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Thursday, February 15, 2018

According to a new study by The Wistar Institute, Philadelphia, EZH2 inhibitors that are currently in clinical development for hematological malignancies and solid tumors may be effectively targeted to epithelial ovarian cancers overexpressing the CARM1 protein. The research was published online in Nature Communications (2018; doi:10.1038/s41467-018-03031-3).

Ovarian cancer is the most lethal gynecological malignancy and only limited therapeutic options are currently available. Because of the high genetic heterogeneity of this type of cancer, scientists are working to expand their knowledge of the molecular alterations underlying tumor onset and progression in order to design individualized therapeutic strategies. Results of this new study demonstrated an elevated expression of the CARM1 protein in a set of ovarian cancer tissues compared with normal tissue. CARM1 is a known oncogene in several cancer types, but prior to this study, there were no reports on its role in ovarian cancer.

"Previous studies suggest that direct targeting of CARM1 activity could result in high toxicity," said lead researcher Rugang Zhang, PhD, Deputy Director of The Wistar Institute Cancer Center, Professor and Co-Program leader of the Gene Expression and Regulation Program. "Therefore, we sought to identify an alternative, clinically applicable therapeutic approach for this specific group of patients. We discovered that inhibitors of EZH2 provide an effective strategy to treat ovarian cancers with elevated CARM1 expression."

Zhang and colleagues analyzed a publicly available atlas of ovarian cancer genetic profiles and observed that CARM1 expression is elevated in approximately 20 percent of cases, and it is associated with poor patient survival. Importantly, high CARM1 expression is mutually exclusive with the presence of mutations in BRCA1/2. They also found that small molecule inhibitors of EZH2, which block the EZH2 enzyme and are in clinical development for hematopoietic malignancies, selectively induce arrest of proliferation and cell death in cells with high CARM1 levels and not in cells with normal CARM1 levels.

Mechanistically, the researchers showed that CARM1 regulates the balance between the antagonistic activities of EZH2 and another protein, BAF155. Both these proteins modify the structure of chromatin in specific positions, exerting opposite effects on expression of a common set of target genes that inhibit tumor progression. Causing BAF155 displacement from these targets, CARM1 favors binding of EZH2, which in turn inhibits expression of these antitumor genes, thus favoring tumor progression. The team demonstrated that EZH2 inhibition is an effective strategy to suppress the growth of tumors expressing CARM1 by reactivating these antitumor genes.

The research also included in vivo studies confirming that the EZH2 inhibitor significantly suppressed tumor growth and improved survival in mouse models of ovarian cancer.

"Our study suggests a therapeutic benefit for repurposing a well-tolerated inhibitor with limited toxicity to treat a specific group of ovarian cancer patients with high levels of CARM1 expression," said Sergey Karakashev, PhD, first author of the study and a postdoctoral researcher in the Zhang Lab. "Given that CARM1 expression is elevated in other types of cancer, our findings may be extended to a broader array of cancer patients."

Wednesday, February 14, 2018

Triple-negative breast cancer (TNBC), a highly aggressive, relapse-prone cancer that accounts for one-fourth of all breast cancers, could be the focus of a new area of study for immune checkpoint blockade therapy.  

A team of researchers at The University of Texas MD Anderson Cancer Center, Houston, revealed that in TNBC a cell process called glycosylation is required for PD-L1/PD1 molecules to interact and identified exactly how and why glycosylation is so crucial. Findings from the study were published in Cancer Cell (2018; doi:10.1016/j.ccell.2018.01.009).

"Glycosylation is a process that attaches portions of sugar molecules called moieties to the protein providing it fuel to grow and spread," said Mien-Chie Hung, PhD, Chair of Molecular and Cellular Oncology. "Glycosylation of PD-L1 in tumor cells stabilizes PD-L1, but it is largely unknown whether sugar moiety by itself is required for binding to PD-1 to suppress anti-tumor immunity." 

Hung's research group shed further light in this area through discovery of glycosylated PD-L1 (gPD-L1), and worked to develop anti-gPD-L1 antibodies that recognize this glycosylated form of PD-L1, killing tumor cells while not harming healthy ones.

To improve the therapeutic efficacy of anti-gPD-l1 antibody, the team linked a potent small molecule chemotherapy agent, called MMAE, to the anti-gPD-L1, creating a new antibody drug conjugate (ADC), called anti-gPD-L1-MMAE, which resulted in higher therapeutic efficacy in animal models. Hung believes the development of this glycosylated PD-L1 ADC (anti-gPD-L1-MMAE) may represent a new generation of immunotherapy that is more targeted with fewer adverse effects.

"We demonstrated that gPD-L1 is an excellent candidate for ADC as sugar moiety is critical for PD-L1's detrimental role in TNBC," said Hung. "Immune checkpoint blockade treatment options remains limited in TNBC, so identifying new immune checkpoint targets to improve upon current therapy is urgently needed."

Tuesday, February 6, 2018

By Mark L. Fuerst

VIDEO: Learn More About the MURANO S​​tudy​

ATLANTA—A combination of venetoclax plus rituximab (VR) is superior to standard chemotherapy with bendamustine plus rituximab (BR) in patients with relapsed/refractory chronic lymphocytic leukemia, according to a new study.

In a phase III trial presented at the 2017 American Society of Hematology Annual Meeting, treatment with the targeted cancer drug venetoclax in combination with rituximab more than doubled the likelihood that patients with chronic lymphocytic leukemia (CLL) would survive for 2 years without cancer progression compared to treatment with the standard chemo-immunotherapy drug bendamustine with rituximab (Abstract LBA-2).

"This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach," said lead author John Seymour, MBBS, PhD, Director of the Haematology Department at the Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, Australia.

"It suggests that venetoclax should replace chemotherapy for relapsed/refractory CLL and is suggestive that the combination with rituximab is the preferred manner to use the drug. There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this setting.

"Venetoclax plus rituximab should be considered as a standard therapeutic option in patients with relapsed/refractory CLL," he added.

Overview of Venetoclax

Venetoclax is designed to hasten the death of leukemia cells by binding to and blocking the activity of the BCL-2 protein. Bendamustine works by interfering with cancer cells' DNA. Rituximab is a monoclonal antibody designed to help the body's immune system recognize and attack leukemia cells, Seymour explained.

Venetoclax is approved for use against CLL in the U.S. and several other countries, but approvals are limited to small subgroups of patients, including those with a specific genetic abnormality. The new trial, carried out at 109 sites globally, sought to assess the safety and efficacy of venetoclax in a broad patient population.

Venetoclax is an orally administered, highly selective, potent BCL-2 inhibitor that induces high overall response rate (ORR) when given as monotherapy to patients with relapsed/refractory CLL, including patients with poor prognostic factors, such as del(17p), Seymour noted. Venetoclax is also well-tolerated when combined with rituximab and achieves improved complete remission rates and minimal residual disease (MRD)-negativity.

MURANO Trial Details

MURANO is an open-label, randomized, phase III trial that included relapsed/refractory CLL patients requiring treatment who had 1-3 prior lines of therapy, including one or more chemotherapy-containing regimens and ECOG performance status of 0 or 1. Seymour presented an interim analysis of 389 patients (VR 194 patients, median age 64.5; BR 195 patients, median age 66 years). About one-quarter of patients in both arms had del(17p).

In the VR arm, a 4-week or 5-week graduated dose ramp-up of venetoclax from 20-400 mg daily was used to mitigate the risk of potential tumor lysis syndrome (TLS). Beginning at week 6, rituximab was then given monthly for six 28-day cycles intravenously 375 mg/m2 first dose, then 500 mg/m2 in combination with venetoclax daily. Patients continued with venetoclax 400 mg for a maximum of 2 years or until disease progression.

In the BR arm, patients were given bendamustine intravenously 70 mg/m2 on days 1 and 2 of each of six 28-day cycles in combination with rituximab using the same rituximab dosing schedule.

After a median follow-up of 2 years, there was a "profound, clear difference in PFS," he said. Patients achieved significantly prolonged median PFS, the primary endpoint, with VR (median PFS, not reached) as compared with BR (median PFS, 17.0 months). The 24-month PFS estimates were 84.9 percent in the VR group versus 36.3 percent in the BR group.

Venetoclax also outperformed bendamustine for the trial's secondary endpoints, which included overall survival and markers of cancer remission. The 2-year overall survival was notably higher with VR (91.9%) than with BR (86.6%). Higher peripheral blood MRD-negativity rates attained at any time were significantly higher with VR (83.5%) than with BR (23.1 %t), and MRD negativity was more durable in the VR arm.

These results suggest venetoclax could be discontinued after 2 years with a low risk of recurrence in those patients with a deep remission, he said. So far, 65 patients who have ceased therapy after 2 years are progression-free, and 12 of these patients have 3 or more months of follow-up.

The safety profiles were consistent with the regimens, with no new signals. Grade 3/4 neutropenia was higher in the VR arm, but there was no increase in febrile neutropenia or grade 3/4 infection. TLS was reported in 3.1 percent of VR patients and 1.1 percent of BR patients. While venetoclax was associated with a greater risk of abnormally low white blood cell counts, there was no increase in severe infections or deaths related to this side effect, Seymour noted.

Confirmed Richter transformation occurred in six VR patients and five BR patients. Adverse events leading to death were seen in 10 (5.2%) VR patients and in 11 (5.9%) BR patients.

"Venetoclax plus rituximab was superior to bendamustine plus rituximab in prolonging PFS in adults with relapsed/refractory CLL," Seymour stated. "The effects are consistent across subgroups, regardless of del(17p) status, with superior ORR and rate of peripheral blood MRD-negativity that was maintained over time and clinically meaningful improvement in overall survival. Safety was consistent with the known safety profile in patients with relapsed/refractory CLL.

"This enhanced disease control was achieved in a multinational setting with an acceptable safety profile, without significant TLS, demonstrating that treatment with VR resulted in outcomes superior to that of BR for patients with relapsed/refractory CLL."

Further follow-up is required to evaluate duration of benefit after venetoclax cessation.

Mark L. Fuerst is a contributing writer.

Tuesday, February 6, 2018

By Mark L. Fuerst

WATCH NOW: Q&A with Ian Flinn, MD, PhD, Sarah Cannon Research Institute​​

ATLANTA—A combination of the anti-CD20 monoclonal antibody obinutuzumab and venetoclax shows a high level of deep, durable responses with unprecedented minimal residual disease (MRD)-negativity rates compared with chemo-immunotherapy regimens and other novel chemotherapy-free therapies in previously untreated patients with chronic lymphocytic leukemia (CLL).

"Despite the recent development of novel targeted therapies to treat CLL or small lymphocytic lymphoma (SLL), the disease remains incurable and many patients will eventually relapse despite optimal treatment. Additional therapies targeting novel pathways are needed for patients with relapsed/refractory disease," said Ian Flinn, MD, PhD, of the Sarah Cannon Research Institute, Nashville, Tenn., at the 2017 American Society of Hematology (ASH) Annual Meeting.

Venetoclax is a highly selective, potent BCL-2 inhibitor with significant anti-tumor activity as a monotherapy and in combination regimens in CLL. Preclinical data suggest that venetoclax plus obinutuzumab, a type II, glycoengineered anti-CD20 antibody, may have synergistic activity in CLL. Preliminary clinical data found this combination showed an acceptable safety profile and promising efficacy in relapsed/refractory or previously untreated CLL.

Flinn presented updated safety, efficacy, and MRD-negativity data in previously untreated CLL patients from this study (Abstract 430). Venetoclax 400 mg was the recommended target dose for the safety-expansion cohorts determined from an earlier dose-finding cohort. A group of 32 patients, median age 63 years, were given first-line therapy with obinutuzumab cycle 1: 100 mg on day 1, 900 mg on day 2, 1,000 mg on days 8 and 15; cycles 2-6: 1,000 mg day 1, based on a 28-day cycle plus venetoclax 400 mg daily.

Risk for tumor lysis syndrome (TLS) was assessed based on lymph node tumor burden and lymphocyte count. A gradual venetoclax ramp-up to the final dose was used to mitigate TLS risk. Previously untreated CLL patients received six cycles of the combination therapy, followed by an additional six cycles of venetoclax monotherapy. Venetoclax could be extended after 1 year of treatment depending on CLL disease status (MRD positivity or partial response).

All 32 patients responded to the treatment, and 72 percent achieved complete remission (CR) or CR with incomplete blood count recovery. In partial response patients, one patient was considered a partial response due to a lymph node of more than 15 mm (20 mm), but all other components were consistent with CR, Flinn noted.

MRD negativity (best response) in peripheral blood was noted in all patients. MRD negativity in bone marrow was noted in 20 patients (74% in patients with samples available). Undetectable peripheral blood MRD rates were maintained after end of treatment. The 18-month estimated progression-free survival (PFS) was 90.5 percent.

The therapy was well-tolerated with no clinical TLS. No deaths were reported. There was no synergistic toxicity. The adverse event profile was consistent with known safety profiles, he said.

"High rates of CR, MRD-negativity, and preliminary PFS results predict durable clinical outcomes for patients treated with this 1-year fixed duration, chemotherapy-free regimen in previously untreated CLL," said Flinn. "Venetoclax plus obinutuzumab is well-tolerated and may be administered with a favorable benefit/risk profile; no clinical TLS or high-grade infusion-related reactions were reported."

MRD-negativity, a measure of disease burden, has been shown to independently predict clinical outcomes of patients receiving combination chemo-immunotherapy. "The high rate of MRD-negativity achieved in patients receiving venetoclax plus obinutuzumab, including del(17p) patients, suggests that this combination may represent a potentially important treatment option for previously untreated CLL patients," Flinn stated.

"Obinutuzumab appears to be a better anti-CD20 antibody than rituximab, with higher efficacy. Combinations with venetoclax are safe, well-tolerated, and moving earlier in the course of treatment into the front-line setting." A combination of venetoclax plus obinutuzumab is now being tested in a phase III trial.

Duvelisib Monotherapy

In another presentation at ASH, Flinn reported that the oral PI3K inhibitor duvelisib as monotherapy holds potential as a new, convenient treatment option for previously treated CLL/SLL patients (Abstract 493).

Duvelisib is an oral dual inhibitor of PI3K-δ and PI3K-γ being developed for the treatment of advanced B-cell malignancies, including CLL/SLL. In a phase I study, the overall response rate (ORR) for duvelisib monotherapy in 55 patients with relapsed/refractory CLL/SLL was 56 percent, with one CR. Based on the safety and efficacy findings in this study, duvelisib 25 mg twice daily was selected as the recommended phase II dose in CLL/SLL.

An international, phase III randomized study evaluated duvelisib monotherapy 25 mg twice daily continuously versus ofatumumab monotherapy 300 mg IV infusion on day 1 and 2,000 mg IV weekly (x7) then monthly (x4) in 319 patients, median age 69 years, with relapsed/refractory CLL/SLL.

About half the patients had bulky disease and about one-third of them had 17p deletion and/or TP53 mutation. They had a median of two prior therapies for a median of about 20 months.

Duvelisib monotherapy met the primary endpoint, achieving significant improvement in PFS (13.3 months) over ofatumumab (9.9 months). Similar benefit was seen in patients with del(17p) (PFS 12.7 months with duvelisib versus 9 months with ofatumumab). "Duvelisib maintained the PFS advantage in all subgroups analyzed," said Flinn.

In addition, duvelisib achieved significant improvement in ORR (74%) as compared to ofatumumab (45%).

Duvelisib significantly reduced lymph node burden more than 50 percent in most patients (85%) as compared to ofatumumab (16%). With a median exposure of 50 weeks, the adverse event profile of duvelisib was manageable and consistent to what has been previously observed. Adverse events of interest (neutropenia, diarrhea, pneumonia, colitis, transaminase elevations, pneumonitis, rash) infrequently led to discontinuation, Flinn noted.

Mark L. Fuerst is a contributing writer.

Tuesday, February 6, 2018

By Mark L. Fuerst​

VIDEO: Q&A With ​Nitin Jain, MBBS, MD Anderson Cancer Center​

ATLANTA—Preliminary results from two clinical trials show combination of ibrutinib plus venetoclax leads to high rates of overall response, complete remission (CR), and minimal residual disease (MRD) eradication in patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to presentations at the 2017 American Society of Hematology Annual Meeting.

In an international study, one-third of patients with previously treated CLL had no detectable disease after 6 months of combination therapy with the targeted agents ibrutinib and venetoclax, with no increase in the occurrence of tumor lysis syndrome (TLS), a serious treatment side effect, reported researchers from the U.K. (Abstract 428).

In the second study (Abstract 429), researchers at MD Anderson Cancer Center, Houston, found that all patients who completed at least 3 months of the combination therapy had a response, and several patients achieved undetectable bone marrow MRD.

U.K. Trial

In the U.K. trial, of 36 patients who completed 6 months of combination treatment, all responded and 33 percent achieved the deepest measurable level of remission, with no detectable disease in the bone marrow, said lead author Peter Hillmen, MBChB, PhD, Professor of Experimental Hematology at Leeds Institute of Cancer and Pathology in the U.K.

"These initial results are particularly impressive in a patient population for whom previous therapies have failed," stated Hillmen. "We have shown that the two drugs can be given in combination without obvious additional toxicity, and the inability to detect disease with the most sensitive tools we have is a very good sign that the combination is proving to be an effective treatment."

The mechanisms of action of the two drugs are complementary. Ibrutinib works by blocking signals that stimulate cancerous cells to multiply; venetoclax promotes tumor cell death by blocking a protein that helps the cells survive. Both medications are approved by the FDA as single-agent therapies to treat CLL.

Hillmen and his colleagues evaluated the combination therapy in the phase III CLARITY trial, which enrolled a total of 50 patients, median age 64 years, with relapsed/refractory CLL. After 8 weeks of ibrutinib monotherapy 420 mg/day, venetoclax was added first at a dose of 10 mg/day with weekly escalations to 20 mg, 50 mg, 100 mg, and 200 mg to a final dose of 400 mg/day. No TLS was seen for the first three patients starting at 10 mg/day of venetoclax, so all subsequent patients began venetoclax at 20 mg/day.

To date, only one patient in the CLARITY trial has developed TLS and that patient was safely treated without adverse effects. "We have not seen an increase in the rate of TLS with the combination regimen compared with what we would expect to see with venetoclax single-agent therapy," said Hillmen.

After 6 months of combination therapy, the trial has already exceeded the expected proportion of patients achieving undetectable CLL, he said. "Our assumption was that the trial would be a success if 30 percent of patients achieved the deepest level of remission after 12 months of combination therapy. But already, at 6 months, 33 percent of patients have undetectable disease," said Hillmen.

Secondary endpoints of safety and absence of detectable disease in the bone marrow after 6 and 24 months of combination therapy will be reported at a later time, he noted.

A key limitation of the study is that it lacked a control group. On the basis of the CLARITY results, Hillmen is leading a randomized, controlled, phase III trial, called FLAIR, to compare ibrutinib plus venetoclax with both ibrutinib alone and a combined regimen of three chemotherapy drugs in patients with previously untreated CLL.

U.S. Trial

The rationale for combining ibrutinib and venetoclax includes preclinical models showing synergism with combined therapy, non-overlapping toxicity profiles, non-overlapping mechanisms of action, and complementary activity in treating disease compartment, said Nitin Jain, MD, Assistant Professor, Department of Leukemia, Division of Cancer Medicine, at MD Anderson Cancer Center.

He reported the preliminary results of a phase II trial of combined ibrutinib and venetoclax for patients with CLL. The researchers enrolled two cohorts, one with relapsed/refractory CLL and one with untreated patients with at least one high-risk feature, either del(17p), mutated tP53, del(11q), unmutated IGHV, or age 65 or older.

Treatment consisted of ibrutinib monotherapy 420 mg daily for the first 3 months, followed by addition of venetoclax weekly dose escalation to the target dose of 400 mg daily. Ibrutinib may be continued indefinitely and venetoclax for a total of 2 years.

Jain reported on 72 patients who have initiated treatment, 33 patients in Cohort 1 and 39 patients in Cohort 2, with a median follow-up of 7.5 months. Overall, 61 patients have completed ibrutinib monotherapy and have initiated venetoclax dose escalation.

Three months of ibrutnib resulted in 51 percent down-grade of TLS risk category. Two of 61 patients (3%) were high-risk for TLS at the time of initiation of venetoclax.

In Cohort 1, of the 29 patients who received ibrutinib monotherapy and then venetoclax, 14 patients who completed at least 3 months of combination therapy had a response. "There was a significant decrease in bone marrow infiltrate with the addition of venetoclax, including MRD-negativity in several patients with high-risk cytogenetics," Jain said.

In Cohort 2, 32 patients received ibrutinib monotherapy followed by venetoclax. All 16 patients who completed at least 3 months of combination therapy had a response, including nine CRs and CRs with incomplete blood count recovery and seven partial responses. "Several of these patients achieved undetectable bone marrow MRD status with the addition of venetoclax," said Jain.

Overall, dose reductions were required for 24 percent of patients on ibrutinib monotherapy and 18 percent with venetoclax. The most common reason for dose reduction was neutropenia. Eight patients developed atrial fibrillation, likely secondary to ibrutinib, he said. One patient had laboratory TLS, but no patients had clinical TLS. A total of 10 patients have come off study, five patients in each cohort.

"The combination of ibrutinib and venetoclax is safe and active in patients with CLL. These early results of efficacy are highly encouraging. Significant improvement in bone marrow CLL infiltrate is noted with several patients achieving undetectable MRD status as early as 3 months of the combination therapy," Jain explained.

Mark L. Fuerst is a contributing writer.