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Saturday, July 26, 2014



BARCELONA, Spain – In patients from Western countries, second-line treatment for advanced gastric and gastro-esophageal cancer with the combination of paclitaxel and the VEGF antagonist ramucirumab is safe and efficacious, significantly increasing overall and progression-free survival and response compared with use of paclitaxel alone.


The combination reduced the risk of death by 27 percent and increased survival from 5.9 to 8.6 months compared with paclitaxel alone, according to a subanalysis of 398 patients from Western countries in the randomized placebo-controlled RAINBOW trial who had disease progression on or after use of platinum and fluoropurimidine-containing chemotherapy.


The subanalysis data were presented here at the European Society for Medical Oncology World Congress on Gastrointestinal Cancer (the full analysis of all of RAINBOW's 665 patients was presented earlier this year at the Gastrointestinal Cancers Symposium (Wilke H et al. Abstract LBA7).


The subanalysis was awaited because some trials have shown significantly different outcomes between patients from Asian and Western countries. In an example cited by several speakers here, the AVAGAST study (Ohtsu et al: JCO 2011;29:3968-3976) of bevacizumab plus capecitabine-cisplatin as first-line treatment of patients with gastric cancer, the addition of bevacizumab provided no overall survival benefit for the Asian study population or the study population as a whole, but did improve survival rates in non-Asian patients with diffuse or distal tumors. (Van Cutsem et al: JCO 2012;30:2119-2127).


In this RAINBOW subanalysis reported at the ESMO meeting, the efficacy and safety of ramucirumab, a vascular endothelial growth factor receptor-2 antagonist, were consistent with the overall study population results, said Eric Van Cutsem, MD, PhD, Professor of Internal Medicine at the University of Leuven and Head of the Digestive Oncology Unit at University Hospital Gasthuisberg in Belgium, first author of this study and second author of the paper presented at the GI Cancers Symposium.


“Ramucirumab plus paclitaxel should be considered as a new standard in second-line treatment for advanced gastric cancer.”


Regional Differences at Baseline and in Outcome

He acknowledged that the goal of RAINBOW was not to formally compare Western versus Asian patients, but the subanalysis did show some small differences in patient outcomes between the entire RAINBOW cohort and patients in Region 1, comprising Europe (including Israel), Australia, and the United States.


Overall survival for all RAINBOW patients was a median of 9.6 months for the drug combination versus 7.4 months for paclitaxel alone, compared with 8.6 months versus 5.9 months, respectively, for the Western countries of Region 1.


And the objective response rates for all RAINBOW patients was 27.9 percent for the drug combination versus 16.1 percent for paclitaxel alone, compared with 26.8 percent versus 13.0 percent, respectively, for Region 1.


Van Cutsem said these differences were possibly due to differences in baseline characteristics. For example, more patients in the overall trial received doublet rather than triplet chemotherapy as first-line therapy -- 75 vs. 24.5 percent, while in Region 1 the mix was 62.1 vs. 37.2 percent.


Patients globally had shorter times to disease progression, 66.8 percent during first-line therapy versus 58.0 percent for Region 1; and more patients had gastric versus gastro-esophageal junction cancer globally -- 79.4 and 20.6 percent, while in Region 1 the mix was 69.3 and 30.7 percent, respectively.


Gastric cancer of all types is more common in Asian countries but the outcomes are typically better -- thought to be due to more extensive screening.


In April the U.S. Food and Drug Administration approved ramucirumab as a single agent for second-line treatment of metastatic gastric cancer and gastro-esophageal adenocarcinoma, following the outcome of the placebo-controlled Phase III REGARD trial of 355 patients (Fuchs et al: Lancet 2014;383:31-39). “We expect that the authorities will also approve the combination of paclitaxel plus ramucirumab, based on the RAINBOW study,” Van Cutsem said in an interview. “That’s an important breakthrough in second-line treatment.”


Era of New Targeted Therapies in GEJ Cancer

Another speaker here, Manish A. Shah, MD, Director of the Department of Gastrointestinal Cancer and Co-director of the Research  Center for Advanced Digestive Care at Weill Cornell Medical College, called the RAINBOW study the most recent success story in GI cancer.


“We’re in an era of new therapies for gastric cancer and gastroesophageal junction adenocarcinoma,” he said in an interview. “Many new targets are available and validated, we're seeing positive results targeting antiangiogenesis and HER2, and new targets are being evaluated such as MET inhibition.”


He said that HER2 is now a validated target for first-line gastric cancer, and that targeting the angiogenesis pathway in gastric and gastroesophageal adenocarcinoma is also validated.


In his own presentation he expanded on data he has published recently, including that of tumor heterogeneity, discussed in a review paper he wrote in Nature Reviews Clinical Oncology (2014;11:10-11). “Historically all the different gastric diseases have been lumped together – proximal stomach cancer, distal stomach cancer, diffuse stomach cancer,” he said. “We put them all together, but their biology might be different and so they may not all respond to the same targets the same way -- which may explain why some of the previous studies didn’t work,” he said. “But we still need to learn who would benefit most from antiangiogenic therapy.”


On July 23, researchers from the Cancer Genome Atlas published results in Nature (doi:10.1038/nature13480) identifying four subtypes of gastric tumors based on shared mutations and other molecular abnormalities.


At the World Congress on GI Cancers, Shah said that researchers are beginning to understand the difference in outcomes between Western and Asian populations. Because Asians, particularly in Korea and Japan, have regular screening, they typically present with earlier disease -- “so most of the time when patients have metastatic disease, their stomach is already removed. Whereas in the West, patients present with metastatic disease with their primary tumor in place and so the disease burden is different and they need to get second-line and third-line therapy.”


Differences in molecular subtypes are also being found between geographic regions. The most exciting studies now are in inhibition of MET, the STAT-3 oncogene, and the immune checkpoint inhibitors PD1/PDL1 pathways.




History of the World Congress                                                              


The World Congress on Gastrointestinal Cancer began in 1999 as Perspectives in Colorectal Cancer, founded by Mario Dicato, MD, and Eric Van Cutsem, MD, PhD, along with Jacques Wils, MD, of Laurentius Hospital in The Netherlands, who retired as chair following the 2003 Congress. Dicato and Van Cutsem remain as Chairs, and Vice-Chair is Josep Tabernero, MD, PhD, of Vall d'Hebron University Hospital and the Institute of Oncology in Barcelona.


An agreement was reached in 2004 between the organizers and the European Society for Medical Oncology to collaborate on the development of the Congress with the goal of increasing the educational value, and expanding the reach to a wider audience.


The meeting originally focused only on colorectal cancer, but after partnering with ESMO the program was expanded to include sessions on gastric cancer, pancreatic cancer, esophageal, pancreas and bile duct, neuro-nephrotic and upper GI cancers, liver, and gastrointestinal stromal tumors.


“Knowing the right people, having good networking, and being on top of the science has helped the Congress evolve,” Van Cutsem said. This year it attracted 2,500 attendees.


Friday, July 25, 2014




WASHINGTON -- At a time when oncology leads U.S. health care in molecular diagnostics and targeted therapies, new survey data from the Personalized Medicine Coalition (PMC), show that two-thirds of Americans have never even heard of personalized medicine. However, when personalized medicine – i.e., also variously called precision medicine or individualized medicine – is explained, the survey showed that 65 percent of Americans do indicate that they recognize the potential benefits to patients and want to learn more.


As one survey respondent put it, what is most compelling is “Mostly that meds and treatments will be customized to my personal needs. Meds and treatments will be more targeted, thus reducing taking excess and unnecessary meds and treatments.” According to figures cited by PMC in the 2014 edition of its “The Case for Personalized Medicine” report, the percentage of cancers driven by genetic mutations that could be drug targets include:

  • Melanoma, 73 percent;
  • Thyroid, 56 percent;
  • Colorectal, 51 percent;
  • Endometrial, 43 percent;
  • Lung, 41 percent;
  • Pancreatic, 41 percent; and
  • Breast, 32 percent.


Speaking at the National Press Club here at a news briefing to release the findings, Mark Richards, PhD, Senior Vice President and Management Supervisor at KRC Research, which conducted the survey for the PMC, explained that the data come from a 25-minute nationally representative telephone survey (landline and mobile phone) of 1,024 American adults age 18 and older, which was conducted in English in March of this year.


He said that while the proportion of survey respondents who know about personalized medicine is lower than four in 10, when the definition was explained to them, “most people reacted to the idea very positively.” He added, “Their goal is to get well…This is something that is not a dream any more.”  So anything that can help patients set priorities in their health care decision-making process is valuable to them. The survey sample was “in proportion to U.S. census data,” he said, and was roughly 50/50 in gender representation.


Specific Findings

The data from the new PMC survey show that:

  • Among respondents who have heard the term “personalized medicine,” only 16 percent feel very informed about what it is.
  • Only 11 percent of respondents said their physician has discussed or recommended personalized medicine to them.
  • Some 69 percent of respondents are interested in learning more about how personalized medicine works. They had specific questions, including: How effective is it? What are the negatives, such as risks or side effects? What are the advantages or benefits? Could I benefit? How will the data be used?
  • Should their physician recommend personalized medicine, such as a genetic test, 77 percent of  respondents said they would be very (37%) or somewhat (40%) willing to have a diagnostic test in order to personalize a prevention or treatment plan. As one consumer in a PMC focus group put it, “I think the medical professional should be the driver.”
  • Access and affordability are the chief concerns of respondents when they understand what personalized medicine is. Some 69 percent said they feared insurers would not cover personalized therapies and 67 percent said they feared patients could not afford them.
  • A majority (63%) of respondents believe health insurance should cover personalized tests and treatments, even if they are more expensive than conventional tests and treatments.

Patient advocate Donna Cryer, JD, President and CEO of the Global Liver Institute, said that she had benefited personally from personalized medicine as a patient with multiple autoimmune diseases. Still, she did not hear about it from her physician, she noted. “As a patient I think there’s a lot of work for us to do” in consumer education, she said.



Consumers need to understand the benefits of personalized therapies because tools for genetic sequencing and testing “are exploding at the present time,” said another speaker, Raju Kucherlapati, PhD, the Paul C. Cabot Professor in the Department of Genetics at Harvard Medical School and Professor in the Department of Medicine at Brigham and Women’s Hospital.


He said that largely because of the sequencing of the human genome and the increasing affordability of genetic testing, he considers this “the golden age of discovery.”  Patients need to know about these new discoveries so they can become excited: “We need to be able to show the public where we are.”


Kucherlapati, along with Richards, noted that the general public responds best to specific examples of personalized medicine at work – such as, for instance, the story of a cancer patient who was treated with a targeted therapy and experienced a remission.


Upcoming Study

Looking ahead, the PMC plans to commission a study on the number of personalized therapies in the pipeline and issues relating to them, said PMC President Edward Abrahams, PhD.


The new survey data also underscore how important it is for the pharmaceutical industry to demonstrate its commitment to the science undergirding personalized medicine, noted Randy Burkholder, Vice President for Policy at the Pharmaceutical Research and Manufacturers of America (PhRMA). There was a phase in the past where the pharmaceutical industry was not seeing the fruit of personalized medicine in its research pipeline and thus was not as enthusiastic as it could have been, he acknowledged. But, he said, the measure of the industry’s commitment to targeted therapies was its willingness to accept the fact that there would be a lag time between a scientific breakthrough and its translation into patient care.


Burkholder cited oncology as having a high number of targeted drugs today, especially for melanoma and lung cancer. Indeed, targeted therapeutics are being approved by the U.S. Food and Drug Administration “in steady succession,” notes the PMC, and hundreds of targeted therapies are in Phase I, II, and III trials worldwide. “These are significant steps forward,” Burkholder said. “I think we’re going to see more and more.” 


He predicted that in a few years there would be an even greater number of new targeted therapies entering the medical marketplace. In recognition of the growth of personalized therapies, FDA released a 60-page report in October called “Paving the Way for Personalized Medicine: FDA’s Role in a New Era of Medical Product Development.” The agency has stated its intention to support rapid advancements in genomic medicine.


Insurance Coverage

Another PMC report shows that respondents to the survey who expressed concern about insurance coverage of personalized tests and therapies are right to be concerned. The new report, “The Future of Coverage and Payment for Personalized Medicine Diagnostics,” released in July, cites the following as potential future problems for personalized medicine:

  • Imminent federal pricing of highly innovative molecular tests, which could result in lower reimbursement levels, especially for Medicare;
  • Inconsistent standards and paradigms for evaluating diagnostic, prognostic, and predictive genomic tests, since assessment of “clinical utility” for such tests is “neither clear nor predictable,” according to the report; and
  • A lack of incentives for the development of genomic medicine, since traditional funding, pricing, or reimbursement systems are not geared to genomic medicine.

In order for molecularly targeted genomic medicine to move forward and fulfill the “golden age of discovery” cited  at the briefing, the PMC report recommends funding the education of physicians and patients in personalized medicine; funding allied health professionals such as genetic counselors; and creating incentives to develop new tools that have the potential to revolutionize some therapeutic areas – for example, understanding the role of a gene in human drug metabolism and clinical outcomes.  

Wednesday, July 23, 2014


The U.S. Food and Drug Administration has today approved Zydelig (idelalisib) for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL). The drug is to be used in combination with rituximab in patients for whom rituximab alone would be considered appropriate therapy due to other existing comorbidities.


“In less than a year, we have seen considerable progress in the availability of treatments for chronic lymphocytic leukemia,” Richard Pazdur, MD, Director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a news release.


Since November last year, the FDA has approved Gazyva (obinutuzumab)(OT 12/10/13 issue), Imbruvica (ibrutinib)(OT 3/10/14 issue), and a new indication for Arzerra (ofatumumab)(OT 5/10/14 issue) to treat CLL. Gazyva, Arzerra, and Zydelig were all granted orphan product designation because they are intended to treat a rare disease.


Also today, Zydelig also received accelerated approval to treat patients with relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL). The drug is intended to be used in patients who have received at least two prior systemic therapies.


The accelerated approval program allows for approval of a drug based on surrogate or intermediate endpoints reasonably likely to predict clinical benefit for patients with serious conditions with unmet medical needs. Drugs receiving accelerated approval are subject to confirmatory trials verifying clinical benefit.


Safety and Effectiveness

The safety and effectiveness for Zydelig for the treatment of patients with CLL were evaluated in a clinical trial of 220 patients randomly assigned to receive Zydelig and rituximab or placebo and rituximab. The trial was stopped for efficacy following the first pre-specified interim analysis point, which showed participants treated with Zydelig and rituximab had a longer progression-free survival (10.7 months) compared with patients treated with the placebo and rituximab (approximately 5.5 months). Results from a second interim analysis continued to show a statistically significant improvement for Zydelig and rituximab over placebo and rituximab.


Zydelig’s safety and effectiveness to treat relapsed FL and relapsed SLL were established in a clinical trial with 123 patients with indolent non-Hodgkin lymphomas. All patients were treated with Zydelig and the results showed that 54 percent of patients with relapsed FL and 58 percent of patients with SLL experienced complete or partial disappearance of their cancer after treatment.


Warnings & Side Effects

Zydelig carries a Boxed Warning alerting patients and health care professionals of fatal and serious toxicities including liver toxicity, diarrhea and colitis, pneumonitis, and intestinal perforation. Zydelig is also being approved with a Risk Evaluation and Mitigation Strategy comprised of a communication plan to ensure healthcare providers who are likely to prescribe Zydelig are fully informed about these risks.


Common side effects reported for Zydelig include diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, and rash. Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia, and elevated levels of liver enzymes.


Zydelig is marketed by Gilead Sciences.

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.