Camptosar Patient Genotype Testing For Neutropenia Risk Marker Advised

Patient genotype is a predictive factor for neutropenic adverse events in patients receiving Pfizer's oncologic Camptosar , FDA's Clinical Pharmacology Subcommittee of the Pharmaceutical Science Advisory Committee agreed Nov. 3.

The subcommittee voted unanimously that Camptosar (irinotecan) patients with a 7/7 UGT1A1 genotype are at a significantly greater risk for developing neutropenia. [Editor's Note: To ¹ watch a webcast or order a video/DVD of this meeting, visit FDAAdvisoryCommittee.com.]

In a 66-patient prospective study conducted by the University of Chicago, 50% of patients (3 out of 6) with the 7/7 UGT1A1 genotype exhibited grade 4 neutropenia, compared to 12.5% (3 out of 24) of patients with 6/7 genotype and 0% (0 out of 29) of patients with 6/6 genotype.

The 7/7 genotype appears in approximately 10% of the North American population. The 6/6 and 6/7 genotypes constitute 50% and 40% of the population, respectively.

FDA said that excluding patients with the 7/7 genotype would reduce the overall neutropenia risk for Camptosar from 10.1% to 5.7%.

FDA Division of Pharmaceutical Evaluation I Acting Deputy Director Atiqur Rahman, PhD, said that "genotype testing combined with bilirubin levels and other predictive factors...will allow the physicians to select irinotecan therapy more judiciously in the high-risk patients."

The subcommittee voted nine to zero with three abstaining that despite the relatively low positive predictive value of the test, it will be a useful tool for prescribers because of its high negative predictive value.

"Is there enough assurance for a patient and/or health care provider to start a treatment? Or, vice versa, is the negative predictive value of saying that I am 90% certain that with a 6/6 you are not going to develop neutropenia, is that comforting?" Subcommittee Chair Jürgen Venitz, MD/PhD (Virginia Commonwealth School of Pharmacy), asked.

"In my assessment, it is - based on clinical judgment, not based on the statistics," Venitz said.

Committee member Jeffrey Barrett, PhD (Children's Hospital of Philadelphia), agreed: "If you said to me would I vote for a test in which the negative predictive value was greater than 90%, as far as an aid to dosing, I would say yes."

Genotype testing could become a primary tool in helping physicians choose among cancer therapies. Camptosar is approved in combination with 5-fluorouracil and leucovorin for first-line treatment of colorectal cancer.

"Alternate therapy, either in the first-line or in the second-line setting, may be a choice for the 7/7 genotype patients," FDA's Rahman suggested.

Mark Ratain, MD (University of Chicago), suggested that the evidence for genotype-related toxicity may push prescribers to opt for Camptosar over Sanofi-Aventis' Eloxatin (oxaliplatin) in first-line therapy in non-7/7 patients.

"If you have a discussion with a patient and sit down and talk with them about irinotecan versus oxaliplatin as a first-line therapy, when you talk about irinotecan you have to talk about neutropenia, diarrhea - which can be severe, life-threatening, even fatal - and as you talk about oxaliplatin you have to talk about neurotoxicity that can be persistent," Ratain said.

"If one could reassure the clinician that their patient is at relatively low risk of these toxicities of irinotecan, a clinician would be more interested in prescribing irinotecan first-line."

"I think that this actually is very helpful to the clinician and potentially very helpful to the sponsor who is marketing the drug," Ratain added.

FDA Office of Clinical Pharmacology and Biopharmaceutics Director Lawrence Lesko, PhD, said that Pfizer and FDA "agree that information on UGT polymorphism and the risk of toxicity in the label is of great importance."

However, Pfizer Clinical Pharmacogenomics Director & Site Head Luis Parodi, PhD, expressed concern that the low positive predictive value of testing for 7/7 genotype as propensity for neutropenia (approximately 50%) could withhold appropriate treatment, if decreased dosing is recommended for all 7/7 patients.

"Given that we cannot accurately predict the development of neutropenia, we have to be cautious when balancing the risk of neutropenia with the benefit of treatment," Parodi said.

"Neutropenia is generally manageable and dosing reductions for UGT1A1 patients will result in unnecessary reductions for 50% of the patients and the outcome" of reducing the dose on efficacy is unknown, Parodi said.

Oncology Drug Products Division Director Richard Pazdur, MD, however, suggested that Camptosar toxicity might be avoided through dose reduction, without sacrificing efficacy.

"If we're talking about a 75% dose reduction, that could be quite problematic," Pazdur said. "If all we are talking about is a 25% dose reduction, I would feel a little more comfortable."

"This drug was developed at time when oncology had the mantra of more is better, more is better, more is better, and we kind of were getting towards what is the absolute highest dose that we could deliver," Pazdur said.

"Having worked with this drug before I came to the agency and having a long history with it, I think it would be fair to say that I think we do not have a really good handle on what is the dose in its relationship to the eventual outcome," Pazdur added.

Pfizer said that it is conducting a dosing study in patients with the 7/7 genotype.

Venitz suggested that the concern about compromising efficacy by lowering the dose may be unfounded. You can "turn that argument around," he said.

"If you improve tolerability and compliance on a long-term treatment, don't delay treatment. As a result of a lower dose you might actually improve efficacy, not just compromise it," he said.

While the 7/7 genotype can be linked to neutropenia, the committee voted 11-0 (with one abstention) that data was insufficient to support a relationship between the genotype and acute and delayed diarrhea.

Subcommittee members suggested that such a relationship might be found upon further examination.

The data does not conclusively support a relationship "at the moment, but the data looks like there is something there." subcommittee ad-hoc member Howard McCleod, Washington University, said.

Two of five studies examining the relationship between the 7/7 genotype and irinotecan dose-related toxicity found significantly increased risk for diarrhea-related adverse events.

Pazdur maintained that diarrhea, rather than neutropenia, is the most prevalent and dangerous Camptosar adverse event.

"If you ask clinical oncologists who actually use this drug, if you ask them what are the top ten toxicities with irinotecan, one to nine would be diarrhea," Pazdur said. "So is it really fair just to look at neutropenia here?" he asked.

"Are we really missing something by not really looking at what is the most clinically relevant toxicity and that is either diarrhea alone which leads to hospitalization or, more importantly, diarrhea in the presence of severe neutropenia, which generally is very problematic and usually is associated with the deaths that we have seen on this drug?"

Committee members also requested further information on the relationship between the 7/7 genotype and efficacy.

McCleod said that "we really don't know about the effect of UGT1A1 on survival," though "there is some data that UGT1A1 may have an influence on response, although the numbers were small and not definitive."

Pazdur pointed out that "the relationship between response rate as a surrogate for survival in this situation" is unknown.

"Perhaps disease stabilization or some influence on time to progression is far more import than simply tumor reduction size," he said.

The Clinical Pharmacology Subcommittee also discussed FDA's concept paper on drug-drug interactions. On Nov. 4, the subcommittee heard about FDA's plan to accelerate the development of biomarkers as part of the agency's "Critical Path Initiative" (see ² (Also see "Biomarker Working Group To Explore Development Of Guidance" - Pink Sheet, 15 Nov, 2004.) ).