FDA Offers Possible Reasons For Vectibix Failure To Show Survival Benefit

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.

"The trial failed to show evidence of an impact on overall survival," Division of Biologic Oncology Products Director Patricia Keegan noted in her recommendation to approve the biologic Sept. 26, 2006. "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."

Panitumumab cleared FDA under the accelerated approval program for treatment of EGFR-expressing metastatic colorectal cancer following chemotherapy (fluoropyrimidine, oxaliplatin and irinotecan) (¹ Pharmaceutical Approvals Monthly October 2006, p. 5).

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:

Vectibix has no effect on survival impact;Longer follow-up in the BSC arm as compared to the panitumumab arm obscured impact on survival; The study is underpowered to detect a very marginal effect predicted by a modest improvement in PFS; or 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 Mathematical Statistician Mark Rothman disagreed with this analysis and the usefulness of using 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. 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.

Approval Of Competing MAbs Affects Enrollment

In December 2004, shortly after approval of ImClone's Erbitux (cetuximab) and Genentech's Avastin (bevacizumab), Amgen reported enrollment challenges with its Phase II single-arm study for third- and fourth-line treatment of patients with metastatic CRC, which was intended to serve as the basis of accelerated approval.

This enrollment failure prompted Amgen to suspend that trial and to propose the pivotal study comparing BSC alone to BSC plus panitumumab, which ultimately resulted in accelerated approval.

The company also proposed using data from two additional studies to support the findings, and asked FDA whether evidence of robust and durable efficacy in third- or fourth-line CRC in the pivotal study, in combination with supportive data from other studies, would be enough to support full approval.

FDA replied in the affirmative, but again drove home the point that a significant advantage in overall survival would be needed to support regular approval. The agency also said it would consider a proposal for submission of reviewable units under its Continuous Marketing Application Pilot 1 program, which offers more interaction with the agency.

FDA also discussed the need for a supplement to the Vectibix BLA for a diagnostic kit used to screen patients for EGFR expression eligibility for the pivotal study (see related story, page 18).

In September 2005 Amgen submitted an amendment to its IND containing a draft protocol for a randomized, multicenter Phase III study to compare the efficacy of panitumumab in combination with chemotherapy (FOLFIRI) to the efficacy of chemotherapy alone in patients with previously treated metastatic colorectal cancer.

"This protocol was identified as the trial intended to verify clinical benefit of panitumumab in support of regular approval in the event that an improvement in overall survival was not demonstrated in [the pivotal trial]," Regulatory Manager Monica Hughes wrote in a Dec. 13, 2005 memo. FDA told the company that "if a highly statistically significant effect on overall survival is demonstrated, with consistent evidence of benefit in meaningful subgroups," then the proposed study could serve to support regular approval and could serve to verify the effects on the surrogate endpoint (PFS) demonstrated in the pivotal study.

However, weeks later FDA told the company that the "[PFS] data and interim overall survival data from these studies do not support a regular approval."

In the pre-BLA meeting, Amgen acknowledged that results from the pivotal trial did not show an effect on overall survival and that this would not change with additional follow-up. The company agreed to submit the confirmatory trial for second-line treatment with overall survival as the primary endpoint in order to verify the clinical benefit of Vectibix. Results of this study will be provided to FDA as a Phase IV commitment.

"The applicant has not provided sufficient data to evaluate the efficacy of panitumumab therapy," Division of Biologic Products Team Leader Kaushik Shastri wrote in a Sept. 26, 2006 memo, noting that Amgen did demonstrate improvement in PFS (p<0.0001).

Despite the modest effect size, FDA reviewers rationalized that for this patient population, there are no other treatment options, and "the benefit-to-risk assessment is favorable for the approval recommendation for panitumumab under accelerated approval guidelines," Shastri wrote.

The toxicity profile seen with panitumumab was similar to that seen with Erbitux, Hughes noted, and "the apparent lower incidence of infusion-related reactions may relate to how data were collected in the two applications." Infusion-related events are noted in the boxed warning section of the panitumumab label.

FDA noted that "some of the safety information is indicative of a class effect for anti-EGFR antibodies and tyrosine kinase inhibitors that affect this downstream signaling pathway ( Tarceva , Iressa )." For example, there is a high amount of "mucocutaneous toxicity (skin rash, acniform, erythema, dermatitis, skin fissures, paronychia, etc.)," Hughes wrote in a Sept. 12, 2006 memo.

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 show responses in the first 500 patients were similar in both treatment arms.

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 ([email protected])