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Tuesday, June 19, 2018

The American Association for Cancer Research (AACR) joins 70 NCI-designated cancer centers and five national cancer organizations in urging increased HPV vaccination rates and screening measures to prevent the human devastation caused by HPV-related cancers. Insufficient vaccination is a public health threat, and the AACR calls upon the nation's physicians, parents, and young adults to take advantage of this opportunity to eliminate several different types of cancer in men and women.

According to the CDC, HPV is responsible for almost all cervical cancers, a substantial proportion of head and neck cancers, and the majority of anal, vulvar, vaginal, and penile cancers. CDC data shows that approximately 41,000 new HPV-related cancers are being diagnosed in the U.S. each year, 17,300 of which are diagnosed in men and about 23,700 of which are diagnosed in women. The overall annual direct medical cost of HPV-related diseases is at least $8 billion.

 "This call to action, which is shared by our nation's leading cancer organizations, is an important first step in the elimination of HPV-related cancers," said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. "The long-term investment in biomedical research has led to a series of scientific discoveries that have enabled us to reach this juncture where we now have highly effective tools and well-defined steps for putting an end to HPV-related cancers."

Since its introduction in 2006, more than 100 million doses of the HPV vaccine have been distributed nationally. The CDC recommends all 11- to 12-year-old girls and boys receive the HPV vaccine. The Department of Health and Human Services, through the Healthy People 2020 initiative, has introduced a goal of reaching a vaccination rate of 80 percent for both girls and boys by the year 2020. However, as of 2016, only 49.5 percent of girls and 37.5 percent of boys in the U.S. had completed the HPV vaccine series, according to the CDC.

Research shows that certain barriers must be overcome to improve vaccination rates. One such barrier is a lack of strong recommendations from physicians; another is that parents may not be aware that this vaccine protects against several types of cancer in both men and women.

Foti added, "Today's call to action will bring the entire cancer research and cancer control community together to focus its efforts on the very achievable and life-saving goal of eliminating HPV-related cancers in the U.S. The AACR looks forward to marshaling its resources in support of this important effort."  

Tuesday, June 5, 2018

By Catlin Nalley

Since the current chronic lymphocytic leukemia literature (CLL) focuses primarily on the objective aspects of diagnosis, active observation, prognosis and management, a group of researchers sought to gain a better understanding of the subjective experiences of patients. Initial data was recently presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 7532).

Led by the CLL Society Inc., a patient-driven, physician-curated nonprofit organization that focuses on the unmet needs of the CLL community, the team aimed to "understand how CLL and its management, including the health care team, diagnosis, education, active observation, prognostic testing, and the options of clinical trial affect the lives of those with CLL and what was important to patients. The goal was to better understand CLL from the patient's perspective to inform health care providers in best meeting their patients' needs."

Study Methodology

With this goal in mind, investigators utilized the 2017 CLL Diagnosis and Treatment Assessment: The Patient View (2017 CLLDATA) survey, which consisted of 64 multi-part questions. The survey was available online or on paper and took place between October and December 2017.

Eligible patients were U.S. residents age 18 years or older who had a diagnosis of CLL/SLL. Participants had to have a working knowledge of English and provide informed consent.

The survey was conducted anonymously and utilized the CLL Society database, Facebook, and online CLL patient forums. Additionally, information cards were distributed in the offices of principal investigators as well as physicians in the community that refer to those investigators.

Researchers analyzed data using descriptive methods. Statistical significance was evaluated using chi-square. According to investigators, analyses and comparisons occurred between multiple subgroups based on age, gender, treatments status, high-risk versus low-risk, and patients treated by a general hematologist/oncologist, CLL expert, or both.

Among the 1,147 useable responses, the median age was 64 years and 46 participants were male. Ninety-six percent were Caucasian. The median time from diagnoses was 5 years and treatment status was as follows: watch and wait (43%); receiving or completed first treatment (25%); and receiving or completed second or later treatment (32%).

Key Observations

Data showed that at the time of diagnosis 48 percent of patients were told they had a "good" cancer by their health care practitioner.

Additionally, 44 percent of participants heard the phrase, "You will die with CLL, not from CLL" and 41 percent were told, "If I had to choose a cancer, this is the one I would want." Patients reported these statements, among others, equally regardless of the type of physician managing their treatment, according to investigators.

Researchers noted that only 13 percent of patients surveyed reported needing treatment within 3 months of diagnosis. Among patients undergoing active observation (87%), 91 percent said that their doctor explained why therapy was not warranted.

The study authors wanted to gain more insight into the emotional response to active observation, according to Betsy Dennison, RN, MS, of the CLL Society. "We wanted to find out more about how [patients] are feeling because they don't see the doctor as often," he noted. "How are they coping with that and what more can we do to support them?"

"When active observation was recommended, patients report anxiety (56%), relief (52%), and confusion (31%). Thirty-four percent and 16 percent of patients report that discussing prognostics increased their anxiety and confusion, respectively," according to study authors.

During active observation, 17 percent of survey respondents reported having no disease-related symptoms. Researchers found that patients reported fatigue (51%), enlarged nodes (47%), anxiety (39%), depression (21%), and night sweats (21%). Among patients undergoing active observation, 653 (66%) utilized herbals and other alternative treatments for CLL management.

The investigators also took a closer look at the patient experience related to clinical trial options. Among patients who were invited to join a clinical trial, but declined cited a number of reasons for their decision, including: preference for a proven treatment (38%), distance from the trial site (29%), fear (20%), and frequent imaging (20%).

Patients who chose to participate in a clinical trial did so because their health care team suggested it as a good option (71%). Other reasons included access to the latest treatments (69%), close monitoring of disease (67%), confidence in the trial team (65%), a desire to help others (56%), and medications provided for free (54%).

"A lot of patients felt very strongly about participating and wanting to feel like they are making a positive effect on society," noted Dennison.

Conclusions, Next Steps

"To our knowledge, this is the largest survey of CLL patients. Much can be learned by detailed surveying of CLL patients throughout their disease," according to researchers. "These include previously unrecognized suboptimal interactions between the CLL patient and the health care provider."

Given that 72 percent of patients reported being offered language similar to "CLL is a good cancer" at the time of diagnoses, investigators recommend that "this might be better replaced with the facts that CLL is a variable disease, with some patients never needing treatment and others experiencing more aggressive disease."

Other recommendations based on these findings include additional support for patients undergoing active observation and access to clinical trials for appropriate patients regardless of where they are being treated.

"Understanding how patients experience their disease is critical to improve communication between patients and their health care providers, which will ultimately advance CLL outcomes," study authors concluded. Additional data from this survey will be reported in the future.

Catlin Nalley is associate editor.

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Tuesday, June 5, 2018

By Catlin Nalley​

Given the therapeutic needs of patients with chronic lymphocytic leukemia (CLL) relapsed/refractory (R/R) to B-cell receptor pathway inhibitors, such as ibrutinib and idelalisib, researchers sought to evaluate the durability of response to venetoclax among this patient population.

Findings from the phase II study were recently presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 7512).

Methodology, Results

Patients with CLL refractory to treatment or who had progressed after discontinuation of prior treatment ibrutinib and/or idelalisib were enrolled in the phase II, open-label, multicenter trial.

Once daily venetoclax was administered with an initial dose of 20 mg daily for 1 week followed by weekly dose ramp up to reach the target dose of 400 mg by week 5, according to researchers. In an effort to mitigate tumor lysis syndrome, beginning at least 72 hours before initial venetoclax administration patients received prophylaxis with uric acid-lowering agents and hydration.

Key inclusion criteria, included an ECOG score of 2 or less, adequate bone marrow function, and creatinine clearance greater than or equal to 50 mL/min. Patients were excluded if they had biopsy-confirmed Richter's transformation, active and uncontrolled autoimmune cytopenias, and a history of allogeneic stem cell transplantation within 1 year of study entry.

The study enrolled 127 patients who had received a median of four prior therapies. Over the course of their treatment, 91 patients received prior ibrutinib while 36 received previous idelalisib and 24 patients underwent both therapies. Forty percent of patients had 17p deletion and 28 percent had mutated TP53.

"After a median of 17 months on venetoclax, the best overall response rate was 66 percent per investigators (INV) and 70 percent by independent review committee (IRC)," researchers reported. "Per INV (median follow-up, 16 months), estimated median progression-free survival (PFS) was 25 months (18-month rate, 66%); neither median duration of response (18-month rate: 75%) nor median overall survival (18-month rate: 88%) was reached."

Among 77 patients assessed, 32 had undetectable blood minimal residual disease (MRD); additionally, nine of these patients were also undetectable in bone marrow. Median PFS for patients with undetectable MRD in blood was not reached compared to 21.9 months for patients with positive blood MRD.

Venetoclax was discontinued by 64 patients, most commonly for CLL progression, adverse events, and Richter's transformation.

Patients experienced at least one adverse event. Data showed that common, any-grade adverse events, included GI AEs (diarrhea [50%], nausea [49%]) and cytopenias (anemia [43%], neutropenia [41%], thrombocytopenia [28%], decreased white blood cell count [28%]).

Discussion

"Based on longer follow-up, venetoclax monotherapy demonstrates robust activity, with good tolerability in patients with CLL R/R to ibrutinib and/or idelalisib," study authors wrote. "Though most patients achieved PR, outcomes appear durable with undetectable MRD."

Commenting on the study results during ASCO, Alexey V. Danilov, MD, PhD, Associate Professor of Medicine at Oregon Health & Science University, noted that the durable responses among this pretreated, high-risk patient group were very impressive.

"Essentially, almost all patients developed some sort of response to [this therapy]," he concluded. "Venetoclax produces durable responses in ibrutinib/idelalisib-resistant CLL."

Catlin Nalley is associate editor. 

Tuesday, June 5, 2018

By Christina Bennett

Researchers compared the findings of three phase II trials evaluating different combinations of an anti-CD20 antibody (ofatumumab or obinutuzumab) with ibrutinib or venetoclax in treatment-naïve or relapsed/refractory chronic lymphocytic leukemia (CLL) patients. Insights from these trial comparisons were reported at the 2018 American Society of Clinical Oncology Annual Meeting (Abstract 7513).

The three phase II trials (NCT02689141, NCT02401503, and NCT02345863) were conducted by the German CLL Study Group. Patients in all the trials had the option of receiving chemotherapeutic agent bendamustine for debulking; subsequent induction therapy differed across trials. In one trial, termed the BIO trial, participants received ibrutinib plus ofatumumab. In the BIG trial, participants received ibrutinib plus obinutuzumab. In the BAG trial, participants received venetoclax plus obinutuzumab. During the maintenance phase of each trial, the same agents were used.

The primary endpoint was overall response rate (ORR) at the end of induction therapy, and secondary endpoints were minimal residual disease (MRD) and safety.

For each trial, 66 participants were enrolled; however, participants who had received fewer than two induction cycles were excluded from the analysis. That left 65 participants for analysis in the BIO trial, 61 in the BIG trial, and 63 in the BAG trial, yielding a total of 189 participants for analysis.

Across all trials, for participants who had debulking, the median time since first diagnosis was 48.2 months, 66.4 percent were previously untreated, 33.6 percent were relapsed/refractory, the median number of prior therapies was one, median age was 62 years, and most (67.1%) were males. For the participants who did not have debulking, the median time since first diagnosis was 69.7 months, 20.4 percent were previously untreated, 79.6 percent were relapsed/refractory, median number of prior therapies was two, median age was 64 years, and most (59.2%) were males.

All trials met their primary endpoint of ORR. Sixty-one participants (100%) in the BIG trial achieved a response, 60 participants (95.2%) in the BAG trial achieved a response, and 60 participants (92.3%) in the BIO trial achieved a response. No participants achieved a complete response (CR) in the BIG or BIO trial. Five participants (7.9%) achieved a CR in the BAG trial.

"The most important message is the MRD negativity rate after six cycles of combination therapy with the [anti-CD20] antibody and the oral drug," said Julia von Tresckow, MD, primary study author, from the Department of Internal Medicine at the University of Cologne in Germany. "For BAG, [the MRD negativity rate was] really the highest with 87.3 percent, compared to ibrutinib plus obinutuzumab [BIG trial] with 47.5 percent, and then ibrutinib plus ofatumumab [BIO trial] with only 13.8 percent."

She asserted, "You can argue that obinutuzumab is superior compared to ofatumumab, and that it might be that venetoclax is the most potent oral drug."

Across all the trials, 140 of 189 participants (74.1%) received bendamustine for debulking. About 60 percent of participants who had bendamustine debulking achieved a response.

"There's a question about the role of debulking. Is it really necessary to give chemotherapy before the combination therapy?" proposed Tresckow. "So far, we cannot answer this question completely because we have no real difference in response rates or MRD negativity for those patients who received debulking or not, and regarding the safety, there are fewer infusion-related reactions with the [anti-CD20] antibody in those patients who received the prior debulking, but there were also tumor lysis syndrome and also infusion-related reactions with bendamustine."

Of the participants who received bendamustine, five (3.4%) had a grade 1 or 2 infusion-related reaction (IRR). After bendamustine treatment, tumor lysis syndrome (TLS) occurred in six participants (4.1%), which included one grade 1 event, four grade 3 events, and one grade 4 event.

During induction therapy, 72 participants (36.4%) had an IRR and three participants (1.5%) had TLS. Of those who had prior debulking, 46 (31.1%) had IRR any grade and 2 (1.4%) had TLS any grade. In both the BIG trial and BIO trial, one fatal adverse event occurred; three occurred in the BAG trial.

"Interestingly, [the researchers] didn't completely see disappearance of TLS," said Alexey V. Danilov, MD, PhD, during a discussion of the study. He is Associate Professor of Medicine in the School of Medicine at Oregon Health and Science University. He said one would think with administration of bendamustine for 2 cycles, one would be able to ameliorate some of the TLS.

Tresckow said the next step in assessing the safety and efficacy of these combination therapies is the ongoing phase III CLL 13 trial (NCT02950051). It is a randomized, prospective open-label study with a target enrollment of 920 participants. The study aims to determine if combination of targeted agents (venetoclax, ibrutinib) with anti-CD20 antibodies (rituximab, obinutuzumab) can replace standard chemoimmunotherapy for CLL patients in the frontline setting.

Christina Bennett is a contributing writer.​

Monday, June 4, 2018

By Richard Simoneaux

CHICAGO—B-cell receptor signaling mediates functions such as adhesion, migration, and proliferation, and as a result, plays an important role in B-cell malignancies such as chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). One enzyme that plays a vital role in these processes is Bruton's tyrosine kinase (BTK). Consequently, inhibition of this enzyme was postulated to be a therapeutic target for B-cell cancers.

This strategy was validated with the November 2013 FDA approval of ibrutinib, a first-in-class irreversible BTK inhibitor, for the treatment of patients with mantle cell lymphoma who had received at least one prior therapy. Additionally, in February 2014, the FDA granted accelerated approval for the use of ibrutinib to treat CLL patients who had undergone disease progression while on at least one prior therapy. Later that year, in July, the FDA granted full approval and expanded the use of ibrutinib to CLL patients having the chromosome 17p deletion, which is often associated with poor response to standard CLL therapy.

Zanubrutinib, formerly known as BGB-3111, is a small molecule, potent, and selective inhibitor of BTK. Like ibrutinib, zanubrutinib inhibits the action of BTK by forming a covalent bond to the enzyme. Preliminary clinical results from phase I studies showed that zanubrutinib was generally well-tolerated and produced deep and sustained responses in both treatment-naïve and relapsed/refractory CLL patients.

In October 2017, patient accrual was initiated for a phase III trial that is evaluating the use of zanubrutinib or the combination of the nitrogen mustard bendamustine with the anti-CD20 monoclonal antibody rituximab in treatment-naïve CLL/SLL patients (NCT03336333). An update on this study was given at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting by Jennifer R. Brown, MD, PhD, Director, CLL Center, Dana-Farber Cancer Institute, Boston (Abstract TPS7581).

"This trial will hopefully lead to the registration of an effective, well-tolerated, second-generation BTK inhibitor, as well as provide a more meaningful comparison between BTK inhibition and chemoimmunotherapy than we have had to date, given that the comparator bendamustine/rituximab is the most commonly used and most effective chemoimmunotherapy for older patients. The relatively large cohort of previously untreated patients with 17p deletion receiving a BTK inhibitor in a large international trial is also unique and will provide invaluable information on the natural history of this high-risk group of patients."

Methodology

This international phase III trial will be drawing patients from 165 cancer centers across North America, Europe, and the Asia-Pacific. Among the key inclusion criteria were the following:

  • confirmed CD20-positive CLL/SLL that requires treatment per international workshop on CLL (iwCLL) criteria;
  • Binet stage C disease or stage A/B disease requiring treatment;
  • age 65 or greater, or if less than 65, not suitable for fludarabine-cyclophosphamide-rituximab therapy;
  • ECOG PS score of 0-2;
  • adequate kidney and liver functioning; and
  • absolute neutrophil count of 1,000/mm3 or greater and a platelet level of 75,000/mm3 or greater (however, if the patient has bone marrow involvement, these cutoff values are ≥ 750/mm3 and ≥ 50,000/mm3, respectively).

The key exclusion criteria were as follows: prior systemic therapy for CLL/SLL; history of central nervous system involvement; active HIV, hepatitis B, or hepatitis C infection; and history of Richter's transformation, prolymphocytic leukemia, severe bleeding, or clinically significant cardiovascular disease.

There is an enrollment goal of 467 treatment-naïve CLL/SLL patients for this study: 420 in Cohort 1, consisting of patients without the chromosome 17p deletion and 47 patients in Cohort 2 having the chromosome 17p deletion.

Cohort 1 patients are randomized into two separate arms; patients in Arm A (n=210) will receive zanubrutinib (PO dosing, 160 mg [two 80 mg capsules] BID), while those in Arm B will receive the bendamustine/rituximab combination bendamustine (IV dosing, 90 mg/m2/day on the first 2 days of each 28‑day cycle for 6 cycles) and rituximab (IV dosing, 375 mg/m2 on day 0 of cycle 1, and 500 mg/m2 on day 1 of cycles 2-6).

"Patient crossover from Arm B will be allowed for those patients that undergo disease progression," Brown noted. Cohort 2 patients having the chromosome 17p deletion, comprising Arm C (n=47), will only be receiving treatment with zanubrutinib (PO dosing, 160 mg [two 80 mg capsules] BID). When asked why the cohorts were separated in this manner and no patients with the chromosome 17p deletion received the standard bendamustine/rituximab combination, Brown replied, "]The bendamustine/rituximab] combination has a very low response rate in patients with 17p deletion and is therefore no longer considered an appropriate therapy for these high risk patients. In the phase I setting, zanubrutinib demonstrated a 96 percent ORR in patients with 17p deletion (n=22) (Seymour, ICML 2017) and Arm C of this trial seeks to follow up on these highly promising results."

When asked about objectives for this study, Brown replied, "The primary objective is to compare the efficacy between the treatment arms in Cohort 1, as measured by independent, centrally determined progression‑free survival (PFS); secondary objectives include the comparison of safety between the Cohort 1 treatment arms and comparison of the efficacy between those same arms using the following: objective response rate (ORR, assessed by both independent central review and investigator); overall survival (OS); duration of response (DOR, assessed by both independent central review and investigator)."

Study Endpoints

"The primary endpoint of this study is the PFS of zanubrutinib versus bendamustine/rituximab in Cohort 1, as measured by independent central review using the iwCLL guidelines with modification for treatment‑related lymphocytosis," Brown explained. Secondary endpoints for this study include the following:

  • efficacy in Cohort 1 patients (all of whom lack the chromosome 17p deletion), as measured by ORR, OS, investigator‑assessed PFS, DOR, patient‑reported outcomes (PROs);
  • safety in Cohort 1;
  • efficacy in Cohort 2 patients having the chromosome 17p deletion (ORR, OS, independent, centrally assessed PFS, DOR); and
  • pharmacokinetics of zanubrutinib in patients who received this treatment (i.e., Arms A and C).

Additionally, exploratory endpoints include investigator‑assessed time to second objective disease progression (PFS2), assessment of prognostic and predictive biomarkers, and PROs in Cohort 2.

Discussion

"The study is ongoing and accruing actively according to the planned expectation," Brown noted. "Zanubrutinib has a differentiated kinase inhibition and PK profile compared to other irreversible BTK inhibitors, as well as nicely optimized BTK occupancy data. As such, the results of this large randomized trial compared to the most standard chemoimmunotherapy for older patients are eagerly awaited."

Those wishing to explore enrollment in this study should contact Aileen Cohen, MD, PhD, or Carol Marimpietri, RN, at clinicaltrials@beigene.com. 

Richard Simoneaux is a contributing writer.