Noise Is Noise – Try A Head To Head With Ibrutinib? While most of the companies at ASH have released data throughout the year – the totality of the data at ASH is what has the consensus under the belief that it is a crowded space with many players that will limit Imbruvica’s potential. And yes they are big players with significant resources and goodwill from investors (GILD, ABBV, Roche, CELG are blue chip Wall Street darlings.) While multiple trials continue to be posted every day, none of the compounds come anyway near the powerful data, database and therapeutic window that ibrutinib has. If anything, these other players believe that this is going to be a blockbuster market and they all want a piece. In our view, PCYC – the only one on the market and that has set the highest bar, destroying everything in its path – will get the lion’s share. What would be interesting but unlikely is if and when one of the other players begins a head-to-head trial versus Imbruvica. While PCYC has begun a few of those studies (most recently vs. Rituxan), it is a risk that few are likely to take (and for good reason). In fact, PCYC has just begun a few other trials for the long-term competitiveness – a watchful waiting study and a large front-line trial.
PCYC – What’s Next? A Whole Lot – One final reason for the PCYC stock drop is that the entire biotech sector has experienced a post-ASH sell-off – as ASH was the last big meeting in a phenomenal year for biotech stocks. For PCYC and other biotech stocks after receiving their first approval, the shareholder base shifts from the pure biotech investors who buy on data and sell on approval – to the sales/earnings growth investors that ALXN, BIIB, CELG, GILD have grown into. With GILD’s market cap approaching $115 billion and a few of the others more than half of that – often based upon 1-3 key drugs, in our view, PCYC has the potential to worth much more than the current $8 billion valuation based on Imbruvica alone. Also, at the end of the year portfolio managers – many of who get paid the big bonuses at December 31 – some have decided not to fight the tape, lock in their wonderful paydays – take the rest of the year off, and start over in 2014.
PCYC still has a lot ahead – a) RESONATE data (no later than January, probably by year-end); b) CLL approval – could happen any day (but officially by February 28); c) autoimmune update (by year end), leading to new program and new markets; d) NCNN guidelines which may include Ibrutinib as new standard of care in MCL and CLL; e) first quarter of Ibrutinib sales (still too early to say but initial signs are impressive and their strong presence at ASH will certainly help).
Now that the ASH noise is behind us, there is no question that Imbruvica has solidified its leadership position in B-cell lymphomas. (It could also surprise folks in autoimmune.) While the short-term sentiment shift is no doubt painful, in our view, it will be short-lived based upon the above scenario and upcoming events. The Imbruvica breakthrough therapy is currently being transferred to PCYC’s P&L.
Sentiment: Strong Buy
PCYC – ASH DATA CONTINUES TO DIFFERENTIATE IBRUTINIB DESPITE THE NOISE – REITERATE BUY – Despite the aggressive stock sell-off, data at the ASH conference this past week further cements ibrutinib as the new standard of care in MCL and CLL. While updated data from GILD (idelalisib, Syk inhibitor), Roche (Rituxan, GA-101), AbbVie (ABT-199), INFI (IPI-145) and NVS (CART) all show impressive efficacy – none can match the therapeutic window that Imbruvica provides. Entering the conference, we anticipated the “noise” level from the competition would reach a peak decibel level. In fact, it was loud enough to create an even further shift in short-term sentiment away from PCYC. In a painful way, this may very well be a good thing – expectations continue to decline while the Ibruvica launch has just begun.Idelalisib And Ibrutinib Are NOT Interchangeable – The key debate going into ASH for the new targeted agents was ibrutinib (“ib”) versus idelalisib (“id”)? GILD management (and most GILD investors/analysts, which are the majority) would like folks to believe they are interchangeable. They are certainly NOT – not by a long shot. In an ASH follow-up call, Dr. Susan O’Brian of MD Anderson, one of the key opinion leaders with experience across the gamut, called ibrutinib superior “for several reasons” and that there was “not one subset of patients where ibrutinib was not the compound of choice.” To simplify, ibrutinib is a once daily pill, that in monotherapy (i.e., standalone drug) has remarkable efficacy and an extremely clean side effect profile – patients not only get better over time, but feel better and their immune system improves over time. This has been proven time and again and will very soon show its single agent power in the RESONATE results. Idelalisib, on the other hand, is a twice-daily pill that in monotherapy has shown positive efficacy but no way near that of ibrutinib. Most importantly, the side effects limit its duration of action. In addition, to liver toxicity and infections, delayed extreme colitis has emerged at ASH as another Grade 3/4 side effect. For example, patients do well on the drug in combination, of course, but after nine months get severe diarrhea due to idelalisib. In stark contrast to idelalisb, the safety profile for Imbruvica actually improves over time. How GILD (the undeniable king of biotech) has been able to convince folks that these drugs are more similar than not shows the power the company has over perception of many. For now.Responses Galore, But At What Price? In several presentations, each of the above competitive compounds achieved a high degree of responses in patients with CLL to their respective drug. While we cannot provide every detail of every study – the noise level is that high – what most investors need to truly take away is that 1) safety and 2) ease of use – are just as, if not more, important than efficacy. Most CLL patients are over 70 years old and, as such, suffer from co-morbidities. Rituxan for example, is given as an infusion, has typical antibody side effects and has disappointing CLL data as a monotherapy. (O’Brian called it “a #$%$ control arm” in the idelalisib+Rituxan vs. Rituxan study. This is the big trial GILD stopped early because of good efficacy – hardly an unexpected result but one that has led to the current “we are just as good as ibrutinib” debate.) ABT-199 is a powerful drug – it results in some complete responses (CRs) and MRD (minimal residual disease ) – CRs, another buzzword at ASH. However, it causes tumor lysis syndrome (TLS), which had led to patient deaths and amendments to clinical trials. Improvements have been made and trials are ongoing, but they are admittedly a year plus behind schedule and still need to enroll and monitor patients very carefully. In the ASH presentation, TSL has not at all gone away. GILD also showed initial data with its Syk inhibitor that showed high responses in monotherapy but also liver enzyme elevations and discontinuations. They are now studying idelalisib – which causes liver tox – in combination with the Syk inhibitor, which also causes liver tox. Good luck. INFI IPI-145 came back to life with larger and longer-term data, but also has a profile similar to idelalisib (infections, liver tox, diarrhea). They believe some of that can be prevented with pre-treatment strategies (i.e, more drugs). They have just begun a Phase III trial against ofatumubab (like the RESONATE trial). Enrollment, (even O’Brian suggested) at least in the U.S., will be challenging. And the CART data from NVS/U Penn showed extremely favorable efficacy, but also can be extremely toxic in practice and will likely, at best, be used in salvage conditions – i.e., when failing ibrutinib and others.
Was There Really Anything New At ASH? Dr. O’Brian said that the only real new data was the GILD data (Id +R, vs. R) but even that was old news although it wasn’t officially presented until ASH – and it wasn’t surprising. PCYC Imbruvica data was published in the Lancet Oncology during the conference, and in front-line untreated patients showed on monotherapy alone – 96% of patients were still alive at 2 years, with minimal side effects – and the duration of response is still ongoing. Dr. O’Brian – again in settling the debate – said the expected duration of response for Imbruvica is now 50 months (4+ years) versus 20 months for idelalisib. (Consensus models have ~2+ years of duration modeled for Imbruvica.)
Sentiment: Strong Buy
-ORAL PRESENTATION- Abstract #852
Combining Ibrutinib With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP): Updated Results From a Phase 1b Study in Treatment-Naive Patients With CD20-Positive B-Cell Non-Hodgkin's Lymphoma (NHL)
Anas Younes, M.D., Memorial Sloan-Kettering Cancer Center, New York, NY
R-CHOP is a standard of care in a number of the most common B-cell malignancies, including several NHL subtypes, such as diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL). This study was an open-label, nonrandomized, multicenter study consisting of 2 parts: dose escalation in patients with DLBCL, MCL and FL (Part 1) and dose expansion only in DLBCL patients (Part 2). The primary objective of this phase 1B study in 33 patients was to determine the recommended phase 2 dose and dose-limiting toxicities of ibrutinib in combination with R-CHOP. Secondary objectives were to evaluate safety, ORR and pharmacokinetics. The results below focus on the 24 DLBCL patients across Parts 1 and 2 of the study.
Across Parts 1 and 2
The ORR for all evaluable patients across Parts 1 and 2 was 91.7%, with 83.3% of patients achieving a CR, and 8.3% achieving a PR.
Pre-Clinical and Non-Clinical Presentation Highlights
During the ASH meetings this year a total of 33 pre-clinical and non-clinical presentations were presented, 7 of these were oral and 26 poster presentations. The data presented provides further insights into ibrutinib including: 1) the potential reconstitution of the immune system in CLL patients 2) valuable findings of mechanism of action of ibrutinib 3) the apoptotic effect (cell death) of ibrutinib in both the tissue and blood for CLL cells and 4) many models illustrating combinations with many other therapies. Below are a select, few abstracts:
Poster Abstract #4182: In Patients With Chronic Lymphocytic Leukemia (CLL) Ibrutinib Effectively Reduces Clonal IgM Paraproteins and Serum Free Light Chains While Increasing Normal IgM, IgA Serum Levels, Suggesting a Nascent Recovery Of Humoral Immunity
Georg Aue, MD, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
This study demonstrated ibrutinib's impact on the recovery of humoral immunity equally amongst treatment naive and relapsed refractory CLL patients. Consistent with other reports we see little change in IgG levels in the first 12 months. Importantly, ibrutinib leads to a significant increase in both IgA and IgM serum levels, suggesting a beginning recovery of humoral immunity. The reduction of clonal light chains, a tumor marker, correlates with clinical response. In contrast, the increasing levels of the non-clonal light chain may herald a recovery of the normal B-cell (and possibly plasma cell compartment) raising the possibility that ibrutinib may selectively target CLL cells while allowing the re-growth of normal B-cells.
Poster Abstract #4166: Kinetics Of Chronic Lymphocytic Leukemia Cells In Tissues and Blood During Therapy With The BTK Inhibitor Ibrutinib
Dominik Wodarz, Department of Ecology and Evolutionary Biology, University of California Irvine, Irvine, CA
This two-compartment analysis provides greater insight into ibrutinib's mechanism of action in CLL. During ibrutinib therapy, on average 1.7% (± 1.1%) of the cells die per day in the blood, while in tissue 2.7% (± 0.99%) of the cells die per day. These death rates during treatment are approximately 3-5 times higher than those estimated in previous studies in the absence of treatment. The amount of CLL cells from the tissue that was redistributed into the blood during ibrutinib therapy accounted for an average of 23.3% (± 17%) of the calculated total tissue disease burden. Therefore the majority of tissue shrinkage is attributed to apoptosis of the CLL cells in the tissue. These findings indicate that generally a relatively small fraction of the total tissue CLL cell burden is re-distributed into the blood during ibrutinib therapy, and that a significant amount of drug-induced cell death occurs in tissue compartments.
Oral Abstract #118: Effective Inhibition Of Tumor Microenvironment Interactions In CLL Patients Treated With The BTK Inhibitor Ibrutinib Results In Sustained Inhibition Of Tumor Proliferation and Survival Pathways
Sarah E. M. Herman, PhD, Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Prior studies have shown that CLL cells in the lymph node and bone marrow microenvironments demonstrate higher levels of BCR and NF-κB signaling as well as increased cell activation and proliferation (Herishanu et al., Blood 2011). This study's goal was to determine the in vivo effect of ibrutinib on tumor cell activation and proliferation in these microenvironmental niches. Analysis of bone marrow from two cycles of treatment shows that ibrutinib effectively inhibits BCR, NF-κB, and ERK signaling. This occurs very quickly as demonstrated in the lymph node and is sustained on treatment as shown in the bone marrow. The strong and sustained reduction in proliferation and activation of CLL cells in the tissue microenvironment suggests that BTK is indeed a central hub mediating the nourishing and protective effects of the tumor microenvironment.
Sentiment: Strong Buy
Pharmacyclics presents ibrutinib trial data for B-cell malignancies at ASH meeting
Published on December 11, 2013 at 3:06 AM · No Comments
Pharmacyclics, Inc. (NASDAQ: PCYC) today announced results of 40 clinical, non-clinical and pre-clinical presentations on ibrutinib (IMBRUVICA™) at the 55TH Annual meeting of the American Society of Hematology (ASH) held in New Orleans, Dec 7 - 10, 2013. There were seven presentations of clinical data, of which five were oral presentations, including one "Best of ASH" presentation on Waldenstrom's macroglobulinemia (WM). In total, 33 additional pre-clinical and non-clinical presentations provided new discoveries using ibrutinib; seven of these were oral presentations. The presentations further elucidated the mechanism of action of ibrutinib and its effect in the tumor microenvironment and provided data on quality of life changes. Results covered various B-cell malignancies: chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), WM, and non-Hodgkin lymphoma (NHL).
"The breadth of data presented at ASH this year demonstrates the scientific community's interest in ibrutinib and builds on the clinical responses seen with ibrutinib as a backbone of combination therapy and as a single agent in multiple B-cell malignancies," said Jesse McGreivy, M.D., Chief Medical Officer, Pharmacyclics. "This year's data explain ibrutinib's effect on the quality of life for patients and build on impressive efficacy and safety results, independent of cytogenetic risk factors. We also now have long-term follow-up in CLL, which suggests continuation of the efficacy and a decrease in overall and severe adverse events."
Clinical Trial Presentation Highlights
Chronic Lymphocytic Leukemia
-POSTER PRESENTATION- Abstract #4163:
The Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Monotherapy Demonstrates Long-term Safety and Durability of Response in Chronic Lymphocytic Leukemia(CLL)/Small Lymphocytic Leukemia (SLL) Patients in an Open-Label Extension Study
Susan O'Brien, M.D., Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX
A long-term analysis of Phase 1/2 studies of single agent ibrutinib in 148 patients with CLL/SLL aimed to evaluate safety based on time on therapy, summarize safety findings in both the treatment-naive and relapsed/refractory (R/R) populations and assess overall response rate (ORR) and duration of response (DOR). The results showed that the percentage of patients who experienced a grade 3 or higher serious adverse event (SAE) declined over time from 43% within the first year of study treatment to 32% after the first year of treatment. Grade 3 or higher adverse events (AEs) and SAEs considered to be related directly to ibrutinib also declined notably compared to the first year of treatment: 24% and 8%, respectively, to 7% and 0%. The most frequent grade 3 or higher adverse events regardless of relationship to study drug were pneumonia (16.9%), hypertension (13.5%), neutropenia (11.5%), thrombocytopenia (7.4%) and diarrhea (5.4%).
Based on these patients the ORR was determined at 80.6% for treatment-naive patients, and 83.8% for R/R patients. The ORR plus partial response with lymphocytosis was 87.1% in the treatment-naive population and 88.9% in the R/R population. Median DOR was not reached in either population. At 30 months, 95.8% of treatment-naive and 69.7% of R/R responders were alive without disease progression.
-ORAL PRESENTATION- CLL Abstract #675:
Ibrutinib In Combination With Rituximab (iR) is Well Tolerated and Induces a High Rate of Durable Remissions in Patients With High-Risk Chronic Lymphocytic Leukemia (CLL): New, Updated Results Of a Phase II Trial In 40 Patients
Jan A. Burger, M.D., Ph.D., Department of Leukemia, MD Anderson Cancer Center, Houston, TX
The objectives of this study were to assess the activity and tolerability of ibrutinib and rituximab in combination, in high-risk CLL patients. The study included 40 patients with CLL, with a median of two prior therapies. Twenty of the patients had del 17p mutations and 13 patients had del11q. Thirty-four patients (85%) achieved a partial response (PR), and four (10%) achieved a complete response (CR), leading to an ORR of 95%. One of four CRs were negative for minimal residual disease (MRD) by flow cytometry.
The most common AEs related to treatment, all grade 1 or 2, were diarrhea
Questionnaires revealed improved overall health and quality of life after 6 months, based on Quality of Life questionnaire (EORTC-QOL-v.3), with 89% of patients reporting a high quality of life score (6 to 7) compared to 46% at baseline and patients achieved a statistically significant increase in body weight.
-POSTER PRESENTATION- CLL Abstract #2872:
Changing the Treatment Paradigm for Previously Treated Chronic Lymphocytic Leukemia Patients with Del(17p) Karyotype
Deborah M. Stephens, D.O., Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
This retrospective analysis aimed to describe the success of treatment of del 17p patients on clinical trials at The Ohio State University (OSU). The study reviewed records of 174 CLL patients with del 17p who had received prior therapy.
At patients' first treatment at OSU (OSU Tx1), 16%
The ORR was significantly different among groups at 56%, 45%, and 24% in the ibrutinib, CDKi, and O groups, respectively. 12-month progression free survival (PFS) estimates were 77%, 38%, and 17% in the ibrutinib, CDKi, and O groups, respectively. 12-month overall survival (OS) estimates were 81%, 78%, and 58%. Notably, age did not correlate with response, PFS, or OS.
-ORAL PRESENTATION- CLL Abstract #673:
Single Agent Ibrutinib Achieves Equal Responses in CLL Patients With and Without Deletion 17p
Mohammed Farooqui, DO, National Institutes of Health, National Heart, Lung and Blood Institute, Bethesda, MD
This phase 2, single center, study of ibrutinib as a single-agent aimed to address the role of ibrutinib in the treatment of CLL patients with del 17p, regardless of their prior treatment history. The study enrolled 29 patients with del 17p, and 24 elderly patients without del 17p (NL 17p). Fifteen of the del 17p patients and eight of the NL 17p patients were treatment naive. The primary endpoint of the study was response after 6 months, assessed by computed tomography (CT) scans, bone marrow biopsies, and routine clinical and laboratory studies.
At six months, 47 patients were evaluable. Of the patients with del 17p, 53% achieved a PR and 43% achieved a PRL, compared to 82% PR and 9% PRL among the NL 17p patients. The apparent difference in response rates is due to slower clearance of the treatment-induced lymphocytosis in the del 17p patients; however, the clinical benefit and disease control in all tissue sites was equal for both cohorts of patients. Twenty-month PFS was 100% in the NL 17p cohort, and 85% in the del 17p cohort.
The most common AEs, predominantly grade 1, were diarrhea (41%); arthralgia (30%); rash (27%); fatigue and bruising (20% each); and cramps (18%). The most common grade 3 or higher AEs were lung infection (5%) and rash (2%).
-ORAL PRESENTATION- CLL Abstract #525:
Ibrutinib in Combination With Bendamustine and Rituximab Is Active and Tolerable in Patients With Relapsed/Refractory CLL/SLL: Final Results Of a Phase 1b Study
Jennifer R. Brown, M.D., Ph.D., Dana-Farber Cancer Institute, Boston, MA
The primary objective of this study of 30 patients was to evaluate the safety of ibrutinib in combination with bendamustine and rituximab in patients with R/R CLL, and the secondary objectives were to evaluate the ORR and PFS. The observed safety profile for this novel combination was generally consistent with the safety profile of bendamustine and rituximab. The most frequently reported treatment-emergent AEs, regardless of attribution were predominantly grade 1 or 2, including diarrhea (70%), nausea (67%), fatigue (47%), neutropenia (40%) and upper respiratory tract infection (37%). The most frequently reported grade 3 or higher AEs were neutropenia (40%), rash and fatigue (10%each), thrombocytopenia and cellulitis (7% each), and febrile neutropenia (6%). Transient treatment-related lymphocytosis occurred less frequently in this combination than with ibrutinib monotherapy (Byrd et al, NEJM 2013).
With a median duration of treatment of 16 months, the ORR was 93.4% (28 out of 30 patients, including 5 CRs and 3nPRs), and one additional patient achieved a partial response with lymphocytosis. The median PFS has not been reached, and responses appeared to be independent of high-risk features. This combination is currently under investigation in a global Phase 3 trial.
-BEST OF ASH ORAL PRESENTATION- Abstract #251:
A Prospective Multicenter Study Of The Bruton's Tyrosine Kinase Inhibitor Ibrutinib In Patients With Relapsed Or Refractory Waldenstrom's Macroglobulinemia
Steven Peter Treon, M.D., M.A., Ph.D., Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA
This study evaluated the efficacy and tolerability of ibrutinib in 63 patients with relapsed or refractory WM, and examined the impact of MYD88 L265P and WHIM-like CXCR4 mutations on ibrutinib response. With a median follow-up at 9 cycles (9 months), the best ORR (minor response or better, using consensus criteria adapted from the 3rd International Workshop on WM) was 83%. Six patients had a very good partial response, 34 achieved a PR, and 12 achieved a minor response (MR), with a major response rate (PR or better) of 64%. Ten patients showed stable disease. In patients who underwent tumor sequencing, attainment of major responses was impacted by mutations in CXCR4, but not MYD88 L265P.
The most common Grade 2 or higher treatment related AEs were neutropenia
Sentiment: Strong Buy
One thing i do not agree with is that some have doubts about FDA approval for CLL after reading (Latest Data Further Support Ibrutinib's Efficacy in CLL) From OncLive nothing but positive Positive Data .I can't see how approval isn't Imminent.JMHO
Sentiment: Strong Buy
Did not read the article but i have to question his motive.Express Scripts Holding Co. gave Chairman and CEO George Paz a 50 percent hike in total compensation for 2012, a year in which the nation's largest pharmacy benefits manager polished off a $29 billion acquisition, patched a key partnership and saw its stock price climb 21 percent.
Paz, 57, received compensation valued at $12.8 million, according to the St. Louis company's annual proxy statement filed Thursday with the Securities and Exchange Commission. That's up from $8.5 million in 2011, when the executive received no bonuses after adjusted earnings fell short of the company's target.Mar. 28, 2013 2:41 PM EDT Express Scripts CEO compensation jumps 50 percent.Check Pharmacyclics what is the CEO s compensation? NOTHING. (O ) Robert Duggan gets no salary and or stock options ever.I know some insurance co. are covering IMBRUVICA off label use for CLL.
Sentiment: Strong Buy
5:19 pm Pharmacyclics announces data presentations for ibrutinibin B-cell malignancies (PCYC): Co announced results of 40 clinical, non-clinical andpre-clinical presentations on ibrutinib (:IMBRUVICA) at the 55THAnnual meeting of the American Society of Hematology (ASH) held in New Orleans, Dec 7 - 10, 2013. There were sevenpresentations of clinical data, of which five were oralpresentations, including one "Best of ASH" presentation onWaldenstrom's macroglobulinemia (WM). In total, 33 additional pre-clinical and non-clinicalpresentations provided new discoveries using ibrutinib; seven ofthese were oral presentations. The presentations further elucidatedthe mechanism of action of ibrutinib and its effect in the tumormicroenvironment and provided data on quality of life changes.Results covered various B-cell malignancies: chronic lymphocyticleukemia (:CLL)/small lymphocytic lymphoma (:SLL), WM, andnon-Hodgkin lymphoma (:NHL).
"The breadth of data presented at ASH this year demonstrates thescientific community's interest in ibrutinib and builds on theclinical responses seen with ibrutinib as a backbone of combinationtherapy and as a single agent in multiple B-cell malignancies,"said Jesse McGreivy, M.D., Chief Medical Officer, Pharmacyclics."This year's data explain ibrutinib's effect on the quality of lifefor patients and build on impressive efficacy and safety results,independent of cytogenetic risk factors. We also now have long-termfollow-up in CLL, which suggests continuation of the efficacy and adecrease in overall and severe adverse events."
Sentiment: Strong Buy
The presentation will be webcast and will be available at Northwest Bio Webcast both live and through March, 2014.
Sentiment: Strong Buy
The sector is down today .The Company will present on Tuesday, December 10, 2013, at 1:35 p.m. Investors interested in meeting one-on-one with senior management during the conference should contact their Oppenheimer representative or the Company.
Sentiment: Strong Buy
Estimated progression-free survival at 24 months was 96.3 percent in this Phase 1b/2 trial--CLL Approval should be FDA approval should be forthcoming .IMO
Sentiment: Strong Buy
The BTK inhibitor ibrutinib rapidly reduced serum immunoglobulin M (IgM) levels and improved hematocrit levels in patients with relapsed or refractory Waldenström’s macroglobulinemia (WM), and the responses to ibrutinib were durable, reported Steven Treon, MD, PhD, at the 55th annual meeting of the American Society of Hematology.
A major response to ibrutinib was less likely in patients who harbored a WHIM-like mutation of CXCR4, present in about 30% of patients with WM, according to Treon, director, Bing Center for Waldenström’s Research and attending physician for medical oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital.
Treon and colleagues initiated the prospective multicenter study after several discoveries in the laboratory. Whole genome sequencing had revealed MYD88 to be a highly prevalent somatic mutation in WM, and allele-specific polymerase chain reaction detected the presence of a MYD88 L265P mutation in persons with IgM monoclonal gammopathy, which suggested that this mutation was an early oncogenic event in WM pathogenesis.
“Later, through deactivation of BTK, ibrutinib was found to abolish binding of MYD88 to BTK in L256P-expressing WM cells,” Treon said. Preclinical studies also demonstrated ibrutinib’s ability to selectively kill tumor cells of L265P-mutant cell lines relative to wild-type controls.
Sentiment: Strong Buy
Agreed.Ibrutinib will be the drug of choice.
Sentiment: Strong Buy
Clinical trials are under way at MD Anderson that combine ibrutinib with rituximab, an antibody that targets CLL cells, to improve response. Burger is presenting an update of one trial (abstract 675) at ASH.
Pharmacyclics funds this clinical trial. O’Brien receives research funding from the company, Burger serves in an unpaid scientific advisory capacity for a different clinical trial.
Co-authors with O’Brien and Berger are William Wierda, M.D., Ph.D., professor of Leukemia, and Nathan Fowler, M.D., associate professor of Lymphoma/Myeloma at MD Anderson; Richard Furman, M.D., of Weill Cornell Medical College; Steven Coutre, M.D., and Ranjana Advani, M.D., of Stanford University School of Medicine; Jeff Sharman, M.D., of Willamette Valley Cancer Institute and Research Center in Eugene, Ore.; Kristie Blum, M.D., Jeffrey Jones, M.D., and John Byrd, M.D., of The Ohio State University; Emiliano Mugnaini, M.D., of Vermont Cancer Center; Ian Flinn, M.D., Ph.D., of Sarah Cannon Research Institute in Nashville, Tenn.; Kathryn Kolibaba, M.D., of Northwest Cancer Specialists in Vancouver, Wash., and Yun Shaw, Fong Clow, ScD., and Danelle James, M.D., all of Pharmacyclics.
Sentiment: Strong Buy
Disease progression halted in 76 percent of patients at 30 months, side effects decline
The targeted therapy ibrutinib continues to stifle relapsed or resistant chronic lymphocytic leukemia for patients in an extended clinical trial while treatment side effects decline in frequency and severity over time, researchers reported at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition.
Out of 140 patients in the phase II trial, 86 percent of those who were previously untreated had a partial or complete response to the oral drug while 88 percent of those with relapsed or treatment-resistant CLL also responded to ibrutinib. Watch video on Ibrutinib keeps CLL in check.
“Progression-free survival at 30 months was about 76 percent, which in previously untreated patients is good, but you could achieve that with other treatment regimens,” said Susan O’Brien, M.D., professor of Leukemia at The University of Texas MD Anderson Cancer Center, who presented the updated results.
“Among patients with relapsed or refractory CLL, it’s really amazing that so many people would still be responding and on the drug well out over two years,” O’Brien said. “This is a very exciting drug.”
Susan O’Brien, M.D.
Ibrutinib continues to be well-tolerated, with most patients staying on the drug until disease progression, O’Brien noted, rather than having to quit due to side effects or other complications.
The median duration of response – the point where half of patients remain on the drug – had not been reached at a median follow-up of 27 months. Ibrutinib does not cure CLL but tamps the disease down to low levels, stalling progression and improving quality of life, O’Brien said.
No new side effects emerge
“When you have a new drug, you always want to be on the lookout for late effects of treatment,” O’Brien said. “We did not see any late, unknown effects after two years and, in fact, the early effects remain early and over time you don’t have as many adverse events.”
CLL is a malignancy of immune system B cells, white blood cells that craft antibodies against infection. Ibrutinib blocks Bruton’s tyrosine kinase (BTK), a vital component of B cell receptor signaling. CLL is the most common adult leukemia. The American Cancer Society estimates about 15,680 new cases will be diagnosed in 2013 and about 4,580 people will die from the disease.
The U.S. Food and Drug Administration approved the drug, known commercially as IMBRUVICA, for treatment of mantle cell lymphoma last month under its breakthrough therapy designation. A similar application for CLL by Pharmacyclics, Inc., the drug’s developer, is pending at the FDA.
Chemotherapy and antibody combinations cause remissions in many CLL patients, however, they are at increased risk of developing secondary cancers related to treatment, mainly acute myeloid leukemia and myelodysplastic syndromes.
The most common side effect from the drug is diarrhea, which resolves over time, O’Brien said.
Adverse events decline during second year
Ibrutinib does not contribute to two common, potentially life-threatening complications of CLL – suppression of creation of blood cells in the bone marrow, or myelosuppression, and infections.
Both CLL and chemotherapy cause myelosuppression, which lowers levels of red blood cells, platelets and white blood cells, exposing patients to anemia, bleeding or infections.
“Ibrutinib is not myelosuppressive,” O’Brien said, “And infections we see mainly are related to extensive prior therapy and those decline in incidence as the disease improves with treatment.”
O’Brien was senior author on a New England Journal of Medicine paper earlier this year that reported ibrutinib clinical trial results for the first 85 patients. Updated findings presented Monday include:
A decline in the overall incidence of grade 3 or 4 adverse events from 43 percent of patients in the first year to 32 percent in the second year. (Grade 3 events are significant but not immediately life-threatening, grade 4 events are life-threatening.)
Drug-related grade 3 and 4 events occurred in 24 percent and 8 percent of patients in the first year, then fell to 7 percent and zero in the second year.
Overall, 62 percent of those with relapsed or resistant CLL experienced a grade 3 or higher adverse event, compared with 29 percent among those treated for the first time.
Adverse events pushed 12 patients off the trial in the first year and six during the second year.
The higher rate of events in the relapsed/resistant group likely reflects the more advanced disease state and previous treatment of those patients rather than the drug, O’Brien noted. The median number of previous treatments was four.
The most common grade 3 or higher events, regardless of cause, were:
Pneumonia (16.9 percent)
Hypertension (13.5 percent)
Low white blood cell count (11.5 percent)
Low platelet count (7.4 percent)
Diarrhea (5.4 percent).
Overall response rate of 93 percent
Initial treatment with ibrutinib elevates levels of white blood cells, including CLL cells, which at first appeared to be a sign of disease progression in the phase I trial. However, at the same time, patients experienced sharp shrinkage in their lymph nodes, where CLL cells accumulate, O’Brien said.
Research by Jan Burger, M.D., Ph.D., associate professor of Leukemia, connected these two events. Ibrutinib attacks chemokines, hormonal regulators that allow CLL cells to cling to their hiding places in the lymph nodes and bone marrow, where they evade treatment and draw nourishment.
Flushing the cells into the blood stream makes them more vulnerable to treatment. And the increased white cell counts – called lymphocytosis – decline over time. When patients who are responding to ibrutinib but still have lymphocytosis are included, the overall response rate jumps to 93 percent.
Sentiment: Strong Buy
Published on Monday, 09 December 2013 14:44 The oral drug, ibrutinib, last month won U.S. approval to treat a rare and aggressive form of non-Hodgkin lymphoma known as mantle cell lymphoma. It is awaiting a Food and Drug Administration decision on treating chronic lymphocytic leukemia (CLL), a slowly progressing form of blood cancer that primarily affects people aged 65 and older.
Some industry analysts had expected the CLL approval to come at the same time as the lymphoma decision. Data from this and other studies being presented at the American Society of Hematology (ASH) meeting in New Orleans could give regulators additional comfort about the medicine's safety and effectiveness in treating CLL.
"Patients receiving ibrutinib are doing much better than historically what we're used to seeing with CLL," Dr John Byrd, a co-leader of the study, said in a telephone interview.
The 148-patient ibrutinib extension study looked at both previously untreated CLL patients and those who had relapsed or stopped responding following prior therapies.
With a median follow-up of more than 27 months of treatment, nearly all of the previously untreated, or treatment-naive, patients and almost three quarters of the relapsed and refractory patients had no evidence of the disease progressing.
"With extended follow-up the remissions with ibrutinib appear to be continuing and the safety of this long-term is being maintained," said Byrd, professor of internal medicine and director of hematology at the Ohio State University Comprehensive Cancer Center in Columbus.
"There has not been an increase of infections or other late-term complications, suggesting that it's going to be a drug that patients can take for a continued, extended period of time without it being a detriment," he added.
Researchers had not yet been able to determine median progression-free survival - the point at which the disease begins to worsen for half the patients in a study.
Among previously untreated patients, about 96 percent had not yet experienced disease progression, with just one of 31 patients in that group relapsing so far, researchers said.
Typically you would expect about 50 percent to see disease progression at two years, Byrd explained.
"You don't even need a statistician to see the difference. The data are better," he said.
Of the 117 previously treated patients in the extension study, 21 had experienced disease progression and 11 had died within 30 days of receiving their last dose of the drug. That left more than 70 percent whose disease remained in check.
"Ibrutinib is the single most active drug that's come into the clinic for CLL in terms of the durability of remission induced with it, so it's going to be a game-changer in CLL," Byrd predicted.
"A lot of the patients from the initial phase II study have been on drug for two to three years," he added.
Serious adverse side effects, such as pneumonia, declined after the first year of treatment, researchers said. The incidence of serious side effects was twice as high in patients who had received prior therapies, which may have had more to do with the state of their disease than a reaction to ibrutinib, they said.
"Long term follow-up has only shown a low risk of infection that you would expect to see in this patient population," said Byrd. "Otherwise the safety has been very favorable relative to other things that have been used in this patient population."
RBC Capital Markets analyst Michael Yee is forecasting eventual annual worldwide sales of $5 billion for the medicine, now being sold for lymphoma under the brand name Imbruvica.
About 15,000 Americans are diagnosed with CLL each year, according to ASH. While there are effective treatments for the disease, such as chemotherapy combined with Roche's Rituxan, current therapies can be highly toxic.
Ibrutinib is one of several new medicines for CLL - including one in late stage development from Gilead Sciences Inc - that have fewer toxicities and safety issues and may lead to better quality of life for patients being treated.
"The future will hold combining this with some of the other new targeted therapies that we have coming forward to get complete remissions and hopefully get us onto the path of cure," Byrd said.
Sentiment: Strong Buy
"These findings led us to hypothesize that the CXCR4 mutation drives the disease – that it spurs Waldenstrom's cells to grow, divide, and metastasize," Ghobrial said. When researchers treated Waldenstrom's-carrying mice with an antibody that targets the mutation, progression of the disease halted.
"We have now identified a specific mutation that drives this rare disease, as well as a potential drug capable of acting against it," Ghobrial remarked. "We hope this work can be a springboard to clinical trials of drugs for patients with Waldenstrom's."
The findings are especially important in light of another study presented at the ASH conference. In it, researchers led by Treon and Maria Lia Palomba, MD, of Memorial Sloan-Kettering Cancer Center, tested ibrutinib – a drug that blocks growth signals in Waldenstrom's cells – in 63 Waldenstrom's patients who had received at least one prior treatment.
When researchers examined the bone marrow of 34 patients who had taken ibrutinib for six months, they found that the amount of marrow impacted by Waldenstrom's had declined between 45 and 70 percent. Patients whose Waldenstrom's cells harbored the CXCR4 mutation, however, did not respond as well to the drug, suggesting that they could particularly benefit from an agent that targets that specific mutation.
"The results show that ibrutinib is very active and well tolerated in patients with relapsed or hard-to-treat Waldenstrom's," Treon remarked. "The discovery of CXCR4 mutations in Waldenstrom's is an important milestone, and provides a means to identify which patients are more likely to benefit from ibrutinib. Our findings also provide a framework for studying combinations of ibrutinib with CXCR4 inhibitors."
Sentiment: Strong Buy
Key dates .Dec 9 Dec, 10 read,Ibrutinib in combination with bendamustine and rituximab is active and tolerable in patients with relapsed/refractory CLL/SLL: final results of a phase 1b study. (Abstract 525)
Oral session: CLL: Therapy, excluding Transplantation: Chemoimmunotherapy Clinical Trials. Monday, December 9 at 3:15 pm CST in Ernest N. Morial Convention Center, 220-222
Combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP): updated results from a phase 1b study in treatment-naïve patients with CD20-positive B-cell non-Hodgkin’s lymphoma (NHL). (Abstract 852)
Oral session: Lymphoma: Therapy with Biological Agents, Excluding Pre-Clinical Models: Aggressive Lymphomas. Tuesday, December 10 at 8:45 am CST in Ernest N. Morial Convention Center, La Nouvelle Ballroom AB The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) monotherapy demonstrates long-term safety and durability of response in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) patients in an open-label extension study. (Abstract 4163)
Poster session: CLL: Therapy, excluding Transplantation: Poster I. Monday, December 9 at 6:00-8:00 pm CST in Ernest N. Morial Convention Center, Hall E Less
Sentiment: Strong Buy