Πέμπτη, 17 Σεπτεμβρίου 2020

ESMO 2020

The use of immunotherapy for upper gastrointestinal tumors and renal cancer, ALK- and EGFR-targeted agents in non–small cell lunger cancer (NSCLC), and the next step in personalized prostate cancer management will all be subjects of headlining presentations at the ESMO Virtual Congress 2020.

The conference will, like so many other major events, be held online this year because of the COVID-19 pandemic.

John B. Haanen, PhD, ESMO 2020 scientific chair, who is from the Netherlands Cancer Institute, Amsterdam, the Netherlands, told Medscape Medical Newsthat because the congress is being held online this year, fewer abstracts were submitted; nevertheless, "We were very happy too see...that the quality was very good."

The number of submissions was not the only problem the organizing committee had to face in transforming the ESMO Congress into a virtual meeting.

They were unable to fit the scientific and educational programs together and so have had to split them over two consecutive weekends. Moreover, many of the sessions were highly interactive and needed to be either adapted or omitted.

"So the program is somewhat different," Haanen said. He noted that "the presentations were also made shorter, especially on the educational sessions, because...we can't expect people to sit behind screens for hours listening to long presentations."

He added: "That was out of the question."

Haanen is nevertheless hopeful that the virtual meeting will be "very exciting."

Solange Peters, MD, PhD, ESMO president, who is also affiliated with the Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, said in a press conference that it was a "sacrifice" to move ESMO 2020 online and that "there were very sad moments" when deciding on the content.

However, there were some benefits from the change.

She said that all of the ESMO meetings this year have seen "huge" increases in the number of attendees and the geographical span or reach of each of the conferences.

"So suddenly you also realize that, what is one of the missions of ESMO being to convey education globally...was probably better reached, better achieved with the virtual format," she commented.

Presidential Symposia 

Turning to the program, Haanen first picked out the third presidential symposium, which will be held on Monday, September 21. This will focus entirely on upper gastrointestinal tumors in both the adjuvant and metastatic setting.

He said that in recent years, "very little progress has been made" in this area, with treatment mostly consisting of chemotherapy and chemoradiotherapy.

However, this year's presentations will explore the addition of immunotherapy either to chemotherapy or as an adjuvant treatment following completion of standard-of-care treatment for local disease.Haanen said that the results will be "very interesting...and may change current practice," something that "is very important for both doctors and their patients."

On Saturday, September 19, the first presidential symposium will include two presentations on lung cancer that Haanen said will offer some "exciting new [results] that I am sure will change clinical practice."

One will be on the CROWN phase 3 trial comparing lorlatinib and crizotinib in the first-line treatment of patients with advanced ALK-positive NSCLC.

The other will present results on central nervous system disease recurrence from the ADURA phase 3 trial of osimertinib adjuvant therapy in patients with resected EGFR-mutated NSCLC.

The same session will also see new data in advanced renal cell carcinoma from CheckMate 9ER, in which the c-Met and VEGFR2 inhibitor cabozantinib (Cabometyx) was combined with nivolumab (Opdivo) and compared to sunitinib (Sutent) in untreated patients.

"Last year, there were already some exciting results of the combination of axitinib [Inlyta], either with pembrolizumab [Keytruda] or with avelumab [Bavencio]...in the first-line setting in metastatic clear cell renal cell lung cancer," Hannen said.

"Clearly there was a survival advantage over the standard of care, sunitinib," he added.

This year, not only will efficacy data from CheckMate 9ER be presented but also quality-of-life results.

"That's very important, because what everybody is afraid of is that, by adding drugs, you always get more impact on the quality of life, but you will see that the quality-of-life results are very exciting," he said.

The second presidential symposium will feature studies on prostate cancer, notably the phase 3 IPATential150 trial of abiraterone (Zytiga) plus either ipatasertib or placebo in metastatic castration-resistant prostate cancer.

Ipatasertib targets Akt, and Haanen said that "by adding it to, let's say, standard-of-care treatment...the question of course of will be, Does that have a better outcome?"

He believes the results will be a "very nice illustration" that prostate cancer management is heading in the direction of personalized treatment.

Alongside the presidential symposia, there will be a number of proffered paper sessions on the latest results in all aspects of oncology, including results from the ASCENT trial in triple-negative breast cancer, as well as a dedicated COVID-19 track.

Haanen said that the ESMO Virtual Congress 2020, coming after the AACR and ASCO annual meetings, has the "advantage" of being able to present the latest outcomes of patients treated with chemotherapy and immunotherapy against the backdrop of the pandemic.

This will include a study from the ESMO Resilience Task Force on the impact of COVID-19 on oncology professionals both in terms of their personal distress and burnout and their job performance.

"I think that is very important," Haanen said, "especially because the whole thing with COVID-19 is not yet over, and everybody is preparing for a second wave in the fall and winter.

"It may help us give us clues on how we can protect ourselves or each other to prevent burnout or other problems that we as healthcare caregivers face in this difficult period."

Next Year 

For next year, Peters remains hopeful that the ESMO 2021 meeting will take place as planned in Paris.

She anticipates that, indeed, ESMO meetings will be able to take place from spring next year.

This will depend on a vaccine for COVID-19 becoming widely available, although oncologists in some countries may still not be able to travel.

This means "starting probably with hybrid formats, with some of the faculty being on site and some not, [and] the same thing for the attendees," Peters said.

She suggested that for ESMO Congress 2021 to work as an on-site meeting will require at least half or two thirds of the originally anticipated number of attendees.

"I hope that Paris next year will happen," Peters said, adding that it "will probably happen with less attendees ― that's fine, but [still] with a large number of faculty and attendees."

The commentators have disclosed no relevant financial relationships. 

European Society for Medical Oncology (ESMO) Annual Meeting 2020.

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SUDDEN DEATH NOT SO SUDDEN

People who experience "sudden" out-of-hospital cardiac arrest (OHCA) may feel malaise days earlier, new research from Denmark suggests.

The new analysis shows that 2 weeks before a cardiac arrest, 54% of people had had phone, email, or in-person contact with their general practitioner, and 6.8% had gone to a hospital emergency department or outpatient clinic or had been hospitalized.

In contrast, roughly 25% and 3%, respectively, had had contact with their general practitioner or a hospital each week in the year preceding the cardiac arrest.

Nertila Zylyftari, MD, Copenhagen University Herlev and Gentofte Hospital, Hellerup, Denmark, presented these study results in a poster at the European Society of Cardiology (ESC) Congress 2020.

The findings show that clinicians and patients need to be aware that people may feel unwell before a "sudden" cardiac arrest, and they highlight the importance of applying cardiovascular disease risk scores in daily clinical practice, Zylyftari told theheart.org | Medscape Cardiology.

This is an "interesting," "important" study "that adds to the growing evidence that OHCA patients experience symptoms in the weeks leading up to their arrest," Karen Smith, PhD, director of the Center for Research and Evaluation at Ambulance Victoria, Australia, told theheart.org | Medscape Cardiology in an email.

Smith wrote an editorial about similar evidence ― a related study that involved more than 38,000 patients with OHCA in Ontario, Canada. Those researchers reported "in contrast to conventional wisdom," which regards OHCA as occurring without prior contact with the healthcare system. Findings from that study indicate that more than 1 in 4 patients with OHCA had visited the emergency department in the previous 90 days (Shuvy M: Resuscitation. 2019;141:158-185).

Although the researchers in the current study lacked information about why the patients contacted their general practitioner or went to the emergency department, some may have experienced shortness of breath, chest discomfort, and palpitations, Zylyftari speculated.

Other patients may have had vague symptoms that would make it difficult for them to be identified as being at high risk, she noted. Still others may have made their first contact with the healthcare system when they had the OHCA.

"There is a lot more work to be done to prevent OHCA and have an algorithm that could help identify at-risk patients," Zylyftari said.

In the meantime, Smith said, this study shows that "the percentage contacting a GP is high and highlights that if rapid screening clinics were available for patients to be referred to, many cardiac arrests could potentially be averted."

This work "adds evidence to the fact that campaigns about warning signs of heart attacks may actually avert cardiac arrests also if patients seek care earlier," she added.

Their research group conducted a study that showed that a comprehensive mass media campaign in Melbourne, Australia, to improve awareness of heart attack symptoms was associated with a substantial reduction in the incidence of OHCA and associated deaths (Nehme Z: Eur Heart J. 2017;38:1666–1673).

Need to Identify High-Risk Individuals

OHCA is the third leading cause of death worldwide; on average, fewer than 10% of patients survive, a fact that "emphasizes the need to identify those at risk," said Zylyftari.

The researchers identified 28,955 people in the Danish Cardiac Arrest Registry who had an OHCA during the period 2001 – 2014; the median age of the patients was 72 years, and 67% were men.

The researchers matched each patient with nine people in the general population on the basis of age, sex, and date of the cardiac arrest.

In the general population, only about 13% and 2%, respectively, had had contact with their general practitioner or a hospital in any week.

Of the 54% of patients who had contacted their general practitioner 2 weeks before their OHCA, 72% had phone or email interactions (these interactions were followed by an in-office visit in 11% of cases); 51% had an in-office visit, and 29% had a home visit.

Of the patients who had had any contact with the healthcare system 2 weeks before the cardiac arrest, 25% had a diagnosis of cardiovascular disease, including heart disease (8%) and heart failure (4.5%); 11% had respiratory disease, including chronic obstructive lung disease (4.3%); and others had experienced trauma/poisoning or had a digestive disease.

Fewer individuals from the general population had a diagnosis of cardiovascular disease (almost 9%).

"More data and research are needed on the reasons for these interactions ― for example, symptoms ― to identify warning signs of those at imminent danger so that future cardiac arrests can be prevented," said Zylyftari.

The study was funded the European Union's Horizon 2020 research and innovation program ESCAPE-NET. The researchers have disclosed no relevant financial relationships.

European Society of Cardiology (ESC) Congress 2020: Presented August 28, 2020.

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WEIGHT LOSS AND DIABETES RISK

Intentional loss of a median of just 13% of body weight reduces the relative risk of developing type 2 diabetes by around 40% in people with obesity, among many other health benefits, shows a large real-world study in half a million adults.

Other findings associated with the same modest weight loss included a reduction in the risk of sleep apnea by 22%-27%, hypertension by 18%-25%, and dyslipidemia by 20%-22%.

Christiane Haase, PhD, Novo Nordisk, Denmark, led the work, and spoke to Medscape Medical News, together with Nick Finer, MD, senior principal clinical scientist, Novo Nordisk.

"This is powerful evidence to say it is worthwhile to help people lose weight and that it is hugely beneficial. These are not small effects, and they show that weight loss has a huge impact on health. It's extraordinary," Finer asserted.

"These data show that if we treat obesity first, rather than the complications, we actually get big results in terms of health. This really should be a game-changer for those health care systems that are still prevaricating about treating obesity seriously," he added.

The size of the study, of over 550,000 UK adults in primary care, makes it unique. In the real-world cohort, people who had lost 10%-25% of their body weight were followed for a mean 8 years to see how this affected their subsequent risk of obesity-related conditions. The results were presented during the virtual European and International Congress on Obesity (ECOICO 2020).

"Weight loss was real-world without any artificial intervention and they experienced a real-life reduction in risk of various obesity-related conditions," Haase told Medscape Medical News. 

Carel le Roux, MD, PhD, from the Diabetes Complications Research Centre, University College Dublin, Ireland, welcomed the study because he says it shows those with obesity who maintained more than 10% weight loss experienced a significant reduction in the complications of obesity.

"In the study, intentional weight loss was achieved using mainly diets and exercise, but also some medications and surgical treatments. However, it did not matter how patients were able to maintain the 10% or more weight loss as regards the positive impact on complications of obesity," he highlighted.

From a clinician standpoint, "it helps to consider all the weight loss options available, but also for those who are not able to achieve weight loss maintenance, to escalate treatment. This is now possible as we gain access to more effective treatments," he added.

Also commenting on the findings, Matt Petersen, vice president of medical information and professional engagement at the American Diabetes Association, said: "It's helpful to have further evidence that weight loss reduces risk for type 2 diabetes."

However, "Finding effective strategies to achieve and maintain long-term weight loss and maintenance remains a significant challenge," he 

Large Database of Half a Million People With Obesity

For the research, anonymized data from over half a million patients documented in the Clinical Practice Research Datalink (CPRD) database, which holds information from 674 general practices in the UK, were linked to Hospital Episode Statistics and prescribing data to determine comorbidity outcomes.

At baseline, characteristics for the full study population included a median age of 54, around 50% of participants had hypertension, around 40% had dyslipidemia, and around 20% had type 2 diabetes. Less than 10% had sleep apnea, hip/knee osteoarthritis, or history of cardiovascular disease. All participants had a body mass index of 25.0–50.0 kg/m2 at the start of the follow-up, between January 2001 and December 2010.

Patients may have been advised to lose weight, or take more exercise, or have been referred to a dietician. Some had been prescribed antiobesity medications available between 2001-2010. (Novo Nordisk medications for obesity were unavailable during this period.) Less than 1% had been referred for bariatric surgery.

"This is typical of real-world management of obesity," Haase pointed out.

Participants were divided into two categories based on their weight pattern during the 4-year period: one whose weight remained stable (492,380 individuals with BMI change within –5% to +5%) and one who lost weight (60,573 with BMI change –10% to –25%).

The median change in BMI in the weight-loss group was –13%. The researchers also extracted information on weight loss interventions and dietary advice to confirm intention to lose weight.

The benefits of losing 13% of body weight were then determined for three risk profiles: BMI reduction from 34.5 to 30 kg/m² (obesity class I level); 40.3 to 35 kg/m² (obesity class II level), and 46 to 40 kg/m² (obesity class III level).

Individuals with a baseline history of any particular outcome were excluded from the risk analysis for that same outcome. All analyses were adjusted for BMI, age, gender, smoking status, and baseline comorbidities.

Study strengths include the large number of participants and the relatively long follow-up period. But the observational nature of the study limits the ability to know the ways in which the participants who lost weight may have differed from those who maintained or gained weight, the authors said.

Type 2 Diabetes, Sleep Apnea Showed Greatest Risk Reductions

The researchers looked at the risk reduction for various comorbidities after weight loss compared to before weight loss. They also examined the risk reductions after weight loss compared to someone who had always had a median 13% lower weight.

Effectively, the analysis provided a measure of the effect of risk reduction due to weight loss compared to having that lower weight as a stable weight.

"The analysis asks if the person's risk was reversed by the weight loss to the risk associated with that of the lower weight level," explained Haase.

"We found that the risks of type 2 diabetes, dyslipidemia, and hypertension were reversed while the risk of sleep apnea and hip/knee osteoarthritis showed some residual risk," she added.

With sleep apnea there was a risk reduction of up to 27% (compared to before weight loss).

"This is a condition that can't be easily reversed except with mechanical sleeping devices and it is under-recognized and causes a lot of distress. There's actually a link between sleep apnea, diabetes, and hypertension in a two-way connection," noted Finer, who is also honorary professor of cardiovascular medicine at University College, London, UK.

"A reduction of this proportion is impressive," he stressed.

Dyslipidemia, hypertension, and type 2 diabetes are well-known cardiovascular risk factors. "We did not see any impact on myocardial infarction," which "might be due to length of follow-up," noted Haase.

Response of Type 2 Diabetes to Weight Loss

Most patients in the study did not have type 2 diabetes at baseline, and Finer commented on how weight loss might affect type 2 diabetes risk.

"The complications of obesity resolve with weight loss at different speeds," he said.

"Type 2 diabetes is very sensitive to weight loss and improvements are obvious in weeks to months."

In contrast, reductions in risk of obstructive sleep apnea "take longer and might depend on the amount of weight lost." And with osteoarthritis, "It's hard to show improvement with weight loss because irreparable damage has [already] been done," he explained.

The degree of improvement in diabetes due to weight loss is partly dependent on how long the person has had diabetes, Finer further explained. "If someone has less excess weight then the diabetes might have had a shorter duration and therefore response might be greater."

Lucy Chambers, PhD, head of research communications at Diabetes UK, said: "We've known for a long time that carrying extra weight can increase your risk of developing type 2 diabetes, and this new study adds to the extensive body of evidence showing that losing some of this weight is associated with reduced risk." 

She acknowledged, however, that losing weight is difficult and that support is important: "We need government to urgently review provision of weight management services and take action to address the barriers to accessing them."

Finer and Haase are both employees of Novo Nordisk. Le Roux has reported no relevant financial relationships.

ECOICO 2020. Presented September 1-4, 2020. Abstract 0497.

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Κυριακή, 13 Σεπτεμβρίου 2020

ATEZOLIZUMAB FAILURE IN PHASE III BREAST CANCER TRIAL

Atezolizumab (Tecentriq) plus paclitaxel is ineffective in patients with previously untreated, inoperable, locally advanced or metastatic triple-negative breast cancer (TNBC), according to an alert from the Food and Drug Administration.

The FDA said the phase 3 IMpassion131 trial showed that atezolizumab plus paclitaxel did not significantly reduce the risk of cancer progression and death, when compared with paclitaxel plus placebo, in programmed death-ligand 1 (PD-L1)–positive patients.

"Additionally, interim overall survival results favored paclitaxel plus placebo over paclitaxel plus atezolizumab in both the PD-L1-positive population and total population," the FDA noted.

As a result, "health care professionals should not replace paclitaxel protein-bound (Abraxane) with paclitaxel in clinical practice," the FDA advised.

Atezolizumab is approved for use in combination with protein-bound paclitaxel, also known as nanoparticle albumin–bound paclitaxel (nab-paclitaxel), to treat patients with unresectable, locally advanced, or metastatic TNBC whose tumors express PD-L1, as detected by an FDA-approved test. The combination was granted accelerated approval for this indication last year.

Atezolizumab plus nab-paclitaxel is the combination most often used in PD-L1-positive TNBC, as opposed to atezolizumab and unbound paclitaxel, said Melinda L. Telli, MD, an associate professor of medicine and director of the Stanford Cancer Institute Breast Cancer Program at Stanford (Calif.) University.

However, as the FDA noted, "continued approval of atezolizumab in combination with [nab-paclitaxel] may be contingent on proven benefit of the treatment in additional trials."

Dr. Telli explained that atezolizumab was granted accelerated approval for the treatment of PD-L1-positive TNBC based on results of the phase 3 IMpassion130 trial, which compared nab-paclitaxel plus atezolizumab with nab-paclitaxel plus placebo.

"Additional data from IMpassion131 was hoped to be used to support the conversion of the accelerated approval to a full approval. Since IMpassion131 was negative, it unfortunately places the status of atezolizumab in [TNBC] in jeopardy as the benefits were not corroborated. The FDA may move to revoke the approval of atezolizumab for [TNBC]," Dr. Telli said.

In its alert, the FDA stated that it "will review the findings of IMpassion131 and will communicate new information regarding the IMpassion131 results and any potential changes to prescribing information."

"We need to wait for full presentation and publication of the study results, but, in my assessment, the negative results in IMpassion131 are most likely due to differences in patient selection [from IMpassion130]," Dr. Telli said.

Results from IMpassion131 are scheduled to be presented at the ESMO Virtual Congress 2020.

The IMpassion trials were funded by Roche, maker of atezolizumab. Dr. Telli disclosed relationships with AbbVie, AstraZeneca, Merck, PharmaMar, Pfizer, and Tesaro.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

ADJUVANT THERAPY FOR MELANOMA

Adjuvant therapy for patients with high-risk resected melanomas is now a standard of care, but the durability of the benefit gained from this treatment is still unclear.

New data show that the benefit is maintained over the longer term.  

At 5 years, just over half of patients (52%) with advanced melanoma who had received a year of adjuvant therapy with two targeted agents were still alive and remained relapse-free, compared with 36% of patients who received placebo.

The combination of dabrafenib (Tafinlar) and trametinib (Mekinist)  conferred a durable long-term, relapse-free survival benefit for patients with resected stage III melanoma with BRAF V600E or V600K mutations, the investigators concluded.

These data come from the COMBI-AD phase 3 trial and were published onlinetoday in the New England Journal of Medicine.

"The treatment duration of this adjuvant therapy was 12 months; however, we do not know whether this is the optimal treatment duration," said lead author Reinhard Dummer, MD, vice-chairman, Department of Dermatology, University of Zurich Hospital, Switzerland. "Early biomarker results suggest that in a subgroup, longer treatment durations might be necessary. In other patients, a shorter treatment could be sufficient."

Approached to comment on the study, Richard Carvajal, MD, director of Melanoma Service at NewYork-Presbyterian Hospital and Columbia University Medical Center in New York City, said the new data "address prior concerns that any benefit achieved with targeted therapy in the adjuvant setting may be limited in duration."

"Indeed, with active therapy, over 50% of patients are alive without relapse and 65% of patients are alive without the development of distant metastasis," he said. "Although overall survival data remain immature, numerical improvement in survival is also reported."

Carvajal told Medscape Medical News that the plateaus observed with relapse and distant metastasis-free survival suggest that true disease cures are being achieved with treatment. "Based upon these results, the discussion of adjuvant therapeutic options should include a 12-month course of adjuvant dabrafenib and trametinib, as well as the option of adjuvant anti-PD1 therapy," he said.

As for how the MEK-BRAF inhibitor combination compares to immunotherapy in this setting, he pointed out that since there has been no head-to-head comparison of adjuvant targeted therapy and adjuvant nivolumab (Opdivo) or pembrolizumab (Keytruda), it is not possible to conclusively state that one regimen is more effective than another.

"For patients with resected BRAF-mutant melanoma at high risk of disease recurrence, we now have data demonstrating the clinical benefit for a course of adjuvant dabrafenib and trametinib, adjuvant nivolumab and adjuvant pembrolizumab," said Carvajal"Although the efficacy of adjuvant ipilimumab [Yervoy] as well as adjuvant interferon have also been previously demonstrated, these agents are now appropriate for consideration in extremely rare clinical circumstances given the clinical efficacy and improved toxicity profile of single agent anti-PD1 therapy."

"The selection of the most appropriate adjuvant therapy should take into account the preferences of individual patients in terms of toxicity profile and drug administration considerations," he added. 

Study Details

The COMBI-AD was a randomized, double-blind, placebo-controlled, phase 3 study conducted in 870 patients with high-risk, stage III, BRAF-V600E/K-mutant melanoma who were treatment naive. Participating patients had undergone surgical resection and had been disease free for ≤12 weeks.

Interim results from this study, reported in 2017, showed 1 year of oral adjuvant therapy with dabrafenib and trametinib provided a 53% lower risk for 3-year recurrence compared with placebo.

Now, the investigators report on the 5-year results for relapse-free survival and survival without distant metastasis. They note that they were unable to analyze overall survival since the required number of events had not been reached.

Patients had been randomly assigned to receive 12 months of oral dabrafenib (at a dose of 150 mg twice daily) plus trametinib (2 mg once daily) or two matched placebos. Patients were followed for 60 months (5 years) for dabrafenib plus trametinib and 58 months for placebo.

At 5 years, the median relapse-free survival was not reached for patients who received the combination therapy group vs 16.6 months in the placebo group (hazard ratio [HR] for relapse or death, 0.51).

The percentage of patients who were alive without distant metastasis at 5 years was 65% in the dabrafenib plus trametinib group and 54% in the placebo arm (HR for distant metastasis or death, 0.55).

The hazard ratio for relapse-free survival favored dabrafenib plus trametinib across all patient subgroups that were evaluated in the study, and survival without distant metastasis showed a similar benefit for the combination regardless of disease stage.

Subsequent therapy was needed in 40% of patients who received dabrafenib + trametinib and by 54% of those in the placebo group, with the most common treatments being immunotherapy in the combination-therapy group [26%] and small-molecule targeted therapy in the placebo group (35%).

A Viable Option

Dummer noted that when this clinical trial was designed, all patients had to undergo aggressive surgery that involved lymph node dissection. "Nowadays, based on the lack of improvement on progression-free survival and overall survival, the surgical procedures are less aggressive and today we do not recommend aggressive lymph node dissection in patients that qualify for adjuvant therapy," he said. "In patients that do not have the BRAF mutation, there is the possibility of giving immunotherapy."

He added that there is an urgent need for biomarkers that can identify early progression during adjuvant therapy. "Potentially, these patients would profit from immunotherapy alone or from combination using targeted therapy and immunotherapy," Dummer said.

The study was funded by GlaxoSmithKline and Novartis. Dummer has declared multiple relationships with industry as noted in the original article.

N Eng J Med. Published online September 2, 2020. Abstract

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URINE TEST FOR BLADDER CANCER

An assay using methylation markers may offer an alternative to more costly, invasive methods for bladder cancer (BCa) detection and surveillance, according to a new study.

"Urine tumor DNA methylation assessment for early diagnosis, minimal, residual tumor detection and surveillance in bladder cancer is a rapid, high-throughput, non-invasive and promising approach, which may reduce the burden of cystoscopy and blind second surgery," Dr. Tianxin Lin of Sun Yat-sen University in Guangzhou, China, and colleagues write in the Journal of Clinical Investigation.

About three-quarters of patients with BCa have non-muscle-invasive (NMIBC) disease, and most of these will recur, the authors note. Cystoscopy and cytology are the gold standard for monitoring patients, they add, although cytology has low sensitivity, particularly for low-grade disease.

While UroVysion fluorescence in situ hybridization (FISH) is more sensitive, it is also less sensitive for low-grade tumors. For patients with high-grade and T1 disease, repeated transurethral resection of bladder tumor (re-TURBT) is recommended, but there is currently no way to determine which patients have residual disease, according to the authors.

DNA-methylation assays tested in Europe have shown promise for monitoring BCa recurrence, they add, but have not been validated in large Asian cohorts.

The team developed the MassARRAY (utMeMA) using 26 markers identified from bladder tumors and normal tissue from three patient cohorts. Validation identified 25 methylation markers in tumor tissue and matched urine samples, but not in normal tissue, while 23 of the markers in urine were significantly correlated with matched tumor tissue.

The researchers trained and tested their diagnostic model in 313 samples and validated it in 175 samples.

A model with two of the markers had a sensitivity of 88% in the training dataset, 90% in the test dataset, and 92% in the validation dataset, with a specificity of 86%, 84% and 77%, respectively.

Among 251 BCa patients, utMeMA was four times as sensitive as cytology (69.2% vs. 16.0%) and three times more sensitive than FISH (69.2% vs. 22.2%) for detecting low-grade tumors. The model was also more sensitive than cytology or FISH for patients with Ta or T1 disease, high-grade disease or muscle-invasive bladder cancer. Cytology and FISH were more specific than uTMeMA, but not significantly so.

Forty-seven patients in the modeling and validation cohorts underwent re-TURBT, with samples available before surgery. Fifteen had residual tumor, which was correctly diagnosed by utMeMA in 14 patients (93%), versus three of 11 patients with cytology (27%) and nine of 14 with FISH (64%).

"Our approach achieved a great improvement in sensitivity over urine cytology and FISH, especially in the detection of early-stage, minimal, residual and recurrent tumors. Therefore, it is adopted in the optional clinical detection of BCa by more than 10 hospitals in China. A large-scale, multicenter and prospective clinical trial (NCT04314245) is ongoing to validate its clinical applicability in China," the authors write.

The authors report no conflicts of interest and no commercial funding.

Dr. Lin was not available for an interview by press time.

SOURCE: https://bit.ly/3hFdFZQ Journal of Clinical Investigation, online August 20, 2020.

SECOND LINE CHMEOTHERAPY FOR SCLC

As reported in The Lancet Oncology by Baize et al, a French phase III trial has shown significant improvement in progression-free survival with second-line carboplatin plus etoposide vs topotecan in patients with chemotherapy-sensitive relapsed small cell lung cancer.

As noted by the investigators, topotecan is currently the only drug approved in Europe for second-line treatment of small cell lung cancer.

Study Details

The open-label multicenter trial enrolled patients with advanced or locally relapsed disease who had responded to first-line platinum plus etoposide treatment and had relapse or progression at ≥ 90 days after completion of first-line treatment. A total of 162 patients (intent-to-treat population) were randomly assigned between July 2013 and July 2018 to a maximum of six 3-week cycles of carboplatin at AUC 5 on day 1 plus etoposide at 100 mg/m² from day 1 to day 3 (n = 81) or oral topotecan at 2.3 mg/m² from day 1 to day 5. The primary endpoint was progression-free survival on central review.

Progression-Free Survival

Median follow-up was 22.7 months. Median progression-free survival was 4.7 months (90% confidence interval [CI] = 3.9–5.5 months) in the combination group vs 2.7 months (90% CI = 2.3–3.2 months) in the topotecan group (hazard ratio [HR] = 0.57, 90% CI = 0.41–0.73; = .0041).

Among the 156 patients with available data, 58% of the combination group and 68% of the topotecan group received third-line chemotherapy after study treatment. Median overall survival was 7.5 months (95% CI = 5.4–9.5 months) in the combination group vs 7.4 months (95% CI = 6.0–8.7 months) in the topotecan group (HR = 1.03, 95% CI = 0.87–1.19, = .94).

Objective response was observed in 49% vs 25% of patients (= .0024) and median duration of response was 5.4 months vs 4.1 months. At 6 months, 31% vs 10% of patients had not experienced a disease progression event.

Adverse Events

The most frequent grade 3 or 4 adverse events were neutropenia (14% in the combination group vs 22% in the topotecan group), thrombocytopenia (31% vs 36%), anemia (25% vs 21%), febrile neutropenia (6% vs 11%), and asthenia (9% vs 10%). Serious adverse events with hospitalization occurred in 37% vs 43% of patients.

Treatment-related adverse events led to treatment discontinuation in 17% vs 12% of patients, with the most common cause being thrombocytopenia. Two treatment-related deaths occurred in the topotecan group—both due to febrile neutropenia with sepsis—and none occurred in the combination group.

The investigators concluded, “Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small cell lung cancer.”


PROGNOSTIC GENE SIGNATURE FOR OVARIAN CANCER?

A new gene expression signature could improve on conventional risk factors when it comes to estimating prognosis and selecting treatment in patients with high-grade serous ovarian cancer, according to a study published in Annals of Oncology.

"Gene expression signature tests for prognosis are available for other cancers, such as breast cancer, and these help with treatment decisions, but no such tests are available for ovarian cancer," senior investigator Susan J. Ramus, PhD, of Lowy Cancer Research Centre, University of NSW Sydney, commented in an interview.

Dr. Ramus and associates developed and validated their 101-gene expression signature using pretreatment tumor tissue from 3,769 women with high-grade serous ovarian cancer treated on 21 studies.

The investigators found this signature, called OTTA-SPOT (Ovarian Tumor Tissue Analysis Consortium–Stratified Prognosis of Ovarian Tumors), performed well at stratifying women according to overall survival. Median overall survival times ranged from about 2 years for patients in the top quintile of scores to more than 9 years for patients in the bottom quintile.

Moreover, OTTA-SPOT significantly improved prognostication when added to age and stage.

"This tumor test works on formalin-fixed, paraffin-embedded tumors, as collected routinely in clinical practice," Dr. Ramus noted. "Women predicted to have poor survival using current treatments could be included in clinical trials to rapidly get alternative treatment. Many of the genes included in this test are targets of known drugs, so this information could lead to alternative targeted treatments.

"This test is not ready for routine clinical care yet," she added. "The next step would be to include this signature as part of a clinical trial. If patients predicted to have poor survival are given alternative treatments that improve their survival, then the test could be included in treatment decisions."

Study Details 

Dr. Ramus and colleagues began this work by measuring tumor expression of 513 genes selected via meta-analysis. The team then developed a gene expression assay and a prognostic signature for overall survival, which they trained on tumors from 2,702 women in 15 studies and validated on an independent set of tumors from 1,067 women in 6 studies.

In analyses adjusted for covariates, expression levels of 276 genes were associated with overall survival. The signature with the best prognostic performance contained 101 genes that were enriched in pathways having treatment implications, such as pathways involved in immune response, mitosis, and homologous recombination repair.

Adding the signature to age and stage alone improved prediction of 2- and 5-year overall survival. The area under the curve increased from 0.61 to 0.69 for 2-year overall survival and from 0.62 to 0.75 for 5-year overall survival (with nonoverlapping 95% confidence intervals for 5-year survival).

Each standard deviation increase in the gene expression score was associated with a more than doubling of the risk of death (hazard ratio, 2.35; P < .001).

The median overall survival by gene expression score quintile was 9.5 years for patients in the first quintile, 5.4 years for patients in the second, 3.8 years for patients in the third, 3.2 years for patients in the fourth, and 2.3 years for patients in the fifth.

This study was funded by the National Institutes of Health/National Cancer Institute, the Canadian Institutes for Health Research, and the Department of Defense Ovarian Cancer Research Program. Some of the authors disclosed financial relationships with a range of companies. Dr. Ramus disclosed no conflicts of interest.

SOURCE: Millstein J et al. Ann Oncol. 2020 Sep;31(9):1240-50.

This article originally appeared on MDedge.com, part of the Medscape Professional Network.

IPILIMUMAB FOR PROSTATE CANCER?

Treatment with ipilimumab following radiotherapy to bone metastases in men with metastatic castration-resistant prostate cancer (mCRPC) who previously received docetaxel is associated with improved overall survival, according to final results from the CA184-043 trial.

"This should prompt us to start revisiting immunotherapy in mCRPC," Dr. Karim Fizazi of Institut Gustav Roussy, University of Paris Saclay, in Villejuif, told Reuters Health by email. "Using immunotherapy was almost stopped 5 years ago after two phase-3 trials had failed to demonstrate overall survival improvement. These data indicate that some men clearly benefit and also that early assessments of survival may not be appropriate to assess immunotherapy benefits."

The monoclonal antibody ipilimumab blocks the inhibitory signal mediated by CTLA-4, thereby enhancing antitumor immunity at the expense of immune-related side effects. In earlier trials, including 043, ipilimumab significantly improved progression-free survival but not overall survival.

In the current study, Dr. Fizazi and colleagues evaluated mature results of the 043 trial with an additional two years of follow-up beyond the primary analysis.

The analysis included all 799 participants in the study, including 399 men in the ipilimumab arm and 400 men in the placebo arm.

Overall, 49 men in the ipilimumab group and 29 men in the placebo group remained alive, with a median follow-up of 50 months for the survivors, the researchers report in European Urology.

Overall survival curves crossed between seven and eight months, after which survival in the ipilimumab arm remained superior to that in the placebo arm. Median overall survival was 11.0 months with ipilimumab, compared with 10.0 months with placebo.

Overall survival rates were significantly higher in the ipilimumab arm than in the placebo arm at two years (25% vs. 17%), three years (15% vs. 7.9%), four years (10% vs. 3.3%) and five years (7.9% vs. 2.7%).

The safety profile for ipilimumab was similar to that reported previously, with immune-related adverse events affecting mostly the gastrointestinal tract and skin and, to a lesser extent, the liver and endocrine organs. Most of these events occurred during the initial four doses of ipilimumab.

"It's becoming key to identify biomarkers predicting immunotherapy benefits," Dr. Fizazi said. "This long-term analysis clearly suggests that only about 10% of men with mCRPC derive major long-term benefits from CTLA-4 targeted immunotherapy."

"Given the side effects of this treatment, it makes no sense treating 10 patients to get only one potentially benefiting," he said. "Fortunately, potential biomarkers (MSI status, cdk12 loss, perhaps tumor mutation burden, etc.) seem to be emerging."

"This should prompt the pharma industry and academia to stop conducting randomized trials in all-comer mCRPC men and rather to preselect subgroups based on biomarkers, to show more meaningful improvements," Dr. Fizazi concluded.

Dr. Russell Pachynski of Washington University, in St. Louis, Missouri, who specializes in prostate cancer, told Reuters Health by email, "Since there's no (US or EU) approval for checkpoint-inhibitor immunotherapy in prostate cancer, (the new finding) doesn't practically change what most providers will or should do."

"But," he added, "there are retrospective data from the only approved immunotherapy for prostate cancer, sipuleucel-T, suggesting that using immunotherapy earlier (i.e., at lower PSA) results in larger improvements in survival from the drug. So, the data looking at the 'good prognosis' patients is supportive of that general concept, that is, using immunotherapy earlier."

"After many trials looking at checkpoint immunotherapy in metastatic prostate cancer didn't show much benefit, a lot of focus was placed on tumor types that were generally more responsive to these drugs," he explained. "This report shows that there is some - albeit small - long-term survival benefit to single-agent immunotherapy in these patients."

"The trick will be improving this using combinations of drugs, and this is going on in a number of trials," Dr. Pachynski said. "So, lots of work to do in prostate-cancer immunotherapy, but we're starting to see some benefit!"

He added, "We need to be smarter about how to optimize immunotherapy in prostate cancer, now that we've seen some but small benefit of single agent checkpoint inhibitors in metastatic prostate cancer. Perhaps focusing less on T cell-based therapies and more on those targeting the myeloid or innate components and thinking more about how to favorably alter the bone tumor microenvironment, which comprises the majority of metastatic sites in these patients."

Dr. Guru P. Sonpavde of Dana Farber Cancer Institute, Harvard Medical School, in Boston, who also studies prostate cancer, told Reuters Health by email, "These data suggest that a subset of patients with mCRPC may enjoy delayed benefit from ipilimumab. However, this final analysis is not practice-changing, given the negative initial analysis."

"The data are clearly intriguing, and further rational development of ipilimumab and other immunotherapeutics in rationally selected mCRPC patients guided by accumulating data for precision medicine may be warranted," he said.

"The development of a role for immunotherapeutics (and other agents) should proceed concurrently with developing predictive biomarkers of benefit," added Dr. Sonpavde, who was not involved in the study.

Bristol-Myers Squibb funded the trial, employed two of the authors and had various relationships with several others, including Dr. Fizazi, and with Dr. Sonpavde.

SOURCE: https://bit.ly/34OiVXP European Urology, online August 15, 2020.

MET AND RET INHIBITORS APPROVED

The first targeted therapy for patients with advanced non–small cell lung cancer (NSCLC) harboring MET mutations, capmatinib (Tabrecta), has shown deep and durable responses, conclude investigators of the pivotal trial that led to the drug's approval. Responses were seen in all patients regardless of how many previous drugs they had been treated with, although responses were particularly pronounced among patients who were treatment naive.

Capmatinib and a companion assay received FDA approval in May 2020 for the treatment of adults with metastatic NSCLC harboring MET exon 14 skipping mutations.

These MET mutations occur in 3% to 4% of NSCLC patients; MET amplifications occur in 1% to 6% of NSCLC patients. They have been associated with poor response to chemotherapy and immunotherapy.

"Prior to the this approval, there weren't any approved therapies for this group of patients," noted Edward Garon, MD, associate professor of hematology and oncology at the David Geffen School of Medicine at the University of California, Los Angeles, who led the pivotal trial.

"There are several drugs that have been used off label for MET exon 14 skipping mutations, but none with an indication for it," he told Medscape Medical News.

Garon emphasized that capmatinib was particularly robust for patients who had not received prior therapy, although he added that it was also very effective or those who had been previously treated.

"The drug has been approved and it is available, and we have already written prescriptions for it at our clinic," said Garon, "although at our clinic, the majority of patients using it were part of the [pivotal] clinical trial."

That trial is the phase 2 GEOMETRY mono-1 study. Results from the study were presented at a meeting earlier this year and have now been published in the The New England Journal of Medicine.

It was conducted in a cohort of 364 patients with advanced NSCLC. Patients were stratified into five cohorts and two expansion cohorts, which were assigned according to MET status and previous lines of therapy. Across cohorts 1 through 5, a total of 97 patients had a MET exon 14 skipping mutation, and 210 had MET amplification. All patients were treated with capmatinib 400 mg twice daily.

Among patients with a MET exon 14 skipping mutation, an overall response was observed in 41% of previously treated patients and in 68% of those who had not previously been treated.

"That is a very high response rate, and clearly this drug is targeting this mutation," said Fred Hirsch, MD, PhD, executive director, Center for Thoracic Oncology, Mount Sinai Health System, New York City, who was approached for comment. "It's very active, and you don't get those response with chemotherapy.The median duration of response was 9.7 months among previously treated patients and 12.6 months among those who were treatment naive. Median progression-free survival (PFS) was 5.4 months and 12.4 months, respectively.

In the cohort of patients with MET amplification, the overall response was 12% among those whose tumor tissue had a gene copy number of 6 to 9. The overall response rate was 9% among those with a gene copy number of 4 or 5, and it was 7% among those with a gene copy number of less than 4.

Median PFS was 2.7 months for patients whose tumor tissue had a gene copy number of 6 to 9 and in those with a gene copy number of 4 or 5. PFS rose to 3.6 months for patients with a gene copy number of less than 4.

The most frequently reported adverse events were peripheral edema (in 51%) and nausea (in 45%); these events were mostly of grade 1 or 2. Treatment-related serious adverse events occurred in 13% of patients. The incidence was lower in the groups with shorter duration of exposure. Treatment was discontinued in 11% of patients (consistent across cohorts) because of adverse events.

Hirsh commented to Medscape Medical News that the results for patients with NSCLC and brain metastases were particularly noteworthy. "Brain metastases are, unfortunately, a common problem in patients with lung cancer," he commented. "Now we have a drug that is effective for MET mutation and CNS involvement and can penetrate the blood-brain barrier, and this is a very encouraging situation."

He pointed out that 7 of 13 patients with brain metastases responded to treatment with capmatinib. "Four patients have a complete response, and that is very encouraging," said Hirsch. "This is clearly a deal breaker in my opinion."

The Future Is Bright 

Hirsch noted that the evidence supporting capmatinib is strong, even though a larger prospective study with a control group is lacking. "If we have a patient with this mutation, and knowing that there is a drug with a response rate of 68%, that is a good reason to try the drug up front," he said. "The data are sufficient that it should be offered to the patient, even without a control group."

Capmatinib is the latest of many targeted drugs that have been launched in recent years, and several immunotherapies are also now available for treatment of this disease. These new therapies are making this is a "very encouraging time in lung cancer," Hirsch commented.

"We are seeing long-term survival, and eventually we may start seeing potential cures for some patients," he said. "But at the very least, we are seeing very good long-term results with many of these targeted therapies, and we are continuing to learn more about resistant mechanisms.

"I can't wait to see future in the field," Hirsch added.

The study was funded by Novartis Pharmaceuticals. Garon reports consulting or advisory roles with Dracen and research funding (institutional) from Merck, Genentech, AstraZeneca, Novartis, Lilly, Bristol-Myers Squibb, Mirati Therapeutics, Dynavax, Iovance Biotherapeutics, and Neon Therapeutics. His coauthors have disclosed numerous relationships with industry, as listed in the original article. Hirsch has disclosed no relevant financial relationships.

N Engl J Med. Published online September 3, 2020. Abstract

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A second drug is now available in the United States for use in the treatment of patients with metastatic non–small cell lung cancer (NSCLC) that tests positive for rearranged during transfection (RET) fusions.

The new drug is pralseltinib (Gavreto). The US Food and Drug Administration (FDA) granted it an accelerated approval for this indication on the basis of response rate data. Continued approval for this indication depends on clinical benefit in a confirmatory trial.

It joins selpercatinib (Retevmo), which was approved in the United States in May 2020 as the first RET-targeted therapy. Selpercatinib is also indicated for use in RET+ NSCLC and was approved for use RETmedullary thyroid cancer and RETthyroid cancer.

Pralseltinib is still awaiting approval for these thyroid cancer indications.

Both drugs are taken orally; pralseltinib is taken once daily, and selpercatinib is taken twice daily.

For both drugs, before treatment is initiated, laboratory testing is needed to show that an RET gene alteration is present in the tumor.

RET fusions are found in approximately 1% to 2% of patients with NSCLC.

They are the latest of a number tumor-specific gene alterations found in NSCLC and that are targeted with an approved drug.

"Targeted therapies have dramatically improved care for patients with non–small cell lung cancer driven by oncogenes, including EGFR and ALK, and the approval of the selective RET inhibitor pralsetinib marks another milestone in a paradigm shift toward precision medicine," commented Vivek Subbiah, MD, medical director of the Clinical Center for Targeted Therapy at the University of Texas MD Anderson Cancer Center, Houston, Texas.

Subbiah was an investigator of the phase 1/1 clinical trial known as ARROW, which provided the data on which the accelerated approval was based. In this trial, patients with NSCLC with RET+ tumors were found by testing with next-generation sequencing, FISH (fluorescence in situ hybridization), or other methods.

The ARROW trial involved one cohort of 87 patients who had previously been treated with platinum-based chemotherapy. In these patients, the overall response rate (ORR) was 57%, and the complete response (CR) rate was 5.7%. The median duration of response (DOR) was not estimable, according to the manufacturer.

The trial also involved 27 treatment-naive patients who were ineligible for platinum-based chemotherapy per the study protocol. In this group, the ORR was 70%, and the CR rate was 11%. The median DOR was 9.0 months.

"Patients treated with pralseltinib had durable clinical responses, with a subset achieving complete responses characterized by the resolution of all target lesions, an uncommon outcome in metastatic lung cancer," Subbiah commented in a company press release.

"We observed this activity with or without prior therapy and regardless of RETfusion partner or the presence of brain metastases. This approval represents an important advance with the potential to change standards of care for patients with RET fusion-positive NSCLC, who have historically had limited treatment options," he added.

Product information for pralseltinib has warnings and precautions of interstitial lung disease/pneumonitis, hypertension, hepatotoxicity, hemorrhagic events, risk for impaired wound healing, and risk for embryo-fetal toxicity.