FDA review documents for Amgen's epidermal growth factor receptor inhibitor Vectibix (panitumumab) outline possible factors that may have led to the biologic's failure to show an overall survival benefit in a pivotal trial.

"Based on data with 5-FU based chemotherapy, improvements in [progression-free survival] are generally accompanied by improvement in overall survival. This is the basis for the recommendation by the [Oncologic Drugs Advisory] Committee that [progression-free survival] is reasonably likely to predict an effect on overall survival and is an acceptable endpoint in support of accelerated approval," Division of Biologic Oncology Products Director Patricia Keegan noted in a Sept. 26, 2006 memo recommending Vectibix's approval.

Panitumumab cleared FDA Sept. 27, 2006 under the accelerated approval pathway for treatment of EGFR-expressing metastatic colorectal cancer following chemotherapy (fluoropyrimidine, oxaliplatin and irinotecan) (¹ Also see "Amgen Vectibix Approved For Metastatic Colorectal Cancer" - Pink Sheet, 27 September, 2006.).

Approval was based on a 463-patient randomized study at 81 non-U.S. sites, which yielded a mean time-to-disease progression or death at 96 days with Vectibix versus 60 days in patients receiving standard supportive care (BSC). Tumor shrinkage occurred in 8 percent of patients.

"The reason for the failure to demonstrate that an effect on PFS resulted in an effect on OS in this study remains unclear," Keegan said.

However, she offered the following possible reasons for the biologic's failure:

1) Vectibix has no effect on survival impact;

2) Longer follow-up in the BSC arm as compared to the panitumumab arm obscured impact on survival;

3) The study is underpowered to detect a very marginal effect predicted by a modest improvement in PFS; or

4) The large proportion of patients in the control arm, half of whom initiated panitumumab therapy eight weeks after study randomization, "obscured detection of an impact on survival."

In his statistical review of overall survival, Lead Statistician Mark Rothman disagreed with this analysis and the usefulness of PFS as a predictor of overall survival: "Among the 232 patients on the BSC arm, 175 received panitumumab after investigator ascertainment of disease progression. For the patients in the study, overall survival was practically equal between the two arms," Rothman said.

"So not giving the patients on the BSC arm any anti-cancer therapy until they had an investigator ascertainment of disease progression or died, and then giving 175 of the survivors panitumumab led to the same overall survival as giving panitumumab upfront to the patients on the panitumumab arm. This does not say much for the meaningfulness of a PFS event in its relationship with overall survival."

Rothman also disagreed with crossover justifications offered by FDA medical reviewers. "An excuse of the impact of 'crossover' from the control arm to the experimental arm has often been provided to explain/rationalize a statistically significant PFS advantage in the absence of an observed (or the absence of a statistically significant) overall survival advantage. This rationale assumes the experimental treatment impacts overall survival positively, i.e., it assumes exactly what it was supposed to (and failed to) [demonstrate]."

As early as a June 2003 end-of-Phase II meeting, Amgen did not appear to expect panitumumab to show a survival benefit. Its BLA proposal for accelerated approval used response rate data from two studies, with a primary endpoint of time to progression. Secondary endpoints were estimation of objective response rate, response duration, overall survival and toxicity.

FDA agreed with the proposal, but said the company would be required to provide definitive evidence of clinical benefit for panitumumab such as "evidence of a robust statistical effect demonstrating improved survival compared to best supportive care."

The agency stressed that accelerated approval could be granted "based on demonstration of a medically important and durable objective response rate or improved time to progression (progression-free survival) if adequate survival [data] are available."

While the agency encouraged Amgen to request fast-track status, it also noted that full approval of another product for the same indication in the same population could also result in withdrawal of the fast-track designation. FDA also questioned whether the study would be adequately powered for survival if patients from the BSC arm crossed over to the panitumumab arm

Amgen's confirmatory overall survival study is currently enrolling patients. The company is conducting a number of studies of Vectibix in earlier stage CRC. The firm hopes to use the 1,000-patient, randomized PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial comparing chemotherapy plus Avastin with a chemotherapy, Avastin and panitumumab regimen to push panitumumab into the first-line setting.

Interim 12-week data from PACCE released in January showed responses in the first 500 patients were similar in both treatment arms (² Also see "Vectibix Vs. Erbitux: The Race For A First-Line Colorectal Cancer Indication" - Pink Sheet, 26 January, 2007.).

Amgen is also planning to submit an sBLA to FDA seeking an indication in third-line metastatic colorectal cancer. Other planned studies include a first line CRC registration trial of panitumumab +/- FOLFOX and studies in first line locally advanced and recurrent form of metastatic squamous cell head and neck cancer.

Vectibix sales as of the fourth quarter were $39 million, Amgen said. The monthly price is bookended by Avastin ($4,400) and Erbitux ($10,560), with a price of $8,000 per month. In October, Amgen announced a program to cap out-of-pocket expenses beyond 5 percent of patients' adjusted gross incomes.

- Tamra Sami (t.sami@elsevier.com)

[Editor's note: For more coverage of the Vectibix review, see the "Drug Review Profile" feature in the March 2007 issue of ³ Pharmaceutical Approvals Monthly. For a sample copy, contact customer service at 1-800-332-2181.]

FDA Vectibix Review Posits Study Design Issues That Could Have Led To Lack Of Survival Benefit

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