May 2014 Edition Vol.11, Issue 5

What’s in Store at ASCO 2014? Kantar Health Offers a Preview

What’s in Store at ASCO 2014? Kantar Health Offers a Preview

By Arnold DuBell, Ph.D., M.B.A.

The annual meeting of the American Society of Clinical Oncology (ASCO) is nearing and Kantar Health has identified several pivotal abstracts that will be presented. The 2014 ASCO annual meeting promises to be packed with the latest data and trends from the world of oncology, and the meeting has the potential to alter treatment practices in several tumor types. A brief synopsis of the 10 abstracts that we think are likely to generate the most discussion and have the highest impact are discussed. 

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Orteronel in Asymptomatic/Minimally Symptomatic CRPC

Orteronel (TAK-700; Millennium, a wholly owned subsidiary of Takeda) inhibits the steroidal enzyme 17-α-hydroxylase/C17,20 lyase; however, it is overshadowed by Zytiga® (abiraterone acetate, Johnson & Johnson), which has a similar mechanism of action and is already approved for prostate cancer. Moreover, orteronel suffered a setback in July 2013 when Takeda announced that the ELM-PC 5 (C21005) trial, which compared orteronel plus prednisone to prednisone plus placebo in about 1,000 metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed during or following chemotherapy, did not meet the primary endpoint of improved overall survival (OS).

Takeda has several other ongoing trials for orteronel, including ELM-PC 4 (C21004), which is comparing orteronel plus prednisone to placebo plus prednisone in more than 1,400 patients with chemotherapy-naïve mCRPC. Data from this trial will be presented at ASCO this year. The degree of benefit will be important to view, as orteronel will need to show a large OS benefit in order to compete with both Zytiga and Xtandi® (enzalutamide, Medivation/Astellas).

Zytiga is currently one of the most utilized agents in chemotherapy-naïve asymptomatic CRPC patients, as about one-third of patients in both the U.S. and Western Europe are treated with this agent, according to Kantar Health’s CancerMPact® Treatment Architecture 2013 data. This use was based on the strong data from the COU-AA-302 trial that showed a radiographic progression-free survival (rPFS) benefit for Zytiga compared to placebo (HR 0.69, p<0.0001) but had an OS benefit that did not cross the prespecified boundary for significance (HR 0.75, p=0.01).[1] In the PREVAIL trial, Xtandi improved both rPFS (HR 0.19, p<0.0001) and OS (HR 0.70, p<0.0001) relative to placebo[2] (please note that data from PREVAIL will be presented immediately following the ELM-PC 4 presentation).

Safety considerations will take a backseat to questions about efficacy. Phase II trials indicated increased fatigue, hypokalemia, hyperglycemia and diarrhea, which are similar to those seen with Zytiga. However, physicians’ ears will perk up if other toxicities are noted.

Although Zytiga was approved by the U.S. Food and Drug Administration (FDA) without showing an OS advantage, Xtandi has shown an OS benefit – and that threshold will most likely be the standard by which orteronel will be judged. A strong showing in this trial also will help overcome any lessened enthusiasm that may be harbored by physicians after news of the failed ELM-PC 5 was released last year.

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CALGB 80405: Will this definitively determine the appropriate sequence of targeted therapies in metastatic CRC?

Both Avastin® (bevacizumab, Genentech/Roche/Chugai) and Erbitux® (cetuximab, Bristol-Myers Squibb/Eli Lilly/Merck KGaA) are approved for the treatment of first-line metastatic colorectal cancer (mCRC) and have demonstrated progression-free survival (PFS) and OS benefits when added to standard chemotherapy in these patients. Avastin is approved for use in all first-line patients, while Erbitux is approved for use only in the subgroup of patients with wildtype KRAS. As with all new therapies that enter the same indication, physicians are left wondering how best to incorporate these agents into their practices. As multiple Phase III trials showed combining the agents are not effective at best (and harmful in the extreme), two trials set about to understand in which order these agents should be offered to patients.

At the 2013 ASCO annual meeting, the data from one of these trials, FIRE-3, was presented.[3] FIRE-3 was a German trial designed to evaluate FOLFIRI plus either Erbitux or Avastin (at 5 mg/kg every two weeks) as first-line therapy; it was amended in 2008 to include only KRAS wildtype patients. Data presented at ASCO 2013 suggested a non-significant benefit compared to Avastin in the overall response rate, which was the primary endpoint (62% versus 58%, p=0.183). Moreover, a PFS benefit was not observed (HR 1.06, p=1.06); however, Erbitux was associated with a significant 3.7-month OS benefit compared to Avastin (HR 0.77, p=0.017). The Kaplan-Meier OS curves were especially intriguing, as the curves for each arm began to separate only after 18 months, well after the 10-month PFS median, and the curves continued to separate past the median OS, where the superiority of Erbitux becomes far more pronounced and is evidently durable.

The conflicting data found in FIRE-3 beg for a repeat, and thankfully we have one: CALGB 80403, for which the data will be presented in the ASCO 2014 plenary session. CALGB 80403 is a North American three-armed trial comparing Avastin (also at 5 mg/kg every two weeks) plus physician’s choice of first-line chemotherapy (FOLFOX or FOLFIRI) versus Erbitux plus chemotherapy versus Avastin plus Erbitux plus chemotherapy in approximately 2,900 first-line mCRC patients. The trial, which was initiated in November 2005, was later amended to include only KRAS wildtype patients. The primary endpoint is overall survival. Given past data, the combination arm may prove to be ineffective; however, the more important comparison will be the direct comparison of Avastin-based chemotherapy versus Erbitux-based chemotherapy.

Quality of life data from CALGB 80405 were released at ASCO 2013. No differences were found among the three treatment groups on global health/quality of life (p=0.164) as well as other EORTC QLQ-C30 scales (physical functioning, role functioning, social functioning, emotional functioning, or cognitive functioning). As might be expected given the toxicity profile associated with EGFR inhibitors such as Erbitux, differences were seen in the Dermatology-Specific Quality of Life Scores “Skin Symptoms” (p<0.001), “limitations in social activities due to skin condition” (p=0.008) and “concern about appearance” (p<0.0001).[4] Therefore, an examination of the toxicity profiles will be of lessened interest, allowing a full consideration of efficacy to guide treatment practice.

Currently, U.S. physicians strongly favor Avastin-based regimens in first-line over Erbitux-based regimens in patients with KRAS wildtype mCRC, according to Kantar Health’s CancerMPact® Treatment Architecture data. This is largely based on order of entry, with Avastin receiving a first-line FDA approval eight years before Erbitux. Western European physicians slightly favor Erbitux-based regimens in first-line over Avastin-based regimens in patients with KRAS wildtype mCRC. This may be based on a preference for biomarker-driven treatment selection, which Erbitux affords. Both are also influenced by a lack of data to understand whether one of these agents is superior to the other. Since questions remain after the results of FIRE-3, in particular how Erbitux can generate a strong OS benefit compared with Avastin but not show a PFS benefit, the results of CALGB 80405 will ultimately be cited in comparisons between the two agents. Should the results of CALGB 80405 favor Avastin or show no significant difference between the two regimens, Kantar Health anticipates little impact on the current market. Therefore, any impact on the market will be driven by results showing superiority of an Erbitux-based regimen, although the impact will be limited to KRAS wildtype patients.

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[1] Ryan, N Engl J Med, 368: 138-148, 2013.

[2] Beer, Abstract LBA1, Genitourinary Cancers Symposium, 2014

[3] Heinemann, Abstract LBA3506, ASCO 2013.

[4] Naughton, Abstract 3611, ASCO 2013.

 

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