Pembrolizumab Superiority For Advanced Melanoma

Final KEYNOTE-006 Findings Confirm Pembrolizumab Superiority For Advanced Melanoma
Pembrolizumab given on a 2- or 3-week schedule offers significantly longer overall survival than ipilimumab for patients with inoperable, advanced melanoma

Date: 21 Aug 2017
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Cancer Immunology and Immunotherapy / Melanoma and other Skin Tumours

medwireNews: Final overall survival (OS) findings from the KEYNOTE-006 trial confirm that pembrolizumab is superior to ipilimumab for the treatment of patients with stage III or IV unresectable melanoma who had previously received no more than one systemic therapy.

After a median follow-up of 22.9 months, median OS was unreached in the 279 patients who received pembrolizumab 10 mg/kg on a 2-week schedule and the 277 patients given the same dose on a 3-week schedule.

This was significantly longer than the median OS of 16.0 months for the 278 patients who were given four doses of ipilimumab 3 mg/kg at 3-week intervals, and the OS benefit was found across all patient subgroups, including age, gender, tumour size, prior therapy, BRAF V600E/K mutation status, and lactate dehydrogenase (LDH) level.

“In terms of patient selection, it is encouraging to see that both pembrolizumab regimens were equally advantageous over ipilimumab in patients with a larger tumour burden, and with higher levels of LDH (presumably reflecting tumour burden), given reports that the clinical success of PD-1 blockade is sensitive to tumour size”, say the authors of a comment discussing the KEYNOTE-006 findings in The Lancet.

“It is also encouraging to see that even patients with PD-L1-negative tumour cells (using a PD-L1 staining cut off of 1% positivity) are still better off with the anti-PD-1 Antibody”, write the commentators, Kilian Wistuba-Hamprecht and Graham Pawelec, from the University Medical Centre Tuebingen in Germany.

Compared with ipilimumab, both the 2-week and 3-week pembrolizumab schedules also offered significantly longer progression-free survival (PFS; 5.6 and 4.1 vs 2.8 months), as well as a significantly higher objective response rate (37 and 36 vs 13%).

The KEYNOTE-006 investigators highlight difficulties in comparing safety profiles for the regimens because almost all of the patients using ipilimumab had completed treatment by week 12; the reporting period for adverse events was shorter in these patients than their pembrolizumab-treated counterparts, at an average of 50 days versus 292–312 days.

Treatment-related adverse events were reported in 82% and 77% of patients in the 2-week and 3-week pembrolizumab groups and 74% of the ipilimumab-treated patients, with grade 3–5 treatment-related events occurring in 17%, 17% and 20%, respectively.

Toxicity led to treatment discontinuation in 7% and 11% of patients given the 2-week and 3-week pembrolizumab regimens, respectively, and 9% of ipilimumab-treated patients. Of the 202 patients who received pembrolizumab for at least 1 year, grade 3–4 toxicity was reported in 19%, while 4% discontinued treatment.

“Pembrolizumab provides a favourable benefit-risk profile in comparison with ipilimumab, supporting pembrolizumab as a standard of care for advanced melanoma”, write lead investigator Jacob Schachter, from Sheba Medical Center in TEL Hashomer, Israel, and co-authors.

Given the “substantiated superiority” of pembrolizumab in this setting, the commentators question whether ipilimumab should be offered, but note that a combination of nivolumab plus ipilimumab has shown better PFS than either agent alone, albeit with greater toxicity.

“Combined pembrolizumab and ipilimumab is currently in a phase 1 study, with preliminary data suggesting a manageable toxicity profile and durable antitumor activity”, remark Kilian Wistuba-Hamprecht and Graham Pawelec.

“The main task for the future will be to better understand the mechanisms that underlie checkpoint inhibition with different antibodies against other targets, and to predict which patients will respond best to each regimen”, they write. “For this, the identification of robust, predictive biomarkers will be important for individual patient selection.”

References

Schachter J, Ribas A, Long GV, et al. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). Lancet; Advance online publication 16 August 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)31601-X

Wistuba-Hamprecht K, Pawelec G. KEYNOTE-006: a success in melanoma, but a long way to go. Lancet; Advance online publication 16 August 2017. DOI: http://dx.doi.org/10.1016/S0140-6736(17)31816-0

Deprescribing proton pump inhibitors

Research ArticlePractice
Deprescribing proton pump inhibitors
Evidence-based clinical practice guideline
Barbara Farrell, Kevin Pottie, Wade Thompson, Taline Boghossian, Lisa Pizzola, Farah Joy Rashid, Carlos Rojas-Fernandez, Kate Walsh, Vivian Welch and Paul Moayyedi
Canadian Family Physician May 2017, 63 (5) 354-364;



Abstract

Objective To develop an evidence-based guideline to help clinicians make decisions about when and how to safely taper or stop proton pump inhibitors (PPIs); to focus on the highest level of evidence available and seek input from primary care professionals in the guideline development, review, and endorsement processes.

Methods
Five health professionals (1 family physician, 3 pharmacists, and 1 gastroenterologist) and 5 nonvoting members comprised the overall team; members disclosed conflicts of interest.
The guideline process included the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach, with a detailed evidence review in in-person, telephone, and online meetings.
Uniquely, the guideline development process included a systematic review of PPI deprescribing trials and examination of reviews of the harm of continued PPI use.
Narrative syntheses of patient preferences and resource-implication literature informed recommendations. The team refined guideline content and recommendation wording through consensus and synthesized clinical considerations to address common front-line clinician questions. The draft guideline was distributed to clinicians and then to health care professional associations for review and revisions made at each stage. A decision-support algorithm was developed in conjunction with the guideline.

Recommendations
This guideline recommends deprescribing PPIs (reducing dose, stopping, or using “on-demand” dosing) in adults who have completed a minimum of 4 weeks of PPI treatment for heartburn or mild to moderate gastroesophageal reflux disease or esophagitis, and whose symptoms are resolved. The recommendations do not apply to those who have or have had Barrett esophagus, severe esophagitis grade C or D, or documented history of bleeding gastrointestinal ulcers.

Conclusion
This guideline provides practical recommendations for making decisions about when and how to reduce the dose of or stop PPIs. Recommendations are meant to assist with, not dictate, decision making in conjunction with patients.

Deprescribing is the planned and supervised process of dose reduction or stopping of medication that might be causing harm or might no longer be providing benefit.1 The goal of deprescribing is to reduce medication burden and harm while maintaining or improving quality of life. However, deprescribing can be difficult, especially when medications do not appear to be causing overt harm.2 In an effort to provide evidence-based recommendations and tools to aid clinicians in stopping medications that might no longer be needed or that might be causing harm, we initiated the Deprescribing Guidelines in the Elderly project (www.open-pharmacy-research.ca/research-projects/emerging-services/deprescribing-guidelines).

Proton pump inhibitors (PPIs) were selected in a national modified Delphi consensus process as an important medication class for developing deprescribing guidelines, given their high prevalence of use and overuse.3

Concern about overuse of PPIs has been growing. 4–6 In a report summarizing prescription drug use in Canada, pantoprazole was the fifth most common drug prescribed, with more than 11 million prescriptions dispensed in 2012.7 Most common indications such as gastroesophageal reflux disease (GERD) require short-term treatment (ie, up to 4 to 8 weeks).8–10 However, chronic use appears to be problematic, with studies showing a lack of documented ongoing indication for between 40% and 65% of hospitalized patients in the United States and Australia11–13 and between 40% and 55% of primary care patients in the United States and the United Kingdom.4,14

Proton pump inhibitors are often viewed as safe and well tolerated medications, and while the incidence of side effects, such as diarrhea,15 impaired B12 absorption, 16 hypomagnesemia,12,17 Clostridium difficile infection, 18 hip fractures,19 and pneumonia20 might be small, older people might be at higher risk of these conditions. 21 When PPIs are inappropriately prescribed or used for too long, they can contribute to polypharmacy with its attendant risks of nonadherence, prescribing cascades, adverse reactions, medication errors, drug interactions, emergency department visits, and hospitalizations. 22–24 In addition, there are economic implications of overuse of PPIs. Spending on PPIs by public drug programs in Canada (excluding Quebec and the territories) totaled $249.6 million of the $7.8 billion spent on prescription drugs by these programs in 2013.25

Our target audience includes primary care physicians, pharmacists, nurse practitioners, and specialists who care for patients who might use PPIs.

The target population includes adults older than 18 years of age (including the elderly) taking a continuous PPI for longer than 28 days for the purpose of treating GERD or esophagitis. The guideline does not apply to those with Barrett esophagus, those with severe esophagitis (grade C or D on endoscopy, as outlined in Box 1),26 or those with documented history of bleeding gastrointestinal (GI) ulcers. Individual situations in which there might be risk factors that warrant continued use of PPIs are also outlined.
Box 1.
Los Angeles Classification for the endoscopic assessment of reflux esophagitis

The classification uses a 4-grade system

Grade A: 1 or more mucosal breaks no longer than 5 mm, none of which extends between the tops of the mucosal folds

Grade B: 1 or more mucosal breaks more than 5 mm long, none of which extends between the tops of 2 mucosal folds

Grade C: Mucosal breaks that extend between the tops of 2 or more mucosal folds but that involve less than 75% of the esophageal circumference

Grade D: Mucosal breaks that involve at least 75% of the esophageal circumference

Data from Saraf et al.26
METHODS

We used a comprehensive checklist for a successful guideline enterprise to develop the methods for the PPI deprescribing guideline.27,28

The Guideline Development Team (GDT) comprised 5 clinicians—a family physician (K.P.), a gastroenterologist (P.M.), and 3 pharmacists (B.F., C.R.F., K.W.)—and 5 nonvoting members—a methodologist (V.W.), 2 pharmacy residents (F.J.R., T.B.), and 2 project coordinators (W.T., L.P.). Additional support was provided by a librarian and a master’s student. Three GDT members were investigators with the Deprescribing Guidelines in the Elderly project (B.F., K.P., C.R.F.). All GDT members had expertise in the clinical management of patients taking PPIs. Team members’ expertise, role descriptions, and conflict of interest statements are available at CFPlus.*

We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system for guideline development (Box 2).29–32 The GDT articulated the main clinical management question as follows, using the PICO (patient or problem, intervention, comparison, outcome) approach: In adults, what are the effects (harms and benefits) associated with deprescribing long-term daily PPI therapy compared with continuous and chronic use? Definitions specific to PPI deprescribing were articulated by the GDT and are listed in Box 3.6,33
Box 2.
Notes on the GRADE framework for guideline development

This guideline was developed in accordance with the methods proposed by the GRADE Working Group29 and was informed by a systematic review30,31 and a subset of data from an existing systematic review32

We focused our review and recommendations on outcomes important to patients, such as harms or benefits resulting from deprescribing a PPI, pill burden, and cost or resource use. Outcomes were proposed by the systematic review team and revised by the Guideline Development Team based on feasibility and the literature available

Ratings of the evidence profile tables included high, moderate, low, or very low and depended on our confidence in estimates of effect. Because only randomized controlled trials were used, they started with a high quality rating, but could be rated down by limitations in any of 4 domains: risk of bias, inconsistency, indirectness, and imprecision. Publication bias could not be rated owing to the paucity of studies.29 Other areas that were considered in formulating a final rating included harms, patient values and preferences, and resource use

The GRADE Working Group outlines appropriate wording for recommendations depending on the rating of strength and confidence in the evidence. A strong recommendation with implications for patients (phrased as “we recommend ...”) implies that all patients in the given situation would want the recommended course of action, and only a small proportion would not. A weak recommendation (phrased as “we suggest ...”) implies that most patients would wish to follow the recommendation, but some patients would not. Clinicians must help patients make management decisions consistent with the patients’ values and preferences. Implications for clinicians are similar such that a strong recommendation implies all or most patients should receive the intervention. A weak recommendation should prompt a clinician to recognize that different choices will be appropriate for individual patients

GRADE—Grading of Recommendations Assessment, Development and Evaluation; PPI—proton pump inhibitor.
Box 3.
Definitions of PPI deprescribing

Deprescribing can include stopping, stepping down, or reducing doses

Stopping can be done either via abrupt discontinuation or a tapering regimen

Stepping down involves abrupt discontinuation or tapering of the PPI followed by prescription of an H2RA (any H2RA at any approved dose and dosing interval according to the drug monograph)

Reducing includes the following subcategories:

-Intermittent PPI use, which is defined by the Canadian Consensus Conference as “daily intake of a medication for a predetermined, finite period (usually two to eight weeks) to produce resolution of reflux-related symptoms or healing of esophageal lesions following relapse of the individual’s condition”33

-On-demand PPI use, which is defined by the Canadian Consensus Conference as “the daily intake of a medication for a period sufficient to achieve resolution of the individual’s reflux-related symptoms; following symptom resolution, the medication is discontinued until the individual’s symptoms recur, at which point, medication is again taken daily until the symptoms resolve”33

-Lower dose, which is a reduction from a standard dose to a maintenance dose6

H2RA—histamine-2 receptor antagonist, PPI—proton pump inhibitor.

To ensure studies of all deprescribing approaches for PPI were captured, 2 search strategies were used. We conducted a de novo systematic review to assess effects of on-demand and abrupt-discontinuation deprescribing for people using PPIs for longer than 4 weeks.30,31 The methodology and the search strategy used to conduct this systematic review are outlined in a published protocol. 30 Next, we updated a previously published Cochrane systematic review on dose lowering and stepping down to histamine-2 receptor antagonist (H2RA) therapy.32 Summarized pooled estimates of treatment effects from both systematic reviews for important and critical outcomes for decision making are provided in GRADE evidence tables, available at CFPlus.*

The systematic reviews focused on outcomes relevant to patients, caregivers, and health care providers. Primary outcomes included change in upper GI symptoms (positive or negative), pill burden, and cost. Secondary outcomes included patient satisfaction, positive drug withdrawal events (eg, resolution of a side effect such as diarrhea), and adverse drug withdrawal events (eg, recurrence of esophagitis on endoscopy).

Draft recommendations were initially formulated by the GDT members (during an in-person meeting) from the evidence tables using confidence in estimated effects (following dose lowering, switching to on-demand therapy, or stepping down to H2RA therapy), and taking into account literature on patient preferences for PPI use, a review of harms of continuing PPIs, team members’ clinical experience with such harms, and resource implications (both in terms of PPI costs and costs that might be associated with complications arising from stopping PPIs). The GDT members met by teleconference to review and discuss recommendations drafted from the in-person meeting. Voting on the recommendations was subsequently conducted anonymously by e-mail. Unanimous agreement was sought; 80% agreement among the 5 GDT members was considered the cutoff for consensus. All 5 members of the PPI deprescribing GDT agreed with the final recommendations.
RECOMMENDATIONS

The recommendations are outlined in Box 4. The algorithm developed for this guideline is provided in Figure 1. The rationale for the recommendations is outlined in Table 1. The recommendations apply to adults who have completed a minimum 4-week course of PPIs for upper GI symptoms. The evidence base mainly relates to patients with GERD or esophagitis but can be extrapolated to other upper GI disorders for which the efficacy of PPIs is more modest or for which short-term use is usually recommended (eg, stress ulcer prophylaxis, peptic ulcer disease) and therefore deprescribing is likely to be more effective.34 The recommendations do not apply to those who have or have had Barrett esophagus, severe esophagitis grade C or D, or documented history of bleeding GI ulcers.

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Figure 1

Proton Pump Inhibitor (PPI) Deprescribing Algorithm

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Table 1.

Evidence to recommendations table: Does deprescribing PPIs (dose reduction, on-demand use, abrupt discontinuation, stepping down to H2RA therapy) compared with continuous PPI use result in benefits or harms for adults > 18 y (excluding those with history of bleeding ulcer, Barrett esophagus, and severe esophagitis grade C and D) in primary care and long-term care settings?
Box 4.
Recommendations

For adults (>18 y) with upper GI symptoms, who have completed a minimum 4-wk course of PPI treatment, resulting in resolution of upper GI symptoms, we recommend the following:

Decrease the daily dose or stop and change to on-demand (as needed) use (strong recommendation, low-quality evidence)

Alternatively, we suggest the following:

Consider an H2RA as an alternative to PPIs (weak recommendation, moderate-quality evidence)

GI—gastrointestinal, H2RA—histamine-2 receptor antagonist, PPI—proton pump inhibitor.

For those with mild to moderate GERD or upper GI symptoms who have no ongoing symptoms, lowering the dose of a PPI does not lead to significantly greater relapse compared with continuing at a standard dose. Lowering the PPI dose was believed to have greater benefit than harm owing to a lack of evidence of harm, the potential to reduce costs, and the potential to reduce the risk of rare PPI side effects and drug interactions. Both on-demand therapy and stepping down to H2RA therapy increase the risk of symptom relapse more so than lowering the dose does. However, on-demand use is associated with lower pill burden and cost, which might be desirable to patients. Please refer to Box 229–32 for definitions of the strength and quality of deprescribing trial evidence and to Table 1 for evidence to recommendations considerations across all decision domains (quality of evidence, balance of benefits and harms, patient values and preferences, and resource implications).

Based on a lack of evidence of serious harm from deprescribing, the evidence for the benefits of reducing inappropriate PPI use in terms of pill burden and reduced risk of side effects, the high societal cost of inappropriate PPI use, and the feasibility of a PPI deprescribing intervention, we rated the recommendation to lower the dose or switch to on-demand PPI use as strong. The recommendation to step down to H2RA therapy was rated as weak owing to the higher risk of symptom return.

Consideration of harm includes the potential for commonly reported side effects such as diarrhea, headache, and vitamin B12 and magnesium deficiency, as well as associations with increased risk of fractures, C difficile infection, community-acquired pneumonia, gastric cancer, gastric atrophy, intestinal metaplasia, colorectal cancer, bacterial peritonitis, small intestine bacterial overgrowth, and possibly increased vascular events in those taking clopidogrel. (Frequency ratios of the harms are available at CFPlus.*)

With regard to patient values and preferences, PPIs are considered to improve quality of life, but patients often do not take them daily as prescribed; some patients taking on-demand PPIs are more willing to continue treatment. Some fear recurrence of symptoms, and for this reason the guideline contains clinical considerations for alternative management strategies for occasional symptoms. (The evidence reviews and related references are available at CFPlus.*)

Spending on PPIs is high ($249.6 million for public drug programs across Canada [except Quebec and the territories] in 2013).25 Studies consistently show inappropriate PPI use in 40% to 65% of patients,4,11–14 suggesting considerable health care dollars are spent on therapy that might not be providing benefit. Step-down, intermittent, and on-demand PPI use reduces direct medical costs; however, there is no evidence comparing these strategies. The cost-effectiveness of continuous treatment for those with severe GERD has been demonstrated, and for this reason, patients with severe GERD should continue PPI treatment at the lowest effective dose. (The evidence reviews and related references are available at CFPlus.*)
Clinical considerations

This guideline is a tool to be used together with consideration of a patient’s personal and medical context. Patients might be less accustomed to dialogue about reducing or stopping medications, and so heightened health care provider awareness to potential concerns might help foster improved patient uptake. The decision to continue, reduce, or discontinue a medication is based on a balance of knowledge about its indication and effectiveness, and risks of use including actual or potential side effects, drug interactions, pill burden, and cost. Patient and family values and preferences play an important role. Decisions about continuing, tapering, or stopping medications should be consistent with the patient’s goals of care. We developed a patient pamphlet to facilitate discussion, which is available at CFPlus.*

The following questions were articulated by the GDT as being important to consider when making decisions about the steps for deprescribing PPIs.

Are there indications or risk factors that warrant continued use?

An important first step is determining the original indication for the PPI and whether there are ongoing risk factors for GI disease that warrant chronic use. Reviewing patient history and consultation notes for evidence of Barrett esophagus, grade C or D esophagitis, or documented history of bleeding GI ulcers will identify patients for whom deprescribing is unlikely to be beneficial. Advice should be sought from gastroenterologists for these patients to assess ongoing risk factors.

Risk of GI ulceration and the need for gastroprotection with a PPI should be given careful consideration in patients receiving regular daily doses of nonsteroidal anti-inflammatory drugs (NSAIDs).

Patients at high risk of GI ulceration include those with a history of a previous complicated ulcer or those with 3 or more risk factors (age older than 65 years; high-dose NSAID use; previous history of uncomplicated ulcer; concurrent use of acetylsalicylic acid [including low-dose acetylsalicylic acid], corticosteroids, or anticoagulants).35,36 Patients at moderate risk of GI ulceration include those with 1 or 2 risk factors, while low-risk patients do not have any of these risk factors. Patients at moderate risk of GI ulceration taking chronic NSAIDs likely require a PPI or misoprostol, or can be treated with cyclooxygenase-2 inhibitors without a PPI.

Patients at high risk should receive a cyclooxygenase-2 inhibitor plus a PPI or misoprostol.35,36 Concomitant use of selective serotonin reuptake inhibitors and NSAIDs has also been associated with an elevated risk of upper GI bleeding. 37 Consideration could be given to using a PPI in such patients if both a selective serotonin reuptake inhibitor and NSAIDs are deemed necessary and the patient has other risk factors as described above.37 For a more detailed overview of indications for gastroprotection, the reader is referred elsewhere.35,36

Once it is determined that a patient has been treated for a minimum of 4 weeks for GERD or mild to moderate (grade A or B) esophagitis and symptoms have resolved, deprescribing can be considered. Similarly, if a patient has completed treatment for known short-term indications like Helicobacter pylori eradication, intensive care unit stress ulcer prophylaxis, or uncomplicated peptic ulcer disease (without ongoing chronic NSAID use), the PPI should be deprescribed in accordance with practice guidelines for these indications.10,38,39

How should tapering be approached?

Our systematic search did not identify trials that adequately addressed optimal tapering approaches to minimize symptom recurrence. There is very low-quality evidence that abrupt discontinuation (without tapering or using on-demand strategies) does increase symptom relapse.
Therefore, it might be prudent to reduce the PPI to the lowest effective dose before discontinuation and to provide patients with a symptom management strategy that might include on-demand PPIs.
Anecdotally, clinicians seem to prefer gradual dose reduction (eg, from twice daily to once daily, from high dose to low dose, from daily to every other day) and any of these approaches can be used, taking into consideration the patient’s current medication supply, as well as the convenience of the approach.

Explaining the rationale for deprescribing PPIs, and the option of beginning with lowering the dose or using on-demand therapy, will facilitate patient and family acceptance.

What monitoring needs to be done and how often, and how should symptoms be managed?

Follow-up times varied among trials of deprescribing.40–50 Typically, patients attended follow-up appointments 4 and 12 weeks after deprescribing and again at 6 to 12 months. Patients also reported recurrence of symptoms by contacting their health care providers. Health care providers can consider following up with patients 4 weeks after deprescribing (or having patients contact them) to assess symptom control (heartburn, regurgitation, epigastric pain, dyspepsia, or pain on swallowing) and at 12 weeks after deprescribing to assess symptoms, frequency of on-demand use (if applicable), and the need for further investigation or a change back to continuous treatment.40–50

Differentiating “rebound hypersecretion” from symptoms of an underlying disorder such as GERD is challenging. 51 While studies of healthy volunteers taking PPIs have resulted in acid-related symptoms following deprescribing, the clinical significance remains unknown.51–53 Regardless, we recommend monitoring for symptom recurrence and managing symptoms with on-demand PPIs, stepping down to H2RA therapy (if appropriate, safe, and effective for the patient), other over-the-counter agents (eg, calcium carbonate), or nonpharmacologic approaches.

Some nonpharmacologic interventions have demonstrated reduction in symptoms, and these include weight loss, avoiding meals within 2 to 3 hours of bedtime, and raising the head of the bed.54 Attention should also be paid to avoiding dietary triggers. In situations where symptoms continue to return despite use of on-demand or intermittent PPIs, the clinician should ensure testing for and treatment of H pylori has been completed.55

What other approaches help with PPI deprescribing?

Inclusion of a pharmacist within the interdisciplinary team has been shown to reduce unnecessary PPI use and can facilitate patient education, dose changes, monitoring, and alerting the prescriber to ongoing symptoms.56,57

Clinical and stakeholder review

External clinical review of the guideline was conducted by a practising family physician and a pharmacist using the AGREE II (Appraisal of Guidelines for Research and Evaluation) Global Rating Scale tool.58 Relevant stakeholder organizations (ie, gastroenterology, family practice, pharmacy, and nurse practitioner) were invited to similarly review and endorse the guidelines (Box 5). Modifications were made to the original guideline draft to address reviewer comments.
How this deprescribing guideline relates to other clinical practice guidelines for PPI

Current GERD and peptic ulcer disease guideline recommendations support a short duration of PPI use and suggest attempting to discontinue PPIs in most patients or maintaining therapy at the lowest effective dose.8,33 There is no information in current guidelines that assists clinicians with deprescribing PPIs (ie, tapering, discontinuation, or use of intermittent, step-down, or on-demand strategies). While a limited number of protocols for deprescribing PPIs have been proposed, there are no comprehensive evidence-based guidelines available for deprescribing PPIs.57,59 A PPI deprescribing guideline works in conjunction with current treatment guidelines because it offers clinicians recommendations and clinical considerations to help them deprescribe PPIs in patients after an appropriate treatment duration or if long-term therapy is being reevaluated.

Guidelines for recommended PPI treatment duration

Guidelines for management of GERD suggest short-term treatment (4 to 8 weeks) for most patients.8,33 After 4 to 8 weeks, in patients without a compelling indication for maintenance therapy (such as erosive esophagitis or Barrett esophagus), PPI therapy should be reassessed.8,33 Canadian GERD management guidelines recommend that in individuals who have responded well to long-term PPI therapy (and who do not have an indication for maintenance therapy), the medication can be discontinued to assess the need for ongoing therapy (rated as poor-quality evidence).33

If maintenance therapy is required, the medication should be instituted at the lowest possible dose, which includes on-demand therapy (recommendation derived from multiple randomized controlled trials, rated as fair-quality evidence).33 The American College of Gastroenterologists 2013 guideline recommends PPI therapy for 8 weeks initially (rated as a strong recommendation with a high level of evidence derived from meta-analyses and randomized controlled trials), after which time the PPI should be discontinued in most patients and the need for maintenance therapy should be assessed.8
If long-term PPI maintenance therapy is required, the lowest effective dose should be used, which can include reducing medication to on-demand or intermittent PPI use (a conditional recommendation based on a low level of evidence).8

Peptic ulcer disease treatment guidelines recommend short-term PPI use in most patients (2 to 12 weeks), after which time PPI therapy should be discontinued unless maintenance therapy is clearly indicated (for example, in patients with daily NSAID use who have GI risk factors).10,38,39,60
These recommendations are based on randomized controlled trial data and systematic reviews. The American College of Gastroenterologists 2012 guideline on management of bleeding ulcers recommends stopping antisecretory therapy after H pylori eradication unless patients require NSAIDs (rated as strong, supported by high-quality evidence).60

Gaps in knowledge

Proton pump inhibitors are used for a number of reasons; however, most deprescribing research has been done in relatively healthy patients (primarily adults and younger elderly patients) with mild or moderate GERD or esophagitis only.
In conditions for which PPI treatment is usually of limited duration (eg, intensive care unit stress ulcer prophylaxis, peptic ulcer disease, H pylori treatment) or uncertain effectiveness (eg, cough), there were no trials that compared a deprescribing approach with continuous PPI use. In addition, the optimal approach to deprescribing PPIs has not been evaluated (eg, tapering before stopping).

Direct comparison of different deprescribing approaches (to one another and to continuous PPI use, as well as various tapering approaches and stepping down to H2RA therapy) would be helpful to determine if there is a best approach. Trials examining the outcomes of deprescribing for the frail elderly or those with other conditions (aside from GERD or esophagitis) would help clinicians weigh the harms and benefits of deprescribing in patients who might also be at higher risk of adverse effects of continued PPI treatment.

Studies employed different definitions of symptom relapse and patient satisfaction; consistency would be helpful to improve the quality of the body of evidence and should include patients’ perspectives in terms of what is meaningful to them. Attention to both the positive (such as resolution of side effects caused by the PPI) and negative (such as recurrence of upper GI symptoms) patient-specific effects of PPI deprescribing, particularly over the longer term, would be helpful. Evaluating cost-effectiveness and long-term medical resource use is also important.
Box 5.

Guideline endorsements

This evidence-based clinical practice guideline for deprescribing PPIs has been endorsed by the following groups:

Canadian Association of Gastroenterology

Canadian Nurses Association

College of Family Physicians of Canada

Canadian Pharmacists Association

Canadian Society of Consultant Pharmacists

Ontario Pharmacists Association

RxFiles

PPI—proton pump inhibitor.
Next steps

The deprescribing team will provide routine guideline updates as new evidence emerges that might change the recommendations. Prospective evaluation of the effects of adoption of this and other deprescribing guidelines will be part of a research strategy in the future.
Conclusion

Overuse of medication is acknowledged to be a key contributor to polypharmacy, with attendant negative effects on health. Proton pump inhibitors are commonly indicated for short-term use, and the potential for harm is not insignificant.
A systematic review identified that PPIs can be safely deprescribed in many patients taking them for the common indications of GERD and mild esophagitis. This evidence-based guideline is the first in a series of guidelines aimed at helping clinicians make decisions about when and how to safely stop medications. Implementation of such guidelines will encourage clinicians to carefully evaluate the ongoing use of medications and potentially reduce the negative effects of polypharmacy.

Nivolumab and Four Week Dosing Schedule

FDA Accepts Applications for Nivolumab Four Week Dosing Schedule Across All Approved Indications

Supplemental Biologics License Applications to update nivolumab dosing

Date: 10 Aug 2017
Topic: Cancer Immunology and Immunotherapy
On 24 July 2017, Bristol-Myers Squibb Company announced that the US Food and Drug Administration (FDA) accepted its supplemental Biologics License Applications (sBLAs) to update nivolumab(Opdivo) dosing to include 480 mg infused over 30 minutes every four weeks (Q4w) for all currently approved monotherapy indications.

Filing for four week dosing infused over 30 minutes across approved nivolumab monotherapy indications supports innovation and making cancer treatment more convenient for healthcare providers, caregivers and patients.

The applications are under review with an action date of 5 March, 2018.

Bristol-Myers Squibb is enhancing the scientific understanding of onco-immunology through extensive portfolio of investigational compounds and approved agents. Their clinical development programme is studying broad patient populations across more than 50 types of cancers with 14 clinical-stage molecules designed to target different immune system pathways. Expertise and innovative clinical trial designs are focused to advance the combination therapies of onco-immunology drugs with other cancer immunotherapeutics, or with chemotherapy, targeted therapies and radiation therapy across multiple tumours. They also continue to pioneer research that will help facilitate a deeper understanding of the role of immune biomarkers and how a patient’s tumour biology can be used as a guide for treatment decisions.

They understand making the promise of onco-immunology a reality for the many patients who may benefit from these therapies requires not only innovation on pharma part but also close collaboration with leading experts in the field through partnerships with academia, government, advocacy and biotech companies.

Nivolumab is a programmed death-1 (PD-1) immune checkpoint inhibitor which global development programme includes a broad range of clinical trials across all phases, including phase III, in a variety of tumour types. To date, the nivolumab clinical development programme has enrolled more than 25,000 patients. The nivolumab trials have contributed to gaining a deeper understanding of the potential role of biomarkers, particularly regarding how patients may benefit from nivolumab across the continuum of PD-L1 expression.

In July 2014, nivolumab was the first PD-1 immune checkpoint inhibitor to receive regulatory approval anywhere in the world. It is currently approved in more than 60 countries. In October 2015, the nivolumab and ipilimumab combination regimen was the first onco-immunology combination to receive regulatory approval for the treatment of metastatic melanoma and is currently approved in more than 50 countries.

The Bristol-Myers Squibb’s press release contains forward-looking statements.

THE CHANGING FACE OF CLINICAL TRIALS

REVIEW ARTICLE
THE CHANGING FACE OF CLINICAL TRIALS
Jeffrey M. Drazen, M.D., David P. Harrington, Ph.D., John J.V. McMurray, M.D., James H. Ware, Ph.D., Janet Woodcock, M.D., Editors
Evidence for Health Decision Making — Beyond Randomized, Controlled Trials
Thomas R. Frieden, M.D., M.P.H.
N Engl J Med 2017; 377:465-475August 3, 2017DOI: 10.1056/NEJMra1614394

Comments open through September 6, 2017


ArticleReferences Comments (2) Metrics
A core principle of good public health practice is to base all policy decisions on the highest-quality scientific data, openly and objectively derived.1
Determining whether data meet these conditions is difficult; uncertainty can lead to inaction by clinicians and public health decision makers.
Although randomized, controlled trials (RCTs) have long been presumed to be the ideal source for data on the effects of treatment, other methods of obtaining evidence for decisive action are receiving increased interest, prompting new approaches to leverage the strengths and overcome the limitations of different data sources.2-8 In this article, I describe the use of RCTs and alternative (and sometimes superior) data sources from the vantage point of public health, illustrate key limitations of RCTs, and suggest ways to improve the use of multiple data sources for health decision making.

In large, well-designed trials, randomization evenly distributes known and unknown factors among control and intervention groups, reducing the potential for confounding.
Despite their strengths, RCTs have substantial limitations. Although they can have strong internal validity, RCTs sometimes lack external validity; generalizations of findings outside the study population may be invalid.2,4,6 RCTs usually do not have sufficient study periods or population sizes to assess duration of treatment effect (e.g., waning immunity of vaccines) or to identify rare but serious adverse effects of treatment, which often become evident during postmarketing surveillance and long-term follow-up but could not be practically assessed in an RCT.
The increasingly high costs and time constraints of RCTs can also lead to reliance on surrogate markers that may not correlate well with the outcome of interest.

Selection of high-risk groups increases the likelihood of having adequate numbers of end points, but these groups may not be relevant to the broader target populations.
These limitations and the fact that RCTs often take years to plan, implement, and analyze reduce the ability of RCTs to keep pace with clinical innovations; new products and standards of care are often developed before earlier models complete evaluation. These limitations also affect the use of RCTs for urgent health issues, such as infectious disease outbreaks, for which public health decisions must be made quickly on the basis of limited and often imperfect available data.
RCTs are also limited in their ability to assess the individualized effect of treatment, as can result from differences in surgical techniques, and are generally impractical for rare diseases.

Many other data sources can provide valid evidence for clinical and public health action. Observational studies, including assessments of results from the implementation of new programs and policies, remain the foremost source, but other examples include analysis of aggregate clinical or epidemiologic data. In the late 1980s, the high rate of the sudden infant death syndrome (SIDS) in New Zealand led to a case–control study comparing information on 128 infants who died from SIDS and 503 control infants.9 The results identified several risk factors for SIDS, including prone sleeping position, and led to the implementation of a program to educate parents to avoid putting their infants to sleep on their stomachs — well before back-sleeping was definitively known to reduce the incidence of SIDS.
The substantial reduction in the incidence of SIDS that resulted from this program became strong evidence of efficacy; implementation of an RCT for SIDS would have presented ethical and logistic difficulties.
Similarly, the evidence base for tobacco-control interventions has depended heavily on analysis of the results of policies, such as taxes, smoke-free laws, and advertising campaigns that have generated robust evidence of effectiveness — that is, practice-based evidence.

Current evidence-grading systems are biased toward RCTs, which may lead to inadequate consideration of non-RCT data.10 Objections to observational studies include the potential for bias from unrecognized factors along with the belief that these studies overestimate treatment effects.11 Although overestimation bias has been shown in some observational studies (e.g., overestimation of the effect of influenza vaccination on reducing mortality among older persons as a result of bias from healthy vaccine recipients12), comparisons of validity between observational studies and RCTs have dispelled many misperceptions.4,6,13,14 A widely cited example involves the cardiovascular health risks associated with the use of menopausal hormone therapy.
Data from an observational study suggested that menopausal hormone therapy would reduce the risk of heart disease15; results from a subsequent RCT showed increased cardiovascular risks.16 Although initially these differences were thought to indicate weaknesses in the observational study, further analyses determined that both studies had valid results for their patient populations and that discrepancies were probably due to the timing of initiation of hormone therapy in relation to the onset of menopause.17-21 If so, then the RCT and observational study showed similar findings. However, a broad recommendation to use hormone therapy was made prematurely.
Determining when data are sufficient for action is difficult, but the bar should be much higher when recommending that millions of persons with no disease take medications. This line of reasoning does not suggest that the Food and Drug Administration should be less stringent in their review of drug safety and efficacy, but rather that there should be rigorous review of all potentially valid data sources.
No study design is flawless, and conflicting findings can emerge from all types of studies. The following examples show the importance of recognizing the strengths and limitations in all data sources and finding ways to obtain the most useful data for health decision making.

VALIDITY OF ALTERNATIVE DATA SOURCES — THE LIVE ATTENUATED INFLUENZA VACCINE
Rigorous analyses after the implementation of a public health program can provide critically important information, such as data on vaccine effectiveness. Analyses of influenza vaccination efforts are a prime example, because, unlike other vaccines, influenza vaccines are given and evaluated for effectiveness yearly.
The ability of an influenza vaccine to prevent influenza-related illness is affected by many factors, including genetic changes in the virus as well as host factors including age, underlying medical conditions, and previous infections and vaccinations. In the United States, the effectiveness of the influenza vaccine is monitored through the Influenza Vaccine Effectiveness Network. These data are used to derive estimates of the number of influenza-related illnesses, hospitalizations, and deaths prevented each year through vaccination, which, in turn, provide critical information to help measure, evaluate, and guide public health interventions.

First licensed in 2003, the live attenuated influenza vaccine, known as the “nasal spray” influenza vaccine, has been approved for use in healthy children and adults 2 to 49 years of age since 2007.22 The vaccine showed good protection for both adults and children in postlicensure RCTs, and, in June 2014, on the basis of results from several RCTs showing superior efficacy of the live attenuated vaccine over the inactivated influenza vaccine in children,23-25 the Advisory Committee for Immunization Practices (ACIP) issued a preference for its use in healthy children 2 to 8 years of age for the 2014–2015 influenza season.26 A subsequent observational study of the effectiveness of the live attenuated and inactivated influenza vaccines, however, showed worse performance for live attenuated vaccine than was shown in the RCTs,27 and the ACIP did not renew its preference for the live attenuated vaccine over inactivated vaccine in healthy children for the 2015–2016 season.
More recently, on the basis of an observed vaccine efficacy for the live attenuated vaccine that was at or near zero, especially against the 2009 H1N1 pandemic influenza virus,27-29 the ACIP recommended that the nasal spray vaccine not be used during the 2016–2017 influenza season.30 In this example, changes in vaccine formulation (from trivalent to quadrivalent), the population vaccinated (e.g., natural immunity resulting in neutralization of live vaccine), or another factor or factors caused the RCT data to lack external validity and be misleading, as compared with prospectively collected vaccine-efficacy data.
Future studies may provide clarification regarding the reasons for these differences, but both RCTs and observational data may be needed.

RELEVANCE TO PROGRAM CONDITIONS — DIRECTLY OBSERVED TREATMENT FOR TUBERCULOSIS
Although the use of a single drug in the 1946 RCT of streptomycin for the treatment of tuberculosis31 rapidly led to resistance, the success of the trial spurred a series of long-term RCTs for tuberculosis treatment conducted over four decades by the British Medical Research Council with collaborators throughout the world.32,33 Each trial built on previous findings, with the effect of refining drug regimens and minimizing the duration of antituberculosis treatment. The importance of directly observed treatment was realized as treatment moved from sanatoriums to homes.34,35 The approach, implemented from 1958 forward,33 evolved to directly observed treatment, short-course (DOTS), with standard, first-line regimens, and, for persons infected with multidrug-resistant strains, “DOTS-plus,” involving second-line, reserve drugs.36

Studies have purported to show that directly observed treatment offers no advantage over self-administered treatment.37,38 A limitation of these studies has been lack of evaluation of the health, epidemiologic, and societal costs of relapse or of the rare but devastating progression to drug-resistant tuberculosis.
Although these studies have been conducted with intensive oversight, they have not established a method of treatment that can be consistently applied to a large program in which thousands or millions of patients are treated.
In addition, an RCT for a tuberculosis treatment method would be unable to predict or account for the harms from the rare but catastrophic secondary, population-wide effects of development and spread of multidrug resistance.

Examples of non-RCT efforts to evaluate the effect of DOTS and DOTS-plus on multidrug-resistant tuberculosis include decision analyses of program effect,39 genotyping of isolates from patients in communities with different directly observed treatment practices,40 and reviews of medical and public health records along with epidemiologic and laboratory analyses of multidrug-resistant tuberculosis outbreaks.41
These non-RCT studies have contributed to continued refinements in treatment and follow-up and reduced risks of resistance.
For these and other reasons, the American Thoracic Society, World Health Organization, and Centers for Disease Control and Prevention continue to recommend directly observed treatment as the standard of practice.

POPULATION-WIDE ANALYSIS — THE EFFECT OF SODIUM INTAKE ON CARDIOVASCULAR HEALTH
Cardiovascular disease remains the leading cause of death in the United States.42 A major risk factor for cardiovascular disease is hypertension, which currently affects approximately 29% of U.S. adults.43 An important strategy for lowering blood pressure is reducing excess sodium intake, particularly through changes to the food supply.44 A robust body of evidence, including an analysis of more than 100 randomized trials, shows that reducing sodium intake reduces blood pressure among adults.45 There is also evidence, based on trends at the population level, that reducing sodium intake prevents cardiovascular disease.46 Meta-analysis of sodium-reduction trials of at least 6 months’ duration in which moderate reductions in intake were achieved, as well as well-designed, long-term cohort studies, have provided strong evidence that lower sodium intake is associated with a reduced incidence of cardiovascular events.47,48

The benefits of sodium reduction have been questioned by some researchers on the basis of several studies that report a J-shaped relationship between sodium intake and cardiovascular outcomes.49-51 These studies, however, have been shown to have methodologic flaws, including those related to the assessment of usual sodium intake, the potential for reverse causality, inadequate follow-up, residual confounding, and insufficient power.52
Accurate assessment of long-term, usual sodium intake is critical in cohort studies that relate individual sodium intake to long-term outcomes and requires multiple 24-hour urine collections over a period of time.52-54 Spot or single 24-hour urine collections have a high degree of intraindividual variation that may not be overcome by correction or large sample size.54-56 Because of challenges in accurately measuring usual sodium intake and excretion and the potential for misclassification of exposure, cohort studies must use multiple 24-hour urine collections48 to be valid, and study designs that use population means, which are subject to less variation than measurements of individual intake, often provide more reliable information.57
This may be why studies that assess sodium intake and cardiovascular events on a population level have shown beneficial effects of sodium-intake reduction,46 whereas studies with less accurate measures of individual intake have not.54,57

Even for established risk factors, RCTs can yield answers that are simply wrong. A well-known example is the large Multiple Risk Factor Intervention Trial (MRFIT) on cardiovascular disease, which showed insufficient differences in health outcomes resulting from interventions such as smoking cessation and exercise.58 Although longer follow-up showed that the trial may have accurately identified benefits from smoking cessation and improvements in nutrition, the study highlighted problems in implementing and measuring the effects of substantial lifestyle changes — in particular, insufficient follow-up duration, possible adoption of interventions by participants in the comparison group, and inadequate adherence to recommended interventions by participants in the study population.

Although some researchers have called for large, long-term RCTs examining the effects of sodium-intake reduction on clinical outcomes to inform population-wide sodium-reduction efforts, this approach is similarly not feasible. Such trials would require tens of thousands of participants undergoing randomization to a high-sodium or low-sodium diet, with adherence to the intervention and follow-up of at least 5 years.47 This study design is impractical, particularly given the challenges with adherence to a low-sodium diet in our current food environment. As with many other topics in public health, conflicting findings from studies that use different methods are to be expected. Critical analysis of study methods and measurement and examination of the totality of the evidence are essential in order to interpret results correctly and make appropriate recommendations for action.59

RARE DISEASES — THE IMPORTANCE OF DISEASE REGISTRIES AND OTHER METHODS
Approximately 5000 to 7000 conditions fit the definition of a rare disease, with more than 50 million people affected throughout the world.60,61 Because of small sample sizes and logistic constraints, it is unlikely that RCTs will be performed for most of these conditions; actionable information may be most likely to be obtained from meticulous analysis of the treatment of different patients by different methods.
Such an approach was used to determine that isoniazid, injectable medications, and fluoroquinolone antibiotic agents were most likely to lead to successful treatment for common strains of multidrug-resistant tuberculosis.41 Despite the Orphan Drug Act, which was passed in 1983 to provide industry incentives for the development of clinical treatments for rare diseases, the options for most patients are limited. A movement to create a global rare-disease patient registry along with a centralized database of biorepositories for rare biospecimens followed from a 2010 workshop, sponsored by the National Institutes of Health, involving researchers, advocacy groups, and stakeholders.62 The Rare Diseases Human Biospecimens/Biorepositories (RD-HuB) makes rare-disease specimens available to researchers and informs patients of ongoing studies.
Although such registries could potentially lead to RCTs, attaining sufficient study-population sizes could remain an impediment. Alternately, these registries could be used to collect detailed case studies, including standardized information on individual treatment and clinical status, which could be used to enhance understanding of a particular disease and its treatment and improve the health of affected patients. For example, standardizing and aggregating data on clinical features, treatment, and outcomes from case reports and case series may reveal ways to improve diagnosis and treatment.

COSTS AND INFRASTRUCTURE — RELIABLE RESULTS FROM MORE FEASIBLE STUDY DESIGNS
Large observational studies, with longer follow-up, can be tailored to minimize bias in a manner analogous to the way bias is minimized in RCTs. In one such study, data from the Veterans Health Administration (VA) and Medicare were used to examine outcomes of treatment with sulfonylureas and thiazolidinediones — two second-line drugs for type 2 diabetes.63 The study used physician-prescribing patterns to approximate an RCT: determinations were made for patients to receive a sulfonylurea or thiazolidinedione on the basis of how often their physician had prescribed the drugs during the previous year (i.e., patients of physicians who usually prescribed sulfonylureas were assigned to receive a sulfonylurea, and those whose physicians usually prescribed thiazolidinediones were assigned to receive a thiazolidinedione).
With more than 80,000 patients monitored for up to 10 years, the study was 20 times larger and had a much longer follow-up than previous RCTs comparing the effectiveness of second-line diabetes drugs. The results showed a 68% higher risk of avoidable hospitalization and a 50% higher risk of death associated with treatment with sulfonylureas, as compared with thiazolidinediones, providing strong evidence-based information for clinical decision making while also avoiding many of the limitations of RCTs.

The VA is also undertaking a new type of randomized trial to compare the use of chlorthalidone versus hydrochlorothiazide for the treatment of hypertension.64 Both medications, which are diuretics, have been used for more than 50 years, but more than 95% of the million or more veterans who are prescribed this type of diuretic receive hydrochlorothiazide, as compared with the 2.5% receiving chlorthalidone.65 However, there is evidence that chlorthalidone, the older of the two drugs, is more effective in preventing cardiovascular events66 and reducing mortality.67,68
Using data from electronic medical records, with reliance on the patients’ primary care physician instead of additional study personnel, the trial plans to enroll approximately 13,500 veterans older than 65 years of age who are currently receiving hydrochlorothiazide. These patients will then be randomly assigned to receive hydrochlorothiazide or chlorthalidone over a 3-year study period. This study design simplifies the infrastructure and greatly reduces the costs involved in a traditional, large RCT.64 With approximately 50 million prescriptions for hydrochlorothiazide filled each year in the United States, even small reductions in cardiovascular events associated with chlorthalidone use that may be identified through this study would have a substantial effect in the prevention of cardiovascular disease.

MOVING FORWARD — OVERCOMING THE “DARK MATTER” OF CLINICAL MEDICINE
For much, and perhaps most, of modern medical practice, RCT-based data are lacking and no RCT is being planned or is likely to be completed to provide evidence for action.
This “dark matter” of clinical medicine leaves practitioners with large information gaps for most conditions and increases reliance on past practices and clinical lore.4,69,70
Elevating RCTs at the expense of other potentially highly valuable sources of data is counterproductive. A better approach is to clarify the health outcome being sought and determine whether existing data are available that can be rigorously and objectively evaluated, independently of or in comparison with data from RCTs, or whether new studies (RCT or otherwise) are needed.

New ways of obtaining valuable health data continue to emerge. “Big data,” including information from electronic health records and expanded patient registries, along with increased willingness of patients to participate and share health information, are generating useful data for large interventional studies and providing new opportunities for complementary use of multiple data sources to gain stronger evidence for action.71
For example, although an RCT may show the benefit of a drug, large observational studies can be conducted to refine dosages and identify rare adverse events. In addition, new strategies have been undertaken to increase the efficacy and efficiency of RCTs, including collaborative and adaptive trials to increase enrollment, reduce costs and time to completion, and better identify populations that benefit from treatments.72-74
Advances in genomic science may allow for better understanding of unique characteristics in patients that can affect outcomes of RCTs and other studies and be used to improve the validity of study findings.
There is no single, best approach to the study of health interventions; clinical and public health decisions are almost always made with imperfect data (Table 1TABLE 1

Selected Strengths and Weaknesses of Various Study Designs, along with Examples of Studies with Effects on Policy or Practice.). Promoting transparency in study methods, ensuring standardized data collection for key outcomes, and using new approaches to improve data synthesis are critical steps in the interpretation of findings and in the identification of data for action, and it must be recognized that conclusions may change over time. There will always be an argument for more research and for better data, but waiting for more data is often an implicit decision not to act or to act on the basis of past practice rather than best available evidence. The goal must be actionable data — data that are sufficient for clinical and public health action that have been derived openly and objectively and that enable us to say, “Here’s what we recommend and why.”

Disclosure forms provided by the author are available with the full text of this article at NEJM.org.
The views expressed in this article are those of the author and do not necessarily represent the views of the Centers for Disease Control and Prevention or the Department of Health and Human Services.
I thank Kathryn Foti, M.P.H., Drew Blakeman, M.S., and Robin Moseley, M.A.T., for assistance with preparation of an earlier version of the manuscript and review of relevant literature, and Joanna Taliano, M.L.S., for assistance with literature searches.

SOURCE INFORMATION
From Atlanta, GA. The author is the former director of the Centers for Disease Control and Prevention.
Address reprint requests to Dr. Frieden at tfrieden@gmail.com.

Metastatic Breast Cancer in Patients with a Germline BRCA Mutation and Olaparib

ORIGINAL ARTICLE
Olaparib for Metastatic Breast Cancer in Patients with a Germline BRCA Mutation
Mark Robson, M.D., Seock-Ah Im, M.D., Ph.D., Elżbieta Senkus, M.D., Ph.D., Binghe Xu, M.D., Ph.D., Susan M. Domchek, M.D., Norikazu Masuda, M.D., Ph.D., Suzette Delaloge, M.D., Wei Li, M.D., Nadine Tung, M.D., Anne Armstrong, M.D., Ph.D., Wenting Wu, Ph.D., Carsten Goessl, M.D., Sarah Runswick, Ph.D., and Pierfranco Conte, M.D.
N Engl J Med 2017; 377:523-533August 10, 2017DOI: 10.1056/NEJMoa1706450

BACKGROUND


Olaparib is an oral poly(adenosine diphosphate–ribose) polymerase inhibitor that has promising antitumor activity in patients with metastatic breast cancer and a germline BRCA mutation.

METHODS

We conducted a randomized, open-label, phase 3 trial in which olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer who had received no more than two previous chemotherapy regimens for metastatic disease. Patients were randomly assigned, in a 2:1 ratio, to receive olaparib tablets (300 mg twice daily) or standard therapy with single-agent chemotherapy of the physician’s choice (capecitabine, eribulin, or vinorelbine in 21-day cycles). The primary end point was progression-free survival, which was assessed by blinded independent central review and was analyzed on an intention-to-treat basis.

RESULTS

Of the 302 patients who underwent randomization, 205 were assigned to receive olaparib and 97 were assigned to receive standard therapy. Median progression-free survival was significantly longer in the olaparib group than in the standard-therapy group (7.0 months vs. 4.2 months; hazard ratio for disease progression or death, 0.58; 95% confidence interval, 0.43 to 0.80; P<0.001). The response rate was 59.9% in the olaparib group and 28.8% in the standard-therapy group. The rate of grade 3 or higher adverse events was 36.6% in the olaparib group and 50.5% in the standard-therapy group, and the rate of treatment discontinuation due to toxic effects was 4.9% and 7.7%, respectively. CONCLUSIONS

Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with olaparib monotherapy than with standard therapy. (Funded by AstraZeneca; OlympiAD ClinicalTrials.gov number, NCT02000622.)

Bladder Cancer Care: Diverse Approaches Needed to Further Advance

Diverse Approaches Needed to Further Advance Bladder Cancer Care
Angelica Welch
Published Online: Wednesday, Jul 26, 2017


Due to the success of pivotal trials such as KEYNOTE-045, 5 immunotherapy agents have been approved for the treatment of patients with urothelial carcinoma so far in 2017—but this does not mean that treatment options are diverse, says Elizabeth Plimack, MD.

Nivolumab (Opdivo), atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), and pembrolizumab (Keytruda) have all achieved FDA approval status, but Plimack says none have differentiated themselves.

“Multiple times on expert panels we get asked the difference between these drugs and we just can’t say yet,” Plimack explains, “There may be a difference between the data, or the way the studies were designed—but we do not see a major difference between the drugs themselves.”

In an interview with OncLive, Plimack, chief of the division of genitourinary medical oncology and director of genitourinary research at Fox Chase Cancer Center in Philadelphia, recapped recent advances in bladder cancer and discussed the need for diverse approaches to further improve patient outcomes.
OncLive: What have been some recent impactful studies in bladder cancer?

Plimack: There were 4 abstracts presented [at the 2017 ASCO Annual Meeting] all of which were very interesting. The first one presented was actually an update on The Cancer Genome Atlas (TCGA). That is where centers across the country, and really the world, donated tissue samples for analysis and they did a deep-dive into varying biomarkers and reported on that. The data is really too dense to sort of encapsulate in a brief blurb, but the paper will be forthcoming. It is extending the numbers into the 400-range, before it was in the 100-range, so we are really going to learn a lot from these data which are publicly available to investigators, and is an excellent resource that should be highlighted.

The second abstract that was discussed was the KEYNOTE-045 study. This was originally published in the New England Journal of Medicine in February. It is a randomized phase III study of pembrolizumab versus chemotherapy in metastatic urothelial carcinoma. This is really the only data that we have seen from a randomized trial in urothelial carcinoma, and fortunately this study was positive and then we saw pembrolizumab get approved in the second-line setting based on this study.

We were very interested in seeing an update based on a fresher data cut, and not surprisingly, the overall survival benefit is maintained with further follow-up. We do see at the [18-month] mark, a more stable estimate of overall survival with at least 10% to 15% benefit for patients treated with pembrolizumab versus chemotherapy. That is certainly encouraging. What we also saw that I thought was interesting was that all patients on the chemo arm have come off of treatment, compared to the 33 patients in the pembrolizumab arm who stayed on treatment. So, this sort of speaks to the tail of the curve that we are seeing—even though we sometimes see responses with chemotherapy, and, indeed the progression-free survival was better with chemotherapy, we know from clinical experience and now from this study, that those responses aren’t durable. Occasionally, and what we hope for, is that responses with pembrolizumab are durable.

We also saw an update from the KEYNOTE-052 study, which investigated pembrolizumab in the frontline setting. We have seen these data previously at ESMO and ASCO GU, but this update, interestingly, looked specifically at biomarkers. The PD-L1 biomarker had been looked at in this study, and in fact, for the pembrolizumab bladder program, defined as part of the KEYNOTE-052 study with a cutoff of 10%, and they represented those data [at ASCO].

In addition, they looked at a gene signature that predicted for response. And it looks like that might select out responders a little bit better, whereas the negative predictive value of that test does look a little bit stronger than the PD-L1. What we’d love to see is those data placed on the KEYNOTE-045 data where we have randomized data to see how that biomarker holds up in a randomized trial. We are really urgently looking for biomarkers that are better than PD-L1 in bladder cancer that can help us select treatment—especially as more novel therapies come around—so that patients have options. Right now, it is less important because we have so few options for patients, but I am pretty confident in the next year or so that will change.

How have recent approvals affected the landscape?
It’s interesting. In the last year, we have seen 5 new drugs approved for bladder cancer, which is phenomenal, especially compared to what had been decades prior to that. The problem is, they really all do the same thing. So, while we have a wealth of options, in a sense they are all the same option.

What we are looking for are novel therapies, and there were 2 really interesting abstracts presented at [ASCO] looking at novel approaches, 1 combined with checkpoint inhibitors and 1 that shows there might be success after checkpoint failure.

The first is combining epacadostat with pembrolizumab. There was a lot of data presented on epacadostat at ASCO 2017. It is an IDO inhibitor so it preps the immune microenvironment for better immune response with checkpoint inhibitor. This particular trial was interesting in that it showed a response rate that was higher than we typically see with checkpoint inhibitors—around the 30% rate.

Notably, when we combine [these agents], we see an increase in immune-mediated toxicity. Although the numbers are small with this phase Ib basket study, we did not see a surge in immune-related toxicities—no colitis, no pneumonitis. We did see rash, but again these weren't clinically impactful and most patients were treated with either topical steroids or a brief course of oral steroids and allowed to continue treatment. I think this regimen warrants further attention, both because it is active in multiple tumor types, but also because that efficacy does not seem to be offset by toxicities. So, hopefully, that will hold out in larger studies and I know those are planned for this combination.

Are there any other novel agents of interest?
Another agent that is novel and different—that is not an immune-acting agent—is the ASG-22CE compound; it is an antibody-drug conjugate targeting nectin-4. These data were presented by Dr Dan Petrylak, and we were very encouraged that this study did allow for checkpoint failures, and, in fact, showed an even higher response in checkpoint failures than the rest of the group, even though the numbers were small. So, we are looking for expansion work in this area and with this agent.

NSCLC: Long-Term Results With Proton Beam Therapy Plus Chemotherapy

Promising Long-Term Results With Proton Beam Therapy Plus Chemotherapy In NSCLC Patients
Five-year phase II results justify further investigation of concurrent proton beam therapy and chemotherapy in patients with inoperable non-small-cell lung cancer

Date: 26 Jul 2017
Author: By Shreeya Nanda, Senior medwireNews Reporter
Topic: Non-Small-Cell Lung Cancer, Locally Advanced / Surgery and/or Radiotherapy of Cancer

medwireNews: The final results of a phase II study show that a concurrent regimen of proton beam therapy (PBT) and chemotherapy is efficacious and has acceptable tolerability in the long-term among patients with unresectable stage III non-small-cell lung cancer (NSCLC).

This combined modality could be “an important option with which to definitively treat locally advanced NSCLC”, say Joe Chang, from the University of Texas MD Anderson Cancer Center in Houston, USA, and fellow researchers.

A total of 84 patients with stage IIIA or IIIB disease were enrolled in the study investigating the use of 74-Gy passively scattered PBT, which the investigators say “is an attractive option with which to reduce toxic effects of [chemoradiotherapy]”, alongside a regimen of carboplatin and paclitaxel.

After excluding participants who did not receive protocol-specific PBT, those with inappropriate staging and those lacking follow-up data, 64 patients were followed up for a median of 27.3 months. The median follow-up was 79.6 months for the 27% of study participants who were alive at the last follow-up.

As reported in JAMA Oncology, the 5-year overall and progression-free survival rates were 29% and 22%, respectively, with corresponding median times of 26.5 and 12.9 months. Treatment failures manifested more often as distant recurrences (48% of patients) than as local (16%) or regional (14%) relapses.

The incidences of acute adverse events occurring within 90 days of the last treatment and late adverse events occurring after the 90-day period were low and compared favourably with historical data using photon-based therapy, the study authors report.

Acute grade 2 and 3 oesophagitis was observed in 28% and 8% of study participants, respectively. The corresponding rates of late oesophagitis were 5% and 2%; there was also one case of late grade 4 oesophagitis.

Two percent of patients experienced acute grade 2 pneumonitis and there were no cases of grade 3 or 4 events, while the corresponding incidences of late pneumonitis were 16%, 12% and 0%.

There were no adverse events of grade 5 in either the acute or late setting.

In an accompanying editor’s note, Charles Thomas Jr, from Oregon Health Sciences University in Portland, USA, describes the study as “important” given that “well-designed, prospective clinical trials have lagged as the number of proton centers has increased.”

Looking to the future, he writes: “The current NRG/RTOG protocol 1308 will seek to clarify any survival benefit when comparing photon and proton thoracic radiotherapy atop a platinum-doublet chemotherapy backbone in a randomized clinical trial.

“If the results are encouraging, next-generation particle therapy trials for locally advanced non–small-cell lung cancer may seek to incorporate adaptive planning and delivery along with more advanced image guidance and proton beam modulation.”

References

Chang JY, Verma V, Li M, et al. Proton beam radiotherapy and concurrent chemotherapy for unresectable stage III non–small-cell lung cancer. Final results of a phase 2 study. JAMA Oncol; Advance online publication 20 July 2017. doi: 10.1001/jamaoncol.2017.2032

Thomas Jr CR. Potential of prospective particle therapy trials to increase the therapeutic ratio for locally advanced lung cancer. JAMA Oncol; Advance online publication 20 July 2017. doi: 10.1001/jamaoncol.2017.2165