Τετάρτη, 1 Ιουλίου 2020

TRIPLE THERAPY FOR METASTATIC BRAF+ MELANOMA

As reported in The Lancet by Gutzmer et al, the phase III IMspire150 trial has shown that the addition of atezolizumab to BRAF and MEK inhibitor therapy with vemurafenib and cobimetinib improved progression-free survival in first-line treatment of patients with unresectable BRAF V600–mutant melanoma.

Study Details 

In the double-blind trial, 514 patients with unresectable stage IIIC to IV disease from sites in 20 countries were randomly assigned between January 2017 and April 2018 to receive 28-day cycles of atezolizumab, vemurafenib, and cobimetinib (n = 256) or atezolizumab placebo, vemurafenib, and cobimetinib (n = 258). Randomization was stratified by lactate dehydrogenase (LDH) concentration and geographical region.

In cycle 1, all patients received twice-daily vemurafenib at 960 mg for 21 days plus once-daily cobimetinib at 60 mg, followed by either twice-daily vemurafenib at 720 mg in the atezolizumab group or at 960 mg for 7 days in the control group. Starting with cycle 2, patients in the atezolizumab group received atezolizumab at 840 mg on days 1 and 15, twice-daily vemurafenib at 720 mg, and once-daily cobimetinib at 60 mg on a 21 days on/7 days off schedule. Patients in the control group received placebo on days 1 and 15, twice-daily vemurafenib at 960 mg, and once-daily cobimetinib at 60 mg on a 21 days on/7 days off schedule. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1.

In the atezolizumab vs control groups:

  • Median age was 54.0 vs 53.5 years (24% vs 23% ≥ 65 years)
  • 59% vs 58% were male
  • 95% vs 95% were non-Hispanic white
  • Geographic region was North America for 5% vs 5%, Europe for 79% vs 79%, and Australia, New Zealand, or other for 16% vs 16%
  • Eastern Cooperative Oncology Group performance status was 0 for 76% vs 77% and 1 for 24% vs 22%
  • Disease stage was IV for 95% vs 93%
  • 33% vs 33% had elevated LDH
  • 57% vs 63% had M1C disease
  • 16% vs 12% had taken prior adjuvant therapy
  • 63% vs 61% had PD-L1–positive disease (≥ 1% immune cells).

Progression-Free Survival

Median follow-up was 18.9 months. Median progression-free survival was 15.1 months (95% confidence interval [CI] = 11.4–18.4 months) in the atezolizumab group vs 10.6 months (95% CI = 9.3–12.7 months) in the control group (hazard ratio [HR] = 0.78, 95% CI = 0.63–0.97, = .025).

Progression-free survival benefit was consistent among patient subgroups examined. With regard to stratification factors, hazard ratios were: 0.85 (95% CI = 0.32–2.27) for patients in North America, 0.79 (95% CI = 0.62–1.00) for Europe, and 0.69 (95% CI = 0.37–1.27) for Australia, New Zealand, or other. Hazard ratios were 0.81 (95% CI = 0.58–1.14) for those with elevated LDH and 0.76 (95% CI = 0.57–1.01) for those with normal LDH, and 0.80 (95% CI = 0.60–1.06) for patients with PD-L1–positive disease and 0.76 (95% CI = 0.53–1.10) for PD-L1–negative disease.

Median progression-free survival as assessed by independent review committee was also prolonged in the atezolizumab group (median = 16.1 months vs 12.3 months, HR = 0.85, 95% CI = 0.67–1.07, = .16), although the difference not achieve statistical significance.

At interim analysis of overall survival, death had occurred in 36% of patients in the atezolizumab group vs 43% of patients in the control group (HR = 0.85, 95% CI = 0.64–1.11, P = .23). Estimated 2-year overall survival was 60% vs 53%. Investigator-assessed confirmed objective response was observed in 66.3% of patients vs 65.0% of patients, with complete response observed in 15.7% vs 17.1%. Median duration of response was 21.0 months (95% CI = 15.1 months–not estimable) vs 12.6 months (95% CI = 10.5–16.6 months).

Adverse Events

Common treatment-related adverse events of any grade (> 30% of patients) in the atezolizumab and control groups were increased creatine phosphokinase (51.3% vs 44.8%), diarrhea (42.2% vs 46.6%), rash (40.9% in both groups), arthralgia (39.1% vs 28.1%), pyrexia (38.7% vs 26.0%), increased alanine aminotransferase (33.9% vs 22.8%), and increased lipase (32.2% vs 27.4%).

Treatment-related grade 3 or 4 adverse events occurred in 79% vs 73% of patients, with the most common in the atezolizumab group being increased lipase (20% vs 21% in control group), increased creatine phosphokinase (20% vs 15%), increased alanine or aspartate aminotransferase (13% vs 9%), and maculopapular rash (13% vs 10%).

Treatment-related serious adverse events occurred in 33% vs 29% of patients. Adverse events led to discontinuation of all treatment in 13% vs 16% of patients. Adverse events led to death in seven patients in each group. Causes of death in the atezolizumab group consisted of sepsis in two patients and cardiac arrest, pneumonia, septic shock, hepatic failure, and fulminant hepatitis in one patient each; causes in the control group consisted of cardiac arrest, cardiac failure, left ventricular failure, cerebrovascular accident, hydrocephalus, gastrointestinal hemorrhage, and pulmonary hemorrhage in one patient each.

Immune-mediated adverse events occurred in 63% vs 51% of patients, with those occurring more commonly in the atezolizumab group (≥ 2% difference) consisting of increased aspartate aminotransferase, increased alanine aminotransferase, pneumonitis, increased amylase, dermatitis-acneiform, uveitis, hyperthyroidism, and acne.

The investigators concluded, “The addition of atezolizumab to targeted therapy with vemurafenib and cobimetinib was safe and tolerable and significantly increased progression-free survival in patients with BRAF V600 mutation–positive advanced melanoma.”

Ralf Gutzmer, MD, of Medizinische Hochschule Hannover, Germany, is the corresponding author for The Lancet article.

Disclosure: The study was funded by F. Hoffmann–La Roche and Genentech. For full disclosures of the study authors, visit thelancet.com.

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®.

Τρίτη, 30 Ιουνίου 2020

FEWER CARDIOVASCULAR ADVERSE EVENTS WITH GnRH ANTAGONISTS

Men with prostate cancer on androgen-deprivation therapy are usually treated with leuprolide, a long-acting injectable luteinizing hormone-releasing hormone (LHRH) agonist requiring an every-3-month injection, but it may be possible for ADT to be delivered by a daily oral treatment, pending regulatory approval. In the phase III HERO study, oral relugolix, given daily, was superior to leuprolide for achieving testosterone suppression in men with advanced prostate cancer who required androgen-deprivation therapy, as reported during the ASCO20 Virtual Scientific Program by Neal D. Shore, MD, FACS, of Carolina Urologic Research Center, Myrtle Beach, South Carolina, and published online in The New England Journal of Medicine to coincide with the presentation.1,2

Neal D. Shore, MD, FACS

Neal D. Shore, MD, FACS

The study met the primary endpoint of sustained castration levels of testosterone at 48 weeks. Almost all men treated with relugolix (96.7%) maintained castration levels of testosterone through 48 weeks vs 88% of men treated with leuprolide (P < .001 for superiority). In addition, the risk of developing a major adverse cardiovascular event was 54% lower with relugolix.

“Prescribing information for leuprolide and other LHRH agonists already contains warnings about increased risk of myocardial infarction, sudden cardiac death, and stroke. In the HERO trial, the oral GnRH antagonist relugolix showed sustained testosterone suppression superior to that of leuprolide [an LHRH agonist],” stated Dr. Shore.

“Relugolix is a novel, oral GnRH antagonist that has the potential to become a new standard for androgen-deprivation therapy in advanced prostate cancer,” he added.

Practice-Changing Results?

This abstract was one of three prostate cancer abstracts selected for the Genitourinary Highlights session at this year’s ASCO meeting. David Wise, MD, of Perlmutter Cancer Center at NYU Langone Health in New York, who discussed the highlights, agreed that relugolix is a new standard of care. “Is this practice-changing? Yes, for a subset of patients with a history of significant cardiovascular disease and without gastrointestinal malabsorption problems,” Dr. Wise stated. “I will use this drug to avoid injection-site reactions commonly experienced with degarelix [another GnRH antagonist]. The concern for noncompliance with an oral drug will necessitate more frequent serum testosterone checks, particularly for monotherapy,” he added.

Relugolix is practice-changing for a subset of patients with a history of significant cardiovascular disease and without gastrointestinal malabsorption problems. 
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Dr. Shore explained that the reduced incidence of major adverse cardiovascular events with relugolix is noteworthy, because men with prostate cancer have an increased risk of cardiovascular events. “Cardiovascular events are the leading cause of death in men with prostate cancer, now accounting for up to one-third of deaths. Approximately 30% of men with prostate cancer have known cardiovascular disease, and many more have risk factors such as obesity, diabetes, hypertension, and hyperlipidemia. In the HERO trial, more than 90% of men had cardiovascular risk factors.”

Study Details

The global trial randomly assigned 930 men with advanced prostate cancer in a 2:1 ratio to receive oral relugolix at 120 mg/d (n = 622) or leuprolide injections (n = 308) every 3 months, for a total of 48 weeks. To be eligible for the trial, men had to be 18 years or older, have histologically confirmed adenocarcinoma of the prostate, and be candidates for at least 1 year of continuous androgen-deprivation therapy. Eligible patients had to have one of the following: evidence of biochemical or clinical relapse after primary therapy with curative intent, newly diagnosed hormone-sensitive metastatic disease, or advanced localized disease unlikely to be cured. Patients who experienced major adverse cardiovascular events within 6 months of enrollment were excluded.

At baseline, the median patient age was 71 years, and 28.6% were older than age 75. About 31% had metastatic disease, 43% had Gleason 8 to 10 disease, 11.9% had previous androgen-deprivation therapy, and 30.3% had previous radiotherapy. The median prostate-specific antigen (PSA) level at baseline was 10.8 ng/mL. The mean testosterone level at baseline was 427.5 ng/dL. More than 90% of men had at least one cardiovascular risk factor, and the percentage of men with risk factors was well balanced in the two arms. Treatment adherence was more than 99% in both groups. The median time to follow-up, including safety, was 52 weeks.

Key Results

In addition to superiority for the primary endpoint of maintained castration levels of testosterone over 48 weeks, relugolix was superior to leuprolide for all key secondary endpoints (P < .001). These endpoints included the cumulative probability of castrate levels on day 4 (56% vs 0%) and on day 15 (98.7% vs 12%) and of testosterone suppression to profound levels (ie, < 20 ng/dL). The percentage of patients with a confirmed PSA response at day 15 was 79.4% with relugolix and 19.8% with leuprolide (< .001).

Men treated with relugolix achieved castration levels of testosterone more rapidly than leuprolide, and this response was maintained throughout treatment. On the other hand, patients who discontinued relugolix treatment had faster testosterone recovery to normal levels.

“Another clinical advantage of oral relugolix over leuprolide is a higher percentage of men achieved testosterone recovery to normal levels within 90 days after treatment discontinuation (54% vs 3%),” Dr. Shore noted. “This should be particularly relevant for men receiving intermittent androgen-deprivation therapy, short-course androgen-deprivation therapy, or stopping treatment to recover from serious and debilitating testosterone suppression adverse effects,” he explained.

Safety

The overall incidence of adverse events was consistent across the two treatment arms. Hot flash was the most common adverse event in both arms: 54.3% for relugolix and 51.6% for leuprolide. Moderate or mild diarrhea was reported in more patients in the relugolix group (12.2%) than in the leuprolide group (6.8%). There were no treatment withdrawals due to diarrhea.

Fatal events occurred in 1.1% of the relugolix group and 2.9% of the leuprolide group. A prespecified analysis after 48 weeks of treatment found the incidence of major adverse cardiovascular events was 2.9% with relugolix compared with 6.2% with leuprolide—a rate 54% lower with the oral androgen-deprivation therapy.

In a subgroup of patients with a reported history of major adverse cardiovascular events, the incidence of such events during treatment was 3.6% for relugolix and 17.8% for leuprolide. “The odds ratio was 5.8 times higher with leuprolide in comparison to relugolix in men with a history of major adverse cardiovascular events,” Dr. Shore stated. 

DISCLOSURE: The HERO study was funded by Myovant Sciences. Dr. Shore has reported consulting relationships with Myovant Sciences, Amgen, Astellas Pharma, AstraZeneca, Bayer, BMS, Dendreon, Ferring, Genentech/Roche, Janssen, Medivation/Astellas, Merck, Pfizer, and Tolmar. Dr. Wise has received honoraria from OncLive; consulting fees from AlphaSights, Foundation Medicine, GLG Pharma, Guidant Global, Leap Therapeutics, Pfizer, and Silverlight; and reimbursement for travel expenses from Pfizer.

REFERENCES

1. Shore ND, George DJ, Saad F, et al: HERO phase III trial: Results comparing relugolix, an oral GnRH receptor antagonist, versus leuprolide acetate for advanced prostate cancer. ASCO20 Virtual Scientific Program. Abstract 5602.

2. Shore ND, Saad F, Cookson MS, et al: Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med 382:2187-2196, 2020.

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®.

FDA APPROVED HER-PER sc COMBINATION

On June 29, the U.S. Food and Drug Administration (FDA) approved a new fixed-dose combination of pertuzumab, trastuzumab, and hyaluronidase-zzxf (Phesgo) for subcutaneous injection in the following indications: 

  • Use in combination with chemotherapy as: 
    • Neoadjuvant treatment for patients with HER2-positive, locally advanced, inflammatory, or early-stage breast cancer (either greater than 2 cm in diameter or node-positive) as part of a complete treatment regimen for early breast cancer
    • Adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.
  • Use in combination with docetaxel for treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

“Currently, most patients with HER2-positive breast cancer receive trastuzumab and pertuzumab at infusion centers. With a new administration route, [this triplet] offers an outpatient option for patients to receive trastuzumab and pertuzumab,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and Acting Director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.

Richard Pazdur, MD

Richard Pazdur, MD

FeDeriCa Trial

Efficacy was investigated in FeDeriCa, an open-label, multicenter, randomized trial that enrolled 500 patients with operable or locally advanced HER2-positive breast cancer. Patients were randomly assigned to receive neoadjuvant chemotherapy with concurrent administration of either the triplet combination or intravenous pertuzumab and intravenous trastuzumab during the neoadjuvant and adjuvant therapies.

The primary endpoint of FeDeriCa was noninferiority of cycle 7 pertuzumab serum trough concentration comparing pertuzumab/trastuzumab/hyaluronidase-zzxf to intravenous pertuzumab. Secondary endpoints included cycle 7 trastuzumab serum trough concentration, pathologic complete response, and safety.

Pertuzumab/trastuzumab/hyaluronidase-zzxf showed noninferior pertuzumab and trastuzumab serum trough concentrations compared to intravenous pertuzumab and trastuzumab. The pathologic complete response rate was 59.7% (95% confidence interval [CI] = 53.3%–65.8%) in the pertuzumab/trastuzumab/hyaluronidase-zzxf arm and 59.5% (95% CI = 53.2%–65.6%) in the intravenous pertuzumab and intravenous trastuzumab arm. 

The safety profile of pertuzumab/trastuzumab/hyaluronidase-zzxf is comparable to intravenous pertuzumab and trastuzumab, except for increased administration-related reactions. The most common adverse reactions in > 30% patients receiving the triplet combination were alopecia, nausea, diarrhea, anemia, and asthenia.

The recommended initial dose of pertuzumab/trastuzumab/hyaluronidase-zzxf is 1,200 mg of pertuzumab, 600 mg of trastuzumab, and 30,000 units of hyaluronidase administered subcutaneously over approximately 8 minutes, followed every 3 weeks by a dose of 600 mg of pertuzumab, 600 mg of trastuzumab, and 20,000 units of hyaluronidase administered subcutaneously over approximately 5 minutes.

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®.

Κυριακή, 28 Ιουνίου 2020

COVID-19 ANTIBODIES CAN DISAPPEAR AFTER 2-3 MONTHS

People who develop antibodies after becoming infected with the coronavirus may not keep them more than a few months, especially if they showed no symptoms to begin with, a Chinese study shows.

Previous studies had found that most people who became infected developed antibodies. Health departments around the world give antibody tests as a way to prove a person has already had the coronavirus.

Scientists in the Wanzhou district of China studied 37 people who became infected with the coronavirus and showed symptoms and 37 people who became infected and showed no symptoms, according to the study published in the online journal Nature Medicine

Eight weeks after recovery, antibody levels fell to undetectable levels in 40% of asymptomatic people and 13% of symptomatic people, Nature Medicine said.

The researchers noted that only a small group of people were studied and that the human body can also use T cells to kill the virus and B cells to produce new antibodies, Business Insider reported. Neither T cells nor B cells were measured in the new study.

Business Insider reported that the researchers tested for two types of antibodies: immunoglobulin G (IgG) and immunoglobulin M (IgM). IgG usually develops over a longer time period, meaning it's a better indicator of long-term immunity, Business Insider said.

The decrease in detectable antibodies was sharp after 8 weeks, with a 71% median drop for IgG levels in the asymptomatic group and a 76% median drop in the symptomatic group, the study said.

The findings call into question the idea of "immunity passports," which some countries want to issue to people who test positive for antibodies. These people would be allowed to go back to work and travel because they're supposedly immune to the virus.

"Together, these data might indicate the risks of using COVID-19 'immunity passports' and support the prolongation of public health interventions, including social distancing, hygiene, isolation of high-risk groups and widespread testing," the authors wrote.

CONDITIONS THAT INCREASE COVID19 MORTALITY

Obesity poses a greater risk as an underlying condition when someone develops COVID-19, whereas newer evidence suggests hypertension poses a lower risk compared with the reports at the beginning of the pandemic in the United States, officials with the Centers for Disease Control and Prevention (CDC) announced today in a press briefing.

CDC Director Robert Redfield, MD, also told reporters on the briefing that the number of people infected with the novel coronavirus might be 10 times higher than reported.

Among those who are infected, the connection between obesity and more severe COVID-19 outcomes — defined as hospitalization, ICU admission, and/or death — early on was "most obvious among people with a BMI over 40," said Jay C. Butler, MD, CDC deputy director of infectious diseases and COVID-19 response incident manager.

"Now with more data, it appears that even obesity at a BMI over 30 may increase the risk as well," he said.

The potential contribution of hypertension to elevated risk shifted over time as well, Butler added during the briefing. He explained that high blood pressure is a risk factor for a number of conditions, and more recent studies helped CDC officials better tease out the individual risk associated with COVID-19.

The agency expanded its list of underlying conditions associated with the more severe COVID-19 outcomes. For example, in addition to a BMI of 30 or more, evidence suggests serious heart conditions, sickle cell diseasetype 2 diabetesand other conditions elevate the risk for severe illness. Joining hypertension in the "might be at increased risk" category are people with moderate-to-severe asthma, dementia, and cystic fibrosis.

"We are talking about the strength of evidence rather than upgrading or downgrading the level of risk" for each of these conditions, Butler said.

No More Specific Age Distinction

The CDC also removed an age cutoff associated with elevated risk for more serious COVID-19, previously set at older than 65 years. Instead, it's more of a continuum. "As you get older, your risk for hospitalization, intensive care, and death increases," said Redfield.

Although increased age is an independent risk factor, the agency acknowledged that older Americans tend to have more underlying conditions as well. 

Pregnancy Risks Linked to COVID-19

Pregnant women with COVID-19 appear to be at elevated risk for hospitalization, intensive care unit admission, and use of mechanical ventilation, according to research published online today in Morbidity and Mortality Weekly Report(MMWR). At the same time, however, this study of 8207 pregnant women with confirmed COVID-19 infection had no significantly increased risk of death.

"The good news is that the data we have so far is that pregnant women are not at increased risk of death," Dana Meaney-Delman, MD, MPH, COVID-19 deputy incident manager at the CDC, said during the briefing."But we do see increased risk of ICU admission and mechanical ventilation," she added. So it remains "important to get the message out there that pregnant women need to take precautions."

Of 91,412 (28%) women with laboratory-confirmed infections reported to the CDC between January 22 and June 7, 9% were pregnant.

Among the women with COVID-19, almost 32% of pregnant women were hospitalized compared with 6% of women who were not pregnant. Furthermore, the pregnant women were 50% more likely to be admitted to an ICU (adjusted relative risk [aRR], 1.5; 95% confidence interval, 1.2 - 1.8) and 70% more likely to be placed on mechanical ventilation (aRR, 1.7; 95% CI, 1.2 - 2.4). These analyses adjusted for age, underlying conditions, and race/ethnicity.

Multiply Confirmed Cases By 10

Addressing a recent increasing number of cases in the United States, Redfield said "there are a number of states, particularly in the Southeast and the Southwest, that are seeing increases in COVID-19 cases."

Many factors are driving the increase, he added, including outbreaks in particularly challenging settings, increased testing, and community transmission.

"This virus causes so much asymptomatic infection, we don't know the exact number," Redfield said.

More data are coming in from antibody testing and public health surveillance. "We probably recognized about 10% of the outbreak during March, April, and May," he said. The agency is working now to enhance detection closer to real time, he added.

"The best estimate for now is, for everyone diagnosed there were 10 other cases," Redfield said. Although data will be refined in next few weeks, "that is a good rough estimate for now."

At the same time that the number of positive cases is increasing, data is pointing to a higher infection rate among younger people, as reported byWebMD Health News.

"Obviously we are seeing infections that are targeting younger individuals, as in Florida or the Southeast and Southwest of the country," Redfield said. "In the past, I don't think we diagnosed these infections."

Redfield "remains concerned" about the public health messaging for people under age 45 or even under 30. "The impact of COVID-19 on them may not be associated with hospitalization and death, but they do act as transmission connectors to individuals who could be at higher risk."

"Everyone needs to understand there is some risk of severe illness, including among young people," he added.

Future Concerns

"It's clear that many individuals in this nation are still susceptible," Redfield said. The risk will vary with different prevalence rates in different states.

He estimated that between 5% to 8% of Americans have experienced COVID-19 infection so far, "whether they recognize it or not." This also means that greater than 90% of the public has not experienced the virus, although they are susceptible.

"This outbreak is not over, this pandemic is not over, and we need to continue to take steps we know are effective at limiting COVID-19," he said. The most powerful tool we have is social distancing. He emphasized the need to maintain 6 feet of distance with others, wearing a face covering "when we cannot maintain social distancing," and continuing frequent hand hygiene practices.

"As we go into the fall and winter, these will be important defense mechanisms," Redfield said. 

Follow Damian McNamara on Twitter: @MedReporter.

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PREVENTION OF TYPE 2 DIABETES

Adults at high risk for type 2 diabetes who had received either lifestyle intervention or metformin in the 3-year Diabetes Prevention Program (DPP) and continued in the Diabetes Prevention Program Outcomes Study (DPPOS) were less likely to develop diabetes than patients in the placebo group over an average 22-year follow-up.  

DPPOS chair David M. Nathan, MD, and other study investigators presented findings last week during the virtual American Diabetes Association (ADA) 80th Scientific Sessions.

At the end of the DPP, conducted in 1996-2001, patients in the lifestyle-intervention or metformin group were 58% and 31% less likely to have incident diabetes, respectively, than patients in the placebo group.

Now, 22 years after they enrolled in the DPP, patients were on average 72 years old and those in the original lifestyle intervention or metformin group were 25% and 18% less likely to have diabetes, respectively.

And participants who did not develop diabetes had significantly lower rates of eye, kidney, and major cardiovascular disease, at 57%, 37%, and 39%, respectively, according to a statement from the ADA.

"What we have shown is that diabetes prevention is possible," Nathan, from Massachusetts General Hospital and Harvard Medical School, Boston, told Medscape Medical News in an interview.

Unique Long-Term Study 

The DPP participants were at very high risk for diabetes, Nathan stressed.

"Their glucose levels were rising. They were overweight, if not obese, and we also overrecruited in ethnic and racial groups that are at particularly high risk — African Americans, Hispanic Americans, American Indians, and Asian Americans."

This unique, long-term study showed "a pretty remarkable — and not unexpected, some may say — reduction in eye disease, kidney disease, and major cardiovascular disease in people who did not develop diabetes," he noted.

"I think it is important for providers and patients with prediabetes to know that even after 22 years, adults at high risk for diabetes have continued to benefit from metformin or prior intensive lifestyle modification in preventing or delaying" diabetes, Christine Lee, MD, told Medscape Medical News in an email.

Lee is program director of the Division of Diabetes, Endocrinology, and Metabolic Diseases, at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Lifestyle Modification Better for Prevention in Adults > 60 Years

In the DPP, 3234 patients at high risk of developing diabetes were randomized to receive placebo or metformin (850 mg twice a day) or an intensive lifestyle counseling program that aimed for 7% weight loss and 150 minutes of moderate exercise per week.

At the end of the DPP, 88% of participants (including those who had developed diabetes) entered the DPPOS; those who were taking metformin stayed on it and all three groups received less intensive lifestyle counseling.As reported earlier, 15 years after enrolling in the DPP, 55% of participants in the lifestyle group and 56% of those in the metformin group had developed diabetes, compared with 62% of those in the placebo group.

At 22 years, 75% of patients from the DPP who were still alive were still participating in the DPPOS.

"The new findings did not show that taking metformin can prevent cancer, cardiovascular disease, or diseases of the eyes and kidney caused by diabetes," Lee pointed out.

However, "the data suggest that there may be some preventive effects of metformin for these outcomes in adults younger than 45 years [eg, a trend to less stroke], but these outcomes were more infrequent in this younger age group and further studies are needed before conclusions can be made for this age group."

"Conversely, there appeared to be a greater risk for kidney disease with metformin in older adults," she continued.

Therefore, "when balancing that risk [from metformin]" with prior, and newer, results that respectively show lifestyle modification works better than metformin for preventing diabetes in older adults, and can also decrease the risk of frailty in this same group, "patients ages 60 and older at high risk for diabetes should focus on intensive lifestyle modification for diabetes prevention," according to Lee.

Metformin is not approved for diabetes prevention in the United States, and it is unlikely that any of the several manufacturers of generic metformin would file a new drug application for this use with the US Food and Drug Administration, according to Nathan.

Widespread Prediabetes, Few Referrals for Community DPPs

In the United States, an estimated 30 million people have diabetes (mostly type 2), including about 7 million not yet diagnosed, Nathen said, and another 90 million have prediabetes.

More research is needed to be able to identify which patients with prediabetes are most vulnerable to developing diabetes and would benefit most from prevention interventions, he stated.

Similarly, Lee said that the current findings "highlight the importance of trying to further understand differences in how metformin or lifestyle modification work in adults at high risk for diabetes."

"Research to better identify who can benefit most from metformin or lifestyle will help providers offer patient-centered approaches for diabetes prevention," she said.

In the meantime, and as previously reported, the US Preventive Services Task Force and the ADA recommend screening and lifestyle counseling to achieve weight loss and reduce diabetes risk in high-risk adults, and diabetes prevention programs are covered by Medicare, many commercial health plans, and some Medicaid and state employee health plans.

About 2 years ago, the Center for Medicare and Medicaid Services began funding the diabetes prevention lifestyle program for qualifying Medicare beneficiaries at high risk of diabetes, said Nathan, and the program is available in many US communities.

And as previously reported, the turnkey lifestyle program to prevent diabetes by the US Centers for Disease Control and Prevention (CDC) replicates the DPP intervention and is offered by 244 YMCAs at more than 1100 locations.

Patients receive coaching from trained individuals about making long-term dietary changes, increasing physical activity, and overcoming challenges to maintaining weight loss and a healthy lifestyle. Counseling is given in 22 sessions over 1 year.

However, few physicians are referring patients with prediabetes to the program. According to a 2019 CDC study, only 5% of individuals with prediabetes and 0.4% of those with an elevated risk of diabetes had been told by their physician to participate in a diabetes prevention program (JAMA Netw Open2019;2:E193160).

DPPOS is supported by the NIDDK, National Cancer Institute, National Heart, Lung, and Blood Institute, National Institute on Aging, National Eye Institute, Office of Research on Women's Health, and CDC. Merck supplied the metformin.  

ADA 2020 Scientific Sessions. June 16, 2020.   

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DEFINITION OF HYPERPROGRESSION

In non-small-cell lung cancer patients on immunotherapy, a new definition, based on the difference between the tumor growth rate (TGR) before and during therapy, may more accurately define hyperprogressive disease (HPD) than the five current definitions, researchers say.

"We applied the different definitions and noted that they did not give the same prevalence of HPD (which was expected) but surprisingly, they did not identify the same patients," Dr. Caroline Caramella of Paris-Saclay University in Villejuif told Reuters Health by email. "We tested different models in order to identify the worst tumor growth leading to the worst overall survival."

"We then proposed a definition based on a difference in TGR before and during therapy of more than 100," she said. "But we are still cautious - this definition would need to be confirmed and/or refined through new studies and external validations."

As reported in JAMA Oncology, the team's retrospective cohort study included 406 patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors from 2012-2017 in eight French institutions. Patients' median age at the start of immune checkpoint inhibitor treatment was 64, and 64% were men.

Measurable lesions were defined using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria on at least two computed tomographic scans before therapy initiation and one scan during treatment.

The different definitions resulted in HPD incidences that varied from 5.4% with a definition based on a >2-fold progression pace and a time to treatment failure of <2 months, to 18.5% based on a definition of the TGR ratio.

Concordance among the different definitions varied from 33.3% to 69.3%. However, for every definition, HPD was associated with poorer survival - i.e., range of median overall survival, 3.4 to 6.0 months.

The new definition - an optimal threshold of a difference in TGR before and after therapy of more than 100 - correlated most with poor overall survival, with an initial plateau for a larger number of patients and a slower increase; it also had the highest ability to distinguish patients with HPD from those with progressive disease not classified as HPD.

As Dr. Caramella noted, more studies on larger groups of patients are needed to validate the proposed definition.

Medical oncologist Dr. Kevin Sullivan of the Northwell Health Cancer Institute in Lake Success, New York, told Reuters Health, "I agree with the researchers that current definitions of HPD make it difficult to fit neatly into one characterization. Their findings certainly confirm that HPD is a rare phenomenon and I think their classification is helpful," he said by email.

"However," he noted, "whether a patient experiences HPD or what is more commonly seen as general disease progression without this phenomenon of 'hyperprogression,' if the patient is not responding to a particular therapy, it indicates that a change in treatment is warranted, or a shift in overall management to...symptom management alone - in the setting of hospice, for example."

"Ultimately, recognizing when a patient's cancer is worsening and whether or not a patient is a candidate for further treatment depends upon astute clinical skills and a good doctor-patient relationship," he concluded.

Dr. Ankur Parikh, Precision Medicine Program Director at Cancer Treatment Centers of America in Philadelphia, told Reuters Health by email, "While I agree their definition utilizing change in TGR of greater than 100 may identify a more at-risk population, this is a retrospective study reviewing non-small cell lung cancers only. The other definitions listed are based on studies done in various cancers."

"Larger prospective studies looking at specific tumor types, tumor genomics and more standard imaging would help assess the validity of the new HPD definition," he said. "This article highlights the challenges and complexities clinicians face and the significant need to identify the specific patient populations that will fare worse by receiving treatment with immune checkpoint inhibitors."

SOURCE: https://bit.ly/2N99Rm0 and https://bit.ly/37E9qcR JAMA Oncology, online June 11, 2020.

SEDENTARY LIFE INCREASE CANCER RISK

Being sedentary was associated with a greatly increased risk for cancer death, but even very light exercise, such as a short daily walk, can help, say researchers reporting data from a cohort of people who wore accelerometers.

The study was published on June 18 in JAMA Oncology.

The finding offers hope for people who are unable to engage in more vigorous activities, such as running or cycling, said lead author Susan Gilchrist, MD, an associate professor of clinical cancer prevention and cardiology at the University of Texas MD Anderson Cancer in Houston.

"It gives people some realistic goals for what they can do for themselves," Gilchrist told Medscape Medical News.

Some previous studies have found an association between sedentary activity and cancer mortality, but others have shown no association. All have relied on participants' self-reports as to their own activity, but most people underestimate how much time they spend sitting, she commented. Also, researchers have had trouble teasing out the benefits of exercise from the harm of motionlessness, Gilchrist said.

To overcome these limitations, her team analyzed data from a cohort of 8002 people who were part of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) and who wore accelerometers. REGARDS is a national study of stroke risk factors. It involved 30,239 black and white US adults older than 44 years who were recruited between 2003 and 2007.

One group of participants wore accelerometers on their hips during waking hours for 7 consecutive days. The mean age of these participants was 69.8 years, and 45.8% were men. None were being treated for cancer at baseline.

The REGARDS researchers collected the accelerometer data from 2009 to 2012. The mean follow-up period was 5.3 years. During that time, 268 participants died of cancer.

The team reports that those participants who died of cancer had spent more minutes per day being sedentary, were sedentary for longer periods at a stretch, and performed less light-intensity physical activity (LIPA) and moderate- to vigorous-intensity physical activity (MVPA).

LIPA generally includes activities such as light housework, shopping, cooking, and easy gardening; MVPA encompasses a wide range of more strenuous activity, including brisk walking, running, dancing, and digging ditches.

The researchers found that participants who spent the most time being sedentary were 82% more likely to die from cancer (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.27 – 2.60).

The researchers adjusted for age, race, sex, region of residence, educational level, season the accelerometer was worn, current smoking, alcohol use, body mass index, diabetes, hypertension, dyslipidemia, history of coronary heart disease, history of stroke, and MVPA. Even after these adjustments, they found that the most sedentary people were 52% more likely to die of cancer (HR, 1.52; 95% CI, 1.02 – 2.27).

People who were sedentary for the longest bouts were also 61% more likely to die of cancer (HR, 1.61; 95% CI, 1.16 – 2.24), but after the researchers adjusted for the other factors, the increased risk was no longer statistically significant (HR, 1.36; 95% CI, 0.96 – 1.93)For every 1 hour that participants spent being sedentary, their risk of dying from cancer increased by 16% (HR, 1.16; 95% CI, 1.03 – 1.31).

On the other hand, substituting 30 minutes of sedentary time with 30 minutes of MVPA a day lowered the risk for cancer death by 31% (HR, 0.69; 95% CI, 0.48 – 0.97). Thirty minutes of LIPA per day reduced the risk by 8% (HR, 0.92; 95% CI, 0.86 – 0.97).

"The thing that surprised me was that light activity was significant," Gilchrist said. "I thought that you would have to replace the sitting activity with moderate to vigorous activity."

This kind of granular association would have been hard to uncover with self-reported data, she said. It is good news for people with sedentary lifestyles and for the physicians trying to help them, she added.

Gilchrist works with patients who find exercise difficult in the best of times and have given up since the COVID-19 pandemic has made group activities and gyms more dangerous. "Let's move around the house for 10 minutes," she tells them. "Let's go to the mailbox and back."

She acknowledged several limitations to the study. Among the most important is that the patients wore the accelerometers on their hips, so the devices couldn't detect differences between sitting and standing and so would not capture activities such as washing dishes.

Although only a clinical trial could prove cause and effect, this study made an important contribution because it provided objective measurements and because it spanned 13 years, said Nigel Brockton, PhD, vice president of research at the American Institute for Cancer Research in Washington, DC.

"This helps with the messaging," he said. "So many people are wearing wearable devices to quantify their own activity."

It is significant that the association of physical activity and cancer mortality in this study was independent of body mass index, Brockton said. Although it's not yet clear how exercise might reduce cancer, the evidence so far points to effects on both metabolism and inflammation, he said.

In the next phase of her research, Gilchrist hopes to zero in on the effects of physical activity on specific types of cancer. That might help answer some of these biochemical questions.

Gilchrist has served as a consultant for Outcomes4Me. Brockton has disclosed no relevant financial relationships.

JAMA Oncol. Published online June 18, 2020. Abstract

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Πέμπτη, 25 Ιουνίου 2020

OPTIMAL COMBINATION FOR AL AMYLOIDOSIS

Patients with newly diagnosed light chain (AL) amyloidosis could soon have a new treatment option: daratumumab (Darzalex, Janssen) along with the standard treatment used in these patients ― the chemotherapy combination of bortezomib, cyclophosphamide, and dexamethasone (CyBorD).

The addition of daratumumab substantially improved hematologic response to treatment and delayed the time to organ failure, according to results from the phase 3 ANDROMEDA study. Those results were presented as part of the virtual European Hematology Association 25th Annual Congress (EHA) 2020.

"This represents a major step forward in the treatment of light chain amyloidosis," Morie A. Gertz, MD, from the Mayo Clinic in Rochester, Minnesota, told Medscape Medical News. He was not involved in the study and was approached for comment. "The high-level activity of adding daratumumab in terms of deeper hematologic responses as well as demonstrated organ responses will likely be practice changing for newly diagnosed AL amyloidosis," he added.

The new data will be used to support an approval application for this new indication for daratumumab, which is currently marketed for use in the treatment of multiple myeloma.

"I think this will likely become the first approved therapy for AL amyloidosis," commented first author Efstathios Kastritis, MD, an associate professor of clinical therapeutics/medical oncology in the Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Greece.

He also predicted that daratumumab plus CyBorD will become "the global standard of care for these patients.

"The combination of subcutaneous daratumumab with the most commonly used combination therapy, CyBorD, improved substantially the complete hematologic responses in patients with newly diagnosed AL amyloidosis compared to the CyBorD combination alone," he told Medscape Medical News.

More Effective Therapies Needed

Systemic AL amyloidosis is a rare and potentially fatal multiorgan disorder. Diagnoses are often delayed, and approximately 30% of patients die within the first year of diagnosis.

Novel combinations based on bortezomib, such as CyBorD, have improved outcomes; however, more effective therapies are urgently needed, Kastritis explained.

"In AL amyloidosis, it is of the utmost importance to achieve rapid, deep, and sustained pathological responses in order to reverse amyloid-mediated organ dysfunction and improve overall survival," he said.

The amyloid depositions that result in organ dysfunction in AL amyloidosis are produced by clonal CD38 plasma cells. Daratumumab, a standard treatment in multiple myeloma, is the only subcutaneous antibody targeting CD38. It is a promising agent in relapsed and refractory AL amyloidosis and has an acceptable safety profile, Kastritis said.

Hematologic Response "Substantial"

The phase 3 ANDROMEDA study involved 388 patients with newly diagnosed AL amyloidosis who had measurable hematologic disease with one or more involved organs.

About a third (37%) of the patients had severe cardiac dysfunction (cardiac stage III) due to amyloidosis; 40% had cardiac stage II, and 23% had stage I.

Patients randomly assigned to the chemotherapy-only group (n = 193) received the CyBorD regimen, which included cyclophosphamide 300 mg/m² PO or IV once weekly (QW); bortezomib 1.3 mg/m² SC QW; and dexamethasone 20 – 40 mg PO or IV QW alone for six 28-day cycles.

Patients who were assigned to the experimental group (n = 195) received the CyBorD regimen along with subcutaneous daratumumab (1800 mg, coformulated with recombinant human hyaluronidase PH20 15 mL; n = 195).

Daratumumab was administered by injection QW in cycles 1–2, Q2W in cycles 3–6, and Q4W thereafter for up to 24 cycles (28-day cycles).

Among patients in the daratumumab group, the median duration of treatment was 9.6 months; among those in the CyBorD group, the median duration was 5.3 monthsFor the primary endpoint of overall hematologic complete response, results at a median follow-up of 11.4 months were 53% in the daratumumab group, compared to just 18% in the CyBorD-only group (odds ratio, 5.1; P < .0001).

"There was a substantial increase in complete hematologic response rates," Kastritis said.

"Complete hematologic responses correspond to the elimination of the toxic free light chains that form the amyloid fibrils and is the strongest predictor for a favorable outcome in patients with AL amyloidosis," he explained.

The median time to the response was 60 days for the daratumumab group and 85 days for CyBorD-alone group.

Organ Response Rates Nearly Doubled

For the secondary endpoint of major organ deterioration progression-free survival, the rate favored the daratumumab group (hazard ratio, 0.58; P = .02).

Other secondary endpoints also were superior in the daratumumab group, including the 6-month cardiac response rate (42% vs 22%; P = .002) and the 6-month renal response rate (54% and 27%, respectively; P < .0001).

The numbers of deaths in each group were similar (daratumumab, 27; CyBorD, 29).

"Patients who were treated with the daratumumab combination had almost doubled organ response rates and also an increase in the time to major organ failure (heart or kidney) or time to hematologic relapse or progression, need for subsequent therapy, or death," Kastritis said.

"It is reassuring that daratumumab with CyBorD showed similar high complete hematologic response rates in patients of different cardiac stages, which is especially important for patients with advanced cardiac disease," he added.

Also important was that the effects were seen in patients with different degrees of renal involvement and in patients with high-risk cytogenetics, which in AL amyloidosis is the presence of t(11;14), he noted.

"Importantly, despite the use of a fixed subcutaneous dose for daratumumab, the complete hematologic response rates were similar for patients with different weights and in both genders," Kastritis said.

The safety profiles in the two groups were consistent with those previously observed with daratumumab or CyBorD alone, he reported. Common grade 3/4 treatment-emergent adverse events that occurred in more than 5% of patients included lymphopenia (daratumumab, 13%; CyBorD, 10%), pneumonia (8%, 4%), diarrhea (6%, 4%), cardiac failure (congestive; 6%, 5%), neutropenia (5%, 3%), syncope (5%, 6%), and peripheral edema (3%, 6%).

Systemic reactions with daratumumab that were associated with the subcutaneous administration in the daratumumab group occurred in 14 (7%) patients; all were rated as grade 1–2, and most occurred during the first infusion.

The study did not include patients with stage 3B disease, who have worse prognoses owing to the advanced disease stage. Kastritis noted that another phase 2 study in Europe is evaluating the treatment in these ultra–high-risk patients.

Diagnosis Often Missed

Kastritis commented that AL amyloidosis often goes unrecognized because the presenting symptoms are often subtle and nonspecific and there is no specific blood test for diagnosis.

These missed diagnoses place the patients in peril, inasmuch as the disease can proceed unchecked and cause organ damage, commented Gertz. "The major unmet need is an earlier diagnosis before significant organ impairment develops," he said. "With end-stage renal or cardiac failure, even the most effective therapies are unlikely to produce significant benefit."

Kastritis called on clinicians to keep a watchful eye for telltale signs of AL amyloidosis.

"Clinicians should suspect the disease in patients with symptoms from several different organ systems, and especially in patients with a known history of a monoclonal gammopathy," he said.

The study was sponsored by Janssen Pharmaceuticals. Kastritis has relationships with Amgen, Genesis Pharma, Janssen, Takeda, and Prothena. Gertz has relationships with Ionis/Akcea, Alnylam, Prothena, Janssen, Spectrum, Annexon, Appellis, Amgen, Medscape, Physicians Education Resource, Abbvie and Celgene, Research to Practice, Sanofi, Teva, Johnson & Johnson, DAVA Oncology; Pharmacyclics, Proclara, and i3Health.

European Hematology Association 25th Annual Congress (EHA) 2020: Abstract LB2604, presented June 12, 2020.

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