Chronic lymphocytic leukemia (CLL) is a disease of the elderly, with a median age of diagnosis at 71 in the U.S. and nearly 40% of patients older than 75 at the time of diagnosis.1 Standard treatment for “fit” patients is aggressive chemotherapy, but existing comorbidities in elderly patients frequently preclude use of these highly toxic regimens. Limited treatment options exist for “unfit” patients, and the most common choices include chlorambucil and Rituxan® (rituximab, Genentech/Roche) – alone or in combination. More recently the combination of Rituxan with Treanda® (bendamustine, Teva) has emerged as a common option in the U.S., although the combination is not approved for this setting. To fill the unmet need for treatment options, a number of novel agents have recently entered clinical development for CLL in elderly, newly diagnosed patients. Phase III trials are ongoing or recently completed for Arzerra® (ofatumumab, GlaxoSmithKline), ibrutinib (BTK inhibitor, Pharmacyclics/Johnson & Johnson), and Gazyva® (obinutuzumab, Genentech/Roche). Results from Stage I of the Phase III trial of Gazyva were presented at the ASCO 2013 in June2, and on December 8 during the plenary session final results from Stage II of this pivotal trial were reported at the American Society of Hematology (ASH).3
The Phase III CLL11 trial (NCT01010061) was a three-arm study that randomized 781 newly diagnosed “unfit” patients to treatment with chlorambucil alone, chlorambucil plus Gazyva, or chlorambucil plus Rituxan. The definition of “unfit” in this trial wasn’t based on patient age but was defined by the level of comorbidities; patients were included if their total Cumulative Illness Rating Scale (CIRS) score was above 6 and/or creatinine clearance was less than 70 ml/min. The first stage of this trial compared the efficacies of each combination arm with the chlorambucil monotherapy arm; the second stage compared the efficacies of the two combination arms and was designed to show superiority of Gazyva versus Rituxan. Results for Stage I were updated and final results of Stage II were presented for the first time.
Updated Stage I results continued to showed clear and robust activity for Gazyva in combination with chlorambucil compared with chlorambucil alone. PFS (the primary endpoint) was significantly improved, with an 82% reduction in risk of progression or death and a 26.7-month median PFS. The level of benefit was very impressive, although perhaps not surprising since chlorambucil is not a very active agent. Rituxan plus chlorambucil also showed a strong level of benefit compared with chlorambucil alone, with a 66% reduction in risk of progression or death and a 16.3-month median PFS. Results of Stage II, which compared efficacy and safety of the combination arms, showed that Gazyva plus chlorambucil is significantly superior to Rituxan plus chlorambucil with regard to the primary endpoint of PFS (26.7 versus 15.2 months), with a 61% reduction in the risk of progression or death. The overall response rate (ORR), complete response (CR), and high rate of minimal residual disease (MRD) negativity (see Table 1) also all favored the Gazyva arm. Overall survival favored the Gazyva arm as well, although this interim analysis is very premature (<15% of events) and the difference did not reach statistical significance when comparing Gazyva-chlorambucil versus Rituxan-chlorambucil (HR 0.66, p=0.0849). Notably, however, the OS benefit was significant when comparing Gazyva-chlorambucil versus chlorambucil (HR 0.41, p=0.0022). A greater incidence of Grade 3/4 adverse events (AEs) was reported in the Gazyva-chlorambucil arm (70% of patients) versus the Rituxan-chlorambucil arm (55%). Infusion-related reactions (20% versus 4%, respectively), neutropenia (33% versus 28%) and thrombocytopenia (10% versus 3%) represented the major differences in Grade 3/4 AEs. While these AEs are of course concerning, the large magnitude of efficacy benefit means that these toxicities are unlikely to sway physicians away from use of the drug, especially since they are easily monitored and resolvable.
Results from Stage I of the trial served as the basis for regulatory filings for Gazyva in newly diagnosed CLL patients with comorbidities that make them unfit for standard chemotherapy and on November 1, 2013, the FDA approved Gazyva for use in combination with chlorambucil for the treatment of patients with previously untreated CLL. Now with the Stage II results in hand, the measures that clearly stand out are the CR rate, the number of patients who achieve negative MRD (in both the peripheral blood and the marrow), and PFS. All of these measures strongly favor Gazyva. CR and MRD-negativity speak to the depth of response that is achieved. Results of the CLL11 trial and the approval of Gazyla represent an improvement upon the efficacy of Rituxan and the first step toward the eventual displacement of Rituxan as a standard of care in B-cell malignancies (conveniently coinciding with rituximab patent expiration).
Within chemo-ineligible/“unfit” newly diagnosed CLL, where will Gazyva fit? As mentioned, development in this indication is crowded with promising new agents seeking to transform the treatment paradigm. Results from the COMPLEMENT-1 trial of Arzerra plus chlorambucil versus chlorambucil monotherapy in previously untreated chemo-ineligible CLL patients will be presented at ASH on Monday December 9, 20134, although it was previously announced via press release to have met its primary endpoint by extending PFS from 13.1 months to 22.4 months (HR 0.57). With this data, CLL will soon have three anti-CD20 antibodies to choose from. In addition, Imbruvica® (ibrutinib, Pharmacyclics/Johnson & Johnson) is also seeking approval in this same patient population, and the relapsed/refractory CLL setting is rife with development by Imbruvica, idelalisib (Gilead), and ABT-199 (GDC-199, Abbvie/Genentech/Roche), all of which are presenting very promising data at ASH 2013. A natural inclination would be to combine these agents with an anti-CD20 antibody, or potentially with each other, as well as bring these agents into the broader and/or upfront CLL population. CLL is very likely to be transformed in the next few years, with potentially more options than physicians know what to do with.
1. Kantar Health, CancerMPact® Patient Metrics United States, accessed June 4, 2013.
2. Goede et al., Abstract 7004, ASCO 2013.
3. Goede et al., Abstract 6, ASH 2013
4. Hillmen et al., Abstract 528, ASH 2013
By: Stephanie Hawthorne, PhD, Director, Clinical and Scientific Assessment, Kantar Health and Greg Wolfe, PhD, Senior Consultant, Clinical and Scientific Assessment, Kantar Health
As you may have already seen, RainTree Oncology Services and Express Scripts recently announced a strategic three year agreement to allow RainTree members with dispensing operations to participate in an expanded pharmacy network. The press release indicates this alliance will benefit Express Scripts, RainTree, payers, and patients. With an announcement as impactful as this one, we asked Jeff Patton, MD, CMO and Founder of RainTree, for a little of his time to see if we could find out more about the deal. In case you don’t know, Express Scripts owned a specialty pharmacy, CuraScript, when it bought Medco in 2011 and through the acquisition acquired Accredo.
OBR: First, please tell us what the alliance is.
JP: We have signed a network agreement with Express Scripts which forms a “services” alliance between RainTree and Express Scripts.
OBR: Can you elaborate on the details of this strategic alliance and how it benefits RainTree?
JP: At RainTree our mission is to assist our member practices in achieving better and more cost-effective treatment of oncology patients while also creating new revenue streams to help keep community practices in business. The alliance will help our practices increase quality care and help them increase revenues from their in-house dispensing. Here’s how…
Currently there are two PBM/specialty pharmacy oral cancer drug distribution models:
1) open network which allows patients in a network to fill the prescription at least once, sometimes twice, at any pharmacy which is part of the network, but then on subsequent prescriptions the patient must go to a predefined specialty pharmacy
2) closed network which is a smaller network where the prescription is controlled from beginning to end
So if the practice dispenses oral cancer agents, they often will only be able to fill the prescription once or twice and then they lose that subsequent revenue opportunity. Now with this agreement the RainTree practices will be able to continue to fill the Express Scripts plan prescriptions for their patients. This will allow greater continuity of care and more revenue to the practice.
OBR: Roughly how big is this deal for RainTree members?
JP: Right now in community oncology, roughly 20-30% of prescriptions flow through Express Scripts. With this deal, over time, the practices in the RainTree network will have a significant increase in pharmacy revenue.
OBR: Please explain the quality of care angle.
JP: Express Scripts offers a host of oral cancer drug services, including educational tools and best practices, mostly related to adherence and compliance, which will now be more effective when they are implemented at the site of care at RainTree practices.
OBR: Why is Express Scripts excited about this alliance? What’s in it for them?
JP: The principal strategic opportunity for Express Scripts is in dealing with payers. Their payer partners have been asking for them to come up with an innovative oncology solution, and that’s what this is. You can’t manage oncology patients without oncologists, and now we’re partnered together.
OBR: What do you think might be a long term benefit of this alliance?
JP: We have never had a collaborative relationship with payers, mostly because the PBMs and specialty pharmacies are agents for the payers. We’ve been meeting with them for years now, but the collaborative spirit hasn’t been there. Express Scripts has a trusted relationship with payers and now, suddenly, when we’re talking with payers, we’re a partner with them. Because of this alliance we should be able to accelerate the move toward value-based medicine.
OBR: We’ve talked about the business aspect of this alliance, but how does this alliance affect cancer patients?
JP: Oral oncolytics are unlike injectables and infusion drugs because injectables and infusion drugs have been around much longer and we have established best practices, we have control of operations, we have established outcomes. On the oral side some patients go to Walgreens, some go to specialty pharmacies, and it is more splintered. We have less control, less ability to close that loop in the oral oncology setting. We have room for improvement through standardized care, standardized education, and improved adherence. It is our hope that we can improve quality of care, thus benefitting patients, through alliances like this.
OBR: Is this an exclusive relationship? What do you think will happen with RainTree in the near term as a result of this deal?
JP: Because the network agreement has enhanced participation requirements, this alliance is effectively only available to oncology practices in the RainTree network. We have about 50 practices and 700 oncologists in the RainTree network, and I hope that other practices will be interested in joining us and growing the network together.
Accountable care organizations (ACOs) are intended to bring physicians into an integrated system that shares the rewards of efficient, coordinated patient care. Continued inadequate reimbursement from payers, both public and private, has increased the attractiveness of participation in novel delivery and reimbursement arrangements for community oncology practices. According to Kantar Health’s 2013 oncologist and practice manager surveys, ACOs are the fastest growing novel reimbursement arrangement with 30% of practices participating, covering 10% of all cancer patients. Participation is expected to grow to 50% within the next one or two years as practices and hospitals experiment with value-based reimbursement and coordinated care.
Pathways are currently the most common novel reimbursement mechanism in community oncology practices, with 43% of practice managers reporting their use, covering 11% of their patients, according to Kantar Health’s surveys. Cancers most commonly affected by pathways include colorectal, breast, non-small cell lung (NSCLC) and prostate cancer, although some programs include a wider array of cancers, including non-Hodgkin’s lymphoma, multiple myeloma, renal cell carcinoma and melanoma. One important key of ACO initiatives is that the expansion of health information technology (HIT) allows pathway programs and other initiatives to combine management of oral and physician-administered injectables across a patient’s pharmacy and medical benefit. This advance crosses a line once perceived as insurmountable to manage across a patient’s continuum of oncology drug utilization.
Changes to Cancer Payer Mix Due to Coverage Expansion
Manufacturers will need to monitor payer mix in light of coverage expansion under the ACA with the state exchanges and the expansion of Medicaid. Commercially insured and uninsured patients are eligible for manufacturer-designed patient assistance programs (PAP), whereas foundations represent the only option for Medicare patients. The Department of Health and Human Services just announced that the state health insurance exchanges will not be subject to regulations similarly to Medicare. The crux is that patients who purchase policies through the exchanges will be eligible for manufacturer-designed PAPs. Figure 1 projects that change in payer mix for the U.S. population through 2021.
Figure 1 – Expanded Coverage under the Affordable Care Act: Expanded access to health insurance coverage could lead to an increase in covered lives by 2014
Hospitals that qualify as 340B institutions (as Disproportionate Share Hospitals) based on the treatment of Medicaid (or other low-income patients) have enjoyed discounts of 21-50% on outpatient drugs for several years. 340B participation has been growing for hospitals and the practices affiliated with them, but as Medicaid expands in 2014, even more entities will be 340B eligible. Institutions in states that opt in for Medicaid expansion will become more likely to exceed the 11.75% disproportionate share threshold required to access 340B drug discounts. Since the end of 2009, 1,588 institutions have become active in the 340B program. Since the end of 2011, 3,423 hospital “sites” joined with the addition of only six hospital entities due to many systems adding more satellite and affiliated sites into the 340B program. With Medicaid expansion, it is estimated 1,500 more institutions may be newly eligible. This is important as exhibited by Genentech. Genentech’s 340B drug discounts totaled $1 billion in 2012 and are growing at 20% to 25% a year, impacting product pricing and causing the company to establish a 340B integrity program to ensure recipients of the discounts are complying with legal requirements.
Figure 2 – 340B PARTICIPATION: 340B expansion in 2010 encouraged 340B hospitals to greatly expand participating sites, including the purchase of oncology practices
Formulary Inclusion in the Exchanges
A key concern for manufacturers is which agents are included in formularies among plans offered through the exchanges. Exchange plans need to include only one benchmark option. While formulary exclusion has been a touchy topic in oncology in the past, there are signs that certain oncology agents and other specialty agents may not be included in all plan formularies, particularly the bronze and silver plans.
Manufacturers will need to develop and continuously reevaluate product value propositions of their drugs to ensure formulary inclusion and for pathway inclusion by payer and provider decision makers. As oncology participation in ACOs grows, manufacturers will also need to place greater emphasis on patient experience, quality and care coordination. Additionally, the evolution coverage expansion will alter the payer mix within a cancer thus will have a direct effect of the affordability of cancer care.
1. ERBI Characteristics of the CDHP Population, 2005–2010.
By Gordon Gochenauer, Director, Oncology Commercial Strategies, Kantar Health