The expedited review and approval of Sanofi-Aventis’ oncologic Jevtana (cabazitaxel) shows the power of a clearly demonstrated survival advantage to overcome regulatory hurdles.

The Jevtana review took only 11 weeks, despite issues of a scale that have been known to derail other NDAs: significant, even fatal, adverse reactions and a dose level that the FDA review team found too high.

“Cabazitaxel is being recommended for approval based on a survival advantage, which is considered a gold standard in the field of oncology,” Division of Drug Oncology Products Deputy Director Amna Ibrahim said in a memo dated June 17, 2010, the day of Jevtana’s approval.

Office of Oncology Drug Products Director Richard Pazdur explained that with the survival benefit, the review was expedited "due to an anticipated impact on public health” in his June 17, 2010, memo.

The "anticipated impact on public health" merited the expedited review, FDA's Pazdur said.

There were no treatment options that offered a survival benefit for the proposed hormone-refractory prostate cancer population, clinical reviewers Amy McKee and Ian Waxman pointed out in their June 2, 2010, review, noting that “the robust results in overall survival" for cabazitaxel would change that. Median overall survival for Jevtana patients in the pivotal 755-patient TROPIC trial was 15.1 months, compared with 12.7 months for mitoxantrone patients in the comparator arm (Also see "With Jevtana Approved For Advanced Prostate Cancer, Sanofi Could See Expansion To First-Line Use" - Pink Sheet, 21 June, 2010.).

Overall survival is especially important in HRPC, where surrogate endpoints are lacking. Pain, the most common stand-in for disease progression in prostate cancer, is a slippery element to measure, at best (Also see "Why Survival Is The Fittest Endpoint For HRPC: The Problem With Pain" - Pink Sheet, 1 March, 2011.).

But even with the survival advantage, many stars had to align to put Jevtana in a position where an expedited review was appropriate.

Survival Benefit > Unusually Severe Toxicity

Sanofi-Aventis, the NDA sponsor, helped FDA move Jevtana through the review process quickly, with "rapid responses … to FDA questions and concerns,” Ibrahim stated. The expedited review action goal date was June 18, 2010, less than three months after Jevtana’s completed submission on March 31, 2010. The regular PDUFA goal date was Sept. 30, 2010, a six-month timeline reflecting Jevtana’s priority review designation (see chronology of Also see "Jevtana Clinical Development" - Pink Sheet, 1 March, 2011.).

McKee and Waxman highlighted the strength of the clinical data; the medical review states that the overall survival results were robust, and "there were very few patients lost to follow-up or censored for other reasons.”

Attesting to another aspect of the robustness of the NDA, Cross-Disciplinary Team Leader John Johnson reported in a June 17, 2010, memo that “there were no disagreements among review team members regarding risk/benefit assessment.”

The strength of the survival benefit was vital to overcoming what Ibrahim called “the unusually high incidence and severity of toxicity” in cabazitaxel-treated patients in the pivotal trial.

“Despite the increased toxicity and increase in deaths due to toxicity in the cabazitaxel arm relative to the control arm, there is still a survival advantage for the cabazitaxel treatment group,” Johnson agreed.

Nonetheless, when the goal is palliation in a group of elderly men, the severity of toxicity is a factor. The median age of prostate cancer diagnosis is 72 years. “The risk/benefit ratio in the Phase III trial is favorable, but suboptimal,” he concluded.

A Setting In Need

Hormone-refractory prostate cancer has been one of oncology’s more elusive targets. “Despite active research, it has been difficult to develop effective drugs to treat metastatic hormone-refractory prostate cancer,” Ibrahim stated. “There are few drugs available for the advanced form of this common cancer and none for this indication.”

Jevtana is approved for a subset of advanced patients who have become refractory to the first line of attack in prostate cancer – medical or surgical castration – and who have then progressed on or become refractory to the first line of therapy for hormone-refractory disease, Sanofi-Aventis’ venerable taxane Taxotere (docetaxel). All the chemotherapies used in this setting have significant toxicities and are approved in combination with the steroid prednisone.

Taxotere was approved for HRPC in 2004, and for the six years until the Jevtana approval it was the last line of therapy approved for these advanced patients.

“For patients who have progression on or after docetaxel-based therapy, there are no treatments that have shown a survival advantage,” McKee and Waxman declared. “Mitoxantrone in combination with prednisone is labeled for pain palliation in this setting, but has not demonstrated a survival advantage,” they noted. Mitoxantrone was the comparator drug in both the pivotal Jevtana TROPIC trial and in the studies supporting docetaxel’s HRPC approval.

HRPC Drugs Are Few Despite Active R&D

“Many single agents and combination regimens have been investigated in this setting but have shown unacceptable toxicity or unpromising response rates,” McKee said, listing a roll call of failed treatments: lenalidomide/paclitaxel, the histone deacetylase inhibitor romidepsin, pemetrexed, multi-kinase inhibitor sunitinib, gefitinib, microtubule inhibitor patupilone and bortezomib, among others.

The clinical reviewers specifically cited the recent failure of GPC Biotech/Pharmion’s satraplatin, a next-generation oral platinum chemotherapy, to achieve the primary endpoint of overall survival as a second-line treatment for HRPC in the lare, placebo-controlled Phase III SPARC study (Also see "GPC Biotech’s Satraplatin Fails To Meet Survival Endpoint In SPARC Trial" - Pink Sheet, 31 October, 2007.).

The history of HRPC R&D is littered with drugs and drug combinations with “unacceptable toxicity or unpromising response rates,” McKee said.

Nonetheless, HRPC remains an active area for drug development. While 85% of prostate cancer patients respond to castration, either surgical or medical via gonadotropin-releasing hormone antagonists, prostate cancer is the most common cancer diagnosed in men, making the remaining 15% a not inconsiderable market. Additionally, the clinical reviewers noted, “responders will eventually become refractory to hormonal intervention.”

In fact, Jevtana was actually the second novel HRPC therapy approved in 2010. Like Jevtana, Dendreon’s cancer vaccine Provenge (sipuleucel-T) was approved on the basis of a survival advantage. However, Provenge’s indication is limited to metastatic HRPC patients with asymptomatic or minimally symptomatic disease, an earlier stage group of patients and a smaller population than Dendreon originally sought (“FDA Considered A Broader Indication For Dendreon’s Provenge,” Pharmaceutical Approvals Monthly, June 2010).

The symptom of pain is widely used as a prognostic factor in prostate cancer. By limiting the Provenge indication to patients with little or no pain, FDA excluded the larger population of patients with more advanced disease.

The late-stage development candidates for HRPC are principally next-generation hormone therapies or alternative drugs to be used when hormone therapy fails (Also see "Prostate Cancer Market Snapshot: More Than Provenge" - Pink Sheet, 22 November, 2010.).

The FDA reviewers highlighted some promising new programs in the castration-resistant population, singling out two projects then in Phase III, One of the drugs is now one of the hottest new molecular entity prospects pending at FDA: abiraterone, a CYP17 inhibitor from Johnson & Johnson’s Cougar Biotech. J&J submitted an NDA for abiraterone late in 2010 for an indication similar to Jevtana’s in taxane-experienced metastatic advanced prostate cancer patients.

The clinical reviewers also pointed to a Phase III trial using an Abbott Laboratories drug that famously stalled out with a “not approvable” letter for HRPC in 2005. The ongoing study highlighted by the reviewers combined Abbott’s atrasentan (Xinlay), an endothelin-A receptor antagonist, with docetaxel.

Familiarity Can Be An Asset

Jevtana is a next-generation member of the same taxane class that includes two of the most well-established chemotherapies in the contemporary armamentarium, Bristol-Myers Squibb’s mainstay Taxol (paclitaxel) and Sanofi-Aventis’ own vulnerable-to-generics Taxotere (docetaxel). Both Taxol and Taxotere are associated with a range of toxicities, which have been managed through labeling.

There was no recommendation for a Risk Evaluation and Mitigation Strategy or medication guide for Jevtana, Deputy Division Director Ibrahim stated. “The issues for cabazitaxel are similar to the Taxotere label, another drug in the same class. There is no REMS or medication guide in Taxotere,” he explained.

The oncology setting in general is amenable to risk management through labeling and surveillance; treatment is usually closely supervised by a physician already experienced with managing the toxicity of chemotherapy, the primary reviewers noted.

As part of labeling discussions, "special attention was directed to clarity and content of the Boxed Warning, Contraindications, Warnings and Precautions sections. Emphasis was on neutropenia, febrile neutropenia, infection, diarrhea, hypersensitivity reactions and renal failure," Johnson said.

Instead of focusing on communicating risk to the patient, as with a MedGuide, Jevtana risk management focuses on new studies to address FDA’s concerns. Indeed, the post-marketing requirements actually include more Phase III studies (two) than the NDA did (one).

The post-marketing program for Jevtana will include more Phase III studies than the pivotal program.

11 Weeks To Approval = 10 PMRs

As FDA becomes more comfortable with the safety tools provided by the FDA Amendments Act, post-marketing requirements are increasingly being used as a tool to provide FDA with enough of a comfort level to approve drugs that nonetheless have issues requiring further exploration (Also see "Out Of The Shadow Of REMS: FDA Review Documents Show Emerging Importance Of Post-Marketing Requirements" - Pink Sheet, 1 January, 2011.).

In settings of unmet medical need, the assurance that FDA’s questions will be answered (or at least asked) even after the drug has been released on the market has been critical to the approval of troubled products like Theratechnologies’ Egrifta (tesamorelin), the first product approved for HIV-associated lipodystrophy (Also see "Egrifta Approval: FDA Balanced Modest Efficacy, Off-Label Use Potential With Unmet Medical Need" - Pink Sheet, 1 February, 2011.) or Takeda’s Uloric (febuxostat), the first new gout drug in decades (Also see "Score One For FDAAA: Uloric Approval Was Clinched By Post-Market Powers" - Pink Sheet, 1 July, 2010.).

The fast approval is not an indication that FDA is wholly confident.

Jevtana’s swift review and approval should not be read as FDA having full confidence in the drug. FDA was impressed by cabazitaxel’s robust survival data, but on the safety side of the equation, significant concerns loomed.

And on those safety questions, the PMR provided a way for FDA to get an efficacious drug to patients without other options, while at the same time ensuring that possible ways to address the toxicity would be studied. One such study will look at reducing the dose.

Other PMRs will fill in the clinical safety profile of the drug. PMRs will “evaluate the potential for intravenous infusion of particulate matter into the blood stream” and will “assess the signals of the serious risks of hepatic impairment, QT prolongation and drug-drug interaction,” Ibrahim summarized.

A Path To Reduced Toxicity: Dose Reduction

As cross-disciplinary team leader Johnson noted, the cabazitaxel dose “causes considerable toxicity and may be unnecessarily high.” But there is no information from RCTs on any other cabazitaxel dose and thus no indication whether a lower dose would be effective.

“Because the risk/benefit ratio is favorable and 25 mg/m² is the only dose we have data on, we are stuck with this dose,” Johnson lamented. “Unfortunately, so are elderly men with HRPC.”

Some signals in the data suggested that a lower dose could moderate the toxicity profile without sacrificing significant efficacy, making the dose issue a good candidate for a required post-marketing study. “We do not want to deny patients the potential benefit of this treatment while the study is ongoing,” the PMR development documents state.

“Some Phase I data indicates that a lower dose could have been studied,” according to FDA’s PMR/PMC development templates for cabazitaxel. Clinical pharmacology data showed “evidence of an exposure-response” relationship for serious neutropenia, McKee and Waxman added.

During the review, FDA and Sanofi-Aventis scoured the cabazitaxel safety database to find patients with cancers not of the prostate who had been treated with 20 mg/m², which could provide support to the idea that the lower dose was worth studying. They found 77 patients. The rate of grade 3-4 neutropenia rate was lower in the 20 mg/m² dose patients than in the pivotal HRPC study’s 25 mg/m² dose arm: 57.1% vs. 82.1%. “Of note, 50 of the 77 patients who received 20 mg/m² dosing were breast cancer patients treated on protocol ARD6191,” Waxman pointed out. “Despite the lower rate of grade 3-4 neutropenia, patients on ARD6191 were found to have a higher overall exposure to cabazitaxel.”

Following the suggestion that the lower dose level could provide adequate efficacy, FDA required two post-marketing Phase III trials testing the lower dose; both are expected to complete in 2017.

One of the required Phase III post-marketing trials will take place in the first-line metastatic HRPC setting, comparing docetaxel with the approved 25 mg/m² dose and the lower 20 mg/m² dose of cabazitaxel. The primary endpoint of overall survival will evaluate the incidence of drug-related death as well as efficacy, the PMR development documents state. It will test a lower dose in a different prostate cancer population, as Johnson recommended.

The other Phase III trial will take place in the same second-line population as TROPIC, metastatic HRPC patients previously treated with docetaxel, but will be larger: 1,222 patients compared with the pivotal trial’s 755. The second-line trial will have two dose arms, cabazitaxel 20 mg/m² and 25 mg/m², and will be “powered to preserve 50% of the treatment effect of cabazitaxel 25 mg/m².” Both Phase III trial designs include interim analyses of efficacy based on “safety and overall survival,”

Another Path To Reduced Toxicity: G-CSF

Data examined during the review also indicate that more aggressive use of granulocyte-colony stimulating factors like Amgen’s Neupogen (filgrastim) could provide another path to reducing toxicities related to neutropenia.

“Post-submission analyses suggest that a proportion of patients who experience neutropenia benefited from G-CSF use or dose reduction,” clinical safety reviewer Waxman said. “Neutropenia led to more treatment discontinuations than any other adverse event on the cabazitaxel arm,” he reported, while the comparator arm had no neutropenia-related discontinuations. “There was a clear relationship between neutropenia and grade 5 infection,” he continued. Infection was a leading cause of treatment-related deaths in cabazitaxel patients.

“Due to the occurrence of four infection-related deaths during cycle 1 of cabazitaxel therapy, primary prophylaxis with G-CSF should be considered in patients at high risk for neutropenia complications,” Waxman concluded. None of the five total patients with infection-related deaths were given G-CSF prophylactically, he added.

Jevtana labeling, in the warnings and precautions, states that “primary prophylaxis with G-CSF should be considered in patients with high-risk clinical features,” including being 65 years of age or older. Older patients “are more likely to experience certain adverse reactions, including neutropenia and febrile neutropenia,” the label notes.

The recommendation for primary prophylaxis with G-CSF was not part of the TROPIC protocol. However, “based on the occurrence of fatal infections in patients >65 years of age, primary prophylaxis appears to be appropriate in this high-risk patient population,” Waxman concluded. The large majority of infection-related deaths (80%) occurred in the first treatment cycle.

Sanofi-Aventis did try to bring the study’s criteria for G-CSF up to date with more recent American Society of Clinical Oncology recommendations, but Waxman speculated that the change came too late in the study to make a meaningful difference.

On July 30, 2008, the sponsor issued a “Dear Investigator” letter reflecting the TROPIC independent data monitoring committee’s recommendation to review and follow ASCO guidelines on use of G-CSF. The “absence of infection-related deaths after the IDMC recommendation more likely reflects the timing of the recommendation rather than any changes in clinical practice,” Waxman said.

Johnson injected a note of caution about the use of G-CSF for primary prophylaxis. “The necessity for almost 50% of patients to be supported by G-CSF is not what we would desire for this setting.” he said.

The flood of Phase III data to come could position Jevtana for broader use.

The torrent of information that could come in from the 10 PMRs could help to obviate this and other concerns about Jevtana toxicity. The interim analyses of the Phase III PMR trials, in particular, could potentially lead to a lowering of the dose with a simultaneous lowering of neutropenia and associated complications.

Perhaps, as the PMR data comes in, the robust efficacy that impressed the FDA review team will be matched with a less worrisome risk profile. With sizable Phase III data coming down the pike thanks to the extensive PMRs, the risk side of the benefit/risk calculation could help move Jevtana from a severely toxic last-ditch therapy to a more mainstream chemotherapy – something like Taxotere, the soon-to-be generic taxane that Sanofi-Aventis would love to replace.

By Bridget Silverman

The Lesson Of Jevtana: With A Survival Advantage, All Things Are Possible

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