Questioning Stivarga’s Cost-Effectiveness In Colon Cancer

The high cost of colon cancer drugs is once again under fire, this time with Bayer and Onyx in the hot seat. In a Lancet editorial accompanying pivotal trial results for regorafenib, U.K. authors doubt the modestly efficacious drug will ever prove cost-effectiveness in colon cancer, but that its role in GIST looks more compelling.

The modest efficacy and toxic effects of Bayer AG/Onyx Pharmaceuticals Inc.’s Stivarga (regorafenib) suggest the drug is unlikely to be cost-effective in advanced colon cancer, according to an editorial in the Lancet, in what is becoming a familiar refrain in the crowded, expensive treatment space.

The Nov. 22 editorial, written by U.K. oncologists, comes as the drug is under review in Europe for metastatic colorectal cancer, following a filing in May 2012. It accompanied publication of the full results of two Phase III trials of regorafenib: CORRECT in metastatic colorectal cancer and GRID in gastrointestinal stromal tumors.

An oral multi-kinase inhibitor, Stivarga was approved by FDA in September as a monotherapy for mCRC patients who already had exhausted multiple options: chemotherapies (fluoropyrimidine, oxaliplatin and irinotecan), an anti-VEGF therapy and – for KRAS wild-type patients – an anti-EGFR drug. In the pivotal CORRECT study of 760 refractory patients, the drug demonstrated a 1.4 month improvement in overall survival compared to best supportive care (Also see "Phase III Trial Of Bayer/Onyx Regorafenib Stopped Early For Efficacy" - Pink Sheet, 26 Oct, 2011.). The companies launched the drug in the U.S. at a price of $9,350 per monthly treatment cycle (Also see "Bayer Prices Stivarga With Crowded Colon Cancer Market In Mind" - Pink Sheet, 27 Sep, 2012.).

Regorafenib is also under priority review in the U.S. as a third-line treatment for GIST. In the GRID study, which tested the drug against best supportive care in 199 patients with metastatic and/or unresectable disease who had failed Novartis AG’s Gleevec (imatinib) and Pfizer Inc.’s Sutent (sunitinib), regorafenib demonstrated a significant 3.9-month benefit for progression-free survival, the primary endpoint, but no significant difference in overall survival, a secondary endpoint.

The case for regorafenib in GIST after sunitinib and imatinib failures is strong even without an OS benefit, which could have been confounded by crossover to the treatment arm, and indicates the drug has a future in gastrointestinal disease, concluded an accompanying editorial by Tom Waddell and David Cunningham, both of the Royal Marsden Hospital in Sutton, Surrey.

However, the editorial authors were pessimistic about regorafenib’s role in colon cancer, based on the results in the CORRECT study. In addition to the 1.4 month OS benefit, the drug demonstrated a very small, but statistically significant, progression-free survival benefit (1.9 months versus 1.7 months). Regorafenib did not improve objective tumor response, though it did show a marked benefit for stabilizing disease.

Those benefits came with a 54% rate of Grade 3-4 side effects, compared to 14% for best supportive care/placebo.

The investigators on the CORRECT trial, led by Mayo Clinic’s Axel Grothey, concluded that the results suggest hope for a new standard of care in the treatment-refractory population (see sidebar). But the editorial writers found otherwise: “We find it difficult to agree with the authors’ conclusion that the drug ‘could be a new standard of care in late-stage metastatic colorectal cancer’ in view of the small incremental survival benefit, reported toxic effects and low likelihood of future analyses finding regorafenib to be a cost-effective option.”

Complaints about high cost have become all too familiar in colon cancer, with the entry of many new options in the last decade like Roche/Genentech Inc.’s Avastin (bevacizumab) and Merck & Co. Inc./Bristol-Myers Squibb Co./Eli Lilly & Co. ’s Erbitux (cetuximab), to name just a few.

Writing about newly approved chemotherapies and two new drugs used in combination with chemo for colon cancer – Avastin and Erbitux –in a New England Journal of Medicine Perspective article about the “price tag on progress” in July 2004, Memorial Sloan-Kettering’s Deborah Schrag observed that the doubling in median survival made possible by new drugs within a decade was “accompanied by a staggering 340-fold increase in drug costs – just for the initial eight weeks of treatment.” In the article, she pointed to CMS’ inability to negotiate prices with the pharmaceutical industry.

The expense of colorectal cancer drugs has also been an issue across the Atlantic. In January, in line with previously released draft guidance, the U.K.’s National Institute for Health and Clinical Excellence published final guidance concluding that Erbitux, Avastin and Amgen Inc.’s Vectibix (panitumumab) were not cost-effective for mCRC that progressed after initial combination chemotherapy . However, Genentech notes that Avastin is covered by the U.K.’s Cancer Drug Fund, a relatively new alternative source of funding for oncology drugs formed to improve access to treatments (Also see "UK's New Cancer Drug Fund Might Not Alleviate Regional Access Disparities" - Pink Sheet, 1 Nov, 2010.). Merck’s Erbitux has a recommendation in first-line mCRC from NICE, but only when several criteria are satisfied – for example the primary colorectal tumor must be resected or potentially operable and the manufacturer must grant a 16% rebate on a per-patient basis.

More recently, Sanofi/Regeneron Pharmaceuticals Inc. were pressured into offering a 50% discount for buyers (physicians and hospitals) of their $11,000-per-month newly approved second-line mCRC drug Zaltrap (zif-aflibercept) (Also see "The Zaltrap Price Debate: Less Than Meets The Eye" - Pink Sheet, 20 Nov, 2012.). The discount followed a critique in The New York Times by Memorial Sloan-Kettering doctors asserting that the cancer center would not be using Zaltrap because it was twice as expensive but only equally as effective as Avastin.

The decision not to give “a phenomenally expensive new drug to our patients,” was a “no-brainer,” wrote Peter Bach, director of MSCKCC’s Center for Health Policy and Outcomes, and colleagues in the NYT op-ed. They pointed out that the median price of cancer drugs since 2010 was $10,000 a month and recent entrants cost as much as $35,000 a month. Medicare must cover every cancer drug that is approved and in most states, private insurers are also held to the same standard, the editorial notes. Ignoring the cost of care is “no longer tenable,” it concludes.

Furthermore, MSCKCC did not appear to be satisfied with the 50% discount. In a Nov. 16 statement, the hospital questioned whether and when the discount will “actually translate into a drop in Medicare reimbursement or copayments for patients, both of which are tied to the wholesale cost of the drug.”

In the U.S., Stivarga may not face the same kind of pricing trap. Stivarga’s pricing is in line with other new oral oncology drugs like Roche’s Zelboraf (vemurafenib) and Pfizer’s Xalkori (crizotinib), points out Gordon Gochenauer, director of the commercial planning group at the consulting firm Kantar Health. Those drugs, both of which rely on companion diagnostics to select appropriate patients, represent a new vanguard of costly cancer therapy and may be setting a new norm (Also see "Pfizer’s Xalkori Joins The Six-Figure Oncology Drug Club" - Pink Sheet, 5 Sep, 2011.).

Plus, when it comes to CRC, there are important differences between Zaltrap and Stivarga, Gochenauer added. Zaltrap has a similar mechanism of action as Avastin, which was available at a lower price due to flexibility in dosing, and Zaltrap was approved for an earlier line of therapy. In contrast, Stivarga was cleared for use after the failure of multiple treatments, when there are no other viable treatment options. “The price looks high, but payers won’t push back on it beyond their usual methods because there is nothing else approved for later lines of therapy in colorectal cancer,” he said.

In response to the Lancet editorial, Bayer commented that it consulted with providers, payers and other key advisors to ensure that Stivarga was priced competitively with other oral cancer medicines and that it is committed to ensuring that every patient who needs Stivarga is able to receive it. The company is offering patient assistance through its Bayer REACH program, including copay assistance and free drug supply to uninsured patients. Since early November, Stivarga has been included in National Comprehensive Cancer Network guidelines as a treatment option for colon cancer after first, second or third progression.

Reimbursement policies in Europe vary country by country. An OS benefit like the one demonstrated in the CORRECT study would typically pave the way for reimbursement in some countries, such as Germany and France, commented Richard Wagner, the Paris-based VP of Kantar’s commercial planning group. Spain and Italy consider cost as well as clinical efficacy; in this scenario they might provide reimbursement but there could be restrictions on access at the local level, depending on price. But in England, where the National Health Service is guided by NICE cost-effectiveness analyses, NICE’s negative reception of other colorectal drugs doesn’t bode well for regorafenib. At a U.S.-like price, regorafenib would have a “low probability of demonstrating cost-effectiveness in a NICE analysis,” Wagner said. Granted, in the U.K., the Cancer Drugs Fund would still be an option in the case of NICE rejection.

Tailoring treatment to patient subsets has the potential to improve the cost-benefit outlook in colorectal cancer. The CORRECT investigators noted that PFS curves in the study suggest differences in treatment response in patient subgroups, and they are now analyzing biomarkers in specimens collected in the study.