Pinnacle Oncology Hematology

Aim: The availability of long-term (>2years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3yearsafter device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant(1776completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3years was 7.6% (n=98). Of these, 32subjects (2.5%) indicated inadequate pain relief as cause for removal. Implantsite infection (11 events) was the most common device-related serious adverse event(<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration: NCT01719055 (ClinicalTrials.gov).

Abstract Introduction. Triple negative breast cancer (TNBC) has a poor prognosis and limited treatment options. Atezolizumab (atezo) is a humanized mAb that inhibits the binding of PD-L1 to PD-1 and B7.1, thus restoring tumor-specific T-cell immunity. Atezo was evaluated in an expansion cohort of mTNBC patients (pts) in a Phase Ia study (NCT01375842). Methods. Enrollment was initially limited to TNBC pts with PD-L1 on ≥5% of tumor-infiltrating immune cells (IC2/3), then opened to pts regardless of PD-L1 status. Pts received atezo IV in 1L or 2L+ q3w at 15 or 20 mg/kg or 1200 mg for 1 y with option to be retreated at PD, or until loss of clinical benefit. ORR was assessed by RECIST v1.1 and irRC, to capture non-conventional responses. Baseline PD-L1 expression on IC was centrally scored as IC0/1/2/3 (VENTANA SP142 assay). Pretreatment tumors and on-therapy biopsies were evaluated for TILs, CD8 T cells and macrophages by IHC. Results. As of Mar 31, 2016, 115 mTNBC pts were safety evaluable; atezo was generally well tolerated. There were no additional safety signals from prior report (Emens AACR 2015). 112 pts with FU ≥12 wk were evaluable for response. Based on irRC, ORR in 1L and 2L+ pts were 26% and 11%, respectively. ORR for PD-L1 IC2/3 pts were 17% vs 8% in IC0/1. mDoR was 21.1 mo (3 to 34+). mOS of responders (n=15) was not reached (4+ to 37+ mo) with no deaths as of data cutoff. mOS of non-responders who lived ≥ 6 wk (n=87) was 9 mo (1+ to 19+ mo). OS rates in all pts at 1, 2, and 3 y were 41%, 22% and 22%, respectively. OS rates at 1, 2, and 3 y for PD-L1 IC2/3 were 45%, 28% and 28%, respectively. Pts whose tumors had &amp;gt;10% TILs or ≥1.35% CD8 in the tumor center trended toward higher ORR and longer OS. Atezo increased intratumoral TILs, CD8, macrophages and IC PD-L1 expression, but no response association was observed. Conclusions. In mTNBC, atezo was well tolerated. Responders showed durable clinical benefit. Response rates were higher in 1L or PD-L1 IC2/3 pts. Baseline TILs and CD8 were associated with greater clinical benefit. Table.EfficacyResponses per RECIST v1.1 (irRC efficacy results presented in text)1L2L+PD-L1 IC2/3PD-L1 IC0/1Alln = 19n = 93n = 71n = 37N = 112ORR, % (95%CI)26% (9, 51)7% (2, 14)13% (6, 23)5% (1, 18)10% (5, 17)CR, n21303PR, n35628SD, n31210415CBR, %42%19%27%16%23%Median (range) DoR, mo21 (8+ to 26+)NE (3 to 13+)21 (3 to 26)NE (10 to 10+)21 (3 to 26+)OS1L2L+PD-L1 IC2/3PD-L1 IC0/1All ptsn = 19n = 94n = 71n = 38N = 1131 y OS (95% CI)63% (37, 89)37% (26, 47)45% (32, 58)37% (21, 53)41% (31, 51)2 y OS (95% CI)47% (14, 80)18% (8, 27)28% (15, 41)NE22% (12, 32)3 y OS (95% CI)NE18% (8, 27)28% (15, 41)NE22% (12, 32)CBR; clinical benefit rate, defined as CR, PR or SD for ≥12 weeks. DoR, duration of response; NE, not evaluable.+, censored. Citation Format: Peter Schmid, Cristina Cruz, Fadi S. Braiteh, Joseph Paul Eder, Sara Tolaney, Irene Kuter, Rita Nanda, Cathie Chung, Philippe Cassier, Jean-Pierre Delord, Michael Gordon, Yijin Li, Bo Liu, Carol O’Hear, Marcella Fasso, Luciana Molinero, Leisha A. Emens. Atezolizumab in metastatic TNBC (mTNBC): Long-term clinical outcomes and biomarker analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2986. doi:10.1158/1538-7445.AM2017-2986

4504 Background: Combining an immune checkpoint inhibitor with a targeted antiangiogenic agent may leverage complementary mechanisms of action for treatment of aRCC. Avelumab is a fully human anti–PD-L1 IgG1 antibody with clinical activity in various tumor types; axitinib, a VEGF receptor inhibitor, is approved for second-line treatment of aRCC. JAVELIN Renal 100 (NCT02493751) is a phase Ib study evaluating safety and clinical activity of avelumab + axitinib in treatment-naïve pts with aRCC; updated results are reported here. Methods: Eligible pts had confirmed clear-cell aRCC, ≥1 measurable lesion, fresh or archival tumor specimen, ECOG PS ≤1, and no prior systemic therapy. Pts received avelumab 10 mg/kg IV Q2W + axitinib 5 mg orally BID until progression, unacceptable toxicity, or withdrawal. Endpoints included safety (NCI CTCAE v4.03) and objective response (RECIST v1.1). Results: As of Dec 30, 2016, 55 pts (median age 60.0 yrs [range 42.0–76.0]; 76.4% male; 34.5% ECOG PS = 1) were enrolled. 54 pts were treated with avelumab for a median of 24.1 wks (range 2.0–62.0); 55 pts were treated with axitinib for a median of 25.3 wks (range 3.0-61.0). 51 pts (92.7%) had an avelumab-related adverse event (AE) with the therapy combination, the most common (≥30% any grade) were fatigue and diarrhea (30.9% each). 10 pts (18.2%) had a max grade 3 and 1 pt (1.8%) had a max grade 4 avelumab-related AE. 52 pts (94.5%) had an axitinib-related AE with the therapy combination; the most common (≥30% any grade) were diarrhea (52.7%), hypertension (45.5%), dysphonia (43.6%), and fatigue (43.6%). 24 pts (43.6%) had a max grade 3 and 5 pts (9.1%) had a max grade 4 axitinib-related AE. 2 deaths occurred in the study during the reporting period: 1 due to progression and 1 related to both treatments (myocarditis). An AE led to discontinuation of avelumab in 5 pts (9.1%) and axitinib in 4 pts (7.3%). Confirmed ORR was 54.5% (95% CI 40.6–68.0) based on 2 CR and 28 PR. Unconfirmed ORR was 60.0% (95% CI 45.9–73.0). Conclusions: The safety profile of the combination of avelumab + axitinib appears manageable and consistent with those agents administered as monotherapy, and early encouraging antitumor activity was observed. Follow-up is ongoing. Clinical trial information: NCT02493751.

3055Background: Avelumab* is a fully human anti-PD-L1 IgG1 antibody showing preliminary efficacy in multiple tumor types. We report updated safety data of single-agent avelumab in patients (pts) wi...

e14119Background: Dabrafenib (DAB) is a BRAF inhibitor approved at a dose of 150 mg twice daily (BID) for treating unresectable or metastatic BRAF V600E/K–mutant melanoma with or without trametinib...

8029 Background: NSCLC exhibits mutational complexity, which is associated with increased tumor immunogenicity. PD-L1 expression in the tumor microenvironment can inhibit antitumor immunity. MPDL32...

To evaluate the safety and maximum tolerated dose (MTD) of afatinib combined with nintedanib. Patients received afatinib 10-20 mg daily plus nintedanib 150-200 mg twice daily (28-day cycle). Dose escalation followed a 3+3 design. Patients received afatinib/nintedanib: 10/150 mg (n = 11); 10/200 mg (n = 13; MTD); 20/200 mg (n = 4). Four patients had dose-limiting toxicities (all grade 3): increased alanine aminotransferase (afatinib/nintedanib: 10/150 mg), diarrhea (10/200 mg), dehydration (20/200 mg), diarrhea with elevated liver enzymes (20/200 mg). Frequent treatment-related adverse events were diarrhea, nausea, anorexia, fatigue and vomiting. In total, 14 patients (46.2%) had objective responses at the MTD. The MTD, afatinib 10 mg daily plus nintedanib 200 mg twice daily, had a manageable safety profile, but was considered subtherapeutic for Phase II evaluation.

Abstract Background: TRC105 is an anti-endoglin chimeric monoclonal antibody that inhibits angiogenesis and tumor growth and is being studied in randomized Phase 2 trials with Bev. TRC105 is cleared through binding to endoglin expressed on proliferating endothelium when given as a single agent to cancer patients (Spencer et al, ASCO 2012). Preclinical data indicate that endoglin expression is increased in response to VEGF targeted treatment, and increased endoglin expression in response to Bev may increase the clearance of TRC105 when administered in combination to cancer patients. Methods: Patients (pts) with solid tumors (ST) or ovarian cancer (OC) received 10 mg/kg/wk TRC105 as a single agent, and additional patients with ST (primarily ovarian and colorectal) received 10 mg/kg/wk TRC105 with Bev. Peak and trough levels were assessed by ELISA in 39 patients who received TRC105 alone and compared to that of 35 patients (largely Bev refractory) who received TRC105 and Bev. Pts administered TRC105 and Bev were considered a population sub-group and treated as a covariate. A population pharmacokinetic model of TRC105 disposition was built using rich sampling from the ST trial, with sparse data from OC and TRC105+Bev included in the base model. A two-compartment model with nonlinear elimination best fit the data, utilizing Michaelis-Menten parameters for saturable clearance. Results: TRC105 peak and trough concentrations exceeded target serum concentrations of TRC105 known to saturate endoglin receptors in all pts dosed with 10 mg/kg/wk of TRC105 with and without Bev. The PK of TRC105 given with Bev had mean predicted (following 10,000 simulations) parameters of volume of distribution in the central compartment (VC), VMAX, and KM that were increased compared to population estimated parameters of TRC105 given as a single agent [VC= 44.5±2 (SE) (mL/kg) Pop mean estimate vs. 68.8±4 (mL/kg) Bev predicted; VMAX = 92.6±16 (μg/hr) vs. 297.5±40 (μg/hr) predicted, and KM= 5.91±2 (μg/mL) vs. 61.6±8.8 (μg/mL)]. All differences were significant (p&amp;lt;0.001). Observable data from patients administered the combination yielded PK parameters that were consistent with increased target-mediated clearance of TRC105 when given with Bev. Conclusions: Peak and trough TRC105 serum levels exceed target serum concentrations when given at 10 mg/kg/wk as a single agent or with Bev. Central compartment distribution of TRC105 increased when given with Bev, which is consistent with increased endoglin expression on proliferating endothelium following Bev treatment. The maximum rate of elimination (Vmax) also increased, consistent with increased turnover; however the intrinsic clearance ratio of Vmax/Km remained the same, suggesting no change in endoglin turnover efficiency. Future studies will assess whether PK parameters correlate with responses to the combination of TRC105 and Bev in Bev refractory patients. Citation Format: Shawn D. Spencer, Lee S. Rosen, Michael S. Gordon, Francisco Robert, Daniela Matei, Cody J. Peer, Bonne Adams, Delia Alvarez, Ben K. Seon, Charles P. Theuer, W. Douglas Figg. Differences in pharmacokinetics of TRC105 (anti-endoglin antibody) when administered as a single agent versus in combination with bevacizumab (Bev). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT222. doi:10.1158/1538-7445.AM2014-CT222