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., C min ) 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 Context.—The metastasis-associated gene 1 (MTA1) is overexpressed in several human cancers. Recent reports suggest that MTA1 may play a role in cancer progression either through transcript...
Abstract Background: Cancer cells deficient in BRCA1/2 are selectively sensitive to the double-stranded DNA breaks induced by poly (ADP-ribose) polymerase (PARP) inhibitors. Multiple ongoing trials are evaluating PARP inhibitors in patients with breast, ovarian, and prostate cancers and germline or somatic BRCA1/2 mutations. There is, however, a great need to determine if the benefit of PARP inhibition can be extended to other tumor types. We sought to assess the efficacy of talazoparib, a potent oral PARP1/2 inhibitor, in patients with germline BRCA mutations in cancer types other than breast and ovarian cancer, and in patients with somatic BRCA alterations or aberrations in other homologous repair genes or PTEN. Methods: This was a single-center, phase II trial in patients with measurable advanced solid tumors. Patients were enrolled on one of four cohorts: 1) somatic alterations of BRCA1/2, 2) mutations/deletions in other BRCA pathway genes, 3) mutations/deletions in PTEN and/or PTEN loss by IHC, and 4) germline BRCA1/2 mutations (not breast/ovarian cancer). Patients were treated with talazoparib at 1 mg PO daily. Response was assessed per RECIST v1.1. Primary end point was clinical benefit rate (CBR; complete response [CR], partial response [PR] or stable disease [SD]>6m). Patients were enrolled based on standard of practice molecular testing. Patients underwent pretreatment biopsies with whole exome sequencing (WES) of tumor and normal DNA. Results: 35 patients (pts) (30 evaluable) were enrolled. Pts had a median of 4 prior lines of treatment. Grade 3-4 treatment-related AEs occurred in 37% of pts, and the most common was thrombocytopenia (23%). The median follow-up was 15.8 mo. CBR was 0%, 44%, 8%, and 29% for cohorts 1-4, respectively. In cohort 1, one patient with a somatic BRCA2 mutation enrolled and did not respond. In cohort 2, two of 9 evaluable pts had a PR: cholangiocarcinoma [CCA] with ATM mutation and bladder cancer with PALB2 mutation, and 2 of 9 pts had prolonged SD (one pt with ovarian cancer and BRIP1 mutation, and one pt with sarcoma and FANCC mutation). Among 13 evaluable pts in the PTEN mutation/loss cohort (cohort 3), one patient with PTEN mutation had prolonged SD. Among 7 evaluable pts with germline BRCA1/2 mutations (cohort 4), one pt with carcinoma of ampulla of Vater had a durable CR, and one pt with CCA had SD for 8 months. WES was performed on 28 evaluable patients. Alterations in two genes, POLQ and PTEN, were significantly associated with progressive disease. PTEN mutations were associated with shorter time to progression (p=0.004) and lower overall survival (p=0.02). Conclusion: Talazoparib demonstrated clinical benefit in selected patients with germline as well as somatic alterations in BRCA pathway genes. Patients with PTEN mutations/loss did not derive significant clinical benefit from PARP inhibition. Further study is needed to confirm these findings and determine implications for patient selection and combination therapy. Clinical trial information: NCT 02286687. Citation Format: Sarina A. Piha-Paul, Wendy Wen Xiong, Tyler Moss, Rosa M. Mostorino, Shelby Sedelmeier, Kenneth Hess, Siqing Fu, David Hong, Filip Janku, Daniel Karp, Aung Naing, Shubham Pant, Jordi Rodon, Vivek Subbiah, A M. Tsimberidou, Timothy Yap, Milind Javle, Coya Tapia, Kenna R. Shaw, Karina Eterovic, Gordon B. Mills, Funda Meric-Bernstam. Phase II study of the PARP inhibitor talazoparib in advanced cancer patients with somatic alterations in BRCA1/2, mutations/deletions in PTEN or PTEN loss, aberrations in other BRCA pathway genes, and germline mutations in BRCA1/2 (not breast or ovarian cancer) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A096.
Clinical relevance of tumor infiltrating lymphocytes (TILs) in breast cancer is controversial. Here, we used a tumor microarray including a large series of ductal and lobular breast cancers with long term follow up data, to analyze clinical impact of TIL expressing specific phenotypes and distribution of TILs within different tumor compartments and in different histological subtypes.A tissue microarray (TMA) including 894 ductal and 164 lobular breast cancers was stained with antibodies recognizing CD4, FOXP3, and IL-17 by standard immunohistochemical techniques. Lymphocyte counts were correlated with clinico-pathological parameters and survival.CD4(+) lymphocytes were more prevalent than FOXP3(+) TILs whereas IL-17(+) TILs were rare. Increased numbers of total CD4(+) and FOXP3(+) TIL were observed in ductal, as compared with lobular carcinomas. High grade (G3) and estrogen receptor (ER) negative ductal carcinomas displayed significantly (p < 0.001) higher CD4(+) and FOXP3(+) lymphocyte infiltration while her2/neu over-expression in ductal carcinomas was significantly (p < 0.001) associated with higher FOXP3(+) TIL counts. In contrast, lymphocyte infiltration was not linked to any clinico-pathological parameters in lobular cancers. In univariate but not in multivariate analysis CD4(+) infiltration was associated with significantly shorter survival in patients bearing ductal, but not lobular cancers. However, a FOXP3(+)/CD4(+) ratio > 1 was associated with improved overall survival even in multivariate analysis (p = 0.033).Ductal and lobular breast cancers appear to be infiltrated by different lymphocyte subpopulations. In ductal cancers increased CD4(+) and FOXP3(+) TIL numbers are associated with more aggressive tumor features. In survival analysis, absolute numbers of TILs do not represent major prognostic indicators in ductal and lobular breast cancer. Remarkably however, a ratio > 1 of total FOXP3(+)/CD4(+) TILs in ductal carcinoma appears to represent an independent favorable prognostic factor.
