLC): primary analysis from the Phase 2 DESTINY-Lung05 (DL-05) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT248.

First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC/GEJC/EAC): CheckMate 649 Chinese subgroup analysis 4-year (yr) follow-up.

318 Background: NIVO + chemo demonstrated clinically meaningful improvement in overall survival (OS) and an acceptable safety profile vs chemo in previously untreated Chinese pts from CheckMate 649, consistent with the overall study population with advanced GC/GEJC/EAC. 1L NIVO + chemo is approved for advanced GC/GEJC/EAC in multiple countries, including China. We report 4-yr results of NIVO + chemo vs chemo in Chinese pts from CheckMate 649. Methods: Adults with previously untreated, unresectable advanced or metastatic, non-HER2+ GC/GEJC/EAC were enrolled regardless of programmed death ligand 1 (PD-L1) expression. Randomized pts received NIVO (360 mg Q3W or 240 mg Q2W) + chemo (XELOX Q3W or FOLFOX Q2W), NIVO + ipilimumab, or chemo. Dual primary endpoints for NIVO + chemo vs chemo were OS and progression-free survival (PFS) by blinded independent central review (BICR) in pts with PD-L1 combined positive score (CPS) ≥ 5. Results: 208 Chinese pts were randomized to NIVO + chemo or chemo. At 49-month (mo) minimum follow-up, NIVO + chemo continued to demonstrate OS and PFS benefit vs chemo in pts with PD-L1 CPS ≥ 5 and in all randomized pts (Table). The 4-yr OS rate was 25% with NIVO + chemo vs 11% with chemo in pts with PD-L1 CPS ≥ 5 and 21% vs 9% in all randomized pts. Objective response rate (ORR; 95% CI) per BICR in pts with PD-L1 CPS ≥ 5 who had measurable lesions at baseline was 68% (56–79) with NIVO + chemo vs 48% (36–60) with chemo; corresponding ORR in all randomized pts was 66% (55–76) and 45% (35–56). Responses were more durable with NIVO + chemo vs chemo both in pts with PD-L1 CPS ≥ 5 (median duration of response [mDOR; 95% CI] 12.5 mo [7.2–23.4] vs 6.9 mo [3.9–8.5]) and in all randomized pts (mDOR [95% CI] 12.5 mo [7.2–17.7] vs 5.6 mo [4.4–8.3]). No new safety signals were identified (Table). Conclusions: After 4 yrs of follow-up, NIVO + chemo continued to demonstrate clinically meaningful survival benefit and more durable responses vs chemo in Chinese pts, with an acceptable safety profile. These results are consistent with previous reports and with the overall study population with advanced GC/GEJC/EAC and further support NIVO + chemo as a standard 1L treatment option for Chinese pts. Clinical trial information: NCT02872116 . [Table: see text]

Pivotal single-arm, phase 2 trial of tasurgratinib for patients with fibroblast growth factor receptor (FGFR)-2 gene fusion-positive cholangiocarcinoma (CCA).

471 Background: CCA represents ~3% of all gastrointestinal malignancies globally; it is particularly prevalent in Asian countries. Additionally, FGFR2 gene fusions occur in ~13% of intrahepatic CCA cases. Tasurgratinib (E7090) is an orally available selective inhibitor of FGFR 1–3; the recommended dose is 140 mg per day per the dose-escalation part of a first-in-human phase 1 study. In this pivotal phase 2 study, this regimen was evaluated in patients (pts) with FGFR2 fusion-positive CCA. Methods: Japanese and Chinese pts with surgically unresectable advanced or metastatic CCA were treated with tasurgratinib 140 mg PO daily. FGFR2 gene fusion was confirmed by fluorescence in situ hybridization performed in central laboratories; ≥ 1 prior chemotherapy regimen including a gemcitabine-based combination was required; pts treated with FGFR2 inhibitors were excluded. The primary endpoint was objective response rate (ORR; complete response [CR] + partial response [PR]). Secondary endpoints included duration of response (DOR), time to response (TTR), disease control rate (DCR; CR + PR + stable disease [SD]), clinical benefit rate (CBR; CR + PR + SD lasting ≥ 23 weeks), progression-free survival (PFS), overall survival (OS), and safety. The study was considered successful if the lower limit of the ORR 90% CI was > 15% in a planned population. Tumor responses were measured every 8 weeks by RECIST v1.1 per independent imaging review. Adverse event (AE) severity was measured per CTCAE v4.03. Results: 63 Pts (Japanese: n = 28; Chinese: n = 35) were treated (median age: 55 years); 23 pts (37%) had received 1 prior regimen, all others had received ≥ 2. By the data cutoff date (March 15, 2023), 55 pts discontinued treatment (disease progression, n = 48; adverse events, n = 4; pt choice, n = 2; loss of clinical benefit, n = 1). 19 Pts (30%) had a PR; 31 pts (49%) had SD and 13 (21%) had SD for ≥ 23 weeks. The ORR was 30% (2-sided 90% CI 20.7–41.0; 95% CI 19.2–43.0); the DCR was 79% (95% CI 67.3–88.5); the CBR was 51% (95% CI 37.9–63.6). The median [m]TTR / DOR for responders were 1.87 mos (IQR 1.77–2.10; range 1.6–14.7) / 5.6 mos (95% CI 3.7–9.3; range 1.0+–14.8+). The mPFS / OS were 5.4 mos (95% CI 3.7–5.6) / 13.1 mos (95% CI 10.8–17.4). 61 Pts (97%) had ≥ 1 treatment-related AE (TRAE), most commonly hyperphosphatemia (n = 51; 81%); 18 pts (29%) had ≥ 1 grade ≥ 3 TRAE, most commonly lipase increased (n = 4; 6%). 34 Pts (54%) had a dose reduction and 18 (29%) had treatment interruption due to TRAEs. 4 Pts (6%) had a fatal AE, none related to treatment. Conclusions: Tasurgratinib had promising antitumor activity in pts with CCA harboring FGFR2 gene fusion and who received ≥ 1 prior chemotherapy regimen. The primary endpoint (ORR) met the study’s predefined success criteria. Tasurgratinib had a manageable safety profile consistent with previous reports and with the known pharmacological profile of FGFR inhibitors. Clinical trial information: NCT04238715 .

Abstract B043: Preliminary results from a phase I/II study evaluating the safety, tolerability, and efficacy of EP0031, a next generation selective RET inhibitor, in patients with advanced RET-altered malignancies

Abstract BACKGROUND Emergence of resistance to 1st generation (gen) selective RET inhibitors (SRIs, selpercatinib/pralsetinib) is an area of high unmet need. EP0031 (A400/KL590586) has promise as a next gen SRI. Clinical data was recently reported from an ongoing Phase I/II study in China that included 109 patients (pts) with RET-altered tumours (NCT05265091, Zhou et al. JCO 2023, 41:16, suppl. 3007). ORR was 80.8 and 69.7%, across 40-120 mg QD doses, in treatment-naïve or pre-treated metastatic NSCLC, respectively. Responses durable with longest 14.5 mo ongoing, median DoR not reached. Responses, including in the CNS, observed in 5/7 pts that previously received 1st gen SRI. EP0031 had an encouraging safety and tolerability profile. 90mg QD was selected as RP2D. Here we report initial data from the dose ranging and optimisation module of a parallel Phase I/II study in the US and Europe. EXPERIMENTAL PROCEDURES This study (NCT05443126) is recruiting pts with RET-altered NSCLC, thyroid cancer or other solid tumours. Study includes male or female pts ≥ 18 years of age, PS 0 or 1 with/without asymptomatic, stable brain metastases. The first module is a dose escalation to investigate safety, tolerability, PK/PD and define the MTD and/or RP2D. This is based on rolling 6 design and is expected to recruit up to 40 pts. RESULTS As of 10th July 2023, a total of 15 pts, 5 medullary thyroid cancer (MTC), 2 CRC and 8 NSCLC, have been included across dose cohorts of 20mg (N=3), 60mg (N=6) and 90mg (N=6). PK profile is comparable with Chinese pts and consistent with QD dosing. 60mg QD predicted to achieve IC50 for inhibition of RET fusions/mutations. No DLTs and no serious adverse events reported. No dose reductions, interruptions or discontinuations have been required. AEs have been mainly Grade 1 or 2. No neutropenia, hypertension, neurotoxicity or QTc prolongation observed. Three pts (all MTC) that received 20 mg QD had their dose escalated to 60mg (after 5-7 cycles at 20mg). 2 of those pts, both SRI naïve, have ongoing stable disease for >23 weeks. 1 pt (prior SRI) with a new target lesion continues to derive clinical benefit and remains on treatment. Of 4 evaluable pts at 60 mg, 2 pts with NSCLC (prior SRI) have achieved a PR, treatment is ongoing and 2 pts with MTC (prior SRI) had PD, one of whom continues to derive clinical benefit and remains on treatment. The remaining pts at 60 or 90mg (potential RP2D) are not yet evaluable for efficacy. Genomic analyses for RET/non-RET resistance mechanisms are ongoing. Expansion of the 60mg and 90mg cohorts is planned for dose optimization. Expanded efficacy, safety and PK/PD data from dose ranging and optimization cohorts will be presented. CONCLUSIONS These preliminary data are encouraging, consistent with that reported from a larger cohort of Chinese patients, with early evidence that EP0031 is active in pts that received prior 1st gen SRI. Once RP2D confirmed, the study will expand cohorts of both SRI-naïve and pre-treated pts with RET-altered NSCLC, thyroid and other solid tumours. Citation Format: Elena Garralda, Alonso Guzman, Pilar Garrido, Andrew G Gianoukakis, Matthew Taylor, Sarina Piha-Paul, Matthew G Krebs, Antoine Italiano, Liz Clark, Geoff Fisher, Tobi Arkenau, Vivek Subbiah. Preliminary results from a phase I/II study evaluating the safety, tolerability, and efficacy of EP0031, a next generation selective RET inhibitor, in patients with advanced RET-altered malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B043.

Clinical Characteristics and Survival Analysis of Richter Transformation: A Single Center Retrospective Study in China

Introduction: Richter transformation (RT) refers to the progression of an aggressive lymphoma arising on the background of chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL). Despite the incidence of RT among CLL/SLL is low (range 2-10%), the prognosis is very poor. Usually, different clinical and biology characteristics were observed between CLL/SLL and RT stages, and their impacts on disease progression remains unknown. In this report, we investigated the clinical characteristics and outcomes of 37 Chinese patients (pts) in CLL/SLL and in RT stages. This 18-year follow-up retrospective study might serve as a basis for future prospective clinical studies. Methods: From Feb 2004 to Feb 2022, all of the CLL/SLL pts who developed biopsy-proven RT in our institution were enrolled. Clinical characteristics and survival data (treatment course, clinical response to treatment as determined by treating physician, and survival information) were collected by chart review. Overall survival 1 (OS 1) was defined as the time from initial CLL/SLL diagnosis to death. Overall survival 2 (OS 2) was defined as the time from RT to death. Results: A total of 37 Chinese pts with pathological proven RT were enrolled from Feb 2004 to Feb 2022. The median age at CLL/SLL diagnosis and at RT were 60 years (range 29-63 years) and 63 years (range 35-77 years), respectively. Twenty-four pts (64.9%) were male. Frequencies of several adverse clinical/laboratory factors were significantly higher at RT diagnosis compared to at CLL/SLL diagnosis, including elderly age (40.5% vs. 16.2%, p=0.020), bulky disease (45.9% vs. 18.9%, p=0.017), extranodal disease (37.8% vs. 5.4%, p=0.001), B symptoms (67.6% vs. 27.0%, p<0.001) and hypogammaglobulinemia (70.3% vs. 51.4%, p=0.026). The rate of advanced Rai staging was higher in RT stage than in CLL/SLL stage. However, no statistically significant difference was observed in Binet staging or CLL-international prognostic index (CLL-IPI). In CLL/SLL stage, 27 pts (27/37, 73.0%) received at least one line of therapy. The median number of treatment lines was 1 (range: 0-4). Ten pts (27.0%) received BTK inhibitor and 4 pts (10.8%) treated with Bcl-2 inhibitor treatment, 11 pts (29.7%) received purine analogue therapy (i.e. fludarabine) and 9 pts (24.3%) were exposed to anti-CD20 antibody. In our study, the median time from CLL/SLL diagnosis to RT was 45.3 months (95% CI 36.0-54.6 months). In RT stage, the median number of treatment lines was 2 (range: 0-6). Twenty-four pts (64.9%) received BTK inhibitors, 4 pts (10.8%) received Bcl-2 inhibitor treatment, 6 pts (16.2%) received anti-PD1 treatment as part of salvage therapy and 2 pts (5.1%) underwent chimeric antigen receptor T (CAR-T) therapy.The best overall response (BOR) data post RT was collected in our study. Among 36 pts who ever received any anti-cancer treatment and had at least one disease assessment, 1 pt (2.8%) achieved complete response (CR), 19 pts(52.8%) achieved partial response (PR), the rest pts resulted in stable disease (SD) (8/36, 22.2%) and progressive disease (PD)(8/36, 22.2%). The median OS 1 was 119.7 months (95% CI 77.78-161.6 months). Clinically significant difference of OS 1 was observed between salvage therapy responders (CR+PR) compared to non-responders (SD+PD). The estimated median OS 1 was not reached (NR) for responders and 78.8 months (95% CI 30.1-127.5, p=0.001) for non-responders. For OS 1, in the univariate analysis, bulky disease, Eastern Cooperative Oncology Group (ECOG) and TP53 aberration are identified as three prognostic factors. In the multivariate analysis, bulky disease and ECOG were confirmed as independent prognostic factors.(Table 1) The median OS 2 was 39.6 months (95% CI 3.4-75.8 months). Patients who responded to salvage therapy had significantly better OS 2 than non-responders. The median OS 2 was NR vs. 8.3 months (95% CI 0-25.2, p<0.001). For OS 2, in both the univariate analysis and multivariate analysis, bulky disease and treatment response were identified as two prognostic factors in RT stage.(Table 2) Conclusion: In this long-term follow-up study, pts presented more aggressive clinical/laboratory characteristics in RT stage than in CLL/SLL stage. The outcome of Chinese pts with RT was very poor. For OS 1, bulky disease and ECOG are identified as prognostic factors. While, bulky disease and treatment response were confirmed as the indepedent prognostic factors in RT stage.

Real-World Analysis of Obinutuzumab-Based Immunochemotherapy in Follicular Lymphoma in Chinese Population

Background Obinutuzumab is a first-in-class glycoengineered humanized type II anti-CD20 antibody. Immunochemotherapy based on obinutuzumab has demonstrated an advantage in prolonging progression-free survival (PFS) in pts with follicular lymphoma(FL) in a number of clinical trials(Marcus R, et al. N Engl J Med. 2017; Cheson BD, et al. J Clin Oncol. 2018). In Jun, 2021, obinutuzumab came into the market of China. However, few studies have investigated the efficacy and safety of obinutuzumab-based immunochemotherapy aiming at Chinese population. Therefore, we retrospectively analyzed the data of Chinese pts with treatment-naïve(TN) or relapsed/refractory(R/R) follicular lymphoma who received obinutuzumab-based immunochemotherapy in our center, hoping to provide treatment reference for Chinese pts. Methods Eligible pts were age ≥18 years with histologically documented, CD20-positive follicular lymphoma (grade 1 to 3a, stage III/IV or stage II with tumor ≥7 cm in the greatest dimension), and at least 2 cycles of obinutuzumab-based treatment. Efficacy was assessed by objective response rate (ORR) and best of response (BOR), with toxicity evaluated based on the Common Terminology Criteria for Adverse Events (CTCAE) (The 5th Edition). In addition, we recorded the incidence and severity of corona virus disease 2019 (COVID-19) infection according to Scheme for Diagnosis and Treatment of COVID-19 (The 10th Trial Edition). Results Between Nov 1, 2021 and Apr 1, 2023, the data of 27 pts with TN FL who received G-CHOP (obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen and 7 R/R pts treated with GB (Obinutuzumab, bendamustine) regimen was collected. The demographic and clinical characteristics at baseline were shown in Table 1. The median age of TN pts was 52 years, and 63.0% were female. The efficacy evaluation of TN pts was displayed in Figure 1. All of 27 pts achieved partial response (PR) after 2 cycles of GCHOP regimen. Eventually, 21 patiens completed 6 cycles of treatment, with 95.5% (21/22) assessed as complete response (CR) and 4.5% (1/21) maintaining PR. Three pts discontinued treatment due to COVID-19 infection and 2 for severe infections of other reasons. The end of treatment (EOT) ORR was 100% and the BOR of 96.3% (26/27) pts was assessed as CR. In 7 R/R pts, 5, 1 and 1 pts received 1, 2 and 3 lines of previous treatment regimens, respectively. The median age of this subgroup was 56 years. Totally, 6 pts achieved CR with an ORR of 85.7%, except for one pt who was evaluated as SD after 2 cycles of GB regimen and switched to another regimen. Two pts continued with maintenance therapy of obinutuzumab, and the rest 5 pts went on with autologous hematopoietic stem cell transplantation. By the end of follow-up, no pts showed progressive disease (PD) except for one who died of COVID-19 infection. All these pts in this study were infected with COVID-19 during the pandemic in China. For TN pts, mild, ordinary, severe and critical cases accounted for 14.8%, 44.4%, 29.6% and 11.1% respectively, and no pt died of COVID-19 infection. The median duration of COVID-19 infection was 23 (14-68) days, and over half of them were tested positive for more than 3 weeks. Of the R/R pts, 57.1% (4/7) presented severe, 14.3% (1/7) was critical and finally died of respiratory failure. The median duration of positive was 26 (21-95) days. Among pts treated wih GCHOP regimen, common grade 3-5 adverse events included infection (excluding COVID-19 infection) (25.9%) and hematological adverse events consisting of neutropenia (51.8%), thrombocytopenia (22.2%). Grade 3 infection, neutropenia and thrombocytopenia were observed in 14.3% (1/7) R/R pt each. The median follow-up time of TN pts and R/R pts was 8.9 (12.1-13.7) months and 11.7 (11.2-14.0) months, respectively. The median PFS of both was not achieved, 1-year PFS rate was 100% and 85.7% in TN and RR pts, respectively. Conclusions This real-world analysis with small sample size indicates that similar efficacy and toxicity was observed in Chinese patients with FL who were treated with obinutuzumab-based immunochemotherapy to that reported in literature. However, it is noteworthy that long-lasting immunosuppression may result in higher incidence and severity of COVID-19 infection in these patients compared to the general population.

Phase 2 Search Study：XPO1 Inhibitor (ATG-010) Monotherapy in Heavily Pretreated Chinese Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background Relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) is an aggressive and most globally prevalent subtype of non-Hodgkin's lymphoma with a dismal prognosis. Selinexor (ATG-010) is an oral selective inhibitor of nuclear export, which blocks exportin1 (XPO1). The US FDA granted accelerated approval to selinexor for the treatment of adult patients (pts) with DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy based on the Phase 2b SADAL study (NCT02227251). SEARCH is a single arm, Phase 2, registrational bridging study to assess efficacy and safety of selinexor in Chinese pts with R/R DLBCL. Method SEARCH was designed to evaluate safety and efficacy of selinexor (60mg Days 1 and 3 of Weeks 1 to 4 of each 4-week cycle) in R/R DLBCL pts in China with 2-5 prior lines of systemic therapy. The primary endpoint was overall response rate (ORR) assessed by an Independent Review Committee (IRC). The study was registered at ClinicalTrials.gov (NCT03992339), with the primary analysis results presented here. Results As of 31 st May 2023 (6 months post last pt dosed), 5 (8.3%) of the 60 treated pts remained on treatment. Median follow-up was 27.7 months (mo) (range: 6.0-37.7). Median age was 58.5 years (20.0%≥70yrs). Median duration from initial DLBCL diagnosis was 1.8 years (range: 0.5-11.2). A total of 7 pts (11.7%) had DLBCL arising from indolent lymphoma, 4 (6.7%) had creatinine clearance <60ml/min and 27 (45.0%)/33 (55.0%) had GCB/non-GCB subtype, respectively. Median number of prior regimens was 3 (range: 2-5); 5 pts (8.3%) had received prior ASCT. Patients had received the following novel treatments, which were not previously received by patients in SADAL: 10 (16.7%) chidamide, 8 (13.3%) BTK inhibitor, 6 (10.0%) PD-1/PD-L1 antibodies, 3 (5.0%) polatuzumab, 1 (1.7%) PI3K inhibitor, and 4 pts (6.7%) had undergone CAR-T cell therapy. Thirty-two pts (53.3%) were with primary refractory DLBCL and 54 pts (90.0%) were refractory to the last systemic therapy for DLBCL. ORR was 21.7% (95% CI: 12.1, 34.2) and CR rate was 16.7%. Median duration of response (DOR) was 7.6 mo, median progression free survival (PFS) was 1.9 mo, and median overall survival (OS) was 8.5 mo. Efficacy was evident in pts who had poor prognostic factors, including elderly pts (≥70yrs) with ORR 16.7%, pts with renal dysfunction with ORR 25.0%, primary refractory pts with ORR 18.8% and pts refractory to their last systemic therapy with ORR 16.7%. And pts with De novo/transformed DLBCL with ORR 17.0%/57.1%, pts with GCB/non-GCB DLBCL with ORR 25.9%/18.2%, pts with/without prior ASCT with ORR 40.0%/20.0%, pts with 2/more than 2 previous regimens with ORR 25.9%/18.2%. One pt (1/4) with prior CAR-T achieved PR assessed by investigators. All pts experienced at least one treatment-emergent adverse event (TEAE), 47 (78.3%) with at least one Grade 3/4 TEAE, and 24 (40.0%) with at least one serious TEAE. The most common non-hematologic TEAE of any grade (≥20%) included decreased appetite (61.7%), nausea (58.3%), weight loss (38.3%), vomiting (33.3%), diarrhea (31.7%), asthenia (30.0%), hyponatremia (26.7%), constipation (25.0%) and AST increased (20.0%). The most common grade≥3 non-hematologic TEAE (≥2%) were decreased appetite (6.7%), diarrhea (5.0%), vomiting (5.0%), hyponatremia (3.3%), asthenia (3.3%), pneumonia (3.3%), dyspnea (3.3%) and COVID-19 pneumonia (3.3%). The most common hematologic TEAE of any grade (≥20%) were thrombocytopenia (83.3%), leukopenia (81.7%), neutropenia (80.0%), anemia (75.0%) and lymphopenia (30.0%). The most common grade≥3 hematologic TEAE (≥10%) were thrombocytopenia (41.7%), leukopenia (40.0%), neutropenia (36.7%), anemia (23.3%) and lymphopenia (16.7%). The most common AEs were generally manageable by dose modification and supportive care. Conclusions R/R DLBCL remains a high unmet medical need, especially in pts who are ineligible/frail to transplantation. The SEARCH study demonstrates clinically meaningful ORR in Chinese R/R DLBCL pts treated with selinexor monotherapy, consistent with the global study. Adverse events were generally manageable with appropriate supportive care and dose modification. These data are generally consistent with the SADAL study and supports the use of selinexor as an oral, chemotherapy-free treatment option for R/R DLBCL patients in China.

Update of Olverembatinib (HQP1351) Overcoming Ponatinib and/or Asciminib Resistance in Patients (Pts) with Heavily Pretreated/Refractory Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph + ALL)

Background Olverembatinib, a novel, potent BCR::ABL1 tyrosine kinase inhibitor (TKI), shows strong antitumor activity in pts with CML and Ph + ALL. Here, we report on the safety, efficacy, and pharmacokinetic (PK) profiles of olverembatinib in pts with CML (all phases) and Ph + ALL outside of China, particularly in pts previously treated with ponatinib and/or asciminib. Methods Olverembatinib was administered orally once every other day (QOD) in continuous 28-day cycles. In the monotherapy cohort, pts were enrolled after treatment failure on at least 2 prior TKIs and randomized to olverembatinib QOD 30, 40, or 50 mg. In the combination cohort, pts with Ph + B-cell precursor (BCP) ALL or lymphoid CML-BP (CML-LBP) resistant to at least 1 TKI were enrolled and received olverembatinib (30 or 40 mg) QOD in combination with blinatumomab. Results As of June 30, 2023, 76 pts were enrolled, including 57 with CML-CP and 19 with advanced Ph + leukemia. The median (range) age was 54.5 (21-80) years, and 56.6% of pts were male. In all, 11 (14.5%), 23 (30.3%), and 39 (51.3%) pts had received 2, 3, and ≥ 4 prior TKIs, respectively. A total of 52.6% of pts were previously treated with ponatinib, of whom 67.5% were resistant and 25.0% intolerant to the drug, and 7.5% experienced treatment failure for other reasons. A total of 27.6% of pts were previously treated with asciminib, of whom 71.4% were resistant and 19.1% intolerant to the agent, and 9.5% experienced treatment failure for other reasons. At baseline, 32% of pts had T315I mutations, 38% hypertension, and 17.1% other cardiovascular comorbidities. Median (range) treatment duration was 24.1 (0-134) weeks, and PK profiles were similar to historical PK data on Chinese pts. Twelve pts with CML-CP and 7 with advanced Ph + leukemia discontinued treatment: 4 because of AEs, 7 disease progression, and 8 other reasons. A total of 54 of 65 (83.1%) pts who received ≥ 1 dose of olverembatinib experienced any-grade TRAEs. Grade ≥ 3 AEs occurring in ≥ 3 pts (≥ 4.6% incidence) included thrombocytopenia (17%); neutropenia (13.8%); elevated blood creatine phosphokinase (13.8%); leukopenia (7.7%); and anemia and elevated lipase (4.6% each). Ten (15.4%) pts experienced olverembatinib treatment-related serious AEs, of which each were experienced by 1 (1.5%) pt. Two (3.1%) pts discontinued the study because of TRAEs. No TRAE-associated deaths were reported. Olverembatinib showed sustained antileukemic activity in pts with CML and Ph + ALL (Table 1). Among 50 efficacy-evaluable pts with CML-CP, the rate of complete cytogenetic response (CCyR) was 57% (25/44) and major molecular response (MMR) 43% (21/49). Efficacy improved over time; the MMR rate in pts with CML-CP treated for 6 months was 66% and 88% in pts treated for 12 months. Among pts whose disease failed ≥ 4 prior TKIs, CCyR and MMR rates were 57% (13/23) and 42% (11/26), respectively. In pts with CML-CP harboring the T315I mutation, rates of CCyR and MMR were 60% (9/15) and 44% (7/16), respectively, and 55% (16/29) and 42% (14/33) in pts without the T315I mutation. Among evaluable ponatinib-failed pts, 8/15 (53%) achieved CCyR and 6/16 (38%) MMR. Among pts who failed asciminib therapy, 3/7 (43%) achieved CCyR and 3/8 (38%) MMR. Of 8 pts with CML-CP who had prior exposure to both ponatinib and asciminib, 2 (25%) achieved MMR. At 24 months, PFS was 75% (95% CI, 56.1-86.7) and OS was 97.6% (95% CI, 90.8-99.4). Thirteen pts with advanced Ph + leukemia were efficacy-evaluable, of whom 3 (23%) achieved MMR; only 1 of 3 pts with the T315I mutation achieved MMR; the other 2 were also resistant to ponatinib treatment. The median (95% CI) PFS of efficacy-evaluable pts with advanced leukemia was 12.7 (4-19.5) months. In the combination cohort, 2 pts with Ph + BCP ALL received olverembatinib 30 mg QOD with blinatumomab; both achieved CCyR and 1 achieved a negative MRD status after 1 treatment cycle. Conclusions Olverembatinib alone or combined with blinatumomab was efficacious and well tolerated in pts with heavily pretreated CML or Ph + ALL . Olverembatinib monotherapy was potent in pts who were either resistant or intolerant to ponatinib and/or asciminib, regardless of T315I mutation status. Olverembatinib may provide an effective new treatment option for pts after failure of 2 or more TKIs. Internal study identifier: HQP1351-CU101. Clinicaltrials.gov identifier: NCT04260022.

Acalabrutinib in Chinese Patients (Pts) with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL): 12-Month Efficacy and Safety Results from an Open-Label, Multicenter Phase 1/2 Trial

Background: CLL is a rare, incurable, relapsing disease occurring in approximately 0.3/100,000 individuals in China. Acalabrutinib (acala) is a highly selective Bruton tyrosine kinase inhibitor with minimal off-target activity approved in the US and Europe for treatment of CLL. Pivotal studies supporting acala's approval had limited inclusion of Asian populations. In the first phase 1/2 trial (NCT03932331) in Chinese pts with R/R CLL, acala demonstrated high response rates and acceptable tolerability at the 6-mo follow-up (Yang S et al. HemaSphere, 2023;7(S3):3716). We present 12-mo results from this trial. Methods: Adults with active CLL, Eastern Cooperative Oncology Group (ECOG) performance status ≤2, and who received ≥1 prior systemic therapies for CLL were enrolled to receive acala 100 mg twice daily in 28-day cycles until disease progression or treatment discontinuation due to adverse events (AEs) presenting substantial clinical risk. The primary endpoint was overall response rate (ORR) per 2018 International Workshop on Chronic Lymphocytic Leukemia criteria as assessed by blinded independent central review (BICR). Secondary endpoints included duration of response (DOR) and progression-free survival (PFS) as assessed by BICR; ORR, DOR, and PFS as assessed by investigators (INV); overall survival (OS); and AEs. Results: Sixty pts from 20 sites in China received acala (median age 62 y; 31.7% female; 21.7% with del(17p) and/or TP53 mutation; 51.7% with unmutated IGHV; median 1 prior line of therapy). At the updated data cutoff of December 22, 2022, 53 pts (88.3%) were receiving acala; reasons for acala discontinuation were progressive disease (5.0%; n=3), AEs (3.3%; n=2), pt decision (1.7%; n=1), and other (1.7%; n=1). Median duration of treatment was 19.4 mo (range 0.6-28.2). BICR-assessed ORR was 85.0% (95% CI 73.4, 92.9); no pt had complete response (CR). Median DOR by BICR was not reached (NR). At a median follow-up of 20.2 mo, median PFS by BICR was NR; the estimated 12-mo and 18-mo PFS rates were 91.5% (95% CI 80.9, 96.4) and 78.8% (95% CI 60.9, 89.2), respectively ( Figure). When assessed by INV, ORR was 85.0% (95% CI 73.4, 92.9) with 1 pt having CR, median DOR was NR, and median PFS was NR; estimated 12-mo and 18-mo PFS rates were 95.0% (95% CI 85.2, 98.3) and 87.2% (95% CI 69.1, 95.0), respectively. Median OS was also NR; the estimated 12-mo and 18-mo OS rates were both 96.7% (95% CI 87.3, 99.2). AEs of any grade were reported in 58 pts (96.7%); 25 pts (41.7%) had grade ≥3 AEs, most commonly decreased neutrophil count (13.3%, n=8), pneumonia, and upper respiratory tract infection (each 6.7%, n=4) ( Table). AEs leading to treatment discontinuation included paraneoplastic pemphigus (n=1) and rectal neoplasm (n=1). AEs leading to dose interruption were reported in 13 pts (21.7%), most commonly COVID-19 (5.0%), neutrophil count decreased (3.3%), and platelet count decreased (3.3%). Nine pts (15.0%) had serious AEs (SAEs); only 1 SAE occurred in >1 pt (pneumonia, n=2). Fatal AEs (occurring ≤30 d after last dose) were reported in 1 pt (cardiac arrest in a 73-y-old pt with multiple cardiorespiratory comorbidities on study day 34). Among events of clinical interest, neutropenia was reported in 24 pts (40.0%) and hypertension was reported in 3 pts (5.0%). There were no cases of atrial fibrillation/flutter, major hemorrhage, interstitial lung disease/pneumonitis, second primary malignancies, or tumor lysis syndrome. Conclusions: Twelve-mo data in Chinese pts with R/R CLL treated with acala demonstrated a high ORR, with responses that were durable and clinically meaningful. Continuous treatment with acala was well tolerated with manageable toxicities; no unexpected safety observations were observed in Chinese pts with R/R CLL.

Health-Related Quality of Life (HRQOL) in Patients (Pts) with Tyrosine Kinase Inhibitor- (TKI)-Resistant Chronic Myeloid Leukemia (CML) Receiving Olverembatinib (HQP1351) Therapy

Background The prognosis of pts with TKI-resistant or T315I-mutated CML has markedly improved since the introduction of third-generation TKIs (3G-TKIs). However, there are limited data on the HRQOL of pts receiving 3G-TKI therapy. Olverembatinib is a novel 3G-TKI, which has shown efficacy and safety in pts with TKI-resistant chronic- or accelerated-phase CML (CP-CML/AP-CML). Here, we report the HRQOL of pts with TKI-resistant CML receiving olverembatinib treatment and associated variables. Method The European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) questionnaire was used to assess the HRQOL of pts with CML enrolled in phase 1/2 clinical trials on olverembatinib conducted in Peking University People's Hospital. HRQOL was evaluated at baseline and 3, 6, 12, 24, and 36 months. All scales and single-item measures were standardized and ranged from 0 to 100. A high score in functional scales and global health/QOL represented improved function or QOL. A high score in symptom scales represented worse symptomatology or problems. We measured score changes over time and changes in scores (CIS) at month 36 compared to baseline. Comparison of means was performed using a Student paired t-test. Mixed-effects models were used to identify which variables were associated with improvements in functional scales and reductions in symptom scales of the EORTC QLQ-C30. Results Overall, 164 Chinese pts with CML (male, n = 106 [65%]) were enrolled and completed the questionnaire at the start of the study. A total of 132 (80%) pts had CP-CML and 32 AP-CML. The median (range) age was 43 (20-74) years. A total of 54 (33%) pts received ≥ 3 types of TKIs before starting olverembatinib therapy. The top three symptom burdens reported by pts at baseline were financial difficulties (64.2 ± 36.1), fatigue (27.0 ± 22.7), and insomnia (20.3 ± 27.3). During the 3-year follow-up, 119 (75%) pts achieved major cytogenetic response (MCyR) and 113 (69%) completed the questionnaire at 36 months. Among the 15 global health status items, functional and symptom scales significantly improved over time, including global health/QOL (CIS, +7.1; p < 0.01); physical functioning (CIS, +4.0; p < 0.01); emotional functioning (CIS, +6.0; p < 0.01); fatigue (CIS, -7.8; p < 0.001); dyspnea (CIS, -5.5; p < 0.05); appetite loss (CIS, -5.5; p < 0.05); diarrhea (CIS, -11.9; p < 0.001); and financial difficulties (CIS, -19.6; p < 0.001) (Figure 1). No scale deteriorated statistically significantly over time. Mixed-effects models that were used to identify variables associated with improvements in functional scales and reductions in symptom scales revealed that greater respective improvements in physical functioning and fatigue scales were significantly associated with younger (< 40 years) age ( p= 0.018; p= 0.029) and achievement of MCyR ( p= 0.008; p= 0.050); in the appetite loss scale, younger (< 40 years) age ( p = 0.001); in the emotional functioning scale, male sex ( p= 0.012); in the global health scale, CP-CML status at baseline ( p= 0.048); in the dyspnea scale, female sex ( p< 0.001) and CP-CML status at baseline ( p= 0.044); and in the diarrhea scale, achievement of MCyR ( p= 0.002). Conclusions The HRQOL of pts with TKI-resistant CML significantly improved during olverembatinib therapy. Younger age, being in CP-CML compared to AP-CML at baseline, and achieving MCyR on treatment were the common variables associated with improved HRQOL. Figure 1. HRQOL profile

Efficacy and safety of darolutamide in Chinese patients with metastatic hormone-sensitive prostate cancer (mHSPC): A subpopulation analysis of the phase 3 ARASENS study.

e17076 Background: Darolutamide (DARO) is an androgen receptor inhibitor approved in China for the treatment of nonmetastatic castration-resistant prostate cancer (CRPC). In the global ARASENS trial, DARO significantly increased overall survival (OS) vs placebo (PBO) in patients (pts) with mHSPC. The efficacy and safety of DARO in the Chinese subpopulation of ARASENS are reported here. Methods: In this randomized, double-blind phase 3 trial, 1305 pts with mHSPC were randomized 1:1 to receive DARO 600 mg orally twice daily or PBO, in combination with androgen-deprivation therapy (ADT) and docetaxel. The primary endpoint was OS. Results: In mainland China, 202 pts were randomized to the DARO group (n = 104) or the PBO group (n = 98). Demographics and baseline characteristics were well balanced between treatment groups and comparable to the overall ARASENS population, except for a slightly higher proportion of pts with Gleason score ≥8, higher proportion with metastatic disease at diagnosis, and higher median baseline prostate-specific antigen (PSA) in Chinese pts vs the overall population. The risk of death was reduced by 36% (HR 0.64, 95% CI 0.41–0.99) with DARO vs PBO in Chinese pts (Table). The key secondary endpoint time to CRPC (HR 0.32, 95% CI 0.20–0.50) and the exploratory endpoint time to PSA progression (HR 0.22, 95% CI 0.13–0.37) also favored DARO. In the DARO group, 81% of pts had a maximum PSA decline of ≥90% from baseline (PSA90) at week 12, while 88% had PSA90 and 71% reached PSA < 0.2 ng/mL at any time. Incidences of treatment-emergent adverse events (TEAEs) in Chinese pts were similar between treatment groups and comparable to the overall population. The most common grade 3/4 TEAE in Chinese pts was neutropenia (DARO 64%, PBO 62%), a known toxicity of docetaxel; grade 3/4 febrile neutropenia occurred in 4.0% of Chinese pts compared with 7.6% in the overall population. Conclusions: In the ARASENS subpopulation of Chinese pts with mHSPC, DARO + ADT + docetaxel showed favorable efficacy and safety vs PBO + ADT + docetaxel: OS and clinically relevant secondary endpoints favored DARO vs PBO, and the incidences of TEAEs were similar in the two treatment groups. These results are consistent with the findings reported for the overall population in ARASENS. Clinical trial information: NCT02799602 . [Table: see text]

EV-203: Phase 2 trial of enfortumab vedotin in patients with previously treated advanced urothelial carcinoma in China.

e16574 Background: Enfortumab vedotin (EV), a fully human monoclonal antibody directed against Nectin-4 delivering intracellular monomethyl auristatin E (MMAE) to tumor cells, demonstrated superior overall survival (OS) with manageable safety/tolerability over standard chemotherapy in patients (pts) with previously treated locally advanced or metastatic urothelial carcinoma (la/mUC) in the pivotal EV-301 trial. EV-301 findings led to approval in 41 countries. As EV monotherapy has not been studied in a Chinese population, EV-203 (NCT04995419) assessed efficacy, safety/tolerability, and pharmacokinetics (PK) of EV in pts with la/mUC in China. Methods: In this single-arm, open-label, phase 2 study, Chinese pts with la/mUC previously treated with platinum-based chemotherapy and PD-1/L1 inhibitor therapy received EV 1.25 mg/kg via intravenous infusion on days 1, 8, and 15 of each 28-d cycle at 6 centers. Pts had Eastern Cooperative Oncology Group performance status 0–1 and were excluded if they had preexisting grade ≥2 sensory/motor neuropathy, active central nervous system metastases, clinically significant toxicity associated with prior treatment, or history of uncontrolled diabetes mellitus. Two study centers enrolled pts for a PK cohort. Primary endpoints were confirmed objective response rate (ORR; by Response Evaluation Criteria in Solid Tumors v1.1) by independent review committee (IRC) and PK parameters of antibody–drug conjugate (ADC), total antibody (TAb), and unconjugated MMAE. Secondary endpoints included investigator-assessed confirmed ORR; investigator-/IRC-assessed duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS); OS; and safety/tolerability. Results: A total of 40 Chinese pts were enrolled; 15 were in the PK cohort. Confirmed ORR by IRC was 37.5% (n/N=15/40; 95% CI: 22.7–54.2); best overall response was complete response for 1 (2.5%) pt and partial response for 14 (35.0%) pts. Investigator-assessed ORR was 42.5% (n=17). DCRs were 82.5% (n=33) by investigator and 72.5% (n=29) by IRC. Median DOR by investigator and IRC were not reached. Median PFS were 4.24 mo by investigator and 4.67 mo by IRC. Median follow-up time was 6.5 mo and median OS was not reached. Most treatment-related adverse events (TRAEs) were grade 1–2. Two pts discontinued EV due to TRAE (acute coronary syndrome and hyperglycemia/rash). Serum ADC and TAb concentrations peaked at end of EV infusion; MMAE concentrations had median peak 2–3 d post dose. Minimal ADC, TAb, and MMAE accumulation were observed with repeat EV dosing. Conclusions: EV-203 results show EV has a favorable benefit–risk profile, demonstrating meaningful clinical activity with a manageable safety profile, in pts with previously treated la/mUC in China. EV data are consistent with those from the global population in phase 2–3 EV trials of la/mUC. No new safety signals were identified. Clinical trial information: NCT04995419 .