Treatment-naive Pts Research Articles

Abstract PD3-06: Association of intrinsic subtypes with pathological complete response (pCR) in the KRISTINE neoadjuvant phase 3 clinical trial in HER2-positive early breast cancer (EBC)

Abstract Introduction: Previous studies have shown that HER2+ breast cancer is biologically heterogenous and intrinsic subtypes can be identified (luminal A, luminal B, HER2-enriched [HER2-E] and basal-like). HER2-E predominates and is associated with higher response rates following anti-HER2-based chemotherapy or dual HER2 blockade (only with lapatinib and trastuzumab). We explored the ability of intrinsic subtypes to predict pCR in pts treated with anti-HER2 neoadjuvant therapy. Methods: KRISTINE (NCT02131064) is an open-label, phase 3 study of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1+P) vs docetaxel + carboplatin + trastuzumab + pertuzumab (TCH+P) in pts with HER2+ EBC. Treatment-naive pts with stage II–IIIC HER2+ EBC were randomized to receive 6 cycles of T-DM1+P or TCH+P and assessed for the primary endpoint, pCR (ypT0/is, ypN0). HER2 and hormone receptor (HR) status were centrally assessed. Gene expression (RNA) was assessed by a custom 800-gene codeset on the nCounter platform. Intrinsic subtypes were assessed with the research-based PAM50 classifier. Results: KRISTINE randomized 444 pts (data cutoff, Dec 3, 2015; TCH+P, n=221; T-DM1+P, n=223). PAM50 results were available for 354 pts (79.7% of the intent-to-treat [ITT] population). Baseline characteristics and efficacy in the PAM50 population were similar to that of the ITT population. The HER2-E subtype represented 54.8% of the samples (Table 1). Differences were observed by HR status. Almost all luminal tumors (131/132) were identified within HR+ disease. Of HR+ tumors, 32% were identified as HER2-E. In the TCH+P arm, the pCR rate was 72.1% for HER2-E vs 32.8% in the other subtypes combined (Table 2.) In the T-DM1+P arm, the pCR rate was 62.2% for HER2-E vs 26.9% in the other subtypes combined. No major differences were observed in pCR rates within the HER2-E subtype according to HR status. Further multivariable analyses assessing differences between treatment arms and treatment benefit across subtypes is ongoing. Table 1. Intrinsic subtypesn (%)ITT (n=354)HR- (n=143)*HR+ (%) (n=200)*HER2-E194 (54.8)123 (86.0)64 (32.0)Luminal A60 (16.9)1 (0.7)57 (28.5)Luminal B74 (20.9)074 (37.0)Basal-like26 (7.3)19 (13.3)5 (2.5)*Central HR status unknown for n=11 Table 2. pCR by intrinsic subtype TCH+PT-DM1+P npCR, n (%)npCR, n (%)pCR difference (95% CI)HER2-E10475 (72.1)9056 (62.2)-9.89 (-23.11, 3.32)HER2-E and HR+ *3724 (64.9)2715 (55.6)-9.31 (-33.56, 14.94)HER2-E and HR- *6448 (75.0)5937(62.7)-12.29 (-28.56, 3.98)Other subtypes combined6722 (32.8)9325 (26.9)-5.9 (-20.36, 8.45)Luminal A254 (16.0)3510 (28.6)12.57 (-8.18, 33.32)Luminal B3211 (34.4)4212 (28.6)-5.80 (-27.19, 15.58)Basal-like107 (70.0)163 (18.8)-51.25 (-85.49, -17.01)*Central HR status unknown for n=7 Conclusions: In this analysis from the KRISTINE study, HER2-E was the most common intrinsic subtype and was associated with the highest pCR rate with both regimens. Results are consistent with previous findings. The luminal A and B subtypes were well associated with HR+ status. A sizeable subgroup of the HER2-E subtype was HR+ (32%), and pCR rates within the HER2-E subtype seemed independent of HR status. Citation Format: Prat A, Slamon D, Hurvitz SA, Press MF, Lewis Phillips G, Lopez Valverde V, Kiermaier A, Helms H-J, Martin M, de Haas SL. Association of intrinsic subtypes with pathological complete response (pCR) in the KRISTINE neoadjuvant phase 3 clinical trial in HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-06.

Preliminary findings from part 1 of COMBI-i: A phase III study of anti–PD-1 antibody PDR001 combined with dabrafenib (D) and trametinib (T) in previously untreated patients (pts) with advanced BRAF V600-mutant melanoma.

189 Background: Checkpoint inhibitors and targeted therapies have improved outcomes in pts with advanced BRAF V600–mutant melanoma; however, many still progress and die from this disease. Thus, new treatment strategies are needed. BRAF and MEK inhibitor combinations (eg, D+T) may reverse immunosuppressive phenotypes induced by oncogenic BRAF and improve sensitivity to checkpoint inhibitors by enhancing HLA and melanocytic antigen expression and tumor antigen–specific T-lymphocyte recognition. Methods: The phase 3 COMBI-i study (NCT02967692) is evaluating the anti–PD-1 antibody PDR001 in combination with D+T in treatment-naive pts with BRAF V600–mutant unresectable or metastatic melanoma in 3 parts: 1, safety run-in; 2, biomarker cohort; and 3, randomized, double-blind, placebo-controlled part. Here we report preliminary findings for 9 pts in part 1 dosed with PDR001 400 mg Q4W + D 150 mg BID + T 2 mg QD. Response was assessed at wk 12 and Q8W thereafter. Results: At data cutoff (16 Jul 2017; median follow-up, 2.7 mo), all 9 pts completed the 8-wk dose-limiting toxicity (DLT) period, during which 1 DLT (transaminitis [AST and ALT > 8 × ULN]; n = 1) occurred. Adverse events (AEs) of any grade occurring in > 3 pts included pyrexia (n = 9), headache (n = 6), chills (n = 4), and vomiting (n = 4). Grade 3/4 AEs reported in > 1 pt included hepatitis (n = 3), increased lipase (n = 2), and increased transaminases (n = 2). AEs leading to discontinuation occurred in 2 pts (22%; transaminitis, n = 1; grade 3 hepatitis, n = 1) who permanently discontinued PDR001 but were still receiving D+T at the data cutoff. All 9 pts responded: 3 (33%) achieved a complete response (confirmed, n = 1), and 6 (67%) had partial responses (confirmed, n = 1). Additional safety and efficacy results for these 9 pts, all ongoing at the data cutoff, will be presented. Conclusions: These preliminary results indicate that PDR001 can be combined with D+T with a manageable safety profile and demonstrate promising activity in pts with BRAF V600–mutant melanoma. Clinical trial information: NCT02967692.

GMI-1271 Improves Efficacy and Safety of Chemotherapy in R/R and Newly Diagnosed Older Patients with AML: Results of a Phase 1/2 Study

Background Binding of E-selectin (E-sel), an adhesion molecule expressed in the vasculature of the bone marrow, to sialyl Lex on the leukemic cell surface activates cell survival pathways and promotes chemotherapy resistance in AML. GMI-1271 is a novel E-selectin antagonist that disrupts activation of cell survival pathways, enhances chemotherapy response with improved survival in mouse xenograft and syngeneic models and protects from chemotherapy toxicity in vivo (Becker 2013; Winkler 2013, 2014, 2016). We added GMI-1271 to salvage with MEC for relapsed/refractory AML patients or to induction with 7+3 for older treatment naive (TN) AML patients. Methods A Phase (Ph) 1 trial escalated GMI-1271 (5-20 mg/kg) combined with MEC (mitoxantrone, etoposide, cytarabine) in pts with R/R AML, to evaluate safety, tolerability and anti-leukemic activity. Dose limiting toxicity (DLT) was defined as persistent cytopenias in the absence of disease or any Grade 3-5 non-hematologic toxicity beyond day 42. The recommended Ph 2 dose (RP2D) of GMI-1271 was 10 mg/kg. A Ph 2 study then enrolled 47 pts with R/R AML for GMI-1271 plus MEC chemotherapy. Responders could receive 1 cycle of consolidation with GMI-1271 plus MEC. We also enrolled a separate Ph 2 cohort of 25 pts ≥60 yrs with TN AML for GMI-1271 (10 mg/kg) plus cytarabine and idarubicin (7+3). Two cycles of induction were allowed. Responders could receive 3 cycles of consolidation with GMI-1271 plus intermediate dose cytarabine. Prior treatment of MDS was allowed; for R/R disease prior SCT was allowed. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post chemotherapy. E-sel ligand expression on leukemic blasts in blood and bone marrow was assessed by flow cytometry, for the percentage of blasts binding to E-sel-Fc chimera and HECA452 (antibody to sialyl Lex). Results 91 pts were enrolled (Ph 1 R/R=19; Ph 2 R/R=47, TN=25). Median age for R/R pts was 59 yrs (range 26-84) and 62% were males. Prior AML history included 32% primary refractory, 33% CR1 Median age for TN pts was 67 yrs (range, 60-79) 56% were males, and 32% had high-risk CG. 56% had secondary AML (sAML), 43% of sAML had prior hypomethylating therapy. GMI-1271 was well tolerated, adverse events were typical for AML induction in the TN population, and Grade 3/4 mucositis was not seen. 30 and 60 d mortality were 8 and 12%, respectively; two deaths were from sepsis before response assessment and one involved persistent disease. Median time to ANC 500 was 28d (range 21-63). 8 pts required two induction courses, and 4 (16%) proceeded to SCT by data cut-off. The CR/CRi rate was 68% (73% for de novo and 64% for sAML) and ORR was 80%. Median OS and DFS are not yet reached; median follow up is 6 mos. Median E-sel ligand expression (binding to HECA452) at baseline was 31% (range, 2-92%) of bone marrow blasts. Conclusion The addition of GMI-1271 to chemotherapy was well tolerated with high remission rate, low induction mortality, and low rate of mucositis suggesting improved tolerance of chemotherapy. In R/R AML, correlative studies showed blasts expressing the E-sel ligand were predictive of response. Initial survival outcomes are promising and updated survival outcomes will be presented at ASH. FDA granted Breakthrough Therapy Designation to GMI-1271 for treatment of adults with R/R AML and randomized trials are planned. Disclosures DeAngelo: Amgen: Consultancy, Research Funding; BMS: Consultancy; Immunogen: Honoraria, Research Funding; Celgene: Research Funding; ARIAD: Consultancy, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Glycomimetics: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals U.S.A., Inc.: Honoraria; Shire: Honoraria; Pfizer Inc.: Consultancy, Honoraria, Research Funding. Jonas: Celgene: Membership on an entity9s Board of Directors or advisory committees; AbbVie, Celgene, Daiichi Sankyo, Pharmacyclics, Genentech/Roche, Glycomimetics, Esanex, Kalobios: Research Funding; Rigel: Consultancy. Liesveld: Seattle Genetics: Honoraria; Onconova: Honoraria. Advani: Pfizer: Consultancy; Takeda/ Millenium: Research Funding. O9Dwyer: Onkimmune Ltd: Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties; GlycoMimetics Inc: Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Magnani: GlycoMimetics, Inc.: Employment, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees. Thackray: GlycoMimetics, Inc.: Employment, Equity Ownership. Becker: GlycoMimetics, Inc.: Research Funding.

Abstract CT074: Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC)

Abstract Background: NIVO (anti-PD-1) is approved for the treatment of several cancers including advanced melanoma, but its efficacy in other types of skin cancer has not yet been evaluated. MCC is a rare and aggressive form of skin cancer, with most tumors being associated with the Merkel cell polyomavirus. MCCs frequently express PD-L1, and MCC-reactive T cells express PD-1. Methods: In CheckMate 358 (NCT02488759), patients (pts) with 5 types of advanced virus-associated cancers who had received ≤2 prior therapies, with an ECOG PS of 0-1, were eligible to receive NIVO 240 mg Q2W until progression or unacceptable toxicity. Key exclusion criteria were active brain metastases, autoimmune disease, hepatitis, and HIV infection. Primary endpoints included objective response rate (ORR by RECIST v1.1) and safety; secondary endpoints were duration of response, progression-free survival (PFS), and overall survival (OS). Twenty-five pts with MCC were treated with a median follow-up of 26 wks (range: 5-35). Results: Among 25 treated pts, median age was 66 yrs, 68% were male, and 60% were treatment-naive; 12 of 18 (67%) tested tumors were virus-positive. In 22 response-evaluable pts, ORR was 68% (table) with ongoing responses in 13 of 15 (87%) pts. Responses occurred in treatment-naive pts (71%), in pts with 1-2 prior systemic therapies (63%), and in both virus-positive and virus-negative tumors; 67% of responses occurred at ~8 weeks. At 3 months, PFS and OS rates were 82% and 92%, respectively. Treatment-related adverse events of any grade and grade 3/4 occurred in 68% and 20% of pts; 12% of pts had treatment-related AEs that led to NIVO discontinuation. Response to treatmentResponse-evaluable pts (N=22)Treatment-naive pts (n=14)Pts with 1-2 prior systemic therapies (n=8)Best overall response – n (%)Complete response3 (14)3 (21)0Partial response12 (55)7 (50)5 (63)Stable disease4 (18)3 (21)1 (13)Progressive disease3 (14)1 (7)2 (25)ORR – % (95% CI)68 (45–86)71 (42–92)63 (25–92)Time to response, months; median (range)2.0 (1.8–5.3)––Duration of response, months; median (range)Not reached (0.0–5.6)–– Conclusions: NIVO induces rapid and durable tumor regressions in the majority of treatment-naive and treatment-experienced pts with advanced MCC, with a manageable safety profile. Updated clinical response and biomarker data will be presented. Citation Format: Suzanne L. Topalian, Shailender Bhatia, Antoine Hollebecque, Ahmad Awada, Jan Paul De Boer, Ragini R. Kudchadkar, Anthony Goncalves, Jean-Pierre Delord, Uwe M. Martens, Jose Maria Lopez Picazo, Ana Oaknin, William C. Spanos, Raid Aljumaily, William H. Sharfman, Shangbang Rao, Ibrahima Soumaoro, Alexander Cao, Paul Nghiem, Dirk Schadendorf. Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC) [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 CT074. doi:10.1158/1538-7445.AM2017-CT074

EFFECT OF SINGLE‐AGENT IBRUTINIB ON TUMOR DEBULKING AND REDUCTIONS IN TUMOR LYSIS SYNDROME (TLS) RISK IN PATIENTS (PTS) WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Introduction: Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the EU for the treatment of CLL. Ibr results in rapid reduction in lymphadenopathy, often accompanied by early, transient lymphocytosis. Venetoclax (ven) received FDA accelerated approval for relapsed del17p CLL and EMEA conditional approval for relapsed CLL and has noteable risk of TLS that is associated with increased disease bulk defined by absolute lymphocyte count (ALC) and lymph node (LN) diameter. Translational studies suggest synergistic anti-tumor activity of ibr plus ven. We assessed how ibr lead-in may reduce TLS risk for ven in considering this combination. Methods: Data from 3 single-agent ibr (420 mg once daily until PD/intolerance) studies in CLL/SLL were analyzed (N = 424): PCYC-1102 in relapsed/refractory (R/R) pts (n = 67) and treatment-naïve (TN) pts ≥65 y (n = 27); RESONATE (PCYC-1112) in R/R pts (n = 195); and RESONATE-2 (PCYC-1115) in TN pts ≥65 y excluding del17p (n = 135). TLS risk categories were defined per ven USPI (Table 1). First CT response assessment occurred on day 56 (PCYC-1102), 78 (RESONATE), and 113 (RESONATE-2). Results: Approximately, 80% of pts were moderate or high risk for TLS at baseline (Table 1). Baseline largest diameter of LN (LDi) ≥5 cm was more common in R/R vs TN pts. In both groups, the proportion of pts with LDi ≥5 cm decreased at first CT assessment (Table 1). Bulky disease resolved to LDi <5 cm in 90% of TN and 85% of R/R pts with baseline LDi ≥5 cm. Median baseline ALC was higher in TN pts vs R/R pts (49 vs 21 × 109/L). ALC initially increased in many pts, but decreased with continued ibr. During ibr therapy, 87% of TN and 45% of R/R pts with high-risk TLS at baseline were reduced to low risk, and the majority of moderate-risk TLS pts were reduced to low risk (Table 1). At first assessment, 54% of TN and 45% of R/R pts were moderate risk, and 7% and 14% were high risk, respectively; a minority of pts had increased risk due to transient ALC increase. In RESONATE-2, 82% of TN pts were moderate to high risk for TLS at baseline (32% high-risk); 88% of high-risk TLS was reduced to low risk. At first assessment in RESONATE-2, 50% were moderate risk, and high-risk TLS was reduced to 8%. Conclusions: Our analyses demonstrate that most pts with baseline high-risk TLS were reduced to moderate or low risk at first assessment. This suggests that tumor debulking with ibr lead-in may effectively reduce TLS risk for ven and the intensity of TLS monitoring for ibr + ven in pts with CLL. table here Keywords: chronic lymphocytic leukemia (CLL); ibrutinib; tumor lysis syndrome.

Evaluation of safety and efficacy of ipilimumab and nivolumab (ipi+nivo) combination in patients (pts) previously treated with anti-PD-1 antibodies (PD1): A single-center experience.

e14556 Background: All clinical trials studying ipi+nivo have involved treatment-naive pts. Knowledge about the safety and efficacy of ipi+nivo is limited for pts previously treated with PD1. Methods: Nine pts were retrospectively evaluated and treated with ipi (3 mg/kg) and nivo (1 mg/kg) q3wk for 4 doses followed by maintenance nivo q2wk after progression on PD1 from 10/2014 to 11/2016. Data regarding clinical history, treatment response, and toxicity were collected. Results: Six pts had advanced melanoma, 2 pts had metastatic HNSCC (mHNSCC), and 1 pt had recurrent parotid myoepithelial carcinoma. Age ranged from 44 to 86. Eight pts had ECOG PS 0-1; 1 pt had ECOG PS 2. Three melanoma pts were BRAF+; 1 was BRAF WT and 2 were NRAS+. Both mHNSCC pts were p16+. Pts received a median of 3 prior lines of treatment including chemotherapy and immune treatments encompassing ipi, PD1, 4-1BB agonist, autologous TILs, high-dose IL2, IFN, T-VEC, and TLR8 agonist. All 9 pts received pembro prior to ipi+nivo; 1 pt received both pembro and nivo separately. Median number of PD1 doses prior to ipi+nivo was 10 (range 3-13). All 9 pts received all 4 doses of ipi+nivo without delay. Seven pts received nivo maintenance for median number of 11 cycles (range 1-22). Two pts were unable to receive nivo maintenance due to progressive disease (PD) and instead were treated with ipi+T-VEC and BRAF/MEK inhibition. Objective responses were seen in 6/9 pts (67%) with 2 radiological CRs and 4 radiological PRs. PD was seen in 3/9 pts (33%) including in the 1 pt with ECOG PS 2; all 3 pts died from clinical deterioration unrelated to ipi+nivo treatment. CRs were observed in 1 BRAF+ and 1 NRAS+. 7/9 pts (78%) had ≥1 clinically significant irAE and 3 of these pts required systemic steroids. Five pts are still receiving maintenance nivo with clinical benefit. One pt with CR was taken off nivo maintenance, remains disease-free, and is now on surveillance. Conclusions: Ipi+nivo demonstrated significant anti-tumor activity in pts previously treated with PD1. The toxicity profile is consistent with known irAEs. While this is a small series, these data support the use of ipi+nivo after PD1 failure.

Phase I/III trial of atezolizumab with carboplatin and etoposide in ES-SCLC in first-line setting (IMpower133).

TPS8584 Background: The first-line standard of care for the majority of patients (pts) with extensive-stage small-cell lung cancer (ES-SCLC) is platinum-based chemotherapy with etoposide, but survival outcomes remain poor (median OS, &lt; 1 year) despite initial response rates ranging from 50-70%. Atezolizumab (atezo), an anti–PD-L1 mAb, prevents the binding of PD-L1 with its receptors PD-1 and B7.1 and restores anticancer T-cell activity. Tolerable safety with promising durability of response has been shown with atezo in pts with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 mo) by RECIST v1.1 and 24% by immune-related response criteria (irRC; n = 4/17, with 2 pts on atezo for ≥ 12 mo). Preliminary data also indicate the potential synergy between atezo and platinum-based chemotherapy in NSCLC, whereby durable responses may translate into improved survival over atezo alone. IMpower133 (NCT02763579), a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial will evaluate the efficacy and safety of 1L atezo + carboplatin + etoposide compared with placebo + carboplatin + etoposide in treatment-naive pts with ES-SCLC. Methods: Pts with measurable (RECIST v1.1) ES-SCLC, who have ECOG PS 0-1 and no prior systemic anticancer treatment, are eligible for the study. Exclusion criteria include untreated CNS metastases and history of autoimmune disease. The study requires submission of tumor tissue, but pts will be enrolled regardless of biomarker status. Pts will be stratified by sex, ECOG PS and presence of treated brain metastases. Eligible pts will be randomized 1:1 to receive four 21-day cycles of atezo (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, d 1) and etoposide (100 mg/m2 IV, d 1-3), followed by maintenance therapy with atezo or placebo until PD per RECIST v1.1. Pts can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints are investigator-assessed PFS per RECIST v1.1 and OS. Secondary efficacy endpoints include investigator-assessed ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 pts will be enrolled. Clinical trial information: NCT02763579.

Avelumab in chemotherapy-refractory metastatic Merkel cell carcinoma: Subgroup analysis of efficacy.

80 Background: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. In a phase 2 trial in previously treated metastatic MCC (mMCC; JAVELIN Merkel 200, NCT02155647), avelumab, a fully human IgG1 anti–PD-L1 antibody, showed durable responses and a manageable safety profile, including confirmed objective response rate (ORR) of 31.8% (95.9% CI 21.9-43.1), 6-mo duration of response (DOR) rate estimate of 92%, and 6-mo progression-free survival (PFS) rate of 40% (95% CI 29-50). We report post-hoc subgroup analyses from this trial. Methods: Pts with mMCC and prior disease progression on chemotherapy received avelumab 10 mg/kg (1h IV) Q2W. Tumors were assessed every 6 wks (RECIST v1.1) by independent review. Kaplan-Meier method was used to estimate 6-mo DOR and PFS rate. Results: 88 pts were treated with avelumab and followed for ≥ 6 mos (data cutoff Mar 3, 2016). Responses occurred in all subgroups analyzed (Table). Trends of higher ORR and 6-mo PFS rates were seen in pts with fewer prior lines, lower disease burden (sum of target lesion diameters), or PD-L1+ tumors. 6-mo response durability was similar across evaluable subgroups. Conclusions: In post-hoc analyses, avelumab showed durable efficacy across subgroups. This trial is enrolling treatment-naive pts with mMCC to receive 1L avelumab. Clinical trial information: NCT02155647. [Table: see text]

Abstract P6-07-09: Biomarker analysis from the neoadjuvant KRISTINE study in HER2-positive early breast cancer (EBC)

Abstract Introduction KRISTINE (NCT02131064) is an open-label, phase 3 study of neoadjuvant trastuzumab emtansine + pertuzumab (T-DM1+P) vs docetaxel + carboplatin + trastuzumab + pertuzumab (TCH+P) in pts with HER2+ EBC (all pts, Table). In exploratory analyses we assessed whether HER2 expression and gene amplification levels and PIK3CA mutation were associated with pathologic complete response (pCR) in KRISTINE. Methods Treatment-naive pts with stage II–IIIC HER2+ EBC were randomized to receive 6 cycles of T-DM1+P or TCH+P and assessed for the primary endpoint, pCR (ypT0/is, ypN0). HER2 status was confirmed centrally as immunohistochemistry (IHC) status of IHC3+ and/or HER2/CEP17 gene ratio ≥2 by in situ hybridization (ISH) before study entry. Baseline HER2 mRNA, PIK3CA mutation, and hormone receptor (HR) status were evaluated. Rates of pCR were compared across biomarker subgroups, including: HER2 mRNA, HER2 IHC staining percentage, HER2 gene ratio, and PIK3CA mutation. Incidence of overlap between biomarkers was assessed. All analyses were descriptive. Results KRISTINE randomized 444 pts (data cutoff, Dec 3, 2015; TCH+P=221; T-DM1+P=223). The biomarker population was representative of the ITT population. Biomarker values and distribution were balanced across treatment arms. Lower pCR rates were seen in both treatment arms across biomarker subgroups with lower vs higher HER2 expression levels (Table). PIK3CA mutation was associated with numerically lower pCR with T-DM1+P but not TCH+P. Evaluation of 15 pts who progressed during T-DM1+P neoadjuvant therapy suggests that nonresponse to therapy in this arm may be associated with low HER2 levels (mRNA, IHC, and ISH). PIK3CA mutation rate was higher in tumors with ≤median HER2 mRNA (38%) vs &amp;gt;median (16%), and in focal (53%) and variable (41%) HER2 expression vs homogeneous (24%). A numerically higher proportion of HR positivity was seen in the HER2 IHC2+ (81%) subgroup vs IHC3+ (55%), and in the focal (83%) and variable (62%) HER2 subgroups vs homogeneous (53%). Table TCH+PT-DM1+P BiomarkernpCR (%)npCR (%)Difference in pCR rates (%)95% CIAll pts22155.722344.4-11.3-20.5, -2.0HER2 IHC3+19460.819549.7-11.1-20.9, -1.3IHC2+2520.0287.1-12.9-31.2, 5.5HER2 IHC 2+/3+ fraction* Focal (&amp;lt;30%)1533.3160-33.3-57.2, -9.5Variable (30–79%)2729.62722.2-7.4-30.7, 15.9Homogeneous (≥80%)17961.518051.7-9.8-20.0, 0.4HER2 mRNA expression ≤median10649.110937.6-11.4-24.6, 1.7&amp;gt;median10763.610851.9-11.7-24.8, 1.4HER2/CEP17 gene ratio ≥2 to &amp;lt;44533.35219.2-14.1-31.6, 3.4≥416662.015853.2-8.9-19.6, 1.8PIK3CA mutation Mutated5354.76131.1-23.6-41.3, -5.8Nonmutated16056.315151.0-5.3-16.3, 5.8*Categorization based on sum of IHC2+ and IHC3+ staining percentage. Conclusions None of the evaluated biomarker subgroups showed superior pCR rates for T-DM1+P vs TCH+P. Lower HER2 levels based on mRNA and protein expression and gene amplification were associated with numerically lower pCR in both treatment arms. PIK3CA mutation results differ from prior observations. Unfavorable biomarkers for pCR, like low HER2, PIK3CA mutation, and HR positivity, showed a tendency for co-expression, which should be considered when planning future trials in HER2+ BC. Citation Format: de Haas SL, Hurvitz SA, Martin M, Kiermaier A, Lewis Phillips G, Xu J, Helms H-J, Slamon D, Press MF. Biomarker analysis from the neoadjuvant KRISTINE study in HER2-positive early breast cancer (EBC) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-09.

Phase I study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (Gem) in solid tumors: Interim results from the pancreatic cancer (PC) cohorts.

412 Background: Immune checkpoint inhibitors, such as nivo, an anti−PD-1 antibody, have demonstrated antitumor activity in various cancers. Chemotherapy has demonstrated immune system activation via multiple mechanisms, providing a rationale for combination approaches. nab-P + Gem is a standard of care in PC which does not require immunosuppressive corticosteroids. Here we report interim results from 2 PC cohorts (Arms A and B) of a phase I study in patients (pts) receiving nivo + nab-P ± Gem for locally advanced or metastatic PC. Methods: This 2-part study was designed to identify dose-limiting toxicities (DLTs) of nivo + nab-P ± Gem in Part 1 and assess tolerability and efficacy in Part 2 dose expansion (+ Gem). Pts were DLT evaluable if they received ≥ 2 cycles of treatment and remained on study for 14 days after last dose or discontinued due to a DLT prior to completing 2 cycles. After Arm A, Part 1 was deemed safe, Arm B, Part 1 was initiated. In Arm A, pts with 1 prior chemotherapy regimen received nab-P 125 mg/m2 on days 1, 8, and 15 of a 28-day cycle (qw 3/4) + nivo 3 mg/kg on days 1 and 15 of a 28-day cycle starting with cycle 1. In Arm B, treatment-naive pts received the same regimen in Arm A + Gem 1000 mg/m2qw 3/4. Results: As of June 28, 2016, 11 and 6 pts were treated in Arms A and B in Part 1, respectively. No DLTs were reported in Arm A, and 1 in Arm B (nonimmune hepatitis, suspected to be due to Gem; resolved and pt continued nivo + nab-P without Gem). The most common grade 3/4 teatment-emergent AEs were pulmonary embolism, neutropenia, and anemia in 2/11 pts (18%) in Arm A and anemia in 2/6 pts (33%) in Arm B. Nine patients discontinued due to progressive disease (8 in Arm A, 1 in Arm B). Best overall response is shown in the Table. Median treatment duration was 12.6 and 15.5 weeks for Arms A and B, respectively. Clinical trial information: NCT02309177. Conclusions: These results indicate that adding nivo to nab-P ± Gem is feasible for pts with advanced PC, and antitumor activity of this regimen appears to be encouraging. Based on promising results from Part 1, Arm B, Part 2, is enrolling pts.[Table: see text]

A Phase II Study of the Combination of Lenalidomide and Rituximab in Patients with Treatment-NaïVe and Relapsed Chronic Lymphocytic Leukemia

Introduction. The combination of Lenalidomide (Len) and rituximab has been investigated in patients (pts) with treatment-naive (TN) and relapsed (R) CLL with an overall response rate (ORR) ranging between 66% and 85%. Fludarabine refractoriness and a median daily Len dose Methods. Pts were eligible for this study if they had treatment indications per IWCLL 2008 criteria, WHO PS ≤2 and adequate hepatic and renal function. Len was started on day 9 of cycle 1 at 10 mg orally and administered daily indefinitely. Rituximab, 375 mg/m2, was administered every 28 days for 12 cycles. Response was assessed at month 3, 6 and every 6 months thereafter. Pts in this study returned to our center at time of response assessment and were allowed to receive R infusion at their oncologist9s office. The primary end point of this study was ORR. Results. One-hundred-twenty pts (61 TN and 59 R) were enrolled between 1/2012 and 11/2014; 83 (69%) pts received their R infusion locally. Baseline pts characteristics are shown in the Table. The median number of cycles administered was 16 [1-54] in TN and 20 [1-59] in R pts. Fifty-five TN and 53 R pts were evaluable for response. Twelve pts discontinued therapy before the first response assessment [toxicity (8), loss to follow-up (3), and death (1)]. ORR was 73% in TN and 64% in R pts, CR/CRi rate was 35% in TN and 28% in R pts. MRD eradication was achieved in 16% of TN and 2% of R pts. Median time to response was 11 [8-14] and 6 [5-7] months in TN and R pts. Median response duration (RD) has not been reached for TN pts and was 37 (29-45) months for R pts; 28% of TN and 62% of R pts have progressed. Characteristics predictive of higher ORR were: B2M ≤ 4 mg/L in TN pts (85% vs 55%, p=0.03); age 60 mL/min in R pts; on MVA, only B2M maintained its association (84% vs 46%; OR 5, 95% CI 1.1-10; p=0.03). FISH and IGHV status did not predict ORR. Characteristics associated with longer RD were age ≤ 65 years (p=0.009) and non-complex karyotype (p=0.05) in TN pts; on MVA, only age maintained its association (not reached vs 33 months; HR 5; 95% CI 1-25.6; p=0.05); Treatment-associated G 3-4 toxicities occurred in 28% of TN and 30% of R pts. Most common toxicities were: infections (10% of TN and 22% of R pts), thromboembolic complications (6%, both groups), skin rash (6% in TN pts only), and tumor flare reaction 6% (TN pts only). Forty-three (70%) TN and 50 (85%) R pts have discontinued treatment, median time to failure (TTF) was 22 [16-28] and 34 [25-43] months, respectively. Reasons for interruption were: progression in 13 (30%) TN and 25 (50%) R pts, toxicity in 25 (57%) TN and 20 (40%) R pts, pt/physician choice in 3 (7%) TN and 4 (8%) R pts, and other cancers in 2 (5%) TN and 1(2%) R pt. Factors predictive of a longer median TTF were eGFR ≥ 60 mL/min in TN pts (23 months vs 7 months, p=0.05) and early Rai stage in R pts (41 vs 36 months, p=0.04). At a median follow-up of 34 [1-53+] months, 4 (7%) TN and 14 (24%) R pts died, with a 4-year OS of 90% and 70%, respectively. Factors associated with shorter median OS were advanced Rai stage in TN pts (75% vs 100%, p=0.02), and > 2 prior treatments in R pts (on MVA; 50% vs 90% 4-years OS; HR 5.2; 95% CI 1.3-21; p=0.02). When comparing pts treated at our center to those receiving R infusion in the community, no significant differences in ORR, G3-4 toxicity rate or OS were observed. Conclusions. In our experience, the combination of Len and R is able to induce responses in 73% of TN and in 64% of R pts. Pts age IGHV status. Similar results in terms of efficacy and toxicity were observed in pts treated at our center or managed in close cooperation with local providers. With the expanding number of active treatment options for pts with CLL, the identification of clinical and biological factors predictive of response is becoming increasingly important. Disclosures Thompson: Pharmacyclics: Consultancy, Honoraria. Jain: Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Consultancy, Honoraria; Infinity: Research Funding; Genentech: Research Funding; Servier: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Incyte: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding. Burger: Pharmacyclics: Research Funding. Wierda: Gilead: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Novartis: Research Funding; Genentech: Research Funding. Kantarjian: Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; ARIAD: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding.

Outcomes of Ibrutinib Therapy By Age in Patients with CLL/SLL: Analyses from Phase 3 Trial Data (RESONATE and RESONATE-2)

Background: Chronic lymphocytic leukemia (CLL) is primarily a disease of the elderly, with the majority of patients (pts) older than 65 y at diagnosis (US SEER). Historically, younger, more fit pts were eligible for aggressive chemoimmunotherapy treatments, but older age and comorbid conditions can limit options due to tolerability concerns. Ibrutinib (ibr), a first-in-class, oral, once-daily inhibitor of Bruton9s tyrosine kinase, is indicated by the US FDA for the treatment of pts with CLL/small lymphocytic lymphoma (SLL) and allows for treatment without chemotherapy. Results from the phase 3 RESONATE (PCYC-1112) and RESONATE-2 (PCYC-1115) trials established ibr as a standard option in relapsed/refractory (R/R) and treatment-naive (TN) CLL/SLL. This analysis examines safety and efficacy from these studies by age. Methods: RESONATE randomized 391 pts with R/R CLL/SLL to receive ibr (n=195; 420 mg once daily) until progressive disease (PD) or unacceptable toxicity or intravenous ofatumumab (n=196; 300 mg at week 1, 2000 mg weekly for 7 w and then every 4 w for 16 w). RESONATE-2 randomized TN pts aged ≥65 y to receive ibr (n=136; 420 mg once daily) until PD or chlorambucil (clb; n=133; 0.5 mg/kg to a maximum of 0.8 mg/kg) on days 1 and 15 of a 28-day cycle for up to 12 cycles. Pt data from both studies were grouped by age (ibr and comparators [comp]) and analyzed for effect of age on outcome. Results: Ibr group included 136 TN pts: 65 to Conclusions: The PFS rate for TN ibr pts was similar regardless of age subgroup, whereas it was shorter for clb-treated pts ≥75 y compared with those 65 to Disclosures Woyach:Karyopharm: Research Funding; Morphosys: Research Funding; Acerta: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Brown:Pfizer: Consultancy, Honoraria, Other: travel, accommodations, expenses; Genentech: Consultancy, Honoraria; Roche: Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Other: travel, accommodations, expenses; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: travel, accommodations, expenses; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria; Sun Biopharma: Honoraria, Other: travel, accommodations, or other expenses. Coutre:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding. Barr:AbbVie: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding. O9Brien:Janssen: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding. Devereux:Janssen: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau; GSK: Consultancy; Roche: Consultancy, Other: Travel, Accommodations, Expenses ; Gilead: Consultancy, Other: Travel, Accommodations, Expenses, Speakers Bureau. Reddy:KITE: Membership on an entity9s Board of Directors or advisory committees; celgene: Membership on an entity9s Board of Directors or advisory committees; GILEAD: Membership on an entity9s Board of Directors or advisory committees; INFINITY: Membership on an entity9s Board of Directors or advisory committees. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Zhou:AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. Ninomoto:AbbVie: Equity Ownership; Amgen: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment. James:Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Burger:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; Portola: Consultancy; Gilead: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; Roche: Other: Travel, Accommodations, Expenses.

FAT1 Mutations Influence Time to First Treatment in Untreated CLL

Introduction:Despite mapping of the mutational landscape in patients (pts) with chronic lymphocytic leukemia (CLL), there remains limited information regarding the functional or clinical impact of less common, recurrently mutated genes. Over the past several years, the influence of high-risk mutations has been reported. With the advent of readily available next generation sequencing (NGS), physicians receive a large amount of genomic data, many times without information regarding the clinical impact of less validated, mutations. Using results from a commercially available NGS platform, we identified a relatively high prevalence of mutations in the gene, FAT1, in treatment naïve (TN) CLL pts.FAT1 encodes a protein in the cadherin superfamily, important in regulating WNT signaling, with a role in tumor suppression. Aberrant mutated FAT1 expression has been associated with acute lymphoblastic leukemias with an intermediate clinical course. Loss of protein, through chromosomal deletions has been implicated in many solid tumors and associated with tumor progression. The majority of mutations arise in the cadherin repeats, previously shown to diminish antagonism of β-catenin, allowing its nuclear localization (Morris Nat Genetics 2013). In CLL, FAT1 mutations have been demonstrated to enrich in fludarabine refractory pts (10.3%) but with a relatively low prevalence in untreated pts (1.1%) (Messina, Blood 2014). Given a high prevalence of FAT1 mutations in our database and evidence suggesting mutated FAT1 contributes to tumor evolution, we investigated the clinical impact of clonal FAT1 mutations in pts with CLL.Methods:Patients were identified for inclusion if mutational analysis was performed prior to, or within 12 months of treatment start date. Only pts treated initially with a signal transduction inhibitor (STI) were included. Treated pts were either on protocol or received their STI as standard of care. All pts underwent whole exome profiling with a lymphoid specific NGS panel, including 75 genes (Genoptix Inc.). Analysis was performed on peripheral blood or bone marrow aspirates. The primary outcome was time to first treatment (TTFT). The log-rank test was used to compare Kaplan-Meir curves. Double-sided P values <0.05 were considered significant. Fischer exact test was used to compare baseline characteristics. All calculations were performed using Prism V6.0.Results:In total we analyzed 172 pts, 118 (69%) remain on observation, 54 (31%), have been treated at data cutoff. Nineteen (11%) pts were found to be FAT1 mutated (mFAT1) and 153 (89%) were FAT1 wild type (wtFAT1). The median time from diagnosis to mutational profiling for the cohort was 35 months (range 0-301). We identified 21 total mutations, 17 unique (82% cadherin domain, 18% EGF like region). Recurrent mutations were identified, each occurring in 2 pts (p.A636T, p.P1614L, p.R1257Q, p.R2041H). One pt had an indel and 1 pt had an inframe deletion, the remaining were missense. We found no significant differences between groups in regards to age, IGVH mutation status or co-occurrence of high-risk mutations in NOTCH1, SF3B1, TP53 or ATM. Only 17p deletions occurred significantly more in mFAT1 pts (24%) vs. wtFAT1 (7%), p=0.04, other cytogenetic abnormalities were balanced. mFAT1 pts had significantly shorter TTFT, 50 versus 143 months respectively, p=0.02. We investigated if mFAT1 status could stratify IGVH mutated pts but found no differences in TTFT. Eleven mFAT1 pts have received treatment (82% ibrutinib, 18% acalabrutinib), 8 remain on observation. All mFAT1 pts have responded.Conclusions:Given the increasing use of rapidly available NGS testing, physicians receive genomic information with limited data regarding clinical impact. We identified a higher prevalence of FAT1 mutations in TN pts, than that previously reported. FAT1 mutations associated with deletion 17p but not other high-risk genetic mutations. Recurrent FAT1 mutations were identified and commonly found in the cadherin domain. mFAT1 pts have a significantly shorter TTFT than wtFAT1 pts. When treated with novel agents, there was no difference in response rates. These findings suggest FAT1 mutations in TN pts may be more common than previously reported and identify an intermediate risk for progression. Additional studies investigating the influence of recurrent FAT1 mutations and association with 17p deletions in TN pts are warranted. DisclosuresAllan:Pharmacyclics: Speakers Bureau.

Single-Agent Ibrutinib Vs Standard of Care for Patients with Relapsed/Refractory (R/R) and Treatment-Naive (TN) Chronic Lymphocytic Leukemia (CLL): An Adjusted Comparison of RESONATETM and RESONATE-2TM with the French Lyon-Sud Database

INTRODUCTION: The benefits of ibrutinib (ibr) have been demonstrated by the phase 3 RESONATE and RESONATE-2 trials for patients (pts) with R/R and TN (≥ 65 years) CLL, respectively. In these studies, ibr showed significantly improved progression-free survival (PFS) and overall survival (OS) vs approved comparators (ofatumumab [ofa] in RESONATE and chlorambucil [clb] in RESONATE-2). However, a number of other treatment regimens are widely used in clinical practice for CLL based on individual patient and disease characteristics; it is currently unknown if ibr results in better survival outcomes when compared directly with each of these other treatments. AIM: In the absence of a head-to-head comparison, we investigated the relative efficacy of ibr vs physician9s choice (PC) in pts with R/R or TN CLL by comparing pt-level data from RESONATE and RESONATE-2 with data from pts in a real-world setting (the Lyon-Sud database). This database holds electronic medical records for 390 pts with CLL from the academic Lyon-Sud Hospital in France; nearly all patients were diagnosed between 1990 and 2014. This is the first analysis of ibr vs PC in a real-world setting for pts with TN CLL. METHODS: Pt-level data from RESONATE (ibr, n = 195; ofa, n = 196) were compared with data on pts with CLL from Lyon-Sud who received 2nd(n = 107) or later-line treatment (3rd [n = 62], 4th [n = 43], and subsequent [n = 51] lines). Similarly, RESONATE-2 (ibr, n = 136; clb, n = 133) pt-level data were compared with those of pts aged ≥ 65 years who received 1st-line treatment (n = 131). In order to account for non-comparability due to lack of randomization, a multivariate Cox proportional hazards model was used to compare PFS and OS between treatments, including line of therapy, age, sex, disease stage (based on Binet/Rai), and deletion 17p or 11q mutations as covariates. For the definition of PFS, missing data for date of disease progression for pts in Lyon-Sud who initiated subsequent therapy were replaced by the conservative proxy of date of initiation of next treatment. Predicted PFS and OS curves for the Lyon-Sud cohort were derived from the multivariate model. RESULTS: For R/R pts in Lyon-Sud, across all treatment lines the most frequent regimens used were rituximab (R) + chemotherapy (n = 46), bendamustine + R (BR; n = 28), fludarabine + cyclophosphamide + R (FCR) (n = 27), clb + R (n = 19), R monotherapy (n = 21), and R-CHOP-based (n = 19); the remaining percentages comprised various other therapies, each used in CONCLUSIONS: Investigation of survival outcomes suggests that ibr administered to pts in RESONATE and RESONATE-2 was more effective than PC used in a real-world cohort of French pts with R/R or TN CLL, suggesting a 4.8-fold improvement in PFS and a 3.4-fold improvement in OS in R/R pts and 4-fold and 2.4-fold improvements in TN pts, respectively. These results further support the growing evidence that ibr significantly improves both PFS and OS vs commonly used regimens in the R/R and TN settings, and could have important implications for improving treatment of CLL in clinical practice. Disclosures Salles:Janssen: Consultancy, Honoraria; Gilead: Honoraria, Research Funding; Mundipharma: Honoraria; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Sarkozy:Sandoz: Research Funding; Janssen Research & Development: Honoraria; Gilead: Honoraria; Takeda: Research Funding. Ghesquieres:Mundipharma: Consultancy; Celgene: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Roche France: Research Funding. Diels:Johnson & Johnson: Employment, Equity Ownership. Besson:Janssen: Employment. MacDougall:Janssen Research & Development: Research Funding; IMS Health: Employment. Hermans:Janssen Research & Development: Research Funding; IMS Health: Employment. Healy:Janssen Research & Development: Employment. Garside:Janssen Research & Development: Employment. Iraqi:Janssen Research & Development: Employment.

Incorporation of Molecular Data into the Current Prognostic Models in Treated Patients with Myelodysplastic Syndromes: Which Model Is the Best

▪BackgroundSeveral prognostic models have been developed to risk stratify patients (pts) with MDS including: the International Prognostic Scoring System (IPSS), Revised IPSS (IPSS-R), World Health Organization classification-based Prognostic Scoring System (WPSS), and MD Anderson Prognostic Scoring System (MDPSS). All except for the MDPSS were developed in treatment-naive pts and, if validated in treated pts, were done so primarily in those receiving one line of therapy. Incorporation of molecular data into the IPSS-R improves its predictive power, and adding molecular data to the IPSS can upstage or downstage some pts. In this study, we compared the prognostic utility of each prognostic model, after adding molecular data, in treated MDS pts.MethodClinical and mutational data from MDS pts diagnosed between 1/2000-1/2013 were analyzed. A panel of 60 gene mutations that were described as commonly mutated in myeloid malignancies was included. Patients who underwent hematopoietic cell transplant (HCT) were censored at the time of transplant. Univariable and multivariable analyses on the training cohort were performed by applying Cox proportional hazards regression analyses that included age, model score, and molecular mutations with an outcome of overall survival (OS). All molecular models were then applied to the validation cohort. The fit of the proposed models to the data was assessed by using Akaike's information criterion (AIC, lower values imply better fit) and concordance (c-) index.ResultsA total of 610 pts were included and divided into two cohorts, training (404 pts), and validation (206 pts). Median age of the training cohort was 67 years (range, 19-88); 83 pts (20%) had MDS/MPN including chronic myelomonocytic leukemia (CMML). Pts received a median of 2 lines of therapies (range, 0-7) and 15% of pts underwent HCT. First line therapies included: supportive care (22%), growth factors (22%), azacitidine +/- combinations (30%), decitabine +/- combinations (6%), lenalidomide (5%), induction chemotherapy (3%), immunosuppressive therapy (3%), and other therapies /clinical trials (9%). The median OS in the training and validation cohorts per scoring system (SS), i.e. IPSS, WPSS, MDPSS, and IPSS-R, is summarized in Table 1. The most common mutations in the training cohort were: TET2 (19%), ASXL1 (16%), SF3B1 (13%), DNMT3A (9%), STAG2 (9%), RUNX1 (8%), and U2AF1 (7%). In univariate analyses, mutations in EZH2 (HR1.8, p = .02), TP53 (HR2.3, p < .001), RUNX1 (HR 1.5, p = .05), and NPM1 (HR1.49, p = .001) had a negative impact on OS while SF3B1 (HR .34, p < .001) mutations were associated with favorable outcome. In multivariate analyses that included SS, mutations (from the list above), and age (except for the MDPSS, which already includes age), the following independent prognostic factors for OS were identified: age, EZH2, SF3B1, TP53, and each SS. Based on the fitted coefficients of each prognostic factor, a molecular version of each model including IPSSm, WPSSm, MDPSSm, and IPSS-Rm was proposed with median OS in the training and validation cohorts as summarized in Table 1. The addition of molecular data improved (reduced) the AIC and (raised) the C-index for the IPSS (2332.6, .69 vs. 2365.8, .64), WPSS (2322.3, .68 vs. 2356.2, .65), MDPSS (2308.4, .71 vs. 2323.4, .69), and IPSS-R (2305.2, .70 vs. 2330.5, .66), respectively. Further, the addition of molecular data to the IPSS upstaged 37% of pts from lower- to higher-risk disease and downstaged 5% of intermediate-1 to low risk disease. In the WPSS, it upstaged 21% of pts and downstaged 24%; in the MDPSS it upstaged 19% and dowstaged 22% of pts from intermediate-1 to low risk; and in the IPSS-R it upstaged 26% to higher-risk disease and 59% of pts with intermediate risk to a higher risk category.ConclusionsThe addition of molecular data to established MDS prognostic models can improve their predictive power, even in treated MDS patients. More importantly, adding molecular information can upstage or downstage pts into different risk categories. This study highlights the importance of incorporating molecular data into clinical prognostic systems. [Display omitted] DisclosuresMukherjee:Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding.

Integrated and Long-Term Safety Analysis of Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Integrated and Long-Term Safety Analysis of Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Three-year overall survival for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001.

9503 Background: The anti–PD-1 antibody pembro (pembro; MK-3475) prevents PD-1 from binding to its ligands, PD-L1 and PD-L2, and is approved for treating advanced melanoma at a dose of 2 mg/kg every 3 wk (Q3W). Pembro demonstrated superior PFS over chemotherapy for ipilimumab (ipi)-refractory melanoma (KEYNOTE-002) and superior OS and PFS over ipi for advanced melanoma (KEYNOTE-006). We present 3-year OS data for all patients (pts) with melanoma enrolled in the phase 1b KEYNOTE-001 study (NCT01295827). Methods: Pts were enrolled in ipi-naive and ipi-treated cohorts and received pembro 2 or 10 mg/kg Q3W or 10 mg/kg Q2W until intolerable toxicity, progression, or investigator decision. Clinically stable pts with radiographic progression could remain on pembro until progression was confirmed. Response was assessed by RECIST v1.1 every 12 wk. After pembro discontinuation, pts were contacted to assess survival every 3 mo. OS was estimated using the Kaplan-Meier method. Results: Of the 655 pts enrolled, 24% had BRAFV600mutation, 78% had stage M1c disease, 38% had elevated LDH, 75% had ≥1 prior therapy, and 52% had prior ipi. As of the Sep 18, 2015, data cutoff date, median follow-up duration was 32 mo (range 24-46) and 358 (55%) pts had died. The 36-mo OS rate was 40% and median OS was 23.8 mo (95% CI, 20.2-29.0), with similar results for each dose (Table). 36-mo OS rates were 41% in both ipi-treated and ipi-naive pts and 45% in treatment-naive pts (Table). Examination of the OS curve suggests a long-term OS benefit for a fraction of pts treated with pembro. Additional data, including PFS, ORR, duration of response, and safety, will be available for presentation. Conclusions: Pembro provides long-term survival benefit in pts with ipi-naive and ipi-treated advanced melanoma, with 40% of pts alive at 3 years. These data support the use of pembrolizumab in pts with advanced melanoma regardless of prior treatment. Clinical trial information: NCT01295827. N Median OS (95% CI), mo 24-mo OS Rate, % 36-mo OS Rate, % Pembro 2 Q3W 162 23.5 (18.3-35.0) 49 38 Pembro 10 Q3W 313 22.9 (18.5-31.1) 49 39 Pembro 10 Q2W 180 25.9 (18.9-41.8) 52 43 Ipi treated 342 20.0 (17.8-27.1) 46 41 Ipi naive 313 28.8 (23.1-32.2) 54 41 Treatment naive* 149 32.0 (27.1-NR) 60 45 *Excludes pts with mucosal melanoma.

Effects of abiraterone (ABI) and enzalutamide (ENZA) on cognitive impairment and depressive symptoms in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

5059Background: Cognitive and mood effects of ABI and ENZA are not well described. An ongoing randomized phase II trial evaluating sequencing of ABI and ENZA in treatment-naive pts with mCRPC (Clin...

Pembrolizumab (MK-3475) for recurrent or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma: Multicohort phase II KEYNOTE-059 study.

TPS184 Background: Pembrolizumab (pembro) is a humanized monoclonal antibody that targets the PD-1 receptor and prevents it from interacting with its ligands, PD-L1 and PD-L2. In the phase I KEYNOTE-012 trial, pembro showed an acceptable safety profile and promising antitumor activity in patients (pts) with PD-L1+ metastatic gastric cancer. The multicohort, phase II KEYNOTE-059 (NCT02335411) trial was designed to further evaluate pembro as monotherapy or in combination with 5-fluorouracil (5-FU) and cisplatin in pts with advanced gastric cancer. Methods: Patients ≥ 18 y who have relapsed or metastatic gastric or GEJ adenocarcinoma, ECOG PS 0-1, no active autoimmune disease or brain metastases, and no prior chemotherapy within 2 wk of the first dose of pembro are eligible. PD-L1 expression status will be determined by IHC using the 22C3 antibody (Merck). In cohort 1 (C1), up to 180 pts with any PD-L1 status whose disease progressed on ≥ 2 prior chemotherapy regimens, including a fluoropyrimidine and platinum doublet and, if HER2+, trastuzumab, will receive pembro 200 mg Q3W. In cohort 2 (C2), ~12 Asian and ~6 non-Asian, treatment-naive, HER2– pts of any PD-L1 status will receive pembro 200 mg Q3W + infusional 5-FU or capecitabine and 6 cycles of cisplatin. In cohort 3 (C3), ~25 treatment-naive pts with HER2–/PD-L1+ tumors will receive pembro 200 mg Q3W. Treatment may continue for up to 24 mo or until progression, intolerable toxicity, or investigator decision. Response will be assessed at wk 9 and every 6 wk thereafter per RECIST v1.1 and RECIST v1.1 adapted for immunotherapy response patterns. Treatment may be discontinued for eligible pts who have a CR. Eligible pts may continue treatment beyond initial RECIST-defined progression. AEs will be collected throughout the study and for 30 d thereafter (90 d for serious AEs) and graded per NCI CTCAE v4.0. The primary efficacy end point for C1 and C3 is ORR per RECIST v1.1 by central review; the primary end point for C2 is safety and tolerability of the combination. Secondary end points include PFS, OS, DCR, and duration of response. Enrollment in KEYNOTE-059 is ongoing and will continue until up to 223 pts are enrolled across all cohorts. Clinical trial information: NCT02335411.

LAPACT: An open-label, multicenter phase II trial of nab-paclitaxel (nab-P) plus gemcitabine (Gem) in patients (pts) with locally advanced pancreatic cancer (LAPC).

TPS477 Background: In pts with LAPC, more effective systemic therapies may be associated with improved local control, delay of metastasis, and overall survival (OS). The phase III MPACT trial in pts with metastatic PC demonstrated longer OS (median, 8.7 vs 6.6 mos; HR, 0.72; P &lt; 0.001) and an ≈ 3-fold greater shrinkage of primary tumors with nab-P + Gem vs Gem alone (−22.15% vs −7.02%), raising the possibility of improved local PC control with nab-P + Gem. LAPACT will assess the efficacy and safety of nab-P + Gem in LAPC. Methods: LAPACT will enroll treatment-naive pts (planned n ≈ 110) in the United States, Canada, and Europe with Eastern Cooperative Oncology Group performance status ≤ 1, confirmed unresectable LAPC, no distant metastases, and adequate organ function. Pts with mixed-origin tumors, any other malignancy within 5 years, peripheral neuropathy grade &gt; 1, or clinically significant ascites are ineligible. Pts will receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Pts without progressive disease (PD) or unacceptable toxicity after 6 cycles will receive investigator’s choice of surgery, chemoradiotherapy, or continued nab-P + Gem. If a major response is observed, surgery may occur prior to completing 6 cycles of nab-P + Gem. The primary endpoint is time to treatment failure (TTF; time from first therapy dose to discontinuation due to PD, start of a new non–protocol-defined anti-cancer therapy, or death). The study design allows for 80% power at a 1-sided α of 0.05 to detect a 30% increase over the 5.1-month median TTF observed for nab-P + Gem in the MPACT study. The secondary endpoints are disease control rate (DCR) after 6 cycles, overall response rate, progression-free survival, OS, safety, and quality of life. The exploratory endpoint is correlation of changes in circulating nucleic acids with PD and treatment response. An interim DCR analysis will occur after all pts have completed 6 cycles of nab-P + Gem, discontinued therapy due to PD, died, or started a new non–protocol-defined therapy before completing 6 cycles of therapy. Enrollment is ongoing (first pt enrolled in April 2015). Clinical trial information: NCT02301143.