Futibatinib for FGFR2-Rearranged Intrahepatic Cholangiocarcinoma.

BACKGROUND: Alterations in fibroblast growth factor receptor 2 (FGFR2) have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer with a poor prognosis. Futibatinib, a next-generation, covalently binding FGFR1-4 inhibitor, has been shown to have both antitumor activity in patients with FGFR-altered tumors and strong preclinical activity against acquired resistance mutations associated with ATP-competitive FGFR inhibitors. METHODS: In this multinational, open-label, single-group, phase 2 study, we enrolled patients with unresectable or metastatic FGFR2 fusion-positive or FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma and disease progression after one or more previous lines of systemic therapy (excluding FGFR inhibitors). The patients received oral futibatinib at a dose of 20 mg once daily in a continuous regimen. The primary end point was objective response (partial or complete response), as assessed by independent central review. Secondary end points included the response duration, progression-free and overall survival, safety, and patient-reported outcomes. RESULTS: Between April 16, 2018, and November 29, 2019, a total of 103 patients were enrolled and received futibatinib. A total of 43 of 103 patients (42%; 95% confidence interval, 32 to 52) had a response, and the median duration of response was 9.7 months. Responses were consistent across patient subgroups, including patients with heavily pretreated disease, older adults, and patients who had co-occurring TP53 mutations. At a median follow-up of 17.1 months, the median progression-free survival was 9.0 months and overall survival was 21.7 months. Common treatment-related grade 3 adverse events were hyperphosphatemia (in 30% of the patients), an increased aspartate aminotransferase level (in 7%), stomatitis (in 6%), and fatigue (in 6%). Treatment-related adverse events led to permanent discontinuation of futibatinib in 2% of the patients. No treatment-related deaths occurred. Quality of life was maintained throughout treatment. CONCLUSIONS: In previously treated patients with FGFR2 fusion or rearrangement-positive intrahepatic cholangiocarcinoma, the use of futibatinib, a covalent FGFR inhibitor, led to measurable clinical benefit. (Funded by Taiho Oncology and Taiho Pharmaceutical; FOENIX-CCA2 ClinicalTrials.gov number, NCT02052778.).

Impact of Hypomethylating Agent Use on Hospital and Emergency Room Visits, and Predictors of Early Discontinuation in Patients With Higher-Risk Myelodysplastic Syndromes.

BACKGROUND: Previous analyses using the SEER-Medicare database have reported substantial underutilization of hypomethylating agents (HMAs) among patients with higher-risk myelodysplastic syndromes (MDS), and an association between poor HMA persistence and high economic burden. We aimed to compare rates of hospitalizations and emergency room (ER) visits among patients with higher-risk MDS according to use or non-use of HMA therapy, and to explore factors associated with early discontinuation of HMA therapy. PATIENTS AND METHODS: We used the 2010-2016 SEER-Medicare database to identify patients aged ≥66 years with a new diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) between 2011 and 2015. New hospitalizations and ER visits during the 12 months following MDS diagnosis were determined. Treatment discontinuation was defined as stopping HMA therapy before 4 cycles. RESULTS: Overall, 664 (55.8%) patients were HMA users and 526 (44.2%) non-users. Non-users had more hospitalizations (mean 0.47 vs. 0.30, P < .001) and ER visits (mean 0.69 vs. 0.41, P = .005) per month than HMA users. Among HMA users, 193 (29.1%) discontinued HMA therapy before 4 cycles, and 91 (47.2%) of these after 1 cycle. Older age and poor performance status were associated with higher risk of HMA discontinuation. CONCLUSION: An increased rate of hospitalizations and ER visits occurred in HMA non-users vs. HMA users. Approximately one-third of patients discontinued HMA therapy early. Predictors of discontinuation included older age and poor performance status. Novel approaches are needed to improve utilization and persistence with HMA therapy and associated outcomes, particularly among these higher-risk groups.

Real-world burden of chemotherapy-induced myelosuppression in patients with small cell lung cancer: a retrospective analysis of electronic medical data from community cancer care providers.

AIMS: Chemotherapy-induced myelosuppression, which commonly exhibits as neutropenia, anemia, or thrombocytopenia, represents a substantial burden for patients with cancer that affects health-related quality of life and increases healthcare resource utilization (HCRU). We evaluated the burden of myelosuppression among chemotherapy-treated patients with small cell lung cancer (SCLC) using real-world data from community cancer care providers in the Western United States. MATERIALS AND METHODS: This was a retrospective, observational analysis of electronic medical records (EMRs) from Providence St. Joseph Health hospital-associated oncology clinics between January 2016 and December 2019. Patient demographics were assessed from the date of first SCLC diagnosis in adult patients with chemotherapy-induced grade ≥3 myelosuppression in first-line (1L) or second-line-and-beyond (2L+) treatment settings. Myelosuppressive adverse events (AEs), treatment patterns, and HCRU were assessed from the date of chemotherapy initiation (index date) until 12 months, date of the last visit, date of death, or study end, whichever occurred earliest. RESULTS: Of 347 eligible patients with SCLC who had received chemotherapy (mean age 66; 49% female), all had received at least 1L treatment, and 103 (29.7%) had a 2L + treatment recorded within the EMR during the study period. Of 338 evaluable patients with longitudinal laboratory data, 206 (60.9%) experienced grade ≥3 myelosuppressive AEs, most commonly neutropenia, anemia, and thrombocytopenia (44.9, 41.1, and 25.4 per 100 patients, respectively). Rates of granulocyte colony-stimulating factor use and red blood cell transfusions were 47.0 and 41.7 per 100 patients, respectively. There was a trend toward increasing the use of supportive care interventions and visits to inpatient and outpatient facilities in patients with myelosuppressive AEs in more than one cell lineage. CONCLUSIONS: Chemotherapy-induced myelosuppression places a substantial real-world burden on patients with SCLC in the community cancer care setting. Innovations to protect bone marrow from chemotherapy-induced damage have the potential to reduce this burden.

PLAIN LANGUAGE SUMMARYThis study looked at the medical records of people with a particular type of lung cancer known as small cell lung cancer. When treated with chemotherapy, people with this cancer may develop a condition called myelosuppression. This causes people to have fewer blood cells, which can lead to tiredness, or increase the risk of infection or bleeding. The study looked at what types of chemotherapy people with small cell lung cancer were given, what the side effects of myelosuppression were, how often the side effects were reported, and what treatments were given to manage these side effects. The study also looked at whether people with side effects from myelosuppression needed more visits to the doctor or hospital. Around 3 out of 5 people in the study experienced serious side effects resulting in reduced numbers of white blood cells (which fight infection), red blood cells (which carry oxygen), or platelets (which help the blood to clot), and many needed drugs or blood transfusions to treat these side effects. On average, people with side effects from myelosuppression had more visits to healthcare facilities than those people without these side effects. The findings suggest that myelosuppression places a large burden on people with small cell lung cancer who are treated with chemotherapy.

Real-world use and outcomes of hypomethylating agent therapy in higher-risk myelodysplastic syndromes: why are we not achieving the promise of clinical trials?

Myelodysplastic syndromes are hematological malignancies characterized by ineffective hematopoiesis and a high risk of progression to acute myeloid leukemia. Hypomethylating agents (HMAs), azacitidine and decitabine, are standard of care therapy for higher-risk myelodysplastic syndromes. However, outcomes reported for real-world studies fall short of those achieved in clinical trials. We conducted a targeted literature review exploring real-world utilization, persistence and outcomes with intravenous and subcutaneous HMA therapies to better understand barriers to achieving optimal outcomes in clinical practice. The potential benefits of oral HMA therapy were also explored. Underutilization and poor persistence with HMA therapy are associated with suboptimal outcomes, highlighting the need for approaches to improve utilization and persistence, so that patients achieve the optimum benefit from HMA therapy.

Lay abstract Myelodysplastic syndromes (MDS) are bone marrow disorders affecting the production of blood cells. In some patients, MDS can progress to acute myeloid leukemia (AML), an aggressive blood cancer with poor prognosis. Patients with higher-risk MDS are often treated with a type of chemotherapy called hypomethylating agents (HMAs). Studies conducted in real-world clinical practice have shown HMAs to be less effective than has been found in clinical trials. We reviewed available studies exploring real-world utilization, persistence and outcomes with current HMA therapies to better understand any barriers to patients achieving the best outcomes. Two important factors were found to be the underuse of HMAs and poor persistence with HMA therapy, highlighting the need for approaches to improve HMA utilization and persistence.

Cancer Patients' Perspectives and Experiences of Chemotherapy-Induced Myelosuppression and Its Impact on Daily Life.

PURPOSE: To evaluate which side effects of chemotherapy are considered most burdensome by patients with cancer, identify which health care professionals pay most attention to symptoms associated with chemotherapy-induced myelosuppression (CIM) from the patient perspective, and capture the "patient voice" describing how CIM impacts their daily lives. PARTICIPANTS AND METHODS: Online survey of participants with breast, lung, or colorectal cancer who had received chemotherapy within the past 12 months and experienced ≥1 episode of CIM in the past year. Participants were asked to answer close-ended questions and provide qualitative responses to: "In your own words, please describe how side effects from myelosuppression have impacted your life." RESULTS: Among 301 survey participants, fatigue was the most frequently reported side effect of chemotherapy; 55% of participants rated fatigue as highly bothersome (9 or 10 on a 1-10 scale of "bothersomeness"). Participants rated symptoms associated with CIM, including fatigue, weakened immune system (infections), bleeding and/or bruising, and shortness of breath, as being as bothersome as other side effects of chemotherapy, including alopecia, neuropathy, and nausea/vomiting. Overall, 24-43% of participants thought that CIM and its symptoms had a negative impact on their daily lives, including their ability to complete tasks at home and work, and to socialize. Qualitative responses supported these findings; participants highlighted that CIM-related symptoms, particularly fatigue and fear of infections, affected their ability to be physically active, complete work, or continue meaningful relationships with friends and family. CONCLUSION: Participants described a real-world impact of CIM that often isolates them from family and friends, and means that they are unable to work or perform tasks of daily living. Using measures that help patients to recognize and communicate the signs and symptoms of CIM might increase the likelihood of maintaining daily lives as close to normal as possible, during and after chemotherapy treatment.

Patient Burden and Real-World Management of Chemotherapy-Induced Myelosuppression: Results from an Online Survey of Patients with Solid Tumors.

INTRODUCTION: Chemotherapy-induced myelosuppression (CIM) is one of the most common dose-limiting complications of cancer treatment, and is associated with a range of debilitating symptoms that can significantly impact patients' quality of life. The purpose of this study was to understand patients' perspectives on how the side effects of CIM are managed in routine clinical practice. METHODS: An online survey was conducted of participants with breast, lung, or colorectal cancer who had received chemotherapy treatment within the past 12 months, and had experienced at least one episode of myelosuppression in the past year. The survey was administered with predominantly close-ended questions, and lay definitions of key terms were provided to aid response selection. RESULTS: Of 301 participants who completed the online survey, 153 (51%) had breast cancer, 100 (33%) had lung cancer, and 48 (16%) had colorectal cancer. Anemia, neutropenia, lymphopenia, and thrombocytopenia were reported by 61%, 59%, 37%, and 34% of participants, respectively. Most participants (79%) reported having received treatment for CIM, and 64% of participants recalled chemotherapy dose modifications as a result of CIM. Although most participants believed their oncologist was aware of the side effects of CIM, and treated them quickly, 30% of participants felt their oncologists did not understand how uncomfortable they were due to the side effects of CIM. Overall, 88% of participants considered CIM to have a moderate or major impact on their lives. CONCLUSION: The data highlight that despite the various methods used to address CIM, and the patient-focused approach of oncologists, the real-world impact of CIM on patients is substantial. Improving communication between patients and health care providers may help improve patients' understanding of CIM, and foster shared decision-making in terms of treatment. Additional insights from patients should be obtained to further elucidate the totality of life burden associated with CIM.

This study looked at people with cancer who received chemotherapy and developed a condition where their bone marrow activity was reduced, called myelosuppression. This meant they had fewer red blood cells that carry oxygen around the body, white blood cells that help fight infections, and platelets that help the blood to clot. The researchers wanted to understand how chemotherapy-induced myelosuppression affects peoples' lives and their cancer treatment, and people's experiences of treatment for myelosuppression. Overall, 301 people in the USA with breast, lung, or large bowel (colorectal) cancer completed an online survey. They had all received chemotherapy in the last year, and had myelosuppression at least once during their treatment. The survey showed that around 8 in 10 people (79%) had to be treated for myelosuppression, and around 7 in 10 people (73%) felt they received treatment for myelosuppression quickly. Chemotherapy was delayed, reduced, or stopped because of myelosuppression in around 6 in 10 people (64%). Around 3 in 10 people (30%) felt their oncologist did not understand the discomfort that myelosuppression caused them, and around 9 in 10 people (88%) felt that myelosuppression made their quality of life worse. The researchers concluded that because myelosuppression impacts peoples' lives and their ability to keep receiving chemotherapy to treat their cancer, effective prevention and treatment for this condition are important. Better communication between people and their health care teams could help them to understand how people experience myelosuppression and make plans for treatment together.

Practice Patterns and Treatment Challenges in Acute Postoperative Pain Management: A Survey of Practicing Physicians.

INTRODUCTION: The management of acute postoperative pain remains a significant challenge for physicians. Poorly controlled postoperative pain is associated with poorer overall outcomes. METHODS: Between April and May 2017, physicians from an online database who regularly prescribe intravenous (IV) medications for acute postoperative pain completed a 47-question survey on topics such as patient demographics, IV analgesia preferences, factors that influence prescribing decisions, and the challenges and unmet needs for the treatment of acute postoperative pain. RESULTS: Of 501 surveyed physicians, 55% practiced in community hospitals, 60% had been in practice for > 10 years, and 60% were surgeons. The three categories of IV pain medications most likely to be prescribed to patients with moderate-to-severe pain immediately after surgery were morphine, hydromorphone, or fentanyl (95.8% of respondents); COX-2 inhibitors or nonsteroidal anti-inflammatory drugs (73.7%); and acetaminophen (60.5%). Past clinical experience (81.6%), surgery type (78.2%), and onset of analgesia (67.1%) were practice-related factors that most determined their medication choice. Key patient-related risk factors, such as avoidance of medication-related adverse events (AEs), each influenced prescription decisions in > 75.0% of physicians. Nausea and vomiting were among the most common challenges associated with postoperative pain management (76.2 and 60.3%, respectively), and avoidance of analgesic medication-related AEs was among the three most influential patient-related factors that determined prescribing decision (75%). Physicians reported the top unmet need for acute pain management in patients experiencing moderate-to-severe postoperative pain was more medications with fewer side effects (i.e., nausea, vomiting, and respiratory depression; 80.7%). CONCLUSIONS: Opioids remain an integral component of multimodal acute analgesic therapy for acute postoperative pain in hospitalized patients. The use of all IV analgesic medications is limited by concerns over AEs, particularly with opioids and in high-risk patients. There remains a key unmet need for effective analgesic medications that are associated with a lower risk of AEs. FUNDING: Trevena, Inc.

A retrospective observational analysis of post-pandemic influenza-related outcomes in the United Kingdom, 2010-2014.

This study set out to evaluate influenza- and respiratory-related illnesses recorded during primary care physician consultations in England following the H1N1 pandemic in 2009 and to enable the development of a dynamic disease model. Data were obtained from the Clinical Practice Research Datalink of primary care records over four influenza seasons (2010-2014). The primary outcome of the study was incidence of influenza- and respiratory-related diagnoses, calculated per practice and by season and age group. Upper respiratory tract infection diagnoses were most frequently recorded (mean seasonal practice level incidence; 3,762 consultations per 100,000 [SD = 1,989]), and influenza-related diagnoses were least frequently recorded across all seasons, except one. Incidence rates for the under 18 population were higher than those for the general population, in particular for upper respiratory tract infection (range of 8,024-9,950 versus 3,228-4,120, respectively) and otitis media diagnoses (2,668-3,652 versus 782-1,057, respectively). For influenza-related diagnoses, the 65+ age group, the 0 to <2 and 2 to <4 groups had a higher risk (risk ratio = 1.33, 1.12 and 1.16, respectively) than other age groups. This study provides valuable insight into the incidence of influenza- and respiratory-related diagnoses in the primary care setting in England, and suggests a higher burden of disease in young children and the elderly. The study also indicates that some influenza illness is likely to be reported under respiratory-related diagnoses, given the low incidence of influenza-related diagnoses in the study.

European and Russian physician awareness of best management approaches for infections due to antibiotic-resistant Gram-negative bacteria.

OBJECTIVES: The rapid spread of infections due to antibiotic-resistant, Gram-negative bacteria in Europe and surrounding regions requires a heightened level of awareness among physicians within their practice settings. METHODS: We surveyed 800 physicians who treat these infections across France, Germany, Spain, Italy, and Russia to assess their awareness of best management approaches. RESULTS: We found that more than two-thirds do not consider themselves highly aware of best management practices. The respondents are facing these resistant infections as evidenced by the antibiotics they report using and their stated interest in newer agents. Respondents indicated that precious time is lost waiting for culture results, but also said they will need more information about accuracy, use, and costs for adopting rapid molecular testing. CONCLUSIONS: The survey further identified the need for treatment guidelines and clinical decision support tools that can be applied at the bedside.

When People with Opioid-Induced Constipation Speak: A Patient Survey.

INTRODUCTION: Opioid-induced constipation (OIC) is a common consequence of opioid use for chronic pain. OIC creates problems for patients independent of their pain syndromes, in addition to threatening pain treatment effectiveness. Healthcare practitioners need to be alert to how patients talk about OIC so that it is not missed. Using a survey mechanism, we sought patient expressions of the personal impact OIC imposes on how they are able to live their lives and on meanings that symptom relief would produce. METHODS: We used an online survey asking adults with OIC about quality of life implications of OIC and focused on open-ended text responses to questions about personal impacts of straining and meanings attached to OIC symptom relief. Participants were from the US, Canada, UK, Germany, Sweden, and Norway. RESULTS: A survey of 513 people with OIC produced 280 text responses concerning the impacts of straining on quality of life and 469 text responses on the meaning OIC symptom relief would confer. Text responses about the quality of life impacts of straining often included explicit descriptions conveying physical, psychological, or practical problems. Text responses about the meaning conferred from OIC symptom relief primarily concentrated around freedom from the constraints that OIC can impose. CONCLUSIONS: Patients are willing and able to comment on the problems OIC cause them, using a variety of terms and phrases. Their comments concerning impacts on their lives will often refer to physical consequences, psychological effects, or practical implications. These insights provide healthcare practitioners guidance on how to engage patients about OIC.

The Early Engagement Model in Product Development: Linking "Proof of Concept" to "Proof of Medical Value".

In a rapidly changing health care environment, it is more important than ever that pharmaceutical manufacturers improve the quality and efficiency of their research and development efforts in order to help ensure the right drug gets to the right patient at the right time. The evolving role of the Medical Affairs, Health Economics & Outcomes Research (HEOR) and other functions engaged in evidence generation within the pharmaceutical industry is leading to earlier involvement in the clinical development process so that the proof of concept for new therapies can be more strongly linked to the proof of medical value. In this article, the authors outline key components of an Early Engagement Model that connects the proof of concept to proof of medical value through a systematic approach linking molecular profile with early insights on disease, unmet needs, stakeholder requirements, and patient-centric differentiation.

Patient preferences for change in symptoms associated with opioid-induced constipation.

INTRODUCTION: While opioids have become a standard treatment option for those experiencing moderate to severe chronic pain, side effects of constipation and related symptoms have interfered with their usage in as many as 40-50% of treated patients. Prior research has elucidated the range of these symptoms, but no study has determined which of these symptoms patients most desire improving or whether improving constipation itself by as little as one more bowel movement per week is deemed an important change. METHODS: We conducted an online patient survey of 513 participants residing in one of six countries who reported having chronic pain, were taking opioids, and experiencing opioid-induced constipation (OIC) to address these questions. RESULTS: Respondents rank ordered their preferences and the following eight symptoms generated >80% endorsement as important to improve: improvement in having bowel movements without rectal pain, soft stools that are not loose or watery, regular bowel movements, a reduction in rectal straining, relief from feeling bloated, feeling less fear about having OIC when following their opioid medication regime, a desire to worry less overall about having a bowel movement, and with less 'stomach' area pain. When asked 'how important is it you to have 1 more bowel movement per week", over 90% endorsed it was 'somewhat', 'very', or 'extremely important' with nearly 70% (n = 354) endorsing the 'extremely' or 'very important' response options. In multivariate models, being in more overall pain or reporting fewer than 3 bowel movements per week were found to be independent predictors of the importance. CONCLUSIONS: These results highlight the notable range of OIC symptoms most desired by patients to improve and demonstrate that bowel movements of only one more per week were important to register a meaningful improvement. The latter is particularly helpful for those assessing the minimal clinically important difference in treating this condition.

A framework for pharmaceutical value-based innovations.

The rapidity of change and increasing complexity of today's healthcare environment dictates that pharmaceutical companies refine their drug development process to ensure that products provide maximal value to consumers. Innovation should receive the support and encouragement it deserves but the balance between cost of therapy and enhanced benefits to the end users, the patients, must not be compromised. The health or quality-of-life outcomes that therapies are likely to achieve need to be clearly stated for patients so they know what to expect before beginning treatment. A drug development program that incorporates principles of 'patient-centered medicine' early on can help define the true value of a health technology. This demands not only demonstrating value as measured by actual patient experience and patient-reported outcomes, but understanding the unmet needs of multiple stakeholders: what is their perception of what represents value? What factors impact healthcare coverage decisions? In this paper, we describe an illustrative framework designed to weave 'patient-centric' medical and real-world evidence into the phases of research and development. This evidence and value development framework works iteratively, providing useful insights parallel to product development from early phase to life-cycle management while forming a progressive evidence chain throughout the phases of research and development. This in turn leads to the creation of value-based innovation with robust foundational evidence for clinical decisions, postlaunch coverage and reimbursement evaluations.

Integrating scientific and real-world evidence within and beyond the drug development process.

Newly developed healthcare treatments face a complex environment with many stakeholders who can accelerate or decelerate adoption, most notably the healthcare system payers. Understanding and integrating their needs earlier in clinical development will ensure a smoother transition from bench to bedside. This paper describes a new approach to shaping a more effective complementary process of 'value' evidence generation both in and outside the clinical drug development process. We propose that biopharmaceutical companies consider bringing new solutions to market by marshaling cross-functional approaches to what we term an evidence-definition phase, evidence-generation phase and evidence-translation phase to drug and technology research and development. The organization of ongoing discovery, evaluation and translation with a 'real- world' perspective should provide a more streamlined approach to ensure both regulatory and eventual marketplace success.

Integrating new approaches for clinical development: translational research and relative effectiveness.

Translational research and relative effectiveness are being incorporated into drug development programs to meet the demands for more robust evidence generation to support the value of new therapies. Translational research includes translating basic research into clinical practice, controlled clinical trials into potential clinical implications, evidence-based guidelines into routine clinical practice and standard practices into population health. These research concepts link with real-world outcomes, and feed into each other to improve the efficiency of research. Translational research can run into road blocks in terms of conveying the added or comparative value of research or during adoption into clinical practice. Understanding these roadblocks and developing solutions are important for success. Comparative effectiveness research can be a useful research technique to accomplish many translational medicine goals. These studies generally include heterogeneous patient populations and evaluate outcomes of relevance to payers and health technology assessors. Comparative effectiveness research can be used in drug development; different methodologies may be useful in different phases. In this article, suggestions and examples of successful use of comparative effectiveness studies are provided. Translational research and comparative effectiveness research, although clearly independent concepts, can provide a focused approach to drug development, resulting in products entering the market that bring added benefit to patients and the healthcare system overall.