Supported by robust data demonstrating knock-out response rates, Roche/Genentech’s Zelboraf (vemurafenib) has sailed through the FDA approval process, aided by a push from the agency.

Zelboraf was approved Aug. 17 for treatment of patients with unresectable or metastatic melanoma with the BRAF V600E mutation as detected by an FDA-approved test.

Submitted April 28, the approval came well ahead of the Oct. 28 priority user fee goal date (Also see "Speedy Approval Of Roche's Zelboraf Puts Pressure On Bristol's Yervoy" - Pink Sheet, 17 August, 2011.).

The double helix in the logo evokes the personalized medicine aspect of the product.

That Zelboraf was approved in three and a half months is a clear sign that FDA was impressed by trial data supporting the NDA. But a review memo also shows that once there was evidence of a significant effect, the agency shepherded the BRAF inhibitor through clinical development to help make the product available to patients sooner.

The agency also managed to clear Roche’s companion diagnostic, the cobas 4800 V600 Mutation Test, in the accelerated timeframe.

FDA has a practice of expediting reviews in cases where the supportive evidence is clear, especially when data shows an impact on survival, as with Sanofi’s Jevtana (cabazitaxel), which was cleared in about 11 weeks (Also see "The Lesson Of Jevtana: With A Survival Advantage, All Things Are Possible" - Pink Sheet, 1 March, 2011.)

Vemurafenib hasn’t reached median PFS and OS data is further off (it is being assessed as a post-marketing commitment). But labeling cites a 48.4% best overall response rate for the drug – a far cry from the 5.5% response rate seen with traditional dacarbazine chemotherapy.

As soon as the level of response was clear, FDA had started acting in ways to expedite the clinical development and upgrade the approval type from accelerated (which would carry additional study requirements that would be difficult to conduct) to full approval.

FDA Found Roche’s Proposals “Too Conservative”

At the end of Phase I meeting in May 2009, Roche had proposed using a response rate of 30% or greater and a two-month improvement in progression-free survival as endpoints to support accelerated approval.

Given that tumor response data for only 16 patients was available, FDA recommended the company run a randomized Phase III trial with overall survival as the primary endpoint – the maximum degree of evidence expected for a cancer drug approval.

But, the agency “expressed willingness to discuss use of their single-arm Phase I and II trials to support accelerated approval once they had more data suggesting impressive efficacy,” according to the Aug. 16 division director summary review memo from Oncology Drug Division head Robert Justice.

FDA followed through on that promise.

By August 2010, Roche had the impressive evidence in hand. The company shared preliminary results from the Phase II BRIM2 trial in 132 patients, showing an objective response rate of approximately 50%. It also submitted results from the extension phase of the Phase I trial, which were published in the New England Journal of Medicine Aug. 26, 2010. That showed that 26 of 32 patients, or 81%, had an objective response.

Showing of “unprecedented activity” led to changes in trial design.

“Given these results the agency proactively communicated with the applicant multiple times to modify the statistical analysis plan of the Phase III trial … adapting with the impressive observed activity of vemurafenib in the Phase I and Phase II studies,” the memo reports.

A chronology of interactions between FDA and Roche included in the review document details a series of meetings about modifying the ongoing Phase III trial, BRIM3. The original trial was based on the preliminary Phase I data, but the emerging data showing “unprecedented activity of vemurafenib in melanoma” led FDA to question whether the trial should continue as originally designed.

The review team requested the interim response rate and duration results, and asked for an earlier interim analysis of overall survival – to be submitted during the review period.

FDA deemed the current treatment effect threshold in BRIM3 “too conservative” and asked Roche to propose different options for estimating treatment effect on overall survival based on the new Phase I and II data. “These analyses would not incur a statistical penalty,” the minutes note.

Uncharacteristically, FDA pushed to relax statistical assumptions.

The agency ultimately agreed to an early interim analysis suggested by Roche, “but requested that the statistical assumptions be relaxed to increase the probability of a positive first interim analysis.”

Phrases like “too conservative” and suggestions to relax statistical bounds to increase the probability of success are unusual for FDA review documents.

FDA also orchestrated modifications that would enable full approval instead of accelerated approval. It decided that “an improvement in overall survival, together with consistency of best overall response rates and progression-free survival in Phase I, Phase II and Phase III trials could serve as the basis for full approval.”

It later noted that “based on the data seen to date, the PFS effect should be large enough to support full approval” and that an OS benefit would not be needed.

From the first submission of the interim Phase II data, and especially given the plan to release results at a conference and the Phase I publication, FDA recommended that Roche prepare an Expanded Access Protocol. At a meeting a month later, the agency “strongly advocated opening an expanded access protocol with a broader patient population and/or reopening BRIM2 to ensure patient access as soon as possible.”

Although BRIM3 had enrolled “within a very short period of time at an unexpected high rate” (a reflection of the public demand) and thus the trial size couldn’t be reduced, “the applicant was able to successfully conduct the analysis early in a planned manner with the timely adaptation of the clinical trial,” FDA’s Justice states.

At the pre-NDA meeting on Jan. 21, Roche outlined plans to submit for accelerated approval based on ORR from the Phase I and II trials or for full approval based on final PFS and interim OS results from the randomized Phase III trials. FDA agreed to review the application under either scenario, the memo notes.

Full approval was granted, with labeling that reflects the robust response rates demonstrated in clinical trials.

A Broad Indication, But Matched By Yervoy

Zelboraf received a broad indication for unresectable or metastatic melanoma without specification as to line of therapy, on par with the indication granted for Bristol-Myers Squibb’s Yervoy (ipilimumab) just five months ago. However vemurafenib’s label limits use to patients with the BRAF V600E mutation as detected by the FDA-approved test.

Though the application for Yervoy was based on a second-line trial, FDA took into consideration the results of a first-line trial that completed just before approval, and granted a broad label for metastatic melanoma (Also see "Yervoy Cuts To The Head Of The Line: Ipilimumab Has Unrestricted Label" - Pink Sheet, 28 March, 2011.).

Yervoy’s approval was based on OS – the first demonstration of a survival benefit for melanoma and the first major breakthrough in a decade, now followed by the Zelboraf clearance. But Yervoy does not work in all patients, and no biomarker is available to predict response.

Though Yervoy made it through FDA with an attractive label, the application did not have the same expedition granted for vemurafenib, and the ipilimumab user fee deadline was even extended. FDA review documents show the agency had concerns about the second-line study and wanted to see data from the first-line trial; both trials showed a survival benefit.

[Editor’s note: Further analysis of the Yervoy review will appear in a coming issue of Pharmaceutical Approvals Monthly. To request a sample copy, please contact customer care at custcare@elsevier.com or 800.332.2181.]

The drugs have different mechanisms of action and different strengths; ipilimumab has a slow arc to an extremely durable response, whereas vemurafenib has a fast and high response in the patients with the mutation, though the BRAF inhibition can fall to further mutation and resistance to Zelboraf (Also see "Front-Line Of Melanoma Market Could Be Marketing Battle" - Pink Sheet, 13 June, 2011.).

Vemurafenib works on BRAF, a protein involved in cell signaling that plays an important role in cell growth. Genetic mutations result in too much BRAF activity and uncontrolled cell growth. Vemurafenib targets V600E, thought to be the most common mutation, suppressing cells with the mutated protein and causing cancer cell death.

RAS-RAF Pathway

That most tumors eventually progress despite treatment and prevention of resistance is a major focus of melanoma research.

Preclinical studies suggest that activation of MEK, a protein involved in relaying growth and survival signals in cells, may allow inoperable or metastatic melanoma to return or get worse in some people who previously responded to Zelboraf, Genentech explains. Roche/Genentech is running a Phase I study of Zelboraf and the investigational MEK inhibitor GDC00973 to test the safety profile of the combination.

FDA is requesting further research on resistance in the post-market setting. As a post-marketing commitment, FDA wants Genentech to explore whether the NRAS mutation plays a role in disease progression in patients with the V600E mutation who have been treated with vemurafenib.

Continuing Research Post-Marketing

The agency also wants another companion diagnostic developed and tested in a single-arm, open-label trial, looking at the V600K mutation, “because some of the patients enrolled on the BRIM3 trial were identified by the cobas 4800 V600 mutation test as having the V600E mutation but were found to have the V600K mutation by Sanger sequencing,” the approval letter states.

The agency used its mandatory authority to require the final analysis of safety in BRIM3 to gather data on longer duration of exposure, as well as drug interaction trials and specific analysis of secondary malignancies from a planned papillary thyroid cancer trial and a proposed adjuvant melanoma trial.

The Warnings And Precautions section of Zelboraf’s label notes that 24% of treated patients developed cutaneous squamous cell carcinomas (cuSCC). These included SCCs of the skin and keratoacanthomas. These cancers usually develop early in treatment, with a median time to first appearance of 7 to 8 weeks.

However, the label also notes that cases of cuSCC were managed with excision, and that patients were able to continue treatment without dose adjustment.

In contrast, ipilimumab’s label has a boxed warning about risk for severe and potentially fatal immune reactions.

The Zelboraf label Warning and Precautions section also notes potential for serious hypersensitivity reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis, liver abnormalities, QT prolongation and new primary malignant melanoma.

The most common adverse events included arthalgia, rash, alopecia, fatigue and photosensitivity reaction.

Surveying The Commercial Landscape

Following approval of vemurafenib, patients with advanced metastatic melanoma will soon have two options.

Daiichi Sankyo Ltd. will be co-promoting Zelboraf in the U.S., following its acquisition this year of the drug’s developer Plexxikon. The whopping $805 million buyout price shows just how valuable even a piece of the molecule is believed to be (Also see "Daiichi's Handsome Buyout Price Validates Plexxikon's Business Model" - In Vivo, 1 March, 2011.).

Genentech's plan is to make the treatment available within weeks at the price of $9,400 a month, which arguably puts the personalized medicine at a lower cost threshold than Yervoy.

A Genentech spokesperson said that given the average length of treatment, which is six months, total cost for vemurafenib will typically amount to about $56,000. That compares to the $120,000 cost for Yervoy, which is given in four injections, administered three weeks apart ([A#1216099165884]).

However, some patients may live a lot longer than six months and in these cases, the cost in a given year could well match that of Yervoy, commented Richard Martin, CEO of Kantar Health Oncology.

Just which drug to use first in BRAF-mutation positive patients – Yervoy or Zelboraf – remains to be seen. Yervoy has a clearer long-term effect; there can be resistance issues with BRAF inhibition.

With such a strong response rate data behind Zelboraf, Melanoma Research Foundation Executive Director Tim Turnham says that if there is a choice between which drug to try first, mutation-positive patients are likely to take a gamble on the BRAF-inhibitor.

Vernon Sondak, chief of cutaneous oncology at the Moffitt Cancer Center, noted that the decision will vary depending on the needs of each individual patient. And the older treatment IL-2 also still has a role, he pointed out.

Given that the drugs have two different mechanisms of action, they will probably ultimately be used in combination in eligible patients. However, ipilimumab trial data suggest liver toxicity and this could be worsened by a side effect of vemurafenib, a very low level of elevation in a liver enzyme (Also see "Front-Line Of Melanoma Market Could Be Marketing Battle" - Pink Sheet, 13 June, 2011.).

A combination trial of the two drugs is set to start enrolling at the end of 2011. Prior to getting that data, Sondak believes that it’s highly unlikely that clinicians will prescribe the two in combination, in light of the potential for additive toxicities.

As for the commercial point of view, Kantar Health’s Martin expects that the value proposition would need to be very strong for payers to justify an expense for two drugs that could be as high as $250,000 in a year.

By Mary Jo Laffler, Emily Hayes

Zelboraf Approval Hastened By FDA Officials Impressed With Early Efficacy

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