The OBR Blog

January 17, 2017 - 07:01 pm Posted in ASH Conference Coverage comments0 Comments

By Lynne Lederman, PhD

At this past December’s American Society of Hematology (ASH) annual meeting, the late-breaking abstract (LBA) session was devoted to presentations selected by the Program Committee for featuring substantive, novel, and groundbreaking data that were not available by the general abstract submission deadline and would not otherwise have been presented at the meeting.

The presentation on phase 2 results of the ZUMA-1 trial of the chimeric antigen receptor (CAR) therapy KTE-C19 (axicabtagene ciloleucel) in patients with chemotherapy-refractory diffuse large B-cell lymphoma1 has attracted a lot of attention.2

Here we report on 4 other presentations in the LBA session that are also likely to affect the outcome of patients with cancer in the future.

Adding Consolidation or Second Transplant to Single Transplant and Maintenance Does Not Improve Outcomes in Multiple Myeloma

Edward A. Stadtmauer, MD, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, presented primary results from the randomized, prospective phase 3 trials of the Bone and Marrow Transplant Clinical Trials Network (BMT CTN) 0702 STaMINA trial (NCT01109004).3

This trial investigated whether the addition of a second autologous hematopoietic stem cell transplant (AHCT) or consolidation therapy combining a proteasome inhibitor (PI) with an immunomodulatory agent (IMiD) to upfront treatment of multiple myeloma (MM) with AHCT plus lenalidomide maintenance would provide additional benefit.

The study enrolled transplant-eligible patients with symptomatic MM who were age £70 years within 2 to 12 months of initiating ³2 cycles of systemic therapy, without prior disease progression, who had sufficient autologous stem cells available. Patients (N=758) were randomly assigned to receive:

  • Melphalan 200 mg/m2 AHCT and 4 cycles of consolidation therapy (lenalidomide 15 mg daily on days 1 to 14; dexamethasone 40 mg days 1, 8, and 15; and bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of every 21-day cycle) (ACM) (n=254) OR
  • Tandem melphalan 200 mg/m2 AHCT (n=247) OR
  • A single AHCT (n=257)

All patients also received maintenance therapy with lenalidomide, initially at 10 mg/day for 3 cycles, then 5 to 15 mg/day for 3 years as tolerated. In 2014 an amendment to the protocol allowed maintenance therapy to continue for an indefinite duration until disease progression.

The primary objective was to compare 38-month progression-free survival (PFS) of patients in the three arms. The events for PFS included progression, non-protocol anti-myeloma therapy, or death. The 38-month period allowed 2 months to obtain the first transplant plus 3 years of follow-up.

Secondary endpoints in all 3 arms included overall survival (OS); response rates; rate of conversion to complete response (CR) for patients who did not have CR; toxicity, including infections, after each intervention and long-term toxicity; rate of non-compliance with protocol therapy; treatment-related mortality; and quality of life (QoL).

Enrollment was completed ahead of the projected time. Patients were stratified by risk, with high-risk MM defined by high beta-2 microglobulin and high risk cytogenetic abnormalities. Demographics were balanced across the groups. Over 90% of patients had either a proteasome inhibitor (PI) or immunomodulatory drug (IMiD) as initial therapy, and over 50% had both. The median follow-up time for myeloma status was 37.8 months.

The second AHCT was not administered to 32.0% in the tandem AHCT arm; 11.8% of patients in the AHCT/consolidation arm did not receive consolidation. Maintenance therapy was not started in 16.6% and 16.9% of patients in these arms, respectively, whereas only 5.4% of patients in the single AHCT arm did not receive maintenance.

There was no difference in the primary endpoint, PFS, among arms, with a 38-month estimate of PFS of 56.5 months in the tandem transplant arm, 56.7 months in the transplant/consolidation arm, and 52.2 months in the single transplant arm. Likewise, there was no significant difference in OS among the groups (82.0, 85.7, and 83.4 months, respectively), or in PFS or OS for patients with either standard-risk or high-risk MM.

Treatment-related mortality was low: 4 deaths in the tandem group, 3 in the consolidation group, and 1 in the single transplant group. Secondary primary malignancies were reported in all arms (5.1% in the total population; 14, 15, and 10, incidents respectively),

This trial is the largest randomized comparison of post-transplant approaches for MM in the United States. It shows that after initial therapy with PIs and IMiDs, an initial AHCT, and prolonged lenalidomide maintenance therapy, the addition of consolidation therapy with bortezomib, lenalidomide, and dexamethasone after transplant or use of a second transplant do not produce incremental PFS benefits.

These results also show that induction triplet therapy containing a PI and IMiD followed by a single transplant is sufficient, and may spare patients the additional burden of a second transplant or consolidation.

Companion protocols to this trial include BMT CTN 07LT, which continues long-term follow-up and maintenance therapy to patients in the original trials who completed 3 years of maintenance therapy without disease progression. An analysis including PFS, OS, second primary malignancies, event-free survival, and quality of life (QoL) will be conducted when all surviving patients are >5 years post-randomization, which is expected around 2018.

The PRiMER protocol adds a minimal residual disease (MRD) assessment by flow, and correlative analyses of bone marrow and blood samples to be conducted in 2017. MRD assessment by gene sequencing is on-going.

Newly Identified Mutations Increase Risk for Hereditary ALL

Inherited mutations in the gene IKZF1 are associated with increased risk of developing childhood acute lymphocytic anemia (ALL), the most common childhood cancer, and a leading cause of cancer-related death in children. Both common and rare germline variants have been previously reported to be associated with inherited risk of childhood ALL.

Michelle L. Churchman, PhD, St. Jude Children’s Research Hospital, Memphis, Tennessee, reported on identification of a germline mutation in the IKZF1 gene that is associated with multiple cases of childhood ALL in a single famliy.4

The IKZF1 gene encodes the protein Ikaros, a member of the family of zinc finger transcription factors, which plays a role in lymphocyte development. Analysis of members of this family suggested that an inherited mutation in IKZF1 was associated with ALL.

The aims of this project were to determine the prevalence of inherited IKZF1 variants in ALL, and to determine if germline variants affect the function of IKZF1.

Germline DNA from 4,957 patients with sporadic ALL enrolled in frontline trials of St. Jude Children’s Research Hospital and the Children’s Oncology Group was subjected to targeted IKZF1 next-generation sequencing.

Common variants, non-coding, and synonymous variants were excluded; 44 patients were found to have germline IKZF1 mutations, of which 27 were unique variants.

These unique variants were shown to de-repress transcriptional targets, deregulate adhesion molecule expression leading to aberrant cell-stroma adhesion in the bone marrow in vivo, and conferred reduced response to treatment with dexamethasone and dasatinib in vitro and in vivo.

The results identify IKZF1 as a new ALL predisposition gene, and that germline variants play a role in the pathogenesis of ALL and response to therapy. An important question to answer is whether or not germline IKZF1 variants can be used to predict prognosis in ALL.

Ibrutinib Resolves Steroid-Resistant GVHD

Chronic graft-versus-host disease (cGVHD) is the most common cause of morbidity in patients who have received an allogeneic stem cell transplant. There are no approved treatments for cGVHD that is unresponsive to corticosteroids. David Miklos, MD, Stanford University, Stanford, California, presented the results of a multicenter, open-label, phase 2 study of ibrutinib in patients whose cGVHD failed to respond to corticosteroids and were in need of further treatment (PCYC-1129; NCT02195869).5

Ibrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK) that also inhibits interleukin-2 (IL-2)-inducible T-cell kinase (ITK), and has been approved for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), including CLL/SLL with 17p deletion, Waldentrom’s macroglobulinemia, and mantle cell lymphoma that has been treated with at least 1 prior therapy.6

Ibrutinib had been shown to reduce the severity of cGVHD in preclinical models and early clinical studies. Early results from the study supported the designation of ibrutinib as breakthrough therapy for cGVHD after failure of one or more lines of systemic therapy.7

The study enrolled patients with cGVHD that had failed £3 prior lines of therapy who had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4.

Ibrutinib was given orally at 420 mg until progression of cGVHD or unacceptable toxicity. The primary endpoint was response per the 2005 NIH consensus response criteria. Secondary endpoints included rate of sustained response, change in symptoms and corticosteroid requirements, and safety. Additional exploratory endpoints included effects on lymphoid and myeloid signaling pathways and plasma cytokines and chemokines.

The 42 enrolled patients had myeloablative (43%) or non-myeloablative (57%) transplants from related (40%) or non-related (60%) donors. Most had matched peripheral stem cells. Indications included acute and chronic anemias and other hematologic malignancies. All had prior corticosteroid, with a median of 2 prior regimens.

At a median follow-up of 14 months, 29% of patients were still taking ibrutinib; adverse events were the most frequent cause of discontinuation (33%).

Adverse events (AEs) were consistent with those reported for B cell malignancies treated with ibrutinib and those observed in patients with cGVHD treated with corticosteroids, and included fatigue, diarrhea, muscle spasms, nausea, and bruising.

Serious AEs occurred in 52% of patients including pneumonia, septic shock, and fever; 2 deaths due to multilobular pneumonia and bronchopulmonary aspergillosis occurred. Dr. Miklos commented that the lack of cardiac complications might be attributed to the small patient population.

A complete response (CR) (defined as complete resolution of all reversible manifestations of cGVHD) was observed in 9 patients; the overall response rate was 67% (CR plus partial response); 71% of the 28 patients with complete or partial responses had a sustained response for at least 5 months.

Responses were observed across multiple affected organs including skin, mouth, liver, and gastrointestinal tract, and patients with multiple organ involvement generally had responses in 2 or more organs. Overall, 62% (n=26) of patients had corticosteroid doses of <0.15 mg/kg daily, representing a reduction in corticosteroid use, during the study, and 5 discontinued all corticosteroids.

Soluble plasma factors related to inflammation, fibrosis, and cGVHD, such as pro-inflammatory cytokines, chemokines, and tissue growth factors, including tumor-necrosis factor alfa, interleukins, and epidermal growth factor, decreased with ibrutinib therapy.

These results support the investigation of ibrutinib for the front-line treatment of cGVHD in a randomized, double-blind study that is on-going.8

Pacritinib Benefits Patients with Myelofibrosis

John Mascarenhas, MD, Tisch Cancer Institute, Icahn School of Medicine, Mount Sinai, New York, New York, presented the results of the PERSIST-2, open-label, phase 3 study, which compared the safety and efficacy of pacritinib (200 mg twice daily or 400 mg once daily) to currently available therapies, including ruxolitinib, in patients with myelofibrosis who had platelet counts of £100,00 per microliter.

Ruxolitinib is a Janus kinase (JAK1/2) inhibitor, approved by the FDA in 2011 to treat intermediate- or high-risk myelofibrosis, which is a life-threatening condition. Ruxolitinib reduces splenomegaly and myelofibrosis symptoms, but causes dose-limiting cytopenias, and is not indicated for those with platelet counts <50,000 per microliter.10 Therefore, individuals with myelofibrosis and severe thrombocytopenia represent a population with unmet needs.

Pacritinib is an oral kinase inhibitor with specificity for JAK2, FLT3, and other enzymes, and reduced spleen volume and controlled symptoms of myelofibrosis compared with best available therapy (BAT excluding JAK2 inhibitors) regardless of platelet count.

Pacritinib was placed on full clinical hold by the FDA on February 8, 2016 due to concerns about interim survival results, bleeding, and cardiovascular events. The trial was shortened due to the clinical hold.11 However, the hold was recently lifted, and a new trial is set to begin that is enrolling as many as 105 participants with primary myelofibrosis who have failed previous ruxolitinib therapy.12

Of patients enrolled in the pacritinib once daily (n=104), pacritinib twice daily (n=107) or BAT (n=100) groups, nearly all discontinued treatment, mostly due to the clinical hold.

Analyses were done at week 24 prior to the hold. Half the patients in the BAT had crossed over to pacritinib treatment. BAT had consisted of ruxolitinib (45%), hydroxyurea (19%), or “watch and wait” (19%).

Pacritinib was associated with statistically significant reduction in spleen volume vs BAT (P=.001 vs pacritinib groups combined, P=.017 vs once daily, P=.001 vs twice daily).

The twice daily dose of pacritinib was associated with significant ≥50% reduction in total symptom score vs BAT, whereas the once daily dose was not. This may be due to higher steady-state plasma levels associated with the twice daily dose.

Platelet count in patients with a baseline platelet count of <50,000 per microliter increased in both pacritinib groups, and to a greater extent in the once daily group.

Patients treated with pacritinib also had lower requirements for red blood cell transfusion that those in the BAT group at weeks 12 and 24. OS for the pacritinib groups and the BAT group censored at the date of clinical hold were not significantly different.

Pacritinib was associated with more AEs than BAT, primarily diarrhea, nausea, vomiting, anemia, and thrombocytopenia, and were generally less frequent with twice daily dosing. Deaths due to AEs and/or progressive disease occurred in all groups at about the same rate.

In the discussion that followed his presentation, Dr. Mascarenhas said pacritinib was well tolerated and offered symptom relief in a patient population that was quite ill. He continued that his opinion as a clinical investigator is that pacritinib is an effective drug, with a benefit-risk ratio in its favor, and he hopes to see the drug move forward, although additional trials will require FDA approval.

 

References

  1. Neelapu SS, Locke FL, Bartlett NL, et al. Kte-C19 (anti-CD19 CAR T Cells) induces complete remissions in patients with refractory diffuse large B-cell lymphoma (DLBCL): results from the pivotal phase 2 Zuma-1. Blood 2016 128:LBA-6.
  2. Wolfe G, Grisolano J. CARs of the future on display at ASH 2016 as ZUMA-1 wows the crowd. The OBR Blog. http://obroncology.com/blog/.
  3. Stadtmauer EA, Pasquini MC, Blackwell B, et al. Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (Len) and dexamethasone (RVD) consolidation with Len maintenance (ACM), tandem autoHCT with Len maintenance (TAM) and autoHCT with Len maintenance (AM) for up-front treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702 - StaMINA Trial). Blood 2016 128:LBA-1.
  4. Churchman ML, Qian M, Zhang R, et al. Germline genetic variation in IKZF1 and predisposition to childhood acute lymphoblastic leukemia. Blood 2016 128:LBA-2.
  5. Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Blood 2016 128:LBA-3.
  6. Imbruvica® (ibrutinib) capsules, for oral use. Prescribing information. Pharmacyclics, LLC, Sunnyvale, California. June, 2016.
  7. Ibrutinib (IMBRUVICA®) Granted Breakthrough Therapy Designation by U.S. Food and Drug Administration (FDA) for the Development of a Treatment for Chronic Graft-Versus-Host Disease (CGVHD).; 2016. Available at: http://www.prnewswire.com/news-releases/ibrutinib-imbruvica-granted-breakthrough-therapy-designation-by-us-food-and-drug-administration-fda-for-the-development-of-a-treatment-for-chronic-graft-versus-host-disease-cgvhd-300291651.html. Accessed January 9, 2017.
  8. Ibrutinib in Combination with Corticosteroids versus Placebo in Combination with Corticosteroids in Subjects with New Onset Chronic Graft Versus Host Disease (cGVHD) (iNTEGRATE). https://clinicaltrials.gov/ct2/show/NCT02959944. Accessed January 9, 2017.
  9. Mascarenhas J, Hoffman R, Talpaz M, et al. Results of the Persist-2 phase 3 study of pacritinib (PAC) versus best available therapy (BAT), including ruxolitinib (RUX), in patients (pts) with myelofibrosis (MF) and platelet counts <100,000/µl. Blood 2016 128:LBA-5.
  10. Jakafi® (ruxolitinib) tablets for oral use. Prescribing information. Incyte Corporation, Wilmington, Delaware. March 2016.
  11. Adams B. Struggling CTI reveals new pacritinb data, misses a primary endpoint. August 29, 2016. http://www.fiercebiotech.com/biotech/struggling-cti-reveals-new-pacritinib-data-misses-a-primary-endpoint. Accessed January 5, 2017.
  12. PR Newswire. CTI BioPharma Announces Removal of Full Clinical Hold On Pacritinib. January 5, 2017. http://finance.yahoo.com/news/cti-biopharma-announces-removal-full-063000655.html. Accessed January 9, 2017.

 

January 17, 2017 - 07:01 pm Posted in ASH Conference Coverage comments0 Comments

Introduction

Presenting you with timely market feedback from the 58th ASH Annual Meeting held in December 2016, OBR and MDoutlook® are pleased to share results from MDoutlook’s OncoPolls™ conducted immediately after the meeting. This report examines US oncologists’ awareness, views and early involvement with the CAR-T cell therapies being developed for a variety of hematologic malignancies.

OncoPoll™ Methodology

  • Primary research phase involved a survey to verified and validated US hematological and medical oncologists with an identified clinical interest in B-cell lymphomas utilizing targeting parameters within the proprietary MDoutlook global cancer treater panel
  • Timing: December 2016. Launched 9 days after close of 2016 American Society of Hematology (ASH) Annual Meeting, held in San Diego, CA, December 3-6, 2016
  • Fielding to proprietary panel of cancer treaters, targeted by clinical interest
  • Data capture via interactive web-based survey instrument, utilizing proven MDoutlook methodology and proprietary technology
  • Multiple formulations / variants of the same target antigen & malignancy combination were often presented but the survey grouped all target antigen + malignancy together. Where relevant, reference was made to multiple abstracts in each category and links to these abstracts on the ASH website were provided within the survey for physician reference
  • Reponses at data collection: 100

Awareness and Expected Impact of Various CAR-T Cell Approaches for B-Lineage Malignancies

Key Conclusions

  • On a 0 – 5 scale of 0 = no awareness to 5 = very aware, clinicians have an average / slightly above average awareness of these presentations
    • A general higher level of awareness is seen by those who attended ASH
    • The average level awareness about the CD19 directed CAR-T cells in B-cell ALL is somewhat higher than others, as expected, since this approach is the furthest along in clinical development
  • All of these approaches, as rated on a 1 – 5 scale of 1 = not at all important to 5 = very important, are seen as being very clinically meaningful
    • CD19-directed CAR-T cell approach for B-cell ALL is held in a slightly higher regard than the other approaches
    • Attendees of the ASH Annual Meeting consistently rate each of these approaches as more important than the non-attendees, but only by a consistently small margin (0.1-0.4 pts)

Current Impact of CAR-T Studies on Clinical Practices

Key Conclusions

  • When asked about patient referrals to clinical trials for CAR-T cell therapies, meeting attendees average nearly 4 patients over the past year, whereas the non-attendees are around 1.5 patients. When separating respondents based on practice setting (academic vs. community), the averages are mostly similar (averages 2.6-3.0 patients per year)
  • When asking how common it was for patients to already ask about being treated with a CAR-T cell approach, ¾ of the attendees state that they have been asked about it (avg. 8 patients in last 6 months) while ~40% of non-attendees have been asked about it (avg. 2 patients in last 6 months)
    • Taking these 2 questions together, it appears that attendees could be considered “clinical investigators” and their patients tend to know this about them. As such, the patients of meeting attendees are more willing to ask for the newest treatment approaches (self-selection of patients to different physician types)
  • The involvement / leadership of NIH investigators in the CAR-T cell therapy development is seen as a positive aspect by US physicians, consistently rating ~7 on a 10-point scale

Conclusions: CAR-T Cell Therapies for B-Lineage Malignancies

  • All of these studies highlight the importance of the ASH Annual Meeting to the entire hematologic oncology community – awareness of each of these presentations are high and can occur quite quickly even for those who did not attend the meeting. Alternative methods to disseminate new clinical information are very important to improving clinical practices and patient outcomes
  • CAR-T cell therapies are already impacting clinicians in their day-to-day practices, even though they are not yet commercially available. Patients are asking their oncologists about them and physicians are regularly referring patients to their clinical trials.

For a more detailed analysis report, please click here to download the full report.

Submitted by Dr Robert Stephan, VP, Research and Physician Society, and Dr Jan Heybroek, President MDoutlook.

January 06, 2017 - 11:01 pm Posted in ASH Conference Coverage Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) comments0 Comments

Introduction

In an effort to provide you with timely market feedback from the 58th ASH Annual Meeting held in December 2016, OBR and MDoutlook® are pleased to share results from MDoutlook’s OncoPolls™ conducted last month immediately after the meeting. This report explores the choice between Rituxan® and Gazyva® in the front line setting for follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and the use of Rituxan and Revlimid® in the maintenance setting for mantle cell and CLL, respectively.

OncoPoll™ Methodology

  • Primary research phase involved a survey to verified and validated US hematological and medical oncologists with an identified clinical interest in B-cell lymphomas utilizing targeting parameters within the proprietary MDoutlook global cancer treater panel
  • Timing: December 2016. Launched 9 days after close of 2016 American Society of Hematology (ASH) Annual Meeting, held in San Diego, CA, December 3-6, 2016
  • Fielding to proprietary panel of cancer treaters, targeted by clinical interest
  • Data capture via interactive web-based survey instrument, utilizing proven MDoutlook methodology and proprietary technology
  • Links to discussed abstracts on the ASH website were provided within the survey
  • Reponses at data collection: 100

Institutional Setting by Attendance of Respondents

oncopoll_nhl_attendance

Use of anti-CD20 mAbs in the Front Line for Different B-cell Lymphomas

Awareness of Abstracts #6 & #470

oncopoll_nhl_awareness

 General Clinical Importance of Different anti-CD20 mAbs in FL & DLBCL

oncopoll_nhl_importance

Expected Impact on anti-CD20 Usage in FL & DLBCL

 oncopoll_nhl_impact

Key Conclusions

  • On a 0 – 5 scale of 0 = no awareness to 5 = very aware, clinicians have only an average / slightly below average awareness of these presentations
    • A general higher level of awareness is seen by those who attended ASH (nearly a full rating point higher for each abstract)
    • The average level awareness about the FL abstract is somewhat lacking considering it was presented in the Plenary Session
  • Clinical impact of these presentations, rated on a 1 – 5 scale of 1 = not at all important to 5 = very important, is seen as being very clinically meaningful
    • US oncologists assign a high importance (>4) to the FL presentation (Abstract #6), regardless of meeting attendance
    • Abstract #470 (concerning DLBCL) is seen as somewhat less important, especially by those who did not attend the meeting
  • Expected impact on anti-CD20 mAb usage in their practice was also measured. A 14-22% absolute growth in usage of Gazyva is predicted in the near future, all at the expense of Rituxan usage. No real changes noted in patients not treated with anti-CD20 antibodies or with other anti-CD20 antibodies (not shown). With greater impact seen with non-attendees, this shows the importance of the information itself, compared to the need to be present at the meeting for changing practices.

Use of Maintenance Strategies for Mantle Cell Lymphoma and CLL

Awareness of Abstracts #145, #229 & #230

oncopoll_nhl_maintenance-mcl-cll

General Clinical Importance of Maintenance Strategies for Mantle Cell Lymphoma and CLL

oncopoll_nhl_importance-mcl-cll

Expected Impact on Maintenance Usage in Mantle Cell Lymphoma and CLL

oncopoll_nhl_impact-mcl-cll

Key Conclusions

  • On the same 0 – 5 scale, attendees of the ASH meeting have an average level awareness about these maintenance presentations, while awareness by non-attendees is low
    • No meaningful differences in awareness among these three abstracts
  • Upon providing these abstracts for review, US oncologists recognize the clinical importance of this information and plan on incorporating these maintenance strategies into their clinical practices immediately
    • Meeting attendance does not really impact these findings. In fact, non-attendees may be more likely to use these approaches in their practices

Conclusions: Immediate Impact of 2016 ASH Presentations on Clinical Practice for B-cell Lymphomas

  • All of these studies highlight the importance of the ASH Annual Meeting to the entire hematologic oncology community – awareness of these presentations are high and can occur quite quickly even for those who did not attend the meeting. Alternative methods to disseminate new clinical information are very important to improving clinical practices and patient outcomes
  • The information in these presentations will be integrated into clinical practice in relatively short order, especially since most of these agents are already widely available and in use

For a more detailed analysis report, please click here to download the full report.

Submitted by Dr Robert Stephan, VP, Research and Physician Society, and Dr Jan Heybroek, President MDoutlook.

December 07, 2016 - 04:12 pm Posted in ASH Conference Coverage Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) comments0 Comments

By: Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

kantarhealthlogo

 

Immunotherapies such as checkpoint inhibitors have had a dramatic impact on treatment paradigms for many tumor types over the past few years, and their full potential is far from being realized. Hot on the heels of checkpoint inhibitors are engineered, adoptive T-cell therapies that represent another promising advancement. These “living drugs” certainly have the potential to lead to yet another paradigm shift in anticancer therapies. Chimeric antigen receptor (CAR) technology, one type of adoptive T-cell therapy, took center stage yesterday at the 2016 American Society of Hematology (ASH) annual meeting.

With the CAR T-cell approach, T-cells (typically patient-derived) are transduced with an engineered receptor that typically comprises an extracellular domain that recognizes a specific epitope on cancer cells (typically from a B-cell-derived monoclonal antibody), coupled with the intracellular CD3ζ  domain derived from the T-cell receptor and one or more co-stimulatory signaling domains. Patients receive “preparative chemotherapy” to achieve lymphodepletion and/or myeloablation to minimize regulatory T-cells and myeloid-derived suppressor cells that inhibit immune-mediated attack, and then genetically modified T-cells that attack cancer cells are infused into the patient.

Kite Pharma is developing KTE-C19 (axicabtagene ciloleucel), an investigational therapy where patients’ T-cells are genetically modified to express a chimeric antigen receptor designed to target the antigen CD19, a protein expressed on the cell surface of B-cell lymphomas and leukemias. The intracellular portion of the KTE-C19 contains the CD3ζ signaling domain in tandem with the co-stimulatory CD28 signaling domain.

Results of the evaluation of KTE-C19 in patients with chemotherapy-refractory diffuse large B-cell lymphoma (DLBCL) from the Phase II portion of the ZUMA-1 trial were presented by Dr. Sattva S. Neelapu yesterday in the Late-Breaking Abstract session of the ASH 2016 annual meeting. The ZUMA-1 trial (NCT02348216) is a single-arm, open-label, multicenter, Phase I/II trial designed to evaluate the safety and efficacy of KTE-C19 in refractory aggressive non-Hodgkin’s lymphoma (NHL). Patients with DLBCL, primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL) were enrolled in the trial. Safety was the primary endpoint in the Phase I portion of the study, and overall response rate was the primary endpoint of the Phase II portion with secondary endpoints that included duration of response, progression-free survival, and overall survival. Results of the Phase I portion of ZUMA-1 were reported previously1 and demonstrated ongoing complete responses in 43% of treated patients at 12 or more months. The Phase II portion of the study has two cohorts based on tumor type: DLBCL (cohort 1) or PMBCL/TFL (cohort 2). Preliminary results from the first prespecified interim analysis of KTE-C19, which included DLBCL patients (cohort 1), from ZUMA-1 were presented.2

Patients (n=111) were enrolled and leukapheresed to collect T-cells for production of KTE-C19. Patients subsequently received a conditioning regimen of cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) x three days. KTE-C19 manufacture was accomplished with an average turnaround time of 17 days, a 99% success rate, and 101 patients each received  a single infusion of KTE-C19 (2 x106 cells/kg).  Patients had a median age of 59 and had received a median of three prior therapies. Of 73 treated DLBCL patients, the best overall response rate (ORR) with a one-month follow-up was 68%, including a complete response (CR) rate of 33%. At a three-month follow-up, the best ORR improved to 76% with a CR rate of 47%, which compares favorably to historical control (p=0.0001), and thus the primary endpoint of the study was achieved. There was a 39% durable CR rate at the three-month assessment. Grade ≥3 adverse events were reported in 93% of DLBCL patients and included cytokine release syndrome in 10 patients (14%) and neurologic events in 18 patients (25%); most of these adverse events were reversible. One KTE-C19-related Grade 5 event was reported in a DLBCL patient.

DLBCL is the most commonly occurring subtype of NHL, with an incidence of 28,449 in 2016 according to Kantar Health’s CancerMPact® Patient Metrics.3 There is a great need for effective treatment options for this patient population as outcomes are quite poor for patients with refractory DLBCL. A recent meta-analysis recently reported an ORR of 26% and median overall survival of 6.6 months based on currently available therapies.4 Efficacy results from the ZUMA-1 study trial far exceed historical controls, like this meta-analysis, and thus ZUMA-1 results generated considerable excitement at ASH 2016. ZUMA-1 is the first multicenter study of anti-CD19 CAR T-cells in refractory, aggressive NHL, and this study demonstrated the successful implementation of management strategies for treatment emergent adverse events associated with this technology. Additional data from ZUMA-1 were presented at ASH 2016 from patients with PMBCL and TFL (cohort 2), and results were equally as encouraging.5

KTE-C19 will likely play an important role in the future treatment of DLBCL and other aggressive NHL subtypes. The U.S. Food and Drug Administration (FDA) awarded KTE-C19 Breakthrough Therapy Designation (BTD) in December 2015. On December 4, 2016, Kite announced that they initiated a rolling submission of a U.S. Biologic License Application (BLA) to the FDA based on the results of ZUMA-1, and completion of the filing is expected by the end of the first quarter of 2017. The BLA is for treatment of relapsed patients with aggressive B-cell NHL who are ineligible for autologous stem cell transplant (ASCT). This submission represents the first BLA filing for a CAR-T therapy. With approval likely, Kite plans to commercially launch KTE-C19 in 2017. Kite also plans a regulatory submission to the European Medicines Agency (EMA) for KTE-C19 in 2017. Earlier this year, the EMA granted Kite access to Priority Medicines (PRIME) regulatory support for axicabtagene ciloleucel for the treatment of refractory DLBCL.

Kite is also sponsoring clinical trials to evaluate KTE-C19 in other B-cell malignancies including indolent NHL, mantle cell lymphoma, acute lymphocytic leukemia, and chronic lymphocytic leukemia. In September 2016, Kite, in collaboration with Roche/Genentech, initiated ZUMA-6, a Phase I/II study designed to evaluate safety and efficacy of KTE-C19 administered in combination with atezolizumab for treatment of patients with refractory DLBCL. The future looks bright for this CAR T-cell product.

References:  

  1. Locke FL, et al. Ongoing complete remissions in phase 1 of ZUMA-1: a phase 1-2 multi-center study evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in patients with refractory aggressive B cell non-Hodgkin lymphoma (NHL). Annals Oncol, 27 (suppl. 6):   Abstract 1048O, 2016.
  2. Neelupa SS, et al. KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1. LBA 6, American Society of Hematology annual meeting, 2016.
  3. Kantar Health, CancerMPact® Patient Metrics U.S., accessed December, 2016
  4. Crump M, et al. Outcomes in refractory aggressive diffuse large b-cell lymphoma (DLBCL): Results from the international SCHOLAR-1 study. J Clin Oncol 34, 2016 (suppl; abstr 7516).
  5. Locke FL, et al. A Phase 2 Multicenter Trial of KTE-C19 (anti-CD19 CAR T Cells) in Patients With Chemorefractory Primary Mediastinal B-Cell Lymphoma (PMBCL) and Transformed Follicular Lymphoma (TFL):  Interim Results From ZUMA-1. Abstract 998, American Society of Hematology annual meeting, 2016.
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