amgn/abgx the lies
FDA Offers Possible Reasons For Vectibix Failure To Show Survival Benefit
FDA review documents for Amgen's Vectibix (panitumumab) outline possible factors that may have lead to the epidermal growth factor receptor inhibitor's failure to show an overall survival benefit in a pivotal trial, including the possibility that the trial was not powered to show a modest effect.
Panitumumab cleared FDA Sept. 27, 2006 under the accelerated approval program for treatment of EGFR-expressing metastatic colorectal cancer following chemotherapy with fluoropyrimidine, oxaliplatin and irinotecan, based on surrogate endpoints (1"The Pink Sheet" Oct. 2, 2006, p. 3).
Although the pivotal trial failed to show evidence of an impact on overall survival, FDA Division of Biologic Oncology Products Director Patricia Keegan noted in her recommendation to approve the biologic that "improvements in [progression-free survival] are generally accompanied by improvement in overall survival."
Vectibix' 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 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," he said. "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."
However, FDA also questioned whether the study would be adequately powered for survival if patients from the BSC arm crossed-over to the Vectibix arm.
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 for panitumumab.
This enrollment failure prompted Amgen to suspend that trial and to propose the pivotal study comparing BSC alone to BSC plus panitumumab. The firm also proposed using data from two other 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, with supportive data from other trials, 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.
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 2following story).
In September 2005 Amgen submitted a draft protocol for a randomized, multicenter Phase III study to compare the efficacy of panitumumab in combination with FOLFIRI to 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 use 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. Despite the modest effect size, FDA reviewers rationalized that for this patient population, there are no other treatment options, and the benefit-risk assessment is favorable under accelerated approval guidelines.
The toxicity profile seen with panitumumab was similar to that seen with Erbitux, Hughes said, noting that "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 Vectibix 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.)."
On March 22 Amgen announced it was halting Vectibix treatment in the 1,000-patient PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) trial comparing chemotherapy plus Avastin with chemotherapy plus Avastin and Vectibix. Amgen had hoped to use PACCE to push Vectibix 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 arms. However, a more recent analysis (after 231 events) found statistically significant differences in favor of the control arm in PFS and overall survival. Amgen said it is continuing to study Vectibix as a single biologic combined with chemotherapy in Phase 3 first- and second-line registrational trials.
Amgen is planning to submit an sBLA to FDA for an indication in third-line metastatic CRC. Other planned studies include a first-line CRC registration trial of panitumumab + FOLFOX and studies in first line locally advanced and recurrent forms of metastatic squamous cell head and neck cancer.
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