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Tuesday, July 22, 2014

 

The U.S. Food and Drug Administration has granted priority review designation for the use of Avastin (bevacizumab) plus chemotherapy for the treatment of patients with recurrent, platinum-resistant ovarian cancer. Avastin is a biologic antibody that binds to vascular endothelial growth factor (VEGF) to prevent tumor metastasis by inhibiting tumor blood supply.

 

Approximately 25 percent of women with ovarian cancer will have platinum resistant disease at the time of a first recurrence, the manufacturer, Genentech, noted in a press release.

 

The news comes one week after the drug was granted priority review for persistent, recurrent, or metastatic cervical cancers. And, Avastin also has approved indications for the treatment of patients with metastatic colorectal cancer (OT 2/25/13 issue); and for the treatment of patients with first-line or previously untreated metastatic colorectal cancer (OT 3/25/04 issue).

 

The FDA’s priority review designation shortens the time to complete a drug’s review and aims to deliver a decision on marketing approval designation for drugs that may offer major advances in treatment or provide a treatment where no adequate therapy exists within six months under the Prescription Drug User Fee Act (PDUFA). The FDA action date for Avastin for this indication is November 19, 2014.

 

The drug’s application is based on data from the multicenter, randomized Phase III AURELIA trial, which included 361 women with platinum-resistant, recurrent epithelial ovarian, primary peritoneal or fallopian tube cancer who had received no more than two anticancer regimens prior to enrollment in the trial. The women were randomized to receive one of six treatment regimens for the trial (paclitaxel, topotecan, or liposomal doxorubicin—each with or without Avastin). The data has shown:

·         Avastin plus chemotherapy prolonged progression-free survival (PFS) by 52 percent compared with chemotherapy alone (PFS was 6.7 months for women taking Avastin vs. 3.4 months for those receiving just chemotherapy);

·         The women receiving Avastin plus chemotherapy had a significantly higher rate of tumor shrinkage compared with chemotherapy alone when evaluated by the RECIST criteria; and

·         Grade 3 to 5 adverse events occurred at a higher incidence in women receiving Avastin plus chemotherapy compared with women receiving chemotherapy alone. Those adverse events were hypertension (seen in 7% of the women receiving Avastin vs. 1% of those receiving just chemotherapy), proteinuria (2% vs. 1%), and gastrointestinal perforations (2% vs. 0%).


Monday, July 21, 2014

 

The U.S. Food and Drug Administration has granted breakthrough therapy designation to CRS-207 and GVAX Pancreas immunotherapies to be used as a combination treatment for pancreatic cancer. CRS-207 expresses the tumor-associated antigen mesothelin, which is over-expressed in mesothelioma and pancreatic, non-small cell lung, ovarian, and gastric cancers. And GVAX Pancreas, derived from human cancer cell lines, is genetically modified to secrete the immune-stimulatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), and also expresses mesothelin.

 

The breakthrough therapy designation, enacted as part of the FDA’s 2012 Safety and Innovation Act, was created to expedite the development and review time of a potential new drug for serious or life-threatening disease where early clinical evidence suggests the drug may demonstrate substantial improvement compared with existing therapies. A news release from the drug’s manufacturer, Aduro Biotech, notes that there are currently no approved therapies for metastatic pancreatic cancer after first-line treatment.

 

The designation for CRS-207 and GVAX Pancreas is based on findings from a randomized, controlled, multi-center Phase II trial of 93 patients with metastatic pancreatic cancer who had not responded to or had decided not to have prior therapy. Median overall survival for patients receiving the immunotherapy combination was 6.1 months compared with 3.9 months for patients receiving GVAX monotherapy.

 

A Phase IIb clinical trial for the combination is currently ongoing, and enrollment is expected to be completed by the end of 2015, according to Aduro.


Saturday, July 19, 2014

This is an updated version of the article OT reporter Ed Susman filed early Friday morning

 

MELBOURNE, Australia – In a somber press conference, International AIDS Society leaders confirmed the deaths of at least six delegates to the 20th International AIDS Conference here who were aboard the doomed Malaysia Airlines Flight MH17 that was shot down over the Ukraine on Thursday.

 

“The extent of our loss is hard to comprehend or express,” IAS President Francoise Barre-Sinoussi said at the press conference, attended by dozens of local and international journalists on the steps of the Melbourne Convention Center. “We grieve alongside all of those throughout the world who have lost friends and family in this senseless tragedy.”

 

Although news reports had indicated that perhaps dozens of people who were heading to the conference were aboard MH17, Dr. Barre-Sinoussi said the IAS was confident from talking with friends and family that the number would not go much above the six people they believe were on the plane.

 

Those believed to have died when a surface-to-air missile destroyed the plane flying at 33,000 feet included Joep Lange, MD, of the Academic Medical Center, the Netherlands, and a former president of the IAS.

 

Chris Beyrer, MD, President-elect of the IAS, read the list of the other delegates to the meeting believed to have been on MH17:

·        Jacqueline van Tongeren, the partner of Dr. Lange, from the Amsterdam Institute for Global Health and Development.

·        Glenn Thomas of the World Health Organization.

·        Pim de Kuijer of Stop AIDS Now.

·        Lucie van Mens, Director of AIDS Action Europe.

·        Maria Adriana de Schutter, also from AIDS Action Europe.

 

There were 298 people aboard MH17 when it was blown to pieces over an area of Eastern Ukraine where conflict ensues between Ukraine government forces and pro-Russian insurgents.

 

Mark Gettleson, a London-based AIDS campaigner, tweeted that AIDS activists were also heading from Europe to Melbourne. ‘‘Several on #MH17 flight were @STOPAIDS activists en route to #AIDS2014 conference in Melbourne, fighting to save lives. Tragic,’’ he wrote.

 

In an official statement, the IAS said: “The International AIDS Society today expresses its sincere sadness at receiving news that a number of colleagues and friends en route to attend the 20th International AIDS Conference taking place in Melbourne, Australia, were on board the Malaysian Airlines MH17 flight that has crashed over Ukraine earlier today.

 

“At this incredibly sad and sensitive time the IAS stands with our international family and sends condolences to the loved ones of those who have been lost to this tragedy.”

 

Friends and colleagues of Dr. Lange went to social media to eulogize their lost colleague: ‘‘He was a kind man and a true humanitarian,’’ tweeted Seema Yasmin, MD, Professor of Public Health at the University of Texas at Dallas. ‘‘How do we measure how much a person has done for humanity? People like Joep change the course of epidemics.’’

 

She said that Dr. Lange personally helped her make her decision to attend medical school. Dr. Lange was the father of five girls. Yasmin tweeted: “I asked him why he worked so much. He said, "Do you know how much it costs to buy shoes for five girls?"

 

UN AIDS executive director Michael Sidibé tweeted: “My thoughts & prayers to families of those tragically lost on flight #MH17. Many passengers were en route to #AIDS2014 here in #Melbourne.”

 

The tragedy recalls another airline catastrophe which took the life of prominent AIDS researcher Jonathan Mann. He was aboard Swissair 111 that plunged into the ocean off the coast near Peggys Cove, Nova Scotia, on Sept. 2, 1998 – scarcely six weeks after another International AIDS Society meeting in Geneva, Switzerland.

 

Many of the participants in that meeting had flown to Switzerland on the same flight from New York to Geneva. Mann was an administrator for WHO and was returning to his office on the doomed aircraft.

 

In addition to Mann and his wife, Mary-Lou Clements-Mann, also an AIDS researcher, 227 other people lost their lives on Swissair 111. An uncontrolled on-board fire was determined to be the cause of the loss of the MD-11 aircraft.


Friday, July 18, 2014

 

 

BY ED SUSMAN

 

MELBOURNE, Australia – Attendees at the 20th International AIDS Conference here were stunned and bewildered today when they learned that perhaps dozens of their colleagues died when Malaysia Airlines Flight 17 was shot down over the Ukraine on Thursday.

 

              Joep Lange, MD

                    1954-2014

 

Among the dead was Joep Lange, MD, Professor of Medicine at the Academic Medical Center, Amsterdam, an AIDS research pioneer and a former president of the International AIDS Society, the sponsor of the meeting.

Also presumed dead in the crash that killed 298 people was Glenn Raymond Thomas, a Geneva-based spokesman for World Health Organization, the agency confirmed.

           

In West Palm Beach, Florida, the Palm Beach County Human Rights Council wrote on its Facebook page: “It is now being reported that as many as 108 passengers on Malaysia Flight #17 were heading to the International AIDS Conference in Melbourne. This could be a brutal night for the Global HIV/AIDS community.”

 

Australian news reports said about 100 passengers on the plane were heading to the conference. The passengers included several AIDS activists. Mark Gettleson, a London-based AIDS campaigner, tweeted that AIDS activists were also heading from Europe to Melbourne. ‘‘Several on #MH17 flight were @STOPAIDS activists en route to #AIDS2014 conference in Melbourne, fighting to save lives. Tragic,’’ he wrote.

 

In an official statement, the IAS said: “The International AIDS Society today expresses its sincere sadness at receiving news that a number of colleagues and friends en route to attend the 20th International AIDS Conference taking place in Melbourne, Australia, were on board the Malaysian Airlines MH17 flight that has crashed over Ukraine earlier today. At this incredibly sad and sensitive time the IAS stands with our international family and sends condolences to the loved ones of those who have been lost to this tragedy.”

 

The Boeing 777 was at 33,000 feet, flying from Amsterdam to Kuala Lumpur, when it was shot down. U.S. authorities, quoted by news media, said the plane was knocked out of the sky by a surface-to-air missile.

Friends and colleagues of Dr. Lange went to social media to eulogize their lost colleague:

 

‘‘He was a kind man and a true humanitarian,’’ tweeted Seema Yasmin, MD, Professor of Public Health at the University of Texas at Dallas. ‘‘How do we measure how much a person has done for humanity? People like Joep change the course of epidemics.’’

 

She said that he had personally helped her make her decision to attend medical school. Dr. Lange was the father of 5 girls. Yasmin tweeted: “I asked him why he worked so much. He said ‘Do you know how much it costs to buy shoes for 5 girls?’"

 

UN AIDS Executive Director Michael Sidibé tweeted: “My thoughts & prayers to families of those tragically lost on flight #MH17. Many passengers were en route to #AIDS2014 here in #Melbourne.”

 

The tragedy recalls another airline catastrophe which took the life of prominent AIDS researcher Jonathan Mann. He was aboard Swissair 111 that plunged into Peggys Cove, off the coast of Nova Scotia on Sept. 2, 1998 --scarcely six weeks after another International AIDS Society meeting in Geneva, Switzerland.

 

Many of the participants in that meeting had flown to Switzerland on the same flight from New York to Geneva. Mann was an administrator for WHO and was returning to his office on the doomed aircraft. In addition to Mann and his wife, Mary-Lou Clements-Mann, also an AIDS researcher, 227 other people lost their lives on Swissair 111. An uncontrolled on-board fire was determined to be the cause of the loss of the MD-11 aircraft.


Wednesday, July 16, 2014

 

BY ROBERT H. CARLSON

 

BARCELONA, Spain -- An update for the CALGB/SWOG 80405 trial presented here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer showed that patients in the chemotherapy-cetuximab arm had a significantly higher response rate than those in the chemotherapy-bevacizumab arm (Abstract O-0019).

 

Alan P. Venook, MD, Professor of Medical Oncology and Translational Research at the  University of California, San Francisco, reported objective response rates but with the caveat that these were based on two-thirds of the entire cohort, from investigator assessment of 369 patients receiving chemotherapy-bevacizumab and 364 patients taking chemotherapy-cetuximab. The data were documented but not yet audited, he said.

 

The overall response rate was 57 percent for chemotherapy-bevacizumab versus 66 percent for chemotherapy-cetuximab.

 

There were a “surprisingly high” number of complete responses, Venook said -- three percent for chemotherapy-bevacizumab and 7.4 percent for chemotherapy-cetuximab.

 

Partial response rates were 54 percent for chemotherapy-bevacizumab and 58 percent for chemotherapy-cetuximab; stable disease rates were 37 and 26 percent, respectively; and a small number of patients with refractory disease, with progressive disease rates of six and eight percent, respectively.

 

When Venook reported the initial results of the study at the plenary session at the American Society of Clinical Oncology this spring, the results showed no meaningful superiority of one regimen over the other (OT 7/10/14 issue). The two antibodies added to chemotherapy consisting of either FOLFOX or FOLFIRI are both acceptable and similarly effective,” he concluded at that time.

 

Eagerly Awaiting Expanded RAS Analysis

Confirmed response rates, depth of response, and expanded RAS analysis for the study are pending; Venook said these will be reported in September at the ESMO Congress in Madrid. Those data will hopefully explain a burning question: Why two similar trials, 80405 and FIRE-3, the Phase III trial presented at last year’s ESMO GI meeting (Ann Oncol 2013;24[suppl 4]: iv22-iv23 – had different overall survival results with the same treatments.

 

As in the 80405 study, FIRE-3 compared first-line chemotherapy-cetuximab with chemotherapy-bevacizumab in metastatic colorectal cancer. But unlike 80405, FIRE-3 showed a higher survival rate for chemotherapy-cetuximab than chemotherapy-bevacizumab.

 

Pending the final analyses, Venook stressed that similar studies “may have different results without being erroneous.”

 

Congress Vice-Chair Josep Tabernero, MD, PhD, Head of Medical Oncology and Director of Clinical Research at Vall d'Hebron University Hospital and the Institute of Oncology in Barcelona, said the full analysis of 80405 is eagerly awaited: We as physicians are really waiting for this data, because it was difficult to explain why the patients who received FOLFIRI-cetuximab [in FIRE-3] had an advantage in overall survival without any meaningful advantage in response rate and progression-free survival,” he said in an interview.

 

What we have seen now is that patients in the FOLFIRI-cetuximab arm had a more pronounced shrinkage of the tumor, so the objective response rate is higher, the depth of response is higher, and early tumor shrinkage is higher with FOLFIRI-cetuximab than with FOLFIRI-bevacizumab.”

 

These factors, he said, suggest a good explanation of how this translates into an advantage in overall survival.

 

Biologicals May Not Require Cytotoxics

In a separate presentation here, Venook hypothesized that the best cytotoxic “backbone” on which to add a biological therapy for metastatic colorectal cancer may be no chemotherapy at all.

 

The research on chemotherapy backbones and biologicals in these regimens is hindered because we do not always understand the mechanisms of action, but it is possible that less chemotherapy may be better,” he said.

 

A chemotherapy backbone is not necessary in treating melanoma, and two biological agents work there very well together, he said.

 

In colorectal cancer, the randomized Phase II BOND-2 study of cetuximab-bevacizumab-irinotecan compared with cetuximab-bevacizumab alone in irinotecan-refractory colorectal cancer showed that the activity of bevacizumab-cetuximab and cetuximab-irinotecan appeared better as compared with historical controls of cetuximab or cetuximab-irinotecan in patients who had not previously received bevacizumab (Saltz L et al: JCO  2007;25:4557-4561).

 

Not all evidence points to the elimination of chemotherapy from regimens for metastatic colorectal cancer, however. Venook said the addition of panitumumab to bevacizumab and oxaliplatin- or irinotecan-based chemotherapy resulted in increased toxicity and decreased progression-free survival in the Phase III PACE study of metastatic colorectal cancer (Hecht J et al: JCO 2009;27:672-680).

 

Without exception, patients [in that trial] who received double biologicals and chemotherapy did worse than patients who had a single biological,” Venook said.

 

But he added that KRAS status was just evolving at that time, and this was an example of the harm done when mutated KRAS patients get cetuximab or panitumomab.

 

Furthermore, in the CAIRO-2 trial, the addition of cetuximab to capecitabine-oxaliplatin-bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life. Patients who got double biologicals did worse than those who did not,” he said.

 

Active Maintenance Beats No Maintenance

In another presentation here in the session on metastatic colorectal cancer, results from the Phase III AIO KRK 0207 trial were reported, showing that maintenance therapy with bevacizumab alone is non-inferior to a fluoroupyrimidine-bevacizumab regimen, and that no active maintenance is inferior to either active regimen (Abstract O-0027).

 

Maintenance therapy for patients with metastatic colorectal cancer using fluoroupyrimidine plus bevacizumab after induction is a widely accepted standard, noted Dirk Arnold, MD, Medical Director of the Hubertus Wald Tumor Center, University Cancer Center Hamburg, Germany, who reported the trial that randomly assigned 473 patients to maintenance with fluoroupyrimidine-bevacizumab versus bevacizumab alone versus no maintenance, after a six-month induction with a fluoroupyrimidine-oxaliplatin-bevacizumab regimen.

 

Progression-free survival after induction is better with active treatment -- either fluoroupyrimidine-bevacizumab or bevacizumab -- but preliminary overall survival data show no significant difference between the two active treatments and no treatment,” he said.

 

Time to first progression from the start of induction was 11.7 months for the combination regimen, 10.2 months for bevacizumab alone, and 9.0 months for no maintenance. Overall survival was a median of 23.8 months for  fluoroupyrimidine-bevacizumab, 26.2 months for bevacizumab alone, and 23.1 months for no maintenance.

 

But immediate re-induction with a fluoroupyrimidine-oxaliplatin-bevacizumab regimen after first progression did not work and cannot be recommended, he said. De-escalation maintenance is confirmed as a standard for most patients, but the lack of a clear overall survival benefit allows individual approaches.”

 

In the future a “moderately active” regimen -- either de-escalation or a biologically defined “switch maintenance” strategies -- should be evaluated, and that in fact is the next AIO Phase III project, he said.