Κυριακή, 18 Οκτωβρίου 2020

DO NOT FORGET BIOMARKER TESTING

Patients with cancers who could be treated with targeted drugs are sometimes not being tested for genetic mutations and other biomarkers that would identify them as candidates.

"Testing rates lag behind clinical guidelines and advancements in the field," according to a white paper from the American Cancer Society Cancer Action Network (ACS CAN) and the LUNGevity Foundation, preventing "cancer patients from receiving therapies that could [improve] outcomes," the authors write.

One example is testing for epidermal growth factor receptor (EGFR) mutations in patients with non–small cell lung cancer (NSCLC), which identifies candidates for drugs such as erlotinib. In community oncology practices across the United States, fewer than 50% of eligible patients were tested for EGFR in 2016, several years after such testing became standard of care.

Another example is biomarker testing for patients with metastatic colorectal cancer (CRC), which is recommended in clinical guidelines; from 2013 to 2017, only 40% of patients in academic and community settings were tested.

A larger overview is provided by a survey conducted by the ACS CAN in May/June 2020, which included 933 cancer patients and survivors. Only 39% reported that they had undergone biomarker testing; a further 25% were unsure. Among 13% of respondents who discussed biomarker testing but who were not tested, almost a third declined because insurance would not cover it or their out-of-pocket costs were too high.

Insurance coverage is a major hurdle.

"Without coverage, patients will not have access," the ACS CAN and the LUNGevity Foundation point out.

Coverage has been increasing overall, especially for single analyte companion diagnostics approved with new therapeutics, but it "differs greatly across the multiple public and private payers in the US health care system," the groups comment.

The problem is particularly acute with regard to panels that check hundreds of genes for mutations at a time. Many of the findings from such testing are actionable, but others currently have no known utility. As a result, some payers consider the entire panel to be experimental or investigational, and they don't cover it.

That needs to change, the groups say: "Payers should provide coverage for multi-gene panel testing as indicated by NCCN [National Comprehensive Cancer Network] guidelines, when it is more efficient, when a single analyte test does not exist, or when tissue availability is too limited for use of multiple single analyte testing."

Multigene panels are sometimes the only approved companion diagnostic for a targeted therapy. One example is capmatinib (Tabrecta), recently approved for NSCLC with mutations that lead to mesenchymal-epithelial transition exon 14 skipping. The only FDA-approved companion diagnostic is the Foundation One CDx assay (F1CDx), which tests 324 genes, the findings for many of which are at present inactionable.

Some commercial payers do cover F1CDx; the number of such payers has "increased substantially" since the last review in 2018, the white paper notes. However, numerous payers, including Aetna, United, and most BlueCross BlueShield, still consider large multigene panels as experimental and investigational, "most certainly due to the number of genes included that are felt to be inactionable."

NSCLC "may be a specific case," in that there are enough actionable biomarkers for some payers to agree to cover multigene next-generation sequencing panels. "However, breast cancercolon cancer, and prostate cancer do not have an adequate number of biomarkers with established utility to warrant coverage of large panels among many payers," the groups say.

ACS CAN and the LUNGevity Foundation also call for commercial payers to cover testing for tumor-agnostic biomarkers, as medically appropriate.

Tumor site agnostic biomarkers include neurotrophic receptor tyrosine kinase (NTRK) gene fusions, for which two targeted drugs are approved ― entrectinib (Rozlytrek) and larotrectinib (Vitrakvi).

Other biomarkers include high tumor mutational burden (TMB-H), high microsatellite instability (MSI-H), and homologous recombination deficiency (HRD).

At present, the immunotherapy pembrolizumab (Keytruda) is approved for use in tumors with MSI-H, mismatch repair deficient (dMMR), or TMB-H indications.

Tumor site agnostic biomarkers are uncommon, but when they are found, targeted treatment can be effective and improve outcomes compared to traditional chemotherapy.

Even so, testing for them is problematic.

NTRK is routinely covered as a specific biomarker by immunohistochemistry, "which is suboptimal," the white paper notes, but NTRK sequencing as well as HRD are generally only available as part of a multigene panel. If the multigene panel test is not covered, then patients with these relatively uncommon disorders are not identified, and they "don't receive the optimal treatment for their malignancy."

"This is even more of an issue" for MSI-H and TMB-H immunotherapy. MSI can be assessed without use of a multigene panel, but in general, TMB cannot.

"Consequently, the pan-tumor approval of the [immuno-oncology] companion therapy...is difficult in practice if panels are not covered. This paradox requires action," the report states.

The groups anticipate expanded coverage of multigene liquid biopsy tests following recent FDA approval of two.

One of the liquid biopsies is Guardant360 CDx, a companion diagnostic for osimertinib (Tagrisso) for identifying patients with NSCLC with targeted EGFR mutations. The other is FoundationOne Liquid CDx, approved for use with rucaparib (Rubraca) for identifying metastatic castration-resistant prostate cancer patients with appropriate BRCA1 and BRCA2 mutations.

Already, "the maturation of the evidence base for liquid biopsy coupled with challenges of biopsy tissue stewardship has resulted in some payer coverage," the report notes.

Biomarker Coverage: The Lay of the Land

Insurance coverage of biomarkers for targeted therapies has increased for some cancers but has remained flat for others, according a report from the American Cancer Society Cancer Action Network and the LUNGevity Foundation.

Non–Small Cell Lung Cancer

At present, for patients with NSCLC, most commercial payers cover select individual biomarkers, including EGFR, ALK, ROS1, BRAF, and NTRK. Some payers also cover KRAS. However, emerging biomarkers, such as HER2, RET, and MET, are covered by fewer payers.

Since the last review in 2018, tissue-based multigene panels for NSCLC are more widely covered, though there are still large gaps in coverage. There seems to be growing recognition by payers that sequential testing of individual biomarkers is not practical when the amount of available tissue is limited and because the results of these tests can inform urgent treatment decisions. Because of the increase in the number of individual actionable analytes in NSCLC, insurance companies are considering covering panels as the most expeditious and potentially most cost-effective approach.

Commercial payers recognize the value of liquid biopsies in NSCLC in certain clinical settings, most notably, in cases involving a patient who is medically unfit for invasive tissue sampling of a metastatic focus or in cases in which there is insufficient material for molecular analysis following pathologic confirmation of a NSCLC diagnosis.

Colorectal Cancer

All payers cover select individual biomarkers in CRC, and they are fairly consistent across plans. Generally, NRAS, KRAS, and BRAF are considered medically necessary. Few payers cover MSI and NTRK testing.

With rare exceptions, payers consider tissue-based multigene panels in CRC to be experimental and investigational, owing to the relative lack of actionable targets. Since the 2018 review, there has been little change in coverage of panels for CRC. Emerging evidence supporting the role of immuno-oncology therapy early in the treatment of metastatic colon cancer will increase the pressure on payers to cover panels.

Breast Cancer

Biomarkers indicated in breast cancer, including ER, PR, HER2, PD-L1, BRCA1, and BRCA2, are widely covered, as is PIK3CA via tumor tissue and liquid biopsy for its companion therapeutic, alpelisib (Piqray).

There has been little change in coverage of panels for breast cancer since 2018. Testing for NTRK fusions and mismatch repair is covered sparingly. Well-established prognostic breast cancer gene expression assays are covered by most payers. Consistent with National Comprehensive Cancer Network guidelines, some payers preferentially cover Oncotype DX Breast.

Prostate Cancer

Coverage of prognostic prostate cancer biomarkers, including AR-V7, and tumor-based molecular assays, including Decipher, OncotypeDx Prostate, Prolaris, and Promark, is inconsistent across payers. Although there is a new companion diagnostic paradigm for BRCA testing in prostate cancer, many payers have yet to update their policies.

Given the rapid expansion in knowledge of the significance of biomarkers in prostate cancer, it is likely that prostate cancer will be an area of increased clinical focus for panel testing. BRACAnalysis CDx and FoundationOne CDx are indicated for patients with metastatic castration-resistant prostate cancer (mCRPC) who may benefit from treatment with olaparib (Lynparza). FoundationOne Liquid CDx is indicated for mCRPC patients who may benefit from treatment with rucaparib (Rubraca).

Source: ACS CAN, LUNGevity Foundation: Payer Coverage Policies of Tumor Biomarker Testing. Full text

The white paper was commissioned by the American Cancer Society Cancer Action Network and the LUNGevity Foundation. LUNGevity's funders include Bristol-Myers Squibb, which manufactures several immunotherapies, and Genentech/Roche, manufacturer of entrectinib and owner of Foundation One Medicine. ACS funders include Merck, manufacturer of pemproblizumab, and Lilly, which has several targeted therapies..

ACS CAN and LUNGevity Foundation. Improving Access to Biomarker Testing. Full text

M. Alexander Otto is a physician assistant and award-winning medical journalist who has previously worked for several major news outlets, including McClatchy and Bloomberg BNA. He is a former MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.

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COVID NEWS

Mortality in patients with COVID-19 and cancer is associated with general clinical and demographic factors, cancer-specific factors, cancer treatment variables, and laboratory parameters, according to two presentations at the European Society for Medical Oncology Virtual Congress 2020.

Two analyses of data from the COVID-19 and Cancer Consortium (CCC19) were presented at the meeting.

The data suggest that older age, male sex, more comorbidities, poor performance status, progressive cancer or multiple cancers, hematologic malignancy, and recent cancer therapy are all associated with higher mortality among patients with cancer and COVID-19. Anti-CD20 therapy is associated with an especially high mortality rate, according to an investigator.

Among hospitalized patients, increased absolute neutrophil count as well as abnormal D-dimer, high-sensitivity troponin, and C-reactive protein are associated with a higher risk of mortality.

Prior analyses of CCC19 data pointed to several factors associated with higher COVID-19 death rates, according to Petros Grivas, MD, PhD, of University of Washington, Seattle, who presented some CCC19 data at the meeting. However, the prior analyses were limited by weak statistical power and low event rates, Grivas said.

Clinical and Laboratory Factors: Abstract LBA72

The aim of Grivas's analysis was to validate a priori identified demographic and clinicopathologic factors associated with 30-day all-cause mortality in patients with COVID-19 and cancer. Grivas and colleagues also explored the potential association between laboratory parameters and 30-day all-cause mortality.

The analysis included 3,899 patients with cancer and COVID-19 from 124 centers. Most centers are in the United States, but 4% are in Canada, and 2% are in Spain. About two-thirds of patients were 60 years of age or younger at baseline, half were men, 79% had solid tumors, and 21% had hematologic malignancies.

Cancer-specific factors associated with an increased risk of 30-day all-cause mortality were having progressive cancer (adjusted odds ratio, 2.9), receiving cancer therapy within 3 months (aOR, 1.2), having a hematologic versus solid tumor (aOR, 1.7), and having multiple malignancies (aOR, 1.5).

Clinical factors associated with an increased risk of 30-day all-cause mortality were Black versus White race (aOR, 1.5), older age (aOR, 1.7 per 10 years), three or more actively treated comorbidities (versus none; aOR, 2.1), and Eastern Cooperative Oncology Group performance status of 2 or more (versus 0; aOR, 4.6).

In hospitalized patients, several laboratory variables were associated with an increased risk of 30-day all-cause mortality. Having an absolute neutrophil count above the upper limit of normal doubled the risk (aOR, 2.0), while abnormal D-dimer, high-sensitivity troponin, and C-reactive protein all more than doubled the risk of mortality (aORs of 2.5, 2.5, and 2.4, respectively).

Further risk modeling with multivariable analysis will be performed after longer follow-up, Grivas noted.

Treatment-Related Outcomes: Abstract LBA71

An additional analysis of CCC19 data encompassed 3,654 patients. In this analysis, researchers investigated the correlation between timing of cancer treatment and COVID-19–related complications and 30-day mortality.

Mortality was highest among cancer patients treated 1-3 months prior to COVID-19 diagnosis, with all-cause mortality at 28%, said Trisha M. Wise-Draper, MD, PhD, of University of Cincinnati, when presenting the data at the meeting.

Rates for other complications (hospitalization, oxygen required, ICU admission, and mechanical ventilation) were similar regardless of treatment timing.

The unadjusted 30-day mortality rate was highest for patients treated most recently with chemoimmunotherapy (30%), followed by chemotherapy (18%), chemoradiotherapy (18%), and targeted therapy (17%).

The mortality rate was "particularly high," at 50%, in patients receiving anti-CD20 therapy 1-3 months prior to COVID-19 diagnosis — the time period for which significant B-cell depletion develops, Wise-Draper observed.

An analysis of disease status among 1,449 patients treated within 3 months of COVID-19 diagnosis showed mortality risk increasing from 6% among patients in remission or with newly emergent disease, to 22% in patients with any active cancer, to 34% in those with progressing disease, Wise-Draper said.

Discussant Benjamin Solomon, MD, PhD, of Peter MacCallum Cancer Centre in Melbourne, made note of the high 30-day mortality rate seen in patients receiving anti-CD20 therapy as well as the elevated standardized mortality ratios with recent chemoimmunotherapy and targeted therapy.

"Although there are some limitations of this analysis, it provides the best data we have to date about the effects of treatment on early mortality in patients with COVID-19 and cancer. It points to a modest but heterogeneous effect of treatment on outcome, one which is likely to become clearer with larger cohorts and additional analysis," Solomon said.

This research was funded by the American Cancer Society, Hope Foundation for Cancer Research, Jim and Carol O'Hare Fund, National Cancer Institute, National Human Genome Research Institute, Vanderbilt Institute for Clinical and Translational Research, and Fonds de Recherche du Quebec-Sante. Grivas disclosed relationships with many companies, but none are related to this work. Wise-Draper disclosed relationships with Merck, Bristol-Myers Squibb, Tesaro, GlaxoSmithKline, AstraZeneca, Shattuck Labs, and Rakuten. Solomon disclosed relationships with Amgen, AstraZeneca, Merck, Bristol-Myers Squibb, Novartis, Pfizer, and Roche-Genentech.

SOURCES: Grivas P et al. ESMO 2020, Abstract LBA72; Wise-Draper TM et al. ESMO 2020, Abstract LBA71.

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

PARP INHIBITORS FOR PROSTATE CANCER

For men with metastatic castration-resistant prostate cancer (mCRPC), any new therapy that offers the chance of a higher response rate or longer survival compared with the standard of the care would be welcome.

The US Food and Drug Administration (FDA) recently approved two such drugs for use in men with mCRPC: the poly (ADP-ribose) polymerase (PARP) inhibitors rucaparib (Rubraca) and olaparib (LynParza).

Both drugs were approved for use in the treatment of men with advanced prostate cancer with deleterious germline and/or somatic BRCA mutations following treatment with androgen receptor–directed therapy and taxane-based chemotherapy.

But there was difference in the wording of the indication that was approved, as noted by Michael T. Schweizer, MD, and colleagues from the Fred Hutchinson Cancer Research Center and the University of Washington in Seattle, Washington, in a recent commentary published in the Journal of Clinical Oncology.

Olaparib received wider approval for treatment of "deleterious or suspected deleterious germline or somatic homologous recombination repair gene (HRR)–mutated metastatic castration-resistant prostate cancer" with disease progression following therapy with either enzalutamide or abiraterone (Zytiga).

It's the "deleterious or suspected deleterious" part of that indication that has these experts concerned, inasmuch as this may lead to the drug being used injudiciously to treat some patients who might better be treated with other approaches.

"Using standard-of-care PARP inhibitors in those with uncertain or little chance of benefit could mean missing a window of opportunity for more effective therapy. This may result in decreased survival and hamper clinical trial enrollment to the very studies that could define the predictive utility of individual genes," they write.

Elaborating in an interview with Medscape Medical News, Schweizer said: "The issue is that olaparib has a long list of genes that would make you eligible to receive it, but it's not clear that many of these genes are good biomarkers for response to that drug."

Although the evidence for a response to PARP inhibitors for patients with BRCA mutations is fairly strong, there has not been sufficient evidence to date to suggest that responses would be adequate for patients with other HRR mutations, he said.

For patients who have "one of the less common HRR genes, maybe without high level of evidence that they are really predictive of response, I would still give careful consideration to some of the other drugs that have been around for a while and that we know have a track record of working well for prostate cancer, such as taxane-based chemotherapy," Schweizer commented.

Mark Pomerantz, MD, a geneticist and specialist in genitourinary oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts, who was not involved in the study, told Medscape Medical News that Schweizer and colleagues are "exactly right."

"The landmark studies leading to the approval of the two PARP inhibitors for prostate cancer were critical studies," Pomerantz said in an interview. "What they do not address, however, is the full expanse or limitation of patients who benefit the most from these drugs."

The editorial is "a call to action" for more extensive studies of specific mutations to see which may be sensitive to PARP inhibitors, he said.

"Permissive Biomarker Strategy"

In their commentary, Schweizer and colleagues note that the approval of olaparib includes several genes that have not been shown in clinical studies to be predictive of response to PARP inhibitors.

"The unintended consequence of using this permissive biomarker strategy for selecting patients for PARP inhibitor treatment may be that patients who have an unclear chance of benefit are exposed to toxicities and delays in utilizing more effective therapies," they write.

"In addition, this broad approval could hamper efforts to enroll patients in studies designed to better delineate the ability of relatively rare mutations to predict response to PARP inhibitors," they continue.

In the pivotal phase 2 TRITON2 trial, which led to rucaparib's accelerated approval for mCRPC, a preliminary analysis showed that the objective radiographic response rate among patients with BRCA-mutated mCRPC and measurable disease was 44%; for slightly more than half of the patients who responded, the duration of response was at least 6 months.

But as the TRITON2 investigators also reported in a separate analysis, "we found limited radiographic/PSA responses to PARP inhibition in men with alterations in ATM, CDK12, or CHEK2. However, patients with alterations in other DDR-associated genes (eg, PALB2) may benefit from PARP inhibition."

Olaparib was approved for mCRPC on the basis of the phase 3 randomized PROfound study. The trial had two cohorts: one for men with at least one alteration in BRCA1, BRCA2, and/or ATM, and one for men with alterations in any of 12 other prespecified genes.

The investigators reported in The New England Journal of Medicine in May 2020 that the trial met its primary progression-free survival endpoint for the BRCA/ATM mutation population, with a median of 7.4 vs 3.6 months for control patients (men assigned to receive the physician's choice of abiraterone or enzalutamide).

But as more recently reported, overall survival was significantly improved with olaparib for men in the BRCA/ATM cohort, but there was no significant survival benefit among men with other HRR gene mutations.

The editorial by Schweizer and colleagues was published a few weeks before these final PROfound results were reported at the European Society of Medical Oncology 2020 Virtual Congress. But even before these additional data were reported, they wrote the following:

"On the basis of the published studies, there are limited data to support use of olaparib in the absence of BRCA1/2 mutations, and without other indications of HR repair deficiency, these patients would be better served by participating in clinical trials or receiving a therapy that is beneficial in unselected patients (eg, taxane-based chemotherapy."

"Disease of Two Genomes"

Dana Farber's Pomerantz said that his center tries whenever possible to perform genetic profiles of mCRPC tumors, in addition to assessing the patient's genetic background.

"Cancer is a disease of two genomes," he explained. "We're always dealing with two genomes: the germline genome ― the genome that's inherited from your parents ― and the somatic genome, the deranged, mutated genome of the tumor."

He said that some germline and somatic DNA-damage repair mutations can make prostate tumors susceptible to PARP inhibition, but further trials are needed to determine the ultimate role of PARP inhibitors in advanced prostate cancer.

"I think there's still a big knowledge gap here," Schweizer said. "We need to really focus on clinical trials to better delineate which biomarkers are really appropriate for selecting patients for these drugs."

The commentary by Schweizer and colleagues was supported by a National Institutes of Health SPORE grant. Schweizer reported a consulting/advisory role for Janssen and Resverlogix and institutional research funding from several companies. Pomerantz has disclosed no relevant financial relationships.

J Clin Oncol. Published online September. 9, 2020. Full text

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SCIENTIFIC JOURNALS AGAINST TRUMP

Prominent medical and scientific journals have broken with tradition and taken a political stand, calling for a change in leadership in Washington, DC

Some are endorsing Joseph Biden Jr in his campaign to unseat President Donald Trump in the November election.

The move, which several editors acknowledge as unprecedented, may threaten the journals reputations as nonpartisan arbiters of science. But editors argue that the risk is warranted because the Trump administration is attacking the work of scientists, ignoring climate change, and bungling the response to the COVID-19 pandemic.

Dr Eric Rubin

"There is a pretty unanimous feeling, certainly among journal editors, but I think that reflects their readers, that things have gone badly wrong, and that it's important that we try to right things," Eric J. Rubin, MD, PhD, editor-in-chief of the New England Journal of Medicine, told Medscape Medical News.

"[O]ur current political leaders have demonstrated that they are dangerously incompetent" in the pandemic and should not be allowed to keep their jobs, Rubin wrote in an October 8 editorial. The journal has so far refrained from naming Trump in its editorials.

But today, Science published an editorial calling on scientists in general, and US Food and Drug Administration Commissioner Stephen Hahn in particular, to resist Trump's interference in COVID-19 vaccines and treatments.

And Scientific American, Nature, and The Lancet Oncology have all endorsed Biden by name, with Scientific American noting that this was its first endorsement in a US presidential campaign in the journal's 175-year history.

The White House did not immediately respond to a request for comment.

Dr Arthur Caplan

Taking political positions comes with peril for medical and professional journals, said Arthur Caplan, PhD, director of the Division of Medical Ethics at the New York University Grossman School of Medicine in New York City. "Many would argue that that's not the right forum," he told Medscape Medical News. "There are plenty of other places to express political points of view. There's a chance that they blur the line themselves between science and politics by speaking up."

However, Caplan says the journals are making the right call because they have an obligation to speak for scientists who have been "bullied" by the Trump administration.

Science editor H. Holden Thorp, PhD, who authored his journal's editorial, told Medscape Medical News that "I came out of my shell" in March when Trump tweeted that COVID-19 was no worse than the seasonal flu. "I thought the 'just the flu' tweet was incredibly dangerous," Thorp said, "because by that time, we were seeing enough of the basic science to know what a massive problem this is going to be."

Science cannot endorse political candidates, because it is part of the nonprofit American Association for the Advancement of Science, Thorp said. But he has followed up that first editorial with a stream of others criticizing the Trump administration.

And he sees the endorsements of Biden by the for-profit journals as no less valid than endorsements traditionally published by newspapers.

Speaking up can have consequences, said Eric Topol, editor-in-chief of Medscape. He first experienced blowback when he began warning about problems with the arthritis medication rofecoxib (Vioxx). "That taught me that there are a lot of hazards involved, because you're going up against, in that case, a very big company that wants to take you apart." Vioxx was eventually withdrawn from the worldwide market in September 2004.

Editorials can have an effect though. For example, Topol says that some of his more recent tweets and editorials have led him into direct conversations with FDA Commissioner Hahn and with representatives of Pfizer. And the Science editorial credits Topol with stiffening Hahn's resistance to the administration's meddling.

Topol, Thorp, and Rubin all said they had received vicious emails and tweets as a result of their recent positions, as well as moderate criticisms and many congratulations.

In the past, scientists may have stayed on the political sidelines out of concern that they might lose government funding. But with the Trump administration interfering in the scientific process, they feel they have little to lose, Thorp said. "If we're not going to play every card we have now, when would we?"

Will scientific journals snap back to their tradition of forbearance if a new administration shows more respect for science?

Caplan predicts they will, especially if new legal barriers can be erected to protect agencies like the FDA and CDC from political pressure. "I do think we're in extraordinary times, and the journals don't want to be political forums," he said.

But Thorp is not so sure that journals should ever pipe down. "I think, if anything, we should have been out there a little more in the past," he said. "But it took something like this to get folks to start saying things in a more courageous way."

Topol has disclosed financial relationships with Dexcom, Illumina, Molecular Stethoscope, Blue Cross Blue Shield, Quest Diagnostics, and MyoKardia. Thorp disclosed financial relationships with Artizan Biosciences and Hatteras Venture Partners. Rubin and Caplan have disclosed no relevant financial relationships.

Nature. Published online October 14, 2020

Scientific American. Published online October 1, 2020

N Engl J Med. Published online October 8, 2020

The Lancet Oncology. Published online October 2020.

Laird Harrison writes about science, health and culture. His work has appeared in national magazines, in newspapers, on public radio and on websites. He is at work on a novel about alternate realities in physics. Visit him at lairdharrison.com or follow him on Twitter: @LairdH.

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DIABETES FIRST LINE TREATMENT

It was no surprise that updated guidelines recently published by the European Society of Cardiology for managing cardiovascular disease in patients with diabetes highlighted optimized treatment from a cardiovascular disease perspective, while a nearly concurrent update from two major diabetes societies saw the same issue from a more glycemic point of view.

This difference led to divergent approaches to managing hyperglycemia in patients with type 2 diabetes (T2D). The two diabetes societies that wrote one set of recommendations, the American Diabetes Association and the European Association for the Study of Diabetes, put metformin at the pinnacle of their drug hierarchy. Patients with T2D and established atherosclerotic cardiovascular disease (CVD), chronic kidney disease, or heart failure should all receive metformin first unless contraindicated or not tolerated, their updated consensus report said.

Once metformin is on board, a clinician can then add a second diabetes agent from among the two drug classes recently proven to also reduce cardiovascular and renal events, either the SGLT2 (sodium-glucose transporter 2) inhibitors, or GLP-1 (glucagonlike peptide-1) receptor agonists, they advised.

Cardiovascular Disease Focus Represents a 'Major Paradigm Shift'

In contrast, the ESC guidelines called for upfront, systematic assessment of CVD risk in patients with T2D before treatment starts, and for patients in high- or very high–risk strata, the guidelines recommended starting the patient first on an SGLT2 inhibitor or a GLP-1 receptor agonist, and only adding metformin in patients who need additional glycemic control.

The guidelines also recommended starting treatment-naive patients with moderate CVD risk on metformin. For patients already on metformin, the new ESC guidelines called for adding an agent from at least one of these two drug classes with proven CVD benefits for those at high or very high CVD risk. The guidelines also note that the CVD benefits of the two newer drug classes differ and hence require further individualization depending on the risks faced by each patient, such as the risk for heart failure hospitalizations.

It's an approach "driven by data from the cardiovascular outcome trials," that showed several drugs from both the SGLT2 inhibitor and GLP-1 receptor agonist classes have substantial benefit for preventing cardiovascular events, renal events, hospitalizations for heart failure, and in some studies all-cause mortality, said Francesco Cosentino, MD, during a discussion of the guideline differences at the virtual annual meeting of the European Association for the Study of Diabetes.

The ESC approach also represents "a major paradigm shift," a "change from a glucose-centric approach to an approach driven by cardiovascular disease events," summed up Cosentino, professor of cardiology at the Karolinska Institute in Stockholm and chair of the task force that wrote the ESC's 2019 updated guidelines. The ESC approach advocates initiating drugs for treating patients with T2D "based on cardiovascular disease risk classification," he highlighted. Results from some SGLT2 inhibitor cardiovascular outcome trials showed that the CVD benefit was similar regardless of whether or not patients also received metformin.

ADA, EASD Call for 'a Different Emphasis'

"There is a different emphasis" in the statement issued by the diabetologists of the ADA and EASD, admitted Peter J. Grant, MD, a professor of diabetes and endocrinology at the University of Leeds (England) and cochair of the ESC guidelines task force. Grant represented the EASD on the task force, and the Association collaborated with the ESC in producing its guidelines.

"The ADA and EASD recommendations "look primarily at glucose control, with cardiovascular disease management as secondary." In contrast, the ESC guidelines "are primarily cardiovascular disease risk guidelines, with a glucose interest," Grant declared.

Despite his involvement in writing the ESC guidelines, Grant tilted toward the ADA/EASD statement as more globally relevant.

"There is much more to vasculopathy in diabetes than just macrovascular disease. Many patients with type 2 diabetes without macrovascular complications have microvascular disease," including the potential for retinopathy, nephropathy, and neuropathy, he said. These complications can also have a strong impact on psychological well being and treatment satisfaction.

"It's important that we're not glucocentric any more, but it's equally important that we treat glucose because it has such a benefit for microvascular disease." Grant also cited metformin's long history of safety and good tolerance, clinician comfort prescribing it, and its low price. Heavier reliance on SGLT2 inhibitors and GLP-1 receptor agonists will be expensive for the short term while the cost of these drugs remains high, which places a higher burden on "knowing we're doing it right," said Grant.

Cosentino pointed out that the higher cost of the drugs in the two classes shown to exert important cardiovascular and renal effects needs to be considered in a cost-effectiveness context, not just by cost alone.

'Clinical Inertia' Could Be a Danger

Cosentino played down a major disagreement between the two guidelines, suggesting that "focusing on the differences leads to clinical inertia" by the practicing community when they are unsure how to reconcile the two positions.

Grant agreed that adding a second drug to metformin right away made sense in at least selected patients. "Look at each patient and decide whether they need glycemic control. If so, and if they also have cardiovascular disease, use both drugs," metformin, plus one agent from one of the two newer classes.

Something both experts agreed on is that it's time to generally steer clear of sulfonylurea drugs. "We have evidence for harmful effects from sulfonylureas," Cosentino said.

"I'd dump sulfonylureas," was Grant's assessment, but he added that they still have a role for patients who need additional glycemic control but can't afford the newer drugs.

Cosentino has had financial relationships with Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck, Mundipharma, Novo Nordisk, and Pfizer, Grant has lectured on behalf of AstraZeneca, GlaxoSmithKline, Merck, Novo Nordisk, the Medicines Company, and Takeda, and he has been an adviser to Amgen, AstraZeneca, Novartis, Novo Nordisk, and Synexus.

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

NO BENEFIT OF INTENSIVE SURVELLENCE FOR COLORECTAL CANCER PATIENTS

ntensive surveillance with carcinoembryonic antigen (CEA) testing and CT scans after colorectal cancer resection did not improve recurrence-free or overall survival when compared with standard abdominal ultrasound and chest x-ray monitoring in a phase 3 trial of almost 2,000 patients.

However, among patients with colon cancer recurrence, those randomized to intensive surveillance more often had a second surgery with curative intent. Even so, there was no overall survival benefit versus standard surveillance in this group.

In short, "none of the follow-up modalities resulted in a difference," said investigator Come Lepage, MD, PhD, of Centre Hospitalier Universitaire de Dijon (France).

Lepage presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

Lepage said the study's results suggest guidelines that include CT and CEA monitoring should be amended, and the standard surveillance methods should be ultrasound and chest x-ray. LePage called CEA surveillance "useless" and said CT scans should be performed only in cases of suspected recurrence.

However, study discussant Tim Price, MBBS, DHSc, of the University of Adelaide, noted that both the intensive and standard arms in this study had abdominal imaging every 3 months, be it ultrasound or CT, so even in the standard arms, surveillance "was still fairly aggressive."

Because of that, the study does not "suggest we should decrease our intensity," Price said.

He added that the study's major finding was that more intensive surveillance led to higher rates of secondary surgery with curative intent, probably because recurrences were caught earlier than they would have been with standard surveillance, when curative surgery was still possible.

Patients in the study were treated during 2009-2015, and that might have also made a difference. "We need to remember that, in 2020, care is very different," Price said. This includes increased surgical interventions and options for oligometastatic disease, plus systemic therapies such as pembrolizumab. With modern treatments, detecting recurrences earlier "may well have an impact on survival."

Perhaps patients would live longer with "earlier diagnosis in today's setting with more active agents and more aggressive surgery and radiotherapy [e.g., stereotactic ablative radiation therapy]," Price said in an interview.

Study Details

The trial, dubbed PRODIGE 13, was done to bring clarity to the surveillance issue. Intensive follow-up after curative surgery for colorectal cancer, including CT and CEA monitoring, is recommended by various scientific societies, but it's based mainly on expert opinion. Results of the few clinical trials on the issue have been controversial, Lepage explained.

PRODIGE 13 included 1,995 subjects with colorectal cancer. About half of patients had stage II disease, and the other half had stage III. Most patients were 75 years or younger at baseline, and there were more men in the study than women. All patients underwent resection with curative intent and had no evidence of residual disease 3 months after surgery. Some patients received adjuvant chemotherapy.

Patients were first randomized to no CEA monitoring or CEA monitoring every 3 months for the first 2 years, then every 6 months for an additional 3 years. Members in both groups were then randomized a second time to either intensive or standard radiologic surveillance.

Surveillance in the standard arm consisted of an abdominal ultrasound every 3 months for the first 3 years, then biannually for an additional 2 years, plus chest x-rays every 6 months for 5 years. Intensive surveillance consisted of CT imaging, including thoracic imaging, alternating with abdominal ultrasound, every 3 months, then biannually for another 2 years.

At baseline, the surveillance groups were well balanced with regard to demographics, primary tumor location, and other factors, but stage III disease was more prevalent among patients randomized to standard radiologic monitoring without CEA.

Results

The median follow up was 6.5 years. There were no significant differences between the surveillance groups with regard to 5-year overall survival (P = .340) or recurrence-free survival (P = .473).

There were no significant differences in recurrence-free or overall survival when patients were stratified by age, sex, stage, CEA at a cut point of 5 mcg/L, and primary tumor characteristics including location, perineural invasion, and occlusion/perforation.

There were 356 recurrences in patients initially treated for colon cancer. CEA surveillance with or without CT scan was associated with an increased incidence of secondary resection with curative intent. The rate of secondary resection was 66.3% in the standard imaging with CEA arm, 59.5% in the CT plus CEA arm, 50.7% with CT imaging but no CEA, and 40.9% with standard imaging and no CEA (P = .0035).

The rates were similar among the 83 patients with recurrence after initial treatment for rectal cancer, but the between-arm differences were not significant. The rate of secondary resection with curative intent was 57.9% in the standard imaging with CEA arm, 47.8% in the CT plus CEA arm, 55% with CT imaging but no CEA, and 42.9% with standard imaging and no CEA.

The research is ongoing, and the team expects to report on secondary outcomes and ancillary studies of circulating tumor DNA, among other things, in 2021.

The study is being funded by the Federation Francophone de Cancerologie Digestive. Lepage disclosed ties with Novartis, Amgen, Bayer, Servier, and AAA. Price disclosed institutional research funding from Amgen and being an uncompensated adviser to Pierre-Fabre and Merck.

SOURCE: Lepage C et al. ESMO 2020, Abstract 398O.

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

TEMOZOLOMIDE BENEFITS GLIOBLASTOMA PATIENTS

A comparison of U.S. and European treatment patterns for glioblastomas provides further evidence that adding systemic chemotherapy with temozolomide to radiotherapy offers a significant survival benefit over radiotherapy alone, and wider uptake of chemoradiation in Europe would extend the benefit to more patients.

That conclusion comes from a study of registry data from both sides of the Atlantic. The study showed a doubling in 2-year survival rates for patients with glioblastomas treated with radiotherapy plus chemotherapy compared with radiotherapy alone, a practice change that was prompted by a phase 3 trial published in The New England Journal of Medicine in 2005.

"Using population data from cancer registries, we observed a huge increase in radiotherapy plus chemotherapy between 1999 and 2013 in Europe and the U.S.," said Francesco Giusti, PhD, of the European Commission Joint Research Center in Ispra, Italy.

"Data from 1999 to 2005 was already showing a clear survival advantage for patients treated with chemotherapy plus radiotherapy compared with radiotherapy alone," he added.

However, when Giusti and colleagues compared practice patterns from before and after the publication of the practice-changing trial, they found that about 10% more patients in the United States were receiving combined chemotherapy and radiation, a difference reflected in superior survival rates in the U.S., he said.

Giusti presented these findings at the European Society for Medical Oncology Virtual Congress 2020.

He and his colleagues looked at data from cancer registries contributing to the European Cancer Information System and the U.S. National Cancer Institute's Surveillance Epidemiology and End Results data.

The data set included patients diagnosed from 1999 through 2013 with glioblastoma as a first tumor.

During that time, results from the aforementioned phase 3 trial were published. They showed that, at a median follow-up of 28 months, the median survival was 14.6 months for the 287 patients assigned to radiotherapy plus temozolomide, compared with 12.1 months for the 286 patients randomized to radiotherapy alone.

The unadjusted hazard ratio for death in the combination therapy group was 0.63 (P < .001). The 2-year survival rate was 26.5% for chemoradiation and 10.4% for radiation alone.

Adding temozolomide to radiotherapy in the trial also appeared to be safe. The incidence of grade 3 or 4 hematologic adverse events was 7%.

Registry Data Study

To see how practice patterns changed in the United States and Europe after publication of the trial, Giusti and colleagues used registry data to calculate the proportion of cases by treatment type and overall survival during 1999-2005 (pre-study) and 2009-2013 (post-study).

The data included 34,229 cases from 11 countries in Europe and 36,925 cases from the United States.

The percentage of patients receiving both chemotherapy and radiation increased steadily over the study period. For example, among 18- to 49-year-olds, the percentage receiving the combined modalities in Europe increased from 20% in 1999-2001 to 70% in 2010-2013. In the United States, 40% of the same age group received combination therapy in 1999-2001, and this percentage grew to 80% in 2010-2013.

Overall survival rates in the general population were similar to those seen in the clinical trial during 1999-2005, when 2-year overall survival rates for patients treated with radiation alone were 11% in Europe and 12% in the United States. For patients treated with combined therapy, the respective 2-year survival rates in Europe and the United States were 24% and 25%.

"In the period after the trial, we observed a increasing 2-year survival rate to 28% in Europe and 29% in the U.S. for patients with radiotherapy plus chemotherapy," Giusti said.

Real-World Results

Invited discussant Matthias Preusser, MD, of the Medical University of Vienna in Austria, said the study shows that "population-based investigations are very valuable and should be further developed so that we can see how treatment patterns vary between countries and what the regional variations are, and whether new treatment standards actually reach clinical practice, and also to see whether there's an effect on a population basis that is different from what is seen in controlled clinical trials."

Preusser said it's clear from the study that survival is increased with the addition of chemotherapy to radiotherapy, and more patients in the United States than in Europe received the combination during the study period.

Pointing to a treatment algorithm from the European Association of Neuro-oncology published in 2017, Preusser noted that radiotherapy alone may still be recommended for patients with unfavorable prognostic factors or patients 70 years and older with methylguanine-DNA methyltransferase promoter non-methylated tumors.

"It seems the differences in the age distribution between the U.S. and European populations that were analyzed could be one explanation why the radiochemotherapy combination was applied more often in the U.S. population," Preusser said.

No outside funding was used to support the study. Giusti and coauthors reported having no conflicts of interest. Preusser disclosed relationships with multiple companies, including Merck, which markets temozolomide under the name Temodar.

SOURCE: Giusti F et al. ESMO 2020. Abstract 365MO.

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