Ortho Biotech's Yondelis In Ovarian Cancer Test Case For Progression Free Survival Endpoint

FDA's Oncologic Drug Advisory Committee also will evaluate the firm's Doxil in combination with docetaxel for locally advanced or metastatic breast cancer.

Ortho Biotech's Yondelis (trabectedin) is giving FDA another opportunity to evaluate the significance of progression-free survival as an acceptable endpoint for regulatory approval, this time in the context of ovarian cancer.

Yondelis, being evaluated for use in combination with Doxil (liposomal doxorubicin) to treat relapsed ovarian cancer, is one of the two Ortho Biotech drugs that will face review by FDA's Oncologic Drugs Advisory Committee July 15.

In the afternoon, Doxil will take center stage. The panel will consider its use in combination with docetaxel for treating locally advanced or metastatic breast cancer patients who have received prior anthracycline treatment.

Based on FDA briefing documents released prior to the meeting, the sponsor's prospects look more positive for the first half of the day.

The agency is seeking substantial input from ODAC pertaining to ability of the PFS endpoint to reliably demonstrate Yondelis' efficacy in ovarian cancer. The parameters to define the clinical benefit of PFS to support full approval of first-line therapies has long been a sticking point for FDA, especially in the breast cancer arena ( (Also see "Progression-Free Survival Represents Clinical Benefit, But How Much? – ODAC" - Pink Sheet, 17 Dec, 2007.), p. 15).

But FDA is silent on the specific questions it will pose to the panel pertaining to Doxil in breast cancer, stating only clear concerns about the treatment's risk-benefit ratio.

FDA questions use, accuracy, validity and relevance of PFS

FDA is presenting ODAC with five issues concerning the Yondelis application, four of which pertain to the use, accuracy, validity and relevance of PFS, which was the primary endpoint used in the study.

The trial was an open-label, multicenter, randomized Phase III study of 672 ovarian cancer patients who previously had been treated with only one platinum based chemotherapy regimen (including adjuvant therapy) and who had experienced either recurrence or progression after the initial line of platinum-based chemotherapy regimen.

Patients were randomized to treatment with a combination of Yondelis and Doxil or to Doxil alone.

The first discussion point for the panel is whether PFS (defined as the time between randomization and disease progression or death) could be reliably assessed in the trial.

The agency's concerns are due to discrepancies among the PFS results as measured by several radiologic reviewers in the trial and also to a high degree of discrepancy in the progressive disease (PD) status and PD date between the independent radiologic review and the investigators in 63 percent of the patients.

FDA is also concerned about the "inaccuracy of disease progression measured only by imaging studies in an ovarian cancer trial." The agency explains in briefing documents that many patients progressed clinically or in non-measurable, non-target lesions, and the independent radiology assessments did not confirm the investigator's PD assessments.

The clinical relevance of the PFS results is also in question. The combination of Yondelis and Doxil showed a median PFS of 7.3 months - only a six-week improvement over Doxil alone (5.8 months), but with additional toxicity.

The main toxicity associated with the combination therapy is hematologic, with grade 3-4 neutropenia in 63 percent of the patients (compared to 22% on Doxil monotherapy) and febrile neutropenia in 8 percent (compared to 2% for Doxil alone). The Yondelis combination is also associated with higher rates of thrombocytopenia, increased transaminases, and cardiac events.

Finally, ODAC will discuss whether FDA should wait for the final survival analysis before making a decision on the Yondelis application.

An interim OS analysis after 300 (46%) deaths showed that the median survival for the Yondelis arm is 20.5 months versus 19.4 months for Doxil. The final OS analysis is planned at 520 death events. FDA states that whether the final OS analysis will show a significant difference between treatment arms remains to be seen.

Part II: Doxil for metastatic breast cancer

Overall survival will probably be a more central discussion point in the second half of the meeting, when the committee evaluates Doxil in combination with docetaxel for first-line metastatic breast cancer.

In its briefing documents, the agency clearly states that it has concerns about the risk-benefit ratio for the Doxil combination:

"The combination resulted in a modest improvement in [time to progression] with no improvement in OS," FDA states, adding that there is already a combination cytotoxic therapy approved for first-line treatment of metastatic breast cancer that has demonstrated at least a strong trend in OS. "Furthermore, Doxil + docetaxel was poorly tolerated, as evidenced by a marked increase in hand-foot syndrome and stomatitis and a 34 percent rate of early discontinuation of Doxil due to adverse events."

The application is supported by a Phase III, multi-center, multinational, randomized, open-label, active controlled trial. A total of 751 women with advanced breast cancer were randomized to the Doxil combination or docetaxel alone.

The protocol was designed under a special protocol assessment with FDA, and Ortho Biotech originally took the agency's advice to use OS as the primary endpoint. But after the study had reached 70 percent enrollment and 138 events had been observed, the sponsor petitioned FDA to change the primary endpoint to time to progression (TTP), and FDA acquiesced with the condition that the study continue to be powered and followed up for OS.

Results showed the median TTP by independent review to be 9.8 months in the Doxil/docetaxel arm and 7 months in the docetaxel monotherapy arm. There were more deaths in the Doxil/docetaxel arm.

-Jamie Hammon ([email protected])