The Food and Drug Adminstration and Genentech have reported that counterfeit Avastin is being distributed in the United States. The counterfeit medicine does not contain
bevacizumab, Avastin’s active ingredient.

The packaging is different from genuine Avastin marketed here by Genentech. It includes a Roche logo which isn’t on the real drug, along with different codes.

Avastin is not in shortage now, and there are adequate supplies to meet the need.

Patients being treated with Avastin are urged to let their doctors know immediately if they have unusual symptoms.

Genentech says,

If a patient taking Avastin is experiencing any side effects, they should contact their healthcare provider immediately. If the patient is experiencing any side effects that the healthcare provider thinks may be related to Avastin or that are different from those commonly associated with Avastin, the healthcare provider should immediately call FDA’s MedWatch Program (1-800-FDA-1088) or Genentech’s Drug Safety Department at 1-888-835-2555.

Nineteen US medical practices have been identified by the FDA as having bought the counterfeit Avastin and have been told to stop using it immediately.

When Avastin is added to the combination of Xeloda and irinotecan as an initial treatment for advanced colorectal cancer, the treatment is equally effective as Avastin with FOLFIRI.

But side effects are more difficult.

After a randomized clinical trial comparing Avastin with XELIRI (Xeloda, irinotecan) to Avastin with FOLFIRI (5-FU, leucovorin, irinotecan), researchers concluded that excessive side effects made using the XELIRI combination unwise.

Efficacy-wise there were no sigificant differences between the two regimens for:

• median progression-free survival(10.0 for FOLFIRI and 8.9 months for XELIRI)
• overall survival (25.7 and 27.5 months)
• response rates (45.5 and 39.8 percent)

However diarrhea, fever due to low white cell blood counts, and hand-foot syndrome were significantly more common in patients treated with XELIRI. They also had more treatment delays and dose reductions, and discontinued treatment because of side effects more often.

J Souglakos and his colleagues concluded,

The progression-free survival of FOLFIRI-Bevacizumab is not superior to that observed with the CAPIRI-Bev regimen. CAPIRI-Bev has a less favourable toxicity profile, requiring dose reductions, in order to be considered as an option in first-line treatment of patients with metastatic colorectal cancer.

SOURCE: Souglakos et al., British Journal of Cancer, January 12, 2012.

Although FDA Commissioner Margaret Hamburg announced a final decision on November 18 to drop breast cancer from the Avastin label, metastatic colorectal cancer continues to be an approved use.

The Avastin® (bevacizumab) label includes the following approved indication:

Metastatic colorectal cancer, with intravenous 5-fluorouracil–based chemotherapy for first- or second-line treatment.

It is important to know that there is currently no approval or evidence for using Avastin alone or in early stage colon or rectal cancer.

The FDA has changed the package insert for Avastin® (bevacizumab) to include information about newly identified risks for the drug including

• Loss of ovarian function (ovarian failure).
• Bone death in the jaw (osteonecrosis).
• Bleeding and additional blood clots in patients who have already had a clot in their veins while on Avastin.

Changes to the Avastin label were announced on September 30, 2011.

Ovarian Failure

Women with  stage II or III colon cancer who were getting Avastin in combination with chemotherapy during a clinical trial had reduced ovarian function compared to women who were only on chemotherapy.

Women with ovarian failure no longer had menstrual periods or had high levels of a hormone associated with menopause. Follicle stimulating hormones (FSH) blood levels were equal to or above 30.

Among 179 women in a subset of a clinical study, 84 were on FOLFOX chemotherapy alone and 95 received both FOLFOX and Avastin.

• 2% of the chemo only group had ovarian failure during treatment compared to
• 34% of those receiving chemo and Avastin.
• Only 1 in 5 of the women with ovarian failure (22%) started menstruating again and had their FSH levels fall back below 30 during post treatment visits.
• According to FDA, “Long term effects of Avastin exposure on fertility are unknown.”

Avastin Warnings and Precautions now includes:

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin.

Avastin is not labeled to treat stage II or III colon cancer and failed to improve 3 year disease free survival in two clinical trials — NSABP C-08 and AVANT.

Osteonecrosis of the Jaw

Since Avastin has been on the market, there have been reports of lesions in patient’s mouth that don’t heal.  The jawbones literally die leading to pain and infection.  These patients were not on bisphosphonates, drugs previously linked to jaw osteonecrosis.  Bisphosphonates are used  to prevent bone loss and in some cancer treatments.

It is possible that changes in blood vessels in the jaw led to poor blood supply to the bones and their deterioration.

Osteonecrosis of the jaw has been added to the Adverse Events section of the package insert.

Venous Thromboembolic and Bleeding Events for Patients Receiving Anti-Coagulation

In clinical trials, patients who were taking Avastin, experienced a blood clot in a vein (venous thromboembolic event or VTE) and were on anticoagulant medicine to prevent more clots had higher rates of both further VTEs and bleeding than patients on chemotherapy alone.

In a trial of 1,400 patients with metastatic colorectal cancer there was a higher percentage of first VTE, subsequent VTE, and bleeding after VTE in the trial arms that contained Avastin added to chemotherapy.

• 13.5 percent of patients in the Avastin arms had an initial VTE compared to 9.6 percent of those only getting chemotherapy.

There were 116 patients who were put on anticoagulant medicine after their first blood clot — 73 on Avastin and 43 on chemotherapy alone:

• 31.5 percent had another blood clot in a vein while on Avastin compared to 25.6 percent only on chemo.
• 27.4 percent had bleeding compared to 20.9 percent of patients in the trial arms without Avastin.

This information was added to the Clinical Trial Experience section of the package insert.

What This Means for Patients

Avastin is a helpful addition to chemotherapy for people with advanced colorectal cancer. It improves survival time over chemotherapy alone in both first and second line treatment of stage IV disease.

However, patients and their doctors need to be aware of potential serious side effects as they make treatment decisions.

They also need to watch for adverse events associated with Avastin, including blood clots and osteonecrosis of the jaw.

Women who still are able to have children need to know that Avastin may affect their future fertility.

Yesterday’s recommendation by the FDA’s Oncology Drug Advisory Committee (ODAC) that approval of Avastin for breast cancer be withdrawn will not affect colorectal cancer treatment.

Avastin® (bevacizumab) remains on the market in the US and is FDA-approved  for advanced colon and rectal cancer in combination with chemotherapy, both as first-line and second-line therapy.

The public hearing held on June 28 and 29 reviewed the process began  in December, 2010 to withdraw the FDA provisional approval of Avastin for metastatic, HER-2 negative breast cancer.  It did not consider or change other label indications for colorectal, kidney, or small cell lung cancers or glioblastoma.

A final decision on breast cancer will be made by the FDA Commissioner Margaret Hamburg, MD.  Until then the indication for breast cancer will remain on the FDA-approved label.

What’s Behind the Hearing?

In 2008, using a procedure called accelerated approval, the FDA gave provisional approval for Avastin to be used to treat metastatic breast cancer based on a randomized clinical trial that showed it took about 5.5 months longer for tumors to get worse (progression-free survival) for women with who received Avastin in addition to chemotherapy than for those who got chemo alone.

However, the provisional approval required that Genentech, the manufacturer of Avastin, conduct further clinical studies to show that the medicine did more — that it actually improved overall survival time.

However, none of the new studies found that survival time increased with Avastin, and they found shorter progression-free survival times than the first trial.  In addition, there were more serious, sometimes life-threatening, side effects associated with using the drug.

In July 2010, ODAC voted to remove the metastatic breast cancer indication from the label.

In December of 2010, FDA announced that they were beginning the process of removing the indication.  Genentech objected to the decision and asked for an new ODAC hearing, which was held this week.

In an unusual step, FDA allowed testimony from advocates and breast cancer survivors at the beginning of the hearing.  In a highly emotionally-charged atmosphere, some so-called “super-responders” told personal stories of successful treatment with Avastin and chemotherapy.

However, at the end of the day, ODAC voted 6-0 that the required further studies had failed to show a clinical benefit when Avastin was added to chemotherapy for metastatic breast cancer.  They further voted 6-0 that the drug was not shown to be safe in those trials, with a 13% higher rate of toxic side effects.

Further written comments from Genentech, the Center for Drug Evaluation and Research, and the public will be accepted until July 28, 2011.  After that the question will closed until Dr. Hamburg makes her decision.

Should the label indication be withdrawn, Avastin can still be prescribed off-label for metastatic breast cancer, but insurance reimbursements for the expensive drug may be in jeopardy.

At the end of yesterday’s hearing the FDA updated its Avastin information, writing:

Following the closing of the docket, the Center for Drug Evaluation and Research will await Commissioner Hamburg’s final decision on Avastin’s use for metastatic breast cancer. The Commissioner’s decision related to breast cancer will not affect Avastin’s approved indications for use in colon, lung, kidney, and brain cancers. That is, regardless of the final decision on metastatic breast cancer approval, Avastin will remain on the market.

What’s the Situation for Avastin and Colorectal Cancer

The ODAC decision does not affect colorectal cancer.  It remains an FDA labeled indication for both first and second line treatment of metastatic (stage IV and recurrent) colorectal cancer.

Avastin was first approved in 2004 for first-line treatment of colorectal cancer when randomized studies showed that it added a median of about five months of life to irinotecan-based chemotherapy alone.

Two years later, second-line therapy for colorectal was added as an indication on the Avastin label, again based on increased survival time when added to FOLFOX chemotherapy.

What About Side Effects?

The clinical trials leading to colorectal cancer approvals found serious, but uncommon side effects, including formation of holes in the colon (gastrointestinal perforation) generally requiring surgery and sometimes leading to abdominal infections, impaired wound healing, and bleeding from the lungs or internally. More common, but less serious, side effects included high blood pressure, fatigue, blood clots, diarrhea, decreased white counts that lowered immunity to infection, mouth sores, and loss of appetite.

Genentech and the FDA also issued two safety warnings in 2004 and 2006:

• A doubling of the risk of serious arterial thromboembolic events, including strokes, heart attack, transient ischemic attacks (TIAs), and angina.
• A rare risk of reversible posterior leukoencephalopathy syndrome (RPLS), a rare brain-capillary leak syndrome.

In 2007, the FDA updated the Avastin label warning of fistula formations,in some cases with fatal outcome. Fistulas involved holes between lungs and esophagus, areas in the lungs, the vagina, bladder, and biliary tract. Events were reported throughout treatment with bevacizumab, with most events occurring within the first six months.

These adverse events and warnings are included on the Avastin label.

While there weren’t new blockbuster announcements for colorectal cancer this year at the American Society for Clinical Oncology’s (ASCO) Annual Meeting, there was plenty of focus on making what we already have work better and on choosing the patients who will benefit the most from treatments, as well as those who might not be helped at all. (Note, many of these issues will be discussed in detail on our upcoming patient webinar.)

Highlights:

• While adding oxaliplatin to 5-FU improves five year survival slightly for stage II colon cancer, it increases side effects, particularly tingling and numbness in the feet.  An analysis of several NSABP trials found that two or three more stage II patients out of every 100 would be alive five years later if they were given oxaliplatin in addition to 5-FU than if they only got 5-FU.  Risk of cancer returning was similar with an absolute improvement of 3 to 5 percent, depending on risk factors.  Doctors and patients need to think about whether the small benefit is worth the risk of neuropathy that may become permanent.
• Two speakers at the Saturday colorectal cancer oral abstract session addressed adding oxaliplatin to 5-FU as part of pre-surgical chemoradiation treatment for rectal cancer.  NSABP R-04 found that oxaliplatin did not help increase complete response rates, avoid colostomies, or downstage cancers. It did increase diarrhea significantly. On the other hand, early results from a German trial did find an increase in complete responses with oxaliplatin, and they didn’t see worse side effects.
• In the PRIME phase III clinical trial, patients receiving their first treatment for advanced colorectal cancer who had normal or wild-type KRAS genes in their tumor did better when Vectibix® (panitumumab) was added to FOLFOX chemotherapy.  But those patients whose tumor KRAS was mutated actually did worse than patients who only got chemotherapy.
• Side effects, while difficult for patients, may predict better outcomes from treatment.  Patients who got capecitabine as part of pre-surgical chemoradiation and developed hand-foot syndrome had fewer recurrences three years later and better survival at five years.  In another study of breast, lung, and colorectal cancer, patients who got high blood pressure while on Avastin® (bevacizumab) lived longer and it took longer before their cancer got worse.

The Cost of Cancer Care

In an editorial in the ASCO Daily News, published every day for ASCO attendees, Jeffrey M. Peppercorn, MD, MPH, discussed the rising out-of-pocket costs of cancer care for patients and their families.  Although cancer care costs overall are growing fast, the costs that patients bear are growing even faster.  About a third of cancer patients say they have trouble paying their bills, and one out of four have exhausted their savings.

Although the ASCO Task Force on Cost of Cancer Care calls for oncologists to discuss out-of-pocket expenses with patients, few do, and a survey found that about half of oncologists are uncomfortable talking about costs in deciding on treatment.

To learn more, join us for our next patient webinar:

The Big News in Colorectal Cancer from the 2011 ASCO Annual Meeting
June 20, 2011
8 – 9 PM Eastern time
Register to join us.

 

Dr. Edith Mitchell

Last night, Dr. Edith Mitchell of Thomas Jefferson University Kimmel Cancer Center in Philadelphia, PA, updated colorectal cancer patients on the latest research and treatment news in an online webinar.

Dr. Mitchell highlighted the most important news for colon and rectal cancer patients to come from the 2011 Gastrointestinal Cancers Symposium held in San Francisco last month. She answer such questions as…

“Can doctors determine the chances that my cancer may return?”

“Can my doctors determine if I need chemotherapy?”

“Does Avastin or Erbitux benefit my stage III cancer treatment?”

“Are there any promising new treatments on the horizon?”

You can view the webinar online here.

The patient webinars are a program of the Colorectal Cancer Coalition and are offered to patients at no cost. If you would like to support this program through a financial donation, visit our Donate page.

A second randomized clinical trial has confirmed what the first one found — adding Avastin to standard chemotherapy does not reduce recurrences after surgery for stage III colon cancer.

The AVANT trial compared standard FOLFOX chemotherapy to either FOLFOX plus Avastin® (bevacizumab) or XELOX plus Avastin.  Chemo was given for 6 months, and Avastin was added during that time and for another 6 months after chemo ended. Nearly 2,870 stage III patients took part in the study.

Like in the C-08 trial, there was a temporary benefit during the year that patients got Avastin, but it didn’t last.  By the end of three years the percentage of people who were alive and cancer-free was slightly less in the two Avastin arms. 

At three years, disease-free survival was:

• 76% in the FOLFOX only arm
• 73% in the FOLFOX plus Avastin arm
• 75% in the XELOX plus Avastin arm

FOLFOX chemotherapy combines oxaliplatin with leucovorin and continuous infusion 5-FU.  XELOX combines oral Xeloda® (capecitabine) with oxaliplatin.

Although it is too early to be certain, there was a trend toward poorer survival in those patients who got Avastin with their chemotherapy.

It is not clear why this might be. There was no serious addition toxicity due to Avastin,  When cancer came back, the sites of recurrence weren’t different among the three arms, with most initially in the liver, leading researchers to believe that there wasn’t a “rebound” after Avastin was stopped.

AVANT included collecting tissue and studying a number of biomarkers to see if there might be some subgroups where adding Avastin to chemo might be beneficial.  Those results are not yet complete.

In presenting the trial results at the 2011 GI Symposium, Aimery De Gramont, MD, PhD, concluded,

• The addition of bevacizumab to FOLFOX4 or XELOX did not improve disease-free survival in the adjuvant treatment of Stage III colon cancer.
• Immature overall survival data suggest a potential detriment.  Continued follow-up is ongoing.
• Bevacizumab treatment effect was not constant over time.
  • In the first year, there was a transient favorable effect, consistent with what was found in C-08.
  • The treatment effect became unfavorable after one year, which is different than what C-08 discovered.  In C-08 there was no difference between arms after one year.
• Bevacizumab is the third agent, after irinotecan and cetuximab, with proven efficacy in metastatic colorectal cancer and no observed benefit in the adjuvant treatment of colon cancer.

SOURCE: De Gramont et al., AVANT: Results from a randomized, three-arm multinational phase III study to investigate bevacizumab with either XELOX or FOLFOX4 versus FOLFOX4 alone as adjuvant treatment for colon cancer, 2011 GI Cancers Symposium, Abstract 362.

Adding Avastin® (bevacizumab) to chemotherapy for early stage colon cancer didn’t reduce the risk that cancer would return.

In fact, preliminary results of the AVANT trial found that chemotherapy alone worked better in preventing recurrences of stage III and high-risk stage II colon cancer, according to a news release from Roche, sponsors of the international clinical trial.

This is the second trial in which adding Avastin to chemotherapy after surgery for early stage colon cancer failed to show a disease-free survival benefit.  The C-08 trial found that, although Avastin did improve disease-free survival during the first year of treatment, the benefit had disappeared by the third year.

The results of the AVANT trial have been eagerly awaited since conclusions of the similar C-08 trial were announced in 2009.

After their surgery was over, the Phase III AVANT study randomly assigned 3,451 patients with stage III or high-risk stage II colon cancer to one of three arms:

• FOLFOX (continuous infusion 5-FU, leucovorin, and oxaliplatin) chemotherapy alone for 24 weeks, followed by observation for 24 weeks.
• FOLFOX plus Avastin for 24 weeks, followed by 24 weeks of Avastin alone.
• XELOX (oral Xeloda and oxaliplatin) in combination with Avastin for 24 weeks, followed by 24 weeks of Avastin alone.

The primary aim of AVANT was to find out if adding Avastin to standard chemotherapy improved the percentage of people alive without a cancer recurrence three years after treatment began (disease-free survival). Researchers also wanted to measure overall survival at five years and the safety of adding Avastin to chemo.

In announcing the AVANT results, Hal Barron, M.D., Head of Global Product Development and Chief Medical Officer at Roche, said.

While we originally hoped the significant survival benefit of Avastin seen in metastatic disease in colorectal cancer would be translated to the early setting, it is becoming increasingly clear that the effects of Avastin are different in the metastatic and early disease settings for patients with colon cancer.

Avastin is FDA approved to treat colorectal cancer that has spread beyond the colon or rectum (metastatic), where it does improve survival time.

Some colorectal cancer patients whose tumors had gotten worse on all standard treatments benefited from a combination of Afinitor® (everolimus) and Avastin® (bevacizumab) during a small trial reported at the 2010 ASCO Annual meeting in Chicago.

While no tumors got smaller on the treatment, about half of patients in the Phase II trial had their cancer remain stable for six months or more.  Three patients have had stable disease for more than a year.

Seven out of ten patients in the trial had at least one serious side effect.  The most common was hypertension, but there were several bowel abscesses or fistulas and one case of bowel perforation.  There was one death due to treatment infection.

Previous Treatment

• All 50 patients in the trial either could not tolerate or had their cancer progress on standard treatments including fluoropyrimidines (5-FU or Xeloda), oxaliplatin, irinotecan, and, if they had normal KRAS, Erbitux or Vectibix.
• 47 had already been treated with Avastin, 42 had cancer get worse while taking it.
• The median number of previous treatments was 4, at least one patient had 8.

Regimen

28 day treatment cycles included:

• 10 mg Avastin every two weeks by IV
• 10 mg Afinitor orally every day

Side Effects

Serious (grade 3 or 4) side effects included hypertension, increased blood lipids, mouth sores (mucositis), rectal inflammation and sores (proctitis), one bowel perforation, increased blood sugar, fatigue, one serious case of gastrointestinal bleeding, and a bowel perforation.  One patient died as a result of a treatment-related infection.

Most patients (68 percent) had some less serious form of mucositis — inflammation or sores — in the mouth, throat, rectum, or vagina.

Two out of three patients (64 percent) had blood lipids increase moderately — cholesterol or triglycerides.

Results

For the 50 patients who were enrolled in the trial:

• Median progression-free survival time was 2.28 months.
• Median overall survival time was 7.87 months.
• 46 percent of patients had disease control that lasted a median of 6.1 months
• No complete or partial responses
• 8  had a minor response lasting median 4.1 months
• 15 had stable disease lasting median 6.7 months

Afinitor is currently approved by the FDA for the treatment of advanced renal cell cancer.  It works by inhibiting a protein within the cancer cell called mTOR.

Reporting results of the trial at the American Society of Clinical Oncology Meeting in June 2010 in Chicago, Ivy Altomare and her colleagues concluded,

Bevacizumab plus everolimus has promising activity in refractory metastatic colorectal cancer (even in patients who have progressed on a bevacizumab-based regimen) with a disease control rate of 46%, suggesting bevacizumab plus everolimus  may overcome resistance to bevacizumab.

SOURCE: Altomare et al., 2010 ASCO Annual Meeting Abstracts, Abstract # 3535, Phase II trial of bevacizumab (B) plus everolimus (E) for refractory metastatic colorectal cancer (mCRC).

What This Means for Patients

Although Afinitor has been approved by the FDA for patients with renal cell cancer and is on the market, the Phase II trial reported at ASCO this year for colorectal cancer was small.  It is certainly too soon to recommend this treatment for colorectal cancer that has progressed on standard treatments.

Larger trials will be necessary to fully discover if combining Afinitor with Avastin is a viable treatment for refractory colorectal cancer.  Much more needs to be known about its effectiveness and some of the serious side effects.

Tumor tissue and other specimens were taken from patients in the trial and are being studied now.  It may be possible to discover what markers were there in the patients who did well on the combination treatment.

There are several Phase I and II clinical trials that are exploring everolimus in combination with both known drugs and some new ones.  Some trials may identify Afinitor as everolimus or RAD100.    If your cancer has progressed on all the standard treatments — what is called refractory metastatic colorectal cancer – you may want to talk to your doctor about one of these trials.