FDA Urgency To Clear TLC Evacet May Be Lessened By Ellence Approval

The impetus for FDA to approve The Liposome Company's Evacet (liposomal doxorubicin, D-99), based on incomplete efficacy data may be lessened by the recent U.S. approval of Pharmacia & Upjohn's Ellence (epirubicin).

Ellence was approved Sept. 15 as a less cardiotoxic alternative to doxorubicin in the anthracycline class of oncologic drugs. Compared to conventional doxorubicin, epirubicin received a very narrow adjuvant breast cancer indication, although it likely will be used in a wide range of breast cancers (¹ ).

The next day, the Oncologic Drugs Advisory Committee voted against approval for TLC's Evacet, citing insufficient efficacy evidence from two of the three Phase III trials. The committee decision mirrored FDA's opinion.

Evacet is a liposomally encapsulated form of doxorubicin (P&U's Adriamycin and generics) designed to prevent cardiac damage by not permitting the cytotoxic drug to accumulate in cardiac cells. Generally, a limit of a lifetime maximum cumulative dose of 400-450 mg/m2 Adriamycin is set due to a 5% chance of developing congestive heart failure from cumulative cardiotoxicity above that dose.

Evacet would attain such toxicity at a dose of 780 mg/m2, TLC VP-Biostatistics, Clinical & Regulatory Affairs Lily Lee, PhD, estimated (² (Also see "TLC Evacet Cardiotoxicity Advantage Does Not Outweigh Unclear Efficacy" - Pink Sheet, 20 Sep, 1999.)). For Ellence, labeling indicates a 3.3% chance of CHF at a cumulative dose of 900 mg/m2.

A direct comparison of the less cardiotoxic anthracyclines was included in the Evacet NDA 50-772: TLC's Study 3 compared 75 mg/m2 of Evacet to 75 mg/m2 of epirubicin in patients with metastatic breast cancer who had not received previous anthracyclines. The drugs were both given in combination with cyclophosphamide 600 mg/m2.

A left ventricular ejection fraction change of over 30% was detected in 12% of Evacet patients compared with 10% of epirubicin patients. No patients in either arm developed CHF. Efficacy parameters showed a 46% tumor response rate and 10 month median duration of response for Evacet vs. 39% and 7.8 months for epirubicin, as well as a median survival of 18 months for Evacet vs. 16 months for epirubicin.

FDA medical officer Patricia Cortazar, MD, noted that one of the problems with the study was that "a relatively low dose of epirubicin was used, 75 mg/m2 instead of 100-120 mg/m2. The study does not [evaluate] TLC D-99 against a proven dose of epirubicin and therefore does not independently substantiate the results of Study 1."

Study 3 was conducted in Europe, without a U.S. IND, and was not completed. TLC reacquired the rights to Evacet from Pfizer in 1997, but discontinued the trial at 160 patients out of a planned 288, because of "resource and administrative considerations," Lee explained.

Committee voting consultant Kathleen Lamborn, PhD, University of California at San Francisco, determined that while the statistical power of the study is by nature reduced with lower enrollment, no adjustment is necessary for ending the trial early because the data were not assessed before stopping the trial.

At a pre-NDA meeting after FDA told TLC that Study 2 (which had a trend towards decreased survival compared to conventional doxorubicin) would not be supportive of the pivotal Study 1, the agency considered Study 3 and "expressed a concern that comparison to epirubicin at this dose would not be interpretable in a regulatory context unless one could establish that epirubicin and doxorubicin are equivalent on a mg per mg basis," Cortazar said.

TLC noted that in European countries, epirubicin is approved for combination chemotherapy at doses as low as 30-75 mg/m2. Lee also cited a recent meta-analysis of six trials in the literature that compared epirubicin to doxorubicin at equivalent doses. "Results show that hazard ratios are very close to one and doxorubicin and epirubicin are equally efficacious in locally advanced or metastatic breast cancer," she summarized.

While the Ellence NDA did not include any studies comparing epirubicin to doxorubicin, TLC's Lee pointed to three studies comparing a low dose of epirubicin (50 mg/m2) to a high dose. "While 100 mg/m2 epirubicin produced higher response rates, there was no difference in survival with the higher doses," she said.

FDA did not approve the metastatic indication for Ellence. Labeling for adjuvant treatment notes a statistically significant advantage for the higher epirubicin dose in relapse-free survival and five-year overall survival.

The agency's preference for epirubicin as a less cardiotoxic anthracycline may first have been indicated when FDA granted Ellence a priority review after the NDA was submitted Dec. 15, but awarded Evacet, submitted a day earlier, only a standard review. Before its NDA submission, TLC had told investors it expected a priority review (³ (Also see "The Liposome Company Evacet Phase III Results Will Support December Filing" - Pink Sheet, 16 Nov, 1998.)).

Committee member Derek Raghavan, MD/PhD, University of Southern California, commented that "the third study [comparing Evacet and epirubicin], while comforting in a general sense, in reality is not comforting at all for the reasons that were enunciated. It is almost valueless data to us because of the lack of controls and the early stopping, and sort of breaking all the rules of good trial design."

Raghavan also questioned whether anthracyclines such as Adriamycin should continue to be used prominently for metastatic breast cancer. "There seems to be a tacit assumption that...treating forever is a good thing for patients with metastatic disease, and that Adriamycin is the only drug out there," he said. "There must be 15 other drugs that can be either approved, used, or [have] some form of literature-approval for breast cancer use."

Raghavan also pointed out that "there are alternatives for those who want to continue to use Adriamycin." P&U manufactures Zinecard (dexrazoxane) to reduce doxorubicin cardiotoxicity as the lifetime dose gets higher but it is not widely used, as it may interfere with efficacy, TLC said.

There is already a marketed liposomal doxorubicin, Alza's Doxil, which is approved for Kaposi's sarcoma and ovarian cancer, but is used for metastatic breast cancer off-label. However, Doxil has a high incidence of Palmer-Plantar Erythrodysesthesia (hand-foot syndrome). TLC noted that unlike Doxil its liposomes are not pegylated and thus do not cause PPE.

Given the alternative treatment options, Raghavan concluded, "I'm not sure that we should lower the bar by comparison for other drugs that are looked at."

FDA also revisited its agreement with TLC regarding Phase III trial design to use response rate as a criteria for demonstrating efficacy equivalence between Evacet and conventional doxorubicin.

FDA Oncologic Drugs Division medical officer Grant Williams, MD, said: "We were doing something different in using response rate for first-line approval of breast cancer here." A response rate was allowed by the agency "because we have the same drug, the same molecule, and we are using it as a surrogate of what we think that effect is going to have on the ultimate survival years down the line."

However, Williams added, "I don't believe we would ever conceive of using a response rate down in the 20s range to demonstrate equivalence for that effect. It was theorized that the response rate would be higher," he noted. TLC had designed the trials expecting a 60% tumor response rate on both arms. Instead, the three trials demonstrated 44% and 46% rates for liposomal doxorubicin in combination with cyclophosphamide and 26% as a single agent.

"If you thought it would be that low then you should have designed the primary endpoint to be survival," Williams told the company. "But with the combination arm the response rate was in a high enough range where it was reasonable to do equivalence trials. So what happened was the response rate was much lower than planned, the study was much underpowered for this outcome and we don't have the study showing equivalence that we wanted," Williams concluded.

Committee member Scott Lippman, MD, M.D. Anderson Cancer Center, questioned the activity of Evacet alone, observing that the better response rates in combination with cyclophosphamide may be indicative of cyclophosphamide's efficacy, not Evacet's.

Committee voting consultant James Krook, MD, Duluth CCOP, disagreed, pointing out that the Phase III trials were indicative of a similar activity to Adriamycin, although he acknowledged that Evacet as a single agent had a negative survival trend.

In August, TLC began three one-year Phase I/II trials in metastatic breast cancer, in combination with Genentech's Herceptin, Bristol-Myers Squibb's Taxol and Rhone-Poulenc Rorer's Taxotere. The trials could lead to additional Phase III trials but would not qualify as supporting trials for the current Evacet NDA. TLC also has two lymphoma studies underway with Evacet, one a pediatric trial.