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176
Background: AA is a standard of care for the treatment of metastatic CRPC, with an approximate retail cost of $8000/month. Despite a large food effect (~17-fold increase in C
Max
...with a high-fat meal), AA was administered under fasting conditions in its pivotal trials. There are no randomized continuous dosing studies examining prandial state dosing on AA PK/PD. We sought to test the hypothesis that LOW (250mg w/food) would have similar PK/PD and safety to standard (STD, 1000mg fasting) in patients with progressive CRPC. Methods: Patients (n = 72) with progressive CRPC from seven institutions in the US and Singapore were randomized to treatment with STD or LOW (with low-fat breakfast). Both arms received prednisone 5mg twice daily. PSA was assessed monthly, and testosterone, DHEA/DHEAS were assessed every 12 weeks along with standard disease burden assessments. PK samples were collected at day 1, 8 and months 2, 3, 4. Log change in PSA response rate from baseline to week 12 was examined as the primary endpoint, with a non-inferiority design based on a non-inferiority margin of 15%. This margin corresponds to a 0.51 standard deviation (SD) difference in the mean log changes between the groups. Results: Accrual was completed with n = 36 on STD and n = 36 on LOW. Median (range) age was 74 (52-89) and baseline PSA was 39.2(range 0.6-1789). Mean log-change in PSA at 12 weeks was nominally greater in the LOW arm (-1.59 vs. -1.19). The 95% confidence for the difference (STD-LOW) ranged from -0.40 to 1.19, with lower limit corresponding to -0.24SD. Thus, non-inferiority of LOW was established. Median time to PSA progression was ~14 month in both arms (p = 0.53). Preliminary analysis of PK showed no difference in C
Max
beyond the first cycle with lower PK variability in the LOW arm. Conclusions: Low-dose (250mg/day) abiraterone acetate with a low-fat breakfast is non-inferior to standard dosing in a fasted state with respect to PSA and PK metrics. Although PSA response and progression are not clinically validated surrogates, given the pharmacoeconomic implications, these data warrant consideration by prescribers and payors. Clinical trial information: NCT01543776.
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25
Background: Suboptimal adh to drugs is a problem in chronic diseases. In mRCC, OAMs are the mainstay of treatment (tx). Adh and its determinants in exclusively mRCC pts has not been ...studied in the US. This study aimed to evaluate adh to OAMs in mRCC pts, and describe pts understanding and beliefs about OAMs and their disease. Methods: Cross-sectional study of pts on OAMs for at least 60 days. Standardized assessment instruments used: Adh—MMAS-8 questionnaire (Q); beliefs and expectations regarding OAMs—Beliefs about Medicines Q (BMQ) and Brief-Illness Perception Q (IPQ); Quality of Life (QOL)—BSI-18, FKSI. Semi-structured interviews assessed financial burden, barriers to adh, understanding of prognosis and goals of therapy. Results: 52 pts interviewed with median age 65 (range 36-90), 73% male, 71% Caucasian, 40% college graduates. OAMs used: 38% sunitinib, 31% pazopanib, 21% everolimus, 8% axitinib. 1
st
line OAM tx: 46%; 2
nd
line tx: 33%; 3
rd
or beyond: 21%. MMAS-8: 10% low adheres, 25% intermediate, 65% high. Income: 35%<40K, 24%=40-60K, 41%>60K. Adh decreased as income increased across the 3 income levels from 82% to 67% to 45% (P=0.02). 13% reported financial difficulty paying for OAMs; 19% had ≥ $100/mo (0-500) out-of-pocket (OOP) cost. BMQ-N: 20 ± 4 (8-25); BMQ-C: 12 ± 4 (5-24). IPQ: 40 ± 12 (6-71). QOL: BSI 9 ± 8 (0-38); FKSI 43 ± 8 (21-60). No significant difference between adherers and non-adherers in regard to demographic, QOL, OOP costs or belief variables was noted. 29% reported not receiving counseling on taking OAMs. 59% believed mRCC is a chronic disease, 41% believed that their OAM can cure them and strongly agreed or agreed with “I expect to be free of cancer in the future.” 48% reported discussing prognosis with their MD. Conclusions: Self-reported adh to OAMs in mRCC is much better than in other chronic diseases, but not ideal. Surprisingly, adherence was negatively associated with income. Many pts felt mRCC was a chronic disease and over 40% believed they could be cured. Further research is needed addressing the development of an oncology-specific adh tool and defining an optimal adh benchmark for OAMs via prospective studies of self-reported adh, serum drug levels, and outcomes.
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4505
Background: While inhibiting VEGF improves outcomes in mRCC pts, most develop resistance, often within a year. Here, we report results from a Ph II study of atezo (anti–PD-L1) and ...bev (anti-VEGF) vs and following atezo or sun (TKI) in mRCC pts. Methods: Pts with untreated mRCC were enrolled in the hypothesis generating IMmotion150 study (NCT01984242) and randomized to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w, atezo alone or sun 50 mg PO QD 4 wk on/2 wk off. After progression on atezo or sun, crossover to atezo + bev was allowed. PD-L1 status was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). The primary analysis was modified prior to final analysis to reflect the coprimary endpoints of IRF-assessed PFS (RECIST v1.1) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: 54% of pts were PD-L1+. In PD-L1+ pts 1L treatment resulted in a PFS hazard ratio (HR) of 0.64 for atezo + bev vs sun (table). After 1L treatment, 78% of sun and 60% of atezo pts who progressed subsequently received atezo + bev and achieved ORRs of 28% and 24%, respectively (table). Safety was comparable to the known individual profiles of atezo and bev. Additional clinical, safety and biomarker data will be presented. Conclusions: Atezo + bev resulted in encouraging antitumor activity in 1L pts with PD-L1+ mRCC. Preliminary activity in the 2L setting was demonstrated in pts who crossed over to atezo + bev, regardless of prior therapy. 1L atezo + bev vs sun is being evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242. Table: see text
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431
Background: While targeting VEGF improves outcomes for mRCC pts, resistance invariably develops, often within the first year. Here, we describe the efficacy and safety of atezo ...(anti-PD-L1) with bev (anti-VEGF) and atezo monotherapy vs sun (TKI) in first-line mRCC. Methods: Treatment-naïve mRCC pts were enrolled in a hypothesis generating Ph II study (IMmotion150; NCT01984242) and randomized to atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w, atezo alone or sun 50 mg PO QD 4 wk on/2 wk off. Crossover to atezo + bev after disease progression was allowed for pts receiving atezo or sun. PD-L1 expression was scored on tumor-infiltrating immune cells (IC, SP142 IHC assay). Coprimary endpoints were PFS (RECIST v1.1 by independent review IRF) in ITT pts and pts with PD-L1 expression on ≥ 1% of IC (PD-L1+). Results: Baseline characteristics were comparable across arms and between ITT and PD-L1+ pts. The majority of sun and atezo pts subsequently received atezo + bev. Median survival follow up was 20.7 mo. The PFS HR in ITT pts for atezo + bev vs sun was 1.00 and 1.19 for atezo vs sun. In PD-L1+ pts, the PFS HR for atezo + bev vs sun was 0.64 and 1.03 for atezo vs sun (table). Tx-related Gr 3-4 AEs were seen in 40%, 16% and 57% of pts in the atezo + bev, atezo and sun arms, respectively. AEs leading to death occurred in 3%, 2% and 2% of pts, respectively. Conclusion: Atezo + bev resulted in encouraging antitumor activity in the PD-L1+ subgroup of first-line RCC pts. Atezo + bev safety is consistent with the known profile of atezo and bev individually. The clinical benefit of atezo + bev vs sun will be evaluated in the ongoing Ph III study IMmotion151 (NCT02420821). Clinical trial information: NCT01984242. Table: see text
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43
Background: Prostate cancer management is influenced by how one views prostate cancer progression and how one calculates the risk of prostate cancer metastases and death. Currently ...this is based largely on histologic appearance, or Gleason score. Cancers with a Gleason score of 6 exhibit indolent behavior and are often considered low risk. NCCN guidelines endorse surveillance for many of these tumors. Malignancies with a Gleason score of 8-10 exhibit aggressive behavior and are considered high risk. Methods: Prostate cancer is usually multifocal, and these concurrent foci are often histologically distinct. In this study the molecular relationship between a Gleason 6 focus and a concurrent Gleason 8 or higher focus was determined for four subjects. In two subjects a lymph node metastasis was also examined. Laser capture microdissection was used to isolate these multiple matched foci, and somatic mutations were identified using exome sequencing. Results: We obtained an average of 40-fold median coverage of the exome, with an average high confidence mutation rate of 0.64/Mb, excluding nonsynonymous mutations. Seventy of 80 (0.875) high confidence somatic mutations in low grade disease were private to the low grade foci. For the cases for which a metastatic focus was available, 17 of 79 (0.215) high confidence somatic mutations in the high grade focus were private. Eight of the 79 (0.101) were shared with low grade foci, and 62 (0.785) were shared with metastatic foci. Conclusions: The pattern of shared versus private mutations was consistent with early divergence between Gleason 6 and Gleason 8 or 9 disease, and late divergence between Gleason 8 disease and lymph node metastases. These data support a model of parallel evolution of lower and higher Gleason score disease, rather than progression from Gleason 6 to higher Gleason scores.
