Late-Breaking Clinical Trials Advance Targeted Therapies for Patients with CLL and Multiple Myeloma

Results Are Expected to Prompt Changes in Practice, Improve Patient Outcomes

(San Diego, December 4, 2018) — Three studies being presented today during the 60th American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego offer more targeted solutions for managing CLL and multiple myeloma.

“The most important take home point is that all three of these late-breaking studies demonstrate how targeted therapies are improving outcomes for our patients,” said press briefing moderator Aaron Gerds, MD, MS, of the Cleveland Clinic Taussig Cancer Institute. “For both multiple myeloma and chronic lymphocytic leukemia, we’re rapidly shifting from cytotoxic to targeted treatments, which is exciting given the toxicities patients can experience with traditional chemotherapy.”

This embargoed press conference will take place on Monday, December 3, at 10 a.m. PST in Room 22, San Diego Convention Center.

Ibrutinib-Based Therapy More Effective, Safer in Younger Patients with Previously Untreated CLL Compared with Current Standard of Care

A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group [LBA-4]

A six-month course of chemotherapy-based treatment with intravenous fludarabine and cyclophosphamide plus rituximab (FCR) has historically been the most effective treatment for chronic lymphocytic leukemia (CLL), especially in patients 70 years of age and younger. But results from a head-to-head phase III trial comparing FCR against a more targeted ibrutinib-based therapy reveal that patients receiving the ibrutinib plus rituximab therapy had a two-thirds reduction in the risk of disease progression relative to those getting standard care. Overall survival was also significantly improved for patients receiving ibrutinib therapy based on current follow-up.

“We found ibrutinib-based therapy is both more effective and less toxic than our previous best therapy for CLL patients,” said lead author Tait D. Shanafelt, MD, of the Stanford University School of Medicine. “These findings have immediate practice-changing implications. They establish the combination of ibrutinib plus rituximab as the most effective first-line treatment for CLL patients age 70 and younger.”

Ibrutinib is a targeted therapy that was designed, in part, to interrupt or target a specific enzyme known to help CLL cells to survive. It inhibits Bruton’s tyrosine kinase, a protein that is critical to the survival of CLL leukemia cells.

“Ibrutinib targets the Achilles’ heel of CLL cells, whereas previous chemotherapy was much less targeted,” Dr. Shanafelt said.

The trial enrolled 529 patients with previously untreated, symptomatic CLL between January 31, 2014, and June 9, 2016. Participants ranged in age from 28 to 70 (median age 57). Two-thirds of patients received ibrutinib plus rituximab and one-third received a six-month course of FCR. Researchers had tracked patient outcomes for a median of 33.4 months at the time of the analysis.

Rates of survival without disease progression were significantly better in patients who received ibrutinib plus rituximab compared with FCR. In addition, the ibrutinib therapy conferred better overall survival. In subgroup analyses for progression-free survival, ibrutinib was superior to FCR independent of age, sex, daily living abilities (performance status), and disease stage.

The ibrutinib-treated patients also experienced fewer side effects. Grade 3 and 4 treatment-related adverse events were observed in 58 percent of the ibrutinib group and 72 percent of the FCR-treated patients. FCR was more frequently associated with grade 3 and 4 neutropenia, a condition associated with a low white blood cell count (44% vs 23% of the ibrutinib group), and infectious complications (17.7% vs. 7% of the ibrutinib group).

Researchers will continue to monitor patients to determine the durability of these results and how they evolve over time.

“We know FCR does some collateral damage to the immune system that can be long-lasting and leave patients vulnerable to infections, whereas ibrutinib can enhance immune function,” Dr. Shanafelt said. “Understanding the long-term effects of these two therapies on the immune system and the risk of infection will be very informative.”

Patients treated with ibrutinib plus rituxumab stay on ibrutinib, a pill taken daily, for the long term. Given this fact, Shanafelt said one question that remains, and falls outside the scope of the study, is the expense of ibrutinib, which is around $10,000 a month.

CLL is a cancer of the white blood cells. It often occurs during or after middle age and rarely in individuals under the age of 40.

This federally funded study was designed by researchers with the ECOG-ACRIN Cancer Research Group under the sponsorship of the National Cancer institute (NCI), part of the National Institutes of Health. It was conducted through the NCI’s National Clinical Trials Network. Pharmacyclics LLC provided ibrutinib and clinical trial support funding under a cooperative research and development agreement with NCI and a separate agreement with ECOG-ACRIN.

E1912 is an FDA registration trial.

Tait D. Shanafelt, MD, Stanford University School of Medicine, will present this study during the late-breaking abstracts session on Tuesday, December 4, 2018, at 7:30 a.m. PST at the San Diego Convention Center, Hall AB.

Daratumumab Increases Progression-Free Survival in Transplant-Ineligible Multiple Myeloma

Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients With Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA) [LBA-2]

Interim results from a large international phase III clinical trial show that adding the immunotherapy daratumumab (DARA) to standard therapy significantly extended the time before cancer got worse in patients newly diagnosed with multiple myeloma who were ineligible for a stem cell transplant.

Patients treated with lenalidomide and dexamethasone (Rd) plus DARA were 44 percent less likely to die or experience disease progression, compared with patients who received Rd alone, said lead author Thierry Facon, MD, of Claude Huriez Hospital in Lille, France.

He added the trial is important because it’s one of the first to test the combination of DARA with a current standard of care in this patient population, and it also enrolled a much higher proportion of patients over the age of 75 than any previous study.

“We see a very strong clinically significant benefit in extending survival without the cancer getting worse, with no major safety concerns,” said Dr. Facon. “In older patients who are not candidates for stem cell transplantation, these are very encouraging results.”

Multiple myeloma is a blood cancer that affects plasma cells, a type of white blood cell. Normal plasma cells help the body fight infection. In multiple myeloma, cancerous plasma cells grow uncontrollably in the bone marrow, crowding out the normal plasma cells. Elevated levels of a substance called M protein in the blood and urine are a hallmark sign of multiple myeloma.

A stem cell transplant is often a recommended treatment option for patients with multiple myeloma who are otherwise in good health. For newly diagnosed patients who aren’t candidates for a stem cell transplant due to age or coexisting health conditions, Rd has been the standard of care since 2013. 

DARA is a targeted drug that blocks a protein called CD38, which is found at abnormally high levels in multiple myeloma cells. The drug is currently approved by the U.S. Food and Drug Administration for use in combination with other agents to treat multiple myeloma that has gotten worse after one or more prior rounds of treatment. 

The current trial, known as the MAIA study, enrolled 737 patients with newly diagnosed multiple myeloma who were deemed ineligible for a stem cell transplant. Their median age was 73, with 44 percent over 75. Slightly over half of the patients were male. The trial was conducted in 14 countries, including the United States, Canada, Australia, Israel, the United Kingdom, and several European countries.

Patients were randomly assigned to be treated with either Rd alone or Rd plus DARA. Treatment continued until the patients’ cancer got worse or intolerable side effects occurred. The primary endpoint was the length of time until patients’ cancer worsened, known as progression-free survival (PFS). Key secondary endpoints included minimal residual disease (MRD) negativity, defined as the absence of cancer cells in the bone marrow; the proportion of patients with a reduction of 50 percent or more of serum or urine monoclonal protein, known as the overall response rate; and the rate and severity of adverse side effects.

An interim analysis of the trial’s results after a median follow-up period of 28 months showed that patients treated with Rd plus DARA were 44 percent less likely to have died or experience disease progression, compared with patients who received Rd alone. Median PFS––the point in time at which half of the patients had disease progression––was 31.9 months for patients treated with Rd alone, and has not been reached yet for those who received Rd plus DARA.

The complete response rate, or proportion of patients with no detectable disease in the blood or urine and less than five percent of cancerous cells remaining in the bone marrow, was 47.6 percent for patients treated with Rd plus DARA, compared with 24.9 percent for those who received Rd alone. The proportion of patients who achieved a very good partial response or better–­–defined as a 90 percent or greater reduction in levels of M protein in the blood and urine––also was significantly better among patients treated with Rd plus DARA (79.3 percent, compared with 53.1 percent for patients treated with Rd alone). There was more than 3-fold improvement in achieving MRD negativity for Rd plus DARA (24.2 vs 7.3 percent) which translates into more patients having longer PFS than standard of care alone. In addition, Rd plus DARA helped more patients achieve a durable MRD response. While the safety profile in MAIA was in line with previous studies, more patients in the Rd-plus-DARA arm than in the Rd-alone arm experienced moderate or severe adverse effects of pneumonia and low white blood cell counts.

“These results support the addition of daratumumab to Rd as the new standard of care for patients with transplant-ineligible NDMM,” Dr. Facon said.

This study was supported by Janssen Research & Development, LLC.

Thierry Facon, MD, of Claude Huriez Hospital in Lille, France, will present this study during the late-breaking abstracts session on Tuesday, December 4, 2018, at 7:30 a.m. PST at the San Diego Convention Center, Hall AB.

Researchers Identify Mutation in BCL2 Protein That Causes Resistance to Venetoclax

Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia [LBA-7]

Investigators from Australia have identified a genetic mutation that causes resistance to the targeted drug venetoclax in patients with chronic lymphocytic leukemia (CLL).

Venetoclax promotes cancer cell death by blocking a protein known as B-cell leukemia/lymphoma 2 protein, or BCL2, that helps cancer cells to survive. Levels of BCL2 are abnormally high in many patients with CLL. The newly discovered mutation in BCL2 significantly reduces the ability of venetoclax to latch on to and block the protein, said lead author Piers Blombery, MD, of the Peter MacCallum Cancer Centre and Royal Melbourne Hospital in Melbourne, Australia.

“Although venetoclax is a highly effective drug for CLL, most patients eventually relapse,” Dr. Blombery said. “The mutation we have found helps to explain why venetoclax stops working in some patients. Furthermore, we have shown that in some cases the mutation can be detected in patients’ bone marrow years before clinical signs of relapse appear.”

Dr. Blombery and his colleagues performed genomic sequencing on tumor samples from 67 patients whose CLL had come back after treatment with venetoclax. For 15 of these patients, the investigators were able to evaluate tumor samples from both before and after venetoclax treatment. The mutation was identified in after-treatment tumor samples from seven of these 15 patients.

“We also tested almost 400 patients with CLL and other blood cancers who had never been treated with venetoclax, and we did not find this mutation in any of those patients,” said Dr. Blombery. “This is evidence that the mutation only develops during venetoclax treatment, so it is something that patients can be screened for. In patients who develop this mutation at a low level, it would be prudent for the hematologist to begin to look for other therapies to use instead.”

Venetoclax was the first drug targeting BCL2 to be approved by the U.S. Food and Drug Administration (FDA). Initially it was approved only for the treatment of patients with CLL whose tumors had a genetic alteration in which a piece of one chromosome was missing. In June 2018, FDA expanded the drug’s approval to include all patients with CLL whose disease progressed after at least one previous treatment, regardless of whether their cancer cells have this genetic alteration.

While identification of the BCL2 mutation helps to explain why CLL recurs in some patients treated with venetoclax, much still remains to be understood about the factors underlying CLL recurrence after venetoclax treatment.

“We don’t know what caused the cancer to relapse in the eight patients in whom we did not find the BCL2 mutation,” Dr. Blombery said. “Moreover, in the seven patients who had the mutation, we found it in only some of their cancer cells–­–and yet the cells that did not carry the mutation were still contributing to the cancer’s growth. So, clearly, even among patients who have the mutation, other factors are at play in causing resistance to venetoclax therapy.”

In one patient, the investigators found a second genetic abnormality generating resistance to venetoclax treatment in cells that did notcarry the BCL2 mutation. “This demonstrates the importance of considering multiple angles of attack with combination therapies––for example, venetoclax and rituximab––rather than relying on a single targeted agent in a disease that has multiple genomic tricks up its sleeve,” Dr. Blombery said.

The investigators are planning to conduct more extensive genomic analysis of the patients who did not develop the BCL2 mutation to identify other mechanisms of resistance to venetoclax. They also plan to gather more data on the time course of acquisition of the BCL2 mutation.

This study was supported by Peter MacCallum Cancer Centre, the Royal Melbourne Hospital, the University of Melbourne and the Walter and Eliza Hall Institute of Medical Research. External funding also supported this research including from the Snowdome Foundation, the Christine and Bruce Wilson Centre for Lymphoma Genomics based at Peter Mac, the Leukemia and Lymphoma Society (USA), the Leukaemia Foundation, NHMRC, Australian Cancer Research Foundation and Cancer Council Victoria.

Piers Blombery, MD, Peter MacCallum Cancer Center and Royal Melbourne Hospital, will present this study during the late-breaking abstracts session on Tuesday, December 4, 2018, at 7:30 a.m. PST at the San Diego Convention Center, Hall AB.

The study will be simultaneously published in Cancer Discovery at the time of the presentation.

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on large-scale practice-changing clinical trials, lasting results in CAR T-cell therapies, sickle cell disease, and looking to the future in the era of personalized medicine. For the complete annual meeting program and abstracts, visit www.hematology.org/annual-meeting. Follow @ASH_hematology and #ASH18 on Twitter and like ASH on Facebook for the most up-to-date information about the 2018 ASH Annual Meeting.

The American Society of Hematology (ASH) (www.hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The Society publishes Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, as well as the newly launched, online, open-access journal, Blood Advances.

Contacts:

Adam Silverstein, FleishmanHillard
917-697-9313; [email protected]

Stephen Fitzmaurice, ASH
561-506-6890; [email protected]