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.
Institutional Setting by Attendance of Respondents
Use of anti-CD20 mAbs in the Front Line for Different B-cell Lymphomas
Awareness of Abstracts #6 & #470
General Clinical Importance of Different anti-CD20 mAbs in FL & DLBCL
Expected Impact on anti-CD20 Usage in FL & DLBCL
Use of Maintenance Strategies for Mantle Cell Lymphoma and CLL
Awareness of Abstracts #145, #229 & #230
General Clinical Importance of Maintenance Strategies for Mantle Cell Lymphoma and CLL
Expected Impact on Maintenance Usage in Mantle Cell Lymphoma and CLL
Conclusions: Immediate Impact of 2016 ASH Presentations on Clinical Practice for B-cell Lymphomas
Submitted by Dr Robert Stephan, VP, Research and Physician Society, and Dr Jan Heybroek, President MDoutlook.
By: Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
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.
By: Len Kusdra, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health
In the management of non-Hodgkin lymphoma (NHL), Rituxan® (MabThera in Europe, rituximab, Genentech/Roche)-based therapy forms the foundation for therapy in all settings. This holds true for most subtypes of NHL, including follicular lymphoma (FL), mantle cell lymphoma (MCL), and diffuse B-cell lymphoma (DLBCL). While Rituxan-based therapy is highly effective and leads to improvement in survival rates, patients are rarely cured, and relapse is common, occurring in about 20-30% of patients.
In addition to this clinical challenge of developing resistance to Rituxan-based regimens, Roche/Genentech also face a commercial challenge as the looming patent expiration for Rituxan approaches and the development of biosimilars threatens to steal Rituxan’s market share. Keeping this in mind, the companies developed an aggressive program with Rituxan’s heir apparent, Gazyva® (Gazyvaro in Europe, obinutuzumab, Roche/Genentech), hoping to maintain their hold in the NHL market. Gazyva is a next-generation CD20 inhibitor designed to be a “biobetter” of Rituxan.
This strategy appeared to have paid off when the Phase III GADOLIN (NCT01059630) trial evaluating Gazyva in combination with Treanda® (bendamustine, Teva/MundiPharma/Symbio) in relapsed patients, presented at the 2015 American Society of Clinical Oncology Conference, showed an improvement in progression-free survival (PFS) when patients were treated with Gazyva plus Treanda followed by Gazyva maintenance.1 Based on these results, Gazyva was subsequently approved in February 2016 for the treatment of FL patients who were refractory to Rituxan-based therapy or had relapsed after Rituxan treatment. The approval propelled Gazyva firmly into the NHL space. (Note that Gazyva is also approved for use in combination with chlorambucil as front-line therapy for chronic lymphocytic leukemia, CLL.) With an approval secured in the relapsed/refractory setting, the question became whether Gazyva would be successful in the front-line setting in patients with FL.
Based on the initial results from the Phase III GALLIUM trial (NCT01332968) presented at the Plenary Session on December 4, 2016, at the American Society of Hematology Conference, the answer appears to be an encouraging “Yes.”2 GALLIUM is an open-label Phase III trial evaluating Gazyva in combination with chemotherapy (CHOP, CVP, or Treanda) followed by Gazyva maintenance versus Rituxan plus chemotherapy followed by Rituxan maintenance. A total of 1,202 patients were randomized to receive Rituxan at 375mg/m2 on day 1 of each cycle or Gazyva at 1000mg on days 1, 8 and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (for CHOP and CVP) or six 28-day cycles (for Treanda). Patients who achieved a complete or partial response at the end of induction received 1000mg of Gazyva (for patients in the Gazyva induction arm) or 375mg/m2 of Rituxan (for patients in the Rituxan induction arm) IV every two months for two years or until progressive disease. GALLIUM met its primary endpoint of investigator-assessed PFS. With a median follow-up of 34.5 months, patients in the Gazyva arm had a statistically significant lower risk of progression or death (HR=0.66; 95% CI: 0.51-0.85, p=0.0012). Similarly, PFS as assessed by an independent review committee showed a statistically significant improvement with Gazyva (HR=0.71; 95% CI: 0.54-0.93, p=0.014). While there was a trend toward an overall survival (OS) benefit with the Gazyva arm, showing a 94% three-year OS rate compared with 92% for the Rituxan arm, the data are not mature enough to determine whether this improvement is clinically significant (HR=0.75, 90% CI: 0.49-1.17, p=0.210). The response rates were also similar between the Rituxan and the Gazyva arms (88.5% for Gazyva plus chemotherapy and 86.9% for Rituxan plus chemotherapy).
A post-hoc analysis stratified by combination regimen showed equal survival benefit with Gazyva regardless of the chemotherapy backbone (HR for Gazyva plus Treanda versus Rituxan plus Treanda=0.61; HR for Gazyva plus CHOP versus Rituxan plus CHOP=0.77; HR for Gazyva plus CVP versus Rituxan plus CVP=0.63). Discontinuation rates between both arms were similar (16.3% for Gazyva and 14.2% for Rituxan), as well as rates of Grade ≥ 3 adverse events (74.6% for Gazyva and 67.8% for Rituxan). The most common Grade ≥ 3 adverse events in the Gazyva arm were neutropenia (43.9%), leucopenia (8.6%), febrile neutropenia (6.9%), and thrombocytopenia (6.1%), which were slightly higher than the Rituxan arm. The rates of Grade 5 adverse events were also similar between both arms (4.0% in the Gazyva arm versus 3.4% in the Rituxan arm).
Results from GALLIUM put Gazyva in a favorable position for a line extension in the front-line setting. Roche and Genentech’s design to allow for physician’s choice of chemotherapy may have been out of practical necessity but will ultimately strengthen Gazyva’s utilization. According to physicians surveyed in the United States, CHOP, CVP, and Treanda are the most common partners used in combination with Rituxan, being utilized in over 80% of patients.3 The clinical benefit seen with Gazyva over Rituxan places it in a strong position to absorb a significant market share that Rituxan currently holds not only in the front-line setting but also in the relapsed setting, thus paving the way for a Gazyva-based therapy to replace Rituxan as standard of care in the future. Collectively, these data may thus provide impetus to use Gazyva upfront, with physicians switching the chemotherapy regimen but maintaining Gazyva as backbone following first relapse.
Despite its strong position, Gazyva faces stiff competition. While GALLIUM showed a PFS benefit of Gazyva over Rituxan, the lack of mature OS data may make physicians reluctant to switch to Gazyva, particularly as Rituxan nears the end of its patent lifespan. This may give time to allow entry of potentially lower-cost rituximab biosimilars to corner a share of the market. Indeed, biosimilars of several other branded products have already begun to make entry into the United States with the recent approvals of Zarxio® (filgrastim-sndz, Sandoz), Inflectra® (infliximab-dyyb, Pfizer), Erelzi (enterecept-szzs, Sandoz), and Amjevita (adalimumab-atto, Amgen), and while oncology biosimilars have yet to make landfall in the United States, this may change in the near future as physicians become familiar with these agents.
Highlighting the growing threat that biosimilars pose to branded agents, Sandoz announced earlier this year that the European Medicines Agency accepted a Marketing Authorization Application for a biosimilar to Roche's Rituxan/MabThera in Europe, signaling the coming battle in the oncology space.4 In addition to biosimilars, Gazyva faces additional threats from novel agents such as Imbruvica (ibrutinib, Abbvie), duvelisib (Infinity), and Revlimid (lenalidomide, Celgene) that are being evaluated in combination with Rituxan in the front-line setting in their respective Phase III trials. Of these agents, the strongest threat to Gazyva appears to be Revlimid, showing a robust response rate when combined with Rituxan (98% ORR) in a Phase II trial of FL patients in the front-line setting.5 If the strong response rate seen in the Phase II trial translates into a survival benefit in the Phase III RELEVANCE (NCT01650701) trial, Revlimid with Rituxan will be in a good position to surpass Gazyva’s current lead in the treatment of FL.
For the time being however, Gazyva represents a leap forward in the treatment of NHL, which is good news indeed for patients.
November 22, 2016 - 03:11 am Posted in ASH Conference Coverage Posted in Leukemia (includes ALL, AML, APL, CLL, CML, MDS, Myeloproliferative Disorders, Myelofibrosis) Posted in Lymphoma (includes NHL, HL, CNS Lymphoma) Posted in Multiple Myeloma 0 Comments
This year's ASH Annual Meeting will be chock-full of interesting, informative, and clinically useful presentations, according to a whirlwind tour of highlights presented at a pre-meeting Webinar by ASH President Charles Abrams, MD, and Stephanie Lee, MD, ASH Secretary.
Starting with the most immediately clinically applicable studies, Dr. Lee singled out two studies of approved agents in narrow disease states: Abstract 182 and 145.
Abstract 182 provides results of the Phase 3 ALCANZA trial comparing brentuximab versus physician's choice of therapy (methotrexate or bexarotene) in CD30-expressing cutaneous T-cell lymphoma (CTCL), a relatively rare disease. The study included 128 randomized patients followed for 17.5 months. For the primary endpoint, overall response rate (ORR) at 4 months, brentuximab was significantly superior to physician's choice of therapy: 56% versus 13%, respectively (P<.0001). Median progression-free survival (PFS) was 16.7 months versus 3.5 months, a highly significant difference favoring brentuximab (P<.0001).
"This study showed that brentuximab has a significant advantage over the other two options used to treat CTCL," Dr. Lee told listeners.
Abstract 145 presents final results of the Phase 3 LyMa trial that compared rituximab maintenance every 2 months for 3 years versus observation in younger patients with mantle cell lymphoma (MCL) in response after undergoing autologous stem cell transplant (ASCT). The study included 240 patients with a median follow-up of 50 months. Four-year event-free survival (EFS) was 78.9% for rituximab maintenance versus 61.4% for observation (P=.0012). Four -year progression-free survival (PFS) and overall survival (OS) were also improved with rituximab maintenance therapy. Four-year PFS was 8.2.% versus 64.6%, respectively (P=.0005), and 4-year OS was 88.7% versus 81.4%, respectively (P=.0413).
"This study provides good evidence that rituximab improves outcomes after ASCT in younger patients with mantle cell lymphoma. Some hematologists are already doing this, and now there is evidence [to support this practice] from a Phase 3 trial," Dr. Lee noted.
Abstract 6 showed a 34% reduction in risk of progression or death with obinutuzumab versus rituximab as induction and maintenance therapy in about 1200 patients with previously untreated follicular lymphoma with Stage 3 or 4 or bulky Stage 3 disease, according to primary results of the Phase 3 GALLIUM trial.. Patients were randomized 1:1 to obinutuzumab versus rituximab (both anti CD20 agents) at induction. No difference in complete response or partial response was observed after induction therapy. Patients continued on maintenance therapy for 2 years. More Grades 3 and 5 severe adverse events occurred with obinutuzumab.
"These data show that obinutuzumab is more effective in prolonging time to relapse, but the caveat is greater toxicity," Dr. Lee commented.
Dr. Abrams highlighted two studies using genetically engineered chimeric antigen receptor (CAR) T cells. A late-breaker (Abstract LBA 6) showed that Kte-CD19 CAR T cells induced responses in 76% of 101 patients from 22 institutions with refractory diffuse large B-cell lymphoma in the pivotal Phase 2 ZUMA-1 trial. ORR was 76% (47% complete response [CR] rate and 29% partial response rate [PR]). PFS was 56% at 3 months, which Dr. Abrams called "impressive."
"The T-cells were engineered within 17 days from apheresis, which is a relatively quick turnaround. This treatment is not for the faint of heart, but it does induce complete remissions in some patients. This novel technology can be extended to many centers in the community, even those with no experience using CAR T," Dr. Abrams noted.
A second study (Abstract 650) found that anti-CD22 CAR T cells had encouraging results in a small study of 9 "tough to treat" patients (children and young adults) with relapsed/refractory acute lymphoblastic leukemia (ALL). All 9 patients had at least 1 prior transplant, and 2 had undergone 2 prior transplants. Patients had chemotherapy and then were given anti-CD22 CAR T. Interim results at 1 month showed that 4 of the 9 patients had CR with no evidence of minimal residual disease.
"This approach with CAR T is a little different, aimed at a different target of T cells with CD 22 expression. This is encouraging, suggesting that the target of CAR T can be expanded. Someday we may be using a panel of targets," Dr. Abrams commented.
OTHER HEMATOLOGIC MALIGNANCIES
Patients with high-risk chronic lymphocytic leukemia (CLL) were randomized 2:1 to lenalidomide maintenance versus placebo after front-line chemotherapy in the randomized, controlled, German CLLM1 trial (Abstract 229). Interim analysis of the first 89 patients of a planned enrollment of 200 showed such robust results for lenalidomide, that the trial was stopped early. At a median follow-up of 17.7 months, PFS was not yet reached in the lenalidomide-treated group versus 14.6 months for placebo. Patients treated with lenalidomide were 80% more likely to be converted to node-negative disease compared with placebo. No difference in OS was observed between the two groups with short follow-up.
"These interim findings suggest that lenalidomide maintenance is beneficial in high-risk CLL. We need continued follow-up of these patients," Dr. Lee commented.
Although the investigational drug pacritinib was found effective in myelofibrosis in a Phase 3 trial (Abstract LBA 5), development of the drug was put on hold by the FDA due to potential cardiovascular excess deaths and hemorrhagic events in the PERSIST-1 trial. The Phase 3 PERSIST-2 study evaluated pacritinib versus best available therapy (including the JAK inhibitor ruloxitinib in 44%) in 311 patients with myelofibrosis and platelet counts <100,000 µ/l. Patients were randomized 1:1 to pacritinib versus best available therapy. Pacritinib was superior, with a 35% reduction in spleen volume, and significantly more improvement in time to symptoms at 24 weeks. Although some gastrointestinal and hematologic toxicities were observed with pacritinib, no difference between the two treatment arms was seen in cardiovascular events and bleeding.
PERSIST-2 is the only randomized trial to date in patients with myelofibrosis and thrombocytopenia and prior JAK2 inhibitor exposure. "This study is intriguing. Pacritinib did improve symptoms and spleen volume, but it remains to be seen what the FDA will do," Dr. Lee said.
Another late-breaking abstract (LBA 1) was based on the randomized, controlled, Phase 3 StaMINA trial, which compared three different approaches to multiple myeloma in transplant-eligible patients using upfront autologous hematologic cell transplant (auto HCT): auto HCT plus RVD (bortezomib, lenalidomide, dexamethasone); tandem auto HCT plus lenalidomide maintenance (TAM); and auto HCT with lenalidomide maintenance (AM). The study enrolled 758 patients. At 38 months, PFS and OS were similar in all three groups. The probability of PFS was 57%, 56%, and 52% for the three approaches, respectively; the probability of OS was 86%, 82%, and 83%, respectively.
This is the largest randomized U.S. transplant trial in myeloma. "Results of StaMINA suggest that the addition of more chemotherapy or more transplant does not improve outcomes. All of these are reasonable approaches," Dr. Lee noted.
SESSION ON QUALITY
Turning to a different area, Dr. Lee cited a Special Symposium on Quality of Care in the Era of Health Improvement Technology. Three different speakers will tackle the question of whether the new technology is having an impact on patient care.
"I hope this symposium will dig into the current experience for patients and for researchers," she said.
"There is something for everyone at the upcoming ASH meeting," she noted.