February 15, 2006. Today’s New York Times runs a business section story by Alex Berenson about Genentech’s Avastin, A Cancer Drug Shows Promise, at a Price That Many Can’t Pay. Buried on the second page Berenson mentions this week’s news about deaths in a clinical trial of Avastin plus chemotherapy.

The patients were taking Avastin (bevacizumab) along with XELOX, an acronym for a therapy combining Roche’s pill Xeloda (capecitabine) plus IV infusion of the platinum chemotherapy drug Oxaliplatin. The trial is divided into three arms depending on what the patients take along with Avastin. Since the trial began in December 2004, Roche said in a press release, seven patients in the XELOX arm died, four of them suddenly. They were younger patients.

The Times already carried the AP’s report of the deaths in the business section when that news came across the wire yesterday, Deaths Halt Enrollments in a Drug Trial. The deaths were reported also by Paul Elias in the Miami Herald, Drug companies stop recruiting for cancer drug test after deaths. Bloomberg and the Herald Trib mentioned it and RedOrbit puts its own obliviously grotesque spin on things (Trial Delay Won’t Choke Avastin’s Growth).

So far Berenson is the one reporter I’ve seen leveraging the timing of the announcement of the deaths to slam the price of Avastin. Putting this story in the business pages instead of in the health section makes it a warning to investors not cancer patients. Is this smart? And will it help or hurt cancer patients?

I suppose the first impact is on the trial itself and any patients who were on the brink of entering it. Roche announced two days ago, February 13, that the AVANT trial is suspending recruitment of new patients for the next 60 days. This action was taken to review safety concerns.

The trial had been attracting patients at a phenomenal rate, 200 a month. Roche says patients who are already enrolled will be allowed to stay on treatment according to the study protocol throughout the 60-day review period.

Staying on treatment can be incredibly important to patients with advanced cancer. The last thing a patient needs is to be ripped off his treatment for no reason relevant to him or herself. Still and all, to select this somber moment to zero in on price indicates how gross and, in the long run, socially unbearable the price is.

“Doctors are excited about the prospect of Avastin,” Berenson writes, “a drug already widely used for colon cancer, as a crucial new treatment for breast and lung cancer, too. But doctors are cringing at the price the maker, Genentech, plans to charge for it: about $100,000 a year.”

That may be an overestimate but Genentech has hoped that Avastin might become the second-best selling drug in the world next to Lipitor. In 2005 some analysts were ecstatic at the prospect of a Genentech Avastin monopoly – “This drug is going to work in every single solid tumor,” said Sven Borho, a partner at Orbimed Advisors in New York. “What’s going to hold this drug back?”

Avastin is a monoclonal antibody with potent effects on the vascular system. It blocks the protein VEGF (Vascular Endothelial Growth Factor). VEGF stimulates the growth and survival of blood vessel cells that help cancer cells and tumors grow and spread to new locations in the body (metastasis). This growth of a network of blood vessels that supply nutrients and oxygen to cancerous tissues is called angiogenesis. Avastin is a VEGF targeting angiogenesis inhibitor.

This makes it an exciting novel drug but it is not without side effects; and drugs it may be taken with have side effects also.

XELOX is a pill plus chemotherapy. Roche’s pill, Xeloda, is a convenient replacement for the old IV hook-up chemotherapy 5-fluorouracil (5-FU)/oral leucovorin. FDA approved it only quite recently, 1998. The thousands of patients attracted by the “wonder” drug Avastin into joining this international trial are battling colon cancer. The protocol is not a cake walk. Xeloda and oxaliplatin have a similar range of side effects.

In most trials today measures are taken to prevent and alleviate side effects and not all patients by any means experience them; but side effects of these two drugs (without Avastin in the pictuire) may include: diarrhea, nausea, vomiting, mouth sores, stomach pain, decreased appetite, dehydration, hand-and-foot numbness, rash, dry or itchy skin, tiredness, dizziness, headache, fever.

Additionally, Xeloda interacts with blood thinners like warfarin (Coumadin). “After Xeloda became available, there have been reports to the FDA of changes in blood clotting and/or bleeding in people taking Xeloda together with certain anticoagulants (blood thinners).” (FDA, Patient Information Sheet).

Three patients died in the non-Avastin arm, four in the Avastin arm — perhaps all those deaths might have been prevented by monitoring the effects of Xeloda on coagulation.

No one is saying much about that though, we’re all too jumped up about the price, with estimates like Berenson’s as high as $100,000 year:

That price, about double the current level as a colon cancer treatment, would raise Avastin to an annual cost typically found only for medicines used to treat rare diseases that affect small numbers of patients. But Avastin, already a billion-dollar drug, has a potential patient pool of hundreds of thousands of people — which is why analysts predict its United States sales could grow nearly sevenfold to $7 billion by 2009. Doctors, though, warn that some cancer patients are already being priced out of the Avastin market. Even some patients with insurance are thinking hard before agreeing to treatment, doctors say, because out-of-pocket co-payments for the drug could easily run $10,000 to $20,000 a year.

Studies have shown that Avastin can prolong the lives of patients with late-stage breast and lung cancer by several months when the drug is combined with existing therapies. Berenson says Genentech “expects to seek federal approval later this year to sell it specifically for those diseases. But even now, doctors, who are free to prescribe the drug as they see fit, are using Avastin for some breast and lung cancer cases — and finding its cost beyond the means of some patients.” How does the oncologist choose who is to receive it?

“Avastin is a superb drug, but its cost is already discouraging patients and doctors from using it,” said one oncologst Bereson interviewed, Dr. David Johnson, head of the cancer unit at Vanderbilt University and a former president of the American Society of Clinical Oncology. “I wish it were one-tenth the cost, and if it were I would be giving it to almost everybody.”

The price of other new cancer drugs, Berenson predicts, may shoot up to match Avastin’s. And patients may pay too much for the drug through Genentech’s failure to test whether lower doses are sufficient:

The higher cost of using Avastin in breast and lung cancer, compared with colon cancer, is a result of cancer drugs’ being priced on the basis of weight. In colon cancer, Genentech tested Avastin at a dose of 5 milligrams of the drug per kilogram . . . of the patient’s body weight. But in lung and breast cancer, the company tested the drug at a dose of 10 milligrams per kilogram of body weight.

Actual cost of producing Avastin is a fraction of what Genentech charges for it. Some analysts and doctors had expected the company to lower Avastin’s price per milligram for use in lung and breast cancer: Dr. Leonard Saltz, an oncologist at Memorial Sloan-Kettering Cancer Center in New York, “noted that Genentech had not tested Avastin at the dose level for colon cancer in large-scale trials of lung and breast cancer. As a result, no one really knows whether the lower dose might turn out to be equally effective in lung and breast cancer, he said. Besides costing less, he said, a lower dose might have fewer side effects. “There are no meaningful data to allow us to address that question,” he said.

It gets worse, almost a conspiracy theory — Dr. Desmond-Hellmann told Berenson that Genentech was assuming that some cancer doctors might, in fact, use Avastin at the lower dosage to treat breast and lung cancer. That is a reason the company does not want to lower Avastin’s per-milligram price, she said, because doing so would cut too deeply into revenues if doctors do not prescribe the higher doses that were used in the breast and lung cancer trials. “We don’t actually know whether physicians will actually use Avastin as was used in the clinical trials,” she said.

But Dr. Saltz and other doctors said that they would almost certainly stick to the higher Avastin dose that was tested in the clinical trials, for fear that a lower dose might not be as effective.

Clinical trials are supposed to establish the most effective dose with tolerable side effects. From Berenson’s account, it sounds like Genetech is so profit-driven that it may be using clinical trials to establish not the safest and most effective but the most profitable dose. The week’s reckoning of deaths is a signal that everyone needs to sober up.

UPDATE: April 18, 2009:

The trial in which seven deaths occurred was formally suspended on Feb 14, 2006 and was allowed to start up again in May, 2006.

Roche said the data safety monitoring board had now concluded that the current safety profile and the death rates from all causes in AVANT were consistent with those seen in other adjuvant colon cancer trials and, therefore, no concerns were raised about continuing recruitment in AVANT.

However, trial procedures were changed to include additional cardiac testing before patients begin treatment and cardiac monitoring during treatment.

Avastin has side effects:
Avastin side effects, manufacturer’s patient brochure.

Xeloda interacts with blood thinners like warfarin (coumadin). In a press release Roche said changes in blood clotting and/or bleeding and death have been reported in other patients taking Xeloda.

Clinically significant increases in the time it takes blood clots to form –prothrombin time (PT) and INR — have been observed within days to months after starting Xeloda, and infrequently within one month of stopping Xeloda.

For patients receiving Avastin and Xeloda at the same time, frequent monitoring of INR or PT is recommended. Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of trouble from blood clotting (coagulopathy).

LINKS

XELODA (capecetabine) FDA Patient Information Sheet

Recruitment Planned To Resume In AVANT International Phase III Trial In Adjuvant Colon Cancer 5/23/2006 Journal of Clinical Oncology, Vol 22, No 11 (June 1), 2004: pp. 2084-2091

Expert Interview – Medscape Hematology-Oncology. 2006;9(2) Posted 10/25/2006
Colorectal Cancer — Moving Biologics Into the Adjuvant Setting: An Expert Interview With Dr. John Marshall