The OBR Blog

May 15, 2019 - 10:05 pm comments0 Comments

In conjunction with the release of the abstracts for the upcoming 2019 ASCO Annual Meeting, a virtual press cast previewed five noteworthy studies that showcase the range of research that will be presented at the meeting.

Topics included the effect of a low-fat diet on breast cancer mortality, identification of a greater than expected number of targetable molecular alterationsin a pediatric MATCH trial, response of rare pediatric tumors with certain gene fusions to the targeted agent entrectinib, optimization of chemotherapy for frail and/or elderly patients with advanced esophageal cancer, and reduction of progression of smoldering to active multiple myeloma by lenalidomide.

Here are summaries of the key findings.

Low-Fat Diet Associated with Reduced Breast Cancer Mortality (Abstract 520)

Observational studies of the effect of dietary fat on breast cancer have produced equivocal results. To address this, the Women’s Health Initiative (WHI) Dietary Modification (DM) trial, a randomized, controlled study looked at the influence of diet breast cancer incidence and mortality.

The WHI-DM trial (NCT00000611) enrolled 48,835 post-menopausal women age 50 to 79 years who were randomly assigned to dietary intervention (n=19,541) or usual diet (comparison group, n=29,294) from 1993 to 1998. Dietary intervention, which continued for 8.5 years, included reducing fat intake to 20% of calories and increasing intake of vegetables, fruit, and grains, similar to the DASH (dietary approaches to prevent hypertension) diet.

Trial endpoints included deaths from and after breast cancer. Cumulative follow-up data have been collected for a median of 19.6 years. Baseline fat intake was at least 32% of calories. Most women in the diet group increased daily intake of vegetables, fruit, and grains and reduced daily fat consumption to 25% of calories; most did not reach the 20% goal.

In the diet group versus the comparison group, there was a significantly lower risk of death from breast cancer (HR, 0.85; 95% CI, 0.74, 0.96; P=.01) and from any cause after a diagnosis of breast cancer (HR, 0.79; 95% CI, 0.64, 0.96; P=.025).

The authors call this the only study providing randomized clinical trial evidence that an intervention can reduce a woman’s risk of dying from breast cancer, although this analysis was not pre-specified in the original trial design, dietary components were assessed by participant recall, and there was no way to measure adherence to the diet.

At the meeting, the effect of the same dietary modification in a subgroup of women with poor metabolic function, defined as obesity, diabetes, elevated cholesterol, or hypertension, will also be presented (Abstract 1539).

More Actionable Targets than Expected Found in Pediatric MATCH Trial (Abstract 10011)

The NCI-COG (Children’s Oncology Group) Pediatric MATCH (Molecular Analysis for Therapy Choice) trial was designed to address whether a precision oncology approach, i.e., treating tumors with agents selected to target specific genetic alterations, would be useful in the pediatric cancer setting.

NCI-COG Pediatric MATCH will enroll at least 1000 children with tumors that have not responded to standard treatment. The initial step is to screen tumors for potential targets, followed by treatment with therapy matched to alterations found in the tumors independent of tumor type. Treatment is in individual phase 2 clinical trials, of which there are currently 10, one for each current single-agent targeted therapy being tested.

There were 422 patients enrolled, from 93 of the 124 COG sites that had the study open, between July 24, 2017 and the data cutoff for this analysis at the end of last year. Tumor samples were received from 92% of enrolled patients and accounted for over 60 different tumor types including central nervous system (CNS) and non-CNS tumors. Turnaround time was 15 days from tumor receipt to treatment assignment.

Study researchers projected a match rate of 10% based on adult data. So far, 24% of screened patients with cancer that did not respond to treatment were eligible for treatment with a targeted agent. Of these, 39 patients (10%) have enrolled in a treatment trial. The trial is ongoing and is expected to add at least four additional single targeted agents. Combination therapies are being considered for future trials.

Rare Pediatric Tumors with Gene Fusions Respond to Entrectinib in Early Trial (Abstract 10009)

Fusions and alterations in intracellular signaling pathways such as TRKA/B/C, ROS1, and ALK genes act as drivers in some tumors by “locking” the pathways in the “on” position. Entrectinib is an oral inhibitor of these pathways and has the additional advantage of being able to cross the blood-brain barrier to enter the CNS.

Pediatric tumors with mutations in TRKA/B/C, ROS1, and ALK genes are rare, and are being identified more frequently as next-generation sequencing is becoming more common. STARTRK-NG (RXDX-101-03) is phase1/1b clinical trial investigating entrectinib in children with recurrent or refractory solid tumors with these gene alterations. Most had undergone prior surgery and radiation.

Of 29 patients enrolled, 16 were in the phase 1 dose-finding part; an additional 13 patients have been enrolled in the ongoing basket phase 1b part at a dose level of 550 mg/m2(initial recommended dose, n=7) or 400 mg/m2for those unable to swallow intact capsules. Diagnoses included primary CNS tumors (n=6), neuroblastoma (n=3), and extracranial solid tumors (n=4). Median patient age is 7 years.

Responses have been seen in all patients whose tumor had a target gene alteration and no responses were seen in patients whose tumors lacked aberrations in target kinases. Therefore, the trial will continue only for patients with target fusions. Presenter Giles W. Robinson, MD, St. Jude Children’s Research Hospital, Memphis, Tennessee, said, “It gives me great pleasure as pediatric brain tumor doctor to show response in CNS tumors” that would otherwise probably have been fatal.

Dose-limiting toxicities included elevated creatinine, dysgeusia, fatigue, and pulmonary edema. Weight gain, problematic for some patients, also occurred as an on-target drug effect. Side effects have resulted in dose reduction to 400 mg/m2.

Dose-Modified Chemotherapy for Frail and/or Elderly Patients with Advanced Gastroesophageal Cancer (Abstract 4006)

Although the average age of patients at the time of diagnosis of advanced, inoperable gastroesophageal cancer is 75 years, and many patients are frail, standard of care chemotherapy has been developed in trials in patients with an average age of 65 years who are generally not frail. This study was motivated by the finding that a survey of oncologists in the UK used reduced dose chemotherapy regimens that were not evidence-based to treat frail and/or elderly patients with gastroesophageal cancer.

A prior phase 2 trial indicated that a 2-drug regimen was preferable to 3-drug or single agent regimens in this setting. The GO2 phase 3 trial was designed to optimize doses of 2-drug chemotherapy regimens and assess benefits and risks.

Patients (n=514) with a median age of about 76 years who were fit for chemotherapy but not for full-dose, 3-drug regimens were enrolled. There were 2 randomization schemes based on whether the patient was considered either certain or likely to benefit from chemotherapy and basic supportive care (BSC) was not appropriate (certain randomization), or would derive uncertain benefit from chemotherapy with BSC possibly appropriate (uncertain randomization). Presenter Peter S Hall, PhD, University of Edinburgh, Edinburgh, UK, discussed the certain randomization option, where patients were randomly assigned to one of 3 dose levels of combinations of oxaliplatin plus capecitabine.

In addition to assessing progression-free survival (PFS), and a non-inferiority boundary agreed upon by a patient focus group and clinicians, the study also determined which dose level resulted in the best “overall treatment utility (OTU),” a novel concept developed in phase 2, which included cancer control, severity of side effects, patient quality of life (QoL), and oncologist’s assessment of benefit.

The lower doses of chemotherapy were non-inferior to the highest dose for median PFS (4.9 months for the highest dose, 4.1 months for the intermediate dose, and 4.3 months for the lowest dose), as well as for median overall survival (7.5 months, 6.7 months, and 7.6 months, respectively). The lowest dose was associated with the best OTU scores, as a result of fewer side effects and better quality of life (QoL).

Lenalidomide Reduces the Risk of Progression from Smoldering to Active Multiple Myeloma (Abstract 8001)

Smoldering or asymptomatic multiple myeloma (SMM) is a precursor to symptomatic MM. The goal of the phase 2/3 E3A06 trial was to determine if early intervention in intermediate or high risk SMM using low-intensity, single-agent lenalidomide could prevent progression to MM. The primary endpoint was time to develop MM.

In phase 2, the safety of 25 mg daily of lenalidomide for 3 out of every 4 weeks was determined. Phase 3 randomly assigned patients to the same dose of lenalidomide (n=90) or to observation (n=92). Prophylactic aspirin was administered with the lenalidomide.

Time to develop MM was delayed with the use of lenalidomide (2-year PFS probability 0.93; 95% CI, 0.88-0.99) compared with observation (2-year PFD probability 0.76; 95% CI 0.66-0.87). Treatment-related grade 3 and 4 hematologic and non-hematologic adverse events were observed with lenalidomide; 51% of patients in the phase 3 portion discontinued due to toxicity, although there was no difference in QoL reported between the 2 groups.

Three-year PFS was 91% in the lenalidomide group, compared with 66% in the observation group (HR 0.28, P=.0005). Follow-up is too short to determine the effect of treatment on overall survival. The investigators will follow patients who discontinued to see if limited doses of lenalidomide can delay progression of SMM to MM. This study shows early intervention, at least in patients with higher risk SMM, can prevent MM and its associated end organ damage.

By Lynne Lederman, PhD

PS – Don’t forget to sign up for our ASCO ’19 Preview webinar featuring Lee Schwartzberg, MD, Zev Wainberg, MD, and Rich Leff, MD. Register here.

May 15, 2019 - 12:05 pm comments0 Comments

by Howard Hochster, MD – In 2009 Congress passed the BPCIA (Biologics Price Competition and Innovation Act) to create an approval pathway for biologic compounds, meaning complex molecules which are not synthesized chemically but made by cells in culture and purified. These include monoclonal antibodies, proteins, and other macromolecules.

The idea behind this was to allow other manufacturers to develop a non-brand name (“originator”) version of the molecule at a cheaper price and the FDA has made this pathway available now for 19 compounds (including rheumatologics, and insulin) as well as oncology agents (trastuzumab, rituximab and bevacizumab).

Conceptually, these biosimilars require more data on their sequence, manufacturing, and post-translational modification than the originator compound, but only one clinical trial showing similar efficacy to the originator (which does not need to be a head to head comparison). So far, so good.

Unfortunately there are some “fine print” issues here which have made widespread use of these drugs impractical. First, all biosimilars are treated as individual drugs with their own identity, using the generic name followed by a four digit suffix (eg, filgrastim-sndz or Zarxio; bevacizumab-awwb or MVASI from Amgen).

This means that each agent must be ordered specifically and essentially makes them their own “branded” product. This is good, in that we can track which biosimilar is being used, but obviously rather different than the way we prescribe generics. More importantly, “interchangeability” or the ability to switch from one product to another in the middle of treatment is a separate category of approval and requires additional trials where the experimental arm includes medications being switched in mid treatment.

This may be practical for insulin which can be given for a short time with defined blood sugar measurements, but not so for drugs like trastuzumab or rituximab which are given long-term with patients going off for progression or toxicity.

Finally, without interchangeability each patient must be continued on the same compound as there is no approval for “switching in midstream” or for the pharmacy just changing products for the health system based on cost. No cancer pharmacy can reasonably keep multiple versions of bevacizumab on the shelves and track which patients get which “bevacizumab-xxxx” version.

This week the FDA issued the final guidance on interchangeability which did lower some of the barriers for drugs such as exclusive use of US marketed and approved product for switching studies and requiring additional studies on dosing errors. Some in Washington have argued that interchangeability is only about non-physicians substituting the biosimilar, since the doctor can order whichever biosimilar she wishes. However, let’s get real.

Doctors today work within large health systems or practices and order drugs in the EMR. Keeping a scorecard for which biosimilar four letter abbreviation is from Amgen, Boehringer, or Teva is not on anyone’s radar, nor is stocking multiple versions of a biologic and tracking individual patient utilization.

We need a better system here for use of biosimilars to actually achieve the goals of the BPCIA and to benefit health care consumers. FDA, please check the clinics and pharmacies for some practical insights.

By:

Howard S. Hochster, MD

Distinguished Professor of Medicine, Rutgers Robert Wood Johnson Medical School

Rutgers-CINJ Associate Director, Clinical Research

Director Clinical Oncology Research,  RWJ-B Health System

Rutgers Cancer institute of New Jersey

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

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