Summary
We assessed the concordance between immunohistochemistry (IHC) and gene expression profiling (GEP) for determining diffuse large B‐cell lymphoma (DLBCL) cell of origin (COO) in the phase III ...PHOENIX trial of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R‐CHOP) with or without ibrutinib. Among 910 of 1114 screened patients with non‐germinal centre B cell‐like (non‐GCB) DLBCL by IHC, the concordance with GEP for non‐GCB calls was 82·7%, with 691 (75·9%) identified as activated B cell‐like (ABC), and 62 (6·8%) as unclassified. Among 746 of 837 enrolled patients with verified non‐GCB DLBCL by IHC, the concordance with GEP was 82·8%, with 567 (76·0%) identified as ABC and 51 (6·8%) unclassified; survival outcomes were similar regardless of COO or treatment, whereas among patients with ABC DLBCL aged <60 years, the overall and event‐free survival were substantially better with ibrutinib versus placebo plus R‐CHOP hazard ratio (HR) 0·365, 95% confidence interval (CI) 0·147–0·909, P = 0·0305; HR 0·561, 95% CI 0·326–0·967, P = 0·0348, respectively. IHC and GEP showed high concordance and consistent survival outcomes among tested patients, indicating centralised IHC may be used to enrich populations for response to ibrutinib plus R‐CHOP.
Introduction: Cytarabine-containing induction chemotherapy followed by high dose therapy and autologous stem cell transplant (ASCT) is currently a standard treatment approach for younger patients ...with mantle cell lymphoma (MCL). This approach, however, may be associated with lesser efficacy in patients with high-risk disease biology (i.e. with elevated proliferative index, blastic morphology, or TP53 alteration). Older patients are treated with rituximab-based chemotherapy regimens without stem cell transplant. In this single-center prospective phase II study, we treated MCL patients, irrespective of their age, with immunochemotherapy combined with lenalidomide without ASCT to evaluate the safety and efficacy of this regimen.
Methods: Treatment consisted of 3 parts: A) 4 cycles of lenalidomide (15mg orally days 1-14) and standard RCHOP chemotherapy in a 21-day cycle B) rituximab and high-dose cytarabine (RHIDAC) administered at a dose of 1,000-3,000 mg/m2 every 12 hours x 4 doses for a total of 2 cycles C) rituximab plus lenalidomide maintenance for 6 months. Eligible patients were untreated MCL, stage II-IV, KPS≥70%, and with adequate organ function. We enriched study enrollment for high risk patients, 31 of a total 47 patients, as defined by Ki-67 ≥30% and/or blastic/blastoid/pleomorphic morphologic subtype. PET/CT after each phase of treatment was completed and interpreted with the 5-point Deauville scale (negative=1-3). The primary endpoint of the study was to evaluate the 3-year progression free survival. Herein we are presenting preliminary data on the end-of-treatment (EOT) response rate and the toxicity of the regimen, including the interim and EOT PET data.
Results: Interim data (as of June 1, 2018) for the first 45 of a planned 47 patients are presented here. Median age was 63 (range 30-79); 82% stage IV; MIPI low, intermediate and high risk were 31%, 31%, and 38%, respectively; 64% of patients had high-risk disease per our definition (28 patients with a Ki-67 ≥30% and 6 patients with blastic morphology).
Of the 39 patients who completed Len-RCHOP induction, 85% were PET-negative and after RHIDAC, 95% of patients achieved a negative PET scan (Figure 1). Of the 26 patients who have completed Len-R maintenance, 92% were PET-negative, 8% PET-positive (Table 1). At EOT, 24 patients (92%) achieved a complete remission, 1 patient achieved a partial response, and 1 patient had progressive disease. Among the 24 patients who achieved a CR, the median follow-up is 9 months. Two relapses have occurred at 18 months and 25 months. The patients with a treatment failure (one PR at EOT, one progressive disease at EOT, and 2 relapses), occurred in patients either with a TP53 mutation (3/3 tested, 1 pending) or blastic morphology (3/4 patients). Overall the treatment program was well-tolerated and predominantly hematologic toxicities were observed, particularly during the RHIDAC phase consistent with past experience with this treatment regimen in MCL. During each phase (Len-RCHOP, RHIDAC, and Len-R maintenance), grade 3/4 neutropenia was observed at a rate of 13%, 52%, 16%, respectively; febrile neutropenia 1%, 4%, 0%, respectively; grade 3/4 anemia 11%, 32%, 1%, respectively; and grade 3/4 thrombocytopenia 8%, 75%, 2%, respectively. Comparing to our historical data in a cohort of 23 MCL patients (57% low risk), Len-RCHOP resulted in a higher PET-negative rate compared to RCHOP alone, 85% versus 65%, respectively.
Conclusion: The addition of lenalidomide to RCHOP chemotherapy appeared to increase the rate of PET-negativity compared to historical results with RCHOP alone. Toxicity occurred as expected and was manageable. Early failures were observed in patients with TP53 mutation or blastic morphology. Although follow-up is limited, early results with this approach are promising.
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Kumar:Seattle Genetics: Research Funding; Abbvie Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Zelenetz:Novartis/Sandoz: Consultancy; Amgen: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Abbvie: Research Funding; Gilead: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding. Hamlin:Portola: Consultancy. Matasar:Seattle Genetics: Honoraria. Moskowitz:Bristol Myers-Squibb: Consultancy, Research Funding; Takeda: Honoraria; Merck: Research Funding; Incyte: Research Funding; ADC Therapeutics: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding. Straus:Bayer: Consultancy; Medical Crossfire: Speakers Bureau; DAVA Oncology: Consultancy, Honoraria; JUNO: Consultancy; Millenium (Takeda): Consultancy, Research Funding; Seattle Genetics: Consultancy; Onco Tracker: Consultancy; Roch China: Speakers Bureau; InPractice Elselvier: Consultancy; Memorial Sloan Kettering Cancer Center: Employment. Younes:BMS: Honoraria, Research Funding; Astra Zeneca: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Roche: Honoraria, Research Funding; Novartis: Research Funding; Janssen: Honoraria, Research Funding; Merck: Honoraria; J&J: Research Funding; Curis: Research Funding; Incyte: Honoraria; Bayer: Honoraria; Sanofi: Honoraria; Seattle Genetics: Honoraria.
Background: The oral selective BCL-2 inhibitor, venetoclax, is FDA-approved for the treatment of Chronic Lymphocytic Leukemia (CLL) patients with 17p deletion del(17p) who have received at least one ...prior therapy.Multiple clinical trials investigating its activity in patients with relapsed or refractory CLL are ongoing, and longer term follow-up is now available since the original publications of the initial Phase 1 and 2 trials. In order to define the response rate and durability of response across a broader population than studied in any individual trial, we performed a pooled analysis of current data available from four ongoing studies.
Methods: Data were analyzed from the following venetoclax trials - NCT01328626 (M12-175 study): phase 1, venetoclax monotherapy in patients with relapsed or refractory CLL (n=116, data as of 04APR2016,); NCT02141282 (M14-032 study): phase 2, venetoclax monotherapy for CLL patients who have progressed on ibrutinib or idelalisib (n=64, data as of 28JUN2016, and excludes safety expansion patients whose long term data are not available); NCT01889186 (M13-982 study): phase 2, venetoclax monotherapy in relapsed or refractory CLL patients with del(17p) (n=158, data as of 29MAR2016); NCT01682616 (M13-365 study): phase 1b, venetoclax plus rituximab in relapsed or refractory CLL (n=49; data as of 04MAR2016).
Bone marrow minimal residual disease (MRD) status was determined using data from the M13-982 and M13-365 studies (n=207). MRD data for the M14-032 study is not yet available and MRD assessment was not systematically performed for the M12-175 study. Del(17p) status was assessed using fluorescence in situ hybridization and TP53 mutation status was determined by next generation sequencing. Descriptive statistics (median, range, proportion) were calculated for demographics, baseline characteristics, and overall response. All post-baseline data were included to determine the overall response and did not account for differences in the follow-up times between studies. Kaplan-Meier methodology was used to calculate 24-month estimates and associated 95% confidence interval (CI) for duration of response (DOR) and progression free survival (PFS).
Results: A total of 387 patients were included in this analysis median age: 66 years (range: 29 - 88). Bulky nodes (≥5 cm) were present in 194/386 (50%) patients and del(17p) was confirmed in 211/356 (59%) patients with available data; 207/387 (53%) patients had ≥3 prior therapies. Venetoclax doses ranged from 150 mg/day to 1200 mg/day; 299/387 (77%) patients received the recommended phase 2 dose (RPTD) of 400 mg/day. Across all four studies, the median duration on venetoclax was 15.3 (range: 0 - 51.8) months and the median time on study was 16.6 months (range: 0 - 51.8). 54% of the patients continue on venetoclax; 46% have discontinued due to: progressive disease (30%), adverse events (9%), stem cell transplant (3%), withdrew consent (3%), investigator request, lost to follow-up, non-compliance (n=1, 0.25% each).
The overall response rate (ORR) in all patients was 77% (Table 1). The CR/CRi (complete remission/complete remission with incomplete marrow recovery) rate was 22% and the number increased over time on venetoclax median time to CR/CRi = 8.3 (range: 2.6 - 28.6) months; MRD-negativity in the marrow was achieved by 21% (44/207) of patients, including 12% (19/157) of those with del(17p).
The impact of clinical response, marrow MRD negativity, and del(17p) or TP53 status on DOR and PFS is summarized in Table 2. For all four studies combined, the median DOR was 29.2 months (95% CI=25.1, 40.1) and the median PFS was 27.9 months (95% CI=24.9, 30.5). The 24-month estimate for DOR in all patients was 64.3% (95% CI=55.5, 71.8) and that for PFS was 56.9% (95% CI=50.3, 63). Patients who achieved marrow MRD negativity had the highest 24-month DOR estimate of 96.6% (95% CI= 77.9, 99.5), followed by those with CR+CRi 89.8% (95% CI=73.5, 96.3) and those without del(17p) or TP53 mutation 74.6 (95% CI=62.3, 83.4). Similar trends were seen for the 24-month PFS estimates.
Conclusions: Pooled data from the four studies show that venetoclax induces deep (22% CR/CRi and 21% marrow MRD negativity rates) and durable responses in patients with relapsed/refractory CLL. DOR and PFS were the most favorable in patients who achieved marrow MRD negativity and CR/CRi and those without del(17p) or TP53 mutation.
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Roberts:Servier: Research Funding; Janssen: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding. Seymour:Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Eichhorst:Abbvie: Consultancy; Mundipharma: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau. Stilgenbauer:Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding. Davids:Pharmacyclics: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Genentech: Consultancy, Honoraria, Research Funding; Gilead: Honoraria; Abbvie: Consultancy, Honoraria; TG Therapeutics: Honoraria, Research Funding; Infinity: Honoraria, Research Funding. Gerecitano:AbbVie: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Samus: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Popovic:AbbVie Inc.: Employment, Other: may own stock. Chyla:AbbVie Inc.: Employment, Other: may own stock. Zhu:AbbVie Inc.: Employment, Other: may own stock. Verdugo:AbbVie: Employment, Other: may own stock. Potluri:AbbVie Inc.: Employment, Other: may own stock. Lash:AbbVie Inc.: Employment, Other: may own stock. Kim:AbbVie Inc.: Employment, Other: may own stock. Hallek:Celgene: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; F. Hoffmann-LaRoche: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Mundipharma: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau.
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Background: Venetoclax (VEN) is a potent, highly selective, orally bioavailable small-molecular BCL2 inhibitor that is FDA-approved for patients (pts) with chronic lymphocytic leukemia (CLL) that ...harbors del(17p) and who have received ≥1 prior therapy. VEN monotherapy induces objective response in ~80% of pts (16-20% complete remission by investigator) with relapsed/refractory (R/R) CLL, including del(17p) CLL (Roberts et al, 2016; Stilgenbauer et al, 2016). Safety of VEN monotherapy was evaluated using an integrated dataset from pts with CLL.
Methods: Pts were included if they received at least one dose of 400 mg VEN as target dose in the M12-175 (first in human), M13-982 (del17p CLL), or M14-032 (prior ibrutinib or idelalisib) Phase I or II studies. All started with weekly dose ramp up to 400 mg daily over 4-5 weeks and continued VEN until disease progression/discontinuation.
Results: Overall, 296 pts were included in the analysis: median age was 66 years (range: 29-85), 94% had ECOG score 0-1, 53% had Binet stage A, 27% B, and 19% C. 66% had del(17p) CLL, 77% had unmutated IGHV, and 69% had β-2 microglobulin >3 mg/L. Pts had received a median of 3 prior therapies (range: 0-12) and 94 (32%) had received prior ibrutinib or idelalisib. A history of cytopenias was common, with neutropenia in 52 (18%) pts, anemia in 118 (40%), and thrombocytopenia in 80 (27%). Forty-six (16%) pts were on G-CSF support prior to enrollment.
At the time of analysis, median duration on VEN was 13 months (range: 0-50), with 55% pts receiving VEN daily for >1 year. Common AEs (any grade) were neutropenia (41%), diarrhea (39%), nausea (36%), anemia (29%), fatigue (26%), and upper respiratory tract infection (23%). The most common Grade 3/4 AEs were neutropenia (37%), anemia (15%), and thrombocytopenia (14%). Grade 3/4 infections were reported for 19% of pts. Common serious AEs were pneumonia and febrile neutropenia (5% each); most serious AEs occurred within the first 3 months on VEN. Twenty-five deaths were reported: 13 due to disease progression and 12 were treatment-emergent AEs due to complications related to underlying CLL (most common were infections 4); none were attributed by the investigator to VEN. The safety profile was similar when analyzed by subgroups, including age, sex, race, or prior ibrutinib/idelalisib.
Four pts had AEs of TLS, though only one met Howard criteria for laboratory TLS (decreased calcium and increased phosphate). No clinical TLS was observed. All events occurred during the 5-week dose ramp up and pts interrupted VEN dosing for median of 3 days (range: 1-5), though all restarted VEN to reach 400 mg. Events were managed by IV hydration and standard of care for laboratory abnormalities.
A major reason for VEN interruptions/reductions was neutropenia, with most dose adjustments occuring within the first 3 months on study. Neutropenia was managed by standard supportive care measures, including G-CSF support for 136 (46%) pts during this time.
Time of first onset for most hematologic toxicities (any grade) occurred during dose ramp up (Figure). First onset of new AEs within or after 3 months on VEN (shown as within/after 3 months) was 34%/7% for neutropenia, 27%/3% anemia, and 14%/5% thrombocytopenia. This temporal pattern is likely due to improving CLL disease control though for some pts this may be the result of increasing time off prior myelosuppresive chemotherapy. Grade 4 neutropenia was reported in 71 (24%) pts and median time to event was 28 days (range: 2-416); 48/71 (67%) had Binet C at screening and median time to event was 23 days (range: 2-415). Grade 4 neutropenia required dose reductions for 21% of pts, 80% received G-CSF support, and 1 event led to study discontinuation. Grade 4 thrombocytopenia occurred in 32 (11%) pts (23 had Binet C) and Grade 4 anemia in 2 (2%) pts (both Binet C).
Gastrointestinal toxicities were mainly Grade 1/2, with 60% new events reported in the first 3 months vs 11% reported > 3 months (Figure). No late toxicity signal has been observed in pts receiving >1 year of therapy.
Conclusions: The safety profile of 400 mg VEN daily was consistent across pts with CLL pooled from 3 studies and remains acceptable with longer follow up in this larger population. No clinical TLS was observed and one event of laboratory TLS was manageable. The majority of AEs, including cytopenias (most common Grade 3/4 AEs), occurred during the first months of VEN and onset of AEs decreased over time in pts with emergent toxicities.
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Seymour:AbbVie Inc.: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Davids:Genentech: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Gilead: Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Infinity: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Roberts:AbbVie: Research Funding; Genentech: Research Funding; Genentech: Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone payments related to venetoclax; Janssen: Research Funding; Servier: Research Funding. Hallek:GSK: Research Funding; Mundipharma: Research Funding; Janssen: Research Funding; Celgene: Research Funding; Gilead: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria. Wierda:Genentech: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding; Gilead: Research Funding. Hillmen:Pharmacyclics: Research Funding; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria, Research Funding; Abbvie: Research Funding. Gerecitano:Samus: Consultancy, Honoraria; Bayer: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Cerri:AbbVie: Employment. Potluri:AbbVie: Employment. Kim:AbbVie: Employment. Busman:AbbVie: Employment. Verdugo:AbbVie: Employment, Other: may own stock. Humerickhouse:AbbVie: Employment. Best:AbbVie: Employment. Desai:AbbVie: Employment. Stilgenbauer:Sanofi: Consultancy, Honoraria, Other: Travel grants , Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel grants, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel grants , Research Funding; Novartis: Consultancy, Honoraria, Other: Travel grants , Research Funding; Hoffmann-La Roche: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genentech: Consultancy, Honoraria, Other: Travel grants , Research Funding; Amgen: Consultancy, Honoraria, Other: Travel grants, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel grants , Research Funding; GSK: Consultancy, Honoraria, Other: Travel grants , Research Funding; Genzyme: Consultancy, Honoraria, Other: Travel grants , Research Funding; Mundipharma: Consultancy, Honoraria, Other: Travel grants , Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel grants , Research Funding; Janssen: Consultancy, Honoraria, Other: Travel grants , Research Funding; Gilead: Consultancy, Honoraria, Other: Travel grants , Research Funding.
Abstract 5120
Bortezomib (VELCADE) is the first proteasome inhibitor to be approved by regulatory agencies for treatment of multiple myeloma and mantle cell lymphoma. Maculopapular rash is a common, ...adverse event to bortezomib. Because the summary incidence of bortezomib-induced skin rash is not well known, we performed a systematic literature review and meta-analysis to determine the incidence and overall risk.
We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology and The American Society of Hematology annual meetings from 1998 to July 2011, to identify relevant clinical studies. Eligible studies included prospective clinical phase II and phase III trials, with data on the incidence of rash in patients taking 1.3mg/m2, 1.5mg/m2, or 1.6 mg/m2 of bortezomib twice weekly for two weeks followed by one week off, in a 21-day cycle. The incidence of rash and relative risk (RR) were calculated using random-effects or fixed-effects model, depending on the heterogeneity of included studies.
A total of 2,469 patients with various hematologic and solid malignancies from 32 clinical trials were included for analysis. Among patients receiving bortezomib, the summary incidences of all-grade and high-grade rash were 18.8 % (95% CI: 14.9% to 23.5%) and 3.6 % (95% CI: 2.3% to 5.7%), respectively. We found no significant increase in rash incidence with higher doses of bortezomib. In addition, bortezomib was associated with an increased risk in both all grade (RR:19.703, 95% CI: 8.734 to 44.446, p<0.001) and high-grade rash (RR: 5.354, 95% CI: 2.158 to 13.285, p<0.001), in comparison with controls.
Bortezomib is associated with a significant risk of developing rash. Management of bortezomib-induced rash is critical to prevent a negative effect on quality of life and dose modifications, both of which may affect clinical outcome.
Wu:Onyx: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Genentech: Speakers Bureau. Gerecitano:Millenium: Research Funding.
Introduction: Enhancer of zeste homolog 2 (EZH2) is the histone methyltrasferase catalytic subunit of the polycomb repressive complex 2 responsible for mono-, di-, and trimethylation of lysine 27 on ...histone 3. Tazemetostat, a potent, selective EZH2 inhibitor, is in phase 2 clinical development in relapsed or refractory (RR) Non-Hodgkin Lymphoma (NHL). Activating mutations in EZH2 are hypothesized to lead to an oncogenic EZH2 dependency. These mutations are most commonly detected in germinal center derived malignancies such as follicular lymphoma and the germinal center B-cell (GCB) subset of Diffuse Large B-cell Lymphoma (DLBCL). During B-cell maturation, EZH2 expression levels are highest in the germinal center and are then reduced following B-cell exit from the germinal center. Pre-clinical studies demonstrated that tazemetostat has greater anti-tumor activity in EZH2 mutant models as compared to EZH2 wild-type (WT) models. Given these data, during initial tazemetostat clinical development, it was anticipated that response rates in DLBCL patients would be highest in EZH2 mutant >EZH2 WT and GCB WT > non-GCB WT. Here we report the preliminary response rate data from the DLBCL cohorts of the ongoing phase 2 tazemetostat trial stratified by cell of origin (COO) using Hans immunohistochemistry (IHC) and NanoString's gene expression profiling (GEP) based Lymphoma Subtyping Test (LST).
Methods: As of June 1, 2017, the phase 2 single agent trial (NCT01897571) of tazemetostat had enrolled 142 RR DLBCL response evaluable patients (≥18 years old; ≥2 prior treatment regimens; measurable disease; and adequate organ function). Patients were allocated to cohorts based on the results from testing of archived tumor tissue using the cobas® EZH2 Mutation Test (Roche Molecular Systems, in development) designed to detect EZH2 hot spot activating mutations (Y646X, A682G, A692V) and IHC using the Hans methodology. Enrollment to the GCB- EZH2 WT and non-GCB cohort was completed in early 2017, while the GCB- EZH2 mutant cohort remains open. Retrospectively, COO was determined using NanoString's research use only version of the Lymph2Cx LST using RNA isolated from archived tumor tissue. Interim response rates for COO subsets using Hans IHC and LST methods were compared and contrasted using a Clopper-Pearson exact confidence interval. Hans classifies patients as GCB or non-GCB therefore, for the purposes of comparison, LST results of both activated B-Cell (ABC) and unclassified were considered to be non-GCB.
Results: Archived tumor from 101 of 142 evaluable DLBCL patients successfully generated data by both COO methods, with success primarily dependent on tissue availability for LST as only one patient sample failed LST data generation. Concordant COO classification was obtained for 89/101 patients (88%) with the majority of discordance due to switching to GCB by LST from non-GCB via Hans. The rate of COO concordance reported here between Hans and LST are in line with results from previously reported comparisons. Interestingly, three EZH2 mutant patients were enrolled in the non-GCB cohort however, via LST these patients were classified as one of each GCB, ABC and unclassified. This is the first known report of EZH2 mutations occurring in the ABC subtype. The number of response evaluable patients with EZH2 MTs is too small to make any conclusions regarding the impact of COO classification on response within such patients at this time. As shown in Table 1, within the EZH2 WT patients, no significant difference in interim objective response rate (Cheson 2007) between the GCB vs. non-GCB subsets was observed using either Hans or LST classifications.
Conclusions: The current interim DLBCL response data from patients with EZH2 MTs in this ongoing phase 2 tazemetostat study has insufficient patient numbers to effectively assess the impact of COO on response in these patients. Intriguingly, in EZH2 WT patients to date, COO does not appear to be a primary driver of response prediction indicating that other factors independent of COO may be more predictive of single agent tazemetostat activity in these patients.
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McDonald:Epizyme, Inc: Employment, Equity Ownership, Research Funding. Morschhauser:Janssen: Consultancy, Honoraria; Servier: Consultancy; Celgene: Consultancy, Honoraria; Gilead: Consultancy; Roche: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Ribrag:Esai: Honoraria, Research Funding; Pharmamar: Consultancy; Servier: Consultancy, Honoraria; ArgenX: Research Funding; Roche: Honoraria, Other: travel, accommodation, expenses; BMS: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Infinity: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Nanostring: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Salles:Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Tilly:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria; Immunogen: Honoraria; Gilead: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gerecitano:Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dickinson:GlaxoSmithKline: Honoraria, Research Funding. Assouline:Novartis Canada Inc.: Honoraria; Bristol Myer Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Paladin: Speakers Bureau; Janssen: Honoraria. Haioun:Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria; JANSSEN: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria; PFIZER: Consultancy, Honoraria. Gribben:Genentech/Roche: Honoraria; Karyopharm: Honoraria; Acerta: Honoraria; TG Therapeutics: Honoraria; Janssen: Honoraria; Kite: Honoraria; Pharmacyclics: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Zinzani:Gilead: Other: Advisory board; Takeda: Other: Advisory Board; Janssen: Other: Advisory board; Celgene: Other: Advisory board; Roche: Other: Advisory board; Sandoz: Other: Advisory board; Pfizer: Other: Advisory board; Karyopharma: Other: Advisory board. Wu:Roche: Employment, Equity Ownership. Kussick:PhenoPath: Employment, Other: part owner; Seattle Genetics Hematopathology Advisory Board: Honoraria. Storhoff:NanoString Technologies: Employment, Equity Ownership. Larus:Epizyme, Inc: Employment, Equity Ownership. Clawson:Epizyme, Inc: Employment, Equity Ownership. Grayson:Epizyme, Inc: Employment, Equity Ownership. Daigle:Epizyme, Inc: Employment, Equity Ownership. Ho:Epizyme, Inc: Employment, Equity Ownership. Miao:Epizyme, Inc: Employment, Equity Ownership. Blakemore:Epizyme Inc.: Employment, Equity Ownership.
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