ASCO Review: A Closer Look At Value By Tumor Type

ASCO's big push on providing value came through loud and clear in annual meeting sessions on multiple myeloma, breast cancer, colon cancer and renal cell carcinoma.

Concerns about the cost of cancer care and drug prices in particular continue to be front and center at the American Society of Clinical Oncology annual meeting, where this year the organizers incorporated discussions of new value assessment tools throughout the agenda.

The group used its annual meeting as a vehicle to highlight issues surrounding value, ASCO Chief Medical Officer Richard Schilsky commented in an interview.

This year's event, held from June 3-7 in Chicago, featured educational sessions dedicated to value issues and as the program developed in the months leading up to the meeting, organizers sought to identify abstracts in scientific sessions where a discussion on value might be interesting and could be incorporated.

"The more we talk about it, the more people will hopefully pay attention and take steps to increase the value of the care we provide our patients," Schilsky said.

ASCO has taken a leading role in the charge toward value assessment. The organization published the first iteration of its value framework in June 2015, which offers an approach to evaluating new therapies based on key efficacy measures from randomized trials like median overall survival, progression-free survival and response rate, as well as toxicity .

"We as physicians would like to be the group of deliverers who weigh in on what's best for patients and we don't want to ever … be told based on something like the ASCO value based assessment to use drug A versus drug B. But I worry that in fact this is something that is down the line for many of us delivering care," Cedars' Figlin said.

The cancer organization is not the only one attempting to develop a valuation tool (Also see "Scoring Value: New Tools Challenge Pharma's US Pricing Bonanza" - In Vivo, 21 Oct, 2015.). From 2015-2016, four other groups also released value assessments, Deborah Schrag, chief of the division of population sciences at the Dana-Farber Cancer Institute, noted during a June 5 plenary presentation at ASCO. They include:

• European Society for Medical Oncology;
• Memorial Sloan Kettering's DrugAbacus (Also see "‘DrugAbacus’ Pricing Tool Helps Payers Calculate Fair Value Of Cancer Drugs" - Pink Sheet, 19 Jun, 2015.);
• Institute for Comparative Effectiveness Review (ICER) (Also see "ICER's Drug Review Agenda Includes Lung Cancer, MS, Psoriasis Products" - Pink Sheet, 24 Nov, 2015.); and the
• National Comprehensive Cancer Network (NCCN) (Also see "Cancer Drug Comparisons Released By NCCN, Include Affordability" - Pink Sheet, 16 Oct, 2015.).

The frameworks ask different questions about value. For example, Memorial Sloan Kettering's DrugAbacus asks what is the appropriate price for an intervention based on adjustable patient preferences, while ICER reviews target payer needs for data on comparative cost-effectiveness and societal value, Schrag said. ICER reviews also incorporate expert deliberative panels that include patients and physicians, she noted.

Schrag acknowledged that there are limitations to value assessments, including the lack of transparency about what drugs actually cost in the marketplace, so they are not practical enough yet for decision-making at the bedside.

The value frameworks provide a "provocative beginning" to help us begin to "think more systemically" about how to incorporate value in the setting of increasingly expensive cancer therapies, she said.

Despite the limitations of current tools, she said that value deliberations cannot be ignored.

Cancer drugs are increasingly unaffordable for many people and, with constrained resources, difficult decisions have to be made, she said.

The following four disease types – multiple myeloma, renal cell carcinoma, breast cancer and colon cancer – highlight the value discussions that occurred throughout ASCO.

Myeloma In The Spotlight

Pivotal results for Johnson & Johnson/Genmab AS's anti-CD38 antibody Darzalex (daratumumab) had a high profile at this year's ASCO meeting, with results for the pivotal CASTOR study presented during the plenary session on June 5.

The results position Darzalex for earlier use, after a first-line therapy, on top of Takeda Pharmaceutical Co. Ltd./J&J's Velcade (bortezomib) with dexamethasone. But that adds significant expense on top of the other drugs in the combination, which are given for a fixed duration; Darzalex is used indefinitely for this indication and carries a list price $134,550 for the first year and $76,050 for subsequent years.

The increasing use of combinations of branded drugs in hematologic malignancies is becoming a problem, Lee Greenberger, chief scientific officer at the Leukemia & Lymphoma Society, noted during Sachs Associates' Immuno-Oncology: BD&L and Investment Forum on June 3. Drug costs can range from $200,000 to $250,000 per year.

Dana Farber's Schrag said that she expects daratumumab would score high on Memorial Sloan Kettering's DrugAbacus, based on the drug's high efficacy and novel mechanism of action. Darzalex has demonstrated a strong progression-free survival benefit that is very likely to translate into an overall survival benefit, she said.

Shrag expects that an ICER review for daratumumab in this indication would conclude that the drug had moderate to high benefit, with a cost per quality-adjusted life year value in the >$200,000 range. ICER recently released a cost effectiveness review of a number of other treatments for multiple myeloma (Also see "Myeloma Drug Access Limits Unlikely Near-term – Aetna, Express Scripts Say" - Pink Sheet, 27 May, 2016.).

Using the ASCO value framework, daratumumab has a high net health benefit score of 48, out of a possible total of 130, she noted.

The clinical value for individuals is high but at the cost of over $10,000 per month, use will result in financial strain for those without adequate health insurance coverage, Schrag said.

The value for health systems is moderate to high and Schrag expects high income countries will adopt this treatment, while middle income countries will "find this promising intervention cost-prohibitive," she said.

Kidney Cancer Crowd

An increasingly crowded kidney cancer market prompted a detailed discussion about value and choice during a June 6 session (see related story, (Also see "Value Measures, Side Effects Help Differentiate Drugs In Crowded Kidney Cancer Market" - Pink Sheet, 20 Jun, 2016.))

Three new drugs were approved for second-line treatment of metastatic renal cell carcinoma from November 2015 to the end of May 2016 – Bristol-Myers Squibb Co.'s Opdivo (nivolumab), Exelixis Inc.'s Cabometyx (cabozantinib), and Eisai Co. Ltd.'s Lenvima (lenvatinib).

There are now nine different NCCN-recommended options for second-line mRCC.

Comparing trials is very difficult due to the differences in trial design, though clinicians need to work with the data they do have and rely on cross-trial analyses to make treatment decisions, presenters agreed.

Questions remain about how to afford therapy, how to define the differences between options and when to have a conversation with patients and health systems about value, said Robert Figlin, director of the division of hematology oncology at Cedars-Sinai's Samuel Oschin Comprehensive Cancer Institute.

Figlin presented an ASCO-based value assessment for second-line treatment of metastatic kidney cancer. Using ASCO's tool, Opdivo had the highest net health benefit score with 52 out of 130 points, and Pfizer Inc.'s Inlyta (axitinib) and Cabometyx had the same benefit (32 of 130), followed by the combination of Lenvima/Afinitor with 28/130 (see table).

ASCO emphasizes that the NHB scores should be viewed in isolation because they reflect the available data on each individual drug. The framework does not attempt cross-study comparisons.

Although Figlin's presentation suggested the ASCO model could be a useful tool, the clinician also had a cautionary note: "The key for me is that we as physicians would like to be the group of deliverers who weigh in on what's best for patients and we don't want to ever, in my own view, don't want to ever be told based on something like the ASCO value based assessment to use drug A versus drug B. But I worry that in fact this is something that is down the line for many of us delivering care."

ASCO Value Based Assessment: Second-Line Treatment (After TKI Therapy) For mRCC
New Agent	Comparator	Clinical Benefit	Toxicity*	NHB Score	Monthly Cost (Average Sale Price, ASP)
Axitinib	Sorafenib	OS: +4.7% (20.1 vs. 19.2 months) OS Score:16	Toxicity score = 0 (+10%)	32/130	$9,580
Nivolumab	Everolimus	OS: +27.6% (25 vs. 19.6 months) OS score= 32	Toxicity score = +20 (-97%)	52/130	$12,435
Cabozantinib	Everolimus	OS: +29.7% (21.4 vs. 16.5 months) OS score= 32	Toxicity score = 0 (+10%)	32/130	$10,229
Lenvatinib + everolimus	Everolimus	OS: +65.6% (25.5 vs. 15.4 months) OS score= 48	Toxicity score = -20 (+100%)	28/130	$22,461
*If a regimen is more toxic than comparator in pivotal trial, toxicity score is subtracted from the clinical benefit score. If the regimen is less toxic than the comparator, toxicity score is added to the clinical benefit score. A regimen less toxic than the control may be awarded up to 20 points. If the toxicity is doubled, 20 points will be subtracted from the clinical benefit score of the test regimen.
Source: Adapted from presentation of R. Figlin, ASCO 2016

Breast Cancer: Biosimilars Wanted

New drugs for HER2+ breast cancer offer high value clinically, though they have missed the bar in cost-effectiveness analyses to date, noted Sunil Verma, University of Calgary.

Verma coauthored an article with colleague Nancy Nixon in ASCO's Education Book this year about a value-based approach to treatment of HER2-positive disease. He also delivered a presentation on the topic and included it in his discussion about the HERITAGE and PHEREXA studies during an oral abstract session June 6 (Also see "ASCO Round-Up: Array, Kite, Exelixis, Pfizer/Merck KGAA, Mylan, Novartis" - Pink Sheet, 7 Jun, 2016.).

HERITAGE was a positive Phase III trial of Mylan NV/Biocon Ltd.'s MYL-14010, a biosimilar version of Roche's Herceptin (trastuzumab, in HER2+ treatment-naïve metastatic breast cancer.

PHEREXA was a negative Phase III study testing the value of adding Roche's Perjeta (pertuzumab) to Herceptin and capecitabine in patients progressing on one line of HER2 therapy in metastatic breast cancer. The drug is currently approved for neoadjuvant and first-line mBC.

There was a trend toward improved PFS, the primary endpoint, in PHEREXA and the trial was underpowered, but looking at the hazard ratio, the magnitude of benefit was lower than what was seen in the CLEOPATRA first-line study, Verma noted. In contrast with PHEREXA, p-values in the CLEOPATRA study were highly statistically significant.

In addition to Perjeta, Roche markets Kadcyla (ado-trastuzumab emtansine), which is approved for second-line HER2+ metastatic breast cancer. The firm had another negative study when the MARIANNE trial failed to show an advantage for using Kadcyla instead of Herceptin as an add-on to Perjeta in the first-line setting (Also see "Roche Defends HER2 Franchise After MARIANNE Failure" - Pink Sheet, 28 Jan, 2015.).

The ASCO and ESMO frameworks are not set up to assess the value of trials using a pCR endpoint so it is not possible to evaluate Perjeta in neoadjuvant therapy. But both tools determined that Perjeta and Kadcyla had high value in the first- and second-line treatment of metastatic breast cancer, respectively.

Verma and Nixon's article cited a Canadian analysis of Perjeta in the neoadjuvant setting that concluded the "addition of pertuzumab is cost-effective" with a cost per quality-adjusted life year (QALY) of less than $100,000. The pan-Canadian Oncology Drug Review (pCODR) calculated a cost of CAD $162,839 for Kadcyla based on the EMILIA trial results.

"The addition of pertuzumab to docetaxel and trastuzumab according to the CLEOPATRA trial, was found to be, again, incrementally higher in a recent publication, with an estimated ICER of $713,219 USD per QALY gained. Despite the high cost, most funding agencies have adopted these therapies into clinical practice. This brings to question what practical considerations can be made to maximize access to highly effective, costly treatments in an environment with limited resources," the article states.

Roche noted that cost-effectiveness frameworks have significant limitations and their usefulness has been questioned, specifically for new therapies that extend overall survival in non-curable diseases.

"A number of health authorities, such as Swissmedic and the G-BA in Germany for example, are not including this method in their reimbursement decision-making. In the UK however, where this type of assessment is still being used, it is worth noting that no new breast cancer medicines, Roche or other, have been made available on the National Health Service (NHS) in the last seven years," the company commented after the meeting.

Currently the ASCO and ESMO value tools are for discussion, not policy making. They cannot compare relative value of drugs and do not consider cost-effectiveness or budget impact, while the cost-effectiveness analyses are not capturing value, Verma said.

"We need to start integrating some of these value propositions with the cost to make sure we are getting the bang for the treatment value to a greater extent," he said.

Biosimilars of trastuzumab offer the potential to broaden access to HER2 therapies and reduce costs in the future, Verma said. He noted that a "tsunami" of biosimilars is on the way. At least 11 trastuzumab copies are in development, two of which two are already available abroad – Celltrion Inc.'s CT-P6 in South Korea and Mylan/Biocon's CanMab in India.

Questions remain about clinicians' comfort level with extrapolating data beyond what is tested in a pivotal study, for example, adjuvant vs. metastatic disease, use with different combinations and also in other tumor types like gastric cancer, Verma said. But there is no doubt, given how expensive cancer drugs are getting, that we need to have biosimilars, he concluded.

Colon Cancer On Financial Diet

The value of the many colorectal cancer therapies available often doesn't correlate with cost, Wells Messersmith, director of gastrointestinal medical oncology program at the University of Colorado, noted during an ASCO/European CanCer Organization (ECCO) joint session on value of care.

Out of 11 drugs approved for colorectal cancer, including cytotoxics and biologics, use of only two is guided by a biomarker – Eli Lilly & Co.'s Erbitux (cetuximab) and Amgen Inc.'s Vectibix (panitumumab), Messersmith pointed out. The other approved drugs benefit a subset, but markers are not available to know which patients will respond.

Pharmacogenomic tests for cytotoxic therapies like 5-FU, oxaliplatin and irintoecan have largely failed in large trials, Messersmith said, and there are no confirmed predictors for VEGFR targeting agents like Roche's Avastin (bevacizumab), Sanofi/Regeneron Pharmaceuticals Inc.'s Zaltrap (ziv-aflibercept) and Lilly's Cyramza (ramucirumab).

Furthermore, the savings gained through KRAS mutation testing and targeted use of EGFR-inhibitors are not very great compared to the costs of the drugs, he added.

For first-line therapies, including 5-FU with or without cetuximab or panitumumab, the response rate in randomized trials ranged from 30%-70%, he noted. Response rates range from 5%-20% in the second-line setting for regimens such as FOLFIRI with Avastin or Zaltrap, or cetuximab or panitumumab. Response rates in trials done in the third- and fourth-line setting range from 2% to 20%.

Median survival in the setting of first-line metastatic colorectal cancer has quintupled over the years with the introduction of new therapies and can be now up to 36 months. Unfortunately, a lot of patients are in their thirties and forties and have children, "so three-year survival really does not sound very good to them," Messersmith said.

Meanwhile, over the years, costs have risen dramatically. Six months of treatment with the 5-FU/LV regimen cost $500 in 1997 whereas 24-30 months of treatment can cost more than $300,000 today, he noted.

Ideally, greater survival would correlate with cost. But studies by John Marshall at Georgetown University have shown little relation between PFS benefit and cost in first-line or second-line therapy.

Like other presenters at the ASCO meeting, Messersmith noted that cancer costs are rising rapidly and "eating up GDP in an unsustainable way."

Value models should take into account side effects, hospitalizations and financial toxicity, he said. "Financial toxicity really does affect patients."

ASCO's Quality Oncology Practice Initiative has been focusing on improving value in a range of ways, including improving operational efficiency, tracking patient safety patient-reported outcomes and physician satisfaction (Also see "Cost-Consciousness Raising: Adding Value To Cancer Drug Development" - Pink Sheet, 24 Mar, 2014.).

Current US care models not sustainable and drugs are a major driver of costs. Messersmith noted in concluding comments. The clinician called for a closer relationship between value and price and patient-centered, value-based models.

"Fixing these challenging issues will require input from multiple stakeholders, most importantly, our patients," he said.