There is evidence that macrophage infiltration in the tumor microenvironment promotes vestibular schwannoma (VS) growth. Efficacy of bevacizumab in NF2-associated VS demonstrates the value of ...therapies targeting the microvascular tumor microenvironment, and tumor-associated macrophages (TAMs) may represent another druggable target.
To characterize the relationship between growth, TAM infiltration, and circulating monocyte chemokines in a large cohort of patients with VS.
Immunostaining for Iba1 (macrophages), CD31 (endothelium), and fibrinogen (permeability) was performed on 101 growing and 19 static sporadic VS. The concentrations of monocyte-specific chemokines were measured in the plasma of 50 patients with growing VS and 25 patients with static VS.
The Iba1 + cell count was significantly higher in growing as compared with static VS (592 vs 226/×20 HPF, P =<0.001). Similarly, the CD31 + % surface area was higher in growing VS (2.19% vs 1.32%, P = .01). There was a positive correlation between TAM infiltration and VS growth rate, which persisted after controlling for the effect of tumor volume (aR2 = 0.263, P =<0.001). The plasma concentrations of several monocytic chemokines were higher in patients with growing rather than static VS.
There is a strong positive correlation between TAM infiltration and volumetric growth of VS, and this relationship is independent of tumor size. There is a colinear relationship between TAM infiltration and tumor vascularity, implying that inflammation and angiogenesis are interlinked in VS. Chemokines known to induce monocyte chemotaxis are found in higher concentrations in patients with growing VS, suggestive of a potential pathophysiological mechanism.
7525
Background: Outcomes are poor for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Effective treatments (tx) that drive deep, durable responses and long-term benefit ...are needed. In the pivotal EPCORE NHL-1 trial (NCT03625037), single-agent epcoritamab (epcor) showed high complete response (CR) and MRD-negativity rates, a median duration of response (mDoR) not reached (NR) in pts who achieved CR, and a manageable safety profile as an off-the-shelf, subcutaneous (SC), CD3xCD20 T-cell–engaging bispecific antibody (Thieblemont et al, JCO 2022). We present updated results with longer follow-up in a challenging-to-treat population. Methods: Pts with R/R CD20
+
LBCL received SC epcor (step-up priming and intermediate doses followed by 48-mg full doses) in 28-d cycles (Cs): QW, C1–3; Q2W, C4–9; Q4W, C≥10 until PD or unacceptable toxicity. Results: As of Nov 18, 2022, of 157 pts (median age, 64 y) with LBCL (including DLBCL n=139, HGBCL n=9, PMBCL n=4, and FL grade 3B n=5; 13/99 double/triple-hit by FISH), 36 remain on tx. Pts had a median of 1.6 y from initial diagnosis to first dose and a median of 3 (range, 2–11) prior tx lines; 61% of pts had primary refractory disease, and 39% had prior CAR T, of whom 75% progressed ≤6 mo of tx. Median follow-up was 20 mo (range, 0.3+ to 28.2). Pts received a mean of 9.1 cycles. LBCL overall response and CR rates were 63.1% and 39.5%, respectively, and were consistent for DLBCL (61.9% and 39.6%). The mDoCR was 20.8 mo. Median time to CR was 2.7 mo; 8 pts converted from partial response to CR at ≥36 wk. Median overall survival (mOS) was 18.5 mo (95% CI, 11.7–NR), with an estimated 58% of pts alive at 12 mo. mOS was NR in pts who achieved CR. Additional outcomes for pts with CR are shown in Table. The most common TEAEs of any grade (G) were: CRS 51%, neutropenia 24%, pyrexia 24%, fatigue 23%, nausea 22%, and diarrhea 21%. Nine pts (6%) had G1–2 ICANS, and 1 pt had a G5 event with confounding factors. Fatal TEAEs occurred in 15 pts; 2 were considered related (COVID-19, ICANS). CRS was predominantly low grade (48% G1–2; 3% G3) and occurred following the first full dose (C1D15). One pt discontinued tx due to G1 CRS. Total metabolic tumor volume (TMTV) data will be presented. Conclusions: These data with longer follow-up reaffirm single-agent SC epcor induces durable CRs with improved outcomes and a manageable safety profile. No new safety signals were observed in these hard-to-treat pts. These impressive data support the ongoing phase 3 studies evaluating epcor across different lines of tx and in various combinations. Clinical trial information: NCT03625037 . Table: see text
7514
Background: Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi. Here, we report updated results of pirtobrutinib in patients (pts) with cBTKi pre-treated relapsed/refractory ...(R/R) MCL and more than 3 years follow-up from start of enrollment. Methods: Pts with cBTKi pre-treated R/R MCL received pirtobrutinib monotherapy in a multicenter phase 1/2 BRUIN trial (NCT03740529). Efficacy was assessed in the prespecified primary efficacy cohort that comprised the first 90 enrolled pts who had measurable disease, had received a prior cBTKi, and had no known central nervous system involvement. The primary endpoint was overall response rate (ORR) as assessed by independent review committee. Secondary endpoints included duration of response (DOR) and safety. A data cut of 29 July 2022 was utilized. Results: Among MCL pts who received a prior cBTKi (n=90), median age was 70 years (range, 46-87), median prior lines of therapy were 3 (range, 1-8), 82% discontinued a prior cBTKi due to disease progression, and 78% had intermediate/high risk sMIPI score. Of samples available, 17/36 (47%) had TP53 mutations and 25/34 (74%) had Ki67 ≥30%. The ORR was 57% (95% CI, 46-67), including 19% complete responses (n=17) and 38% partial responses (n=34). At a median follow-up time of 13 months, the median DOR among the 51 responding pts was 17.6 months (95% CI, 7.3-27.2). The 12- and 18-month estimated DOR rates were 58% (95% CI, 41-72) and 45% (95% CI, 27-61), respectively. ORR and DOR by subgroups are shown in the Table. The median progression-free survival was 7.4 months (95% CI, 5.3–13.3). The median overall survival was 23.5 months (95% CI, 15.9-NE). In the MCL safety cohort (n=166), the most frequent treatment-emergent adverse events (TEAE) were fatigue (31%), diarrhea (22%), and anemia (17%). The most common Grade ≥3 TEAE was neutropenia (15%). Grade ≥3 TEAE of hemorrhage (3%) and atrial fibrillation/flutter (2%) were infrequent. Only 5 (3%) pts discontinued due to a treatment-related AE. Conclusions: Pirtobrutinib continues to show durable efficacy and a favorable safety profile in heavily pre-treated R/R MCL pts with prior cBTKi therapy. Responses were observed in pts with high-risk disease features including pts with blastoid/pleomorphic variants, elevated Ki67 index, and TP53 mutations. Clinical trial information: NCT03740529 . Table: see text
LBA7502
Background: Elderly patients (pts) with MCL are unsuitable for intensive chemotherapy or transplantation due to excessive toxicities. Single-agent ibrutinib (Ibr), a first-in-class, oral ...Bruton’s tyrosine kinase inhibitor (BTKi), has transformed the care of pts with relapsed or refractory MCL with durable activity. We conducted a phase III trial (SHINE; NCT01776840) to evaluate combining Ibr with a standard chemoimmunotherapy (BR) and R maintenance in older pts with untreated MCL. Methods: Pts aged ≥ 65 years, enrolled between May 2013 and November 2014 from 183 sites across all geographical regions, were stratified by simplified MIPI score (low vs intermediate vs high risk) and were randomized 1:1 to Ibr (560 mg orally daily) or placebo (Pbo), plus 6 cycles of B (90 mg/m
2
) and R (375 mg/m
2
). Pts who achieved an objective response received R maintenance, administered every 8 weeks for up to 12 additional doses in both arms. Ibr and Pbo were administered until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by the investigators. Results: A total of 523 pts were randomized to Ibr + BR (n = 261) or Pbo + BR (n = 262). Median age was 71 years (range, 65–87), 65.6% of pts had low/intermediate simplified MIPI, and 8.6% had blastoid/pleiomorphic histology. At the primary analysis, median follow up was 84.7 months. The primary endpoint was met as PFS was significantly improved in the Ibr arm vs the Pbo arm (hazard ratio, 0.75; one-sided P = 0.011). Median PFS was 80.6 months with Ibr in combination with BR and R maintenance, a 50% improvement over Pbo in combination with BR and R maintenance (median PFS of 52.9 months). The complete response rate was 65.5% in the Ibr arm and 57.6% in the Pbo arm ( P = 0.0567). There was no difference in overall survival between treatment arms ( P = 0.648). Time to next treatment was longer in the Ibr arm compared with the Pbo arm ( P < 0.001). Fifty-two (19.9%) and 106 (40.5%) pts received subsequent anti-lymphoma therapy in the Ibr and Pbo arms, respectively; 41/106 (38.7%) received a second-line BTKi in the Pbo arm. Rates of grade 3 or 4 treatment-emergent adverse events were 81.5% and 77.3% in the Ibr and Pbo arms, respectively. Of adverse events of clinical interest for BTKis, atrial fibrillation was reported in 13.9% and 6.5% of pts in the Ibr and Pbo arms, respectively. Rates of major hemorrhage, hypertension, arthralgia, and secondary primary malignancies were similar in both arms. Quality of life was also similar in both arms. Conclusions: This phase III study in untreated MCL demonstrated that Ibr combined with BR and R maintenance significantly improved PFS compared with standard chemoimmunotherapy, with a median PFS of 6.7 years. The safety profile was consistent with the known profiles of the individual drugs. Clinical trial information: NCT01776840.
Abstract
OBJECTIVE
To evaluate the safety and feasibility of combining resection with immediate initiation of radiation and subsequent Stupp protocol in newly-diagnosed glioblastoma (GBM).
BACKGROUND
...Rapid early local progression (REP) after resection, prior to the initiation of EBRT+/-chemotherapy, occurs in 25-50%. This high-rate of REP supports initiation of an effective postoperative treatment as early as safely possible. Bio-resorbable collagen tiles with imbedded cesium-131 radiation sources (Gammatiles™) are FDA cleared for this use. Intraoperatively, tiles are placed within the resection bed, thus achieving an immediate initiation of surgically targeted radiation therapy (STaRT). DESIGN/
METHODS
GESTALT is a single-arm 61 patient multi-center trial. Consented adults with suspected or confirmed GBM undergo a maximum safe resection with Gammatile™ (STaRT). Patients with molecular GBM (WHO 2021 criteria) start concurrent EBRT/Temozolomide beginning 25±4 days post-surgery. Subsequent EBRT (20 fractions, 4 weeks) to low and high-risk PTV takes Gammatile™ dose into account to a combined biologically equivalent dose of 46 and 60 Gy delivered in 2Gy/fraction, respectively. Adjuvant TMZ (6 cycles) begins 28±7 days after EBRT/Temozolomide. TTF is allowed. IDH-mutated gliomas are followed for safety. Outcomes include feasibility of incorporating Gammatile™ without delay of Stupp protocol, consent/attrition rates, safety, performance status trajectory (ECOG, KPS), immune competence (absolute lymphocyte counts), local control, PFS, and OS.
RESULTS
The trial opened in Fall 2022 at 4 sites. 12 additional sites are onboarding (NCT05342883). 16 patients are on trial as of abstract submission. Currently, this trial appears feasible and without any unexpected intolerances/toxicities.
CONCLUSIONS
This is the first trial in newly diagnosed GBM patients to combine resection, Gammatile™, and the Stupp protocol, in an attempt to reduce REP, as well as possibly, improve other outcomes.
RESULTS
will inform the routine and investigational use of Gammatile™, and if suggestive, will form the basis for a subsequent randomized trial.
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