The clinical significance of the progression-free survival benefit seen with Merck & Co. Inc./Ariad Pharmaceuticals Inc.’s investigational sarcoma treatment Taltorvic (ridaforolimus) is likely to be a key discussion point for FDA’s Oncologic Drugs Advisory Committee during its March 20 review of the mTOR inhibitor.

Ridaforolimus was associated with a median PFS benefit of three weeks in its pivotal trial, an advantage that FDA reviewers and ODAC members may look upon skeptically given the recent debate surrounding the clinical significance of a one-to-two month median PFS benefit in confirmatory trials of Genentech Inc.’s Avastin (bevacizumab) in metastatic breast cancer.

ODAC will consider a sarcoma indication for GSK’s Votrient in the morning, and initial approval of Merck/Ariad’s Taltorvic in the afternoon.

Ridaforolimus will be the second of two sarcoma agents to be discussed at ODAC’s March 20 meeting. During the committee’s morning session that day, the panel will consider an sNDA for use of GlaxoSmithKline PLC’s Votrient (pazopanib) in patients with advanced soft tissue sarcoma.

Maintenance Therapy

The proposed indication for ridaforolimus is maintenance therapy in adult and pediatric (ages 13-17 years) patients with metastatic soft tissue sarcoma or bone sarcoma who have completed at least four cycles of chemotherapy without evidence of progression.

Merck co-developed the drug under a 2007 deal with its originator, Ariad. That deal was revised in 2010 to give Merck full development and commercialization rights in oncology indications Also see "Revised mTOR Deal With Merck Gives Ariad Time" - Pink Sheet, 5 May, 2010.. In March 2011, Ariad exercised its option to co-promote ridaforolimus in the U.S. Also see "Ariad Opts-in To Co-Promote mTOR With Merck" - Pink Sheet, 18 March, 2011..

The companies announced the NDA filing in the sarcoma indication in October; the drug is undergoing a standard review.

The NDA is supported by the Phase III SUCCEED trial, results of which were presented at the American Society of Clinical Oncology’s annual meeting in June 2011.

Conducted under a special protocol assessment with FDA, SUCCEED was a double-blind study of 711 patients with metastatic soft tissue or bone sarcomas who previously had a favorable response to chemotherapy. Patients were randomized to either placebo or oral ridaforolimus administered at 40 mg/day (five of seven days per week). In their presentation at ASCO, the SUCCEED study investigators said it was the largest randomized study ever in the soft tissue and bone sarcoma population.

Big Difference In Radiological Review Versus Investigator Assessment Of PFS

The primary endpoint was PFS as assessed by an independent radiologic review committee, with secondary endpoints including overall survival, objective response, cancer-related symptoms, safety and tolerability.

According to data presented at ASCO, ridaforolimus was associated with a statistically significant 28% reduced risk of progression or death (p=0.0001). Median PFS was 17.7 weeks in the ridaforolimus arm, compared with 14.6 weeks in the placebo arm.

The PFS advantage as determined by investigator assessment was more substantial, with ridaforolimus demonstrating a statistically significant 31% reduced risk of progression or death compared to placebo. In the investigator assessment analysis, median PFS was 22.4 weeks in the ridaforolimus arm, compared with 14.7 weeks in the placebo arm.

Overall survival data were not mature, but there was a trend favoring ridaforolimus that did not reach statistical significance (21.4 months vs. 19.2 months; HR=0.88, p=0.2256). “No conclusions could be drawn from the exploratory analysis of cancer-related symptoms based on patient questionnaires about pain, cough and shortness of breath due to incomplete questionnaire data,” Merck and Ariad said in their press release announcing the SUCCEED results.

Medians Vs. Hazard Ratios

In discussing the study results, Ariad management asserted that it was more important to look at the PFS hazard ratio rather than the three-week median PFS benefit under the primary analysis Also see "Ariad Comes Of Age With Oncology Drugs, Readies For Commercial Leap" - Pink Sheet, 27 June, 2011..

However, FDA is unlikely to see it that way.

Debate over the importance of medians versus hazard ratios played out on a grand stage last June during a two-day hearing on the Center for Drug Evaluation and Research’s proposal to withdrawal accelerated approval of Avastin’s metastatic breast cancer claim. CDER sought to revoke the indication because the confirmatory trials showed bevacizumab to be associated with median PFS benefits of 0.9-2.9 months, well shy of the 5.5-month improvement seen in the pivotal trial supporting the MBC indication.

At the hearing, Genentech representatives asserted that focusing solely on median differences is flawed and can underestimate treatment effect. Rather, the company asserted that the hazard ratio, which reflects the entire treatment curve and more data points, provides a better view of a drug’s efficacy.

However, CDER officials stalwartly maintained that it is necessary to look at median values in order to understand the temporal implications of a drug’s clinical effects Also see "Avastin Debate Could Provide Clarity On Use Of Progression-Free Survival Endpoints" - Pink Sheet, 11 July, 2011..

ODAC agreed with CDER’s view that the PFS advantage seen in the Avastin confirmatory trials was not clinically significant; in November, FDA Commissioner Margaret Hamburg ordered Avastin’s MBC indication withdrawn.

Given the experience with Avastin’s breast cancer claim, Merck/Ariad may face an uphill battle in explaining why a three-week median PFS advantage is clinically significant.

Given the Avastin experience, Merck and Ariad may face an uphill battle in making a case for why a three-week median PFS advantage is clinically significant.

FDA and ODAC’s evaluation of ridaforolimus’ clinical benefit will take place against a backdrop of safety issues. In SUCCEED, there were six deaths (1.8% of patients) due to pulmonary disorders in the active treatment group, compared with zero pulmonary-related deaths in the placebo arm. Ridaforolimus also was associated with higher rates of severe adverse events involving thrombocytopenia, stomatitis, anemia and hyperglycemia.

A New Indication For Votrient

Pazopanib, GSK’s tyrosine kinase inhibitor, initially was approved for renal cell carcinoma in October 2009 Also see "GSK's Votrient Will Need To Show Efficacy Outweighs Black Box" - Pink Sheet, 20 October, 2009.. GSK seeks to extend the drug’s use to patients with advanced soft tissue sarcoma who have received prior chemotherapy; the indication is undergoing a standard review.

The NDA submission announced in July 2011 is based on the Phase III PALETTE trial, results of which also were presented at ASCO last June.

Jointly conducted by GSK and the European Organisation for Research and Treatment of Cancer, PALETTE enrolled 369 adults with metastatic soft tissue sarcomas, excluding gastrointestinal stromal tumors and adipocytic sarcomas. Patients were randomized on a 2:1 basis to pazopanib or placebo. The primary endpoint was progression-free survival based upon independent radiologic assessment. Secondary endpoints included overall survival, overall response, duration of response and safety outcomes.

Pazopanib was associated with a statistically significant 69% reduced risk of progression or death (p<0.0001). median="" pfs="" in="" the="" pazopanib="" group="" was="" 4.6="" months,="" compared="" to="" 1.5="" months="" on="" placebo.="" in="" the="" interim="" analysis,="" there="" was="" an="" overall="" survival="" trend="" favoring="" pazopanib,="" but="" it="" did="" not="" reach="" the="" level="" of="" statistical="" significance="" (11.9="" months="" vs.="" 10.4="" months,="" p="">

With a three-month PFS advantage for pazopanib, GSK may have an easier argument on the clinical significance question than Merck and Ariad. However, pazopanib’s toxicities may be problematic, particularly since the drug already carries a “black box” warning about severe and fatal hepatotoxicity.

When GSK brought pazopanib to ODAC in 2009 for consideration of the renal cancer indication, FDA raised significant concerns about hepatic injury, citing four cases in the underlying pivotal trial that fulfilled Hy’s Law criteria. Nevertheless, ODAC voted unanimously in support of approval for renal cancer, deeming the hepatotoxicity concerns acceptable in light of the drug’s efficacy Also see "GSK's Votrient Clears ODAC Despite Outdated Trial, FDA Safety Concerns" - Pink Sheet, 12 October, 2009..

In PALETTE, a higher percentage of patients experienced liver enzyme elevations with pazopanib compared to placebo. Other Grade 3-4 toxicities that occurred more frequently with pazopanib were fatigue, diarrhea, nausea, hypertension and decreased appetite. Cardiac dysfunction, venous thromboembolic events, pneumothorax and fatal adverse events also were reported with more frequency in the pazopanib group.

FDA Panel Review Of Merck/Ariad’s Sarcoma Drug Could Hinge On Clinical Significance Of Progression-Free Survival Benefit

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