The OBR Blog

February 27, 2019 - 02:02 pm comments0 Comments

As part of its attempt to lower drug costs and increase transparency, the US Department of Health and Human Services (HHS) announced a proposed rule on January 31, 2019, to overhaul the current prescription drug rebate system in Medicare Part D. The rule would end “safe harbor” protection under the Anti-Kickback Statute for rebates paid by pharmaceutical manufacturers to pharmacy benefit managers (PBMs) after the point of sale of a prescription drug and create a new protection for discounts given at the point of sale. The rule would also create a new safe harbor protection for fixed fees paid to PBMs.

“Right now, manufacturers can’t give discounts to patients,” said Ted Okon, executive director of the Community Oncology Alliance (COA). According to Okon, the rule is trying to take these after-point-of-sale rebates away that artificially inflate drug prices and give patients the benefit of any discounts by making them legal.

Medicare Part D beneficiaries’ out-of-pocket costs for prescription drugs are calculated off the drug’s list price at the point of sale, not the lower net price, after rebates from the pharmaceutical manufacturer have been applied. As noted in the proposed rule, about a quarter of a drug’s list price is made up of rebates and “nearly” every drug company that announced a price increase in January 2019 claimed that “all or nearly all” of the increased cost was going toward rebates paid to PBMs or insurers.

“There is a belief that not only [are rebates] harming beneficiaries, it’s costing the Medicare program more,” explained Okon.

The proposed rule claims that by ending rebates and allowing discounts at the point of sale, Medicare beneficiaries’ would have lower out-of-pocket costs for Part D drugs, but whether such cost-savings would happen is unclear given the complexity of the system and other proposed changes to Medicare being considered.

“We have more questions than answers right now,” summed up Blair Burnett, senior policy analyst at the Association of Community Cancer Centers (ACCC) who noted that ACCC is still assessing the proposed rule before releasing a statement. She explained that this proposal is running concurrently to many other changes to the Medicare Part D benefit. For instance, HHS has proposed shifting certain drugs from coverage under the Part B benefit to Part D, and the Centers for Medicare and Medicaid Services (CMS) recently proposed in November allowing step therapy in Medicare Advantage plans for Part B drugs as way to manage utilization. She said it’s a question of when all the pieces fit together, will patients see that benefit that’s being proposed.

“Obviously, from our perspective, we certainly hope that [patients] do,” she said, “but the CMS actuarial analysis did cite potential significant changes to a Medicare beneficiary’s premium, and we wouldn’t want to see a lower[ing] in drug prices come at the cost of an exorbitant increase in premiums.”

Okon agreed that the proposed rule would not occur “in a vacuum” and offered a different perspective, saying the drug distribution and payment system has too many middlemen in it and that there’s not one solution. His belief is that this proposal will be a solution. “You have no idea other than taking the plan sponsor’s word for it that [having rebates] actually help bring down premiums,” he said.

Okon also said that the proposed changes will put insurers “on the hook” for explaining why they raise premiums so much, and that pharmaceutical manufacturers will now be “exposed” if drug prices don’t come down after the Medicare rebates go away. “We can’t say it’s a magic bullet, but we think it’s a good first step,” he said.

At the latest Senate committee hearing on drug prices on February 26, 2019, Senator Chuck Grassley asked the panel of seven pharmaceutical company executives, if the rule is finalized, would they commit to lowering drug prices? The executives expressed support for the rule, but whether lower list prices would follow seemed contingent on eliminating rebates from commercial plans, in addition to Medicare.

“If the rebates were removed from the commercial sector as well, we would definitely reduce our list prices,” said Pascal Soriot, executive director and chief executive officer of AstraZeneca.

The executives also cautioned that they would need to see the rule in its final form. Jennifer Taubert, Executive Vice President and Worldwide Chairman at Janssen Pharmaceuticals Johnson & Johnson, explained that she is supportive, if “there aren’t additional fees that are added into the system to compensate for the rebates given.”

The comment period for the proposed rule is open and ends April 8, 2019. If the proposed rule follows the usual timeline, Okon predicts that the final rule would come out within 45 to 60 days, or around June, followed by another comment period. The idea, he said, would be to have the rule completely finalized before plans from insurers are submitted in the fall for the upcoming calendar year. The rule would then take full effect January 1, 2020.

by Christina Bennett, MS

As the Genitourinary Cancers (GU) Symposium gets under way in San Francisco February 13-16 2019, at a pre-meeting Presscast, ASCO experts singled out three abstracts to be presented at the meeting as of special interest: two on prostate cancer and one on kidney cancer. As would be expected, these three abstracts are just the tip of the iceberg among many important studies to be discussed at the 3-day meeting.

Prostate Cancer – Racial Disparity in Survival?

A large retrospective study to be presented at the meeting suggests that African-American men with chemotherapy-naïve metastatic castrate-resistant prostate cancer (mCRPC) have improved survival on the newer androgen-directed therapies abiraterone or enzalutamide compared with Caucasians (Abstract 212). This is the first study to suggest a survival benefit for both drugs in African-American men, and further study is needed to validate this finding.

“We’ve historically seen that prostate cancer is more common, more aggressive, and more lethal in African Americans compared with men of other racial groups. Balancing against other health-related risks, we found that treatment with newer hormonal medicines led to a significantly greater survival for African-American men in this analysis, compared with white men,” said lead study author Megan Ann McNamara, MD, Assistant Professor of Medicine, Duke University School of Medicine, Durham, NC.

“These findings provide important evidence that African-American men with metastatic prostate cancer, who have long had among the highest incidence and poorest outcomes of this disease, may now have better survival when treated with newer prostate cancer medications as compared with other men,” said ASCO Expert Robert Dreicer, MD, moderator of the Presscast.

The study was based on the Veterans Health Administration database from April 1, 2013 to March 31, 2018. Researchers identified 787 African American men and 2123 Caucasians aged 18 or older with prostate cancer and disease progression after surgical or medical castration; all men received  either abiraterone or enzalutamide, but no chemotherapy. Patients were followed until death or disenrollment in their VA health plan. Median follow-up was 570 days for African-American men and 561 days for Caucasians.

African-American men were more likely than Caucasians to have the following co-morbidities: hypertension (77.1% versus 67.1%, respectively, P<.0001); type II diabetes (38.1% versus 29.3%, respectively, P<.0001); and liver damage or abnormality (8.8% versus 5.2%, respectively, P=.0003).

In an analysis adjusted for demographic and clinical characteristics, median overall survival was 30 months for African-American men compared with 26 months for Caucasians.

“This study was conducted in men with access to care through a single-payer system. The evidence suggests that African-American men have improved survival on standard of care treatments. Prospective trials are needed to validate these findings,” Dr. McNamara said.

Prostate Cancer – Radioligand Therapy

A novel approach using a tumor-specific radioligand therapy that binds to prostate specific membrane antigen (LuPSMA) had a strong showing in an expanded Phase II study of men with metastatic castrate-resistant prostate cancer (mCRPC) who progressed on standard therapies (Abstract 228). The study showed high rates of PSA response with low toxicity, and high response rates were also seen in men who subsequently progressed on LuPSMA and were treated with further LuPSMA, the authors said.

Moreover, men treated with LuPSMA lived a median of 13.3 months after treatment, surpassing expected survival of 9 months for this stage of disease.

The study, the first prospective study of LuPSMA, is based on an expanded cohort of 50 patients; results in the first 30 patients treated were reported previously in The Lancet Oncology in June of 2018. The present study confirms earlier findings using LuPSMA, and two randomized controlled trials will compare LuPSMA versus cabazitaxel and LuPSMA versus best standard of care, respectively.

“For men with localized prostate cancer, brachytherapy, or radioactive seeds implanted by needle directly into the tumor, as well as external beam radiotherapy, have been effective forms of treatment. However, for men in this trial with cancer cells spread throughout the body, LuPSMA provides a new approach to a form of the disease that has been difficult to treat,” said lead author Michael Hofman, MBBS, professor of nuclear medicine at the Peter MacCallum Cancer Centre, Melbourne, Australia.

“In this trial, we treated men who would have otherwise been directed to palliative care. It’s exciting to see that LuPSMA can potentially offer benefits for many men with these very aggressive cancers, with few side effects and significant improvements in quality of life. Importantly, we saw continued benefit with LuPSMA retreatment in some men whose cancer progressed,” Dr. Hofman said.

Patients enrolled in the Phase II study were diagnosed with PSMA-positive mCRPC by upfront PET scan and were treated with up to 4 cycles of LuPSMA every 6 weeks. The primary endpoints were PSA response and toxicity. In the 50 patients enrolled in the trial, median PSA doubling time was 2.6 months. The majority of patients received prior treatment (docetaxel, 84%; cabazitaxel (48%), and abiraterone or enzalutamide (90%).

A PSA decline of >50% was observed in 32 of 50 patients (64%), including 22 patients (44%) with a PSA decline >80%. Among 27 patients with soft tissue disease at baseline, 56% had a partial or complete response according to RECIST criteria. Fourteen patients who progressed on LuPSMA received a median of 2 more cycles of LuPSMA; PSA >50% decline was observed in 9 patients (64%).

Adverse events were similar to those reported earlier in 30 patients: transient grades 1-2 dry mouth (68%), nausea (48%),and fatigue (36%).

Grades 3 to 4 toxicities were thrombocytopenia and anemia (10% for each). Median PSA progression-free survival was 6.9 months and median overall survival was 13.3 months.

“Survival rates are low for patients with prostate cancer that has spread to distant parts of the body, and providing effective treatments for this type of cancer has been an ongoing challenge. For this group of patients in dire need of new options, using an entirely new approach provides hope that we can start to change their outcomes,” said ASCO Expert Robert Dreicer, MD, Presscast moderator.

Immunotherapy Combo in RCC

Immunotherapy is making inroads in the treatment of metastatic renal cell carcinoma (mRCC), according to promising results of the phase III KEYNOTE-426 study. The global, open-label phase III study demonstrated the superiority of the combination of pembrolizumab plus axitinib versus standard of care sunitinib as first-line therapy for mRCC (Abstract 543).

Pembrolizumab plus axitinib showed significant improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) at a median follow-up of 12.8 months (P<.0001 for all three comparisons with suninitib). Twelve-month OS was 89.9% for the combination versus 78.3% for sunitinib (P= .0001). Median PFS was 15.1 months versus 11.1 months, respectively, and ORR was 59.3% versus 35.7%, respectively. Duration of response was not yet reached for the combination therapy arm versus a median of 15 months for sunitinib.

“These results are exciting. By adding pembrolizumab to a VEGF-targeted TKI we are seeing powerful anticancer responses, including improved survival, and importantly, results are seen across broad subgroups of patients. These data suggest that pembrolizumab plus axitinib should be a new standard of care for this population, in my opinion,” said lead author Thomas Powles, MD, Professor of Urology Oncology, Barts Cancer Institute, London, U.K.

Following promising results of a phase Ib study, the phase III KEYNOTE-426 trial randomized 861 patients with clear-cell RCC and no previous systemic therapy for mRCC to either arm. Pembrolizumab was given 200 mg IV every 3 weeks for a maximum of 35 cycles plus oral axitinib 5 mg b.i.d. versus oral sunitinib 50 mg every day on a 4 week on/2 week off schedule. Patients were treated until disease progression, unacceptable toxicity, or investigator’s decision.

“There have been few significant advances in treating this advanced form of disease. These findings may help provide an important new option for patients with mRCC,” said ASCO Expert Robert Dreicer, MD, Presscast moderator.

By Adrian Barfield, President, Medallion Healthcare

December 12, 2018 - 03:12 pm comments0 Comments

SAN DIEGO—Too often, strategies known to be effective within the realm of supportive and palliative cancer care remain on the back burner. This often-observed fact was reinforced at a recently convened ASCO-sponsored symposium, where results from several studies revealed that guidelines are being ignored or overlooked to the detriment of optimal care.

Prophylaxis for chemotherapy-induced vomiting is one of two examples that illustrate the point. Many patients with cancer do not receive what has been proven to improve quality of life, according to data presented at the Palliative Care and Supportive Care Oncology Symposium by Eric J. Roeland, MD, a hospice and palliative care physician at Massachusetts General Hospital, Boston.

The data were pulled from an electronic medical database with records from 40 institutions. New starts of highly emetogenic chemotherapy (HEC) were matched with new starts of antiemetic prophylaxis. Current guidelines for control of emesis from ASCO, ESMO, and the NCCN in patients initiating HEC call for triple-drug prophylaxis with an NK1 receptor inhibitor, such as aprepitant; a 5-HT3 receptor inhibitor, such as ondansetron; and dexamethasone.

Of the three regimens currently classified as HEC that were evaluated, physicians were found to be more than 90% adherent to guideline-directed triple-drug antiemetic prophylaxis in 56% of patients initiating a course of cyclophosphamide plus anthracycline; 32% in patients initiating a course of cisplatin; and 2% in patients initiating carboplatin, Dr. Roeland reported.

The low adherence rate for carboplatin can be discounted because this drug only received a HEC designation in 2017, which came after the study period, but cisplatin had a listing as a HEC requiring triple-drug prophylaxis during the time of the study, and it is notorious for its emetogenic propensity. Published studies suggest up to 90% of patients receiving cisplatin in a dose of 50 mg/m2develop nausea and vomiting within 24 hours if prophylaxis is not provided. The results from Dr. Roeland’s study database suggest that up to 68% of these patients are exposed to toxicity that could be modified.

Triple therapy “is an achievable target,” he said, citing the low but still substantial proportion of physicians who did reach 90% adherence. Of physicians who failed to achieve this level of adherence, many did not come close. The distribution of adherence among below 90% adherence was “scattered across lower levels down to zero.”

“Opportunities still exist for most physicians to improve individual adherence of evidence-based guideline-recommended antiemetic prophylaxis,” he said.

As the risk of emesis from HEC-designated drugs in guidelines is known, “upfront triple prophylaxis” should be standard, according to Dr. Roeland.

His data provide another reminder that clinicians often overlook proven and guideline-recommended strategies beyond standard anti-cancer regimens with the potential to make their patients’ lives better. A similar statement could be made about palliative care based on data presented at the same meeting.

Palliative care strategies

Neither of two studies that evaluated palliative care strategies was focused on the proportion of patients who go untreated, but both implied that this therapy is not being offered routinely. The reason is that each had control groups who were not treated even though ASCO has already released clinical practice guidelines for the routine integration of palliative care (Ferrel BR et al. J Clin Oncol 2017;35:96-112).

Not surprisingly, given the background, both studies associated palliative care with benefit. On the basis of the results, both sets of authors recommended routine palliative care despite existing evidence-based guidelines that make the same recommendation.

One of the two studies was a multicenter randomized trial. In this trial, 302 patients with unresectable lung (40%), gastrointestinal (27%), prostatic (18%) or other solid tumors were randomized to palliative care, which included psychosocial support and physical exercise guided by a specialized team, or usual care without palliative strategies.

Patients customized their care by identifying aspects of quality of life for which they needed help. These were evaluated with a validated tool called EORTC-QLC-C30. Change from baseline in the same domains with EORTC-QLC-C30 was the primary study outcome. The absolute 3.0-point difference favoring palliative care reached significance (P=0.047). When assessed with a sensitivity analysis, the 3.3-point difference favoring palliative care was even more robust (P=0.005).

The conclusion, delivered by Lise Nottelmann, MD, Palliative Team, Department of Oncology, Vejle Hospital, Vejle, Denmark, was that palliative care “integrated into the standard oncology treatment” offers meaningful benefit to patients.

In a second study, which enrolled 118 lung cancer patients and 62 caregivers, evaluated a palliative care protocol for the outpatient community-based setting. The author of this study, Huong Q. Nguyen, PhD, RN, Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, acknowledged that palliative care has been shown to be beneficial previously. However, “most trials have been conducted in specialized centers with limited translation into the real-world setting.”

This study was conducted in two phases. After a first phase of usual care over 14 months, nurse-led palliative care was initiated and evaluated over 23 months. Again, care was customized by concerns defined as most important by enrolled patients. Change from baseline in quality of life was evaluated in both patients and caregivers with multiple tools, including FACT-L and FACIT-SP12.

In patients, “significant immediate improvements observed in physical, emotional, and functional well being at one month [on palliative care] were sustained at three months when compared to usual care (P=0.01),” reported Dr. Nguyen. In caregivers, improvements in physical (P=0.04) and spiritual (P=0.03) domains were also documented relative to usual care.

The findings demonstrate that palliative care “can be successfully adapted to the community setting,” Dr. Nguyen concluded.

On the basis of their results, both authors advocated the integration of palliative care into standard management of patients with late stage cancer, but they only reinforce current guidelines. The fact that the studies were considered necessary underscores an unstated premise that acceptance of palliative care remains incomplete. Like antiemetic prophylaxis for emetogenic drugs, the question is not whether palliative care can improve quality of life, the question is why the opportunity for benefit is so often overlooked.

By Ted Bosworth

As the ASH Annual Meeting concludes, the late-breaking abstracts are always of great interest. We take a brief look at one non-malignant hematology presentation that has implications for oncology, as well as three malignant hematology presentations on advances in targeted therapies for CLL and multiple myeloma.

Rivaroxaban Thromboprophylaxis in High-Risk Ambulatory Cancer Patients Receiving Systemic Therapy: Results of a Randomized Clinical Trial (CASSINI) (LBA-1)—short summary of this one

Patients with cancer have a higher risk for venous thromboembolism (VTE), which can lead to death, morbidity, hospitalization, and delay in cancer treatment.

Alok A. Khorana, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, reported results of the CASSINI trial (NCT02555878), a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE, defined as Khorana score ≥ 2 for a risk-adapted approach to prophylaxis.

Patients were randomly assigned to rivaroxaban, a direct oral anticoagulant (n=420), or to placebo (n=421) for 6 months. An important aspect of the trial was the use of ultrasonography of the lower extremity at baseline to identify pre-existing clots, which occurred in 4.5% of screened patients who were therefore not enrolled.

There was no significant difference between groups in the primary efficacy outcome of cumulative thromboembolic events; 38.7% of events occurred in patients who had discontinued treatment. For patients who remained on treatment, rivaroxaban significantly reduced events (2.62%) versus placebo (6.41%; P=.007), and significantly reduced a composite of the primary endpoint and all-cause mortality (P=.003).

There were no significant differences in safety outcomes between the groups for bleeding. A risk-benefit analysis showed that the number needed to treat (NNT) was 26 for patients who remained on treatment. The number needed to harm (NNH) was 101 for major bleeding and 135 for clinically relevant non-major bleeding for patients on treatment.

Dr. Khorana concluded that baseline screening for VTE could be considered for patients starting systemic cancer therapy. The findings of this study, along with a similar study that has just concluded, should inform future recommendations for thromboprophylaxis for higher-risk ambulatory patients with cancer.

Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA) (LBA-2)

Thierry Facon, Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France, presented the pre-specified interim analysis of the MAIA study, a phase 3 trial evaluating daratumumab plus lenalidomide and low dose dexamethasone (D-Rd) versus Rd in patients with transplant-ineligible, newly diagnosed multiple myeloma. Daratumumab is a human, CD38-targeted, IgG1κ monoclonal antibody.

Patients were randomly assigned to D-Rd (n=368) or Rd (369); treatment continued until disease progression. Median age was 73 years, and notably, 44% of patients were age ≥75 years. The primary endpoint was progression-free survival (PFS).

At a median follow-up of 28 months there was a 44% reduction in risk of progression or death in the D-Rd group (71% at 30 months vs 56% for placebo; HR 0.56; 95% CI 0.43-0.73; P<.0001). Median PFS in the Rd group was 31.9 months and not reached in the D-Rd group. This benefit was seen across most sub-groups analyzed.

The overall response rate was 93% for D-Rd versus 81% for Rd (P<.0001); complete response rates and at least very good partial response rates were higher for D-Rd than for Rd. The minimal residual disease (MRD)-negative rate was significantly higher for D-Rd (24%) than for Rd (7%; P<.0001). Patients who were MRD negative had longer PFS. There is no difference between groups in overall survival (OS) at this follow-up time.

The safety profile was consistent with that seen for these combinations in other studies. Because of the inclusion of lenalidomide, the incidence of secondary primary malignancies (SPM) was determined; it was 3% for D-Rd and 4% for Rd; hematologic SPM occurred in 0.5% of each arm.

Dr. Facon concluded that the results of this study support D-Rd as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma.

A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912) (LBA-4)

The E1912 (NCT02048813) trial showed that ibrutinib plus rituximab (IR) improves PFS and OS compared with fludarabine, cyclophosphamide, and rituximab (FCR) in younger patients with previously untreated CLL. FCR has been the most active chemo-immunotherapy to date for CLL and has not been compared with ibrutinib as an initial treatment for younger patient with CLL.

Patients age ≤70 years (median age 58 years) with CLL were randomly assigned 2:1 to IR (n=354) or to 6 cycles of FCR (n=175). Patients in the IR group received 1 cycle ibrutinib, 6 cycles IR, then ibrutinib until disease progression.

At a median follow-up of about 3 years, PFS was significantly longer in the IR group (HR 0.35; 95% CI 0.22-0.5; P≤.00001), as was OS (HR 0.17; 95% CI .05-0.54; P≤.0003). Neutropenia, anemia, thrombocytopenia, and neutropenic fever occurred significantly less often with IR than FCR; atrial fibrillation and hypertension occurred significantly more often with IR than FCR. There were no significant difference in infection, bleeding, or diarrhea.

Presenter Tait D. Shanafelt, MD, Stanford University, Stanford, CA, concluded that these results establish IR as the most effective first-line therapy in patients age ≤70 years with CLL.

Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia (LBA-7)

Venetoclax, a selective BCL2 inhibitor induces deep and durable responses in CLL. However, most patients treated with venetoclax will eventually experience disease progression, and the mechanisms of resistance to venetoclax in patients are largely unknown.

This study looked at 67 patients with relapsed CLL; 21 had CLL-type progressions; of these, 15 had samples suitable for genomic analysis. A new mutation that was not present in pre-treatment samples, BCL2 Gly101Val, was detected in four patients using targeted amplicon sequencing. This is the first acquired BCL2 mutation described in patients with CLL treated with venetoclax. BCL2 Gly101Val occurs in the BH3-binding groove and has not been detected in other B-cell malignancies. BCL2 Gly101Val reduces the binding of venetoclax to BCL2 as much as 180-fold.

Piers Blombery, MBBS, University of Melbourne, Melbourne, Australia, said that they have detected BCL2 Gly101Val in patient samples months to years before relapse, and the mutation has subsequently been detected in three additional patients in the original group of 15 studied.

Cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax and the mutation confers a growth advantage over wild-type cells in the presence of the drug.

Dr. Blombery pointed out that alternative resistance mechanisms can co-exist with BCL2 Gly101Val. These study results could provide a rationale for a limited time course for venetoclax.

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