The indication for the DigniCap Cooling System has been expanded by the FDA to include alopecia reduction across all solid tumors. The cooling cap system was previously only indicated for reducing hair loss in patients with breast cancer.

The initial breast cancer approval, which was granted in 2015, was based on a study showing that 66% of those utilizing the cooling cap lost less than 50% of their hair. No patients met this criteria in the control arm. Additional findings were also submitted to the FDA for those with other solid tumors, although the FDA did not disclose details.

“We are pleased to expand the use of this product for cancer patients with solid tumors to potentially minimize chemotherapy-induced hair loss,” Binita Ashar, MD, director, Division of Surgical Devices, in the FDA’s Center for Devices and Radiological Health, said in a statement. “Managing the side effects of chemotherapy is a critical component to overall health and quality of life.”

The cooling cap, manufactured by Sweden-based Dignitana, circulates cold liquid through a silicone cap that is worn on the head during treatment with chemotherapy. The cap is connected to a unit that distributes the cooled liquid that is controlled using touchscreen prompts. A second cap made of neoprene holds the initial cap in place and prevents loss of cooling.

The near-freezing temperatures are intended to constrict the blood vessels in the scalp, making it difficult for toxic chemotherapy agents to reach and harm the hair follicles. The cold also decreases the activity of the hair roots, which slows down cell division and makes them less affected by chemotherapy.

In the breast cancer study, patients had an average age of 53.0 years (range, 28-77). Patients were treated with docetaxel/cyclophosphamide (75%), docetaxel/carboplatin (12%), weekly paclitaxel (12%), and docetaxel (1%). Patients also received HER2-targeted therapy along with docetaxel/carboplatin and docetaxel.

In the DigniCap group, 5% of patients did not lose any hair compared with 0% in the chemotherapy arm. Additionally, 30.7% of patients in the DigniCap arm had less than 25% hair loss, compared with none in the control group. Just 14.9% of patients in the DigniCap arm lost more than 75% of their hair compared with 93.8% in the control arm.

By chemotherapy utilized, those receiving docetaxel/carboplatin had an 83.3% success rate, defined as less than 50% hair loss. Those receiving docetaxel/cyclophosphamide had a 60.2% success rate, and those treated with a taxane alone had an 83.3% success rate.

The most common adverse events associated with the cooling cap were cold-induced headaches and neck and shoulder discomfort, chills, and pain associated with wearing the cooling cap for an extended period. Three patients in the breast cancer study discontinued using the cooling cap due to cold discomfort. Forty-one percent of women had at least 1 headache while using the cooling cap.

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The indication for the DigniCap Cooling System has been expanded by the FDA to include alopecia reduction across all solid tumors.

FDA Approves Cooling Cap Across Solid Tumors

In a retrospective cohort study, a higher incidence of venous thromboembolism (VTE) was observed in patients treated with cisplatin-based chemotherapy compared with other forms of chemotherapy.

Patients who had received chemotherapy between November 2010 and October 2012 were retrospectively identified from the registry at Aga Khan University Hospital in Karachi, Pakistan. This included 200 patients identified as the "exposed group" and 200 patients who had received 1 of approximately 12 non-cisplatin—based chemotherapy treatments, identified as the "nonexposed group." Patients were followed for development of VTE throughout the entire duration of therapy plus 1 month.

Overall, 31 patients in the exposed group and 11 patients in the nonexposed cohort experienced VTEs. The most common VTE event, the study notes, was deep vein thrombosis: 18 in the exposed group, 7 in the nonexposed group. Among those who experienced a VTE event, 4 patients in the exposed group died, while 1 patient in the nonexposed group died.

The crude relative risk of VTE in the exposed group was 2.8 times higher than in the non- exposed group. When the investigators adjusted for gender, ECOG status, granulocytecolony stimulating factor, presence of a central venous catheter, and Khorana risk score, the adjusted relative risk was 3.32 times higher in the exposed group than in the nonexposed group.

The study also considered the dose of cisplatin in the exposed group. Of the patients in this group, 31 VTE events occurred when the mean cumulative dose of cisplatin was 471 mg/m

. In the same group, VTE events did not occur when the mean cumulative dose of cisplatin was 322 mg/m

The study concludes that until focus is turned onto the discovery of newer and safer chemotherapeutic agents, prophylaxis against VTE with antiplatelets or anticoagulants should be given to patients receiving cisplatin-based chemotherapy.

Zahir MN, Shaikh Q, Shabbir-Moosajee M, Jabbar AA. Incidence of venous thromboembolism in cancer patients treated with cisplatin-based chemotherapy—a cohort study. BMC Cancer. 2017;17(1):57. doi: 10.1186/s12885-016-3032-4.

Patients treated with cisplatin-based chemotherapy had a higher risk of venous thromboembolism.

Higher VTE Incidence With Cisplatin Chemotherapy

Researchers are seeking to determine whether adding the PARP inhibitor valparib to a chemotherapy combination will improve outcomes for patients with HER2-negative, germline 

-associated metastatic or locally advanced breast cancer.

The international Brocade 3 trial, which is currently enrolling participants at more than 200 locations, seeks to randomize an estimated 500 patients in a 2:1 ratio to either veliparib with carboplatin and paclitaxel or a placebo plus the 2 chemotherapy agents (

“What we’re hoping to learn is whether, irrespective of hormonal status, the BRCA mutation is driving the response, as opposed to other factors,” explained principal investigator Shannon L. Puhalla, MD, who is director of the breast cancer clinical research program at the University of Pittsburgh Cancer Institute.

If successful, the addition of veliparib to a chemotherapy regimen would provide another option for a sizable subgroup of patients with the mutation Germline 

 mutations account for 5% to 10% of all breast cancers, from 20% to 25% of hereditary breast cancers. "Where this study will fill a void is for the patients who requires chemotherapy but also has a BRCA mutation,” said Puhalla. “Then there would be an advantage to giving the PARP inhibitor with chemotherapy.”

Nearly 78% of patients who were treated with a combination of veliparib and carboplatin/paclitaxel responded to treatment in phase II clinical trial results presented at the 2016 San Antonio Breast Cancer Symposium. However, progression-free survival (PFS) and overall survival (OS) did not meet the threshold for statistically significant improvement compared with the same chemotherapy regimen plus placebo.

Puhalla and colleagues believe there were enough positive signals in the results to remain optimistic about the prospects for success in the Brocade 3 study, however.

The phase II study also demonstrated that the backbone treatment of carboplatin and paclitaxel is extremely effective as first- or second-line therapy for patients who are BRCA mutation carriers.

Participants will be randomized 2:1 to veliparib plus paclitaxel/carboplatin or placebo with the combination chemotherapy.

The phase III trial allows for veliparib/ placebo monotherapy (depending on which arm the patient is on) if there is toxicity with combination treatment, a difference between the phase II and II trials. The primary endpoint is PFS; secondary endpoints include OS, clinical benefit rate, and objective response rate. Upon confirmation of progression, patients randomized to placebo will have the option to crossover to receive single-agent veliparib.

Women and men ≥18, with locally advanced (unresectable) or metastatic HER2-negative breast cancer who have a deleterious BRCA1 or BRCA2 germline mutation, ≤2 prior lines of DNA-damaging therapy, and stable CNS metastases are eligible for the trial.

The Brocade 3 trial is being conducted by AbbVie, which is also the company developing the drug. The study is expected to be completed in March 2018.

An ongoing trial is evaluating the addition of PARP inhibitor velaparib to a chemotherapy combination, for patients with HER2-negative, germline BRCA-associated metastatic or locally advanced breast cancer.

Phase III Trial to Examine Veliparib in BRCA Positive Breast Cancer

An immunotherapy combination that adds the interleukin-10 (IL-10) agonist AM0010 to FOLFOX chemotherapy will be evaluated in a phase III trial for patients with metastatic pancreatic cancer (NCT02923921). AM0010, which is being developed by ARMO BioSciences, is a pegylated form of IL-10, shown to stimulate an immune response by inducing the activation and proliferation of tumor-specific CD8-positive T cells, resulting in an antitumor immune memory.

The rationale for the trial was established in a phase I dose-escalation study for patients with advanced solid tumors including pancreatic cancer. Antitumor responses were assessed according to immune-related response criteria, and 41 of the 51 enrolled patients (80.4%) were evaluable. Of the 2 evaluable patients with pancreatic cancer, 1 achieved stable disease that lasted 4 months, and both had strong reduction in the tumor marker CA19-9. In an expansion monotherapy cohort of 22 patients with pancreatic cancer treated with AM0010 with a median of 4 prior therapies, 53% had stable disease, 27% had a more than 50% reduction of the tumor marker CA19-9, and the 1-year survival rate was 22%. Early results of a combination of AM0010 and FOLFOX showed encouraging responses.

The most common adverse events are fatigue, anemia, and thrombocytopenia, which are usually manageable, according to Jeffrey R. Infante, MD, director of the Drug Development Program at Sarah Cannon Research Institute in Nashville.

Anemia and thrombocytopenia are also common with cytotoxic chemotherapy; the protocol for the phase III trial is set up to help clinicians manage the toxicities, with flexibility around dose reductions and the ability to hold medications until the patient has recovered. The effect from AM0010 is rapidly reversible upon withholding the medication.

The multicenter trial, which is not yet open for enrollment, will compare the efficacy of AM0010 in combination with FOLFOX versus FOLFOX alone in an estimated 566 patients. Patients randomized to the experimental arm will receive AM0010 (5mcg/kg) administered on days 1-5 and 8-12 via subcutaneous injection, plus standard FOLFOX-based therapy for pancreas and colon cancer (dl-LV 400 mg/m2 and oxaliplatin 85 mg/m2 followed by bolus 5-FU 400 mg/m2 and a 46-hour infusion of 5-FU 2400 mg/m2) given intravenously once every 2 weeks. The primary endpoint of the study is overall survival (OS), and the secondary endpoints are progression-free survival and overall response rate.

The trial is designed for patients 18 years and older with adenocarcinoma of the pancreas whose disease has progressed after first-line gemcitabine therapy. Patients must complete prior chemotherapy at least 2 weeks before randomization, with recovery from toxicity to grade 1 or baseline and no prior radiation therapy or investigational therapy for metastatic disease.

If successful when paired with FOLFOX, the combination has potential to fulfill an unmet need for these patients, particularly those with metastatic disease who progress from initial chemotherapy and have an OS of ≤6 months.

An ongoing trial is evaluating the combination therapy of interleukin-10 agonist AM0010 and FOLFOX chemotherapy, for patients with metastatic pancreatic cancer.

Novel Immunotherapy Under Study in Pancreatic Cancer

Maintenance therapy with olaparib (Lynparza) showed a 70% reduction in the risk of progression or death compared with placebo for patients with platinum-sensitive, relapsed

-mutant ovarian cancer, according to phase III SOLO2 findings reported at the 2017 Society of Gynecologic Oncology meeting.

Patients randomized to receive olaparib had a median investigator-assessed progression-free survival (PFS) of 19.1 months compared with 5.5 months in the placebo arm (HR, 0.30; 95% CI, 0.22-0.41; 

 <.0001). A prespecified analysis of PFS by a blinded central review committee showed a median PFS of 30.2 months for the olaparib group versus 5.5 months for placebo, a 75% reduction in the hazard for progression and death (HR, 0.25; 95% CI, 0.18-0.35; 

“The progression-free survival benefit was supported by a significant delay in time to first subsequent therapy, second progression-free survival, and time to second subsequent therapy,” said Eric Pujade-Lauraine, MD, PhD, of the University of Paris Descartes. “With the exception of anemia, toxicity was mostly low grade. SOLO2 is the first phase III trial of olaparib tablets as maintenance treatment and showed a significant benefit in patients with platinum-sensitive, relapsed ovarian cancer and 

Pujade-Lauraine reported findings from the phase III SOLO2 trial that evaluated the efficacy and tolerability of a 300-mg tablet formulation of olaparib as maintenance therapy. Eligible patients had relapsed ovarian cancer, confirmed 

 mutation, and were in response to their most recent platinum-containing regimen following 2 or more prior systemic regimens.

Investigators in the multicenter international trial randomized patients 2:1 to olaparib 300 mg BID or to matching placebo. Treatment continued until disease progression. The primary endpoint was investigator-assessed PFS. The trial protocol included a sensitivity analysis of PFS, performed by a blinded independent central review committee. Secondary endpoints included second PFS (PFS2), overall survival, and safety and tolerability.

Data analysis included 294 randomized patients who received the assigned study treatment. Baseline characteristics did not differ substantively between treatment groups, as 53% to 54% of patients in each group had attained a partial remission at enrollment; 40% of each group had a platinum-free interval of 6 to 12 months; and about 40% of patients had received 3 or more prior lines of therapy.

The secondary endpoint of median time to first subsequent therapy or death was 27.9 months with olaparib and 7.1 months with placebo (

 <.0001). The median PFS2 had yet to be reached in the olaparib group, whereas the placebo group had median of 18.4 months, representing a 50% reduction in the hazard ratio in favor of the PARP inhibitor (

 = .0002). Time to second subsequent therapy or death also had yet to be reached in the olaparib arm compared with a median of 18.2 months in the placebo group (

 <.0001). Data remained too immature for an analysis of overall survival.

Pujade-Lauraine said olaparib was generally well tolerated, as no new or unexpected treatment-associated adverse events (AEs) occurred in patients who received the PARP inhibitor. The most common AEs of any grade were nausea (75.9% vs 33.3%), fatigue/asthenia (65.6% vs 39.4%), anemia (43.6% vs 8.1%), vomiting (37.4% vs 19.2%), and diarrhea (32.8% vs 20.2%). Neutropenia occurred in 19.5% of the olaparib group versus 6.1% of the placebo group, and thrombocytopenia in 13.8% versus 3.0%.

Grade ≥3 AEs included anemia (19.5% vs 2.0%), neutropenia (5.1% vs 4.0%), and thrombocytopenia (1.0% in both groups).

“The SOLO-2 data demonstrated a statistically significant and clinically meaningful improvement in outcomes for those who took olaparib," co-author of the study Richard Penson, MD, associate professor of Medicine at Harvard Medical School and Clinical Director of Medical Gynecologic Oncology at Massachusetts General Hospital, said in a statement. "The results, which showed a delay in disease progression in the maintenance setting, highlight the impact of PARP inhibition at the forefront of the important advances we are making in targeting ovarian cancer.”

The results confirmed and extended those of a phase II trial that demonstrated a PFS advantage for olaparib maintenance therapy in relapsed, platinum-sensitive ovarian cancer (

. 2012;366:1382-1392). The earlier study did not select patients based on 

status, and patients received a different formulation of olaparib.

Although the earlier trial showed a PFS benefit in the overall population and across various subgroups, patients with 

-mutated ovarian cancer had the most prolonged PFS. Additionally, the capsule formulation of olaparib used in the phase II trial required patients to take as many as 16 pills a day whereas the 300-mg tablet formulation reduced the pill burden to 2 per day.

The FDA approved the 400 mg dose of olaparib for the treatment of women with 

-positive advanced ovarian cancer following treatment with three or more prior lines of chemotherapy in December 2014. AstraZeneca, the company developing olaparib, is seeking approval for the new tablet formulation “as quickly as possible.”

For patients with BRCA+ ovarian cancer, olaparib in the maintenance setting has shown impressive progression free survival benefits.

Survival Benefit Confirmed With Maintenance Olaparib in BRCA+ Ovarian Cancer

In an effort to understand the relatively low uptake of the human papillomavirus (HPV) vaccine in the United States, a survey of parents of teenage girls has found that a lack of knowledge about the vaccine and a failure by healthcare providers to recommend it, superseded parental concern about their daughters’ not needing it because they are not sexually active.

In 2010 the third most common reason parents gave for not vaccinating their teenager was lack of sexual activity, but in 2014, that concern dropped to the bottom of the 5 most commonly cited reasons for failure to vaccinate. During the same time period, lack of knowledge about vaccine and lack of healthcare provider recommendation moved from the bottom of the list to the middle.

Concern about vaccine safety and perceived lack of necessity headed the list at both points in time, Anna Beavis, MD, a gynecologic oncology fellow at the Johns Hopkins Bloomberg School of Public Health, reported at the 2017 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.

“Our results demonstrate that safety and perceived lack of necessity, as well as lack of knowledge, make up 50% of the reason why parents don’t initiate HPV vaccination,” said Beavis. “The results also demonstrate that concern about the vaccine and its connection with sexual activity are less important to parents and that these concerns decreased over time.

“Healthcare providers should not feel dissuaded from recommending HPV vaccine simply because they feel the parents don’t want to discuss sexual activity,” she added.

Preliminary analysis of data from the 2015 survey showed that failure to vaccinate was associated with white race, younger age, and socioeconomic status above the poverty level. An HPV message targeted to those demographic characteristics is needed, said Beavis.

Given the strong association between cervical cancer and HPV infection, universal uptake of the 9-valent HPV vaccine could prevent 90% of all cervical cancer. Despite its demonstrated efficacy for preventing infection the rate of HPV vaccine uptake in the United States has lagged behind other Western nations.

In 2007, the first full year after HPV vaccine was introduced in the United States, 12% of adolescent girls were vaccinated. By 2014, the rate had increased to about 60%, still well below the 80% target established in the Healthy People 2020 initiative. In contrast, HPV vaccination rates in Australia, which has a school-based vaccination program, have exceeded 80% since 2007, Beavis noted.

Explanations for the low US uptake rate remain incomplete. Physician recommendation has a strong influence of vaccination rates, but recommendation rates vary by specialty, geography, and other factors. Access to healthcare also affects uptake.

Previous studies have shown that providers with low recommendation rates feel the need to discuss sexual activity with parents before recommending the vaccine for a child, which has contributed to the low uptake.

Studies of parental attitudes toward HPV vaccine have yielded conflicting results. Whether attitudes have changed over time has not been studied extensively, providing a rationale to examine the issue in greater detail. Beavis and colleagues hypothesized that recent data would show that parental attitudes about vaccine safety and sexual issues have decreased.

The study involved data from the CDC’s National Immunization Survey: Teen. The survey tracks national vaccination trends and elicits information about reasons for not initiating vaccination in children and teenagers. Providers are contacted to verify vaccination-related data. About 35,000 households are contacted annually, and the data are used to estimate national trends in vaccination.

Beavis and colleagues limited their analysis to households with girls aged 13 to 17. The analysis covered 85,269 individual surveys conducted during 2010-2014. Provider verification was available in 49,345 cases, which showed that HPV vaccine had not been initiated in 22,642 cases and that 26,703 girls had received at least 1 dose of HPV vaccine. Of the unvaccinated group, 12,401 parents indicated no intention to initiate HPV vaccination.

In the subgroup not intending to initiate vaccination, the median age of the child was 15. Race/ethnicity was white in 70% of cases, two-thirds had private insurance, and 89% had income that exceeded the poverty level.

The vaccine initiation rate increased gradually but steadily from 49% in 2010 to 60% in 2014 (

<.001). With regard to reasons for not initiating the vaccine, the top 2 reasons in 2010 were concerns about vaccine safety/side effects (23%) and perceived lack of need/necessity for vaccination (20%). As the third most common reason, parents said their daughters were not sexually active and did not need the vaccine (18%). Lack of knowledge (14%) and lack of provider recommendation completed the list (9%).

In 2014, however, the top 5 reasons parents gave for not pursuing HPV vaccination for their children were:

Perceived lack of need/necessity topped the list (19%)

Lack of knowledge about vaccines and vaccination (14%)

The belief that the vaccine was not necessary because children were not sexually active (9%)

Comparison of 2010 and 2014 responses showed statistically significantly differences for safety/side effect concerns, perceived lack of necessity, beliefs about sexual activity, and lack of provider recommendation (

Beavis AL, Krakow M, Levinson K, Rositch AF. Reasons for persistent suboptimal rates of HPV vaccination in the US: shifting the focus from sexuality to education and awareness. In: Proceedings from the Society for Gynecologic Oncology Annual Meeting on Women’s Cancer; March 12-14, 2017; National Harbor, MD.

According to a recent survey, the main causes for a lack of HPV vaccine uptake are a lack of knowledge and a failure by healthcare providers to recommend it.

Survey Examines Why US Uptake of HPV Vaccine Remains Relatively Low

The FDA has granted an accelerated approval to ibrutinib (Imbruvica) as a treatment for patients who require systemic therapy for marginal zone lymphoma (MZL) following at least one prior anti-CD20-based therapy, based on findings from a single-arm phase II study.

In the pivotal open-label study, the objective response rates (ORR) with ibrutinib was 46%, with a complete response rate of 3.2%, according to findings presented at the 2016 ASH Annual Meeting. The median progression-free survival was 14.2 months with ibrutinib (95% CI, 8.3-NR) and the median overall survival was not yet reached at a median follow-up of 19.4 months.

"Patients with relapsed/refractory marginal zone lymphoma are in critical need of treatment options to manage living with this rare, serious blood cancer," lead investigator Ariela Noy, MD, Hematologic Oncologist at Memorial Sloan Kettering Cancer Center, said in a statement. "This approval of Imbruvica represents a welcome new oral option for the MZL community and is the first approved therapy for these patients."

In the trial, which was known as PCYC-1121, 63 patients with relapsed or refractory MZL received ibrutinib at 560 mg orally once daily. The trial included patients with splenic (n = 14), nodal (n = 17), or extranodal MZL (n = 32) who had received 1 or more prior therapies, including an anti-CD20 antibody. All patients had an ECOG performance status of ≤2 and 33% had bone marrow involvement. All patients had an estimated life expectancy of >3 months.

Overall, 6% of patients had undergone a prior splenectomy and 14% had received prior radiotherapy. Prior to entering the trial, rituximab monotherapy was received by 27% of patients and a CD20 antibody-containing chemoimmunotherapy regimen was received by 64% of participants.

In those with extranodal or mucosa-associated lymphoid tissue disease, the ORR was 46.9%. In the nodal group, the ORR was 41.2% and in the splenic arm the ORR was 50%. After a median follow-up of 19.4 months, the median duration of response was not reached (range, 16.7-NR). The median time to initial response was 4.5 months (range, 2.3-16.4).

“The responses and clinical benefit seen with single-agent ibrutinib in patients with marginal zone lymphoma who have already failed at least one other therapy are very encouraging,” Noy said, during the ASH meeting. “It is important for these patients to have treatment options.”

The most common adverse events (AEs) of all grades included thrombocytopenia (49%), fatigue (44%), anemia (43%), diarrhea (43%), bruising (41%), musculoskeletal pain (40%), hemorrhage (30%), rash (29%), nausea (25%), peripheral edema (24%), arthralgia (24%), neutropenia (22%), cough (22%), dyspnea (21%), and upper respiratory tract infection (21%). The most common grade 3/4 AEs were decreases in hemoglobin (13%), neutrophil decrease (13%), and pneumonia (10%).

"This approval broadens the indication for Imbruvica to include relapsed/refractory marginal zone lymphoma. It addresses a great unmet need for patients living with this serious blood cancer," said Peter F. Lebowitz, MD, PhD, global oncology head, Janssen Biotech, which is the company jointly developing and commercializing the agent along with the AbbVie company Pharmacyclics.

"Building on our longstanding commitment of providing meaningful treatment solutions for people living with hematological malignancies, this milestone marks the fifth blood cancer indication for this medication," said Lebowitz. "We continue to research its potential across a range of B-cell malignancies based on the drug's mechanism of action."

The accelerated approval for MZL is contingent upon findings from a larger confirmatory study. Ibrutinib has previously been approved by the FDA for the treatment of patients with mantle cell lymphoma, chronic lymphocytic leukemia and small lymphocytic lymphoma, and Waldenström’s macroglobulinemia.

Noy A, de Vos S. Thieblemont C, et al. Single-Agent Ibrutinib Demonstrates Efficacy and Safety in Patients with Relapsed/Refractory Marginal Zone Lymphoma: A Multicenter, Open-Label, Phase 2 Study. Presented at: ASH 2016 Annual Meeting. Abstract 1213.

The FDA has granted accelerated approval of ibrutinib for treatment of marginal zone lymphona (MZL).

Ibrutinib Granted FDA Approval for Marginal Zone Lymphoma

Patients with myeloproliferative disorders have a high symptom burden that significantly affects emotional status, quality of life, and functional ability, an international patient survey showed.

The survey showed that 90% of patients reported 1 or more symptoms within the past 12 months, the most common symptom being fatigue/tiredness. A substantial proportion of patients with myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) reported multiple troubling symptoms, which often were rated as 6 or higher on a severity scale of 0-10.

A dozen types of symptoms affected a fourth or more of the 699 survey participants, Claire N. Harrison, DM, deputy clinical director of cancer and hematology at Guy’s and St. Thomas’ Hospital in London, reported at the American Society of Hematology meeting in San Diego.

“The findings from this international survey indicate that many patients with myeloproliferative neoplasms (MPNs) experience a high disease burden, including a high prevalence of symptoms and reduction in emotional wellbeing, quality of life, activities of daily living, and ability to work,” Harrison and colleagues concluded in a poster presentation.

“When patients with myeloproliferative neoplasms are treated, care should be taken in trying to manage patient disease burden to minimize the impact on patients’ daily lives.”

The findings came from the global MPN LANDMARK survey, conducted in Australia, Canada, Germany, Italy, Japan, and the United Kingdom. Patients in those countries completed comprehensive surveys designed to assess the impact of MPNs on symptoms, quality of life, and normal activities.

This global survey involved 174 patients with MF, 223 with PV, and 302 with ET. Geographic distribution consisted of 10 patients from Australia, 64 from Canada, 149 from Germany, 106 from Italy, 84 from Japan, and 286 from the UK. Patients were recruited by clinical practices and patient support groups.

The survey consisted of 63 questions, some of which had multiple items. Patients completed the questionnaire online, and the survey required 25 to 30 minutes to complete. Physicians completed a companion survey, results of which will be reported at a later date, according to Harrison.

Fatigue or tiredness was the single most common symptom, reported by 64%, 54%, and 45% of patients with ET, MF, and PV, respectively. The types of symptoms and symptom burden varied by MPN type:

MF—Abdominal discomfort (30%), shortness of breath (29%), night sweats (29%), and difficulty sleeping (27%)

PV—Pruritus (28%), loss of concentration (27%), night sweats (25%), and dizziness (25%)

ET—Dizziness (33%), night sweats (31%), bruising (30%), and difficulty sleeping (28%)

Similarly, fatigue ranked at the top of the list of “most severe symptoms” for patients with all 3 types of MPNs. The mean severity scores for fatigue (scale of 0-10) were 6.68 for MF, 6.53 for PV, and 6.44 for ET. “Inactivity” followed, with mean scores of 6.7 for MF, 5.97 for ET, and 5.54 for PV. Patients with ET had a mean severity score of 7.89 for “other symptoms not listed” and 6.92 for blood clots.

Overall, more than 25 different symptoms had mean severity scores exceeding 5.

Asked whether MPN symptoms affected quality of life, three-fourths of the patients agreed strongly (29%) or somewhat (47%). The proportion of agreement was similar across the 3 types of MPN.

A fourth of all the patients said their disease frequently caused emotional hardship, and 29% said they frequently felt anxious or worried.

An 8-item assessment of MPNs’ effect on quality of life showed generally similar responses across patients with the 3 types of conditions. A test for statistical significance showed that patients with MF had higher mean scores for feeling anxious or worried (

About half (48%) of the patients said they frequently felt satisfied with their ability to cope with their disease. Harrison and colleagues found that 33%, 24%, and 23% of patients with MF, PV, and ET, respectively, said their condition caused emotional hardship. Additionally, 34%, 29%, and 26% of patients with MF, PV, and ET reported feeling anxious or worried about their disease.

Twenty-seven percent of patients felt their condition had a high impact on them or their caregivers. Other evidence of interference with activities of daily living included pain-limiting activities (24%), interference with family or social life (26%), and interference with daily activities (26%). Two-thirds of patients with PV or ET reported never needing a caregiver, as compared with 42% of patients with MF (

The survey also revealed that 20% of patients had to reduce hours at work because of their disease. Overall, almost 7% reported increased absenteeism from work because of MPNs, 31% worked while sick, and 35% felt their condition impaired their ability to work. Employed patients with MF reported missing an average of 4.8 hours from work the previous 7 days, followed by 3.3 hours among patients with PV, and 2.6 hours among those with ET.

Finally, 37.8%, 35.5%, and 33.4% of patients with MF, PV, and ET, respectively, reported work impairment as a result of their condition. Additionally, 44.9%, 39.9%, and 38.1% of patients with MF, PV, and ET reported impairment in their overall activity.

The researchers noted that additional analyses of clinician—patient interaction, differences by country, and treatment patterns are planned, they added.

 Harrison CN, Koschmieder S, Foltz, et al. The impact of myeloproliferative neoplasms (MPNs) on patient quality of life and productivity: results from the international MPN LANDMARK survey. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract 4267.

A recent survey indicates that many patients with MPNs experience a high symptom burden that affects their emotional wellbeing, quality of life, and functionality.

Survey Spotlights Symptom Burden With Myeloproliferative Neoplasms

In the recent phase III SOLO-2 trial, patients with ovarian cancer in the olaparib (Lynparza) arm demonstrated improved progression-free survival in comparison to those in the placebo arm. The single-agent PARP inhibitor was tested in the maintenance setting for patients with advanced 

Although specific data from the trial are not yet available, AstraZeneca, the manufacturer of Lynparza, reported that the median PFS with olaparib was significantly higher than in the olaparib arm of the phase II Study 19 in a similar population. The safety profile for the PARP inhibitor was consistent with results reported from previous trials.

“We are pleased with the robust improvement in progression-free survival demonstrated by Lynparza in the SOLO-2 trial. We will work with regulatory authorities to make Lynparza tablets available as quickly as possible to patients with ovarian cancer. We remain committed to investigating the full potential of Lynparza, both as monotherapy and in combinations, and to identifying all patients who may benefit from this important medicine,” Sean Bohen, MD, PhD, executive vice president, Global Medicines Development, and Chief Medical Officer at AstraZeneca, said in a statement.

The multicenter phase III SOLO-2 trial included 295 patients with platinum-sensitive, relapsed/recurrent, 

-positive ovarian cancer who had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomized to receive either olaparib at 300 mg twice daily or placebo until disease progression.

The latest data from the phase II Study 19, which were presented at the 2016 ASCO Annual Meeting, showed that in patients with platinum-sensitive relapsed serous ovarian cancer, olaparib increased overall survival (OS) when given as maintenance therapy.

Results of the study's extension showed that the PARP inhibitor demonstrated the greatest OS advantage in women who had a 

 mutation (HR, 0.62), according to lead author Jonathan Ledermann, MD, professor of Medical Oncology at the University College London Cancer Institute and director of the Cancer Research UK & UCL Cancer Trials Centre, who presented the results at ASCO. However, the P values were nominal and did not meet the criterion for statistical significance (

Additional key findings were that both time to first subsequent therapy or death (TFST) and time to second subsequent therapy or death (TSST) were substantially prolonged in patients taking olaparib; again, the greatest benefit was seen in those with a 

mutation. Additionally, the unprecedented long-term exposure meant that 13% of all trial patients (15% of 

-mutated patients) received maintenance olaparib for at least 5 years. In 3 years of follow-up since the 2012 analysis, there were no new safety findings.

Study 19 assessed patients with platinum-sensitive, recurrent high-grade serous ovarian cancer (n = 265). They had received 2 or more prior regimens of platinum-based chemotherapy and experienced complete response or partial response to their most recent regimen. In a double-blind, 1:1 randomization, half the patients received olaparib 400 mg capsules twice daily as maintenance therapy (n = 136) and half received placebo capsules twice daily (n = 129).

 testing occurred for all patients in the form of case reports that contained the results of previous local germline 

 testing. The division between patients was nearly even between those 

 mutations (n = 136) and those with wild-type 

 findings (n = 118), meaning that they either did not have a detected 

In Study 19, the median PFS for patients taking maintenance olaparib was 8.4 months, compared to 4.8 months for the control group. The difference in the 

 mutation subgroup was even more pronounced: 11.2 months with olaparib and 4.3 months with placebo.

The third data analysis of Study 19, with data cutoff at September 30, 2015, was performed with data at 77% maturity, OS in the overall study population (n = 265) was a median 29.8 months in the olaparib group and 27.8 months in the placebo. In the 

 mutation group (n = 136), where the data were at 70% maturity, median OS was 34.9 months for the olaparib group and 30.2 months for placebo.

With a median follow-up interval of 5.9 years, 15 patients (11%) were still receiving olaparib (8 with 

-mutated patient was still receiving placebo. Twelve percent of 

 wild-type patients on olaparib achieved median follow-up of between 5 and 6 years.

In the overall study population, 59 patients (43%) experienced an adverse event (AE) of grade 3 or above, while only 28 (22%) of those on placebo did. Those percentages remained fairly consistent among patients who remained on trial for 2 years or more: 15 (47%) in the olaparib arm and 1 (20%) in the control arm.

Likewise, the percentages of dose reductions due to AEs were consistent over time, and there were few treatment discontinuations due to AEs: 8 active and 2 control patients overall and 3 olaparib patients from the long-term treatment group. No patients from the long-term placebo group discontinued treatment due to AEs.

In June 2014, the FDA’s Oncologic Drugs Advisory Committee voted 11-2 against the accelerated approval of olaparib as a maintenance therapy for women with platinum-sensitive relapsed ovarian cancer with germline 

 mutations. By voting no, the committee recommended waiting for results from the SOLO-2 trial before approving olaparib in this setting.

Following this vote, AstraZeneca submitted an amendment to olaparib’s new drug application upon the FDA’s request, which led to the drug’s eventual approval in December 2014 for the treatment of women with 

-positive advanced ovarian cancer following treatment with 3 or more prior lines of chemotherapy.

 Ledermann JA, Harter P, Gourley C, et al. Overall survival (OS) in patients (pts) with platinum-sensitive relapsed serous ovarian cancer (PSR SOC) receiving olaparib maintenance monotherapy: an interim analysis. 

In a recent phase III study, the PARP-inhibitor olaparib was shown to improve progression-free survival for patients with BRCA-positive ovarian cancer. 

Survival Advantage with Olaparib for Patients with Ovarian Cancer in Phase III Study

A number of highly effective cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors are currently in development as treatments for patients with metastatic breast cancer. At this point, palbociclib (Ibrance) has gained FDA approval as a frontline therapy with letrozole and as a second-line therapy with fulvestrant for patients with hormone receptor (HR)—positive breast cancer.

Palbociclib demonstrated a consistent progression-free survival (PFS) benefit in patients with advanced estrogen receptor (ER)-positive breast cancer, according to a biomarker analysis of the phase III PALOMA-2 trial presented at the recent annual meeting of the European Society of Medical Oncology (ESMO).

Abemaciclib is another agent that is rapidly advancing through clinical trials. This potent agent has received a breakthrough therapy designation from the FDA for its potential use as a monotherapy for patients with refractory HR-positive advanced breast cancer.

Findings of the single arm, phase II MONARCH 1 trial presented at the 2016 ASCO Annual Meeting showed that abemaciclib induced a response rate of nearly 20% in heavily pretreated patients with refractory HR-positive, HER2-negative advanced breast cancer. Median progression-free survival (PFS) was 6 months and median overall survival (OS) was 17.7 months.

In addition to single-agent activity, abemaciclib is being explored in other subtypes of breast cancer, including findings from a phase 1b study, also presented at ESMO.

 This study showed that when combined with tamoxifen, trastuzumab, or one of many endocrine-based therapies the agent demonstrates significant antitumor activity and clinical benefit in patients with advanced breast cancer.

The FDA also granted a breakthrough designation to another drug in this class, ribociclib, in combination with letrozole for its potential as a frontline therapy for patients with HR-positive, HER2-negative advanced breast cancer. The designation, which is meant to expedite the development of promising new therapies, was based on findings from the phase III MONALEESA-2 trial, in which ribociclib and letrozole significantly improved progression-free survival (PFS) compared with letrozole alone.

In additional findings for ribociclib in breast cancer reported at the 2016 ESMO Annual Congress, the drug demonstrated significant slowing of disease progression when added to endocrine therapy in postmenopausal women with HR-positive metastatic breast cancer.

Palbociclib received its FDA approval based on a doubling of PFS (20.2 months) versus 10.2 months for letrozole alone seen in the phase II PALOMA-1 trial. Debu Tripathy, MD, chair of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center explained that although the drug is reasonably well-tolerated, it does require more monitoring of blood counts due to the risk of neutropenia, and dose adjustments may be needed. Febrile neutropenia is very rare with palbociclib. Other common side effects (occurring in >30% patients taking palbociclib) are fatigue and upper respiratory infection.

The most notable difference between the CDK 4/6 inhibitors is their toxicity profiles. Myelosuppression, particularly neutropenia, is the primary dose-limiting toxicity (DLT)for palbociclib and ribociclib. Rates of neutropenia are approximately 40% for both agents.

In studies of abemaciclib, patients had milder hematologic toxicity, and it was not a DLT. Because myelosuppression is less of a side effect with abemaciclib, it can be given continually without an off-treatment week per cycle.

Gastrointestinal toxicity, however, is more common with abemaciclib than with the other CDK 4&6 inhibitors. In a phase I trial, the incidence of diarrhea was 66%, although only 6% of patients had grade 3 diarrhea, and none had grade 4. Lowering the dosage of abemaciclib may help eliminate or reduce the severity of this side effect, and supportive medications may help. Two trials investigating the agent (NCT020677844 and NCT02441946) now administer the drug with prophylactic loperamide.

Finally, abemaciclib crosses the blood—brain barrier, which makes it an attractive agent for treating primary and secondary central nervous system malignancies. The drug has also shown promise in several other tumor types, including non–small cell lung cancer, melanoma, and colorectal cancer.

Finn R, Jiang Y, Rugo HS, et al. Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib with letrozole compared with placebo plus letrozole in postmenopausal women with ER+/HER2- advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016, Copenhagen, Denmark.

Beeram M, et al. A Phase 1 Study of Abemaciclib, an inhibitor of CDK4 and CDK6 in Combination with Endocrine and HER2 Targeted Therapies for Patients with Metastatic Breast Cancer. Presented at: 2016 ESMO Congress; October 7-11 2016; Copenhagen, Denmark. Abstract LBA18.

Hortobagyi GN, Stemmer SM, Burris HA, et al. First-line ribociclib + letrozole for postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA1.

An update on CDK4 and CDK6 inhibitors in treatment for patients with metastatic breast cancer.

Staff Writer