Δευτέρα, 11 Δεκεμβρίου 2017

NEW HYPERTENSION GUIDELINES

Key Changes in the New Guidelines
  • New targets for treatment: These recommend reductions in blood pressure to less than 130 mm Hg systolic and less than 80 mm Hg diastolic in most adults (down from 140/90 mm Hg).
  • Earlier classification of hypertension: Adults with an average systolic pressure of 130 to 139 mm Hg or diastolic pressure of 80 to 89 mm Hg are now categorized as having stage 1 hypertension (these patients would have previously been considered as having "prehypertension").
  • Atherosclerotic risk estimation to guide decisions in stage 1 hypertension: For patients at low atherosclerotic risk (10-year risk <10 advised.="" alone="" and="" are="" at="" changes="" diabetes="" disease="" drug="" for="" high="" including="" is="" kidney="" lifestyle="" p="" patients="" plus="" recommended="" risk="" therapy="" those="" whereas="" with="">
  • New stage 2 classification: Patients with average systolic pressure higher than 140 mm Hg or diastolic above 90 mm Hg are now classified at stage 2 hypertension. As before, drug therapy is recommended for all these patients irrespective of atherosclerotic risk.
  • Older patients: Older adults have the same treatment target as younger patients, and drug therapy is recommended for all older adults (age >65 years) with an average systolic pressure of 130 mm Hg or greater.
  • Starting with two drugs: Most adults with blood pressure sufficiently elevated to warrant drug therapy should be treated initially with two agents, especially patients who are black or have stage 2 hypertension.
  • More accurate estimation of blood pressure: Use average of measures taken over several visits, as well as out-of-office measurements.

7 YEARS OF ADJUVANT AI MAY BE ENOUGH

Postmenopausal women with hormone receptor–positive breast cancer who have already taken endocrine therapy for 5 years can proceed with just 2 more years, rather than another 5 years, of additional therapy with the aromatase inhibitor (AI) anastrozole (Arimidex, AstraZeneca), an Austrian study concludes.
The 2- and 5-year regimens gave the same reduction in relapse risk but had less adverse effect on bone health, potentially protecting women from fractures.
The results come from  the ABCSG-16 trial, a randomized controlled trial of almost 3500 women reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017.
Lead investigator, Michael Gnant, MD, director and chairman of the Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria, said in a release: "There is simply no rationale to keep most patients on extended AI for longer than two years."
"This result can help save a lot of unnecessary side effects for many women around the world," he said, adding: "I believe that these trial results should be implemented into daily practice at once."
I believe that these trial results should be implemented into daily practice at once. Dr Michael Gnant
Presenting his findings, Dr Gnant began by highlighting that hormone receptor–positive breast cancer has a significant long-term risk for relapse and that more than 50% of relapses occur after the first 5 years of follow-up.
There has consequently been a tendency to extend the duration of adjuvant hormone therapy. The results of several studies exploring how best to extend therapy have shown that after 5 years of tamoxifen, there is a clear benefit from extended adjuvant therapy with AIs, although the picture is less clear after initial AI treatment.
Dr Gnant said, "So, the question remains: If we extended adjuvant aromatase inhibitors, for how long do we have to treat?"
The researchers therefore undertook the ABCSG-16 trial, in which 3484 postmenopausal women with hormone receptor–positive stage I to III breast cancer from 75 centers in Austria were randomly assigned to 2 years or 5 years of anastrazole, 1 mg/day.
All the women had already undergone 4 to 6 years of endocrine therapy with tamoxifen, an AI, or an AI after tamoxifen following initial surgery with or without radiotherapy.
The median age of the women was 64 years. The tumor size was less than 2 cm in most (72%) cases, and 31% of patents had node-positive disease.
Eighty percent of women had undergone breast-conserving surgery, and 29% had received additional (neo)adjuvant chemotherapy. In the first 5 years after local therapy, 51% of women had been given tamoxifen only, while 49% had received an AI.
Dr Gnant described the trial population as "what I would call a typical or average postmenopausal luminal breast cancer cohort, as we see in the US or in European countries."
By the cutoff date of June 30, 2016, the researchers had found that 757 patients were disease-free: 377 (22%) from the 2-year anastrozole group and 380 (22%) from the 5-year anastrozole group.
The team calculated that after a median follow-up period of 106.2 months, there was no significant difference in the proportion of women with disease-free survival, at 71.1% in the 2-year therapy group and 70.3% among patients treated for 5 years, at a hazard ratio of 1.007 (P = .925).
Furthermore, in no subgroups did treatment duration significantly affect disease-free survival, even after stratification of the patients by age, tumor stage, nodal status, histologic grade, hormone receptor status, previous hormone therapy, or previous chemotherapy.
Overall survival also did not differ between the 2-year and 5-year treatment group, with 10-year overall survival rates of 85.3% and 84.9%, respectively (hazard ratio, 1.007; P = .947).
Dr Gnant noted that treatment adherence in the trial was consistent with what would be expected for patients who had already received endocrine therapy for 5 years before randomization, with a "relatively constant rate of patients dropping off standard aromatase inhibitor therapy over time."
He added: "Interestingly, those patients who also received chemotherapy or more aromatase inhibitors in the first 5 years were more likely to be compliant; probably this can be explained by a perception of a higher relapse risk in these subgroups."
Dr Gnant pointed out that an exploratory analysis in only patients who were "perfectly adherent" also showed that disease-free survival did not differ between the 2-year and 5-year groups, "so I think this further supports the validity of the overall message of the trial."
Crucially, the team did find a difference in adverse events between the two treatment groups, with a nonsignificant trend toward a higher rate of fractures among patients given anastrozole for 5 years vs those treated for just 2 years, at a hazard ratio of 1.353 (P = .053), based on a rate of 6.3% vs 4.7% at the 5-year follow-up.
Speaking at a press conference, Dr Gnant said, "While not providing outcome benefits, the extension of treatment to 5 additional years leads to increased side effects, including more fractures, and should thus be avoided."
"We can conclude that, after 5 years of standard endocrine treatment, 2 additional years of aromatase inhibitors are sufficient as extended therapy," he said.
In the future, specific molecular characteristics may be found to identify patients who would benefit from prolonged adjuvant therapy. "But, for now, we can conclude that 7 years are good enough for almost every patient with luminal breast cancer," he said.

Negative Study, Positive News 

Dr Gnant commented that "for us as clinical scientists, a negative trial is always disappointing, [but] I think the clinical take-home message can help to avoid unnecessary side effects for many, many women."
SABCS co-director Carlos L. Arteaga, MD, who is director of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, Dallas, Texas, and moderated the press conference, agreed, saying: "Negative study, positive news."
He added that he would have no problem putting the findings into practice, and he expressed a hope that there will be more de-escalation studies, particularly as AIs are now being combined with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors.
Dr Arteaga said, "I think we should do better than just extending, extending, extending [therapy]. We have to come up with better ideas."
He told Medscape Medical News: "I think, for the last few years, we have realized that, for a long time, we have treated too many women for too long, and the reason is because we can afford the standards of care."
"But the fact of the matter is, just in a minority of women those interventions make a difference. We are in a time of maturity [in the field], so let's give it a try, let's de-escalate."
Dr Arteaga sounded a note of caution, however, emphasizing that de-escalation must be backed up by randomized studies.
"In the process of de-escalating, we may be depriving some women, so we have to be very careful and do studies like the one you heard today," he said.
The study was funded by AstraZeneca. Dr Gnant has received honoraria, travel or accommodations funding, and research funding from AstraZeneca.
San Antonio Breast Cancer Symposium (SABCS) 2017. Abstract GS3-01. Presented December 7, 2017. 

9 WEEKS OF ADJUVANT HERCEPTIN?

Nine weeks of treatment with trastuzumab (multiple brands) fell short of being noninferior to 1 year of treatment in a randomized controlled trial in early-stage HER2-positive breast cancer, according to findings reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017.
It fell short by only a small margin. The 5-year rate of disease-free survival (DFS), which was the primary outcome, was 90.5% for the 1-year arm vs 88% for the 9-week arm (hazard ratio [HR], 1.39; 90% confidence interval [CI], 1.12 - 1.72).
All of the patients had received trastuzumab in addition to chemotherapy.
Lead investigator Heikki Joensuu, MD, of the University of Helsinki in Finland, was clear about the meaning of the results: "Chemotherapy plus 1 year of anti-HER2 therapy should remain the standard."
Chemotherapy plus 1 year of anti-HER2 therapy should remain the standard. Dr Heikki Joensuu
Dr Joensuu was speaking here at a press briefing for the SABCS. He presented these results from the Synergism or Long Duration Trial (SOLD)
He noted that there was less cardiac toxicity in the group that received trastuzumab for 9 weeks compared to the 1-year group (cardiac adverse events: 2% vs 3.9%, = .01; congestive heart failure: 1.9% vs 3.3%, P = .04). For patients with underlying heart disease, "9 weeks may be an option," he said.
That comment was supported by Carlos Arteaga, MD, of the Harold Simmons Comprehensive Cancer Center at the UT Southwester Medical Center in Dallas, Texas, who moderated the press conference: "Patient safety is first."
Bishal Gyawali, MD, of the Institute of Cancer Policy, King's College London, United Kingdom, who was not involved in the trial, repeated the study conclusion. "As of now, 12 months of trastuzumab should remain the standard of care, where affordability is not a concern."
But Dr Gyawali told Medscape Medical News that cost is a concern with the longer schedule, especially in low- to middle-income countries.
Dr Joensuu agreed, saying that in "many countries," 1 year of treatment with trastuzumab was "too expensive."
Dr Gyawali, who also practices in his native Nepal, a low- to middle-income country, observed that 9 weeks of treament with the drug there would cost around $3000, which is much less than the 12-month price tag of $18,000 and is "within the affordability range for many patients."
Dr Joensuu agreed, saying that in "many countries," 1 year of trastuzumab therapy was "too expensive."
He also pointed out that "there was...not much difference between the groups in two other important clinical endpoints, distant disease-free survival [DDFS] and overall survival [OS], which were secondary endpoints in the trial."
For the 9-week and 1-year groups, the 5-year DDFS was 93.2% vs 94.2% (HR, 1.24; 90% CI, 0.93 - 1.65), and the 5-year OS was 94.7% vs 95.9% (HR, 1.36; 90% CI, 0.98 - 1.89).
Dr Gyawali observed that the absolute difference in the 5-year OS rates is 1.2%, which is small, not statistically significant, and "doesn't seem very clinically relevant." He also explained that noninferiority was not an issue with the secondary endpoint of OS.
"The power calculations were revised midway, and the design changed to noninferiority for the primary endpoint of DFS but not OS," he pointed out.
The sum of findings gives clinicians a lot to think about, he suggested.
"The interpretation of this trial is intriguing: if you look at DFS alone, the 12-month arm looks better, but there is no difference in OS or DDFS. So, probably the difference in DFS is primarily due to local recurrence, which can still be treated with curative intent, thus leading to the similar OS," he commented.
Dr Gyawali plans on using the findings in the clinic with appropriate patients.
"We can now counsel our patients that 9 weeks of trastuzumab would be much better than no trastuzumab at all and could provide nearly same survival as 1 year on trastuzumab with lower toxicities, although at a slightly higher risk of disease relapse," he said.
Dr Joensuu more or less agreed, saying 9 weeks of trastuzumab is "better than nothing."
Dr Gyawali said that SOLD must be seen in the context of similar trials in which 1 year of treatment with trastuzumab, which was an arbitrary duration created by the original investigators, was compared with therapy of shorter durations.
In a recent meta-analysis of four such trials with shorter-duration arms (ranging from 9 weeks to 6 months), Dr Gyawali and a colleague found that the 1-year treatment remained superior to the shorter regimens in terms of both DFS and OS, as reported by Medscape Medical News.
"It would be interesting to see if the addition of SOLD data would change that conclusion," he said.
For now, 12 months is still best, Dr Gyawali emphasized.
"In my practice, for patients who can afford 12 months of trastuzumab and can commute to the cancer center frequently, I would encourage 12-month therapy," he said.

SOLD Details

SOLD took place at 65 centers in Finland, Sweden, the United Kingdom, Belgium, New Zealand, Iceland, and Serbia; 2174 patients were enrolled from 2008 to 2014. All patients in the trials had histologically confirmed node-negative or node-positive HER2+ breast cancer; for patients with node-negative disease, the primary tumor diameter was >5 mm.
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The two-arm design consisted of an identical 9-week initial systemic treatment schedule ― three cycles of docetaxel plus trastuzumab three times a week followed by three cycles of fluorouracil, epirubicin, and cyclophosphamide.
Thereafter, patients in the 9-week arm received no further treatment, whereas those in the 1-year arm received trastuzumab three times a week for 14 cycles for a period of 1 year.
Radiation therapy and endocrine therapy (for patients with ER+ cancer) were given according to the institutional practice; the minimum scheduled duration of endocrine therapy was 5 years.
Notably, the docetaxel dose was either 80 mg/m2 or 100 mg/m2 (prespecified for each center). The dose of docetaxel may have influenced the DFS outcome, said Dr Joensuu.
He noted that among patients who received the lower does (80 mg/m 2) of docetaxel, 1 year of treatment with trastuzumab provided superior DFS compared with 9 weeks, but this was not the case in patients who received the higher dose of docetaxel. This finding warrants further study, said Dr Joensuu.
LVEF was measured before initiation of therapy and throughout treatment. LVEF was higher in patients in the 9-week arm than for those in the 1-year arm. LVEF values "mostly" returned to baseline within 3 years after the time of randomization, said Dr Joensuu.
The study was sponsored by the Finnish Breast Cancer Group. Dr Joensuu and Dr Gawayli have disclosed no relevant financial relationships. Dr Arteaga has relationships with multiple companies, including Roche, a manufacturer of trastuzumab. 
San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS3-04, presented December 7, 2017.

NO BENEFIT OF TRASTUZUMAB IN LOW HER2 BREAST CANCER

Adding trastuzumab (multiple brands) to standard adjuvant chemotherapy does not improve invasive disease-free survival (IDFS) in early-stage breast cancer patients with low levels of HER2, despite earlier analyses indicating that there might be a benefit, conclude US researchers.
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However, new results conflict with those past analyses. The National Surgical Adjuvant Breast and Bowel Project (NSABP) study of more than 3000 patients reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017 has shown that patients with HER2-low disease do not benefit from 1 year of trastuzumab therapy, regardless of patient stratification.
Louis Fehrenbacher, MD, medical director of Kaiser Permanente Oncology Clinical Trials and an oncologist with the Kaiser Permanente Vallejo Medical Center, California, who presented the research, said that he and his colleagues were "surprised" at the result.
Although he believes that heterogeneity among tumor samples may explain the earlier apparent benefit seen with trastuzumab, he said that "it's hard to imagine that a FISH ratio of 2.1 can still benefit, and a FISH ratio of 1.9 does not benefit, so it's a little biologically difficult to completely understand."
Virginia Kaklamani, MD, codirector of the SABCS and leader of the Breast Cancer Program at the UT Health San Antonio Cancer Center, Texas, reported at a press conference that the results are "extremely important."
She said: "We typically don't choose to present negative slides at this forum, but the reason we chose this presentation is the fact that there are many patients that are ICH 1+ or 2+, and we've been wondering whether or not we should be giving a pretty expensive drug, which also has toxicities."

Previous Studies

Previous landmark studies, such as the NSABP B-31 and N9831 trials, showed that adding 1 year of therapy with trastuzumab to standard adjuvant chemotherapy significantly reduced the risk for recurrence and improved survival in patients with early-stage HER2+ breast cancer, which has been defined as IHC 3+ or FISH ≥2.0.
Dr Fehrenbacher noted, however, that for the NSABP B-31 trial, the initial study entry criteria required that HER2 testing be performed at a local laboratory and that a tissue specimen be sent to the NSABP for later testing.
The subsequent testing showed that 9.7% of submitted tissues did not meet the criteria for being HER2+ and were, in fact, HER2-low.
"Low and behold, when the analysis was performed looking at the benefit of using trastuzumab in these 174 patients considered to be HER2-low, it was found that the result was essentially identical [to the overall result]: the hazard ratio was less than 0.5, the benefit was equal, and statistical testing showed there was no interaction between either FISH or IHC testing," Dr Fehrenbacher said.
This was quite bewildering, as the hypothesis had been that it would be only the HER2-amplified patients who would benefit," he added.
The samples were then sent to several laboratories, all of which confirmed that they were indeed HER2-low and not amplified.
The potential benefit of trastuzumab in these patients was underlined in an analysisof N9831 outcomes stratified on the basis of HER2 status. That analysis showed a similar, if not significant, improvement in outcomes.
Given that up 45% of breast cancers have low HER2 levels and so any effect of trastuzumab in this population could be of "enormous potential benefit," Dr Fehrenbacher and colleagues set out to explore the issue in the NSABP B-47 study, which has now been presented at the meeting.

New Results From NSABP B-47 Trial

The NSABP B-47 study was conducted in 3207 women with HER2-low breast cancer. The patients were recruited from January 2011 to February 2015 and were randomly allocated to receive standard adjuvant chemotherapy (chosen by participating physicians from two regimens), either with or without the addition of 1 year of therapy with trastuzumab.
Patients were followed for a median of 46.1 months, during which 264 patients either experienced recurrence of the original tumor, were diagnosed with a new breast cancer, were diagnosed with a new cancer outside the breast, or had died.
After 5 years, the rate of IDFS was 89.6% among patients given additional trastuzumab and 89.2% among those treated with standard adjuvant chemotherapy alone, at an overall hazard ratio for IDFS of 0.98 ( = .90).
Further analysis showed that there was no significant difference in IDFS between the two treatment arms when the patients are stratified by IHC score 1+ or 2+, by the number of positive lymph nodes, by hormone receptor status, and by the chosen chemotherapy regimen.
Dr Fehrenbacher concluded that neither the primary objective of improving IDFS nor any of the secondary endpoints were met, and there were no trends for efficacy. Importantly, there was also no difference in outcomes between IHC 1+ and IHC 2+ tumors.
Although noting that the patients in both arms of the study "did quite well," he said that "the retrospective outcome differences between locally tested HER2+ and HER2-low patients identified in two major trials are not readily explained."
He added: "There is no benefit with trastuzumab therapy in patients with FISH ratios of less than 2.0 and IHC staining intensity of 1+ and 2+."
Asked by Medscape Medical News about the now apparently anomalous findings in the previous trials, Dr Fehrenbacher said: "Certainly one of the explanations for this outcome is that it's a different sample sent to the central laboratory, and tumors, we know, can be very heterogeneous."
Dr Kaklamani agreed with Dr Fehrenbacher's assessment, telling Medscape Medical News that she was "not surprised" by the results of the study and that tumor heterogeneity between the locally and centrally tested samples was the most likely explanation for the benefit with trastuzumab in HER2-low tumors seen previously.
She said: "We see this more and more now that we're doing neoadjuvant chemotherapy and we give anti-HER2 therapy, for example, and then what remains is triple-negative [disease].
"Or, we give regular chemotherapy and then all of a sudden we do HER2 testing and it's positive," she added. "I've had several patients that I had to go back to and give them a year of Herceptin that I wasn't going to give them before, because I killed the part of the tumor that was HER2-, but there was a part that I never knew existed before that was HER2+ that remained."
On the question of whether patients should be tested multiple times to identify HER2+ disease within the tumor, Dr Kaklamani said that "one of the issues is whether the insurance pays for the second test."
She continued: "In many cases, insurance doesn't [pay for the second test], which means that the patient won't, which means that the pathology lab is going to be stuck with a bill, and, as cheap as IHC is (a few hundred dollars), if you add that to all the patients per year, it's a lot of tests that they're not going to get paid for."
Dr Kaklamani emphasized that the earlier data revealed that only 9.7% of patients were incorrectly identified, which means that "we get it right 90% of the time," although she pointed out that "that 9% of is pretty important for the patient."
The study was supported by funds from the National Cancer Institute and Genentech. Dr Fehrenbacher has received contracts for research for Genentech/Roche, CellDez, AbbVie, Macrogenics, Cascadian, and Pfizer, as well as study participation. Other researchers also have disclosed conflicts of interest. Dr Kaklamani has disclosed no relevant financial relationships. 
San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS1-01. Presented December 6, 2017.

ORAL INHIBITORS FOR CANCER RELATED VENOUS THROMBOEMBOLISM

People with cancer have an increased risk of developing blood clots, with roughly one in five experiencing venous thromboembolism (VTE). International guidelines recommend treatment using low–molecular-weight heparin, an anticoagulant that is injected subcutaneously; however, new results from a large pilot trial suggest that direct oral anticoagulants—newer blood thinners administered as a daily pill—could be a safe and beneficial alternative for treating VTE in selected patients. These findings were presented by Young et al at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 625).
Although there are many causes and risk factors for VTE, its increased prevalence in patients with cancer is thought to be related to a combination of factors, such as immobility from remaining in bed, procoagulants produced by the tumor, and chemotherapy. Because VTE can be life-threatening, blood thinners are used to shrink existing clots and prevent others from forming.
select-d Trial
The select-d trial enrolled 406 patients who had cancer and VTE; most (69%) were receiving cancer treatment (typically chemotherapy) at the time of their VTE. Half were randomly assigned to receive low–molecular-weight heparin (dalteparin), and half were assigned to receive a direct oral anticoagulant (rivaroxaban).
After 6 months of treatment, the VTE recurrence rate was 4% among those receiving the direct oral anticoagulant and 11% in those receiving dalteparin.
The results for secondary outcomes were mixed. In patients receiving the direct oral anticoagulant, there were more major bleeding events (11 patients) and a marked increase in clinically relevant nonmajor bleeding events (25 patients) compared with those taking heparin (6 and 6 patients, respectively). The researchers are conducting further analyses to try to understand the factors that may have contributed to this difference.
“Clinicians are already adopting direct oral anticoagulants into practice for these patients,” said lead study author Annie Young, PhD, Professor of Nursing at the University of Warwick, “and now they have data from this study to indicate that direct oral anticoagulants are potentially safe in cancer patients. We need to be looking at different groups of people and different types of bleeds in more detail, so we can choose the best treatment for each patient.”
Disclosure: This study was supported by an unrestricted grant from Bayer AG.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

A NOVEL KITD816V INHIBITOR FOR SYSTEMIC MASTOCYTOSIS

In a phase I trial, patients with an advanced or aggressive form of systemic mastocytosis, a rare blood disorder, had rapid and durable responses with few adverse effects following treatment with an investigational drug that targets the genetic mutation found in more than 90% of cases. Results were presented by DeAngelo et al at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 2).
The once-daily pill, BLU-285, targets a mutation in KIT D816V that is found in almost all cases of advanced systemic mastocytosis, a disease that originates in mast cells. The normal role of mast cells is to help protect the body from infection and aid in wound healing. Systemic mastocytosis occurs when mast cells start to grow uncontrollably. In its aggressive form, it spreads rapidly throughout the body, invading the liver, spleen, and organs of the gastrointestinal tract. It can also develop into a rare blood cancer, mast cell leukemia. Existing treatments for advanced systemic mastocytosis are of limited effectiveness.   
“We are seeing a high rate of rapid and durable responses—with a very low rate of adverse side effects—in patients with an advanced or aggressive form of the disease,” said lead study author Daniel J. DeAngelo, MD, PhD, Associate Professor of Medicine at Harvard Medical School and a member of the adult leukemia program at the Dana-Farber Cancer Institute. “The rapidity of the improvement is extremely dramatic.”
More on BLU-285
BLU-285 was designed specifically to block the genetic mutation that drives the growth and spread of mast cells in advanced systemic mastocytosis, Dr. DeAngelo said.
The primary objective of the phase I study was to identify the maximum tolerated dose of BLU-285. Secondary objectives were to assess the drug’s activity in the body, including anticancer activity.
In the BLU-285 dose-escalation study, the first three patients enrolled received a low dose of the study drug and were monitored for adverse effects. If no adverse events were seen, the next three patients received a higher dose, and so on. Dose escalation was stopped when adverse events were seen in 30% of the patients treated. Dosing began at 30 mg/d and increased in a stepwise fashion to 400 mg/d.
In the study, BLU-285 quickly produced lasting reductions in both cellular levels of mast cells and molecular levels of the mutated gene. Of 18 evaluable patients with aggressive systemic mastocytosis, 72% had an overall response, and 100% had disease control.
This phase I trial was designed primarily to identify a safe dose of BLU-285, not to evaluate the drug’s effectiveness. The investigators are now planning a phase II study that will assess the effectiveness of a once-daily dose of 300 mg of BLU-285 in a larger number of patients

RIBOCICLIB EFFECTIVE IN YOUNGER PATIENTS

The CDK4/6 inhibitor ribociclib (Kisqali, Novartis) dramatically improves progression-free survival (PFS) when added to endocrine therapy in ovarian-suppressed younger patients with hormone receptor-positive (HR+), human epidermal receptor 2-negative (HER2-) advanced breast cancer, according to first-of-its-kind data.
In short, it's beneficial to add the drug to what is an established first-line treatment for pre- and perimenopausal women with this type of breast cancer.
"MONALEESA-7 is the first clinical trial to have the statistical power to show that ribociclib has clinical benefit specifically for pre- and perimenopausal women," Debu Tripathy, MD, professor of medicine and chair of the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston, said in a statement.
Ribociclib is "an important potential new treatment option for premenopausal patients with this type of advanced breast cancer," he added in a press briefing.
The study was reported here at the San Antonio Breast Cancer Symposium (SABCS) 2017.
In the MONALEESA-2 trial investigators showed that the addition of ribociclib to first-line endocrine prolonged PFS in postmenopausal women with HR+, HER2- advanced disease.
In the new phase 3 trial, Dr Tripathy and coinvestigators randomized 335 women to ribociclib plus endocrine therapy and 337 women to placebo plus endocrine therapy. Approximately one-quarter of the cohort received tamoxifen and the rest received an aromatase inhibitor. All patients were ovarian suppressed with the luteinizing hormone-releasing hormone, goserelin (Zoladex, AstraZeneca).
"Patient demographics were well balanced and the expected median age was low at 43 for the additional ribociclib group and 45 for the placebo group," Dr Tripathy noted.
The median follow-up at the cut-off point of the trial was 19.2 months.
At follow-up, median PFS in the ribociclib plus endocrine therapy group was 23.8 months compared with 13.0 months for the control group, suggesting that treatment with the additional CDK4/6 inhibitor effectively halved the risk for progression (hazard ratio, 0.55; < .001).
The type of endocrine therapy patients received did not appear to have any effect on the superior PFS rate in the ribociclib arm either.
PFS Rates by Endocrine Therapy Partner
 Tamoxifen Plus RibociclibTamoxifen Plus PlaceboAromatase Inhibitor Plus RibociclibAromatase Inhibitor Plus Placebo
Median PFS22.1 months11 months27.5 months13.8
HR0.58  0.56
PFS = progression-free survival; HR = hazard ratio

Separate Analysis

In a separate analysis made by a blinded independent review committee, median PFS had not been reached at study cut-off in patients who received ribociclib compared with a median PFS of 11.1 months for the placebo arm.
"Benefits were also similar among key subgroups including age, race, estrogen-receptor status, liver or lung involvement, disease-free interval or prior chemotherapy for advanced disease," Dr Tripathy observed.
There were also significant differences in the secondary endpoint of overall response rate (40.9% in the ribociclib arm vs 29.7% in the placebo arm).
Far more interruptions in dose occurred in the CDK4/6 inhibitor arm, mostly due to adverse events (AEs). Approximately one-third of patients in the ribociclib arm also required a reduction in the dose.
Grade 3 and 4 neutropenia was the most common hematologic AE seen in association with the CDK4/6 inhibitor, occurring in approximately 60% of patients in the ribociclib arm. Febrile neutropenia was rare and occurred in only about 2% of patients.
Rates of nonhematologic toxicities were similar in both treatment groups; the most common were hot flushes and arthralgia, likely related to the use of tamoxifen or an aromatase inhibitor.
Discontinuation rates due to AEs were similar in both groups, at approximately 3%.
Importantly, patient-reported quality-of-life outcomes reflecting global health status showed that there was a sustained improvement in time to definitive deterioration in the ribociclib arm compared with placebo controls.
Similarly, a "clinically meaningful" improvement from baseline in pain scores was detected as early as 8 weeks following initiation of treatment with ribociclib, and the improvement was sustained over time.
"Longer follow-up is needed to determine whether the trial will meet its secondary endpoint of overall survival," Dr Tripathy noted.
"However, MONALEESA-7 is the first trial to show that ribociclib can be safely and effectively combined with either tamoxifen or a nonsteroidal aromatase inhibitor together with ovarian suppression using goserelin," he added.

Standard of Care

Asked by Medscape Medical News if the MONALEESA-7 study confirms that ribociclib plus endocrine therapy should become the standard of care for this patient population, conference moderator Virginia Kaklamani, MD, professor of medicine, UT Health Science Center, San Antonio, Texas, said that it already is, in her opinion.
"It's very simple," she said. "We have enough data from the other trials to show that once you give this drug along with endocrine therapy — even in premenopausal women that you are making postmenopausal by using goserelin therapy — it is going to work," Dr Kaklamani explained.
"So the concept is there — I am making a young woman postmenopausal by giving her goserelin and then I'm going to give her endocrine therapy on top of that to see if I can benefit her even more — so now we have a large trial in premenopausal women and since these drugs are already approved [in the postmenopausal setting], I'll be using them on every single patient I have that has first-line metastatic breast cancer," she said.
The study was funded by Novartis.
Dr Tripathy declares that Novartis has paid for him to serve on steering committees, consulting fees, and research fees to his institution. Dr Kaklamani has disclosed no relevant financial relationships .
San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract: GS2-05. Presented December 6, 2017.

DOSE DENSE CHEMOTHERAPY MAY INCREASE SURVIVAL IN BREAST CANCER

Shortening the interval between chemotherapy cycles or administrating anthracycline and a taxane sequentially instead of giving them together significantly lowers the risk for breast cancer recurrence and death from breast cancer compared to standard chemotherapy given every 3 weeks, a major meta-analysis demonstrates.
"If you can cram more dose into the same time, you are intensifying treatment and you don't give the cancer as much time to grow back as you do with standard chemotherapy, so you are more likely to eradicate it," Richard Gray, PhD, professor of medical statistics, University of Oxford, United Kingdom, said at a press briefing here.
You don't give the cancer as much time to grow back. Dr Richard Gray
"And we found that all patients benefited from dose intensification, so this helps us fine-tune what we are giving, and we might as well optimize the chemotherapy that patients are going to get anyway," he added.
The study was presented here at the San Antonio Breast Cancer Symposium (SABCS) 2017.
The meta-analysis included 25 trials in which 34,122 patients with early-stage breast cancer were treated with some form of dose-intensification regimen.
Dose intensity trials included seven trials in which the same chemotherapy drugs and the same doses were given in either dose-dense, 2-weekly cycles or as a standard 3-weekly regimen. Five trials evaluated the same two schedules, but there were some differences in the drugs that were compared.
Five other trials evaluated the benefit of giving the same drugs sequentially in 3-weekly cycles vs giving the same drugs concurrently, again in 3-weekly cycles. One trial evaluated the same sequential vs concurrent schedules, but there were some differences in the drugs used between trials.
Six trials evaluated whether drugs given sequentially in 2-weekly cycles led to superior outcomes compared with a concurrent, 3-weekly cycle. Importantly, there were some differences in drugs used in these six trials.
In all trials, patients were required to receive concurrent treatment with granulocyte colony-stimulating factor for immune system support.
Breast cancer recurrence rates as well as mortality from breast cancer at 10 years were the coprimary endpoints of the meta-analysis.

Primary Outcome

Trials involving over 10,000 women showed that giving patients the same drugs but for a shorter interval reduced the absolute risk for breast cancer recurrence by 4.3% at 10 years compared to the standard every-3-week regimen (24% vs 28.3%; = .00004).
Mortality from breast cancer at 10 years was 2.8% lower with dose-dense regimens compared with standard chemotherapy (16.8% vs 19.6%; = .004),
More than 11,000 women were treated with either sequential or concurrent chemotherapy, both given every 3 weeks.
Here again, Dr Gray and colleagues found that the risk for recurrence was lower when the drugs were given sequentially instead of together.
At 10 years, 28.1% of women who were treated sequentially experienced disease recurrence, compared with 31.2% of those treated concurrently ( = .0006).
The mortality at 10 years was 1.9% lower in favor of the sequential vs the concurrent approach (17.7% vs 19.8%; = .03),.
Trials in which more than 6500 women were treated using both a sequential approach and a shorter interval between cycles again showed a major benefit in favor of dual intensification.
At 10 years, absolute recurrence rates were 4.5% lower among women receiving sequential therapy every 2 weeks compared with those receiving concurrent chemotherapy every 3 weeks (30.4% vs 34.9%; = .0001).
Mortality from breast cancer at 10 years was reduced by 3.9% in favor of dose intensification compared with standard chemotherapy (= .001), with mortality rates of 22.1% for sequential, every-2-week regimens compared to 26% for concurrent every-3-week schedules.
Pooled analysis of all 25 dose intensification trials showed very similar results, Dr Gray observed. At 10 years, the risk for recurrence was 4.4% lower in favor of dose intensification, at 28.4%, compared with 32% for standard every-3-week chemotherapy (< .00001).
In the pooled analysis, mortality from breast cancer at 10 years was 3.7% lower in favor of dose-dense regimens (< .00001), with mortality rates of 19.5% for dose-dense regimens compared with 22.2% for standard chemotherapy schedules.
The investigators also found that reductions in rates of recurrence were similar for both estrogen-receptor (ER) positive and ER-negative disease. Tumor type or patient characteristics did not influence outcomes.
Importantly, there was no increase in mortality from non-breast-cancer causes between dose-intense treatment and standard chemotherapy.
Indeed, if anything, there were fewer deaths from causes other than breast cancer during the first year in which chemotherapy was given, the investigators noted.
Growth factor support is required for the administration of dose-dense chemotherapy, yet there did not appear to be any significant increase in toxicity with the dose-dense approach, although toxicity is difficult to measure in meta-analyses, Dr Gray noted.
"However, these trials achieved dose intensification. There were fewer recurrences and lower mortality rates at 10 years compared with standard chemotherapy, and it is quite remarkable how consistent all of these various approaches were in favoring dose intensification," Dr Gray emphasized.
"Since a standard schedule of anthracycline followed by a taxane reduces breast cancer mortality by about one third, using a dose-intensification approach means you get almost a 50% reduction in the [relative] risk of breast cancer mortality [compared to no chemotherapy], so it's very important to identify the step-by-step gains we've been making in this disease," Dr Gray concluded.
Commenting on the study, conference moderator Virginia Kaklamani, MD, professor of medicine, UT Health Science Center, San Antonio, Texas, told the press that in fact, many oncologists in the United States are already using dose-intensification strategies for the treatment of breast cancer on the basis of findings from several previously reported pivotal trials that support the superiority of dose intensification over conventional chemotherapy.
"What's interesting is we used to give chemotherapy over 6 months, and with this approach, we can give it over 4 months, so patients prefer it, and with growth factor support, the toxicity can actually be less than it is with standard chemotherapy," Dr Kaklamani said.
"So if you give chemotherapy the right way, you greatly enhance its benefit, and even though we are all talking about new treatments like immunotherapy, the main treatment I offer my patients every single day is still chemotherapy, and I'd rather make that chemotherapy better ― and better tolerated," Dr Kaklamani added.
The study was funded by Cancer Research UK, the Medical Research Council, the British Heart Foundation, and the University of Oxford. Dr Gray and Dr Kaklamani have disclosed no relevant financial relationships. 
San Antonio Breast Cancer Symposium (SABCS) 2017: Abstract GS1-0. Presented December 6, 2017.

TEMPORARY OVARIN SUPPRESION MAY PRESERVE FERTILITY DURING CHEMOTHERAPY FOR BREAST CANCER

Meta-analysis of individual patient data from five randomized clinical trials provided a high level of evidence that treatment with a gonadotropin-releasing hormone analog (GnRHa) could safely and effectively protect ovarian function and potentially preserve fertility in premenopausal women receiving chemotherapy for early-stage breast cancer, according to a study presented by Lambertini et al at the 2017 San Antonio Breast Cancer Symposium (Abstract GS4-01).
“Temporary ovarian suppression obtained by administering GnRHa during chemotherapy is a medical intervention with the potential to preserve ovarian function and fertility in premenopausal breast cancer patients; however, to date, the role of this option remains controversial and it is still considered an experimental technique by ASCO and the European Society for Medical Oncology (ESMO),” said Matteo Lambertini, MD, medical oncologist and ESMO fellow at the Institut Jules Bordet in Brussels, Belgium.
Fertility Preservation
The possibility that anticancer treatments will cause premature ovarian insufficiency and subsequent infertility are prevalent concerns affecting young women diagnosed with breast cancer, which adds significant anxiety and emotional strain as they make treatment decisions, explained Dr. Lambertini.
Temporary ovarian suppression with GnRHa during chemotherapy was primarily developed more as a strategy to reduce the risk of developing treatment-induced premature ovarian insufficiency than as a fertility-preserving procedure; therefore, the majority of the trials that investigated this strategy had a very short follow-up and did not report on post-treatment pregnancies, Dr. Lambertini said. Further, different randomized clinical trials that investigated the efficacy of this approach showed conflicting results, and some of these trials included very few patients, making it difficult to draw solid conclusions based on the results of individual studies, he added.
Meta-Analysis Findings
Dr. Lambertini and team aimed to provide more conclusive clinical evidence on this topic by conducting an individual patient data meta-analysis of five randomized clinical trials in which premenopausal women with early-stage breast cancer were randomly assigned to receive chemotherapy alone (437 women) or with concurrent GnRHa (436 women).
The study found that the premature ovarian insufficiency rate in the GnRHa group was 14.1% vs 30.9% in the control group; patients in the GnRHa group had 62% less risk to develop premature ovarian insufficiency as compared to those treated with chemotherapy alone. Treatment effect was homogeneous among the different patient subgroups.
Patients in the GnRHa group had 1- and 2-year amenorrhea (absence of menstrual periods) rates of 36.8% and 18.2%, respectively. One- and 2-year amenorrhea rates in the control group were 40.4% and 30%, respectively.
“Although the absolute numbers remain low, we observed a doubling in the number of post-treatment pregnancies in patients in the GnRHa group compared with those treated with chemotherapy alone. This suggests that GnRHa during chemotherapy is not only a strategy to preserve ovarian function but may also potentially improve future fertility,” Dr. Lambertini said.
Thirty-seven patients in the GnRHa group had at least one post-treatment pregnancy during the follow-up period vs 20 patients in the control group.
There were no significant differences in disease-free survival and overall survival between the two groups; this suggests that administering GnRHa during chemotherapy can be considered safe in breast cancer patients, Dr. Lambertini said.
“Our study adds important evidence on both the efficacy and the safety of temporary ovarian suppression with GnRHa during chemotherapy, not only in patients with estrogen receptor [ER]-negative disease but also in women with ER-positive tumors, who account for the majority of new cases of breast cancer in young women,” Dr. Lambertini commented.
“This study provides solid evidence on this specific topic,” he said. “We believe that the results of our study would serve as the reference evidence for updating the international ASCO and ESMO guidelines on the use of this strategy.”
The five clinical trials studied were PROMISE-GIM6, POEMS/SWOG S0230, Angelo Celtic Group OPTION, GBG-37 ZORO, and a Moffitt Cancer Center-led trial.

IBRUTINIB TREATMENT FOR MANTLE CELL LYMPHOMA

The results of a pooled analysis of patients with relapsed or refractory mantle cell lymphoma (MCL) treated with ibrutinib (Imbruvica) were presented at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 151). The extended follow-up data demonstrated that patients treated with ibrutinib earlier (after first relapse) experienced the best clinical outcomes in terms of both efficacy and tolerability.
“Data from this large clinical trial data set with extended follow-up support the early use of ibrutinib in patients with relapsed or refractory mantle cell lymphoma,” said Simon Rule, MD, Professor in Hematology at Plymouth University Medical School, United Kingdom, and lead investigator and presenter of the pooled analysis. “Long-term follow-up for ibrutinib demonstrates that in addition to efficacy, new-onset adverse events decrease over time and are generally less common when patients are treated earlier.”
Pooled Analysis Findings
The pooled analysis includes results from phase II and III studies (SPARK, PCYC-1104, and RAY; n = 370), and additional follow-up of 87 patients across these studies who enrolled in the long-term open-label extension study, CAN3001.
Eighty-three patients were treated with ibrutinib for 3 or more years, and 40 patients were treated with ibrutinib for 4 or more years.
With 3.5 years (41 months) of follow-up, the median progression-free survival overall was 13 months, and 33.6 months (range, 19.4–42.1 months) in patients with one prior line of therapy. The median progression-free survival in patients achieving a complete response was 46.2 months (range, 42.1–not estimable), and the duration of response in these patients was 55.7 months (range, 55.7–not estimable). Patients with favorable baseline disease characteristics were more likely to remain on ibrutinib for more than 3 years. Overall, 53%, 45%, and 37% of patients were alive at 2, 3, and 5 years, respectively, and the median overall survival was 26.7 months.
Grade 3 or higher treatment-emergent adverse events occurred in 79.7% of patients, with the new-onset events decreasing after the first year. New-onset grade 3/4 treatment-emergent adverse events were generally less common in patients who were treated earlier with ibrutinib. In studies that permitted enrollment of patients with multiple cardiac risk factors, and among patients experiencing grade 3/4 atrial fibrillation, no patients discontinued treatment, and less than 1% had a dose reduction.

IBRUTINIB TREATMENT FOR CLL

t the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition, the 3-year follow-up data from the RESONATE-2 study (PCYC-1115/1116) were presented. The investigators found that patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) reported sustained improvements in the measures of well-being with ibrutinib (Imbruvica) vs chemotherapy with chlorambucil (Abstract 1746).
Patient-Reported Outcomes
These new data provide the longest quality-of-life follow-up for ibrutinib to date using patient-reported outcomes. Patients reported their quality-of-life outcomes for fatigue, mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
Patients 65 years and older (median age, 73) were randomized to receive 420 mg of ibrutinib once daily until progressive disease or chlorambucil for up to 12 months. Median treatment duration was 34.1 months with ibrutinib vs 7.1 months with chlorambucil.
At a median follow-up of 3 years, ibrutinib treatment resulted in significantly longer progression-free survival (median, not reached vs 15 months with chlorambucil), with an 87% reduction in the risk of disease progression or death vs chlorambucil (hazard ratio = 0.130; 95% confidence interval: 0.081–0.208). The progression-free survival rate for ibrutinib was 85% vs 28% with chlorambucil. Greater and sustained improvements in patient-reported outcomes were observed with ibrutinib, resulting in significantly greater improvements over time vs chlorambucil.
In patients treated with chlorambucil with progressive disease, patient-reported outcomes improved after crossing over to ibrutinib. Approximately 87% of patients receiving ibrutinib (vs 52% receiving chlorambucil) had decreased/normalized lymphadenopathy within 2 months, which was sustained through 36 months, and disease symptoms, including fatigue and night sweats, improved more frequently for patients treated with ibrutinib. A greater proportion of patients with baseline cytopenia showed sustained hematologic improvement with ibrutinib vs chlorambucil for hemoglobin (90% vs 45%) and platelets (83% vs 46%).
Further data showed the burden of hematologic support medical resource utilization was less with ibrutinib than with chlorambucil in the first year and subsequently continued to decrease.
The most common adverse events of any grade with ibrutinib were diarrhea (47%), fatigue (33%), and cough (30%). Eight grade 3 or higher adverse events had a prevalence of less than 3% in ibrutinib patients and generally decreased or were stable over time. During the first year of treatment, patients treated with ibrutinib vs chlorambucil experienced less grade 3 or higher neutropenia (8% and 18%), anemia (6% and 8%), and thrombocytopenia (2% and 5%); other common grade 3 or higher adverse events were pneumonia (5% and 2%), hypertension (4% and 0%), and infections as combined term (17% and 8%). Grade 3 or higher bleeding occurred in 7% of ibrutinib patients over the 3-year follow-up. Adverse events leading to treatment discontinuation occurred in 16% with ibrutinib over 3 years vs 23% for chlorambucil over 7 months of therapy, respectively.
“In the RESONATE-2 study, patients who were treated with ibrutinib reported greater and sustained improvements in overall health and well-being and experienced decreased disease-related symptoms,” said Danelle James, MD, MAS, Head of Clinical Science, Pharmacyclics LLC. “For patients with chronic lymphocytic leukemia, a disease that affects primarily older patients, quality of life is an important consideration that should be factored into treatment choices initially and throughout long-term use.”

COMBINATION TARGETED THERAPY FOR CLL

One-third of patients with previously treated chronic lymphocytic leukemia (CLL) had no detectable disease after 6 months of combination therapy with the targeted agents ibrutinib (Imbruvica) and venetoclax (Venclexta), with no increase in the occurrence of tumor-lysis syndrome, a serious treatment side effect, Hillmen et al reported at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 428).
Of 36 patients who completed 6 months of combination treatment, all responded and 33% achieved the deepest measurable level of remission, with no detectable disease in the bone marrow, said lead study author Peter Hillmen, MBChB, PhD, Professor of Experimental Hematology at Leeds Institute of Cancer and Pathology in the United Kingdom.
“These initial results are particularly impressive in a patient population for whom previous therapies have failed,” he said. “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.”
Ibrutinib works by blocking signals that stimulate cancerous cells to multiply, whereas venetoclax promotes tumor cell death by blocking a protein that helps the cells survive. Both medications are approved by the U.S. Food and Drug Administration as single-agent therapies to treat CLL. Because the mechanisms of action of the two drugs are complementary, Dr. Hillmen and his colleagues wanted to evaluate them as combination therapy.
CLARITY Trial
The phase III CLARITY trial enrolled a total of 50 patients with CLL that had relapsed or had not responded to prior treatment. Patients’ median age was 64 years. After 8 weeks of treatment with ibrutinib alone, venetoclax was added at a low dose that increased over several weeks. Before starting venetoclax, patients also began taking a drug to prevent tumor-lysis syndrome. To date, only one patient in the CLARITY trial has developed tumor-lysis syndrome and was safely treated without adverse effects.
“We have not seen an increase in the rate of [tumor-lysis syndrome] with the combination regimen compared with what we would expect to see with venetoclax single-agent therapy,” Dr. Hillmen said.
After 6 months of combination therapy, the trial has already exceeded the expected proportion of patients achieving undetectable CLL, Dr. Hillmen added.
“Our assumption was that the trial would be a success if 30% of patients achieved the deepest level of remission after 12 months of combination therapy,” he said. “But already, at 6 months, 33% of patients have undetectable disease.”
Results for the trial’s 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, Dr. Hillmen said.
A key limitation of the study is that it lacked a control group. On the basis of the CLARITY results, Dr. Hillmen is leading a randomized controlled phase III study—the FLAIR trial—to compare the ibrutinib-plus-venetoclax combination with both ibrutinib alone and a combined regimen of three chemotherapy drugs in patients with previously untreated CLL. 

NOVEL TARGETED THERAPY FOR CTCL

In a large, international, randomized phase III trial presented by Kim et al at the 59th American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 817), patients with previously treated cutaneous T-cell lymphoma (CTCL) who received the investigational targeted drug mogamulizumab had significantly better progression-free survival, response rate, and quality of life than patients who received vorinostat (Zolinza), a U.S. Food and Drug Administration (FDA)-approved standard-of-care treatment for patients with CTCL. The adverse events observed with mogamulizumab treatment were generally mild to moderate in severity.
CTCL is a rare cancer of the white blood cells—specifically, T lymphocytes—that primarily occurs in the skin. CTCL can also involve the blood, lymph nodes, and internal organs.
Mogamulizumab targets the CCR4 protein, which is frequently found on the surface of cancer cells in patients with CTCL. As a CCR4 antibody, the drug exploits the patient’s immune cells to attack the cancer.
Vorinostat, one of several drugs approved by the FDA to treat CTCL, works by blocking the action of an enzyme that helps cancerous T cells survive and multiply.
Study Findings
The primary endpoint of the phase III trial was progression-free survival or death for any reason.
Among 372 patients included in the trial, the median progression-free survival was 7.7 months for patients treated with mogamulizumab compared with 3.1 months for those treated with vorinostat, reported lead study author Youn H. Kim, MD, Professor of Dermatology and Director of the Multidisciplinary Cutaneous Lymphoma Program at the Stanford University School of Medicine.
Adverse effects such as diarrhea, nausea, altered taste, decreased appetite, increased blood creatinine levels, and decreased platelet counts occurred more than twice as frequently in patients treated with vorinostat than in those treated with mogamulizumab, said Dr. Kim. By contrast, the adverse effects seen most frequently in patients treated with mogamulizumab were drug rash and infusion-related reactions, such as chills and flushing.
Mogamulizumab was administered as a once-weekly intravenous infusion for the first 28-day cycle and every 2 weeks during subsequent cycles. Vorinostat was taken as a once-daily pill.
Dr. Kim said the next step will be to learn more about biomarkers that can predict treatment outcome and to test whether clinical benefit can be further improved by combining mogamulizumab with skin-directed or other systemic therapies that have different mechanisms of action.
“We found that mogamulizumab has convincing clinical activity, not just in skin, but also in clearing malignant T cells in the blood and lymph nodes,” said Dr. Kim. “Progression-free survival and overall global response outcomes are clearly superior, the side effects are tolerable, and we see measurable improvements in quality of life with mogamulizumab compared with vorinostat. Taken together, these findings represent a durable and clinically meaningful benefit for patients with CTCL.”

NO DECREASE IN ADVANCED CANCER RATES WITH SCREENING MAMMOGRAPHY

Screening mammography over a period of 24 years among women age 50 to 74 years has had little effect on reducing rates of advanced breast cancer or mortality from breast cancer in the Netherlands, according to new research.
Screening did, however, dramatically increase the detection of early-stage breast cancer, both ductal carcinoma in situ (DCIS) and stage I and, in so doing, contributed to increased rates of overdiagnosis — defined as detection of tumors on screening that would never lead to clinical symptoms in a woman's lifetime.
The study, published in the BMJ, concludes that screening would be associated with zero to 5% reductions in breast cancer mortality in women aged 50 years and older, whereas improved treatments would be associated with a 28% reduction in mortality.
Additionally, screening mammography was associated with a 32% increase in overdiagnosis, an increase driven by the advent of digital mammography and the extension of screening to women aged 70 to 75 years, the authors write.
"The main purpose of cancer screening is to catch the cancer at an early stage before it becomes metastatic disease," lead author, Philippe Autier, MD, from University of Strathclyde Institute of Global Public Health, Lyon, France, told Medscape Medical News.
"If screening works, then you must observe a decreased incidence in the burden of advanced, poor-prognosis cancer in the population. While we have seen decreases in the incidence rate of advanced cervical and colorectal cancer, the same thing has not been true for breast cancer," Dr Autier said.
"Everybody was expecting, myself included, that the same would be true for mammography screening, but unfortunately, after years and years of screening, we are realizing that we are not seeing reductions in advanced breast cancer. This is something that is being observed not just in the Netherlands but in all countries where there is a lot of screening, including the United States," he said.

Results From the Netherlands  

Since 1989, women age 50 to 69 in the Netherlands have been invited to have a screening mammogram every 2 years. In 1997, screening was extended to include women age 70 to 75 years.
Digital mammography became available in the Netherlands in 2006.
Dr Autier and his group studied trends in stage-specific age-adjusted incidence of breast cancer among women participating in the Netherlands national breast screening program from 1989 to 2012.
They found that the incidence of stage II to IV breast cancers in women aged 50 years or older was 168 per 100,000 in 1989 and 166 per 100,000 in 2012.
They also found that, after deducting of clinical lead time cancers, 32% of cancers found in women who were screened in 2010 to 2012 were overdiagnosed, and also that 59% of screen-detected cancers would be overdiagnosed.
Women aged 70 to 74 were particularly prone to overdiagnosis. In that age group, the overdiagnosis of stage I cancers was about two times higher than in women aged 50 to 69.
"These observations are in line with other data showing that the replacement of film-based mammography by digital mammography has substantially increased the burden of in situ breast tumors without decreasing rates of interval cancers," Dr Autier said.
"It strongly suggests that the advent of digital technologies has probably worsened the overdiagnosis problem without clear evidence for improvements in the ability of screening to curb the risk of breast cancer death," he said.

A Radiologist's Take

Approached for a reaction to the new findings from the Netherlands,
Stamatia Destounis, MD, clinical professor, Rochester University School of Medicine, New York, told Medscape Medical News: "I think they are misinterpreting their data."
Dr Stamatia Destounis
"They are making assumptions here that are not supported. For instance, the rate of invasive cancers before screening mammography had been increasing, so the fact that this rate remained stable during the period of the study actually represents a decrease and proves that there is a benefit for screening," Dr Destounis said.
Dr Destounis also takes issue with combining DCIS and stage I breast cancer as one entity, which she says confounds the issue of overdiagnosis.
 "There are some legitimate issues with DCIS with regard to overdiagnosis, but to combine the two [DCIS and stage I] complicates their analysis. The benefit of screening, whether it's for breast, or colon, or any body part is to find the small invasive cancer so that it does not become stage II," she said.
While some in situ cancers may be indolent and may not develop into an invasive cancer, there is currently no way of knowing which ones they are, Dr Destounis said.
"Our job as radiologists is to detect every new abnormality, and that is what mammography screening is very good at doing. There may be room to change our position after the pathologist interprets the screen as being very early low-grade DCIS, and I think there are changes occurring right now in the US with regard to what to do about those very early in situ tumors, but the authors have done a disservice by lumping DCIS and stage I together," she said.
"The way these authors analyzed their data is faulty. The point of screening mammography is to find those stage I cancers and obviously we are doing a good job at doing that. Even their own analysis shows that we are doing a good job finding these stage I tumors, and in all age groups," she added.

Calls Benefits of Screening Into Question 

However, an expert in public health who has raised questions about the benefits of regular mammography screenings for many women says the new results from the Netherlands affirm other findings.
"This study in the Netherlands basically replicates the picture in the United States," H. Gilbert Welch, MD, MPH, professor of medicine, Dartmouth Institute for Health Policy & Clinical Practice, Lebanon, New Hampshire, told  Medscape Medical News.
The widespread introduction of mammography is associated with a dramatic increase in the detection of early-stage breast cancer but little concomitant decline in the rate at which women present with late-stage breast cancer. This combination suggests that screening mammography has little effect on breast cancer mortality, and that the decline in mortality that we have seen in the last 20 years or so is largely the result of better treatment," Dr Welch commented.
Dr Welch coauthored a 2012 study with Archie Bleyer, MD, Oregon Health and Science University, Portland, which showed similar results, including a 30% increase in rates of overdiagnosis and only a small effect on the rate of death from breast cancer. That study was published in the New England Journal of Medicine 
"An important message is that you don't solve the problem by throwing more technology at it. Adding an ultrasound, adding an MRI, adding digital mammography, this only makes the problem of overdiagnosis worse. The harder you look for this stuff, the more likely you are going to get into the overdiagnosis problem," Dr Welch said.
"We have been pushing screening mammography too much. We've totally overstated its benefits and understated its harms. It can lead a woman to be treated for breast cancer who otherwise would never need to know about it," he said.
Older individuals in particular should be wary of undergoing cancer screening, he said.
"When you start getting older, you don't want to be doing any kind of cancer screening. It creates more problems than it solves. It leads to a lot more procedures, you end up getting medicalized, and some people have surgery. Urologists agreed very early on that people with limited life expectancy should not be screened for prostate cancer [as] only bad things can happen as a result of that. I think the general story is we've gone a little overboard in our desire to find cancer early," Dr Welch said.
"Women aged 70 to 75 are the ones who really have a shoot-up in incidence when they start screening. Most of the cancers that are found are not relevant and for those that are, most can be treated. I know it's a counterculture message, but I think it's the truth," he said.
Breast cancer mortality is falling, not because of screening but because treatments have improved, Dr Welch said.
"That's the good news that a lot of people miss. We are much better at treating breast cancer than we were 20 years ago. Ironically, the better we become at treating breast cancer, the less important screening becomes," he added.
The study was supported by the International Prevention Research Institute. Dr Autier, Dr Welch, and Dr. Destounis have disclosed no relevant financial relationships. 
BMJ  2017;359:j5224. Full text