Bispecific Antibody Targeting Research Articles

Lbl-034, a Highly Differentiated T-Cell Engaging Bispecific Antibody Targeting GPRC5D for the Treatment of Relapsed or Refractory Multiple Myeloma

G protein-coupled receptor, class C group 5 member D (GPRC5D) is a type-C 7-pass transmembrane receptor protein that selectively overexpresses on malignant plasma cells in multiple myeloma (MM). The expression of GPRC5D is rarely seen in normal tissues or cells, and is not detectable on other hematopoietic derived cells, therefore indicating that GPRC5D may be a novel target for anti-multiple myeloma therapy. LBL-034, a novel T-cell engaging bispecific antibody targeting GPRC5D, is developed with a specifically designed molecular format and unique 2:1 structure. It showed a potent binding on cell lines with various levels of GPRC5D expression, while its binding to CD3 on Jurkat cells was much lower examined by flow cytometry. Furthermore, LBL-034 re-directed engagement of GPRC5D+ cells and T cells was validated by gating engaged cell population with flow cytometry and confirmed visually with laser scanning confocal microscopy. LBL-034 induced potent T cell dependent cell killing (TDCC) of various types of GPRC5D expressing cells (high to low expression: MM.1R, NCI-H929, MOLP-8 and RPMI 8226 cells), and elevated activation marker (CD25, CD69) expression and cytokine release (IFN-γ, TNF-α, IL-6). LBL-034 demonstrated weak binding to CD3 and minimal effects on cytokine release in the absence of GPRC5D expressing cells and it indicates that LBL-034 activates T cells only in the presence of GPRC5D target cells. LBL-034 was further examined in the MC38-GPRC5D syngeneic model and NCI-H929 xenograft model. Robust antitumor efficacy was observed at the low dose of LBL-034 at 1 mg/kg and 0.3mg/kg respectively. LBL-034 GLP toxicology study with repeated doses was conducted in cynomolgus monkeys. 5, 15 and 50 mg/kg of LBL-034 was given intravenously with Q1W for up to 5 doses. LBL-034 was well tolerated with a good safety profile as determined by pharmacology, pathology and biochemistry analysis. The NOAEL of LBL-034 in cynomolgus monkeys was confirmed at 50 mg/kg. In summary, LBL-034 is a novel T cell engaging bispecific antibody targeting GPRC5D expressing R/R MM with well differentiated binding of GPRC5D and CD3 to enhance anti-tumor activity, while mitigate the risk of CD3-induced CRS, showing a great in vitro potency and in vivo anti-tumor efficacy. LBL-034 IND has been approved by both FDA and NMPA and a FIH study in patients with R/R MM will begin in the 2 nd half of 2023.

XFab-α4-1BB/CD40L fusion protein activates dendritic cells, improves expansion of antigen-specific T cells, and exhibits antitumour efficacy in multiple solid tumour models.

Additional immunotherapies are still warranted for non-responders to checkpoint inhibitors with refractory or relapsing cancers, especially for patients with "cold" tumours lacking significant immune infiltration at treatment onset. We developed XFab-α4-1BB/CD40L, a bispecific antibody targeting 4-1BB and CD40 for dendritic cell activation and priming of tumour-reactive T cells to inhibit tumours. XFab-α4-1BB/CD40L was developed by engineering an anti-4-1BB Fab arm into a CD40L trimer based on XFab® platform. Characterisation of the bispecific antibody was performed by cell-based reporter assays, maturation of dendritic cell assays, and mixed lymphocyte reactions. The abilities of antigen-specific T-cell expansion and antitumour efficacy were assessed in syngeneic mouse tumour models. Toxicological and pharmacodynamic profiles were investigated in non-human primates. XFab-α4-1BB/CD40L demonstrated independent CD40 agonistic activity and conditional 4-1BB activity mediated by CD40 crosslinking, leading to dendritic cell maturation and T-cell proliferation in vitro. We confirmed the expansion of antigen-specific T cells in the vaccination model and potent tumour regression induced by the bispecific antibody alone or in combination with gemcitabine in vivo, concomitant with improved tumour-reactive T-cell infiltration. XFab-α4-1BB/CD40L showed no signs of liver toxicity at doses up to 51mg/kg in a repeated-dose regimen in non-human primates. XFab-α4-1BB/CD40L is capable of enhancing antitumour immunity by modulating dendritic cell and T-cell functions via targeting 4-1BB agonism to areas of CD40 expression. The focused, potent, and safe immune response induced by the bispecific antibody supports further clinical investigations for the treatment of solid tumours.

Talquetamab in multiple myeloma.

Initial results of the phase I trial of talquetamab, a bispecific antibody targeting GPRC5D and CD3, were reported in December of 2022 for the treatment of relapsed or refractory multiple myeloma in the fourth line or later setting. It demonstrated a similar efficacy profile and durability of response to teclistamab, the first bispecific antibody therapy to be approved in multiple myeloma. Additionally, it has less infections than teclistamab but demonstrates unique class-specific side effects including skin, oral, and nail-related adverse events. Despite this, it is still a highly efficacious and well-tolerated therapy that will add to the armamentarium of therapeutics against heavily pretreated multiple myeloma.

A phase 1a/1b first-in-human study (COMPASSION-01) evaluating cadonilimab in patients with advanced solid tumors

Simultaneous inhibition of programmed cell death protein-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) with bispecific antibodies may improve efficacy over single-agent treatment while limiting toxicity. Cadonilimab is a humanized, bispecific antibody targeting PD-1 and CTLA-4. This is a phase 1 study of cadonilimab including dose escalation (n= 39) and dose expansion (n= 80). One dose-limiting toxicity event is observed, with the maximum tolerated dose not reached. 6mg/kg cadonilimab once every 2weeks is established as the recommended dose for future studies. The most common treatment-related adverse event is infusion-related reaction (18.5%), mostly grade 1/2 in severity. The incidences of any grade and grade ≥3 immune-related adverse events are 44.5% and 6.7%, respectively. The confirmed overall response rate is 13.4%, and the median duration of response is 12.9months. Cadonilimab is well tolerated and showed promising efficacy in patients with advanced solid tumors. This study is registered with ClinicalTrials.gov: NCT03261011.

1313MO Safety and preliminary efficacy of AZD7789, a bispecific antibody targeting PD-1 and TIM-3, in patients (pts) with stage IIIB–IV non-small-cell lung cancer (NSCLC) with previous anti-PD-(L)1 therapy

1313MO Safety and preliminary efficacy of AZD7789, a bispecific antibody targeting PD-1 and TIM-3, in patients (pts) with stage IIIB–IV non-small-cell lung cancer (NSCLC) with previous anti-PD-(L)1 therapy

1446P Preliminary efficacy and safety of rilvegostomig (AZD2936), a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-pretreated advanced/metastatic non-small-cell lung cancer (NSCLC): ARTEMIDE-01

1446P Preliminary efficacy and safety of rilvegostomig (AZD2936), a bispecific antibody targeting PD-1 and TIGIT, in checkpoint inhibitor (CPI)-pretreated advanced/metastatic non-small-cell lung cancer (NSCLC): ARTEMIDE-01

AK112, a novel PD-1/VEGF bispecific antibody, in combination with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC): an open-label, multicenter, phase II trial

Inhibiting vascular endothelial growth factor (VEGF) function can improve the efficacy of immunotherapy by modulating the tumor immune microenvironment. AK112 is the first-in-class humanized IgG1 bispecific antibody targeting programmed death-1 (PD-1) and VEGF. This study aimed to evaluate the efficacy and safety of AK112 combined with chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). This open-label, multicenter, phase II clinical trial was conducted in 11 hospitals in China. Eligible participants were adults aged 18-75 years with locally advanced or metastatic NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, at least one measurable lesion, and an estimated life expectancy of at least 3 months. The participants were categorized into three cohorts based on prior therapy and functional genomic alterations. Patients in cohort 1 were previously untreated advanced NSCLC, had no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) gene modifications, and received AK112 combined with pemetrexed (500mg/m2) for non-squamous (non-sq)-NSCLC or paclitaxel (175mg/m2) for sq-NSCLC plus carboplatin (area under the curve of 5mg/mL per min) for four cycles, followed by AK112 with pemetrexed for non-sq-NSCLC and AK112 alone for sq-NSCLC as maintenance therapy. The participants in cohort 2 had advanced NSCLC with EGFR-sensitive mutations, failed previous EGFR-tyrosine kinase inhibitor (TKI) therapy, and received pemetrexed plus AK112 and carboplatin for four cycles, followed by pemetrexed plus AK112 as maintenance therapy. The participants in cohort 3 had advanced NSCLC who failed systemic platinum-based chemotherapy and anti-PD-1/programmed death-ligand 1 (PD-L1) treatments and received AK112 plus docetaxel (75mg/m2). Two dosages of AK112 (10 or 20mg/kg) were examined in each cohort, and the drug was administered intravenously on day 1 of each 3-week treatment cycle. The primary endpoints were the investigator-assessed objective response rate (ORR) and safety. This study was registered with ClinicalTrials.gov (NCT04736823). Eighty-three patients were enrolled from February 2021 to August 2022 and received the study treatment. Cohorts 1, 2, and 3 had 44, 19, and 20 patients, respectively. The confirmed ORR was 53.5% (23/43) [95% CI, 36.9-67.1], 68.4% (13/19) [95% CI, 43.4-87.4], and 40.0% (8/20) [95% CI, 19.1-63.9] in cohorts 1, 2, and 3, respectively. In cohort 1, the median PFS was not reached, and the 12-month PFS rate was 59.1%. In cohorts 2 and 3, the median PFS were 8.5 [95% CI, 5.5-NE] and 7.5 [95% CI, 2.3-NE] months, and the 12-month PFS rates were 35.5% and 44.5%, respectively. The most common grade ≥3 treatment-related adverse events were decreased white blood cell count [7 (8.4%)], neutropenia [5 (6.0%)], thrombocytopenia [2 (2.4%)], anemia [4 (4.8%)], and myelosuppression [2 (2.4%)]. AK112 plus platinum-doublet showed promising antitumor activity and safety not only in first-line treatment of advanced NSCLC patients without driver mutation but also in patients with EGFR-functional mutation who failed previous EGFR-TKI therapy and advanced NSCLC patients who failed prior systemic platinum-based chemotherapy and PD-1/PD-L1 inhibitor treatments, suggesting a valuable potential new treatment option for this patient population. Akeso Biopharma, Inc., Zhongshan, China, and National Natural Science Foundation of China.

Suppression of MUC1-Overexpressing Tumors by a Novel MUC1/CD3 Bispecific Antibody.

Mucin1 (MUC1) is abnormally glycosylated and overexpressed in a variety of epithelial cancers and plays a critical role in tumor progression. MUC1 has received remark attention as an oncogenic molecule and is considered a valuable tumor target for immunotherapy, while many monoclonal antibodies (mAbs) targeting MUC1-positive cancers in clinical studies lack satisfactory results. It would be highly desirable to develop an effective therapy against MUC1-expressing cancers. In this study, we constructed a novel T cell-engaging bispecific antibody (BsAb) targeting MUC1 and CD3 with the Fab-ScFv-IgG format. A high quality of MUC1-CD3 BsAb can be acquired through a standard method. Our study suggested that this BsAb could specifically bind to MUC1- and CD3-positive cells and efficiently enhance T cell activation, cytokine release, and cytotoxicity. Furthermore, our study demonstrated that this BsAb could potently redirect T cells to eliminate MUC1-expressing tumor cells in vitro and significantly suppress MUC1-positive tumor growth in a xenograft mouse model. Thus, T cell-engaging MUC1/CD3 BsAb could be an effective therapeutic approach to combat MUC1-positive tumors and our MUC1/CD3 BsAb could be a promising candidate in clinical applications for the treatment of MUC1-positive cancer patients.

Bispecific antibody targeting TGF-β and PD-L1 for synergistic cancer immunotherapy.

The PD-1/PD-L1 signaling pathway plays a crucial role in cancer immune evasion, and the use of anti-PD-1/PD-L1 antibodies represents a significant milestone in cancer immunotherapy. However, the low response rate observed in unselected patients and the development of therapeutic resistance remain major obstacles to their clinical application. Accumulating studies showed that overexpressed TGF-β is another immunosuppressive factor apart from traditional immune checkpoints. Actually, the effects of PD-1 and TGF-β pathways are independent and interactive, which work together contributing to the immune evasion of cancer cell. It has been verified that blocking TGF-β and PD-L1 simultaneously could enhance the efficacy of PD-L1 monoclonal antibody and overcome its treatment resistance. Based on the bispecific antibody or fusion protein technology, multiple bispecific and bifunctional antibodies have been developed. In the preclinical and clinical studies, these updated antibodies exhibited potent anti-tumor activity, superior to anti-PD-1/PD-L1 monotherapies. In the review, we summarized the advances of bispecific antibodies targeting TGF-β and PD-L1 in cancer immunotherapy. We believe these next-generation immune checkpoint inhibitors would substantially alter the cancer treatment paradigm, especially in anti-PD-1/PD-L1-resistant patients.

Binding domain on CD22 molecules contributing to the biological activity of T cell-engaging bispecific antibodies

CD22, as the B-cell malignancies antigen, has been targeted for immunotherapies through CAR-T cells, antibody-drug conjugates (ADCs) and immunotoxins via interaction of antibodies with binding domains on the receptor. We hypothesized that avidity and binding domain of antibody to target cells may have significant impact on the biological function in tumor immunotherapy, and T cell-engaging bispecific antibody (TCB) targeting CD22 could be used in the therapy of hematologic malignancies. So, to address the question, we utilized the information of six previously reported CD22 mAbs to generate CD22-TCBs with different avidity to different domains on CD22 protein. We found that the avidity of CD22-TCBs to protein was not consistent with the avidity to target cells, indicating that TCBs had different binding mode to the protein and cells. In vitro results indicated that CD22-TCBs mediated cytotoxicity depended on the avidity of antibodies to target cells rather than to protein. Moreover, distal binding domain of the antigen contributed to the avidity and biological activity of IgG-[L]-scfv-like CD22-TCBs. The T cells' proliferation, activation, cytotoxicity as well as cytokine release were compared, and G5/44 BsAb was selected for further in vivo assessment in anti-tumor activity. In vivo results demonstrated that CD22-TCB (G5/44 BsAb) significantly inhibited the tumors growth in mice. All these data suggested that CD22-TCBs could be developed as a promising candidate for B-cell malignancies therapy through optimizing the design with avidity and binding domain to CD22 target in consideration.

Zanidatamab for HER2-amplified, unresectable, locally advanced or metastatic biliary tract cancer (HERIZON-BTC-01): a multicentre, single-arm, phase 2b study

HER2 is overexpressed or amplified in a subset of biliary tract cancer. Zanidatamab, a bispecific antibody targeting two distinct HER2 epitopes, exhibited tolerability and preliminary anti-tumour activity in HER2-expressing or HER2 (also known as ERBB2)-amplified treatment-refractory biliary tract cancer. HERIZON-BTC-01 is a global, multicentre, single-arm, phase 2b trial of zanidatamab in patients with HER2-amplified, unresectable, locally advanced, or metastatic biliary tract cancer with disease progression on previous gemcitabine-based therapy, recruited at 32 clinical trial sites in nine countries in North America, South America, Asia, and Europe. Eligible patients were aged 18 years or older with HER2-amplified biliary tract cancer confirmed by in-situ hybridisation per central testing, at least one measurable target lesion per Response Evaluation Criteria in Solid Tumours (version 1.1), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned into cohorts based on HER2 immunohistochemistry (IHC) score: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). Patients received zanidatamab 20 mg/kg intravenously every 2 weeks. The primary endpoint was confirmed objective response rate in cohort 1 as assessed by independent central review. Anti-tumour activity and safety were assessed in all participants who received any dose of zanidatamab. This trial is registered with ClinicalTrials.gov, NCT04466891, is ongoing, and is closed to recruitment. Between Sept 15, 2020, and March 16, 2022, 87 patients were enrolled in HERIZON-BTC-01: 80 in cohort 1 (45 [56%] were female and 35 [44%] were male; 52 [65%] were Asian; median age was 64 years [IQR 58-70]) and seven in cohort 2 (five [71%] were male and two [29%] were female; five [71%] were Asian; median age was 62 years [IQR 58-77]). At the time of the data cutoff (Oct 10, 2022), 18 (21%) patients (17 in cohort 1 and one in cohort 2) were continuing to receive zanidatamab; 69 (79%) discontinued treatment (radiographic progression in 64 [74%] patients). The median duration of follow-up was 12·4 months (IQR 9·4-17·2). Confirmed objective responses by independent central review were observed in 33 patients in cohort 1 (41·3% [95% CI 30·4-52·8]). 16 (18%) patients had grade 3 treatment-related adverse events; the most common were diarrhoea (four [5%] patients) and decreased ejection fraction (three [3%] patients). There were no grade 4 treatment-related adverse events and no treatment-related deaths. Zanidatamab demonstrated meaningful clinical benefit with a manageable safety profile in patients with treatment-refractory, HER2-positive biliary tract cancer. These results support the potential of zanidatamab as a future treatment option in HER2-positive biliary tract cancer. Zymeworks, Jazz, and BeiGene.

Phase Ib/IIa safety and efficacy of PM8002, a bispecific antibody targeting PD-L1 and VEGF-A, as a monotherapy in patients with advanced solid tumors.

2536 Background: PM8002 is a bispecific antibody targeting both PD-L1 and VEGF-A. We had completed dose escalation from 1mg/kg to 45mg/kg and had not found DLT/MTD. In a Phase Ib dose expansion and Phase IIa studies we are evaluating the safety and preliminary anti-tumor activity of PM8002 as a monotherapy. Here, we provide an update of PM8002 Phase Ib/IIa results. Methods: During Phase Ib dose-expansion and Phase IIa studies, the majority of patients received PM8002 at 20mg/kg Q2W or 30mg/kg Q3W as a monotherapy (recommended phase II doses). The primary endpoint was ORR with secondary endpoints/objectives including safety. Results: As of Feb 3, 2023, 263 patients of advanced solid tumor with prior 0 to 4 line systematic treatment had been enrolled (1mg/kg Q2W [n=1], 10mg/kg Q2W [n =1], 20mg/kg Q2W [n=190], 20mg/kg Q3W [n=4], 30mg/kg Q2W [n=4], 30mg/kg Q3W [n=52], and 45mg/kg Q3W [n=11]). The median duration of exposure was 10.6 weeks (range, 0.1—51.0). Of the 263 enrolled patients, 211 had completed their first evaluation for efficacy. The overall ORR, regardless of tumor type, was 15.2% (32/211) with 32 PRs (20 confirmed PRs), and the DCR was 75.4% (159/211) per RECIST 1.1. Twenty-five patients with cervical cancer had an ORR of 28% (7/25). Twenty-six patients with renal cell carcinoma had an ORR of 26.9% (7/26). Twenty-six patients with platinum-resistant ovarian cancer had an ORR of 15.4% (4/26), and 27 patients with NSCLC (with EGFR mutations) had an ORR of 18.5% (5/27). Any-grade TRAEs occurred in 68.8% patients (181/263), with 18.3% Grade ≥3 (48/263). The most common TRAEs were proteinuria (17.5%), hypertriglyceridemia (11.4%), Aspartate aminotransferase (9.9%), Alanine aminotransferase increased (9.5%), Hypoalbuminemia (8.7%), and increased gamma-glutamyl transferase levels (6.8%). Thirty-six patients (13.7%) discontinued PM8002 due to TRAEs. No death-related cases occurred, and most patients remain on treatment. Conclusions: PM8002 showed encouraging antitumor activity and good safety in patients with advanced solid tumors. Phase 1b/IIa of PM8002 as a monotherapy and Phase II combination trials of PM8002 with chemotherapy are ongoing for multiple indications. Clinical trial information: ChiCTR2000040552.

Phase I trial of KN046, a novel bispecific antibody targeting PD-L1 and CTLA-4 in patients with advanced solid tumors

BackgroundKN046 is a novel bispecific antibody targeting programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4). This multicenter phase I trial investigated the safety, tolerability, pharmacokinetics (PK),...

Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated TRIMM-2 results.

8003 Background: Tal is a T-cell redirecting bispecific antibody (BsAb) targeting G protein–coupled receptor family C group 5 member D. Dara is an anti-CD38 mAb with direct on-tumor and immunomodulatory actions. Combining immunomodulatory effects of tal + dara may lead to synergistic efficacy. Initial TRIMM-2 (NCT04108195) results showed that SC tal RP2Ds, 0.4 mg/kg QW or 0.8 mg/kg Q2W, + SC dara had promising efficacy and increased CD38+/CD8+ T cells and proinflammatory cytokines. We report updated results with additional pts and longer follow-up. Methods: Pts had MM, ≥3 prior lines of therapy (LOT; including a proteasome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double refractory to a PI and IMiD, and had not received anti-CD38 therapy in ≤90 d. Pts received tal RP2Ds with step-up dosing + dara 1800 mg per approved schedule. AEs were graded per CTCAE v5.0; cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Responses were assessed per IMWG criteria. Results: As of Dec 12, 2022 (N = 65), median follow-up was 11.5 mo (range 1.0–27.3). Median age was 63 y (range 37–81); 18% of pts had high-risk cytogenetics; 25% had extramedullary plasmacytomas. Median prior LOT was 5 (range 2–16): 63% penta-drug exposed; 58% triple-class refractory. Prior treatments included anti-CD38 (88% [77% refractory]), anti-BCMA (54% [38%]), BsAb (25% [25%]), and anti-BCMA CAR-T (17% [2%]) therapy. All pts had ≥1 AE (grade [Gr] 3/4 78%), most commonly CRS (78%; all Gr 1/2), dysgeusia (75%), dry mouth (55%), anemia (52%), fatigue (45%), and skin exfoliation (45%). CRS had a median time to onset of 1 d after the most recent dose with median duration of 2 d. 63% of pts had infections (Gr 3/4 22%; Gr 5 3% [n = 2 pneumonia, possibly related to tal + dara]). 38% of pts had neutropenia (Gr 3/4 26%). 85% had postbaseline IgG < 500 mg/dL; of these, 32% received IVIg. ICANS occurred in 3 pts (5%; all Gr 1/2 and resolved in 1–2 d). ORR was 78% (66% ≥VGPR; 45% ≥CR) across RP2Ds (100% in anti-CD38 naïve pts), and responses deepened over time. In pts exposed/refractory to prior therapy, ORRs were 75%/76% for anti-CD38, 74%/64% for anti-BCMA, and 75%/75% for BsAb. Median time to first response was 1 mo (range 0.9–8.3); at 12 mo, 86% of responders (89% of pts with ≥CR) still had responses. At data cutoff, 84% of responders remain on therapy (83%/82% anti-CD38 exposed/refractory). mPFS was 19.4 mo; 12-mo PFS and OS rates were 76% and 93%, respectively. Conclusions: Steroid-sparing tal + dara showed deep and durable responses with promising mPFS in heavily pretreated pts with RRMM, including pts refractory to anti-CD38/BCMA and T-cell redirecting therapy, suggesting combined immunomodulatory actions can yield robust responses in pts with refractory disease. The safety profile was clinically manageable; no new signals were identified with longer follow-up.

EE76 Budget Impact of Faricimab in Patients with Diabetic Macular Edema and Neovascular Age Related Degeneration in Canada

Faricimab is a bispecific antibody targeting ANG-2 and VEGF for the treatment of DME and nAMD. In the pivotal clinical trials, patients treated with faricimab in a Treat & Extend (T&E) regime required less frequent treatments compared to Aflibercept given every eight weeks (Q8W) with non-inferior vision changes. Clinical practice in Canada is typically characterized by pro re nata regimens as well as T&E. This research aims to assess the budget impact of faricimab vs. anti-VEGF treatments applied in such regimens.

A phase Ib/II study to assess the safety and preliminary efficacy of PM8002 in combination with nab-paclitaxel in patients with triple-negative breast cancer.

e13091 Background: PD-L1 and VEGF play important roles in immune escape and tumor angiogenesis and enhance cancer growth and metastasis. PM8002 is a bispecific antibody targeting PD-L1 and VEGF-A. Here, we present our results from a Phase Ib/II study of PM8002 in combination with nab-paclitaxel in subjects with locally advanced or metastatic triple negative breast cancer without previous systematic treatment. Methods: Sixty subjects with locally advanced or metastatic triple-negative breast cancer (with no previous systematic treatment), shall be enrolled into Phase Ib and II studies for testing the safety and efficacy of PM8002 in combination with nab-paclitaxel. Six subjects were enrolled during Phase Ib with safety as the primary endpoint, with the remaining subjects enrolled for the Phase II study to evaluate both safety and efficacy with ORR as the primary endpoint. Each cycle contains 28 days. All subjects received PM8002 at 20 mg/kg (Q2W) and nab-paclitaxel at 100 mg/m2 on the 1st, 8th, and 15th days of each cycle until unacceptable toxicity or disease progression were observed. Tumor responses were evaluated every 8 weeks. Results: As of February 03, 2023, a total of 25 subjects had received at least 1 dose of PM8002 in combination with nab-paclitaxel, including 6 subjects for Phase Ib and 19 subjects for Phase II. For Phase Ib, all 6 subjects received a full dose of PM8002 and nab-paclitaxel during the first cycle and no adverse events of special interest were observed during the 28-day period. Any-grade treatment emergent adverse events (TEAEs) occurred in 17 subjects (68.0%, 17/25); 3 subjects (12.0%, 3/25) with ≥ Grade 3 TEAEs. TEAEs related to PM8002 occurred in 12 subjects (48.0%, 12/25); 2 subjects (8.0%, 2/25) with ≥ Grade 3 TEAEs. Two subjects (8.0%, 2/25) discontinued PM8002 administration due to treatment-related adverse reactions (TRAEs), such as ascites and hypertension, both may be related to PM8002 and nab-paclitaxel. The most common TRAEs with PM8002 and nab-paclitaxel were anemia (16.0%, 4/25), fever (12.0%, 3/25) and neutropenia (12.0%, 3/25). Any-grade immune-related adverse events (irAEs) occurred in 2 subjects (8.0%, 2/25), such as hyperthyreosis; there was no ≥ Grade 3 irAEs occurred. Thirteen subjects completed at least one efficacy evaluation. Objective response rate (ORR) per RECIST 1.1 was 69.2%, including 9 partial responses (PRs), with 9 PRs occurring during the first evaluation. Three subjects achieved stable disease, with a total disease control rate (DCR) of 92.3%. Twenty-two subjects are still on treatment. Conclusions: PM8002 in combination with nab-paclitaxel showed acceptable safety and encouraging antitumor activity in locally advanced or metastatic triple-negative breast cancer. The Phase II study is still ongoing, and we are actively enrolling subjects to complete the study. Clinical trial information: ChiCTR2200060400 .

Phase 1 first-in-human study of PF-07257876, a novel CD47/PD-L1 bispecific checkpoint inhibitor, in patients with PD-1/PD-L1-refractory and -naïve advanced solid tumors.

2529 Background: Tumor expression of the antiphagocytic protein CD47 (integrin associated protein) may lead to immunotherapy resistance (IO-R). PF-07257876 is a novel, IgG1, Fc-active, bispecific antibody targeting CD47 and PD-L1 designed to reverse IO-R, decrease anemia risk, and eliminate a priming dose. We report a Phase 1 dose escalation study (NCT04881045) in patients (pts) with advanced solid tumors, both IO-refractory and IO-naïve. Methods: The study enrolled pts ≥18 yrs with advanced non–small-cell lung carcinoma (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN) with PD-L1 expression >1% post anti-PD-1/PD-L1 therapy. Pts with other PD-L1+ tumors known to express CD47 were included (prior IO not required). Pts received PF-07257876 at escalating dose levels in 28-day cycles. Primary objectives were safety (dose-limiting toxicity [DLT] rate), tolerability, and determination of Recommended Phase 2 Dose (RP2D). Secondary and exploratory objectives included pharmacokinetics (PK), blood receptor occupancy (RO), CD47 levels by immunohistochemistry (IHC), tissue biopsy findings, and objective response rate (ORR) per RECIST v.1.1. Results: As of 20OCT2022, 18 pts were enrolled (NSCLC: n = 6; SCCHN: n = 4; other: n = 8). Median (range) age 68 (46–79) yrs. PF-07257876 was given at ascending doses, 150-2400 mg by subcutaneous (SC) injection or SC infusion every 2 weeks. 16 (89%) pts had treatment-related adverse events (TRAEs): Grades 1/2: n = 12 (67%); Grade 3: n = 1 (6%); Grade 4: n = 3 (17%); no Grade 5. Most common TRAEs: injection site reaction/erythema (n = 13, 72%), thrombocytopenia (n = 6, 33%), anemia (n = 5, 28%), and nausea (n = 4, 22%). DLTs occurred in 2 of 3 pts at the highest tested dose (Grade 4 neutropenia and thrombocytopenia, n = 1; Grade 4 thrombocytopenia, n = 1; both pts recovered). One pt with IO-R SCCHN had a confirmed partial response (duration of response 16 wks). ORR was 5.6% (1/18). Drug exposure increase after 1st dose was not dose proportional. Blood RO was > 95% for PD-L1 and > 70% for CD47 with drug exposure. All pts’ baseline CD47 IHC levels were moderate to high. Pharmacodynamics cytokine profiling showed notable dose-response increases of IFNg, TNFa, CXCL9/10, CCL3/4, without IL-6 increase. Conclusions: PF-07257876 was well tolerated with manageable toxicity. Incidence and grade of anemia or thrombocytopenia were manageable. Target engagement of CD47 and PD-L1 in peripheral blood was high. Innate and adaptive cytokine modulation was observed. Antitumor activity was modest. Expansion is ongoing at 1800 mg. Clinical trial information: NCT04881045 .

A matching-adjusted indirect treatment comparison of elranatamab in patients with triple-class exposed relapsed/refractory multiple myeloma: Comparisons with belantamab mafodotin, selinexor plus dexamethasone, and real-world physician’s choice of treatment.

e20038 Background: Elranatamab, a bispecific antibody targeting B-cell maturation antigen on multiple myeloma (MM) cells and CD3 on T cells, is being evaluated as a monotherapy in the MagnetisMM-3 trial (MM3; NCT04649359) in patients with triple-class exposed (TCE) relapsed/refractory MM. While there is no standard of care for TCE MM, belantamab mafodotin (belamaf) and selinexor plus dexamethasone (sel-dex) are treatment options. LocoMMotion is a prospective, non-interventional study investigating real-world physician’s choice of treatment (PCT) in patients with TCE MM. In the absence of head-to-head trials, unanchored matching-adjusted indirect comparisons (MAIC) were conducted to compare the relative efficacy across comparators. Methods: Individual patient-level data were obtained for elranatamab from MM-3 (data cut Oct 2022). Aggregated data for belamaf, sel-dex, and PCT were obtained from DREAMM-2 (NCT03525678), STORM (NCT02336815), and LocoMMotion (NCT04035226). Unanchored MAICs were conducted to compare the relative treatment effect on objective response rate (ORR) accounting for potential different distributions of prognostic variables (PVs) and effect modifiers (EMs). In the base case, PVs identified via logistic regressions based on MM-3 data were adjusted. In sensitivity analyses, PVs/EMs identified from the literature were added. Relative treatment effects were measured by rate differences and odds ratios. Results: After MAIC adjustments, the selected PVs/EMs were balanced in each comparison. The table presents the results from the naïve comparison with no MAIC adjustment plus the MAIC base case. The ORR of elranatamab was statistically higher than belamaf, sel-dex, and PCT in LocoMMotion. Results were consistent across all sensitivity analyses. Conclusions: Elranatamab had a significantly higher ORR than belamaf, sel-dex, and real-world PCT in LocoMMotion for patients with TCE MM, demonstrating its clear clinical benefit for this population. [Table: see text]

Predictive biomarkers for treatment with amivantamab plus lazertinib among EGFR-mutated NSCLC in the post-osimertinib setting: Analysis of tissue IHC and ctDNA NGS.

9013 Background: Amivantamab (ami) is a bispecific antibody targeting EGFR and MET with immune cell-directing activity, and lazertinib (laz) is a brain-penetrant, third-generation EGFR tyrosine kinase inhibitor. In a previous report, the overall response rate (ORR) of ami+laz in the post-osimertinib (osi) setting was 36%, with median duration of response of 9.6 months (Bauml JCO 2021; 39:15_suppl, 9006). Exploratory analyses suggested certain immunohistochemistry (IHC) and ctDNA-based next-generation sequencing (NGS) biomarkers may enrich for response. A prospective study was conducted to further evaluate these potential biomarkers. Methods: CHRYSALIS-2 (NCT04077463), an ongoing phase 1/1b study, examines the efficacy (ORR per RECIST v1.1) of ami+laz in patients (pts) with EGFR-mutated NSCLC. Cohort D enrolled osi-relapsed, chemotherapy-naïve pts with EGFR exon 19 deletion or L858R mutated advanced NSCLC who had tumor tissue for IHC staining and plasma for ctDNA NGS collected after their most recent therapy. Training and validation subsets identified biomarker criteria and predictive validity, respectively. A Bayesian posterior probability (biomarker positive group ORR is ≥35% and negative group ORR is ≤20%) was predefined to be ≥85% for acceptance. Results: There were 101 response-evaluable pts enrolled in Cohort D. A total of 87 pts had detectable baseline ctDNA and 77 pts had evaluable MET IHC. The training set (n = 50) identified IHC-based MET expression of 3+ staining on ≥25% of tumor cells (MET+) as a potential predictive biomarker, and the validation set (n = 27) confirmed these results. Of those with MET IHC data, 28/77 (36%) were MET+. The overall ORR for MET+ was 61% (95% CI, 41–78) and 12% (95% CI, 5–25) for MET-, with median PFS for MET+ not reached (95% CI, 4.3–NE) vs 4.1 months (95% CI, 2.8–5.7) for MET-. NGS evaluation of ctDNA did not identify predictive biomarkers meeting predetermined criteria. Of note, only 1 pt was identified by ctDNA as having MET amplification (the pt was also MET+ by IHC). Further details will be provided at the time of presentation. Conclusions: MET+ by IHC may be a predictive biomarker for response to ami+laz in the post-osi, chemotherapy-naïve setting. In contrast, molecular profiling with ctDNA failed to identify a subgroup of pts more likely to benefit. Ami+laz represents a potential chemotherapy-free option for pts with EGFR-mutated advanced NSCLC who have progressed on osi and are also MET+ by IHC. Clinical trial information: NCT04077463 .

Phase II trial of XmAb20717 (vudalimab) in patients with advanced biliary tract cancers.

TPS4184 Background: For patients with advanced biliary tract cancers (BTCs), gemcitabine and cisplatin has been the standard-of-care first-line therapy, with a median overall survival (OS) of 11.7 months. More recently, TOPAZ-1 demonstrated a modest, but significant overall survival benefit (HR 0.80; 95% CI 0.66 – 0.97) to the addition of durvalumab to gemcitabine and cisplatin with a median OS of 12.8 months. However, for patients without targetable molecular variants, second-line and beyond options are limited, with FOLFOX demonstrating an overall response rate (ORR) of 5% and increase in median overall survival by 0.9 months compared to active symptom control. In patients with advanced BTCs, combination immunotherapy approaches with PD-1 or PD-L1 plus CTLA-4 inhibitors have been associated with improved ORRs of 10.8% - 23% compared to ORRs of 3 – 7% observed with single agent PD-1 or PD-L1 inhibitors. XmAb20717 (vudalimab) is a novel, bispecific antibody targeting PD-1 and CTLA-4 which demonstrated an ORR of 14.1% in a phase I dose expansion cohort of patients with advanced malignancies, including patients that had experienced disease progression on prior immune checkpoint inhibitors. Methods: We initiated a single-arm, phase II clinical trial with a Simon two-stage mini-max design to evaluate the efficacy of XmAb20717, in terms of ORR, in patients with advanced biliary tract cancers previously treated with gemcitabine-based chemotherapy. In the first stage, 13 patients evaluable for efficacy will be accrued. If no responses are observed in these 13 patients, the study will be stopped for futility. Otherwise, 14 additional patients evaluable for efficacy will be accrued to total 27 evaluable patients. If 4 or more responses are observed in these 27 patients, then the null hypothesis will be rejected. XmAb20717 (10 mg/kg) is administered intravenously on days 1 and 15 of a 28-day cycle. Important inclusion criteria include that patients with FGFR2 fusions, NTRK fusions, or IDH1 mutations must have received molecularly targeted therapy unless contraindicated or refused. Patients are not eligible if they have received prior immune checkpoint inhibitor therapy. Correlative studies will include longitudinal peripheral blood collection for circulating immune cell profiling. As of January, 2023, 8 patients have been enrolled with enrollment ongoing. Clinical trial information: NCT05297903 .