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.” 

Articles

Evidence-Based Oncology

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

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.

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

Clinical Findings

Michael J. Birrer, MD, PhD, Director, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham

How well is oncology research being integrated into clinical management of patients? How can it be done better?

Well, [in] my long, illustrious experience in oncology, I’ve sort of seen it all, and I think that in the late ’70s, ’80s, and I’ll even go into the ‘90s, so much of oncology development was empirical. We would take drugs off the shelf that essentially had been shown to damage DNA or showed some cytotoxic effects against the tumor cells and then we would bring that in an empiric way into the clinic. I think that sort-of almost unscientific approach explained at that time why things moved so slowly.

Why were we stuck on carboplatinum-taxol for ovarian cancer for so long? Because we were doing this, yet another cytotoxic agent from off the shelf, from the lab, into the clinic. That’s completely changed, and to answer the question directly, I think we’re bringing laboratory discoveries into the clinic in a much more efficient and rational way than we ever have in oncology. What I’ve seen change in the last 5 or 10 years has been just astonishing. And there’s multiple advantages of this. So first of all, the transit time is quick. Whereas it used to take 20 years to develop a drug, we’ve now had some drugs approved in the phase 1 setting. That’s certainly true in lung cancer.

So, I can’t say that we’ve gotten it down to 3 to 5 years, but we probably are developing drugs effectively under the 10-year limit, which is half of what it used to be. 

The second issue, [which is] really important for patients, and I tell my patients this, the science is so robust that when the drug gets into the phase 1 [trial], you now have a drug for which the chance of a success is high, the chance of efficacy is higher, and the chance of toxicity is lower.

So, I used to have an old adage. I’d tell my patients that I would never recommend them go for a phase 1 trial if it was outside of a 50-mile radius because traveling all that distance for something that was unlikely to work and maybe toxic wasn’t worth it. It’s completely changed now….

Catherine M. Diefenbach, MD, Hematologist—Oncologist, NYU Langone Health

Now I have patients fly in for a phase 1 trial because it’s a novel combination, because there’s a lot of really interesting science behind it, and its chance of being successful is much higher than it was 10 or 15 years ago.

Can you discuss the importance of reducing toxicity in the treatment of lymphoma? How does this affect patients’ overall health, in addition to quality of life?

I think in general, it’s really important to use the new drugs that we’re discovering that are targeted and to combine them intelligently with standard chemotherapy. Because we know that intensive chemotherapy regimens, while very effective in the first line for patients who have [a] short response or refractory disease, are generally not effective in later lines, unless you go to really high doses.

And most patients don’t tolerate this well, especially if they’re older or if they have significant toxicity. So, trying to take existing chemotherapy at lower doses and combine it with targeted strategies or immunotherapy is a way to both circumvent the higher toxicity of cytotoxic chemotherapy and rely on tumor biology to be smarter, rather than more aggressive, about targeting lymphoma.

Roy S. Herbst, MD, PhD, Chief of Medical Oncology, Yale Cancer Center

There is a lot of research into predictive biomarkers in cancer. How well is that research making it into practices and actually being used with patients who can benefit?

It’s incredible what’s happened now with personalized therapy of cancer. Targeted therapy for lung cancer, we now have 8 or 9 different markers, which if you have them, different oncogenes can allow a physician to give their patient a targeted drug, which might have a response rate upwards of

50% with much less toxicity than chemotherapy.

These are being used, [but] the problem is some of the drivers are rather new, such as RET, NTRK, MET, and we’re still not in all places screening patients for these markers. So it’s going to be very important that people watching this, whether patients or physicians, ask, “Is the profiling test that’s being done at your center or your hospital, that you’re getting as a patient, including all the newest drivers for lung cancer?” Because only if you look for them can you then try to find the therapy either in your local providers office, or if not, since some of these agents are still rather new, there are clinical trials running at many sites.

The nice thing about 2019 is clinical trials really occur almost every place in the United States. So, these things are beginning to get into common practice. At my institution at Yale, we have a center in downtown New Haven, we have 12 to 13 sites around Connecticut, we’re making sure everyone uses the profiling system.

Andrew H. Ko, MD, Colorectal and Gastrointestinal Cancer Specialist, University of California San Francisco

And then there have to be discussions. And things like this [interview] will help people to discuss and learn and understand the importance of these new markers and how to match for the right drug.

You helped write the National Comprehensive Cancer Network (NCCN) Guidelines Insights for pancreatic adenocarcinoma. What was the treatment recommendation for these patients?

NCCN guidelines are a panel of experts in a particular field who gather together to analyze data and interpret them to help guide recommendations for how we manage and treat patients with a particular disease. I’m on the guidelines panel for pancreatic cancer. So, again, some of the specifics in terms of choices of chemotherapy and uses in the advanced or metastatic setting or the adjuvant setting, those are based—as much as possible&mdash;usually on randomized data.

In terms of the latest updates, I think probably the most impactful one is the importance of at least considering genetic testing [in] all patients.

In the past, we used to be a little bit selective in whom we would recommend that for, but now it’s almost a universal recommendation that we at least consider doing genetic testing. By that I mean, even if someone doesn’t have a provocative family history of cancer, we should think about doing genetic testing on those individuals to see if they have any hereditary susceptibility genes.

The classic one would be someone [who] has a germline BRCA, either BRCA1 or especially BRCA2, mutation because not only does that have particular implications for screening family members, but now we know that it actually has very substantive therapeutic implications for the patients themselves, with the use of PARP inhibitors and a greater sensitivity to platinum agents, for example. 

I think that’s a very important piece that perhaps goes underrecognized still in the community, and that’s a little different from just tumor-based molecular testing, which also, actually we believe, should be done or at least be thought of on a more consistent basis. And that’s basically looking at any mutations or genetic alterations within the tumor itself, so sematic mutations or genetic changes, because what I usually tell patients is any information is good to have. It’s not always actionable, but if we happen to find the patient who has evidence of microsatellite instability, or an NTRK fusion, well we have very specific treatments for those situations, and we have clinical trials available sometimes for patients with other mutations [who] are selected for those specific mutations. So I think doing that as much as possible, doing that kind of molecular profiling, is also something that should be considered routinely. 

Despite there being a growing number of therapeutic options for pancreatic cancer, a recent study found one-third of these patients don’t see a medical oncologist and more don’t receive treatment. Why do you think that’s the case? Can anything be done to improve those numbers?

I think pancreas cancer, because it’s historically been felt to be a pretty dismal disease in terms of prognosis and patients faring poorly, I think there’s perhaps been a sometimes-nihilistic philosophy that some providers even still have despite our growing array of options for patients. So, I think part of it is that education piece for providers, but also for patients and families themselves. I think aggressive symptom management—because sometimes when a patient presents, the thought is, “Well, they’re not a candidate for treatment because they have such severe pain or because they’re losing so much weight”&mdash;if we can aggressively manage those cancer-related symptoms, it may afford the opportunity to at least offer them some treatments. We recognize that our current treatments may help some individuals a lot, some maybe just a little, and some not at all, but I think just giving them that opportunity, if they’re well enough, to even try…I always want that option to be available to patients, and I think that’s perhaps one of the main challenges

AJMCtv Interviews: ASCO 2019

Removing Barriers to Improve the Use of Diagnostic Tests for Precision Cancer Care

Currently, the number of patients who are actually utilizing precision cancer care treatments is small, but it is growing fast. As that happens, physicians will need to get comfortable with ordering the right tests, explained Clynt Taylor, chief executive officer of Intervention Insights, and Lee Newcomer, MD, formerly of UnitedHealth Group.

There are, according to Newcomer, 3 big barriers to getting access to diagnostic tests and wider adoption of precision medicines. First is the challenge of figuring out what panel the clinician needs to order. Do they need to order a single-gene or a 7-gene or even a 500-gene panel?

“So, that clinical question is pretty tough for physicians to answer right now,” he said. “All of this is new. It’s evolving. They struggle with it.”

A second barrier is choosing the laboratory that offers the best test for what the physician needs. The third barrier is figuring out which tests are covered by the payer. There is a lot of work on the part of the physician to get through all 3 of those barriers, involving multiple phone calls.

Newcomer is now on the board of Intervention Insights, which has a product, Trapelo, that tries to remove some of those barriers. According to Taylor, there is wide variability in oncologist level of comfort with using precision medicines, which is another barrier that Trapelo tries to overcome.

Intervention Insights had started in the area by developing a knowledge base of all evidence related to genes or biomarkers and their diseases. That information was used to provide a summary for reports coming back from the lab to make it easier for physicians to interpret the results, Taylor explained. Trapelo is the next step and moves downstream a little to help physicians start making decisions around which tests to order.

After working with physicians, the company decided that a single platform could help align the interests of oncologists, laboratories, and payers in real time, “so that our colleagues could look to order from a single place that would help that doctor know, for each patient, what to order, from which labs, what genes

needed to be tested, [and] what would be paid for them,” Taylor said.

This work takes place in the electronic medical record (EMR), and according to Taylor, the company was very aware that Trapelo needed to work very synergistically with the EMR so as not to add more work to the day for oncologists. The usability of the program was key, Newcomer added.

For a while now, the diagnostics field has been tough to reimburse because of the Current Procedural Terminology codes used, Newcomer said. These codes have been nondescript and confusing, and health plans have been looking for vendors who can make it easier to understand what test is being ordered and how to pay for it.

New payment models, such as the Oncology Care Model (OCM), help to get diagnostic tests used more, because OCM rewards practices that are cost-efficient and get better outcomes.

“So, if you were to know in advance from the gene test, that drug probably isn’t going to work, whereas another one will, that’s very useful information…” Newcomer said. 

Despite Growth, Uptake of Downside Risk in ACO Contracts Remains Low

Although the number of accountable care organization (ACO) contracts with downside risk is growing, the majority of ACOs remain in upside-only risk contracts, according to a new study. In 2012, 28% of accountable care organizations (ACOs) had a contract with downside risk. That rate increased modestly to 33% in 2018.

However, according to study researchers, the number of ACOs has increased approximately 5-fold during the time period, which could mean that the number of ACO downside risk contracts also grew significantly. 

Although the increase in the amount of ACOs taking on downside risk remains modest, there has been significant growth in not just the number but also the variety of contracts implemented by ACOs, including in the number of payers they contract with. In 2012, 42% of newly formed ACOs had contracts with 2 or more payer types compared with 63% of ACOs in 2018.

As ACOs have emerged as one of the most broadly implemented value-based payment models, CMS has been pushing ACOs to take on more financial risk. In December 2018, the agency finalized Pathways to Success, its overhaul of the Medicare Shared Savings Program, which will push ACOs to assume risk more quickly. Notably, the program replaced the traditional 3 tracks with 2 new tracks in which ACOs will start in a 1-sided model and incrementally phase in higher levels of risk. Down from the current 6 years, ACOs will be able to stay in 1-sided risk for 2 years and existing ACOs will be able to stay for 1 more year.

The researchers of the new study, published in Health Affairs, drew on data from the National Survey of Accountable Care Organizations, finding that ACOs taking on downside risk were more likely to have more experience with other forms of risk-bearing contracts.

“Prior work indicates that ACO participants with risk-bearing experience are more likely to achieve shared savings with the Medicare program,” wrote the researchers. “Therefore, the assumption that inducing more ACOs to bear downside risk would result in increased savings should be questioned, based on what is known to date.”

Among the 419 ACOs that completed the survey in 2018, those assuming downside risk were less likely to be physician led (43% vs 57%) and instead more likely to be jointly led by a hospital and physicians, led by a hospital, or led by another arrangement, including coalitions and regional, county, or state organizations. They were also less likely to be physician owned than other ACOs were (30% vs 39%).

“While similar in proportion of ownership by hospitals, downside-risk ACOs were more likely than other ACOs to be owned by other entities, including public ownership, non-profit ownership, or another privately owned for-profit entity,” reported the researchers.

The survey results also indicated that ACOs taking on downside risk were more likely to:

• Be integrated delivery systems (58% vs 42%) and include a hospital and have a greater number of hospitals

• Directly provide or contract to deliver inpatient rehabilitation, routine specialty care, palliative or hospice care, home health or visiting nurse services, and skilled nursing facility care • Report that 50% to 100% of their primary care patients were covered by an ACO contract.

13 Years After the HPV Vaccine Was Introduced, US Uptake Remains Low

1. Peck K, Usadi B, Mainor A, Fisher E, Colla C. ACO contracts with downside financial risk growing, but still remain in the minority [published online July 1, 2019]. Health Aff (Millwood). doi: 10.1377/hlthaff.2018.05386.

Parth Shah, PharmD, PhD, of the Fred Hutchinson Cancer Research Center, led a session to discuss the uptake challenges of the human papilloma virus (HPV) vaccine at the 2019 Annual Meeting of the American Society of Clinical Oncology.

He began by explaining the known percentages of cancers attributable to the virus in the United States: cervical cancer, 91%; vagina cancer, 75%; and vulva cancer, 69%, among others.

Although multiple cancers are attributable to the virus, explained Shah, of the ages in the United States that should be vaccinated—13 to 17 years&mdash;both boys and girls, only 49% receive the vaccine.

The challenges around facilitating larger uptake of a vaccine that prevents cancer can be frustrating for providers. Parents’ hesitancy about the HPV vaccine has been around since it was approved in 2006, although it has garnered more attention as the antivaxxer movement has taken hold in the United States, as seen by the 1044 confirmed cases of measles this year. (This is the greatest number of cases reported in the United States since 1994, and since the disease was declared eradicated in 2000.)

In terms of the low uptake of the HPV vaccine, Shah believes the reasons are multifactorial. Namely, low uptake can be attributed to societal and cultural norms, community, and relational and individual reasons.

“As far as societal reasons, a few states currently have [initiated] or tried to initiate school mandates for the vaccination,” he said. “Not only were they controversial, but they were largely ineffective. When the vaccine came out and school mandates were being discussed, it was largely pushed by the manufacturers, which generated distrust. In terms of community challenges, we’re vaccinating in some schools, but schools are governed by local jurisdictions and sometimes providing preventive services is not a priority. And finally, for relational and individual reasons, you need to consider the parents’ perspective.”

Shah explained that over the past few years, the CDC has collected data on why parents choose to not vaccinate their child for HPV. Top reported reasons include safety concerns, adverse effects, lack of knowledge about the vaccine, not believing it was necessary, and no provider recommendation. Parents also reported that their child was not sexually active, so they did not need it.

Based on prior data and studies, Shah recommended that when speaking with patients who are due for the vaccine and their parents, the physician should make a statement that notes the child’s age, announce that they are due for vaccines that prevent several diseases, place the HPV vaccine in the middle of the list, and say that you’re available to vaccinate today.

Deanna Teoh, MD, MS, FACOG, FACS, of the University of Minnesota, emphasized the impact of social media on vaccination trends. The younger population is more likely to receive their news from social media, while Facebook is the site where adults get most of their news. Multiple social media sites—Facebook, YouTube, Twitter, and more&mdash;have been in hot water recently for providing a space for the antivaxxer movement to gain strength. Oversight of inconsistent site governance policies has been attempted since the rise of the measles outbreak.

To offer a different perspective, Ian Frazer, MBBS, MD, DSc, of the University of Queensland in Australia, explained that uptake of the vaccination is not a problem in Australia, in part because “we bribe them to get vaccinated. There is a substantial social security handout if your child is fully vaccinated by 5 years old, so we find that most countrywide vaccination rates are high.”

Frazer and his late colleague, Jian Zhou, PhD, developed and patented the basic technology behind the vaccine. Because most Australians saw the vaccine as a local invention, Frazer explained that uptake was quite good. In fact, the question being asked now in Australia is should it continue with screening for the disease since the vaccination rates are so high.

However, the question is not as straightforward as it seems, because the only screening tool available for HPV is a Papanicolaou (Pap) smear. This presents a problem, as only females, or roughly half the population, can be screened.

An audience member brought the room’s attention to another problem in regard to lack of knowledge about the importance of the vaccine not previously mentioned: “Some patients truly don’t even know that they have an HPV-related cancer. We need to first educate patients about their own disease and then address the fact that there’s a vaccine to prevent it,” she said. This way, they’ll share that information with their loved ones and maybe a greater uptake will start to occur. 

Measles cases in 2019. CDC website. cdc.gov/measles/cases-outbreaks.html. Updated June 10, 2019. Accessed June 1, 2019.

Exploring Oncology Financial Toxicity, Cost of Care

Two posters presented at the 2019 Annual Meeting of the American Society of Clinical Oncology discussed the growing issue of financial toxicity and the costs of care in cancer treatment.

In the first poster, researchers selected 4 phase 3 trials of immuno-oncology (IO) treatments for non-small cell lung cancer (NSCLC) in a first-line setting and found that while median progression-free survival has doubled, so did costs. The researchers said the expense has to be quantified in relation to per capita gross national product in the United States ($53,128 in 2017). Costs appear economically unsustainable even when accepting a higher threshold of $100,000 for 1 quality adjusted life year gained, they wrote. But given the significant PFS gains, there is a need to use IOs through innovative cost sharing platforms, they said.

In the second poster, researchers hypothesized that weight-based dosing of pembrolizumab and nivolumab in order to allow vial sharing among patients would result in substantial cost savings.

 The 2 drugs were originally investigated and FDA-approved with weight-based dosing strategies, but later the approval label was amended to a fixed-dose administration.

Researchers retrospectively examined all outpatient doses of pembrolizumab and nivolumab given at 3 Stanford Medicine infusion centers between July 1, 2018, and October 31, 2018, using the Stanford Medicine Research Data Repository (STARR) database. Cost-minimization analysis was conducted to model the impact of dosing strategies based upon patient weight versus fixed dosing (2 mg/kg vs 200 mg every 3 weeks for pembrolizumab; 3 mg/kg vs 240 mg every 2 weeks or 6 mg/kg vs 480 every 4 weeks for nivolumab).

“Dose-minimization” (DM) was defined as whichever dose was lower (weightbased or fixed dose). The impact of allowing vial sharing (considering commercially available vial sizes) between patients treated at the same site and on the same date was assessed. Average sales price from CMS for Part B drugs was used for cost estimates.

A total of 1029 doses of pembrolizumab or nivolumab were administered across a variety of cancer types. For most doses (n = 789, 77%), the calculated weight-based dose was less than the fixed dose. DM resulted in decreased usage and expenditures of both pembrolizumab and nivolumab, and a further decrease was observed with vial sharing.

Total savings estimated with DM and vial sharing strategy were greater than $1.4 million. This amounted to savings of >22,000 mg of pembrolizumab (112 fixed doses) and >11,000 mg of nivolumab (47 fixed doses). Savings were greatest at the highest volume infusion center.

Alternative dosing strategies of pembrolizumab and nivolumab would result in significantly less drug utilization and pharmaceutical spending, without anticipated impact on efficacy, but there are barriers to this approach, such as existing policies regarding vial sharing and drug vial sizes. 

1. Ashraf SMM, Pandita S, Alimpertis E, et al. Progression free survival (PFS) benefits of immuno-oncology agents (IOs) and implications for market cost-sharing inefficiencies. Presented at: American Society of Clinical Oncology Annual Meeting, May 31-June 4, 2019; Chicago, Illinois. Poster 334.

2. Hall ET, Zhang J, Kim EJ, Economic analysis of alternative pembrolizumab and nivolumab dosing strategies at an academic cancer center. Presented at: American Society of Clinical Oncology Annual Meeting, May 31-June 4, 2019; Chicago, Illinois. Abstract 6504.

Financial toxicity, ACO contracts, removing barriers to care.

Medical World News: Managed Care Updates

Nivolumab, Ipilimumab Combo Demonstrates Clinical Benefit Among Adults With Pediatric Solid Tumors

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) demonstrated significant clinical benefit in patients with solid pediatric tumors that progressed into adulthood—a patient population with few treatment options&mdash;according to new study findings. 

According to the findings of the first cohort from the phase 2, single-arm study, during a median follow-up of 4.3 months, the combination yielded a 39.3% clinical benefit rate among the 30 patients evaluated.

“Solid pediatric tumors that appear in adulthood are a heterogeneous group characterized by a low incidence, lack of therapeutic options, and reduced survival,” wrote the investigators. While on the treatment, patients achieved a median overall survival of 6.8 months. All patients had locally advanced or metastatic pediatric malignancies that had progressed or were not candidates for traditional therapy.

“One case of metastatic esthesioneuroblastoma achieved a dramatic tumor response and represents the first patient with this extremely rare histology treated with immunotherapy,” noted the investigators. In addition to the 1 patient who achieved a deep partial response during treatment, 10 had stable disease, 17 had progressive disease, and 2 patients died before radiologic evaluation.

The patients, aged 20 to 75 years who were enrolled across 15 centers of the Spanish Group for Rare Cancer, included 4 with medulloblastoma, 4 with neuroblastoma, and 3 with Ewing family tumors. The majority (90%) of patients had received prior systemic therapy, with partial response representing the best response, which occurred in 37% of these patients. The median amount of previous treatment lines was 3.

The treatment regimen consisted of nivolumab 3 mg/kg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks for 6 months or until disease progression or discontinuation due to treatment toxicity, for a maximum of 24 months. Among the 30-person cohort, 6 patients have been treated for at least 6 months, with 1 discontinuing due to adverse events (AEs).

A total of 12 (40%) patients experienced adverse events of any grade and 6 (20%) experienced an AE possibly related to the treatment. 

Mielgo X, Diaz-Beveridge R, Sepulveda JM, et al. Interim analysis of a phase II study of nivolumab combined with ipilimumab in patients with pediatric solid tumors in adulthood (GETHI021). Presented at: American Society of Clinical Oncology 2019 Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract: 2613. https://abstracts.asco.org/239/AbstView_239_251263.html.

Nivolumab, Ipilimumab Combo Yields Clinically Meaningful Responses in Advanced Hepatocellular Carcinoma

Nivolumab (Opdivo) monotherapy is currently indicated for the treatment of patients with hepatocellular carcinoma who were previously treated with the targeted therapy sorafenib (sold as Nexavar) based on the CheckMate 040 trial.

Assessing the safety and efficacy of nivolumab in combination with ipilimumab (Yervoy) among these patients, investigators have observed clinically meaningful responses and an acceptable safety profile.

These findings showed an overall response rate (ORR) associated with the combination that  was double that seen with nivolumab therapy alone. During the CheckMate 040 trial, nivolumab monotherapy yielded an ORR of 14%. These new data on the treatment combination showed an ORR of 31%. Seven patients achieved a complete response with a median duration of response of 17 months. There was a disease control rate of 49%.

According to the investigators, this is the first report of efficacy and safety for this combination in the patient population.

With a cutoff date of September 25, 2018, the investigators observed a total of 148 patients (treated with sorafenib) randomized to 3 treatment groups:

• Group A: Four doses of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks

• Group B: Four doses of nivolumab 3 mg/kg plus ipilimumab

1 mg/kg once every 3 weeks, each followed by nivolumab 240 mg once every 2 weeks

• Group C: nivolumab 3 mg/kg once every 2 weeks plus ipilimumab 1 mg/kg once every 6 weeks.

Patients were treated until disease progression or intolerable toxicity. At the end of 24 months of follow-up, there was an overall survival (OS) rate of 40%.

Patients in Group A demonstrated the greatest response, with a median OS of 23 months. At 12 months, OS was 61%, and at 24 months, OS was 48%.

Sixteen (32%) of the 50 patients achieved any response, with 4 experiencing a complete response and 12 experiencing a partial response. Nine patients experienced disease stability and 20 experienced disease progression.

In Group B, there was a median OS of 12 months among the 49 patients. At 12 months, OS was 56%, and at 24 months, OS was 30%. Fifteen patients achieved any response, with 3 experiencing a complete response and 12 experiencing a partial response. Five patients had disease stability and 24 experienced disease progression.

Median OS among the 49 patients in Group C was 13 months, with a 12-month survival rate of 51% and a 24-month survival rate of 42%. No patients achieved a complete response and 15 patients achieved a partial response; 9 experienced disease stability and 21 experienced disease progression.

Selected abstracts from the 2019 Annual Meeting of the American Society of Clinical Oncology. 

July 2019

How Real-World Data Can Affect NSCLC Treatment

Clinical Findings

AJMCtv Interviews: ASCO 2019

Medical World News: Managed Care Updates

Research Report: ASCO 2019

Biosimilars: ASCO 2019

Policy Updates: ASCO 2019

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