34 research outputs found
61MO Biomarker analysis of men with enzalutamide (enza)-resistant metastatic castration-resistant prostate cancer (mCRPC) treated with pembrolizumab (pembro) + enza in KEYNOTE-199
Background: In KEYNOTE-199 (NCT02787005), pembro + enza had durable antitumor activity in enza-refractory mCRPC. We evaluated the association between prespecified biomarkers and clinical outcomes.
Methods: Cohorts 4 (C4; RECIST-measurable disease) and 5 (C5; nonmeasurable, bone-predominant disease) enrolled men with chemotherapy-naive mCRPC, irrespective of PD-L1 status, that progressed after initial response to enza. We evaluated TMB by whole exome sequencing (n = 64), PD-L1 combined positive score (CPS) by IHC (n = 124), and 18-gene T-cell–inflamed gene expression profile (TcellinfGEP) by NanoString (n = 51). Outcomes were DCR, PFS, PSA response, PSA progression, OS, and ORR per blinded independent review (C4 only). Significance of continuous biomarkers (CPS, TMB, GEP) was prespecified at 0.05 for 1-sided P values from logistic (ORR, DCR, PSA response) and Cox proportional hazard (PFS, OS, PSA progression) regression adjusted for ECOG PS.
Results: In C4, ORR was 10% (5/48) in pts with evaluable TMB data and 12% (10/81) in pts with CPS data. In C4 and C5, 16% (10/64) and 14% (17/124) of pts with TMB and CPS data, respectively, achieved a PSA response. TMB was significantly associated with DCR (P = 0.03) and trended toward an association with PSA response (P = 0.08). TMB (AUROC [95% CI]: 0.68 [0.51-0.86]), but not CPS (0.54 [0.41-0.67]) or TcellinfGEP (0.55 [0.37-0.74]), enriched for PSA response. TMB (P = 0.04), but not CPS (P = 0.57) or TcellinfGEP (P = 0.32), was significantly associated with PSA progression. There was 1 MSI-H pt (per Promega PCR assay); this pt achieved an objective and PSA response and had PFS \u3e6 months. TMB, CPS, and TcellinfGEP were not associated with PFS or OS. There was a low prevalence of TMB ≥175 mut/exome (11%) and TcellinfGEP-high (≥−0.318; 16%).
Conclusions: In this biomarker analysis of KEYNOTE-199 C4-C5, PD-L1 CPS and TcellinfGEP were not significantly associated with clinical outcome. Despite the low prevalence of TMB ≥175 mut/exome, TMB was positively associated with outcomes of pembro + enza in pts with mCRPC. The sample sizes for the exploratory analyses were small, and results should be interpreted with caution
Demonstration of a novel technique to measure two-photon exchange effects in elastic scattering
The discrepancy between proton electromagnetic form factors extracted using
unpolarized and polarized scattering data is believed to be a consequence of
two-photon exchange (TPE) effects. However, the calculations of TPE corrections
have significant model dependence, and there is limited direct experimental
evidence for such corrections. We present the results of a new experimental
technique for making direct comparisons, which has the potential to
make precise measurements over a broad range in and scattering angles. We
use the Jefferson Lab electron beam and the Hall B photon tagger to generate a
clean but untagged photon beam. The photon beam impinges on a converter foil to
generate a mixed beam of electrons, positrons, and photons. A chicane is used
to separate and recombine the electron and positron beams while the photon beam
is stopped by a photon blocker. This provides a combined electron and positron
beam, with energies from 0.5 to 3.2 GeV, which impinges on a liquid hydrogen
target. The large acceptance CLAS detector is used to identify and reconstruct
elastic scattering events, determining both the initial lepton energy and the
sign of the scattered lepton. The data were collected in two days with a
primary electron beam energy of only 3.3 GeV, limiting the data from this run
to smaller values of and scattering angle. Nonetheless, this measurement
yields a data sample for with statistics comparable to those of the
best previous measurements. We have shown that we can cleanly identify elastic
scattering events and correct for the difference in acceptance for electron and
positron scattering. The final ratio of positron to electron scattering:
for GeV and