Prior anti-HER2 Therapy Research Articles

Evaluation of the safety, pharmacokinetics, and efficacy of JSKN003 in patients with advanced solid tumors: A phase I/II clinical study.

3031 Background: JSKN003 is a bispecific HER2-directed antibody-drug conjugate (ADC) conjugated to a topoisomerase I inhibitor via a dibenzocyclooctyne tetrapeptide linker on the glycan of a humanized bispecific antibody. Pre-clinical studies showed that JSKN003 had a good serum stability, that may lead to a broader therapeutic window. Methods: JSKN003-102 (NCT05744427) is a phase I (dose escalation and dose expansion) and phase II (cohort expansion) study in Chinese patients (pts) with advanced solid tumors. Pts (ECOG PS 0-1) with HER2-expressing (IHC ≥ 1+) or HER2-mutant cancers who failed prior systemic therapies were recruited and received JSKN003 monotherapy intravenously Q3W. The objectives were safety, MTD or RP2D, pharmacokinetics, and preliminary antitumor activity. Here the results from phase I were reported. Results: As of 5th Jan 2024, 46 pts (25 breast cancers, 11 gastric cancers, 8 colorectal cancers, 1 lung cancer, and 1 ovarian cancer) were enrolled and received JSKN003 across 6 dose levels, including 2.1 (n=1), 4.2 (n=10), 5.2 (n=14), 6.3 (n=15), 7.3 (n=3), and 8.4 mg/kg (n=3), Q3W, in phase I period. Among the 46 pts, 18 were IHC 3+, 21 were IHC 2+, and 7 were IHC 1+. Most pts (73.9%) received ≥ 3 prior lines of therapy, including 60.9% and 45.6% of pts received prior anti-HER2 and anti-HER2 ADC therapy, respectively. The median duration of treatment was 13.1 (range, 2.1 - 42.4) weeks, and 37 pts (80.4%) remained on treatment. Treatment-related adverse events (TRAEs) occurred in 44 pts (95.7%), and the common, mostly grade 1 and 2, were diarrhea (37.0%) and nausea (32.6%). Only 6 pts (13.0%) experienced grade ≥3 TRAEs, and the common were lymphopenia (4.3%) and neutropenia(4.3%). 1 pt (2.2%) had treatment related SAE (nausea, grade 3). No pts experienced DLT or interstitial lung disease, and no TRAE led to death or discontinuation. Following a single dose, exposures (Cmax and AUC) of JSKN003 increased proportionally over a dose range of 4.2 mg/kg to 6.3mg/kg. T1/2 of JSKN003 is approximately 3-5 days. No significant accumulation was observed after 4 cycles treatment. The exposure of released payload was very low, demonstrating the stability of the JSKN003 in circulation. 37 pts had at least one post-baseline tumor assessment. The ORR and DCR was 51.4% (95%CI: 34.4, 68.1) and 91.9% (95%CI: 78.1, 98.3), respectively. The ORR in pts with HER2 IHC 1+, 2+ and 3+ was 20.0% (95% CI: 0.5, 71.6), 33.3% (95% CI: 11.8, 61.6), and 76.5% (95% CI: 50.1, 93.2), respectively. For pts who received prior anti-HER2 ADC, the ORR was 57.9% (95% CI: 33.5, 79.7). For HER2 positive breast cancer and gastric cancer, the ORR was 66.7% (95% CI: 38.4, 88.2) in 15 pts and 100% (95% CI: 39.8, 100) in 4 pts, respectively. Conclusions: MTD of JSKN003 was not reached yet. And safety of JSKN003 was extremely excellent with encouraging preliminary antitumor activity in heavily pretreated pts with advanced solid tumors. Clinical trial information: NCT05744427 .

Abstract PO1-20-06: Phase 2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 +/- pertuzumab in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan

Abstract Background: Therapies to effectively manage patients (pts) with metastatic HER2+ breast cancer have significantly improved over the years, but improvement is still needed in both efficacy and tolerability. BDC-1001 is an ISAC consisting of a trastuzumab biosimilar conjugated to a proprietary cell membrane impermeable TLR7/8 agonist via a non-cleavable linker, administered IV every 2 weeks. It is designed to trigger the innate immune system and generate a durable tumor-targeted adaptive immune response. Preclinical studies indicate that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, leading to complete tumor regression in a TLR- and Fc receptor-dependent manner [1]. Moreover, preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) indicate improved anti-tumor activity with trastuzumab-T785 compared with trastuzumab/pertuzumab. In these preclinical studies, the combination of trastuzumab-T785 and pertuzumab demonstrated significantly enhanced efficacy in multiple HER2-expressing tumor models, including those with lower HER2 expression [1]. The addition of pertuzumab decreased the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. Moreover, the combination of pertuzumab with the ISAC significantly increased the cytokine and chemokine concentrations in the tumor xenografts, compared with monotherapy or trastuzumab/pertuzumab, indicating enhanced myeloid activation in the tumor. These preclinical studies suggest that this combination may enhance the clinical activity of trastuzumab-based ISACs. The completed part of the BDC-1001 dose escalation trial (NCT04278144) demonstrated safety, PK and pharmacodynamic changes compatible with the ISAC mechanism of action, and a wide range of antitumor activity (incl. cases with breast cancer); resulting in a RP2D of 20 mg/kg q2w [2]. Two trials are underway, including a Phase 2 trial in other HER2+ malignancies, and a randomized Phase 2 trial with BDC-1001 alone and in combination with pertuzumab in patients with HER2-positive MBC previously treated with 2 or more prior anti-HER2 therapies, including trastuzumab deruxtecan. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 pts with HER2-positive (ASCO/CAP guidelines 2018) MBC previously treated with 2 or more prior anti-HER2 therapies, including trastuzumab deruxtecan as one of the prior therapies. Pts must be 18 years or older, have measurable disease (RECIST v1.1), and have Eastern Cooperative Oncology Group performance status of 0 or 1. Pts will be administered BDC-1001 20 mg/kg every 2 weeks (IV q2w) and randomized 1:1 to receive BDC-1001 as a single agent or in combination with pertuzumab. The trial has a Simon 2-stage design within each arm. The primary objective is to determine the overall response rate per RECIST v1.1 of BDC-1001 alone and in combination with pertuzumab. Secondary objectives will evaluate safety, additional efficacy parameters, pharmacokinetics, and immunogenicity of BDC-1001 alone and in combination with pertuzumab. Exploratory objectives will include pharmacodynamic biomarkers in tumor tissue (baseline and on-treatment biopsies if feasible) and in peripheral blood to elucidate the mechanism of action and seek to identify biomarkers associated with BDC-1001 biological activity with or without pertuzumab. This study is expected to initiate accrual in 2H 2023. For additional information, please contact Bolt Biotherapeutics at 1-650-665-9295 or info@boltbio.com.

Abstract PO2-19-05: Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+/HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06)

Abstract Background: Neratinib (NER), and irreversible pan-HER tyrosine kinase inhibitor, is approved for the extended adjuvant treatment of HER2+/HR+ early breast cancer (EBC) patients within 1 year of trastuzumab (T)-based therapy completion. The ExteNET trial showed that the extended adjuvant NER compared with placebo modifies the risk of recurrence by an absolute rate of 2.5% at 5 years in HR+/HER2+ patients (Martin et al., 2017). However, without prespecified prophylaxis, diarrhoea was the most common reason for NER discontinuation in the first three cycles in said study. The CONTROL trial evaluated effectiveness of different anti-diarrhoeal strategies showing a reduction of severe diarrhoea and early discontinuation when indirectly compared to ExteNET (Chan et al., 2022). DIANER (NCT05252988) evaluates the 3 best reported anti-diarrhoeal strategies from CONTROL in patients receiving NER as per European approved label. Trial design and patients: DIANER is an international, multicenter, controlled, randomized, phase II study. Patients with HER2+/HR+ EBC (stage IB-IIIC) who completed prior neo/adjuvant T-based therapy within 2 weeks and 1 year will be included and randomized 1:1:1 to 3 treatment arms. Arm A: NER (240 mg/day[d] x 1 year) + loperamide (12 mg/d x 14 d → 8 mg/d till end of cycle 2 → as needed [PRN]), Arm B: NER dose escalation (120 mg/d x 7 d → 160 mg/d till d 14 → 240 mg/d x 13 cycles) + loperamide PRN, and Arm C: NER (like Arm A) + loperamide (12 mg/d x 14 d → 8 mg/d till end of cycle 1 → PRN) + colesevelam (3,750 mg/d x 28 d). Patients are stratified by menopausal status and prior anti-HER2 therapy (T versus T + pertuzumab). Specific aims: Primary objective is incidence of NER discontinuations due to diarrhoea in the first 3 cycles. Secondary objectives are: incidence of NER discontinuations; AEs and hospitalizations; duration, severity, and treatments for diarrhoea; NER exposure; and health-related quality of life (HRQoL) using FACT B and EQ5D-5L. Exploratory objectives include HRQoL using STIDAT; minimal residual disease and molecular alterations. Statistical methods: A maximum of 315 pts (105 per arm) will be needed using a Simon’s optimal two-stage design with the hypotheses of a desirable early discontinuation rate of 5% (H1) versus an undesirable early discontinuation rate of 13% (H0). In the first stage, arms with ≥ 4 pts discontinuing due to diarrhoea in the first 3 cycles, will be closed for enrolment. The 2-sided 90% confidence intervals using the method described by Koyama et al. (Koyama and Chen 2008) will be provided for the primary endpoint at the end of the 2nd stage of the Simon 2-stage design. Present accrual and target accrual: DIANER will take place in 81 sites in 5 European countries. As of Jul 10/2023 the study is open in 52 sites in Spain with 80 randomized patients. Contact information for people with a specific interest in the trial: Evelia Cortazar (Geicam PM): ecortazar@geicam.org Citation Format: Miguel Gil-Gil, Miguel Martín, Eva Carrasco, Elena Galve, Noelia Martínez-Jáñez, Santiago González-Santiago, Barbara Adamo, María Valero, Clara Martínez, Angel Guerrero, Silvia Antolin Novoa, Manuel Ruíz - Borrego, Isabel Blancas, Raquel Andrés, José L Alonso-Romero, ANDREA Vethencourt, J. Ignacio Chacón, Natalia Chavarría, Enrique Espinosa, Blanca Hernando, Encarnación Adrover, Federico Rojo, Maribel Casas, Leanne McCulloch, Jean-Claude Vedovato. Randomized Phase II trial evaluating three anti-diarrhoeal prophylaxis strategies in patients with HER2+/HR+ early breast cancer treated with extended adjuvant neratinib (DIANER GEICAM/2018-06) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-05.

Abstract PO4-11-07: Early response to Adaptive Nutrition and Exercise Weight loss (A-NEW) Study for Breast Cancer Survivors with Overweight or Obesity

Abstract BACKGROUND: Obesity is associated with inferior survival and increased risk of recurrence in breast cancer (BC) survivors. In the Look AHEAD trial, 45% of patients attained ≥5% weight loss at 2 months, and those who lost 3-6% of weight at 2 months had higher odds of >5% weight loss at 1 year. Behavioral weight loss (BWL) studies consistently demonstrate that only half of BC survivors lose >5% weight, emphasizing the need for new approaches to aid those not benefiting from BWL alone. We hypothesized that early weight loss could identify BC survivors with excess body weight who may not benefit from BWL alone, and my benefit from the addition of a FDA-approved anti-obesity pharmaceutical agent. METHODS: Women with stage 0-III BC and BMI >27 kg/m2 who completed recommended local therapy and chemotherapy were enrolled in a 6-month BWL program consisting of remote coaching, an online curriculum, and tracking of diet, activity and weight. Patients completed demographic surveys and were weighed in clinic at baseline and 2 months. We used an adaptive design utilizing weight loss at 2 months to identify those with greater likelihood of weight loss at 6 months with BWL alone. Patients with and without ≥5% weight loss at 2 months were stratified as FAST-BWL and SLOW-BWL, respectively. Those in FAST-BWL continued BWL alone for 4 months, while those in SLOW-BWL also receive anti-obesity medication (Contrave®) until end of study. We anticipate 55% of 55 subjects enrolled will be in the SLOW-BWL group, resulting in a sample size of approximately 30 SLOW-BWL women and 25 FAST-BWL women. Simon's two-stage minimax design was used for the SLOW-BWL group. The null hypothesis that the true rate of attaining ≥5% weight loss is 10.9%, which is chosen based on the rate of women attaining ≥5% weight loss in the self-directed arm in the previously conducted POWER-remote study. The null hypothesis will be rejected if 7 or more women are observed in the 30 patients who attain ≥5% weight loss. This design yields a power of 80% at type I error rate of 5% when the true rate of attaining ≥5% weight loss of the baseline weight for the SLOW-BWL women is 29%, a clinical meaningful rate for the SLOW-BWL women group. We performed a descriptive analysis and evaluated outcomes at 2 months. RESULTS: Total enrollment is complete, and at time of presentation, 54 of 55 participants will be at end of study. Mean age at enrollment was 56 [30 -73], and majority were white (73%), postmenopausal (84%), had an ECOG of 0 (77%) and were employed (69%). The median time from diagnosis to enrollment was 3.9 years [0.6-10.0]. Over half received chemotherapy (54%), radiation (73%), and current endocrine therapy (75%); only 13% received prior antiHER2 therapy. Mean baseline weight was 213 (SD 30) pounds and baseline BMI was 35.5 (4.7). Mean HbA1c, total cholesterol, LDL, and triglycerides were 5.6% (0.4), 203 (29), 120 (26), and 135 (64), respectively. After 2 months of the BWL intervention, 14 (27%) attained ≥5% weight loss (FAST-BWL) and 38 (73%) did not (SLOW-BWL). CONCLUSIONS: We have successfully enrolled to this novel adaptive design and will present full data at the conference. Understanding predictors of successful weight loss inform populations that may benefit from anti-obesity medication, and design future studies that allow more patients to achieve significant weight loss. Citation Format: Jennifer Sheng, Amanda Montanari, Jennifer Trost, Mengyang Lu, Justin Mahosky, Sheetal Parida, Amanda Blackford, Dipali Sharma, Marci Laudenslager, Kimberly Gudzune, Janelle Coughlin, Vered Stearns. Early response to Adaptive Nutrition and Exercise Weight loss (A-NEW) Study for Breast Cancer Survivors with Overweight or Obesity [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-11-07.

Abstract PO4-04-02: Real-world first line use of trastuzumab biosimilar (HLX02), pertuzumab and chemotherapy for Chinese patients with HER2-positive metastatic breast cancer

Abstract Background: HLX02 (Zercepac®) is the first manufactured trastuzumab biosimilar in China. Its similar efficacy, safety, and immunogenicity compared with Herceptin was confirmed in phase III clinical trials in patients with HER2-positive advanced breast cancer. Nevertheless, the real-world evidence of HLX02 combined with pertuzumab and chemotherapy in HER2-positive advanced breast cancer in China is still warranted. Methods: In this real world observational study, patients with HER2-positive advanced breast cancer who received HLX02, pertuzuamb and chemotherapy as first line treatment at Beijing Cancer Hospital from April 2020 to April 2023 were retrospectively and prospectively included. The primary outcome was progression-free survival (PFS), and secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR) and adverse events (AEs). Results: A total of 55 patients (including one male) were included in this study and analyzed. The median age was 57 (range: 49, 62) years. Nearly one-third of tumors were estrogen receptor-positive (n=20, 36.4%). Thirty patients (54.5%) had newly-diagnosed stage IV disease. Visceral metastasis was reported in 40 patients (72.7%), most commonly observed in liver (n=22, 40%) and lung (n=19, 34.5%). Seven patients received prior anti-HER2 therapy during (neo-) adjuvant therapy (n=7, 12.7%). Taxane was the most commonly administrated chemotherapy regimen (n=51, 92.7%), including 56.4% albumin-bound paclitaxel, 20% liposomal paclitaxel and 18.2% docetaxel. Objective response was observed in 44 patients, leading to an ORR of 80%, and the DCR achieved 100%. HLX02 and pertuzumab was continued as maintenance therapy in 50 patients (90.9%), among which 17 combined with endocrine therapy (30.9%) and 6 combined with oral chemotherapy (10.9%). With a median follow-up of 9.8 months (range: 0.6-38.2). Progressive disease (PD) occurred in 12 of 55 patients (21.8%) and no deaths occurred. The median PFS was 24.8 months (95% confidence interval [CI]: 16.9- not estimated). The 12-month and 18-month PFS rate was 84.0% (95%CI: 72.9-96.9) and 58.8% (95%CI: 41.5 ~ 83.2), respectively. OS cannot be estimated yet due to immature data. HLX02-related diarrhea and infusion-related reaction was reported in 2 (3.6%) and 1 (1.8%) patients, respectively. LVEF values were monitored before and after drug administration, no clinical significant decline in LVEF and cardiac toxicity was observed. Conclusions: The trastuzumab biosimilar HLX02 demonstrated comparable efficacy and safety to Herceptin when combined with pertuzumab and chemotherapy for Chinese patients with HER2-positive advanced breast cancer in real world first-line treatment, which suggested that HLX02 may provide another option of Her2-targeted therapy combined with pertuzumab for Chinese patients. The benefit regarding long-term survival need to be further verified. Table 1. Effectiveness Citation Format: Ruyan Zhang, Guohong Song, Xiaoran Liu, Hui-Ping Li. Real-world first line use of trastuzumab biosimilar (HLX02), pertuzumab and chemotherapy for Chinese patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-02.

HER2-Positive Metastatic Colorectal Cancer.

Targeted treatment strategies are available for human epidermal growth factor receptor 2 (HER2)-positive (amplified and/or overexpressed) metastatic colorectal cancer (mCRC), and HER2 testing is indicated in patients with mCRC. At present, standard of care first-line treatment for those with HER2-positive mCRC remains chemotherapy in combination with epidermal growth factor receptor (EGFR) inhibitors or bevacizumab, depending on RAS/BRAF mutational status and tumor sidedness. HER2-targeted agents should be considered for those with RAS/BRAF wild-type disease in subsequent-line treatment and in first-line treatment for patients not appropriate for intensive therapy. While the choice of anti-HER2 therapy is empiric given lack of head-to-head comparisons, the combination of trastuzumab plus tucatinib has received FDA accelerated approval for use in this setting and is generally the authors' preference. Trastuzumab plus lapatinib, trastuzumab plus pertuzumab, and trastuzumab deruxtecan (T-DXd) also have evidence of efficacy in this setting. As T-DXd has demonstrated activity following treatment with other HER2-targeted regimens and carries an increased risk of high-grade toxicities, the authors favor reserving it for use after progression on prior anti-HER2 therapy. HER2-targeted therapies that inhibit signal transduction appear to have limited activity in those with RAS mutations, including trastuzumab-containing regimens. However, the antibody drug conjugate T-DXd has some data showing efficacy in this setting, and the authors would consider T-DXd in subsequent-line therapy for HER2-positive, RAS-mutated mCRC. Several areas of uncertainty remain regarding how to best utilize HER2-targeted therapies in mCRC. These include the optimal sequence of anti-HER2 therapies with chemotherapy and anti-EGFR therapies, the optimal combination partners for anti-HER2 therapies, and the incorporation of predictive biomarkers to guide use of anti-HER2 therapies. Results of ongoing studies may thus alter the treatment paradigm above in the coming years.

Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-overexpressing/amplified (HER2+) metastatic colorectal cancer (mCRC): Primary results from the multicenter, randomized, phase 2 DESTINY-CRC02 study.

3501 Background: T-DXd (6.4 mg/kg, every 3 weeks [Q3W]) demonstrated antitumor activity in pts with HER2+ mCRC in DESTINY-CRC01 (Siena et al. Lancet Oncol. 2021). We present primary results of DESTINY-CRC02 (NCT04744831), which assessed the efficacy and safety of T-DXd (5.4 and 6.4 mg/kg) in pts with HER2+ mCRC. Methods: This was a multicenter phase 2 study. Eligible pts had centrally confirmed HER2+ (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) mCRC. Pts with RAS wild-type (wt) or mutant (m) mCRC were eligible. Pts had received prior standard therapy, unless contraindicated; prior anti-HER2 therapy was allowed. In stage 1, 80 pts were randomized 1:1 to 5.4 (n = 40) or 6.4 (n = 40) mg/kg T-DXd Q3W. In stage 2, an additional 42 pts received 5.4 mg/kg T-DXd. Primary endpoint was confirmed objective response rate (cORR) by blinded independent central review (BICR). Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. Results: At data cutoff (Nov 1, 2022), most pts in the 5.4 and 6.4 mg/kg T-DXd arms had HER2 IHC 3+ (78.0% and 85.0%), RAS wt tumors (82.9% and 85.0%), and a median of 3 and 4 prior lines of therapy, respectively. cORR was 37.8% (95% CI, 27.3-49.2%) in the 5.4 mg/kg arm and 27.5% (95% CI, 14.6-43.9%) in the 6.4 mg/kg arm (all partial responses in both arms). Key efficacy data are shown in the Table: Grade ≥3 treatment-emergent adverse events (AEs) were observed in 41/83 pts (49.4%) and 23/39 pts (59.0%) in the 5.4 and 6.4 mg/kg T-DXd arms, respectively. Serious AEs were observed in 20/83 pts (24.1%) and 12/39 pts (30.8%) in the 5.4 and 6.4 mg/kg arms, respectively. Independently adjudicated drug-related interstitial lung disease occurred in 7/83 pts (8.4%) with 5.4 mg/kg T-DXd and 5/39 pts (12.8%) with 6.4 mg/kg T-DXd, and most events were grade 1/2 (1 grade 5 in the 6.4 mg/kg arm). Conclusions: T-DXd showed promising antitumor activity in pts with HER2+ mCRC at both 5.4 and 6.4 mg/kg doses. Antitumor efficacy was observed irrespective of RAS mutation status at 5.4 mg/kg T-DXd, and in those with prior anti-HER2 therapy. Overall, safety was consistent with the known safety profile of T-DXd and favored the 5.4 mg/kg dose. Clinical trial information: NCT04744831 . [Table: see text]

A phase 1/2 study of a first-in-human immune-stimulating antibody conjugate (ISAC) BDC-1001 in patients with advanced HER2-expressing solid tumors.

2538 Background: BDC-1001 is a HER2-targeted immune-stimulating antibody conjugate (ISAC), designed to trigger local activation of the innate immune system and generate a durable tumor-targeted adaptive immune response. BDC-1001 incorporates a trastuzumab biosimilar (EG12014) conjugated to a proprietary TLR7/8 agonist using a non-cleavable linker and a cell membrane-impermeable payload. An international phase 1/2 study was initiated to evaluate the safety of BDC-1001 ± nivolumab (nivo) and to identify the recommended phase 2 dose (RP2D) considering PK/PD analyses and preliminary efficacy. Methods: Dose-escalation (3+3, +backfills) enrolled patients (pts) with HER2-positive (amplified, or IHC 3+) or HER2 low (IHC 2+ and not amplified) solid tumors who had progressed after standard therapies. BDC-1001 was given IV q3w, q2w, or q1w as monotherapy (mono; n=91) and q2w or q1w with nivo 240 mg q2w (combo; n=27). Results: As of Nov 23, 2022, 118 pts with 16 different tumor types, were enrolled with BDC-1001 doses ranging from 0.15 to 20 mg/kg. Mean age was 61 yrs with a median of 4 and 5 prior lines of therapy (range, 1-11; 1-14; prior anti-HER2 therapy (HER2Tx) [66%/70%], immunotherapy (IO) [23%/22%]) for mono and combo, respectively. Median follow-up time was 5.0-6.1 months. Treatment was well tolerated with only 1 DLT (Gr3 supraventricular tachycardia) at 8 mg/kg q1w combo cohort. Low-grade IRRs were the most common related TEAEs (mono, 26.5%; combo, 25.9%). A related SAE (Gr4, bronchopulmonary hemorrhage) was seen in 1 pt (mono, 1.1%). Antitumor activity was observed at a range of doses and malignancies. There were 4 confirmed (RECIST 1.1) durable PRs (all in MSS tumors with low/intermediate TMB, prior Tx: 1 HER2Tx, 1 IO) including 1 pt with colon cancer (CRC) in the 5 mg/kg q3w mono cohort, and 3 in the 20 mg/kg q2w cohorts (mono 1/7; combo 2/7; ovarian, biliary, and rectal cancers). After the data cut, an additional PR (unconfirmed) was reported at week 6 in a pt with CRC receiving 12m/kg 1qw combo. Ten additional pts had SD lasting ≥6 months (8 mono; 2 combo; prior Tx: 6 HER2Tx; 1 IO; e.g., ovarian, endometrial, colorectal, gastric). Durable SDs were most frequent in the q2w cohorts. BDC-1001 exposure (e.g., Cmin) correlated with activity among pts in q2w cohorts. Increases in myeloid and T cell infiltration markers in post-Tx tumor biopsies align with mechanism of action (MoA). No anti-drug antibodies were detected. Conclusions: BDC-1001 mono and combo were well-tolerated. Targeted serum exposure levels were achieved, and encouraging clinical activity was noted in heavily pretreated pts with various HER2 positive tumors, especially in the 20 mg/kg q2w cohorts. Immune biomarker changes from plasma and tumor were consistent with MoA of this ISAC. These data support further development of BDC-1001 with phase 2 expansion in HER2-expressing solid tumors at the RP2D. Clinical trial information: NCT04278144 .

Abstract P5-02-34: Single-cell Analysis of KN026 in Combination with KN046 in Treating Patients with Advanced HER2-positive Breast Cancer

Abstract Background: KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes (two different HER2 epitopes shared by trastuzumab and pertuzumab). KN046 is a novel bispecific antibody that blocks both PD-L1 interaction with PD-1/CD80 and CTLA-4 interaction with CD80/CD86. Our on-going multi-centered phase II trial (NCT04521179) demonstrated that in advanced HER2-positive breast cancer (HER2+ BC) patients, who have progressed after prior anti-HER2 combinational therapies, the objective response rate (ORR) of this chemo-free therapy of KN026 in combination of KN046 was about 50.0% (SABCS 2021 poster P5-16-04). To explore the underlying mechanism of this regimen, we collected tumor specimens from patients before and after receiving this combinational treatment for single-cell analysis to provide an in-depth description of the tumor immune microenvironment and its correlation with treatment response. Methods: Paired tumor specimens before and after treatment of patients enrolled in the trial were collected for single-cell transcriptome and TCR sequencing. In addition, to reveal the immune cell characteristics of anti-HER2 resistant patients, we compared our data with previously reported single-cell analysis of treatment-naïve HER2+ BC. Results: We obtained 30 specimens from 17 patients, including 17 of pre-treatment and 13 of post-treatment. TCR expansion did not correlate with clinical efficacy. In-depth analysis of subpopulations revealed that compared to treatment-naive HER2+ BC, these enrolled prior anti-HER2-resistant patients had an additional population of T cells subpopulation characterized by CD4-low and CD8-low in their baseline tumor tissues, and the proportion of this subpopulation was significantly decreased after KN046 plus KN026 treatment in responding patients. Moreover, we found that patients with baseline CD8+ T/naïve T >1 tended to benefit more from this regimen. Conclusion: We identified a subpopulation of CD4-low and CD8-low T cells that may be associated with anti-HER2 resistance. And decreased of this subpopulation of T cells was associated with better ORR of KN046 in combination with KN026 treatment in heavily pretreated advanced HER2+ BC. Baseline CD8+ T/naïve T ratio in tumor is expected to be a predictor of ORR as well. Citation Format: Jieqiong Liu, Jianyou Liao, Zhenluan Tian, Jien Wang, Chuangui Song. Single-cell Analysis of KN026 in Combination with KN046 in Treating Patients with Advanced HER2-positive Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-34.

Abstract PD18-09: ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1

Abstract Background: Amplification of the human epidermal growth factor receptor 2 (HER2) gene with consequent HER2 protein overexpression occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. The HER2-targeted ADC trastuzumab emtansine (T-DM1) has been approved for the treatment of HER2-positive metastatic BC (mBC) after prior trastuzumab and taxane therapy. However, disease progression occurs in all patients requiring additional therapeutic options. The use of second-generation anti-HER2 ADCs using alternative molecules is being investigated to overcome drug resistance. ARX788 is a next-generation ADC using a technology platform whereby a HER2-specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 lead to its slow release and prolongation of the peak serum pAF-AS269 concentration, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Here, early evidence of activity of ARX788 in patients previously treated with T-DM1 is shown. Methods: ACE-Breast-03 (NCT04829604) is an ongoing global, phase 2, single-arm study evaluating ARX788 in patients with HER2+ mBC whose disease has progressed following T-DM1, T-DXd, and/or tucatinib-containing regimens. The ARX788 is administered with an initial dose of 1.5 mg/kg Q4W and subsequent doses of 1.3 mg/kg Q4W. Eligibility criteria included central laboratory confirmed HER2+ mBC per ASCO/CAP guidelines, measurable disease, and adequate organ function. Stable treated brain metastases are allowed. Patients with interstitial lung disease (ILD) or pneumonitis in prior 12 months; active ocular infections or any chronic corneal disorder; are excluded. The primary endpoint is overall response rate (ORR). Results: At the data cutoff of 11-Jul-2022, 7 patients were enrolled in ACE-Breast-03 (v1.0) who previously experienced disease progression on T-DM1 and had response-evaluable disease. Pts had a median age of 59 years and had received a median of 5 lines of prior anti-HER2 cancer therapy (range: 2-8). None of the pts in this subset had received T-DXd or tucatinib. 5 pts were previously treated with HER2-targeted TKIs (neratinib and lapatinib), as well as an investigational HER2 ADC and responded to ARX788 (3 PR; 2 SD). Two patients had hormone receptor (HR)-positive disease and 5 had HR-negative mBC. Treatment with ARX788 remains ongoing with the median time of ARX788 therapy of 4.5 months. The confirmed ORR was 57.1% (4/7 pts) and an unconfirmed ORR of 71.4% (5/7 pts) as one pt experienced an unconfirmed response with PR after 2 cycles. The disease control rate (DCR) was 100% (7/7 pts). No drug-related grade ≥3 AEs were reported; 57.1% (4/7 pts) reported ocular AEs including grade 1 events in 3 pts (i.e., dry eye, blurred vision) and a grade 2 event in one pt (lagophthalmos). No pneumonitis or ILD was observed. ARX788 was well-tolerated, and AEs were manageable. Conclusion: In this small cohort of patients previously treated with T-DM1, ARX788 had a manageable AE profile and demonstrated promising clinical activity (confirmed ORR 57%; DCR 100%). Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 Figure 1: ACE-Breast-03 Spider Plot for patients with mBC who were previously treated with T-DM1 ARX788 demonstrated promising clinical activity in patients previously treated with T-DM1. Citation Format: Sara Hurvitz, Kevin Kalinsky, Vinod Ganju, Kashif Ali, Laila Agrawal, William Gradishar, George Sledge, Anu Thummala, Arlene Chan, Sophia Frentzas, Joo Hyuk Sohn, Kyong-Hwa Park, Keon Uk Park, Catherine Shannon, Joshua Drago, Sara Tolaney, Hope Rugo, Michael F. Press, Alex Alika, Dong Xu, Janice Lu, Debu Tripathy. ACE-Breast-03: Efficacy and safety of ARX788 in patients with HER2+ metastatic breast cancer previously treated with T-DM1 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD18-09.

Incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases.

ER, PgR and HER-2 status are the cornerstones of choosing systemic therapy for breast cancer, but can change during the disease course. Guidelines recommended the biopsy of the metastatic tumor to reassess receptor status. Bone is the most frequent metastatic site of breast cancer but remained technically difficult to biopsy. Our study aimed to evaluate the incidence and prognostic significance of receptor discordance between primary breast cancer and paired bone metastases. One hundred and fifty-five breast cancer patients were diagnosed with pathology-confirmed bone metastasis at Fudan University Shanghai Cancer Center. Ninety-three patients with receptor status available on both primary tumor and bone metastases were included in our study. ER, PgR and HER-2 status converted from positive to negative in 10.8% (10/93), 28.0% (26/93) and 8.6% (8/93) of the patients, while ER, PgR and HER-2 status converted from negative to positive in 3.2% (3/93), 4.3% (4/93) and 1.1% (1/93) of the patients, respectively. 40.4% (17/42) of the HER2-0 tumors converted to HER2-low, which enabled them to receive the treatment of new antibody-drug conjugates (ADCs). Prior endocrine and anti-HER2 therapy were the independent risk factors for receptor conversion. Loss of HR expression in bone metastases was significantly associated with worse first-line PFS (adjusted hazard ratio=3.271, P-value=.039) and OS (adjusted hazard ratio=6.09, P-value=.011). In conclusion, our study confirmed that patients may experience receptor conversion between primary breast cancer and bone metastases, possibly influenced by prior treatments, which significantly influenced prognosis. The rebiopsy of bone metastases in patients with primary HER2-0 tumors may benefit from the new ADC drugs.

A phase 1, first-in-human (FIH) study of the anti-HER2 CAR macrophage CT-0508 in subjects with HER2 overexpressing solid tumors.

2533 Background: Most solid tumors are resistant to immunotherapy. In pre-clinical studies, CAR-M infiltrate tumors, phagocytose tumor cells, activate the tumor micro environment (TME), recruit T cells, and present tumor antigens to T cells leading to robust anti-tumor immunity. CT-0508 is a first in class CAR-M, comprised of autologous monocyte derived macrophages expressing an anti-HER2 CAR. Here we present preliminary clinical results from the CT-0508 Phase 1 FIH study. Methods: This multi-center, open-label study is evaluating CT-0508’s safety, tolerability, and manufacturing feasibility in 18 participants (pts) with advanced solid tumors overexpressing HER2 who have progressed on prior therapies. Monocytes are isolated from mobilized apheresis products, differentiated into macrophages and engineered with an anti-HER2 CAR. Group 1 pts (n = 9) receive a fractionated dose (D1, D3, D5) and Group 2 pts (n = 9) receive the full dose on D1. CT-0508 is administered without preparative chemotherapy (bridging is permitted). Serial blood samples, 1 pre and 2 post-treatment biopsies are collected to investigate safety, pharmacokinetics and mechanism of action. Results: Seven pts (4F/3M), median age 64 (49-73), have been treated [breast (2), esophageal (2), cholangiocarcinoma, ovarian and parotid gland cancers]. A median of 3 (2-10) prior lines of therapy have been administered, most pts (85.7%) received prior anti HER2 therapy. CT-0508 was successfully manufactured with high viability, purity and CAR expression, and was well tolerated with no dose limiting toxicities or AEs leading to discontinuation or dose modification. Two related SAEs were reported in the same pt (Grade 1 CRS, hospitalized for monitoring and Grade 2 infusion reaction, resolved within 1h). Three other pts had Grade 1-2 CRS; resolved within 4d with no use of tocilizumab needed. There were no major organ toxicities and no on-target off-tumor toxicities. Post-infusion cytokines were transiently elevated in most pts and were self-limiting. Among the 4 pts who reached week 8, the best overall response was stable disease (n = 3) and 1 pt progressed, with a median follow up of 8w. CT-0508 rapidly egressed from peripheral blood. CT-0508 CAR mRNA was detected in all tumor biopsies of the first 2 pts. CT-0508 activated the TME, with increased myeloid cell activation, T cell infiltration, activation and proliferation. TCR sequencing demonstrated peripherally expanding T cells enriched for tumor infiltrating lymphocyte clones, suggesting expansion of tumor reactive T cells. Correlative data from additional pts will be presented. Conclusions: In 7 pts, CT-0508 was safe and feasible to manufacture. Early correlative data demonstrate trafficking, TME modulation, and potential induction of anti-tumor T cell immunity. The study is actively enrolling. Clinical trial information: NCT04660929.

Phase I Trial of a Novel Anti-HER2 Antibody-Drug Conjugate, ARX788, for the Treatment of HER2-Positive Metastatic Breast Cancer.

ARX788 is a novel antibody-drug conjugate (ADC) comprised of an anti-HER2 mAb and a potent tubulin inhibitor payload AS269 that is site-specifically conjugated to the antibody via a nonnatural amino acid incorporated into the antibody. Herein, we present the results of a phase I study of the safety, pharmacokinetics, and antitumor activity of ARX788 in patients with HER2-positive metastatic breast cancer (MBC). Patients with HER2-positive MBC received ARX788 at doses of 0.33, 0.66, 0.88, 1.1, 1.3, or 1.5 mg/kg every 3 weeks, or 0.88, 1.1, or 1.3 mg/kg every 4 weeks. The dose-limiting toxicity (DLT) was assessed for 84 days for pulmonary toxicity and at a duration of one cycle (21 or 28 days) for other toxicities. In total, 69 patients were enrolled. No DLT or drug-related deaths occurred. Most patients (67/69; 97.1%) experienced at least one treatment-related adverse event (TRAE). Common (≥ 30%) TRAEs included an increase in aspartate aminotransferase, an increase in alanine aminotransferase, corneal epitheliopathy, alopecia, hypokalemia, interstitial lung disease (ILD)/pneumonitis, and an increase in aldosterone. While 34.8% of participants experienced ILD/pneumonitis, only 2 had a severity of grade 3. At 1.5 mg/kg every 3 weeks, the recommended phase II dose, the objective response rate was 65.5% [19/29, 95% confidence interval (CI), 45.7-82.1], the disease control rate was 100% (95% CI, 81.2-100), and the median progression-free survival was 17.02 months (95% CI, 10.09-not reached). ARX788 demonstrated a manageable safety profile with promising preliminary signs of activity in patients with HER2-positive MBC who progressed on prior anti-HER2 therapies.

Safety and efficacy of adjuvant subcutaneous trastuzumab in human epidermal growth factor receptor 2-positive early breast cancer: Final results of the SafeHER study

AimTo report the final results of the 5-year follow-up of the non-randomized SafeHER Phase III study (NCT01566721) describing the safety, tolerability, and efficacy of subcutaneous (SC) trastuzumab alone and in combination with concurrent or sequential chemotherapy. MethodsPatients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) with no prior anti-HER2 therapy were included. SC trastuzumab was administered every 3 weeks for 18 cycles as adjuvant therapy with or without chemotherapy (concurrent or sequential). The primary objective was overall safety and tolerability of SC trastuzumab; efficacy was a secondary objective. ResultsNo new safety signals were observed during the final evaluation. The majority of adverse events (AEs) were grade 1 or 2 across the chemotherapy subgroups. Treatment discontinuation due to AEs was 5.1% for the intent-to-treat (ITT) population and similar for all chemotherapy subgroups. The overall disease-free survival (DFS) 5-year event-free rate in the ITT population (n = 2573) was 86.6% (95% CI, 85.2%–87.9%) with a median follow-up of 72 months. Based on chemotherapy timing, the no (n = 235), concurrent (n = 1533), and sequential (n = 805) chemotherapy subgroups had DFS 5-year event-free rates (95% CI) of 88.5% (83.4%–92.2%), 88.4% (86.6%–89.9%), and 82.6 (79.7%–85.2%), respectively. ConclusionsThe 5-year follow-up analysis of the SafeHER trial demonstrating that SC trastuzumab has an acceptable safety profile, including cardiac toxicity, and efficacy for the treatment of HER2-positive EBC with and without chemotherapy, corresponding with historical data with trastuzumab.

Abstract PD8-01: Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies: Final overall survival (OS) analysis

Abstract Background: CTX + dual HER2-targeting monoclonal antibodies (mAb) remains a standard of care for treatment (Tx) of both HER2+ early-stage and MBC. However, when the SOPHIA trial was launched, limited Tx options existed after progression on T, pertuzumab (P), and ado-trastuzumab emtansine. M, an Fc-engineered anti-HER2 mAb, targets the same epitope as T and exerts similar antiproliferative effects. M enhances CD16A-mediated ADCC compared to T. Furthermore, M treatment is associated with increased HER2-specific T- and B-cell responses and increased T-cell clonality compared to baseline. The phase 3 SOPHIA (NCT02492711) study demonstrated PFS benefit of M vs T, both + CTX, in HER2+ MBC pts. M improved PFS over T, with a 24% relative risk reduction (HR .76; 95% CI .59-.98; P=.033; median, 5.8 [95% CI 5.5-7.0] months (mo) vs 4.9 [95% CI 4.2-5.6] mo (Rugo HS, et al. JAMA Oncol 2021), resulting in FDA approval. Median OS after 270 mortality events (2nd interim analysis) was 21.6 mo with M vs 19.8 mo with T (HR .89; 95% CI .69-1.13; P=.33). Here we report final OS after 385 events, as well as updated safety.Methods: Pts with disease progression after ≥2 lines of anti-HER2 Tx, including P, and 1-3 lines of Tx for HER2+ MBC were randomized 1:1 to CTX + either M (15 mg/kg) or T (8 mg/kg loading dose, then 6 mg/kg), both given IV every 3 weeks. Randomization was stratified by number of metastatic sites (≤2, >2), lines of Tx for MBC (≤2, >2), and CTX choice (capecitabine, eribulin, gemcitabine, or vinorelbine). Sequential primary end points were central-blinded review of PFS and OS.Results: The intent-to-treat (ITT) population comprised 536 pts (M, 266; T, 270). At the median follow-up of 20.2 mo among all ITT pts, pts received a median of 7 cycles of M + CTX vs 6 cycles of T + CTX. Median OS after 385 events in the ITT population was 21.6 mo with M vs 21.9 mo with T (HR .95; 95% CI .77-1.17; P=.62; Table). Based on a prespecified, non-α-allocated exploratory analysis, a numerical OS advantage in favor of the M arm was observed in the subgroup of pts homozygous for the CD16A-158F low-affinity allele (median OS, 23.6 vs 19.2 mo; HR .72; 95% CI .52-1.00; nominal P=.05). In contrast, in the small subgroup of CD16A-158V homozygotes, median OS was longer for T vs M (31.1 mo vs 22.0 mo; HR 1.77; 95% CI 1.01-3.12; nominal P=.04). Grade ≥3 adverse events (AE) occurred in 146 pts (55.3%) receiving M vs 141 pts (53.0%) receiving T. Serious AEs were seen in 47 pts (17.8%) receiving M vs 51 pts (19.2%) receiving T. Incidence of infusion-related reactions was higher with M (36 [13.6%]) vs T (9 [3.4%]). Left ventricular dysfunction requiring delay or cessation of M/T administration occurred in 4 pts (1.5%) receiving M and in 7 pts (2.6%) receiving T. Conclusions: The median OS in the ITT population was not statistically different between the 2 arms. An exploratory analysis of CD16A genotyping indicates a numerical OS advantage in favor of M in F homozygous pts, along with a numerical OS advantage in favor of T in V homozygous pts. Safety of M + CTX was similar to previous reports and consistent with M FDA-approved label. Studies of M in HER2+ breast cancer pts with different CD16A allelic variants are warranted, including MARGOT, the neoadjuvant investigator-initiated study on the efficacy of M vs T in pts carrying F-allelic variants of CD16A. Median OSITT analysisPrespecified, non-α-allocated exploratory analysis (n=506)N=536CD16A-158F carriers (F/F and F/V)(n=437)CD16A-158F homozygotes (F/F)(n=192)CD16A-158F/V heterozygotes(n=245)CD16A-158V homozygotes (V/V)(n=69)aM + CTX, mo21.6 (n=266)23.3 (n=221)23.6 (n=102)21.3 (n=119)22.0 (n=37)T + CTX, mo21.9 (n=270)20.8 (n=216)19.2 (n=90)22.0 (n=126)31.1 (n=32)HR (95% CI)0.95 (0.77-1.17)0.86 (0.69-1.08)0.72 (0.52-1.00)0.96 (0.71-1.30)1.77 (1.01-3.12)P value0.620.19b0.05b0.78b0.04bAbbreviations: CTX, chemotherapy; HR, hazard ratio; ITT, intent to treat; M, margetuximab; mo, months; OS, overall survival; T, trastuzumab. Cutoff date: June 14, 2021. aThis subgroup was characterized by an imbalance in poor prognostic features. bNominal P value. Citation Format: Hope Rugo, Seock-Ah Im, Fatima Cardoso, Javier Cortes, Giuseppe Curigliano, Antonino Musolino, Mark D. Pegram, Thomas Bachelot, Gail S. Wright, Cristina Saura, Santiago Escrivá-de-Romaní, Michelino De Laurentiis, Gary N. Schwartz, Timothy Pluard, Francesco Ricci, William Gwin, III, Christelle Levy, Ursa Brown-Glaberman, Jean-Marc Ferrero, Maaike de Boer, Sung-Bae Kim, Katarína Petráková, Denise A. Yardley, Orit Freedman, Erik H. Jakobsen, Einav Nili Gal-Yam, Rinat Yerushalmi, Peter A. Fasching, Emily Ashley, Shengyan Hong, Minori Rosales, William J. Gradishar. Phase 3 SOPHIA study of margetuximab (M) + chemotherapy (CTX) vs trastuzumab (T) + CTX in patients (pts) with HER2+ metastatic breast cancer (MBC) after prior anti-HER2 therapies: Final overall survival (OS) analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD8-01.

Selected Articles from This Issue

Approximately 20% of breast cancers harbor human epidermal growth factor receptor 2 (HER2/ERBB2) overexpression or amplification. KN026, a novel HER2 bispecific antibody, has been shown to overcome resistance to HER2 target therapies in preclinical models. Zhang and colleagues conducted a phase I trial of KN026 in patients with HER2-positive metastatic breast cancer who had progressed on prior anti-HER2 therapies. KN026 was well tolerated, and treatment led to an objective response rate of 28.1%. Furthermore, the authors associated CDK12 co-amplification with an improved response to KN026, supporting further assessment of this potential biomarker. Although these results are interesting, further clinical trials of this novel bispecific antibody are warranted.Metastasis is a common occurrence in patients with osteosarcoma. Although current therapeutics have shown limited ability to reduce metastasis, CCR2+ monocytes have emerged as an actionable target for the prevention of lung metastasis. Regan and colleagues conducted a clinical trial in pet dogs with spontaneous advanced metastatic osteosarcoma to assess high-dose losartan, an angiotensin receptor inhibitor, in this context. In combination with the kinase inhibitor toceranib, losartan inhibited the CCL2-CCR2 pathway, was well tolerated and led to a clinical benefit rate of 50%. These results support further clinical study of losartan, especially human clinical trials.Although immunotherapy has provided a benefit to many patients, predictive biomarkers are still needed to more effectively guide treatment in patients with advanced renal cell carcinoma (RCC). To identify potential biomarkers in patients with advanced RCC treated with avelumab plus axitinib or sunitinib, Bilen and colleagues conducted a post hoc analysis of data from the phase 3 JAVELIN Renal 101 trial. The authors found that a low neutrophil-to-lymphocyte ratio (NLR) was associated with longer progression-free survival, overall survival, and objective response rate. These results support the continued development of NLR as a predictive biomarker for immunotherapy in patients with advanced RCC.Prior studies have shown that cabozantinib, an inhibitor of VEGFRs and additional tyrosine kinases, is effective for the treatment of metastatic clear cell renal cell carcinoma (mccRCC). However, it is unclear whether the mechanism of this agent is via its targeting of VEGFR or another target. To address this question, Denize and colleagues assessed angiogenesis markers in patients treated with cabozantinib or everolimus as part of the METEOR trial. Microvascular density and mast cell density, both markers of angiogenesis, were both associated with longer progression-free survival. Furthermore, patients treated with cabozantinib had improved progression-free survival, overall survival, and objective response rate compared with those treated with everolimus; importantly, these results were not dependent on levels of microvascular density or mast cell density. These results support the activity of cabozantinib in patients with mccRCC and suggest that VEGFR-independent effects may be part of the mechanism of this agent.

Abstract P2-13-10: First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: Results from a phase I study

Abstract PURPOSE KN026 is a novel bispecific antibody that simultaneously binds to two distinct HER2 epitopes. This firstinhuman Phase I study evaluated the safety/tolerability, pharmacokinetics (PK), preliminary efficacy, and potential predictive biomarker activity of KN026 administered as monotherapy to HER2-positive metastatic breast cancer (MBC) patients. METHODS Female patients with HER2 positive MBC who failed prior antiHER2 therapies received intravenous KN026 monotherapy at 5 mg/kg (QW), 10 mg/kg (QW), 20 mg/kg (Q2W), or 30 mg/kg (Q3W). Dose escalation was guided by a “3+3” doseescalation rule followed by dose expansion. The primary endpoint of the study was to assess safety and ascertain the recommended phase 2 dose (RP2D). RESULTS 63 patients were enrolled with a median of 3 prior lines of systemic therapies and 2 prior lines of HER2 targeted therapies. Treatment was well tolerated with no DLTs observed. The most common treatment related adverse events (TRAEs) were pyrexia (23.8%), diarrhea (22.2%), aspartate aminotransferase increased (22.2%), alanine aminotransferase increased (22.2%). 4 patients reported Grade 3 TRAEs. Pharmacokinetic analysis indicated that KN026 exposure was dose-dependent, with a terminal elimination halflife of 146 to 282 hours after multiple doses. Results from exposure-response analysis supported the selection of the RP2Ds at 20 mg/kg Q2W or 30 mg/kg Q3W, which had corresponding objective response rates (ORRs) of 32.1% and 24.1%, disease control rates of 60.7% and 82.8%, and median progression-free survival (PFS) of 5.5 and 7.4 months, respectively. Anti-drug antibodies (ADAs) were detected in 3.2% (2/63) of patients at the end of treatment. Cell line data showed that coamplification of HER2 and CDK12 were related to the efficacy of KN026. Translational research in 20 HER2-amplified patients further confirmed that co-amplification (vs. no coamplification) of CDK12 was a promising biomarker in predicting better response to KN026 (ORR of 50% vs. 0% and PFS of 8.2 vs. 2.7 months, P = 0.05 and 0.04, respectively). CONCLUSION KN026, a HER2 bispecific antibody, is well tolerated, with a favorable safety profile and promising anti-tumor activity in the context of its class in patients with HER2-positive breast cancer. Co-amplification of HER2/CDK12 may define patients who benefit more from KN026. Citation Format: Jian Zhang, Dongmei Ji, Li Cai, Herui Yao, Min Yan, Xiaojia Wang, Weina Shen, Yiqun Du, Hui Pang, Xiuping Lai, Huiai Zeng, Jian Huang, Yan Sun, Xinxin Peng, Junfang Xu, Jing Yang, Fei Yang, Ting Xu, Xichun Hu. First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: Results from a phase I study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-10.

Abstract OT2-15-01: Updated analysis of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in patients (pts) with HER2 positive/amplified (HER2+) metastatic breast cancer (MBC) who progressed on previous anti-HER2 ADCs

Abstract Background Zenocutuzumab is a humanized bispecific full-length IgG1 antibody targeting both HER2 and HER3 with enhanced ADCC activity. The unique Dock & Block mechanism inhibits HER3 from interacting with its ligands by targeting HER2 at a different epitope than trastuzumab, that optimally positions it to block HER2/HER3 dimerization and downstream PI3K/AKT/mTOR signaling. In MBC, HER3 overexpression and/or HER3 ligand upregulation are important drivers of carcinogenesis leading to trastuzumab resistance, indicating a potential role for zenocutuzumab. Preclinical activity was seen in HER2+ breast cancer models when zenocutuzumab was combined with trastuzumab. Single-agent zenocutuzumab showed consistent antitumor activity in heavily pretreated HER2+ MBC pts. This phase 2, open-label study explored zenocutuzumab/trastuzumab/vinorelbine in MBC. Methods This open-label study planned to enroll up to 40 evaluable pts with HER2+ MBC progressing after up to 5 anti-HER2 lines of therapy including trastuzumab, pertuzumab, and an anti-HER2 ADC. This sample size with a clinical benefit rate (CBR) of 45% would provide adequate precision to exclude 30% (lower limit of 90% CI > 30%). The threshold for the CBR rate at 24 w was based on the assumption that progression-free survival (PFS) follows an exponential distribution with a median of 5 months (clinically relevant) and 3.5 months (not clinically relevant).Pts received zenocutuzumab (750 mg, 2h IV), trastuzumab (8 mg/kg loading, then 6 mg/kg), and vinorelbine (25 mg/m², D1 and 8), q3w. A safety run-in of zenocutuzumab + trastuzumab ± vinorelbine was performed. The primary endpoint of the study was CBR at 24 w (tumor assessment [TA] by RECIST 1.1, per investigator), secondary endpoints include CBR at 24 w (TA by RECIST 1.1, per central review), overall response rate (ORR), safety, biomarkers, and pharmacokinetics. Cutoff date for the efficacy endpoints was 31Mar2021. This is an updated analysis of the 2020 ASCO abstract after all patients had completed at least 6 months of treatment or discontinued. Result total of 39 pts with a median of 3 lines (range 2-5) of prior anti-HER2 therapy including TDM1 received a median of 6 (range 1-23) cycles of zenocutuzumab. In the 37 pts evaluable for efficacy and with locally confirmed HER2 overexpression (3+ IHC or 2+ IHC confirmed by FISH), CBR at 24 w per investigator was 49% (90% CI: 34-63%); ORR was 27% (95% CI: 15-42%). The CBR at 24 w was consistent across different methods of HER2 overexpression/amplification detection (local vs central laboratory) and response assessment (investigator and central independent radiological review; see table below). As of a 12Jan2021 safety data update, the most common related AEs (all grades; G3-4) were neutropenia/neutrophil count decrease (61%; 46%), diarrhea (61%; 4%), asthenia/fatigue (46%; 0), and nausea (29%; 0). The PK half-life was 117h. The correlation of HER2-HER3 pathway activation at baseline with best ORR, duration of response, PFS, and overall survival was analyzed and will be presented in the poster. Conclusion Updated analyses confirm that the efficacy of zenocutuzumab combinations with trastuzumab/vinorelbine in heavily pretreated, HER2+ MBC, with progression after TDM-1, met prespecified protocol criteria for success. The regimen is safe and well tolerated with AEs mostly related to chemotherapy. CBR with zenocutuzumab, trastuzumab, and vinorelbinePopulationNCBR at 24 wks, %. (90% CI)HER2+ by local test/TA by RECIST1.1 per investigator3749 (34-63)HER2+ by central test/TA by RECIST1.1 per investigator2955.1 (38-71)HER2+ by local test/TA by RECIST1.1 by central independent radiologist review3644 (30-59)HER2+ by central test/TA by RECIST1.1 by central independent radiologist review2850.0 (33-67) Citation Format: Erika Hamilton, Thierry Petit, Barbara Pistilli, Anthony Goncalves, Ana Alexandra Ferreira, Florence Dalenc, Fatima Cardoso, Monica M Mita, Luis Manso, Syed M Karim, Francois-Clement Bidard, Philippe Aftimos, Santiago Escriváa-de-Romaníi, Noemia Afonso, Ernesto Wasserman, Kees Bol, Viktoriya Stalbovskaya, Anastasia Vliet, Anastasia Murat, Mohamed Bekradda, Thomas Bachelot. Updated analysis of MCLA-128 (zenocutuzumab), trastuzumab, and vinorelbine in patients (pts) with HER2 positive/amplified (HER2+) metastatic breast cancer (MBC) who progressed on previous anti-HER2 ADCs [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-15-01.

Trastuzumab deruxtecan in patients with HER2-overexpressing locally advanced, unresectable, or metastatic colorectal cancer (mCRC): A randomized, multicenter, phase 2 study (DESTINY-CRC02).

TPS224 Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate comprising an anti-HER2 antibody (trastuzumab) linked to a potent topoisomerase I inhibitor (DXd). T-DXd has been approved to treat HER2-positive metastatic breast cancer (United States [US], Japan, Europe, Israel) and advanced gastric cancer (US, Japan, Israel). It is currently being evaluated in other solid tumor types including colorectal cancer. The phase 2 DESTINY-CRC01 study included patients with RAS wild-type mCRC, with a median 4 (range, 2-11) prior lines of therapy. Preliminary results in patients with HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) mCRC showed T-DXd treatment (6.4-mg/kg intravenously [IV] every 3 weeks [Q3W]) resulted in a confirmed objective response rate (ORR) of 45.3% (24/53; 95% CI, 31.6-59.6%) and a median progression-free survival (PFS) of 6.9 months (95% CI, 4.1-not estimable; Siena J Clin Oncol. 2020). Activity was also seen in patients treated with prior anti-HER2 therapy. Although 5.4-mg/kg and 6.4-mg/kg doses of T-DXd have shown clinical efficacy in multiple cancer indications, the lower dose has not yet been tested in patients with HER2-overexpressing mCRC. Preliminary data also suggest T-DXd may be active in RAS mutant mCRC, unlike other anti-HER2 therapies. The DESTINY-CRC02 study aims to determine efficacy and safety of T-DXd in patients with HER2-overexpressing, RAS wild-type or mutant mCRC at 5.4-mg/kg and 6.4-mg/kg doses. Methods: DESTINY-CRC02 (NCT04744831) is a multicenter, randomized, double-blind, 2-arm, parallel phase 2 study that will be conducted in 2 stages. Eligible patients (≥18 years; ≥20 years in Japan, Taiwan, and Korea) will have HER2-overexpressing (IHC 3+ or IHC 2+/ISH+) locally advanced, unresectable or metastatic CRC and have previously received chemotherapy, anti-EGFR therapy, anti-VEGF treatment, and/or anti–PD-1/PD-L1 therapy, as clinically indicated. Prior anti-HER2 therapy will be allowed. In stage 1, patients will be randomly assigned 1:1 to receive T-DXd IV Q3W at a dose of 5.4-mg/kg (n = 40; arm 1) or 6.4-mg/kg (n = 40; arm 2). Randomization will be stratified by ECOG PS (0 or 1), HER2 status (IHC 3+ or IHC 2+/ISH+), and RAS status (wild-type or mutant). After stage 1 enrollment is complete, eligible patients in stage 2 (n = 40) will receive T-DXd 5.4 mg/kg until disease progression or other treatment discontinuation criteria are met. The study is actively enrolling and aims to enroll 120 patients across 60 sites. The primary objective is to assess efficacy of T-DXd at the 5.4-mg/kg and 6.4-mg/kg doses, with a primary endpoint of confirmed ORR by blinded independent central review. Secondary endpoints include investigator-assessed ORR, PFS, duration of response, disease control rate, clinical benefit rate, overall survival, pharmacokinetics, and safety. Clinical trial information: NCT04744831.

Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): Final results from a phase 2, multicenter, open-label study (DESTINY-CRC01).

119 Background: T-DXd is an antibody-drug conjugate of a humanized anti-HER2 antibody bound to a topoisomerase I inhibitor by a cleavable linker. The primary analysis of DESTINY-CRC01 (DS8201-A-J203; NCT03384940), a phase 2, open-label, multicenter study of T-DXd in pts with HER2-expressing mCRC showed promising antitumor activity and a manageable safety profile (cohort A median follow-up [FU], 27.1 weeks; Siena S, ASCO 2020). We present updated longer-term efficacy and safety data. Methods: Pts had centrally confirmed HER2-expressing, RAS wild-type mCRC that progressed after ≥2 prior regimens. 6.4 mg/kg of T-DXd was administered every 3 weeks (Q3W) in 3 cohorts (A: HER2 IHC3+ or IHC2+/ISH+; B: IHC2+/ISH−; C: IHC1+). The primary endpoint was confirmed objective response rate (ORR) by independent central review in cohort A. Secondary endpoints were disease control rate (DCR; CR + PR + SD), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results: At data cutoff (Dec 28, 2020), 86 pts (A, 53; B, 15; C, 18) received T-DXd. Median age was 58.5 y (range, 27-79), 53.5% were male, and 90.7% had left colon or rectum cancer. Median prior regimens for metastatic disease was 4 (range, 2-11). All pts had prior irinotecan; 30.2% in cohort A had prior anti-HER2 therapy. Median (m) treatment duration (all pts) was 3.0 mo (95% CI, 2.1-4.1; cohort A, 5.1 mo [95% CI, 3.9-7.6]). In cohort A (median FU, 62.4 weeks), confirmed ORR was 45.3% (24/53 pts; 95% CI, 31.6-59.6), DCR was 83.0% (44/53 pts; 95% CI, 70.2-91.9), mDOR was 7.0 mo (95% CI, 5.8-9.5), mPFS was 6.9 mo (95% CI, 4.1-8.7) with 37 (69.8%) PFS events, and mOS was 15.5 mo (95% CI, 8.8-20.8) with 36 (67.9%) OS events. These results are consistent with the primary analysis. Confirmed ORR was 43.8% (7/53 pts; 95% CI, 19.8-70.1) for pts with prior anti-HER2 therapy, 57.5% (23/53 pts; 95% CI, 40.9-73.0) for pts with IHC3+ status, and 7.7% (1/53 pts; 95% CI, 0.2-36.0) for pts with IHC2+/ISH+ status. In cohorts B and C, mPFS was 2.1 mo (95% CI, 1.4-4.1) and 1.4 mo (95% CI, 1.3-2.1); mOS was 7.3 mo (95% CI, 3.0-NE) and 7.7 mo (95% CI, 2.2-13.9), respectively. Treatment-emergent adverse events (TEAEs) of grade (G) ≥3 occurred in 65.1% of pts (56/86); the most common TEAEs were hematologic and gastrointestinal. TEAEs leading to drug discontinuation occurred in 13 pts (15.1%). 8 pts (9.3%) had interstitial lung disease (ILD) adjudicated by an independent committee as related to T-DXd (4 G2; 1 G3; 3 G5). Conclusions: T-DXd at 6.4 mg/kg Q3W showed promising activity and durability with longer-term FU in pts with HER2-expressing mCRC. The safety profile was consistent with prior results; ILD continues to be an important identified risk that requires careful monitoring and intervention as needed. These results support continued exploration of T-DXd in this patient population. Clinical trial information: NCT03384940.