Venetoclax—Obinutuzumab Demonstrates Efficacy Over Chlorambucil Combo in Untreated CLL

Venetoclax has previously demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL). Now, the results of a new study comparing the treatment plus obinutuzumab with the combination of chlorambucil and obinutuzumab have demonstrated that the venetoclax combination is associated with longer progression-free survival (PFS) among previously untreated patients with CLL and coexisting conditions.

At 24 months, PFS was 88.2% among patients receiving venetoclax—obinutuzumab compared with 64.1% among patients receiving chlorambucil–obinutuzumab. This survival benefit was observed regardless of TP53 deletion, mutation, or both, in patients with unmutated IGHV and in other subgroups.

Results of the CLL14 trial, which were presented at the 2019 Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois, and published in the New England Journal of Medicine, led to the approval of the venetoclax combination for these patients in May.

The phase 3 trial was spread across 21 countries at 196 sites and enrolled 432 patients with CD20+ CLL who were randomized 1:1 to receive either venetoclax—obinutuzumab or chlorambucil–obinutuzumab for 12 cycles of treatment that lasted 28 days each.

Obinutuzumab was administered intravenously for 6 cycles starting with 100 mg on day 1 and 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1, and subsequently 1000 mg on day 1 during cycles 2 through 6. Chlorambucil was administered orally at 0.5 mg/kg on days 1 and 15 of each cycle until completion of the 12 cycles. Venetoclax was initiated on day 22 of cycle 1, starting with a 5-week dose ramp-up (1 week each of 20, 50, 100, and 200 mg, then 400 mg daily for 1 week), and then was administered at 400 mg daily until completion of cycle 12.

At data cutoff, patients had discontinued therapy for a median of 17.1 months in the venetoclax—obinutuzumab group and 17.9 months in the chlorambucil–obinutuzumab group. In the 3 months following completion, there were higher rates of patients in the venetoclax group who were negative for minimal residual disease in peripheral blood (75.5% vs 35.2%) and in bone marrow (56.9% vs 17.1%).

“Minimal residual disease negativity was consistently more common across all subgroups and was more sustainable with venetoclax—obinutuzumab than with chlorambucil–obinutuzumab,” explained the researchers. 

Patients treated with the venetoclax combination also had significantly higher rates of partial response (84.7% vs 71.3%) and complete response (49.5% vs 23.1%).

After a median follow-up of 28.1 months, there were 14 events of disease progression and 16 deaths among those receiving venetoclax—obinutuzumab and 69 events of disease progression and 8 deaths among those receiving chlorambucil–obinutuzumab.

Median overall survival (OS) was not reached in either treatment group, and during the complete observation period, OS did not differ significantly between the 2 groups. There was at least 1 adverse event (AE) of any grade among 94.3% of patients receiving venetoclax—obinutuzumab and in 99.5% of patients receiving chlorambucil–obinutuzumab. These AEs resulted in treatment discontinuation among 16% of patients receiving the venetoclax combination and among 15.4% of patients receiving the chlorambucil combination.

The most common grade 3 or 4 AE was febrile neutropenia, and grade 3 or 4 infections were reported in 5.2% and 17.5% of patients, respectively, receiving the venetoclax combination, and in 3.7% and 15% of patients receiving the chlorambucil combination. During treatment, 5 fatal AEs occurred in the venetoclax—obinutuzumab group and 4 occurred in the chlorambucil–obinutuzumab group. Following treatment, 11 fatal AEs occurred in the venetoclax–obinutuzumab group and 4 occurred in the chlorambucil–obinutuzumab group. 

More From TAILORx: Adding Clinical Risk to Genomic Testing Can Guide Therapy Choices in Breast Cancer

Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi: 10.1056/NEJMoa1815281.

The 21-gene assay, Oncotype DX, which a year ago was found to help many women with a common type of breast cancer avoid chemotherapy, may be best used alongside an assessment of tumor size and stage, according to investigators of the TAILORx trial.

But these new results published in the New England Journal of Medicine,

appear with an editorial that explores why they come a year after the original results. Precision medicine, the commentators say, is sometimes “messier” than the name suggests.

Last year’s practice-changing results were a headline of the 2018 meeting: chemotherapy with endocrine therapy after surgery offered no benefit for 70% of women with hormone receptor—positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer.

This time, Joseph A. Sparano, MD, of the Albert Einstein College of Medicine, and his coauthors used the same data to show that adding “clinical risk” to the equation—tumor size and histologic grade&mdash;offers extra prognostic value, “that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy.”

However, the recommendations from these new results are drawn from other studies, not from the data.  The Oncotype DX assay provides a recurrence score of 0 to 100, with higher scores indicting worse prognosis. TAILORx enrolled 10,273 women with early breast cancer to learn more about the risks for patients with this type of cancer, specifically the risks for women with scores in the middle range, 11 to 25. Based on results from earlier trials, those with scores of 0 to 10

received endocrine therapy only; those with scores above 26 received endocrine therapy and chemotherapy. Those in the middle range were randomized

to receive either chemotherapy and endocrine therapy or endocrine therapy alone. Patients were followed for 9 years.

Results reported in June 2018 showed that although most women in this range did not need chemotherapy, some women would still benefit from it: those age 50 or younger with a recurrence score of 16 to 25.

The investigators used a binary classification system from the MINDACT trial that divided patients into high or low risk based on tumor size and histologic grade. They report that the “integration of genomic and clinical information may provide a more accurate estimate of prognosis for individual patients than could be provided by either the genomic or clinical information alone.”

Notably, the analysis found predictive information about recurrence, but not benefits of chemotherapy. Results showed:

• For women with recurrence scores of 11 to 25 who received endocrine therapy only, the hazard ratio comparing high clinical risk to low clinical risk was 2.73 (95% CI, 1.93-3.87).

• For women with recurrence scores of 11 to 25 who received chemotherapy and endocrine therapy, the hazard ratio for high versus low risk was 2.41 (95% CI, 1.66-3.48).

• For women with recurrence scores of 26 or higher, who all had both chemotherapy and endocrine therapy, the hazard ratio for high versus low risk was 3.17 (95% CI, 1.94-5.19).

Among women who were 50 years or younger who had endocrine therapy alone, the investigators wrote, “The estimated rate of distant recurrence at 9 years was less than 5%,” with a low recurrence score, regardless of clinical risk.

The risk rose above 10% among younger women who had an intermediate recurrence score and high clinical risk.

So, what to do for these patients? Sparano et al noted that some of chemotherapy’s ability to reduce death rates in younger women is attributed to its ability to induce menopause; while offering plenty of caution, they suggest that for some younger women, adding an aromatase inhibitor to tamoxifen may be in order.

They wrote, “Given the incremental benefits observed with ovarian suppression plus tamoxifen or an aromatase inhibitor, as compared with tamoxifen alone in premenopausal women, and the low percentage of premenopausal women who received ovarian suppression in TAILORx, it is possible that similar incremental benefits observed in younger women who received chemotherapy and had a recurrence score of 16 to 25 could be achieved with ovarian suppression and an aromatase inhibitor, as observed in other trials.”

Unlike the clarity of last year’s findings, the authors of the editorial said this time the TAILORx team must rely on interpretations. David J. Hunter, MBBS, and David L. Longo, MD, wrote that the investigators “speculate on the basis of previous studies that adding ovarian suppression and an aromatase inhibitor might give a reduction in risk equivalent to that observed using adjuvant chemotherapy.”

“The promise of ‘precision’ medicine has collided with the rather messier world of using all available evidence to try to make educated guesses to improve patient outcomes. How could this be?” Hunter and Longo asked.

The answer, they said, comes from the need to reuse data from large studies like TAILORx, because such studies are too expensive to repeat every time there is a question—and the one asked in this new study will apply to many women. The commentators commend the TAILORx investigators for taking on the questions they have asked, and note, “Distinguishing between results that warrant a change in practice and those that do not will not lead to a ‘precise’ process.” 

1. Sparano JA, Gray RJ, Ravdin PM, et al. Clinical and genomic risk to guide the use of adjuvant therapy for breast cancer [published online June 3, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1904819.

2. Hunter DJ, Longo DL. The precision of evidence needed to practice “precision medicine.” [published online June 3, 2019]. N Engl J Med. doi: 10.1056/NEJMe1906088.

-Mutated Metastatic Pancreatic Cancer, but Not OS

3. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710.

Patients with advanced pancreatic cancer linked to germline genetic mutations did not see their disease worsen for an additional 3.6 months when treated with olaparib (Lynparza), but an early interim analysis did not show a statistically significant difference in overall survival (OS) either, according to recent study results.

The results of the subset of patients with germline mutations in the 

. Topline results were released in February.

Pancreatic cancer affects nearly 57,000 Americans annually; once it spreads, fewer than 10% of patients are alive 5 years after initial diagnosis. About 4% to 7% of patients with pancreatic cancer have a germline BRCA mutation. The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib is sold by Astra Zeneca and Merck. AstraZeneca and a grant from the National Institutes of Health funded the study.

The phase 3 study, called POLO (Pancreas Cancer Olaparib Ongoing), included 154 patients; 92 received olaparib at 300 mg twice a day and 62 received placebo. The 154 patients had confirmed 

 mutations via use of the BRACAnalysis CDx companion diagnostic from Myriad Genetics. It is currently the only FDA-approved test to find germline 

To be eligible for the randomized controlled trial, the patients had to have received at least 16 weeks of continuous first-line platinum-based chemotherapy, with no evidence of disease progression. The primary end point of the study, median progression-free survival, was significantly longer in the olaparib group than in the placebo group (7.4 vs 3.8 months; hazard ratio [HR] for disease progression or death, 0.53; 95% CI, 0.35-0.82; P = .004). At 24 months, 22% of the patients in the treatment group had not seen the disease progress compared with 9.6% of the placebo group.

Given the deadly nature of advanced pancreatic cancer, the fact that maintenance olaparib could stop progression for a few months for this group of patients “is really quite remarkable,” said Johnathan M. Lancaster, MD, PhD, the chief medical officer for Myriad Genetics, in an interview with 

The interim analysis of OS, a secondary end point, showed no significant difference, with a median 18.9 months for the olaparib group and 18.1 months for the placebo group (HR for death 0.91; 95% CI, 0.56-1.46; P = .68). Patient-reported outcomes (health-related quality of life scores) were also not significantly different.

Lancaster said those results are not surprising given the crossover that can occur between different therapies; the study reported that 15% of the placebo group received a PARP inhibitor after disease progression.

“For the first time now, we have the opportunity to use precision medicine intervention to identify patients with pancreatic cancer [who] will likely benefit from PARP inhibition,” he said.

There are a few reasons why the results are important, Lancaster said. POLO has clinical implications for a select group of patients who have few options, and it highlights not only the role of genetic testing for cancer in general but also for pancreatic cancer specifically, where BRCA is more well known for its role for breast and ovarian cancers for some populations. He also noted that the National Comprehensive Cancer Network updated its guidelines earlier this year to recommend universal germline BRCA testing for all patients with pancreatic cancer. In addition, this study defines the potential and very nature of precision medicine, Lancaster said, despite the small numbers and percentages in the study.

“The whole paradigm of precision medicine, is, indeed, to identify the 1 in 20 patients who carry a biomarker and offer them a drug,” as opposed to offering the drug to everyone, where, he said, “the effect is washed out.”

Myriad announced earlier this year that it intends to seek FDA approval to use BRACAnalysis CDx as a companion diagnostic for olaparib in patients with pancreatic cancer; it is already used to identify patients with germline BRCA-mutated advanced epithelial ovarian, fallopian tube, or primary peritoneal

cancer. It is also being studied in prostate cancer.

A first-in-class PARP inhibitor, olaparib is approved to treat multiple indications of advanced ovarian, fallopian, and metastatic breast cancer, including those with both inherited and acquired BRCA mutations. The 

genes help cells repair DNA damage, and inherited mutations can make both women and men more likely to develop certain cancers.

Olaparib works by blocking the DNA damage response in cells and tumors. 

Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline 

-mutated metastatic pancreatic cancer [published online June 3, 2019]. N Engl J Med. doi: 10.1056/NEJMoa1903387.

Articles

Evidence-Based Oncology

Clinical findings presented at the 2019 Annual Meeting of the American Society of Clinical Oncology in Chicago, Illinois.

Clinical Findings

A number of abstracts at the 2019 Annual Meeting of the American Society of Clinical Oncology (ASCO) featured studies that focused on using real-world data to advance research and cancer care in non—small cell lung cancer (NSCLC).

“Now, what do we mean by real-world data? We mean data relating to patient health status or the delivery of healthcare routinely collected from a variety of

sources including electronic health records, claims data, and more,” explained Sumithra J. Mandrekar, PhD, of Mayo Clinic, during an oral presentation of the abstracts. “But that’s different from real-world evidence, which is the clinical evidence regarding the usage and potential benefits, or risks of a medical

product derived from the analysis of real-world data.”

The first presenter, R. Donald Harvey, PharmD, BCOP, FCCP, FHOPA, of the Winship Cancer Institute, discussed the results of a real-world study that

surveyed the impact of broadening clinical trial criteria for patients with advanced NSCLC (aNSCLC).

He explained that the study utilized the guidelines put out by groups like the American Society of Clinical Oncology and Friends of Cancer Research for

broadening eligibility criteria. The goal was to make the trial population more representative of what is seen in the real world and make the results more generalizable, as well as accelerate trial accrual.

The study found that using expanded criteria would enable nearly twice as many patients with aNSCLC to qualify and consider trial participation, and it

would also likely result in trial participants who are more reflective of a broader patient population.

However, Mandrekar offered a note of hesitation when expanding trial criteria: “Sometimes expanding trial criteria actually leaves you with a lack of

randomization. Randomization is critical for the success of a trial.”

Interestingly, another study looked at a predictive model for determining 1-year survival in NSCLC based on electronic health records (EHRs) and tumor

sequencing data available at the Department of Veterans Affairs (VA).

The cohort characteristics identified 365 patients who were older, predominantly male, and had a high rate of prior or current smokers. The study also

found that a large number of patients in the cohort were classified as having stage IV NSCLC.

The genomic features of the predictive model defined binary features that reflected the presence or absence of variation in 96 genes that were included in

both the EHR and tumor sequencing data, as well as the number of these genes that were present without variation.

“We were able to build an accurate predictive model of 1-year survival in patients with NSCLC at the VA, which integrates real-world clinical and genomic

data,” said Nathanael Fillmore, PhD, of the VA Boston Healthcare System. “This provides a good foundation to move forward in being able to offer support for clinical decision making for VA clinicians. However, the model does not yet include certain features, including weight loss and treatment details.”

Another study was presented on utilizing big data to advance personalized therapies. Robert Doebele, MD, PhD, of the University of Colorado, began his

presentation by first asking the question, “Is big data always best?” He offered an answer to his own question, explaining that sometimes using big data or big clinical trials can allow researchers to miss smaller, yet significant, findings.

He presented data from a study that enrolled 1692 patients and then broke that study out to just 9 patients with NSCLC. In a graph of all patients, all

responses to the drug seemed to fall along the same curve. However, in the smaller cohort of patients, the data showed that this group actually had a

“phenomenal response to the EGFR mutation,” he said.

In keeping with the theme of ASCO’s meeting this year, “Caring for every patient, learning from every patient,” Doebele closed by saying that,

“Models derived from large cohorts need robust data and, ultimately, need to be independently validated. Small data [have] ongoing merit and value

for new discoveries, and with NSCLC especially, it can’t be thought of as a single disease.” 

Real-world evidence is being embraced by FDA as a way to expand the review of data beyond the trial population, which may not be representative of the patients seen in clinics on a daily basis.

How Real-World Data Can Affect NSCLC Treatment

Although chimeric antigen receptor (CAR) T-cell therapy has been largely touted as one of the most important advances in cancer care in recent

years, the therapy comes with the risk of severe toxicities as well as an increased financial burden due to the high cost of the drugs.

During the meeting, data were presented regarding “the other side of CAR T-cell therapy,” namely, cytokine release syndrome (CRS), neurologic toxicity, and financial burden.

“[CAR T-cell therapy] is truly now the fourth arm of treatment for [patients with cancer] and has allowed our patients to get great therapeutic rewards,” said Elizabeth Shpall, MD, of The University of Texas MD Anderson Cancer Center.

“However, about half of the patients included in the study that was the basis of approval for Yescarta needed ICU [intensive care unit] management. In 3 of the published studies to date [for the therapies], almost all the patients developed some grade of cytokine release syndrome.”

The authors of the study concluded that there are several factors that can predict the onset of CRS, such as a high marrow tumor burden, lymphodepletion using cyclophosphamide and fludarabine, and administering a higher CAR T-cell dose. Thrombocytopenia also seemed to be a predictor. 

“So how can we ameliorate CRS? We need to focus on the identification of predictive biomarkers, prompt and correct use of anti-IL6 [interleukin-6] and steroid therapy, and educate our physicians extensively,” Shpall said.

However, once a patient has hopefully overcome the week or so that CRS usually lasts, according to Shpall, the next challenge is to identify whether or not the patient has signs of neurotoxicity, which can often occur after CRS resolves.

“The immediate first fever happens early. That’s usually the first sign, if a patient develops a fever early on. Overwhelmingly, though, neurotoxicity is reversible and usually subsides within 7 days,” said Bianca Santomasso, PhD, MD, of Memorial Sloan Kettering Cancer Center.

Historically, Santomasso explained, neurotoxicity used to be included in CRS. But when studying the toxicity, it began to be identified by different characteristics, such as global encephalopathy and aphasia, among others.

“We’ve definitely learned some lessons and figured out what to look for when it comes to neurotoxicity. We know that we need to do a baseline MRI [magnetic resonance imaging], watch a patient’s vitals and electrolytes, and definitely a declining level of consciousness without another cause is concerning,” said Santomasso.

Putting aside the physical cost of the therapies, the actual price of the therapies can be cause for patient concern as well, considering the price of the 2 FDA-approved therapies currently on the market are $495,000 and $373,000. 

“Currently, there are 475 cell and gene therapy companies in North America. In 2018, there were about $20 billion worth of cell therapy deals, IPOs [initial public offerings] of nearly $1 billion, and $750 million in company series funding,” said Carlos Bachier, MD, of the Sarah Canon Center for Blood Cancer. “And yet, if you take out the university programs and big cancer centers, there are only 17 community institutions left that administer CAR T-cell therapy.”

It is important to note that while the cost to the patient is significant, the cost to the institution is also substantial. In order to be able to administer the therapy, the institution must have a triage CAR T nurse or coordinator, train its medical staff on CAR Ts, have the proper collection/shipping/storage containers for the product, and ensure proper reporting to the FDA in order to allow for proper regulation.

“Best practices of experienced centers include building a multidisciplinary team that not all institutions are prepared or capable of implementing…[and] financial barriers for both the patient and the institution providing the therapies can prevent wide use of the treatments,” said Bachier.

To date, reimbursement has not been finalized for these products, and is currently being discussed by CMS.

Cytokine release syndrome represents a major concern, and source of costs, associated with the life-saving gene therapy.

Cost of Care: Outlining the Risks That Go Along With the Benefit of CAR T-Cell Therapy

Oncology Reimbursement Reform Leaves Stakeholders With More Questions Than Answers

Oncologists and representatives from UnitedHealthcare and the Center for Medicare and Medicaid Innovation (CMMI) took the stage at the 2019 Annual Meeting of the American Society of Clinical Oncology to discuss oncology reimbursement reform and possible changes on the horizon for the promotion of higher-value care.

Jennifer Malin, MD, PhD, FASCO, senior medical director of oncology and genetics at UnitedHealthcare, started off the session by explaining what oncologists and patients already know:

“When we talk about the cost in healthcare, oftentimes we focus on just the pricing of the drugs and what individual out-of-pocket costs are. But the overall impact on the total cost of care is what impacts people’s premiums and what the federal or state government has to pay for Medicaid. That impacts the overall affordability for people to buy insurance in the first place,” said Malin.

She then reviewed some strategies oncologists are all too familiar with that payers use to improve the value of cancer therapy, such as clinical pathways, episode-payment shared savings, bundled payments, and shared-risk capitation.

UnitedHealthcare utilized each of these strategies in creating their own cancer episode program. The program, first implemented by Malin’s predecessor Lee Newcomer, underwent a proof-of-concept pilot study from 2009 to 2012. Afterward, results showed that the program had a 34% reduction in costs for the 5 practices that were enrolled.

“Our cancer episode program is a new payment model based on the treatment of cancer episodes instead of drug margins. The program removes an oncology practice’s dependency on drug margins and rewards physicians for improved quality and reduction in the total cost of cancer treatment. It also builds a learning system to identify best practices for improved quality and value,” she said.

After the results of the initial pilot, UnitedHealthcare rolled the program out to 250 practice sites. Due to the larger number of practices enrolled, collaboration between UnitedHealthcare and the practices went from monthly interactions in the pilot to less often. This, in part, contributed to the lower amount of savings—13%&mdash;seen once the program expanded.

In talking about the revolution toward value-based care, the faults with traditional fee-for-service (FFS) programs are often discussed. Karen Hoffman, MD, MPH, of The University of Texas MD Anderson Cancer Center, presented provocative data regarding practices that use FFS costing more money and more often referring their patients for more expensive treatments.

“In a model where physicians and healthcare providers are reimbursed for each service rendered, it may provide financial incentives to increase utilization of services or recommend services that are more expensive,” said Hoffman.

She explained that while physicians are prohibited by national statute from referring Medicare patients for designated health services at entities with which they have a financial relationship, study results show more services are used by physician “owners” versus nonowners.

“Specifically, the data show that there is an increase in anatomic pathology services by self-referring providers. In 2010, it was estimated that self-referring providers made 918,000 more referrals for pathology, which ended up costing Medicare $69 million,” she said.

Finally, Lara Strawbridge, MPH, of CMMI, presented about an effort to address costs that oncologists are quite familiar with: the Oncology Care Model (OCM). The OCM, which was implemented in 2016 as a 5-year model, is an episode-based payment model that targets chemotherapy and related care during a 6-month period that begins with a patient’s receipt of chemotherapy.

“The OCM has 176 practices, about 7000 practitioners, and sees 200,000 unique beneficiaries per year, with 260,000 episodes of care per year,” said Strawbridge. She provided an overview of some of the positive outcomes of the program, including an anecdotal story from a provider saying that “[the OCM] enables us to provide the care we’ve always wanted to do.” However, as the program nears the end of its 5-year pilot phase and CMMI looks to implement changes for the next version of the program, what spoke louder in Strawbridge’s presentation were the unanswered questions.

The OCM has generated a lot of actionable, valuable data for practices, although this has come at a cost of a high administrative reporting burden. Strawbridge didn’t mention those reporting burdens when discussing the challenges the OCM has seen over the past few years. What was mentioned, such as the limitations of the Medicare claims system and the complexity of practice business and coding models, are multifaceted issues that may not be addressed by the next rendition of the program.

For example, in a recent meeting of the Institute for Value-Based Medicine®, Jessica Walradt, manager of Managed Care of Government Programs, Value-Based Care at Northwestern Memorial Healthcare, explained there’s a lot of confusion around how episodes are triggered with the OCM due to an episode starting at the receipt of chemotherapy. This is because patients could be administered chemotherapy as maintenance therapy as well as an active treatment. Due to this, Waldradt said her institution is sometimes unsure which patients are even meant to be included in the OCM. This too, was not mentioned by Strawbridge.

In terms of the future of the OCM, much remains unclear. Strawbridge said, “We’re working on the next version of the model to include further improvement in quality of care and health outcomes, moving farther away from fee-for-service infrastructure for payments, considering chemotherapy and supportive care, and looking into the adoption of 2-sided risk.”

ASCO Town Hall Brings Tense Conversation on Drug Pricing

The American Society of Clinical Oncology (ASCO) held a town hall meeting to discuss drug pricing at its 2019 meeting, with moderator Jeffrey Ward, MD, FASCO, hematologist at the Swedish Cancer Institute, joining Rodney Whitlock, PhD, of McDermott+Consulting. 

Drug pricing seemed like an appropriate topic for ASCO’s town hall as the Trump administration has made lowering the cost of medications a major objective. The administration has put out a series of proposals looking to address the cost of drugs, such as the International Pricing Index (IPI) and the recently finalized rule around direct-to-consumer advertising for pharmaceutical companies.

“What we have is 3 types of issues out there that you see policymakers discussing,” Whitlock said. “There are blockbuster drugs coming out with significant price tags attached, speculation issues around astronomical drug price increases given the ‘villian’ made-for-our-time Martin Shkreli, and finally, there’re regular drug price increases where drug companies raise their prices in January. Why? Because it’s January. And then again in June. Why? Well, because it’s June.”

However, the issue of drug pricing has not yet been linked to a single direct, surefire cause. It’s no secret that patients are feeling the effects of out-of-pocket costs of drugs, whether it’s in co-pays or co-insurance costs, but who is to blame? “There’s a tremendous amount of ‘not it’ and finger pointing going on. Drug makers want you to believe that the issues are the $700 aspirins at the hospital—that it’s everyone but them. But on the other side, you see other stakeholders who set the prices and they’re also saying it’s not them, but we don’t know because it’s not a transparent system,” he said.

When asked if he believes the politics will change around whether the government should have a place in instituting drug prices, Whitlock said there’s definitely renewed interest in and openness now to say that if the marketplace isn’t working for consumers under the current system, then the government will come in and set pricing.

“An example would be, look what’s happening with surprise billing. Congress has given that great interest, and once they heard about it, they took it on and basically said, ‘Well then, let’s just stop this right now,’” said Whitlock. “It’s a gateway drug to larger price controls. Once you do it there, can’t you go other places to set price controls? I mean, the government has been doing that in the Medicare space for quite some time now.”

Regarding the IPI model, Whitlock offered a word of caution for what the drug companies’ response to such a model would be. He hypothesized whether the companies would try to get underneath the IPI and raise costs in other countries, so as to not lose money in the United States, or would they simply accept the lower payments?

“[This is something] that hasn’t been discussed with this issue. It’s the point that there is clearly a trade issue at hand here. Other countries are able to tell drug companies, ‘You have to sell at this price to sell in our countries.’ Now, yes, drug companies could get out of [the problem the IPI poses] by raising the prices in other countries. But what isn’t being addressed—and this is truly a trade issue&mdash;is the inability of drug companies to raise prices in other countries even a nickel,” said Whitlock.

The question remains, “What will the administration do regarding the IPI? Although there was a final rule put out, it has yet to take an effect. Whitlock floated the notion that the administration is using this proposal, and others, as a bargaining chip for what may come together in the fall as a larger deal with Congress. Perhaps not. Either way, Whitlock stressed that healthcare stakeholders need to pay attention to what’s happening in Washington, DC, and stay clued in as to what’s to come. “As they say, if you’re not at the table, you’re on the table.”

In an attempt to bring the conversation back to the oncology stakeholders in the room, Michael Kolodziej, MD, vice president and chief innovation officer at ADVI Health, Inc, poised his question in earnest: “We, as oncologists, are floating on the Titanic, and we’re worried about what next song the orchestra will play because all of the stuff we’ve been doing forever is going to become incredibly irrelevant as we move into combination I-O [immuno-oncology] therapy, CRISPR [Clustered Regularly Interspaced Short Palindromic Repeats], and CAR T [chimeric antigen receptor T-cell therapy].

These are therapies that will cost, per patient, $500,000 to $1 million…. Help me understand why we’re not interested in pursuing outcomes-based contracting—through a model, through legislation, anything&mdash;because as we move technology forward, and the prices will go up with that advance, we need to find a way to pay for it.”

Whitlock’s response largely explained what healthcare stakeholders already know: Policymakers really don’t understand how this world works.

“The core mission of the FDA in approving a drug is safety and efficacy. That’s it. The FDA is not in any way tasked to determine whether or not drugs have comparative value or that they meet a certain outcome-based type metric. CMS, their core task is to pay the freaking bills,” he said. “So, when you talk about the 2 federal agencies most capable of engaging the conversation you just raised—which is critically important&mdash;you first need to grasp how utterly [incapable] they are at raising the conversation, because they don’t have the skill set to do it.”

Rather than taking on the challenge and bringing the suggestion back to Washington, DC, Whitlock called on the stakeholders in the room and ASCO members to push the conversation forward. “Moving in the direction of value, we are so far removed from that. Don’t wait on the federal government. If you, as an organization, want to drive that conversation, you’re better equipped than waiting for someone else at the ‘mothership’ in Baltimore where CMS is located, to come up with the idea,” Whitlock said.

The Importance of Including Primary Care Physicians in a Patient’s Cancer Journey

“How do you currently collaborate with your primary care colleagues in caring for patients with cancer?” This was how Larissa Nekhlyudov, MD, MPH, opened the session, “Bringing the Primary Care Physician Back Into Cancer Care.”

Answers to Nekhlyudov’s question ranged from communication through electronic health record (EHR) systems to picking up the phone and calling the primary care physician (PCP). One thing remained consistent throughout every answer: We need to be doing better.

Nekhlyudov was joined by panelists Piyush Srivastava, MD, gastrointestinal medical oncologist at Kaiser Permanente; Trevor Jolly, MBBS, medical oncologist at UNC Health Care; and Elizabeth Schiff, a patient advocate and 2-time cancer survivor, to discuss and present interactive case studies in which PCPs should be a part of the conversation.

The first case involved a 75-year-old post-menopausal female with newly diagnosed, screen-detected, left-sided invasive breast cancer; her medical history included a body mass index of 31.4 and several years of hypertension. The audience and panelists were asked which medical condition was most likely to cause the patient’s death in the next 10 years. Most answered cardiovascular disease, as one of the highest risk factors for cardiovascular disease is hypertension. When the audience was asked who they would prefer to manage the patient’s blood pressure and other cardiovascular disease risk factors, a cardiologist or a PCP, most preferred a PCP.

This surprised Nekhlyudov, who expected most audience members to recommend a cardiologist. She presented data from a study published in JAMA in February 2019, which showed that PCPs “have a huge effect on mortality for [patients with cancer]. Every 10 additional PCPs per 100,000 population is associated with 51.5 extra days of life expectancy versus 19.2 days for additional specialists. Also, every 10 additional PCPs per 100,000 population was associated with reduced cardiovascular, cancer, and respiratory mortality by 0.9% to 1.4%,” said Nekhlyudov.

Jolly couldn’t agree more regarding the importance of a PCP in the journey of a patient with cancer. He explained that what he often sees in practices is that the oncologist will let the PCP deal with the hypertension and the oncologist will deal with the cancer, as with the case study. “But we need to collaborate more. If you see that your patient has hypertension, call her physician. Bring it to their attention. Ask them to follow up, if you started her on a hypertension medication. That communication is key.”

Although the panelists and the audience seemed to agree on this matter, 1 audience member brought up a point that had not yet been mentioned: “You haven’t addressed the medical economics of these visits. Some patients have a co-pay, and they can’t afford to see their primary care physician as often as they see their oncologist during active treatment.”

Schiff agreed. Having been through her own cancer journey, she explained that she knew the care coordination could get complicated. “If you need to choose between seeing your oncologist and seeing your PCP, well, that would be hard. If you’re in active treatment, I would imagine you’d see your oncologist. But this is where the communication between the oncologist and the PCP is essential. If the patient can only economically see the oncologist on a regular basis, that oncologist needs to communicate with the PCP to make sure they’re kept up-to-date on the patient’s treatment journey and condition.”

Cannabis Risks and Benefits in Cancer Symptom Management: Much Remains Unknown

When asked to describe ways to improve communication between PCPs and oncologists, the overarching responses included creating an integrated EHR system across the providers and needing more time to meet with each patient. 

Open chairs were scarce as a session titled “Is There a Role for Cannabis in Cancer Symptom Management?” was set to begin. The session featured knowledgeable oncologists Mellar Davis, MD, of Geisinger Health System; Claude Cyr, MD, of McGill University; Brooke Worster, MD, of Thomas Jefferson University; and Ilana Braun, MD, of Dana-Farber Cancer Institute.

Oncologists, patient advocates, patients, and other stakeholders from around the world gathered to hear different perspectives regarding the use of cannabis in symptom management for patients with cancer. Panelist after panelist went up to present available data, and each reiterated the same point: We need more research.

As it stands right now, the legal landscape of cannabis use, particularly in the United States, is puzzling, to say the least. At the time of the presentation, 33 states have some form of legal marijuana. Of these, 10 offer a parallel recreational law, 14 have approved only limited medical use, and only 3 fully prohibit it. Federally, however, marijuana remains a Schedule 1 drug, which deems that it offers “no acceptable medical use, lacking [a] safety profile acceptable for use under medical supervision, and a high abuse potential,” according to Braun.  

This creates problems in terms of prescribing, administering, and even researching the drug. Additionally, it presents a problem for patients with cancer who do want to access it—sometimes with the permission or urging of their healthcare provider. These same patients might walk into a dispensary and be offered products that have not gone under FDA review for safety, efficacy, or potency.

“Cannabis is commonly used by patients during cancer therapy, frequently without the oncologist’s knowledge,” said Davis. This presents a problem because, as each panelist pointed out, “how cannabis influences cancer therapy and cancer course is completely unknown.”

Cyr began his presentation by taking a poll of the audience. He asked, “How many people feel uncomfortable offering cannabis to patients?” Although a decent number of oncologists raised their hands, it was noted that there were significantly fewer than in recent years. He then asked the audience why they were uncomfortable, and the response was largely that they were waiting for more evidence.

Cyr’s presentation was somewhat unconventional by usual standards of cannabis use in patients with cancer. He explained that many of the most common adverse events (euphoria, aversive memory extinction, slowed down sense of time, and relaxation, among others) could actually be positive for patients with cancer.

“If you have a patient who is nearing end of life, who is feeling extremely depressed, well cannabis may be the safest drug to prescribe that elicits euphoria,” he said. “Though aversive memory extinction may seem like a bad thing for other patients, I would offer that cancer patients may not want to remember every minute of sitting through chemotherapy. And for patients who consistently report feeling like their lives are slipping away from them and that they don’t have much time left, a slowed down sense of time could be a great thing.”

Although the available research is mixed regarding the risks and benefits of cannabis use in patients with cancer, Worster works with the geriatric population and stressed that she has some different concerns than her colleagues working with younger patients with cancer.

“Age is just a number. There are large differences in the rate of aging, and different organ systems age at different rates. An individual’s age, per se, is not the problem; however, it does raise the statistical likelihood of certain events—such as falls&mdash;if patients are initiating cannabis use,” she said.

In this population, she explained, adverse events of cannabis use, such as dizziness, could have life-threatening consequences.

From the Oncology Care Model to the possibilities of cannabis, policy issues drew big crowds at the 2019 Annual Meeting of the American Society of Clinical Oncology.

Policy Updates: ASCO 2019

Researchers Report on 3 Bevacizumab Biosimilar Development Programs

The anti-vascular endothelial growth factor (anti-VEGF) agent bevacizumab (Avastin) carries indications for lung cancer, colorectal cancer, breast cancer (in Europe), and glioblastoma, and has been the target of multiple hopeful biosimilar challengers, 2 of which are approved. Three developers reported on their progress with developing biosimilars of this anticancer agent.

The first bevacizumab biosimilar to be approved by the FDA and authorized by the European Commission, ABP 215 (Amgen’s MVASI), earned the FDA’s clearance on the basis of data that included findings from the phase 3 MAPLE study, which compared the biosimilar to the reference in patients with advanced nonsquamous non—small cell lung cancer (NSCLC).

During the meeting, researchers reported on the totality of the evidence on ABP 215 that led to approval.

The researchers compared VEGF-A kinetic parameters for common isoforms: 121, 165, and 189. They determined that binding to all 3 isoforms was similar for the biosimilar and the reference product.

Patients were randomized to receive the biosimilar (n = 328) or the reference (n = 314) with carboplatin and paclitaxel for up to 6 cycles, and efficacy was based on objective tumor assessments. The primary efficacy end point was the risk ratio of objective response rate (ORR), and clinical equivalence was confirmed if the 2-sided 90% CI of the risk ratio (RR) was within the prespecified margin of 0.67 to 1.5.

Based on a central analysis, ORR was achieved in 39.0% of patients in the biosimilar arm and in 41.7% of patients in the reference arm (ORR risk ratio, 0.93; 90% CI, 0.80-1.09). Based on an investigator analysis, ORR was achieved in 47.9% of patients in the biosimilar arm and in 48.1% of patients in the reference arm (ORR risk ratio, 1.01; 90% CI, 0.88-1.16).

These results, wrote the authors, further confirm the similarity of ABP 215 to its reference, and support the extrapolation to all available indications for bevacizumab. 

Innovent provided greater detail on its phase 3 comparative study in patients with NSCLC after having announced positive topline results of the study

In the newly reported data, Innovent said that 450 patients with NSCLC who were receiving first-line treatment with carboplatin and paclitaxel were randomized to receive either the proposed biosimilar (n = 224) or the reference bevacizumab (n = 226) until progression.

The primary end point was ORR, evaluated by comparing the 2-sided 90% CI of the risk ratio between the study arms. The prespecified equivalence margin was 0.75 to 1.33.

ORR in the full analysis set was 44.3% in the biosimilar arm and 46.4% in the reference arm; the RR for ORR was 0.95 (90% CI, 0.803-1.135), which fell within the prespecified margin. 

Medium progression-free survival was 8.4 months in the biosimilar arm and 8.3 months in the reference arm. Treatment-emergent adverse events were balanced between arms and consistent with the known profile of bevacizumab.

The incidence of antidrug antibodies (ADAs) was 0.5% in the biosimilar arm and 0% in the reference arm, and no patients developed neutralizing antibodies. 

Finally, researchers reported that the STELLA trial of MB02—a proposed bevacizumab biosimilar being developed by mAbxience&mdash;is underway.

The study is a multinational, double-blind, randomized, parallel-group, equivalence study to compare the efficacy and safety of the biosimilar versus its reference, both in combination with plus chemotherapy in patients with stage IIIB to IV NSCLC.

Patients will be randomized to the biosimilar or the reference along with chemotherapy, and after 6 cycles, they will receive bevacizumab monotherapy every 3 weeks until progression, intolerance, death, withdrawal, or the end of the study. The primary objective is to compare the ORR between arms at week 18. Progression-free survival and overall survival at weeks 18 and 52, safety, and immunogenicity will also be assessed.

A sample size of 600 was calculated to provide 89% power to show equivalence on a primary end point of RR based on ORR, and 596 individuals have been recruited, say the investigators. 

1. Thomas M, Thatcher N, Goldschmidt JH, et al. Totality of evidence in development of the bevacizumab biosimilar ABP 215: central and investigator evaluation of efficacy from the MAPLE study. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract e201708. https://abstracts.asco.org/239/AbstView_239_270387.html.

2. Zhang L, Wu B, Huang L, et al. Efficacy and safety of IBI305 compared with bevacizumab in advanced non-squamous NSCLC patients as first-line treatment in a randomized, double-blind, phase III study. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract 9095. https://abstracts.asco.org/239/AbstView_239_267151.html.

3. Shparyk YV, Bondarenko I, Paravisini A, et al. Bevacizumab biosimilar and reference bevacizumab in subjects with stage IIIB/IV non-squamous non-small cell lung cancer (STELLA): design of a confirmatory, double-blind, randomized, controlled study. Presented at: American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract e20731. https://abstracts.asco.org/239/AbstView_239_258561.html.

No Significant Difference in EFS, OS Between Herceptin and Biosimilar, Ontruzant, at 3 Years

Samsung Bioepsis' SB3 (Ontruzant) has been approved in the United States and European Union as a biosimilar of the brand name trastuzumab, Herceptin. 

Approval relied in part on a phase 3 study comparing the biosimilar with the reference in women with HER2-positive early or locally advanced breast cancer in the neoadjuvant setting.

Notably, some of the lots of the reference trastuzumab that were used in the study—with expiry dates from August 2018 to December 2019&mdash;had been impacted by a product shift that resulted in downward changes to antibodydependent cell-mediated cytotoxicity (ADCC).

At the time, ADCC was not fully understood to be key to the efficacy of trastuzumab. However, in results that were presented in late 2018 at the San Antonio Breast Cancer Symposium, the importance of this quality attribute and its impact on event-free survival (EFS) came into clearer focus.

According the 2018 study data, 126 patients had been exposed to at least 1 lot of reference trastuzumab that had lower ADCC activity.

 Another 55 patients given the reference therapy were not exposed to these lots. After a median of 30.1 months of treatment with the biosimilar—which was given to 186 patients&mdash;and 30.2 months of treatment with the reference which was administered to 181 patients, there was no statistically significant difference in EFS between the biosimilar arm (96.7%) and the patients who were not exposed to the lower-ADCC activity lots of the reference (98.2%). However, in the patients exposed to the lower-ADCC activity reference, 2-year EFS was lower (92.5%). Researchers presented the 3-year results of an evaluation of survival by ADCC status.

At a median follow-up of 40.8 months in the biosimilar arm and 40.5 months in the reference arm, EFS rates were 92.5% in the biosimilar arm, 94.5% among patients treated with the reference who were not exposed to the lower-ADCC activity lots, and 82.5% among patients who were exposed. Overall survival (OS) rates were 97.0%, 100%, and 90.6% in the 3 groups, respectively.

Among those treated with the reference, exposure was associated with decreased EFS compared with no exposure (hazard ratio [HR], 0.14; 95% CI, 0.04-0.51; P = .003). Decreased OS was noticed as a trend in the exposed group compared with the unexposed group, but no significant difference emerged (HR, 0.14; 95% CI, 0.02-1.15; P = .068).

Between patients treated with the biosimilar and those treated with the reference product who were not exposed to the lower-ADCC lots, no difference was observed in EFS (HR, 1.06; 95% CI, 0.33-3.44; P = .923) or OS (HR, 0.54; 95% CI, 0.05-5.44; P = .600).

The investigators concluded that patients exposed to the lower-ADCC lots of the reference had significantly lower EFS than those who were not exposed, whereas the biosimilar-treated patients and those unexposed to the affected lots had no significant differences in EFS or OS. 

1. Pegram MD, Pivot X, Cortes J, et al. Event-free survival by ADCC status from a follow-up study comparing SB3 (trastuzumab biosimilar) with reference trastuzumab for HER2 positive breast cancer in neoadjuvant setting. Presented at: 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, Texas. Abstract P6-17-09. http://cancerres.aacrjournals.org/content/79/4_Supplement/P6-17-09.

2. Pivot X, Pegram MD, Cortes J, et al. Evaluation of survival by ADCC status: subgroup analysis of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients with HER2-positive early breast cancer at three-year follow-up. Presented at: the American Society of Clinical Oncology Annual Meeting 2019; May 31-June 4, 2019; Chicago, Illinois. Abstract 580. https://abstracts.asco.org/239/AbstView_239_262069.html.

Research on biosimilars presented at the 2019 Annual Meeting of the American Society of Clinical Oncology.

July 2019

Clinical Findings

How Real-World Data Can Affect NSCLC Treatment

Cost of Care: Outlining the Risks That Go Along With the Benefit of CAR T-Cell Therapy

Policy Updates: ASCO 2019

Biosimilars: ASCO 2019

Research Report: ASCO 2019

Medical World News: Managed Care Updates

AJMCtv Interviews: ASCO 2019