Review Committee Research Articles

Phase II randomized clinical trial comparing albumin-bound docetaxel vs. docetaxel in patients with previously treated advanced gastric or gastroesophageal junction adenocarcinoma.

e16018 Background: Albumin-bound docetaxel (HB1801) is a new kind of taxane and has many advantages compared with docetaxel. Previous phase I study has demonstrated that HB1801 showed preliminary efficacy in patients with gastric cancer. Here we presented the efficacy and safety of HB1801 in patients with gastric or gastroesophageal junction (G/GEJ) adenocarcinoma. Methods: In this phase II study, eligible patients were aged 18-75 years with histologically confirmed G/GEJ adenocarcinoma, who progressed on at least first line of combined chemotherapy of platinum and fluorouracil. Patients were randomized (1:1) to receive HB1801 (100 mg/m2) or docetaxel (Taxotere, 75 mg/m2) administered every 3 weeks by intravenous infusion. Stratified factors included previous treatment with immunotherapy (yes or no) and ECOG PS (0 or 1). Primary endpoint was progression free survival (PFS) per RECIST version 1.1 assessed by independent review committee. Secondary endpoints included overall survival, objective response rate (ORR), disease control rate (DCR), duration of response (DOR) and safety. Results: As of December 31, 2023, 125 patients were enrolled and randomized to HB1801group ( n= 63) or docetaxel group ( n= 62). The two groups were comparable on baseline characteristics. Overall, the median age was 59.0 (range 27-75) years, 98 (78.4%) patients had ECOG PS of 1. 73 (58.4%), 7 (5.6%) and 6 (4.8%) patients had received previous treatment with immunotherapy, antiangiogenic agents and anti-HER2 therapy. 45 patients in HB1801 group and 47 patients in docetaxel group were evaluable for efficacy. ORR and DCR were 24.4% (11 PRs, 95%CI 12.88-39.54) and 57.8% (15SDs, 95%CI 42.15-72.34) for HB1801 group, 14.9% (1 CR+6 PRs, 95%CI 6.20-28.31) and 46.8% (15 SDs, 95%CI 32.11-61.92) for docetaxel group. Patients in HB1801 group had a numerically longer DOR than those docetaxel group (median DOR: 2.9 months (95% CI 1.41-NA) vs 1.5 months (95% CI 1.41-NA)). Treatment-related adverse events (TRAEs) occurred in 87.1% of patients receiving HB1801, and 82.3% of patients receiving docetaxel. Alopecia (38.7% vs. 37.1%) and anemia (33.9% vs 35.5%) were the most predominant TRAEs in both groups, fatigue (38.7% vs 17.7%), hypoalbuminemia (27.4% vs 8.1%), decreased appetite (17.7% vs 12.9%), peripheral edema (16.1% vs 4.8%) were also observed in HB1801 group and docetaxel group. 14 patients (22.6%) in HB1801 group and 15 patients (24.2%) in docetaxel group experienced ≥grade 3 TRAEs, with the most common being anemia, leukopenia, decreased appetite, fatigue and lymphopenia. There were no treatment-related deaths. No new safety signal was observed in HB1801 group. Conclusions: These preliminary results suggest that HB1801 had manageable safety profile and promising efficacy in patients with previously treated advanced G/GEJ cancer. Clinical trial information: NCT05705635 .

A multi-center, open-label phase 1/1b dose finding, safety, and pharmacokinetic study of MBRC-101, an Anth-EphA5 monomethyl auristatin (MMAE) antibody drug conjugate, in advanced refractory solid tumors.

TPS3161 Background: EphA5 receptor is a member of the Ephrin receptor tyrosine kinase family. Several lines of compelling nonclinical evidence indicate EphA5 is a novel and selective target for solid tumor-directed therapy. Expressed only minimally in normal tissues, it is highly expressed in non-small cell lung carcinoma (NSCLC), head and neck squamous cell carcinoma (HNSCC), and breast, colorectal, pancreatic, gastric, and hepatic malignancies. MBRC-101 is a novel antibody drug conjugate (ADC) composed of an anti-EphA5 antibody conjugated to an MMAE payload (drug-to-antibody ratio of 4) through a valine citrulline cleavable linker. In pre-clinical toxicology studies and testing against a variety of cell-derived (CDX) and patient-derived (PDX) xenograft solid tumor models expressing EphA5--including NSCLC, triple negative breast cancer (TNBC), and HNSCC--MBRC-101 demonstrated favorable safety profiles and robust anti-tumor activity. Methods: This first-in-human, Phase 1/1b, multicenter, open-label study is examining the safety and efficacy of MBRC-101 in patients with advanced metastatic solid tumors refractory to standard treatment. Phase 1 will identify potential optimal biologically relevant doses (OBRD) and the maximum tolerated dose (MTD) of MBRC-101 at one or more dosing regimens. Phase 1b will evaluate the safety and preliminary clinical activity of MBRC-101 at potential OBRDs. Phase 1 will enroll patients (n ≈ 30) with advanced or metastatic solid tumors. EphA5 expression will not be required for enrollment into Phase 1 but will be assessed retrospectively. A modified toxicity probability interval (mTPI-2) method will guide dose escalation using a pre-specified decision matrix. The primary endpoints are MTD, dose limiting toxicities (DLTs), treatment emergent adverse events (TEAEs), and clinical laboratory tests. Phase 1b (n ≈ 60 patients) will include 3 expansion cohorts (n ≈ 20 patients per cohort): Cohort A, NSCLC; Cohort B, triple negative or HR+/HER2- breast cancer; and Cohort C, solid tumors irrespective of histologic tissue type (i.e., tumor agnostic) excluding NSCLC and breast cancer. Expression of EphA5 in primary or metastatic tumor tissue will not be required for enrollment into cohorts A and B but will be required for Cohort C. The primary endpoints are TEAEs, clinical laboratory tests, and investigator-assessed objective response rate (ORR) by RECIST v1.1 and clinical evaluation. Secondary endpoints for Ph1 and 1b include PK analytes and EphA5 expression as determined by immunohistochemistry (IHC). A Safety Review Committee will monitor safety at each dose escalation in Phase 1 and at regular intervals throughout Phase 1b. Clinical trial information: NCT06014658 .

OPTec: A phase 2 study to evaluate outpatient (OP) step-up administration of teclistamab (Tec), a BCMA-targeting bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM).

7528 Background: Tec is the only approved BCMA×CD3 bispecific antibody with personalized, weight-based dosing for triple-class exposed RRMM. In the MajesTEC-1 study, Tec showed deep, durable responses and a manageable safety profile. Cytokine release syndrome (CRS) occurred in 72% of pts during Cycles 1-2, and 33% of pts had recurrent CRS grade (gr) ≤3 (gr 3, 0.6%). Tocilizumab (Toci) is used to manage CRS. In a separate MajesTEC-1 cohort, pts who received prophylactic Toci (proToci) experienced less CRS, compared with pts who did not (26% vs 72%). Administering the Tec step-up dosing (SUD) regimen in the OP setting may make Tec more accessible, especially at community centers. Therefore, we are investigating whether proToci can reduce the incidence and severity of CRS associated with Tec and facilitate safe OP administration. Methods: This single-arm, non-randomized, multicenter, prospective study (NCT05972135) will evaluate proToci in pts treated with Tec using an OP SUD regimen. The primary endpoint is the overall incidence of CRS. Secondary endpoints include recurrent CRS gr ≥3, and any gr infections, neurotoxicity (NT) including ICANS, neutropenia, and efficacy. Eligible pts are ≥18 years with RRMM and ≥4 prior lines of therapy. Pts with rapidly progressing MM, CNS involvement, active infection, or contraindication to Toci are excluded. Toci 8 mg/kg IV is administered 2 to 4 hours prior to SUD 1 of Tec in an OP setting. The Tec SUD regimen consists of 0.06 mg/kg subcutaneously (SC), 0.3 mg/kg SC 2 to 4 days later, and 1.5 mg/kg SC 1 week after SUD 1. Tec 1.5 mg/kg SC is then given weekly for 12 cycles (28-day) or until MM progression or unacceptable toxicity. Pts with ≥PR after 6 mo can receive 1.5 mg/kg SC biweekly. IVIG is allowed in pts with serum IgG <400 mg/dL. Results: Ten pts will be enrolled at 4 Sarah Cannon / US Oncology community sites in a safety and PK/PD cohort, followed by 40 pts at 12 sites. After the first 6 pts, a Data Review Committee (DRC) meeting was held. Median age was 74 (56 to 83) yrs; half of pts were male. Pts had received a median of 4.5 (4 to 6) prior therapies. One pt with diffuse bony lesions had an SAE of bilateral leg weakness and pain unrelated to Toci or Tec, did not complete the SUD regimen, and died on C1D40 of unknown causes. The other 5 pts completed the SUD regimen per protocol. AEs in >1 pt were fatigue, headache and neutropenia (2 each). Gr 2 hypotension (1 pt) and gr 1 confusion and dizziness (1 pt each) were not felt due to CRS or ICANS. Stopping criteria (gr >3 CRS or NT/ICANS) were not met. The DRC recommended proceeding with enrollment. Conclusions: Initial results indicate that proToci prior to SUD 1 of Tec may mitigate the risk of CRS. Enrollment is ongoing to determine if proToci may make Tec safe to give in an OP setting and increase accessibility in community centers. The full safety cohort will be presented at ASCO. Clinical trial information: NCT05972135 .

Polymeric micellar paclitaxel plus cisplatin combined with tislelizumab as the first-line treatment of advanced unresectable esophageal squamous cell carcinoma: A phase II study.

e16022 Background: Immunotherapy combined with chemotherapy has become the standard first-line treatment for advanced and metastatic esophageal squamous cell carcinoma (ESCC). However, the prophylactic use of hormones, a routine preconditioning regimen of paclitaxel, may weaken the immune response. Polymeric micellar paclitaxel is a new formulation of paclitaxel without polyoxyethylene castor oil solvent, which do not need for pretreatment with anti-allergy drugs before administration. We aimed to evaluate the efficacy and safety of polymeric micellar paclitaxel (pm-Pac) plus cisplatin combined with tislelizumab for unresectable advanced ESCC. Methods: This is a single-center, single-arm, prospective phase II clinical trial. Stage IV ESCC patients diagnosed histologically or cytologically without systemic treatment are eligible for this study. Polymeric micellar paclitaxel plus cisplatin combined with tislelizumab was treated for 2 cycles. After imaging evaluation, if there was no disease progression, an additional two cycles of treatment were completed, followed by maintenance treatment with tislelizumab for one year. At day 1 of each therapy cycle, patients were given pm-Pac 230 mg/m2 followed by cisplatin 70 mg/m2 combined with tislelizumab 200 mg via intravenous infusion, every three weeks. This trial planned to include 30 patients. The primary endpoint was objective response rate (ORR) determined by the independent review committee. And the secondary endpoints included overall survival, progression-free survival evaluated based on the Response Evaluation Criteria in Solid Tumors (version 1.1), as well as the incidence and severity of adverse events. Results: From September 2022 to January 2024, 31 patients were included in the trial. Median age was 65 years, 29 (93.5%) patients were male. Median follow-up was 13.1 months, 2 patient achieved complete response (CR), 19 of them showed partial response (PR), 8 stable disease (SD), illustrating an ORR of 67.7% and a DCR of 93.5%. Median PFS was 7.3 months. The most common AEs were neutropenia (90.3%), nausea(83.8%) and thrombocytopenia (25.8%). No grade 3 or higher immune-related AE was observed, and there were no treatment-related deaths. Conclusions: The pm-Pac plus cisplatin combined with tislelizumab as first-line treatment of unresectable advanced ESCC showed effective without new safety signal. This combination therapy may have great efficacy, but multi-center randomized trials with larger sample size are warranted in further.

ACE-Breast-02: A pivotal phase II/III trial of ARX788, a novel anti-HER2 antibody-drug conjugate (ADC), versus lapatinib plus capecitabine for HER2+ advanced breast cancer (ABC).

1020 Background: ARX788 is a next-generation ADC of HER2 monoclonal antibody site-specifically conjugated with Amberstatin 269, a potent cytotoxic tubulin inhibitor. Here we report the interim result from this seamless phase II/III trial in patients who progressed on trastuzumab based therapy. Methods: This randomized study was conducted in HER2+ (FISH+ or IHC3+) ABC in 85 centers in China. Patients with unresectable or metastatic breast cancer pretreated with trastuzumab and taxane were randomized 1:1 to receive ARX788 (1.5mg/kg, IV, Q3W) or lapatinib plus capecitabine (LC, lapatinib 1250mg, QD; capecitabine 1000mg/m2 BID, d1-14, Q3W), stratified by previous chemotherapy lines (0-1 vs. >1) and visceral metastasis (yes vs. no). ARX788 was not pre-medicated with any prophylactic measures. Primary endpoint was progress-free survival (PFS) determined by Independent Review Committee (IRC). Results: As of Dec. 21, 2022, 221 patients were randomly assigned to ARX788 and 220 to LC, and 240 PFS events occurred. Efficacy results are listed in table 1. The median PFS was 11.33 months with ARX788 versus 8.25 months with LC as per IRC (HR 0.64, p=0.0006). Treatment-related adverse events (TRAEs) of any grade occurred in 98.6% (217/220) and 99.1% (213/215) of patients, respectively. TRAEs of grade 3-5 was similar in two groups (41.4% and 40.0%, respectively), commonest being blurred vision (12.3%), dry eye (9.1%), keratopathy (5.9%) and interstitial lung disease (5.9%) with ARX788 and hand-foot syndrome (18.1%), hypokalemia (5.1%), diarrhea (4.2%) with LC. 71 patients (32.3%) had interstitial lung disease with ARX788, primarily grade 1 or 2 (26.8%) with 3 (1.4%) possibly having drug-related deaths. 164 patients (74.5%) had ocular events related to ARX788, primarily grade 1 or 2 (55.5%) with no grade 4 or 5. Conclusions: ARX788 significantly prolonged PFS comparing to LC in patients with HER2+ ABC previously treated with trastuzumab and taxane. While ocular toxicity and interstitial lung disease were common and manageable, its hematological and GI toxicities under no prophylactic premedication compared favorably with already available ADCs. Clinical trial information: CTR20201708. [Table: see text]

An open-label, multicenter phase 1 study to characterize safety, tolerability, preliminary antitumor activity, pharmacokinetics, and pharmacodynamics of VIP943 monotherapy in patients with advanced CD123+ hematologic malignancies.

TPS3167 Background: VIP943 is an anti-CD123 antibody-drug conjugate (ADC) with a unique linker cleaved only by legumain and a novel kinesin spindle protein inhibitor payload. The linker-payload was engineered to increase the therapeutic index thereby improving efficacy and reducing severe toxicities compared with current ADCs. In an in vivo MOLM-13 model, VIP943 had statistically significant (p <0.001) improvement in tumor growth inhibition compared with the only ADC approved for the treatment of acute myeloid leukemia (AML), gemtuzumab ozogamicin (GO). In a nonhuman primate (NHP) single dose toxicology study, VIP943 (20 mg/kg) showed no signs of toxicity as measured by hematology, serum chemistry and survival. In contrast, NHP treated with a single dose of GO (3 mg/kg) had significant toxicity including death and mandatory euthanasia. The single-dose toxicity of GO was ameliorated by substituting the VIP943 proprietary linker and payload on an anti-CD33 antibody (3 mg/kg) as measured by hematology, serum chemistry and survival. (1,2). Methods: This trial in progress (NCT06034275) is an open-label, multicenter, Phase 1, first-in-human (FIH), dose-escalation and dose-optimization study of VIP943 in subjects with relapsed or refractory CD123+ hematologic malignancies including AML, myelodysplastic syndrome, and B-cell acute lymphoblastic leukemia. A cycle of VIP943 treatment is 28 days of once weekly intravenous infusions with no pause between cycles. The dose-escalation portion of this study follows a standard 3+3 design. Dose escalation decisions will be made by the safety review committee, and decisions will be based on the incidence of dose-limiting toxicities (DLTs). Based on FDA guidance, a dose-optimization portion of this study will randomize subjects into ≥2 dose cohorts to derive a recommended dose range for Phase 2. The study will also characterize the pharmacokinetics of VIP943 and its components and explore potential biologic activity by assessing pharmacodynamic/exploratory biomarkers, and antitumor activity using standard response criteria. As this is a FIH study, only subjects with CD123+ hematologic malignancies who have exhausted all available therapies or are not fit for standard of care can be enrolled. The results from this study will form the basis for decisions for future studies. Enrollment for cohorts 1 (no DLTs) and 2 (safety review ongoing) has completed. 1. Stelte-Ludwig et al ASH 2022. 2. Stelte-Ludwig et al ASH 2023. Clinical trial information: NCT06034275 .

DREAMM-7 update: Subgroup analyses from a phase 3 trial of belantamab mafodotin (belamaf) + bortezomib and dexamethasone (BVd) vs daratumumab, bortezomib, and dexamethasone (DVd) in relapsed/refractory multiple myeloma (RRMM).

7503 Background: Patients (pts) with RRMM and poor prognostic features, such as high-risk cytogenetics or disease refractory to major drug classes, have an unmet need. In DREAMM-7 (NCT04246047), BVd demonstrated a statistically significant and clinically meaningful progression-free survival (PFS) benefit vs standard-of-care (SOC) DVd in pts with RRMM and ≥1 prior line of treatment (LOT). We present further analyses from DREAMM-7 to better understand efficacy in key subgroups. Methods: Pts with ≥1 prior LOT were randomized (1:1) to BVd, B 2.5 mg/kg IV Q3W + V 1.3 mg/m2 (D1, 4, 8, 11 of 21-day cycles [C]; up to 8 C) and d 20 mg (D1, 2, 4, 5, 8, 9, 11, 12; up to 8 C), or DVd, D 16 mg/kg (21-day C: C1-3, Q1W; C4-8, Q3W; Q4W from C9 on)—V and d schedules were the same. The primary endpoint was independent review committee–assessed PFS. Secondary endpoints include overall survival (OS), duration of response, and overall response rate (ORR). Pts with high-risk cytogenetics had ≥1 of t(4;14), t(14;16), or del(17p13). Results: The intent to treat (ITT) included 494 pts: BVd, n=243; DVd, n=251. Median PFS (mPFS) in the ITT was 36.6 mo with BVd vs 13.4 mo with DVd (HR, 0.41; 95% CI, 0.31-0.53; P<.00001). ORR in the ITT was 82.7% (95% CI, 77.4%-87.3%) with BVd and 71.3% (65.3%-76.8%) with DVd. BVd had a higher complete response rate vs DVd (34.6% vs 17.1%). At baseline, 79 pts (33%) in the BVd arm and 87 pts (35%) in the DVd arm were refractory to lenalidomide (LEN). In the LEN-refractory subgroup, mPFS favored BVd (25.0 mo; 95% CI, 18.1 mo to NR) vs DVd (8.6 mo; 6.4-13.5 mo) (HR, 0.31; 95% CI, 0.19-0.48). A higher ORR was reported with BVd (84%; 95% CI, 73.5%-90.9%) vs DVd (61%; 49.9%-71.2%) in LEN-refractory pts. In the BVd and DVd arms, 67 (28%) and 69 (27%) pts had ≥1 high-risk cytogenetic abnormality. In the high-risk cytogenetic subgroup, the mPFS was 33.2 mo (95% CI, 20.3 mo to NR) with BVd vs 10.5 mo (7.6-13.4 mo) with DVd (HR, 0.31; 95% CI, 0.18-0.52). ORR favored BVd (85%; 95% CI, 74.3%-92.6%) vs DVd (67%; 54.3%-77.6%) in this subgroup. Additional data including other subgroup analyses will be presented. More deaths occurred with DVd (35%) than BVd (22%) in the ITT; neither arm reached median OS (HR, 0.57; 95% CI, 0.40-0.80; nominal P=.00049). In the ITT, all pts in both arms had ≥1 AE, and 95% (exposure-adjusted rate [exp-adj], 69 per 100 person-years [PY]) of BVd pts and 76% (exp-adj, 62 per 100 PY) of DVd pts reported grade 3/4 AEs. Serious AEs were reported in 50% (exp-adj, 36 per 100 PY) of BVd pts vs 37% DVd (exp-adj, 30 per 100 PY) pts. Ocular AEs were more frequent with BVd vs DVd (79% vs 29%). Conclusions: In DREAMM-7 BVd demonstrated PFS benefit over DVd with an mPFS improvement of 23 mo in pts with RRMM and ≥1 prior LOT. These results, demonstrating efficacy benefit in key subgroups with a high unmet need, support BVd as a potential new SOC in this setting. Clinical trial information: NCT04246047 .

Clinicopathologic features of patients with breast cancer in a single tertiary hospital in the Philippines.

e23313 Background: Breast cancer incidence in the Philippines is among the highest in Asia - the WHO reported it to be as high as 33,079 in 2022. Data provided by the Philippine Cancer Society and Department of Health Rizal Cancer Registry in 2009 included 1,615 breast cancer patients and noted a significant increase in breast cancer incidence from the year 1980 to 2002 in 7 cities in Metro Manila. This retrospective study aims to describe and analyze clinicopathologic and treatment data of Filipino breast cancer patients in a tertiary hospital. This study represents the largest pooled data in the Philippines on breast cancer demographics. Methods: Patients diagnosed with invasive breast cancer in St. Luke’s Medical Center (SLMC) from 2009 to 2020 were included. Patients diagnosed with other breast histopathologic results [i.e. ductal and lobular carcinoma in situ without invasive component] and double primaries were excluded. The study was approved by the Ethics Review Committee (Reference No.: SL-19157). Results: A total of 5,462 breast cancer patients were included. Majority of the patients were late perimenopausal (50-59 yo, 30.06%), menopausal (60-69 yo, 23.03%), and premenopausal (below 44 yo, 19.28%,) at the time of diagnosis. Patients were diagnosed with stage II (N = 1,816, 47.24%), followed by stage I (N = 943, 24%), and stage III (N = 662, 17%). Sixty four percent (N = 1,498) were node negative while 46% (N = 1,300) were node positive. Among patients with de novo metastasis, 14.6% metastasized to the bone while visceral sites include chest wall (17.4%), lung (16.6%), liver (11.5%) and brain (7.45%). Luminal her2- (48.9%) was the most common clinical subtype followed by non-luminal her2+ (15.6%) and triple negative (6.7%). Definitive surgery was the mainstay of treatment – 94% (N = 4116) underwent modified radical mastectomy (MRM) while 5% (N = 223) underwent breast conserving surgery (BCS). Eight hundred patients (19%) received neoadjuvant treatment (hormonal and/or systemic chemotherapy) while 2,246 patients (54%) received adjuvant treatment. Total number of breast cancer patients who underwent adjuvant radiation was 1,399 (25.6%). Conclusions: Compared to middle-high income countries, data suggests that MRM is the preferred surgical technique over BCS. Majority of patients in the study are luminal her2-. However, only 54% received adjuvant treatment. Another observation is the low rate of neoadjuvant treatment by the study population. Further research on the risk factors or reasons for not receiving treatment as well as the outcomes of these patient cohorts is needed to shed light on these cancer care gaps.

A multinational pivotal study of sunvozertinib in platinum pretreated non-small cell lung cancer with EGFR exon 20 insertion mutations: Primary analysis of WU-KONG1 study.

8513 Background: A multinational pivotal study WU-KONG1 (NCT03974022) has been conducted to assess sunvozertinib (DZD9008) in pre-treated non-small cell lung cancer (NSCLC) with EGFR exon 20 insertion mutations (exon20ins). Here we report the results of primary analysis. Methods: WU-KONG1 Part B is a phase 2, multinational pivotal study to assess the antitumor efficacy of sunvozertinib at two dose levels, 200 mg and 300 mg, in platinum pre-treated NSCLC patients with EGFR exon20ins. Eligible patients were randomized at the ratio of 1:1 to receive 200 mg or 300 mg sunvozertinib once daily until discontinuation criteria were met. Randomization was stratified by brain metastasis at baseline and number of regimens of prior systemic anti-cancer therapy. The primary endpoint was Independent Review Committee (IRC) assessed objective response rate (ORR) (per RECIST v1.1) and key secondary endpoint included IRC assessed duration of response (DoR). Results: As of January 4, 2024, a total of 184 patients were randomized to receive sunvozertinib treatment at 200 mg or 300 mg. Patients who met the predefined criteria for efficacy analysis were included in the primary analysis. The majority of patients (96.0%) had metastatic diseases, 60.7% had ECOG PS of 1, and 23.7% had baseline brain metastasis. All patients received prior platinum-based chemotherapy for advanced NSCLC, and 43.4% and 13.3% had prior onco-immunotherapy or amivantamab treatment. Per IRC assessment, the best ORR was 54.3% (41.0% confirmed and 5.8% pending confirmation). Confirmed complete response (CR) was achieved in 2.9% patients. The disease control rate (including CR, PR and stable disease) was 90.8%. The primary endpoint met its predefined target, with statistical significance. Tumor response was observed in patients with baseline brain metastasis, different demographics and EGFR exon20ins subtypes. With median follow-up time of 5.5 months for responders, the duration of response has not been reached, with 74.6% responders still responding. The PFS data are not mature with approximately 6-month follow-up. Safety findings were similar to previously reported results of sunvozertinib in other clinical studies. The most common drug-related TEAEs included diarrhea, skin rash and CPK increase. The majority of the TEAEs were CTCAE grade 1 or 2 and clinically manageable. Conclusions: In this primary analysis of WU-KONG1 multinational pivotal study, sunvozertinib demonstrated promising antitumor efficacy in platinum pre-treated NSCLC with EGFR exon20ins, with a tolerable safety profile. The updated data will be presented at the meeting. Clinical trial information: NCT03974022 .

EXPRESS study: A trial exploring the association of low level of genomic alteration with exceptional and unexpected response to targeted therapies in patients with advanced solid tumors.

e15140 Background: Small subsets of pts treated with targeted therapies (TT) present exceptional and unexpected response (1-10%), which could be driven and correlated by a low level of genomic alterations in genes identified as causally implicated in cancer. Conversely, the multiplication of the genomic alterations in such genes would decrease the oncogenic de-addiction process. Methods: EXPRESS is an exploratory, multicenter, prospective trial conducted in pts with locally advanced or metastatic solid tumors, who presented an exceptional and unexpected response to an antineoplastic TT. This research aimed to explore whether tumors with a low level genomic alteration (mutation, amplification, deletion) as assessed by whole exome sequencing (WES) are associated with exceptional and unexpected response. Secondary endpoints including the identification of novel candidate somatic molecular profiles and host immunologic characteristics susceptible to drive exceptional and unexpected response will be reported later. Results: 439 pts were identified over 32 centres from December 2016 to April 2021. Out of 270 pts confirmed with an exceptional response by our review committee of cases, 183 were included in the EXPRESS study. Exceptional responder population is summarised (Table). Out of 183, WES analysis was performed for 103 pts (56.3%). Genomic analysis failure was predominant in the breast and lung cohort (60.9% and 52.5%). The number of genomic alterations in the EXPRESS cohort was lower than in the TCGA control cohort (median[Q1-Q3]: 11[7-17] vs 19 [11-32], p<0.001). A lower number of genomic alterations was also reported in the melanoma (8[5-13] vs 33[17-51], p<0.001) and lung cancer cohort (8[5-17] vs 22[13-34], p<0.001) but not in the breast and kidney cohorts (13[10-21] vs 17[10-29], p=0.41 and 12[9-14] vs 11[7-17], p=0.89). Conclusions: Compared to the TCGA cohort, a low level of genomic alteration is associated with exceptional response in pts with lung cancer and melanoma. A comparison with a matched population based on genomic criteria in the TCGA is undergoing and will be presented at the conference. Clinical trial information: NCT02701907 . [Table: see text]

Efficacy and safety of erdafitinib in adults with breast cancer and prespecified fibroblast growth factor receptor alterations in the phase 2 open-label, single-arm RAGNAR trial.

1088 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for adult patients (pts) with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after ≥1 line of prior systemic therapy. The primary analysis results from the RAGNAR study demonstrated tumor agnostic efficacy in patients with advanced solid tumors with predefined FGFR alterations after failure of standard therapies (Pant 2023). Here, we report results on patients with breast cancer in the RAGNAR study. Methods: Patients with breast cancer and prespecified FGFR1-4 alterations (mutations or fusions) who had documented disease progression after exhausting standard therapies received oral erdafitinib 8 mg daily with optional up-titration until disease progression or intolerable toxicity. The primary end point was objective response rate by Independent Review Committee (IRC). Secondary endpoints include duration of response, disease control rate, progression-free survival, overall survival, and safety. Results: At data cutoff (median follow up, 30.3 months), 16 patients with breast cancer received erdafitinib. Median age was 54 y (range 37-74); all (100%) patients were female and had visceral metastases. Patients had a median of 5 prior lines of systemic therapies (range 2-12); one (6%) patient had responded to the last line of therapy. Ten (63%) patients had FGFR fusions, and 6 (38%) had FGFR mutations. Mutations of TP53 and PIK3CA were found in 6/16 patients. Objective response rate and disease control rate by IRC were 31% (95% CI 11-59) and 69% (95% CI 41-89); objective response rate and disease control rate by investigator were 38% (95% CI 15-65) and 69% (95% CI 41-89), respectively. Median time to onset of response was 1.4 months. Responses were observed in patients with both FGFR2 fusions and with FGFR2/3 mutations. Median duration of response, progression free survival, and overall survival were 6.9 months, 5.7 months, and 8.9 months, respectively. Common adverse events (AEs) included stomatitis (81%), diarrhea (69%), and hyperphosphatemia (69%), dry mouth (63%), and palmar-plantar erythrodysesthesia (44%). Six (38%) patients had serious AEs. No patients discontinued erdafitinib due to AEs. No treatment-related deaths were observed. Conclusions: Erdafitinib demonstrated clinically meaningful activity in heavily pretreated patients with breast cancer and prespecified FGFR alterations. Safety data were consistent with the erdafitinib safety profile. Clinical trial information: NCT04083976 .

A phase III, open-label, multicenter, randomized controlled trial of tunlametinib versus investigator-selected chemotherapy in patients with advanced NRAS-mutant melanoma who had previously received immunotherapy.

TPS9606 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we present the design of phase III randomized controlled study. Methods: This is a multicenter, two-arm, open-label, randomized controlled phase III confirmatory clinical trial to evaluate the efficacy and safety of tunlametinib in comparison with the combination chemotherapy of investigator's choice in advanced NRAS-mutant melanoma patients who had previously received immunotherapy. A total of 165 subjects from about 12 sites in China will be included and randomly assigned to the corresponding treatment group in 2:1 ratio. Two stratification factors before randomization: LDH level and whether have received chemotherapy. The key inclusion criteria included: a) Patients with unresectable stage III or metastatic IV melanoma confirmed by histology or cytology; b) History of immunotherapy failure or could not tolerate immunotherapy; c) Be able to provide NRAS mutation positive test report at baseline and provide sufficient histological specimens for NRAS mutation confirmation by central laboratory. Experimental group subjects will receive continuous administration of tunlametinib 12mg BID, 28 days per cycle. Control group subjects will receive one of the following regimens which according to investigator's choice (paclitaxel plus carboplatin, or temozolomide plus cisplatin, or dacarbazine plus cisplatin) , 28 days per cycle. The two groups will receive continuous therapy until disease progression or intolerable toxicity. The primary endpoint is progression-free survival which assessed by independent radiology review committee. Secondary endpoints included overall survival, objective response rate, disease control rate, duration of response, safety, pharmacokinetics and exposure-response. Exploratory endpoints are to evaluate quality of life between two groups and to development a companion diagnostic kit for NRAS gene mutations detection. This study is currently open for enrollment. Clinical trial information: NCT06008106 .

Sacituzumab govitecan (SG) + pembrolizumab (pembro) in first-line (1L) metastatic non-small cell lung cancer (mNSCLC) with PD-L1 ≥ 50%: Cohort A of EVOKE-02.

8592 Background: SG, a Trop-2–directed antibody-drug conjugate, has clinical activity and manageable safety in heavily pretreated patients with mNSCLC. EVOKE-02 (NCT05186974) is an ongoing, global, open-label, multicohort phase 2 study evaluating SG + pembro ± platinum agent as 1L treatment for mNSCLC. We report safety and efficacy results from Cohort A of EVOKE-02, with a median follow-up of 11.3 months. Methods: Patients aged ≥18 years with no prior systemic mNSCLC treatment, no actionable genomic alterations, and an ECOG performance status of 0 or 1 were enrolled into Cohort A [PD-(L)1 tumor proportion score ≥50%, 22C3 assay]. Patients received SG 10 mg/kg intravenously on days 1 and 8 + pembro 200 mg intravenously on day 1 of 21-day cycles. Primary endpoints include objective response rate (ORR; RECIST v1.1) per independent review committee (IRC); secondary endpoints include progression-free survival (PFS), duration of response (DOR), disease control rate (all per IRC), overall survival (OS), and safety. Results: As of December 1, 2023, 30 patients in Cohort A were enrolled and had received SG + pembro. Median age was 67 (range, 47-77) years; 60% had nonsquamous histology and 80% had an ECOG performance status of 1. Among all treated patients (n=30), ORR was 67% (95% CI, 47-83%) (squamous, 67% [95% CI, 35-90%]; nonsquamous, 67% [95% CI, 41-87%]). Median PFS was 13.1 (95% CI, 5.5-not reached [NR]) months (squamous, NR [95% CI, 1.2-NR] months; nonsquamous, 13.1 [95% CI, 5.5-NR] months). Median DOR was NR. In the safety population (n=30), the incidence of grade ≥3 treatment-emergent adverse events (TEAEs) and of grade ≥3 TEAEs related to any study drug were 67% and 40%, respectively. Grade ≥3 TEAEs in ≥10% of patients were neutropenia (17%), diarrhea (10%), and respiratory failure (10%). TEAEs leading to SG discontinuation occurred in 17%. There was 1 (3%) treatment-related death due to neutropenic sepsis. Conclusions: SG + pembro demonstrated promising activity in patients with tumor proportion score ≥50% mNSCLC. AEs were manageable and consistent with the known safety profile of each individual agent. The EVOKE-03 study (NCT05609968) of pembro vs SG + pembro in mNSCLC is ongoing. Clinical trial information: NCT05186974 . [Table: see text]

Overall survival and efficacy subgroup analysis of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.

9545 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085) has showed an encouraging efficacy (confirmed ORR:34.8%, mPFS:4.2 months) with a manageable safety profile in phase II pivotal registrational study, which was published in ASCO 2023 annal meeting (NO.:9510). Here, we report the updated efficacy results. Methods: This is a multicenter, single-arm, phase II, pivotal registrational study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. The primary endpoint was confirmed objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors, version 1.1 assessed by independent radiology review committee (IRRC). Results: A total of 100 pts were enrolled and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (October 31, 2023), median follow-up was 24.4 months (95% CI: 21.9, 27.9). The confirmed ORR was 35.8% (95%CI: 26.3%, 46.3%). Median progression-free survival (mPFS) was 4.2 months (95%CI: 3.5, 5.6). The median overall survival (mOS) was immature during last year's ASCO annual meeting, and the present mOS was 13.7 months (95% CI of 10.3–18.0). The IRRC-assessed ORRs by melanoma subtype were 42.9% (95% CI of 29.7–56.8) in acral melanoma, 25.0% (95% CI of 7.3–52.4) in mucosal melanoma. ORRs by NRASmutation site were 41.3% (95% CI of 30.1–53.3), 13.3% (95% CI of 1.7–40.5) and 20.0% (95% CI of 0.5–71.6) for Q61, G12, and G13, respectively. ORR in patients who had been treated with immunotherapy was 40.6% (95% CI of 28.5–53.6), while in those without immunotherapy, ORR was 25.8% (95% CI of 11.9–44.6). The difference in PFS was not statistically significant across subgroups, regardless of melanoma type, NRAS mutation site, line of previous treatment, type of previous treatment and previous treatment with immunotherapy. The safety profile is similar with last year's ASCO annual meeting. The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, facial oedema, peripheral oedema, and increased aspartate aminotransferase. No treatment-related death was reported. Conclusions: Tunlametinib demonstrated an encouraging treatment response rate in patients with advanced NRAS-mutant melanoma with a manageable safety profile. These results suggest that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those who had previously received immunotherapy. Clinical trial information: NCT05217303 .

Ipatasertib in patients with AKT1/2/3 mutation-positive (AKTmut) tumors: TAPISTRY study.

3092 Background: AKT1/2/3 point mutations are found in ~1% of all solid tumors, with varying prevalence across different tumor types. Ipatasertib is an inhibitor of the AKT kinase, but its antitumor activity as monotherapy in patients with AKTmut tumors is unknown. We present efficacy and safety data of ipatasertib in patients with advanced/metastatic AKTmut solid tumors from Cohort E of the TAPISTRY trial (NCT04589845). Methods: TAPISTRY is a phase II, global, open-label, multi-cohort trial evaluating the efficacy and safety of different therapies in patients with advanced/metastatic solid tumors. Patients in Cohort E were aged ≥12 years and had solid tumors harboring an AKT1/2/3mutation identified by next-generation sequencing and measurable disease by RECIST v1.1. Oral ipatasertib 400 mg was administered once daily. Tumor assessments were performed at screening, every eight weeks from Day 1/Cycle 1 for one year, and every 12 weeks after that. The primary endpoint was objective response rate (ORR) by independent review committee (IRC). Key secondary endpoints included ORR by investigator, duration of response, progression-free survival, overall survival and safety. Results: At data cut-off (16 Jul 2023), 50 patients were safety evaluable and 48 were efficacy evaluable. In the safety-evaluable population, median age was 59 years (range, 30–79); 98% of patients (n/N = 49/50) had an AKT1 mutation ( AKT1 E17K, n=47) and 2% (n/N = 1/50) had an AKT2 E17K mutation; 41/50 patients (82%) had received ≥2 prior lines of treatment. Efficacy-evaluable patients had 10 different tumor types, the most common being breast cancer (n/N = 21/48; 44%). Key outcomes are summarized in the Table. After a median follow-up of 11.3 months, ORR by IRC in efficacy-evaluable patients was 31.3% (n/N = 15/48; 95% CI 18.7–46.3), driven by responses in three tumor types: breast (n/N = 7/21; 33%), endometrial (n/N = 7/7; 100%), and head and neck (n/N = 1/2; 50%). The most frequent adverse event was diarrhea (n/N = 39/50; 78%). Safety was consistent with the known profile of ipatasertib; no new safety signals were identified. Conclusions: Treatment with ipatasertib led to a marked and durable antitumor activity in some tumor types such as endometrial cancer, but not in the overall tumor-agnostic cohort. Further studies are needed to understand the relevance of AKT inhibition in these tumor types. Clinical trial information: NCT04589845 . [Table: see text]

Atezolizumab (A), cobimetinib (C), and vemurafenib (V) in patients (pts) with BRAFV600 mutation–positive melanoma with central nervous system (CNS) metastases (mets): Final results and exploratory biomarker analysis from the phase 2 TRICOTEL study.

9550 Background: Primary analysis results from the phase 2 TRICOTEL study showed intracranial activity with the triplet combination of A + C + V in pts with BRAFV600-mutated melanoma with CNS mets (1). Here, we report final analysis results and exploratory biomarker analyses for pts with BRAFV600-mutated melanoma in the triplet combination cohort from TRICOTEL. Methods: Eligible pts were aged ≥18 y and had melanoma, MRI-confirmed CNS mets ≥5 mm in ≥1 dimension, and no prior systemic treatment for metastatic disease. Pts received A (840 mg on days 1 and 15 of each 28-d cycle) + C (60 mg once daily for 21 d on, 7 d off) + V (720 mg twice daily) except in cycle 1, during which A was withheld. Tumor tissue and circulating tumor DNA (ctDNA) samples collected at baseline (cycle 1, day 1) and ctDNA at the time of progressive disease (PD) were profiled for mutations using next-generation sequencing. Tumor tissue was profiled using a pipeline programmed for MelArray, and ctDNA was measured based on the tissue genetic profile. Results: A total of65 pts were enrolled in the triplet combination cohort. At final analysis, median follow-up was 12.4 mo. Per independent review committee (IRC) assessment, intracranial ORR (confirmed by assessments ≥4 wk apart) was 38% (95% CI, 27–51) and median intracranial PFS was 5.1 mo (95% CI, 3.7–6.9) (Table). Median OS was 13.4 mo (95% CI, 10.7–16.9). No new safety signals were observed since primary analysis. Mutations were detected in baseline ctDNA samples of 60 pts (5 pts not reported) and showed high prevalence of NF1, NRAS, and GNAI2 mutations; relative to tumor tissue, 11 additional BRAF mutations were detected in ctDNA at baseline. Acquired mutations in AKT1 were detected in ctDNA at PD. Median OS shortened in pts with >2 versus ≤2 mutated MAPK pathway genes in ctDNA at baseline (9.1 vs 14.5 mo; hazard ratio, 2.0 [95% CI, 1.0–3.7]; p<0.05). In tumor tissue, baseline mutations in PIK3C2A and PLEKHG4 were enriched in nonresponders, while RAD51B mutations were enriched in responders. Conclusions: Combination A + C + V had clinical intracranial activity in pts with BRAFV600-mutated melanoma with CNS mets. Exploratory biomarker analyses in this small cohort demonstrate the presence of ctDNA in pts with melanoma and CNS mets and provide insight into mutations associated with response and resistance to the triplet combination. 1. Dummer R et al, Lancet Oncol 2023. Clinical trial information: NCT03625141 . [Table: see text]

A phase II multicenter study of abexinostat, an oral histone deacetylase inhibitor, in patients with relapsed/refractory follicular lymphoma.

7059 Background: Epigenetic alterations are major drivers of Follicular lymphoma (FL). Histone deacetylase (HDAC) inhibitors have potential to counteract the loss of histone acetylation that results from CREBBP or EP300 mutations. Abexinostat (Abx) is a novel potent oral pan-HDAC inhibitor with a pharmacokinetic profile that allows maintenance of sufficient drug concentrations for anti-tumor activity with twice daily (BID) dosing. Abx was shown to be well-tolerated with significant response in pts with relapsed/refractory (R/R) FL. Methods: This phase Ⅱ study evaluated Abx 80 mg administered orally BID 4 hours apart in a “one week on, one week off” schedule (days 1 to 7 & 15 to 21 of a 28-day cycle) in pts with R/R FL (grade 1-3a). Key inclusion criteria included age ≥18 years, ≥ 2 prior treatment regimens, ECOG of 0-2, and measurable disease per Lugano 2014 criteria. Pts undergo efficacy assessment by enhanced CT/MRI every 8 weeks for the first 24 weeks, and every 12 weeks thereafter, and PET-CT at weeks 12 and 24 and to confirm a complete response (CR), in accordance with the Lugano 2014 criteria. Bone marrow (BM) evaluation was mandated in pts with baseline BM involvement who achieved radiographic CR. The primary endpoint is independent review committee (IRC)-assessed overall response rate (ORR). Secondary endpoints include duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: At the data cut-off date of December 15, 2023, data were available for 90 pts. Median age was 55.0 (range 27-79), 57.8% of pts were male, and 22.2% had ≥ 3 FLIPI-2. Pts had a median of 3 prior lines of therapy (range 2-9), and 24.4% were refractory to the last prior regimen, 27.8% of pts had been treated with PI3K inhibitors before. With a median follow-up of 20.8 months, of 82 pts evaluable for efficacy, the IRC-assessed ORR was 67.1% (95% CI: 55.8%-77.1%), including 12.2% CR. The ORR for pts with > 3 lines of prior therapy was 69.0% (95% CI: 49.2%-84.7%). The median PFS and median DoR was 13.77 (95% CI: 9.69-not evaluable [NE]) months and 13.96 (95% CI: 8.34-NE) months, respectively. Median OS was not reached, and the 42-month OS rate was 74.3% (95% CI: 58.1%-85.0%). Of 90 pts evaluable for safety, the most common (≥ 40%) treatment-emergent adverse events (TEAEs) were thrombocytopenia (85.6%), neutropenia (58.9%), leukopenia (52.2%), nausea (50.0%), anemia (48.9%) and diarrhea (46.7%); ≥grade 3 TEAEs (≥ 5%) included thrombocytopenia (37.8%), neutropenia (23.3%), leukopenia (7.8%), and lymphopenia (5.6%). TEAEs led to dose reductions and discontinuations in 28.9% and 3.3% of all pts, respectively. Conclusions: Abx was well tolerated at dose of 80 mg BID as monotherapy, and demonstrated a significant response in pts with heavily pretreated R/R FL. Clinical trial information: NCT03934567 .

A phase 2, multicenter, open-label, dose-optimization study evaluating telomere-targeting agent THIO sequenced with cemiplimab in patients with advanced NSCLC: Updated results.

8601 Background: Despite recent approvals for the first-line (1L) treatment of advanced non-small-cell lung cancer (NSCLC), long-term prognosis remains poor with a 5-year survival rate of 28% and limited options exist in patients (pts) refractory or resistant to immune checkpoint inhibitors (ICI). THIO (6-thio-2’-deoxyguanosine) is a small molecule, first-in-class direct cancer telomere-targeting agent that selectively targets telomerase positive (TERT+) cancer cells. It is incorporated de novo in synthesized telomeres leading to chromatin uncapping, generation of DNA damage signals, and rapid apoptosis. In advanced cancer animal models, THIO followed by an ICI demonstrated the ability to overcome ICI resistance. Methods: Here we describe a phase 2 dose-optimization study (NCT05208944) for adults with advanced NSCLC who progressed or relapsed after 1–4 prior treatment (tx) lines including 1L ICI alone or in combination with platinum chemotherapy. Following a safety lead-in of 10 pts who received THIO 360 mg IV [120 mg QD, D1–3] followed by 350 mg IV cemiplimab on D5 Q3W, the study proceeded to a 2-stage design with pts randomized to 1 of 3 arms: THIO 60 mg, 180 mg, or 360 mg, all followed by cemiplimab Q3W. In Stage 1 if at least 8 of 19 pts/arm achieved disease control, an additional 22 pts could be enrolled in that arm (up to 41 pts/arm). Study endpoints include safety (DLTs and AEs/SAEs) and efficacy (ORR, DCR, DOR, PFS, and OS). Results: Recruitment into the 360 mg arm was paused after 4 pts following 1 instance of G4 ALT Increase and AST Increase (without clinical presentation). At the end of Stage 1 cut-off (13-Nov-2023), the DCR greatly exceeded the threshold required for Stage 2 expansion in both arms: 60 mg 14/16 (88%); 180 mg 11/13 (85%). The 180 mg dose was selected for further investigation by the trial’s Safety Review Committee based on superior efficacy (31% PR rate; 54% reduction in tumor burden). As of 8-Jan-2024, 56 pts received ≥1 dose of THIO in the 60 and 180 mg arms (24 and 32 pts, respectively). Prior lines of tx at study entry were: 60 mg (1L 75%, 2L 21%, 3L 4%); 180 mg (1L 66%, 2L 31%, 4L 3%). Most pts received platinum chemotherapy prior to study entry (60 mg 88%; 180 mg 78%). Across all pts treated n=70, most AEs were G1/2. The most frequent related AEs were AST increase (23%), ALT increase (20%), and nausea (11%). All instances of LFT elevations were without clinical symptoms and resolved to baseline. Conclusions: THIOfollowed by cemiplimab was generally well tolerated in this difficult-to-treat population (all pts progressing following ICI tx and the majority following platinum chemotherapy). Based on safety and promising efficacy, the 180 mg dose was selected for further development. Enrollment is ongoing and is expected to be completed in Feb-2024. Updated primary endpoint data, including preliminary durability data, will be presented. Clinical trial information: NCT05208944 .

Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma.

7540 Background: Teclistamab, the first approved B-cell maturation antigen × CD3 bispecific antibody (BsAb) with weight-based dosing for the treatment of patients (pts) with triple-class exposed relapsed/refractory multiple myeloma (RRMM), demonstrated rapid, deep, and durable responses in the pivotal MajesTEC-1 study. Here, we report updated results from MajesTEC-1. Methods: Eligible pts received teclistamab at the recommended phase 2 dose (RP2D; 1.5 mg/kg subcutaneous QW preceded by step-up dosing) with the option to switch to Q2W dosing if a partial response or better after ≥4 cycles of therapy (phase 1) or complete response or better (≥CR) for ≥6 mo (phase 2) was achieved; pts not in ≥CR could switch due to adverse events (AEs). Pts could subsequently switch to less frequent dosing if they continued to demonstrate a response. The primary endpoint was overall response rate (ORR) assessed by independent review committee per International Myeloma Working Group 2016 criteria. AEs were graded per Common Terminology Criteria for Adverse Events v4.03. Cytokine release syndrome (CRS) was graded per American Society for Transplantation and Cellular Therapy guidelines. Results: At median follow-up of 30.4 mo, 165 pts had received teclistamab at the RP2D. ORR was 63.0%, and responses continued to deepen, with 46.1% achieving ≥CR. 85.7% (48/56) of MRD-evaluable pts were MRD negative (10-5 threshold). Median duration of response (mDOR) increased to 24.0 mo; median progression-free survival (mPFS) and overall survival (mOS) improved to 11.4 and 22.2 mo, respectively. For pts with ≥CR, mDOR, mPFS, and mOS were not yet reached, and estimated 30-mo DOR, PFS, and OS rates were 60.8%, 61.0%, and 74.2%, respectively. Of the 38 pts who remain on treatment, 37 have switched to a less frequent dosing schedule (eg, Q2W), all of whom maintained responses. Hematologic AEs (any grade/grade 3/4) included neutropenia (72%/65%), anemia (55%/38%), thrombocytopenia (42%/23%), and lymphopenia (36%/35%). Infections occurred in 79% of pts (55% grade 3/4). Of grade 5 infections, 18/22 were due to COVID-19, reflecting study conduct during the COVID-19 pandemic. Onset of new grade ≥3 infections generally decreased over time, which aligned approximately with the median time of switch to Q2W dosing; other factors, such as increasing use of IVIG, may also contribute to this trend. AEs leading to dose reduction (n=1) or discontinuation (n=8; 5 due to infection) were infrequent. No new safety signals were reported. Conclusions: With the longest follow-up of any BsAb in MM, teclistamab continues to demonstrate deep and durable responses, including in pts who switch to less frequent dosing. The safety profile of teclistamab remains consistent with that of BCMA-targeted bispecific therapies, with a notable decrease in new onset of severe infections with time. Clinical trial information: NCT03145181 / NCT04557098 .

Comparison of clinical outcomes of stable disease with confirmed tumor reduction and RECIST partial response for tebentafusp in metastatic uveal melanoma (mUM).

9529 Background: Tebentafusp (gp100 x CD3) has demonstrated an overall survival (OS) benefit in mUM. Benefit was observed in patients (pts) who achieved a RECIST v1.1 partial response (PR), stable disease (SD) and even progressive disease (PD) (Nathan 2021). In Phase (Ph) 1, some melanoma pts had SD with tumor reduction > 10% that was confirmed at ≥ 1 subsequent scan (referred to as minor response, MR). In Ph 2, an analysis of MR was pre-specified as an endpoint and presented here. Methods: 127 HLA-A*02:01+ pts with previously treated mUM received weekly intravenous tebentafusp following intra-pt dose escalation of 20mcg Week 1, 30mcg Week 2 and 68mcg Week 3+ (NCT02570308; Carvajal 2022). Radiologic assessments were performed every 8 weeks until week 40, then q12 weeks. Tumor assessment was evaluated by a blinded independent review committee per RECISTv1.1. MR was prospectively defined as RECISTv1.1 best response of SD with reduction in sum of target lesions of -10% to -29% and which was confirmed ≥ 4 weeks later. ctDNA levels were assessed using a targeted mPCR-NGS assay for mutations in 15 genes including mUM oncogenes GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX (Natera). Molecular response was defined as ≥ 0.5 log [68%] ctDNA reduction by week 9. Data cut off: Oct 2022. Median duration of follow-up was 46 months. Results: Of 127 pts, the clinical benefit rate of PR + SD was 50% (64/127). 25% (32/127) had any tumor reduction that was confirmed on ≥ 1 subsequent scan, including 6 PR (ORR 5%) and 26 SD (20%). 8/26 SD (6% of 127) met the pre-defined threshold for MR, most (5/8) had >20% reduction. The median duration of response for PR and MR were 8.7 months and 10.6 months, respectively. The estimated percent of pts with PR and MR remaining in response at Month 20 were 20% and 33%, respectively. 3/6 PR pts were alive ≥ 3 years vs 3/8. 58% of PR + SD pts with evaluable ctDNA had a molecular response (26/45), including 2/4 PRs and 5/5 MRs. Conclusions: This Ph2 UM study prospectively confirmed that a subset of SD patients had tumor reduction over multiple scans. The frequency of minor response was similar to that of PR and had similar durability, OS and ctDNA molecular response. SD with confirmed tumor reduction is an emerging endpoint for the ImmTAC platform and will be studied in other trials (NCT05549297, NCT04262466). Clinical trial information: NCT02570308 .