Medical World News: April 2020

April 12, 2020

Policy, clinical, and targeted therapy updates in oncology.

Oncology Care First Is a Big Step Toward Bundled Payments in Cancer Care, Authors Say

Oncology Care First (OCF), proposed as the successor to the Oncology Care Model (OCM), will be a major step toward shifting cancer care to bundled payments, according to leaders from an emerging network of community oncology practices.

Writing in JCO Oncology Practice, published by the American Society of Clinical Oncology, authors from OneOncology highlighted 3 key insights about the OCF, which could take eff ect by January 1, 2021. The Center for Medicare and Medicaid Innovation (CMMI) sent out a Request for Information on November 1, 2019, to replace the OCM, which involves 175 practices in a 5-year pilot to bring risk-sharing strategies to oncology care.

The OCM is built on a fee-for-service (FFS) framework, with practices receiving monthly payments to cover the cost of bringing services to patients that include better care coordination, 24/7 access to medical records, greater access to same-day appointments, and a focus on care planning and survivorship care. Most evaluations of the OCM say it has been good for patients, but that the pricing formulas lag behind the escalating costs of some innovative drugs. While there are similarities to the OCM, the new model has features “that could have a substantial impact on practices that choose to participate,” the authors write.

The OneOncology authors note the following:

• CMS wants to shift some of the FFS payment to capitation, which “will pose challenges for OCF participants.” Evaluation and management (E/M) services and drug administration fees, which were previously outside the monthly practice transformation fee, would be folded inside it.

• Improved performance-based-payment formulas would do a better job of accommodating rapidly rising drug costs‚and protect oncologists from being held responsible for events that are beyond their control.

• New requirements may be added to require practices to gather patient-reported outcomes (PROs).

The potential challenges of gathering PROs were noted during a CMMI listening session, and the Community Oncology Alliance, an advocacy group, has called for this requirement to be phased in. Coauthor Stephen M. Schleicher, MD, MBA, discussed with Evidence-Based Oncology™ the apparent‚ positive changes to the drug reimbursement formula of the OCF, which calls for making pricing adjustments by cancer type.

However, “the bundling of E/M and drug administration services into 1 prospective payment could be a sign of what may come,” the authors write. They compare the proposal with what CMMI tried to do with the Radiation Oncology Model, which faced signifi cant pushback.

Many leading OCM practices have just started the fi rst year of 2-sided or “downside” risk, in which they face the prospect of owing Medicare money if they fail to reach predetermined fi nancial benchmarks. With this in mind, the Community Oncology Alliance (COA), an advocacy group that has pressed for changes to the OCM, has called on CMMI to delay the start of the OCF until January 2022.

“We believe the proposed timeline is not feasible for both participating OCM practices and practices attempting to apply for OCF Model participation without prior participation in the OCM,” COA said‚in its response‚to the November call for feedback. “Some practices have only just accepted a shift to down-side risk in the OCM, and most have not yet received substantial data to help them understand their performance in 2-sided risk.‚Forcing practices with OCM experience to immediately join 2-sided risk in the OCF Model would expose practices to signifi cant volatility due to a range of uncertainties in the proposed payment methodology.”

The authors in JCO Oncology Practice warn that the shift from OCM to the OCF is a greater transition than practices may realize: “These proposed changes not only represent a near-term progression toward the CMS’ goal to augment its value-based payment models for cancer, they also provide signals on how CMMI may view the future of value-based care in oncology.”

Reference

Young G, Schleicher SM, Dickson NR, Lyss AJ. Insights from the Oncology Care First proposal—where we’ve been and where we’re going in value-based care [published online February 25, 2020].‚JCO Oncol Pract. doi: 10.1200/JOP.20.00015.

Novel Blood Biopsy Detects MRD in Early-Stage Breast Cancer

Metastatic disease is the leading cause of death in the more than 600,000 people worldwide who die of‚breast cancer‚each year. A new blood-based assay to detect minimal residual disease (MRD) in patients with stage 0 to 3 breast cancer was shown to have 100-fold greater sensitivity compared with digital droplet polymerase chain reaction, according to‚results published online‚in‚Clinical Cancer Research.

The new test was developed by a team of Boston-based investigators, who cited the need for “more sensitive liquid biopsies, with greater dynamic range, to identify patients with MRD sooner.” They noted that the new tests could also help identify higher-risk patients in some instances and avoid deleterious treatment in others.

“Our goal is to be able to turn patients who would have developed metastatic disease into patients who won’t,”‚stated‚co-first author Heather Parsons, MD, MPH, a medical oncologist at‚Dana-Farber Cancer Institute‚and associated scientist at the‚Broad Institute‚of Massachusetts Institute of Technology. “In the future, if we can find those patients with residual cancer early enough, determine whether they would benefi t from another course of therapy, and give them an effective additional treatment, we could potentially change the course of their disease.”

The investigators used retrospective analysis to identify 142 patients who underwent treatment for early-stage disease, tracking their MRD levels after curative-intent surgery at 2 main time points: postoperative (postop) (median, 3.53 months; range, 0.23-8.43) and 1 year out (median, 14.2 months; range, 6.77-21.7). The patients were followed for up to 13 years.

The patients’ tumors were fi rst analyzed via‚whole-exome sequencing‚(WES), with those results used to tailor individualized MRD tests that were run on the patients’ 370 circulating cell-free DNA samples. A median of 57 mutations (range, 2-346) were targeted in each patient. Seventy-eight percent (n = 111) of patients had postop samples available, while 86% (n = 122) had 1-year samples. In addition, the median lead time between the first MRD-positive result and disease recurrence was 18.9 months (range, 3.4-39.2) in the patients with the most mutations tracked.

Distant disease recurrence was shown to be more likely if MRD was detected at the 1-year mark (HR, 20.8; 95% CI, 7.3-58.9) compared with the postop setting (HR, 5.1; 95% CI, 2.0-12.7). Also in these patients, the positive and negative predictive values came in at 0.70 and 0.77, respectively. Overall, the clinical sensitivities were 81% in patients with newly diagnosed metastatic breast cancer, 23% in the postop setting, and 19% at the 1-year mark.

“We’re working to further improve the technology now to catch as many of these patients as possible,” said Viktor Adalsteinsson, PhD, associate director of the Gerstner Center for Cancer Diagnostics‚at Broad. “When we did detect residual disease in blood, following initial courses of treatment, it was a strong predictor of future recurrence. While this was a retrospective study, if a blood biopsy can give clinicians this early warning in real time, that might provide the opportunity to alter a patient’s outcome.”

Despite the positive results, the authors did bring attention to 2 important study limitations. They mentioned how their blood sampling was infrequent, compared with other studies, and took place close to the same time as treatment decisions. In addition, WES was not able to identify enough mutations in every patient. As a next step, the authors recommend that future blood-based assays aiming for extra sensitivity use whole-genome sequencing “to identify more mutations to track in all patients.” They also call for prospective studies of MRD in breast cancer that can further prove its value to the fi eld.­

Reference

Parsons HA, Rhoades J, Reed SC, et al. Sensitive detection of minimal residual disease in patients treated for early-stage breast cancer [published online March 13, 2020]. Clin Can Res. doi: 10.1158/1078-0432.CCR-19-3005.

Study Examines Fixed-Duration Therapy in Patients With MM Ineligible for Transplants

Continuous therapy is likely the best choice for most patients with newly diagnosed, transplant-ineligible multiple myeloma (MM), but results of a new study indicate that treatment-free intervals (TFIs) might be a good option for some patients, provided the fi rst-line therapy is effective. MM tends to aff ect the elderly. As many as 45% of new cases diagnosed in the United Kingdom are cases in which the patient is aged at least 75 years. Three in 10 patients with MM are considered frail, meaning their ability to withstand grueling treatment is limited.

At the same time, new advancements in the treatment of the incurable disease are making it possible for more people to live without the cancer progressing.

Continuous lenalidomide and dexamethasone has been shown to boost progression-free survival (PFS), as hasŠcontinuous daratumumab with bortezomib, melphalan, and prednisolone. Newer research has suggested that daratumumab with lenalidomide and dexamethasone isŠalso an eff ective treatment. The combination of an elderly population with new, eff ective treatment options presents a conundrum for some patients and their physicians: What is the best way to maintain or boost quality of life for these patients given the incurability of the disease? In some cases, physicians and patients opt for fi xed-duration therapy (FDT), with TFIs. In other cases, treatment interruptions prove necessary due to toxicities.

In a study published this month in PLoS One, a team of British researchers attempted to understand the results of using TFIs in MM therapy. “In view of the recent shift towards continuous therapy, we looked to evaluate the TFI as an additional metric of effi cacy in routine practice, after 1st and subsequent lines of therapy, in a large cohort of [transplant-ineligible, newly diagnosed MM] patients,” wrote corresponding author Faouzi Djebbari, MPharm (Hons), MSc, of Oxford University Hospitals, in the United Kingdom. To better understand the impact of treatment intervals, Djebbari and colleagues looked at a data set from the UK Thames Valley Cancer Network, identifying patients with transplant-ineligible, newly diagnosed MM who underwent at least 1 cycle of systemic chemotherapy between the years 2009 and 2017.

Patients who had been involved in clinical trials were excluded, leaving a total of 292 subjects. The investigators wanted to evaluate the length of treatment intervals, and also compare them with overall survival (OS) rates and PFS rates. Two-thirds of patients (67%) in the cohort responded to fi rst-line therapy. After that round, the median TFI was 6.9 months. However, after the second round of therapy, the TFI dropped to just 1.8 months. After the third round, the TFI was just 0.6 months.

OS in the cohort was 30.2 months and median PFS was 9.0 months, although the latter varied based on the therapy chosen. The data showed that patients aged over 75 years had inferior OS and PFS rates compared with patients 75 years and younger.

Djebbari and colleagues concluded that continuous therapy is preferable to FDT for most patients, and thus providers ought to shift toward the former. “However, when continuous therapy is not appropriate due to patient choice, or toxicities leading to discontinuation, an effi cacious (not limited to thalidomide or bortezomib) but tolerable FDT strategy remains a reasonable alternative approach, which can produce a meaningful TFI,” they wrote.

Reference

Djebbari F, Sharpley FA, McLain-Smith S, et al. Treatment-free interval as an additional measure of efficacy in a large UK dataset of transplant ineligible myeloma patients. PLoS ONE. 2020;15(2):e0229469. doi: 10.1371/journal.pone.0229469.

New Study Offers First Direct Comparison Between Venetoclax, Ibrutinib in CLL

Venetoclax has increasingly become a prominent therapeutic option for patients with chronic lymphocytic leukemia (CLL). Now, a new study evaluates its eff ectiveness against another well-known therapy, ibrutinib. Writing in the journal Haematologica, investigators from the United States and United Kingdom note that no such comparison has previously been made between the 2 therapies.

The study comes as treatment of the relapsing/remitting form of CLL (R/R CLL) has been dramatically reshaped by the development and approval of novel agents. Ibrutinib is a Bruton tyrosine kinase inhibitor targeting B-cell receptor pathway signaling. First author Toby A. Eyre, MBChB, of Oxford University Hospitals in the United Kingdom, notes that the drug has shown signifi cant benefit as a monotherapy for patients with relapsing CLL. Another drug, idelalisib, targets the same pathway and has been approved for use in combination with rituximab, an anti-CD20 agent. However, despite improvements in progression-free survival (PFS) among patients who have taken idelalisib, Eyre and colleagues say toxicity concerns have limited its use.

Venetoclax is a B-cell lymphoma—2 inhibitor, approved for use with or without rituximab. “Venetoclax is increasingly utilized at fi rst relapse in combination with rituximab for a 2-year fi xed duration,” the investigators write. “However, to date, no prospective trials have directly compared ibrutinib [with] venetoclax as [first novel agent] (NA1) in R/R CLL.”

Eyre and his team sought to change that by creating a large-scale, international, multicenter study; they utilized data from previous studies evaluating each novel agent. They found data regarding 433 patients who had received ibrutinib or venetoclax as NA1, with or without an anti-CD20 agent. Of those, PFS data were available for 417 patients. Median follow-up was 14.0 months for the patients on ibrutinib (n = 385), and 13.5 months for the patients receiving venetoclax (n = 48).

The primary end points of the study were overall response rate (ORR) and PFS.

The investigators found that ibrutinib was associated with a median ORR of 71% and a median PFS rate of 12%, while patients on venetoclax experienced a median ORR of 96% and a median PFS rate of 56%. Dose interruptions were reported in about one-third of patients in each cohort, and dose reductions were reported in roughly a quarter of patients for both ibrutinib (22%) and venetoclax (26%). Discontinuation rates were 41% for ibrutinib and 25% for venetoclax. In the case of ibrutinib, the most common reasons given for discontinuation were adverse events (22%), CLL progression (8%), and Richter’s transformation (2%), Eyre and colleagues write.

Allogeneic stem-cell transplantation was the most common reason for discontinuation in the venetoclax cohort (10%), followed by CLL progression (4%) and unrelated death event (4%). Venetoclax also had a superior complete response rate, which Eyre and colleagues say likely contributed to its PFS advantage over ibrutinib, but the advantage did not carry over to overall survival.

“In light of this, and in the absence of randomized data comparing these approaches, our data [provide] reassurance that either option remains a reasonable approach as NA1 in R/R CLL,” the authors write. Therefore, they conclude, the choice of an NA1 ought to be based on factors such as “individual patient factors, drug access, deliverability and patient preference.”­

Reference

Eyre TA, Lamanna N, Roeker LE, et al. Comparative analysis of targeted novel therapies in relapsed, refractory chronic lymphocytic leukaemia [published online February 20, 2020].ŠHaematologica. doi: 10.3324/haematol.2019.241539.