Does Cyramza RAISE the Bar in Second-line CRC, or Do Efficacy and Cost Hold It Back?

Patients with metastatic colorectal cancer (mCRC) are typically treated at some point with at least one angiogenesis inhibitor. According to Kantar Health’s CancerMPact® Treatment Architecture U.S. data, Avastin® (bevacizumab, Genentech/Roche) is offered to approximately one-half of KRAS wild-type chemotherapy-naïve patients and three-quarters of KRAS mutated chemotherapy-naïve patients in the first-line setting. In the second- or third-line setting, patients might be treated with Avastin, Zaltrap® (ziv-aflibercept, Sanofi) or Stivarga® (regorafenib, Bayer/Onyx). Given data from the 2015 ASCO Gastrointestinal Cancers Symposium, Cyramza® (ramucirumab, Eli Lilly) may soon be added to the list of agents for second- or third-line therapy.

The use of Cyramza in this setting was examined in the Phase III RAISE trial, which enrolled 1,050 mCRC patients who had progressed during or after first-line Avastin, oxaliplatin and a fluoropyrimidine and randomized them to treatment with FOLFIRI q2w or FOLFIRI plus Cyramza 8 mg/kg q2w.1 Treatment would continue until disease progression or unacceptable toxicity. The trial roughly included similar numbers of KRAS wild-type and mutant patients, and this status was a stratification factor for the trial.

RAISE met its primary endpoint of improving overall survival (OS) as the addition of Cyramza reduced the risk of death by 16% (median OS: 13.3 months versus 11.7 months, HR 0.84, p=0.0219). Both KRAS wild-type and mutant patients achieved benefit, although neither subgroup analysis was statistically significant. RAISE also met a secondary endpoint of progression-free survival (median PFS: 5.7 months versus 4.5 months, HR 0.79, p=0.0005) but did not significantly improve the response rate (13.4% versus 12.5%, p=0.6336) or disease control rate (74.1% versus 68.8%, p=0.0587). The toxicity profile was not surprising given Cyramza’s current approvals in both relapsed/refractory gastric cancer and non-small cell lung cancer (NSCLC). Common Grade 3 or higher toxicities that were significantly increased with Cyramza included neutropenia (38.4% versus 23.3%), fatigue (11.5% versus 7.8%), hypertension (10.8% versus 2.8%) and thrombocytopenia (3.0% versus 0.8%).

Given the statistically significant improvement in overall survival, Cyramza should ultimately be approved by the U.S. Food and Drug Administration (FDA) for use in this setting. Although the degree of benefit in RAISE borders on clinically meaningful (1.6-month OS benefit, HR 0.84, p=0.0219), the FDA approved it in December for use in second-line NSCLC based on similar borderline benefit in the REVEL trial2 (1.4-month OS benefit, HR 0.857, p=0.0235). In both of these trials, the magnitude of benefit fell short of the Recommended Targets for Meaningful Clinical Trial Goals that were put forth by an ASCO working group in early 2014 for these two indications.3 Nevertheless, the FDA approved Cyramza in NSCLC and may do the same in mCRC given the demonstrated OS benefit.

However, earning regulatory approval may be the least of Cyramza’s difficulties for gaining future utilization in mCRC. Once approved, Cyramza will compete in the second-line setting with Avastin and Zaltrap as noted above. Both of these agents have been tested in patients pretreated with Avastin. Second-line Avastin in Avastin pretreated patients was directly examined in the Phase III ML 18147 trial, colloquially referred as TML (for Treatment across Multiple Lines).4 TML evaluated the addition of Avastin to chemotherapy (either oxaliplatin- or irinotecan-based). Zaltrap was approved for second-line use based on data from the Phase III VELOUR study, which evaluated the addition of Zaltrap to FOLFIRI in second-line patients. Subgroup analysis in patients who were treated with first-line Avastin has been published.5 As shown in the table below, all three anti-angiogenic agents show similar underwhelming (>0.80) hazard ratios for OS.

Efficacy Comparisons Between Avastin, Zaltrap and Cyramza in 2nd-Line mCRC
  TML (Avastin-Pretreated3) VELOUR (Prior Avastin Subgroup Only4) RAISE (Avastin-Pretreated1)
  Placebo + CT (n=410) Avastin + CT (n=409) HR (p-value) Placebo + FOLFIRI (=187) Zaltrap + FOLFIRI (n=186) HR (p-value) Placebo + FOLFIRI (n=525) Cyramza + FOLFIRI (n=525) HR (p-value)
Median OS 9.8 11.2 0.81 (p=0.0211) 11.7 12.5 0.862 (NP) 11.7 13.3 0.84 (p=0.0219)
Median PFS 4.1 5.7 0.68 (p<0.0001) 3.9 6.7 0.661 (NP) 4.5 5.7 0.79 (p=0.0005)
CT: Chemotherapy; NP: Not provided


Not only is Cyramza attempting to compete with agents that have been approved for this setting since 2012 (Zaltrap) and 2013 (Avastin for use in Avastin-pretreated CRC), but it may be doing so with a pricing problem. One physician in attendance at the ASCO GI presentation directly asked why he should offer Cyramza if it costs “twice as much” as Avastin. Estimated costs of these agents support this claim: Avastin per cycle, assuming the use of the lower dosage of 5 mg/kg q2w, is approximately $2,400. Cyramza is expected to cost $5,900 per cycle of therapy based on the dose used in this trial and its current price for approved indications. This is eerily reminiscent of difficulties for Zaltrap, when several physicians from the Memorial Sloan-Kettering Cancer Center wrote an opinion piece in The New York Times stating they would not provide Zaltrap to their patients since it was more than twice the cost of Avastin; the negative publicity associated with the article forced Sanofi to drop its pricing for Zaltrap.  

The situation doesn’t improve for Cyramza even if it is considered in later lines of therapy. Not only would Cyramza need to compete with the anti-angiogenic agent Stivarga, which was approved in 2012 by the FDA, but it also will likely need to compete against TAS-102 (Lonsurf® in Japan, Taiho Oncology), a formulation of two antimetabolic agents that met its primary endpoint of OS in the Phase III RECOURSE study.6 The FDA has granted TAS-102 a fast-track designation, and Taiho confirmed that it had already initiated a rolling submission for approval.

Cyramza faces tough hurdles ahead given the data presented at the ASCO Gastrointestinal Cancers Symposium: activity comparable to other anti-angiogenic agents that are already approved in the same setting, and at a potentially higher cost. With these hurdles, it is hard to imagine Cyramza “RAISEing” the bar in second-line CRC in the near future.


1. Tabernero et al.; Abstract 512, 2015 ASCO Gastrointestinal Cancers Symposium
2. Perol, et al.; Abstract LBA8006, ASCO 2014
3. Ellis, et al.; J Clin Oncol, 32(12): 1277-1280, 2014.
4. Bennouna, et al.; Lancet Oncol, 2013
5. Tabernero, et al.; Eur J Cancer, 2014
6. Yoshino, et al.; Abstract O-0022, 2014 ESMO World Congress on Gastrointestinal Cancer.

By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical and Scientific Assessment, Kantar Health and Arnold DuBell, Ph.D., M.B.A, Consultant, Clinical and Scientific Assessment, Kantar Health

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