Citations

1088 Background: Standard first-line treatment for mTNBC is chemotherapy. However, outcomes are poor, and new treatment options are needed. Cohort B of KEYNOTE-086 (NCT02447003) assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients (pts) with PD-L1–positive mTNBC. Methods: Men and women with centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, ECOG PS 0-1, and a tumor PD-L1 combined positive score (CPS) ≥1% received pembrolizumab 200 mg Q3W for 24 mo or until disease progression, intolerable toxicity, or investigator or pt decision. Tumor imaging was performed Q9W for 12 mo and Q12W thereafter. Clinically stable pts with PD could remain on pembrolizumab until PD was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, DOR, and PFS (RECIST v1.1, central review). Planned enrollment was 80 pts. This analysis included all pts who had ≥18 wk of follow-up as of Nov 10, 2016. Results: 79 of the first 137 pts with PD-L1–evaluable tumors (58%) had PD-L1 CPS ≥1%. Of the first 52 pts enrolled, 100% were women, median age was 53 y, 40% had elevated LDH, 69% had visceral metastases, and 87% received prior (neo)adjuvant therapy. After a median follow-up of 7.0 mo (range 4.4-12.5), 15 (29%) pts remained on pembrolizumab. Treatment-related AEs occurred in 37 (71%) pts, most commonly fatigue (31%), nausea (15%), and diarrhea (13%). 4 (8%) pts experienced 5 grade 3-4 treatment-related AEs: back pain, fatigue, hyponatremia, hypotension, and migraine (n = 1 each). No pts died or discontinued pembrolizumab due to an AE. ORR was 23% (95% CI 14%-36%). Best overall response was CR in 4%, PR in 19%, SD in 17%, PD in 58%, and not assessed in 2%. Median time to response was 8.7 wk (range 8.1-17.7). Median DOR was 8.4 mo (range, 2.1+ to 8.4), with 8 (67%) responses ongoing at cutoff. Median PFS was 2.1 mo (95% CI, 2.0-3.9); estimated 6-mo PFS rate was 29%. Conclusions: Data from the first 52 pts enrolled in KEYNOTE-086 cohort B suggest that pembrolizumab monotherapy has a manageable safety profile and promising antitumor activity as first-line therapy for PD-L1–positive mTNBC. Clinical trial information: NCT02447003.

506 Background: Pembro is an anti-PD-1 antibody with single agent activity in HER2– metastatic BC. I-SPY 2 is a multicenter, phase 2 platform trial which evaluates novel neoadjuvant therapies; the primary endpoint is pathological complete response (pCR, ypT0/Tis ypN0). We report current efficacy results, with final results at ASCO. Methods: Patients (pts) with invasive BC ≥2.5 cm by exam or ≥2 cm by imaging are assigned weekly paclitaxel x 12 (control) +/- an experimental agent, followed by doxorubicin/cyclophosphamide x 4. Combinations of hormone-receptor (HR), HER2, & MammaPrint (MP) status define the 8 signatures studied. MP low HR+ BC is excluded. Adaptive randomization is based on each arm’s Bayesian probability of superiority over control. Graduation by signature is based on an arm’s Bayesian predictive probability of a successful 1:1 randomized phase 3 trial with a pCR endpoint. We provide raw & Bayesian estimated pCR rates adjusted for covariates, time effects over the course of the trial, & serial MRI modeling for pts not yet assessed for pCR surgically. Results: 69 pts were randomized to pembro (HER2- subsets only) from Dec 2015 until it graduated in Nov 2016. 46 pts have undergone surgery (table); the other 23 have on-therapy MRI assessments. In 29 HR–/HER2– (TNBC) pts, pembro increased raw & estimated pCR rates by >50% & 40%, respectively; in 40 HR+/HER– pts, it did so by 13% and 21%. 5 pts had immune-related grade 3 adverse events (AEs); 1 hypophysitis & 4 adrenal insufficiency. 4 pts presented after completion of AC (149-179 d after starting pembro); 1 presented prior to AC (37 d after starting pembro). 7 pts had grade 1-2 thyroid abnormalities. Conclusion: Pembro added to standard therapy improved pCR rates in all HER2- BCs that meet I-SPY 2 eligibility, especially in TNBC. Immune-mediated AEs were observed; pt follow up is ongoing. Clinical trial information: NCT01042379. [Table: see text]

AbstractBackgroundBeta‐galactosidase‐1 (GLB1) is a lysosomal hydrolase that is responsible for breaking down specific glycoconjugates, particularly GM1 (monosialotetrahexosylganglioside). Pathogenic variants in GLB1 cause two different lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB. In GM1 gangliosidosis, decreased β‐galactosidase‐1 enzymatic activity leads to the accumulation of GM1 gangliosides, predominantly within the CNS. We present a 22‐month‐old proband with GM1 gangliosidosis type II (late‐infantile form) in whom a novel homozygous in‐frame deletion (c.1468_1470delAAC, p.Asn490del) in GLB1 was detected.MethodsWe used an experimental protein structure of β‐galactosidase‐1 to generate a model of the p.Asn490del mutant and performed molecular dynamic simulations to determine whether this mutation leads to altered ligand positioning compared to the wild‐type protein. In addition, residual mutant enzyme activity in patient leukocytes was evaluated using a fluorometric assay.ResultsMolecular dynamics simulations showed the deletion to alter the catalytic site leading to misalignment of the catalytic residues and loss of collective motion within the model. We predict this misalignment will lead to impaired catalysis of β‐galactosidase‐1 substrates. Enzyme assays confirmed diminished GLB1 enzymatic activity (~3% of normal activity) in the proband.ConclusionsWe have described a novel, pathogenic in‐frame deletion of GLB1 in a patient with GM1 gangliosidosis type II.