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  • Want to develop a new drug? Got $2.56 billion?

    The estimated average pre-tax industry cost per new prescription drug approval now peaks at $2.56 billion—an increase of 145% since 2003. According to a study conducted by the Tufts Center for the Study of Drug Development at Tufts University in Boston, Massachusetts, this cost includes failures and capital costs, with the vast majority of drugs failing at some point during clinical testing.

    This study is one of a series of apples-to-apples comparisons that date back to the 1970s, explained presenter and principal investigator Joseph DiMasi, PhD, in a press conference. In the Tufts study, the term “drug” was used for both drugs and biologics, or both large and small molecules.

    The cost dataset in the study included 106 investigational new drugs and biologics that were first tested in humans anywhere in the world between 1995 and 2007, and came from 10 firms. Clinical period development cost data were collected up to 2013, with 5 compounds still active at the time of data collection. The study broke down annual company biopharmaceutical R&D expenditures between 1990 and 2010 in various ways to estimate pre-human R&D costs.

    Among the 1,442 compounds included, 7% were FDA approved, 80% were abandoned at some point in the development process, and 12.6% were still active in some phase. DiMasi said that, since many compounds fail in testing, phase costs must be weighted by probability of entering the phase to obtain costs per investigational compound. The probabilities of transitioning from one clinical phase to the next were:

    • 59.5% from phase I-II
    • 35.5% from phase II-III
    • 62.0% from phase III-NDA/BLA submission
    • 90.4% from NDA/BLA submission to NDA/BLA approval
    • Overall, 11.8% from phase I to NDA/BLA approval

    Stated another way, DiMasi explained that it takes an average of 8.5 compounds to get to 1 clinical approval.

    The time from synthesis of a compound to its regulatory approval was estimated to be 128 months—roughly 11 years. Pre-human expenditures, meaning R&D before a drug enters clinical testing, were estimated to be 30.8% of costs per approved compound.

    The total out-of-pocket cost per approved new compound was $1,395 billion, while the total capitalized cost was $2.558 billion. Including post-approval costs added $466 million in out-of-pocket costs and $312 million in capitalized costs.

    Capitalized R&D costs were adjusted for inflation and had a compound annual inflation-adjusted growth rate of 8.5% from the 1990s to the early 2010s. The out-of-pocket cost per approved new drug increased at an annual rate of 9.3%, which was higher than the prior studies when annual rates were 7.6% (1980s- 1990s) and 7% (1970s-1980s).

    Most of the estimated increase in R&D costs is due to increases in cash outlays used to conduct clinical development and higher drug failure rates. The direct cash outlay costs in the Tufts study had an 82.5% cost increase for out-of-pocket clinical phase costs when compared to the 2003 study. The overall risk profile, which came from the clinical approval success rate plus the distribution of failures, had costs increased by 47.3% compared to the 2003 study.

    One positive finding was that the cost in time decreased by 4.9% for the pre-human phase, by 3.0% for the regulatory review phase, and by 5.6% for the overall development timeline. This slightly affected the increase in total R&D cost for new drugs.

    by Kathy Boltz, PhD


    Palliative care is finally getting its due, with the kickoff of the Inaugural Palliative Care in Oncology Symposium in Boston, MA, Friday, October 24, 2014. The Symposium is jointly sponsored by four medical societies: American Society of Clinical Oncology (ASCO), American Academy of Hospice and Palliative Medicine (AAHPM), American Society for Radiation Oncology (ASTRO), and the Multinational Association of Supportive Care in Cancer (MASCC).

    Themes of the Palliative Care in Oncology Symposium segue from presentations at last week’s ASCO Quality Care Symposium. At that meeting, the focus was on palliative care—an important component of quality care, especially at end of life. Billions of dollars a year are wasted on unnecessary direct care, much of it on end of life care (in fact a 2012 IOM report states that it reaches $210 billion each year).  The field is moving toward greater acceptance and use of palliative care when appropriate.

    The pre-symposium press cast for the Palliative Care Symposium featured four presentations that addressed strategies to improve palliative care and the treatment-related financial burdens of cancer care for patients (referred to by quality care experts as “financial toxicity”).

    Addressing Patients’ Financial Burdens (Abstracts 238 and 161)

    In an analysis of nearly 1600 cancer survivors, a sizeable proportion of cancer patients reported financial and work-related burdens: about half were under age 65; 96% reported some kind of insurance; 27% reported at least one financial difficulty (defined as borrowing money, debt, bankruptcy, worry, and financial sacrifices), and 37% reported having to make at least one work modification (defined as early retirement, changing jobs, turning a promotion down, unpaid or extended leave) due to a cancer diagnosis.

    People younger than age 65 reported 130% more financial difficulties than older survivors; the uninsured had 67% more financial difficulties than the insured; and minority groups reported 42% more financial difficulties than whites. The 14% of patients currently in active treatment made 120% more work modifications than those less than 5 years post-treatment; non-white minorities made 57% more work modifications than whites.

    Lead author Robin Whitney, RN, BSN, a cancer survivor and PhD student at the University of California, Davis, Betty Irene Moore School of Nursing, said: “Many cancer survivors, particularly those who are younger and from underserved populations, experience financial or work-related hardship –even when insured and years out from treatment.” She and her co-authors say the findings of this study are generalizable to the U.S. population and reveal the need for screening and support for financial and work challenges across the survivorship trajectory.

    “We now have more than 12 million cancer survivors,” said press cast moderator Jyoti Patel, MD, representing ASCO, “We need to address their financial hardships. As we deal with the consequences of cancer treatment and therapy, we need to find creative ways to address these burdens.”

    Cancer Patients Make Lifestyle Adjustments

    A related nationwide survey showed that due to treatment-related financial burdens, many insured cancer patients either make adjustments in lifestyle or make a compromise with their medical care. The study included 174 patients currently undergoing treatment for solid tumors—all of them insured and requesting financial assistance through a national copay assistance program.

    Overall, 89% reported at least one lifestyle-altering strategy while 39% reported at least one medical care-altering strategy. Most common medical care-altering strategies were not filling a prescription (28%) and taking less medication than prescribed (23%). Lifestyle-altering coping strategies included spending less money on leisure activities (78%), spending less on food and clothing (57%), borrowing money (54%), and spending savings (50%).Younger age and lower income people were associated with increased care-altering strategies; while younger age, higher education level, and shorter time on chemotherapy were associated with greater likelihood of adopting lifestyle coping strategies compared with their counterparts.

    “We need a better, more open dialog between patients and providers about the financial burdens associated with cancer care costs. People use a range of coping strategies, and we need to engage with patients on their choices and develop screening tools to identify patients who are likely to make potentially harmful decisions about their treatment,” said lead author Ryan Nipp, MD, an oncology fellow at Dana-Farber Cancer Institute in Boston.

    Dr. Patel commented, “As we make strides in understanding the whole patient, it is incumbent upon us to have these discussions about financial burden with them. We need guided efforts to help support these patients, especially those at risk.”

    “Co-Rounding” at Duke (Abstract 3)

    According to a retrospective cohort analysis of a pioneering approach of “co-rounding” at Duke University Medical Center, daily collaboration between medical oncologists and palliative care specialists improved health system-related and patient-related outcomes. “Co-rounding” teams included 1 medical oncologist and 1 palliative care specialist as attending physicians, as well as ancillary healthcare providers. The teams met each day to discuss individual patients.

    This first evaluation of “co-rounding” at Duke took place after one year of the new partnership which functioned in the hospital’s inpatient solid tumor oncology unit. Comparison between 731 patients admitted pre-intervention and 783 admitted in the first year of the intervention showed that “co-rounding” was associated with a significant decrease in length of hospital stay (4.17 days versus 4.51 days, respectively, P=.02); 15% reduction in the risk of 7-day readmission (P<.0001), and a 23% risk reduction for 30-day readmission (P=.048). ICU transfers were decreased by 15% from pre- to post-intervention, and hospice referrals were increased by 17% after “co-rounding” was instituted. Doctors and nurses expressed satisfaction with the new approach.

    “Leveraging the skill sets of both palliative care physicians and medical oncologists has allowed us to better manage symptoms, shorten hospital stays, and prevent readmissions. We’ve also been able to dispel any misconceptions that individuals may have had about the role of palliative care, and we’ve shown that nursing and physician impressions of palliative care, as a whole, are very favorable,” stated lead author Richard Riedel, MD, Duke University Medical Center, Durham, NC.

    “This study shows that integrating palliative care into oncology defines good oncologic care. We see that a novel approach called ‘co-rounding’ has achieved impressive results,” Dr. Patel stated.

    “Smart Phone” System for Home Hospice (Abstract 85)

    Preliminary findings from a randomized study of 319 hospice dyads and 121 nurses (some cared for multiple families) suggest that daily use of “smart technology” with an automated telephone-based remote symptom monitoring and coaching system alleviated patients’ symptoms and caregiver burden during home hospice care in the final weeks of life. The study population was drawn from 12 hospices in four different states. Almost half the patients (n=153) were randomly assigned to the intervention and the other patients (n=166) received usual care, which entailed symptom reporting alone.

    “This is the first study to evaluate automated collection of patient-reported symptoms and its effect on family caregiver well-being and on coaching families on ways to improve care for their family member,” said lead study author Kathi Mooney, PhD, RN, Utah College of Nursing and the Huntsman Cancer Institute in Salt Lake City.

    “Remote symptom care, working through the caregiver, provides benefits to the dying patient and caregiver,” stated Bob Wong, PhD, a statistician from the same institution who was an author of the study.

    The automated, telephone-based symptom monitoring system used computer-based technology; the caregiver entered daily ratings (0-10, with 10 being the most severe) for 11 common symptoms that the patient could have experienced in the past 24 hours, and then got feedback from the system if any of the symptoms were rated 4 or higher. The feedback included tips for the caregiver about how to relieve patient’s symptoms; for example, coaching on such maneuvers as positioning the patient for greater comfort or improved breathing, and how to improve time together. Caregivers also reported their own difficulties during the past 24 hours, such as fatigue, anxiety, difficulty sleeping and negative mood.

    Over a 91-day period, patients whose caregivers were assigned to the automated system experienced 44% fewer days of moderate or severe fatigue or anxiety compared with patients in the usual care group. Caregivers in the intervention group had no worsening of vitality (as measured by daily functioning and sleep) over that period, while the usual care caregivers had worsened vitality.

    “Caregiving is a 24-hour-a-day, 7-days-a-week job,” Dr. Patel commented. “Most caregivers cannot do it alone. This remote monitoring system proactively supports the caregiver at this difficult time when the patient is near death.”

    By Alice Goodman

    HER2+ Breast Cancer: Immediate Impact of 2014 ESMO Presentations on Clinical Practice


    In an effort to provide you with timely market feedback from ESMO 2014, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPoll™ from the meeting. This report explored presentations in HER2+ Breast Cancer.

    OncoPoll™ Methodology

    • Primary research phase involved a global survey to verified and validated medical oncologists and multi-disciplinary physicians with an identified clinical interest in breast cancer utilizing targeting parameters within the proprietary MDoutlook® global cancer treater database
    • Timing: October 2014. Launched three days after close of ESMO 2014 Congress, held in Madrid, Spain September 26th – 30th, 2014
    • Fielding via <10 minute long interactive internet survey utilizing proven effective methodology via the MDoutlook® survey tool
    • Links to discussed abstracts on the ESMO website were provided within the survey
    • Reponses at data collection: 104 on October 13th
      • 37 US respondents
      • 67 EU/Rest of World (RoW) respondents
      • 28 countries represented
    • No financial incentives provided for participation

    Attendance at 2014 ESMO Congress

    Key Conclusions

    • Nearly a 50/50 split of EU/Rest of world (RoW) respondents* attended the ESMO 2014 Congress
    • US survey respondents were nearly five times less likely to attend ESMO 2014, in comparison to their international counterparts

    * Survey Participants = Medical Oncologists with an identified clinical interest in breast cancer

    Survey Participants’ Metastatic Breast Cancer Patient Flow: Average Over 40 Breast Cancer Cases Each Quarter

    Key Conclusions

    • On average, US oncologists reported seeing more patients in all three subtypes in the last three months, in comparison to their international colleagues
    • US oncologists see nearly 14 HER2+ patients per quarter
      • EU/RoW oncologists see nearly 11 HER2+ patients per quarter
    • Cases of HR+/HER- metastatic breast cancer were more common for both US oncologists (avg. 28/quarter) and EU/RoW oncologists (avg. 26/quarter) than other metastatic breast cancers

    Impact of the Phase III Cleopatra Study: EU/RoW Oncologists Expecting to Increase Usage of Trastuzumab+Pertuzumab in the Next Year for HER2+ Metastatic Breast Cancer Patients

    Key Conclusions

    EU/RoW Clinicians

    • The majority of EU/RoW oncologists (65%) are currently using Trastuzumab combined with chemotherapy alone for their HER2+ metastatic breast cancer (in all lines of therapy). 23% of EU/RoW oncologists are using Trastuzumab+Pertuzumab, and 11% are using Trastuzumab emtansine
    • In the next year, nearly all EU/RoW oncologists expect to completely forego the use of Trastuzumab alone for their metastatic patients (in all lines of therapy)
    • In the next year, 52% of EU/RoW oncologists expect to use Trastuzumab + Pertuzumab. Additionally, 55% of EU/RoW oncologists expect to use Trastuzumab emtansine for their HER2+ metatstatic breast cancer patients (in all lines of therapy)

    US clinicians

    • Currently, US oncologists are utilizing several HER2+ targeted therapies, with 49% using Trastuzumab, 49% using Trastuzumab+Pertuzumab, and 38% using Trastuzumab emtansine for their HER2+ metastatic patients (in all lines of therapy)
    • In the next year, a minimal proportion (10%) of US oncologists will be using Trastuzumab alone
    • In the next year, 64% expect to use Trastuzumab emtansine while only 39% of US oncologists expect to use Trastuzumab + Pertuzumab for their HER2+ metastatic patients (in all lines of therapy)

    Impact of the Phase III Cleopatra Study: US and EU/RoW Oncologists Expect to Use Trastuzumab+Pertuzumab in the First Line for their HER2+ Metastatic Breast Cancer Patients

    Key Conclusion

    • When Trastuzumab+Pertuzumab is used, ~75% of both US and EU/RoW oncologists expect to use it as a first line therapy for their HER2+ metastatic patients

    Impact of the CherLOB Study: The Majority of US and EU/RoW Oncologists Believe the Data Presented in the CherLOB Study is Clinically Important

    Key Conclusions

    • 75% of US oncologists rated the clinical importance of this study highly (either a four or five)
      • Similarly, 61% of EU/RoW oncologists rated this data to be either a four or five
      • Very few (<5%) oncologists rated this study as not having clinical importance

    Impact of the CherLOB Study: US and EU/RoW Oncologists Expect to Increase Testing for the PIK3CA Mutations in HER2+ Breast Cancer Patients

    Key Conclusions

    • In the past year, minimal PIK3CA mutation testing by US and EU/RoW oncologists was occurring for HER2+ breast cancer patients (<10%)
    • Due to the correlation between the PIK3CA mutation and pathological complete response (pCR) in patients with HER2+ early breast cancer being treated with neoadjuvant lapatinib and trastuzumab, both US and EU/RoW oncologists expect to increase testing for PIK3CA mutations in both early and metastatic breast cancer patients
      • 31% of early breast cancer patients being treated by US oncologists will be tested for the PIK3CA mutation in the next year
        • This data had less of an effect on EU/RoW oncologists: 16% of early breast cancer patients will be tested
    • Over 40% of metastatic breast cancer patients being treated by US oncologists will be tested
      • Nearly 1 in 5 of metastatic breast cancer patients being treated by EU/RoW oncologists will be tested for the PIK3CA mutation

    Conclusions: Impact of ESMO 2014 Presentations on Clinical Practices for HER2+ Breast Cancer

    • US oncologists see nearly 14 HER2+ patients per quarter
      • EU/RoW oncologists see nearly 11 HER2+ patients per quarter
    • Trastuzumab is currently the most commonly used HER2 targeted therapy by EU/RoW oncologists (64%)
      • Trastuzumab and Trastuzumab+Pertuzumab are being equally used (~45%) by US oncologists
      • Impact of the Phase III Cleopatra Study:
        • EU/RoW oncologists are expecting to increase their usage of Trastuzumab + Pertuzumab in the next year for their HER2+ metastatic breast cancer patients (52%) (in all lines of therapy)
        • US oncologists are expecting to decrease their usage of Trastuzumab+Pertuzumab for HER2+ metastatic patients (39%) (in all lines of therapy)
          • US oncologists (64%) are expecting increase usage of Trastuzumab emtansine
          • Impact of the CherLOB Study:
            • The majority of US and EU/RoW oncologists believe the data presented in the CherLOB study is clinically important
            • In the past year, minimal PIK3CA mutation testing by US and EU/RoW oncologists was occurring for HER2+ breast cancer patients (<10%)
            • 31% of early breast cancer patients being treated by US oncologists will be tested for the PIK3CA mutation in the next year
              • 16% of early breast cancer patients treated by EU/RoW oncologists will be tested
    • Over 40% of metastatic breast cancer patients being treated by US oncologists will be tested in the next year
      • 19% of metastatic breast cancer patients being treated by EU/RoW oncologists will be tested for the PIK3CA mutation

    For a more detailed analysis report, please click here to download the full report.

    Submitted by Jessica Harnisch, Assoc. Global Medical Analyst; Robert Stephan, Sr. Director Medical Services and Strategy; Justin Boag, Consultant; and Jan Heybroek, President MDoutlook.


    ALEXANDRIA, VA – A pre-meeting presscast gives a bird’s eye view of research that will be presented when ASCO’s 2014 Quality Care Symposium meeting swings into full gear in Boston, Mass., this coming Friday.  Separate studies featured at the presscast focused on the influence of sociodemographic factors on treatment selection and mortality, as well as physician and patient factors associated with improved cancer care.

    Parental Status and Treatment Choice

    A pilot survey of 42 patients indicates that having children influences choice of cancer treatments for patients with advanced cancer (Abstract 65). The majority of parents (64%) in the study indicated that parenthood motivates them to purse life-extending treatment so that they can gain more time with their children. About 15% said that preserving parental functioning was a treatment priority, and 12% cited the importance of receiving treatments close to home rather than travel for a second opinion or have treatment that requires long hospital stays. Interestingly, 24% of respondents did not perceive having children as an influence on their treatment decisions.

    About 50% viewed hospice as a supportive resource, taking the burden off of family, and about 21% were not interested in hospice. Respondents seemed to conflate palliative care with end of life care, suggesting an area where more clarification is needed for patients.

    These findings suggest that physicians should discuss factors related to parental status with their patients when deciding on a course of treatment. “This study provides some insights into parenting considerations for the first time, and should encourage conversations between oncologists and patients about treatment priorities,” said lead author Devon Check, a PhD candidate at the University of Carolina in Chapel Hill, NC.

    This is the first study to ask advanced cancer patients with dependent children directly about the effect of parental status on treatment decision-making.  The researchers are planning a larger study to explore the associations among parental status, parental concerns, and medical decision-making for patients with advanced cancer.

    “This study stresses the need to individualize care according to the patient’s circumstances. It would be great to see other studies of this sort,” said presscast moderator Gregory A. Masters, MD, Chair of ASCO’s Cancer Care Communications Committee.

    Financial Assistance Improves Adherence

    It is well known that adherence to adjuvant hormone therapy improves survival, yet it is suboptimal among women with hormone receptor-positive breast cancer. A large study of more than 23,000 women suggests that Medicare Part D Extra Help program, which provides low-income subsidies for medications, boosts adherence to adjuvant hormonal therapy across the board in racial/ethnic groups and reduces disparities in health care (Abstract 2). These findings suggest that addressing economic barriers to medication access has the potential to reduce disparities in outcomes, especially among racial minority groups.

    “Patients are more likely to take their medications if they can afford them. Our study shows that federal policy interventions that help cover out-of pocket costs may be able to reduce the gap in breast cancer outcome between white patients and racial minorities,” stated lead author Alana Biggers, MD, MPH, Medical College of Milwaukee, Wisc.

    The study population included 23,299 Medicare Part D enrollees with early-stage breast cancer who received hormone therapy within 1 year of surgery. Overall, 27% were enrolled in the Extra Help low-income subsidy program. Women from racial minority groups were more likely to be enrolled in the program; 70% of black women and 56% of Hispanic women received Extra Help, compared with 21% of white women.

    Overall, 3-year adherence rates for hormonal therapy were similar across all races; but in the subgroup not enrolled in the Extra Help program, white women had significantly higher adherence rates (62%) compared with black and Hispanic women (55%). Adherence rates were highest among women receiving the low-income subsidy versus those who did not for all racial groups: 71% for white women versus 62% for white women; 67% versus 55% for black women; 71% versus 55% for Hispanics.

    “This interesting study shows that using low-income subsidies can help us understand how these programs support adherence and improve overall survival. Adherence is linked to better care,” Dr. Masters commented.

    Tumor Board Participation Improves Outcomes in Certain Cancers

    Oncologist participation in weekly tumor board meetings appears to improve survival for patients with stage IV small-cell lung cancer and stage IV colorectal cancers, according to a population-based observational study of almost 5000 patients with lung or colorectal cancer and 1600 oncologists (Abstract 179). Oncologist participation in tumor board meetings also boosted the chances of patient enrollment in clinical trials and increased the likelihood of patients with early-stage non-small cell lung cancer (NSCLC) receiving guideline-based curative surgery.

    “These findings are exploratory and will be the basis of future study. Patients with these tumors may want to ask their doctors if their cases will be discussed by a tumor board that includes multidisciplinary experts,” said lead author Kenneth L. Kehl, MD, a fellow in cancer medicine at the University of Texas MD Anderson Cancer Center in Houston.

    The study revealed different patterns of oncologist participation in multidisciplinary tumor boards. About 54% participated weekly, 26% participated monthly, 8% participated quarterly.

    Dr. Kehl cautioned that this was not a randomized trial, so one should not leap to the conclusion that tumor board participation directly improves survival. The study identifies associations rather than direct effects.

    “This study supports our belief that multidisciplinary communication improves outcomes and enrollment in clinical trials. Tumor boards are one educational tool that can improve care for cancer patients and the effect is difficult to measure,” Dr. Masters noted.

    Sociodemographic Disparities Affect Death Rates

    Being married, having insurance, being white, female gender, younger age, higher education level, higher income level, insurance coverage, and earlier stage of cancer all appear to reduce the likelihood of dying 1 month after cancer-related surgery (Abstract 282) These findings come from a study of more than 1.1 million patients in the SEER database undergoing surgery for the most common or most fatal cancers; among these, 53,498 (4.8%) died within 1 month of surgery.

    Previous research suggests that 1-month mortality following surgery is associated with hospital and surgeon volume. Minority race, uninsured status, and low-income level are known factors associated with less likelihood of receiving care at a high-volume, high performance hospital.

    A limitation of the study is that SEER does not include data on comorbidity or place of care.

    “Our results suggest that there is a lot we can do for all patients to improve outcomes. We can start by identifying and supporting improvements for under performing hospitals as well as proactively offering social support services to patients at high risk of poorer outcomes,” said lead author Brandon A. Mahal, a fourth-year medical student at Harvard Medical School and research fellow at Dana-Farber Cancer Institute in Boston.

    “This study highlights special risk groups and emphasizes the need for strong psychosocial support to improve their outcomes,” Dr. Masters said.


    At the presscast, Deborah A. Mayer, PhD, University of North Carolina, Chapel Hill,  informed listeners about the availability of ASCO’s new streamlined template for a care plan for cancer survivors. This 2-year effort makes the care plan easier to implement and will hopefully transition care from oncologists to primary care physicians for the growing number of cancer survivors who benefit from advances in treatment.  The template is available on the ASCO website.

    By Alice Goodman

    The showdown between PD-1 targeted therapeutics spans several tumor types

    By: Len Kusdra, Analyst, Clinical & Scientific Assessment, Kantar Health, Tatiana Spicakova, Consultant, Clinical & Scientific Assessment, Kantar Health, Greg Wolfe, Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health

    The role of Programmed Death-1 (PD-1) pathway in suppression of antitumor immunity has become one of the hottest topics in oncology over the past couple of years. PD-1 is a key immune checkpoint receptor expressed on activated T-cells, and binding of PD-1 to its ligand (PD-L1) results in the suppression of the immune response. While the PD-1 pathway normally plays a protective role by attenuating immune-mediated destruction of healthy tissue, the pathway can be exploited by cancer cells to protect themselves from the attack by tumor-specific T-cells. A number of immune checkpoint inhibitors are in late-stage clinical development; these agents work by blocking the interaction between PD-1 and PD-L1, thereby activating the immune system against cancer cells.

    PD-1 Pathway Inhibitors in Phase III Development

    Drug Manufacturer Antibody Target Development Stage Ongoing pivotal trials
    Keytruda Merck Humanized IgG4 PD-1 Approved in Yervoy-treated melanoma (U.S.); Phase III Melanoma, NSCLC, Head and Neck
    Opdivo BMS Human IgG4 PD-1 Filed in Yervoy-treated melanoma (US/EU)

    Filed in squamous 3rd line NSCLC (US/EU); Phase III

    Melanoma, NSCLC, RCC, Head and Neck
    MPDL3280A Roche Human IgG1 PD-L1 Phase III Bladder, NSCLC
    MEDI-4736 AstraZeneca Human IgG1 PD-L1 Phase III NSCLC

    For these novel immune checkpoint inhibitors, the fight to capture the lead in high-profile tumor types such as melanoma and non-small cell lung cancer (NSCLC) is becoming increasingly fierce. But their clinical development does not end there and, in fact, continues to expand into other indications, such as renal cell carcinoma (RCC), urothelial cancer, head and neck cancer, gastrointestinal cancer and hematological malignancies. Data continued to report promising activity across different tumor types at the annual 2014 European Society for Medical Oncology (ESMO), as summarized below.

    Opdivo improves response rate versus chemotherapy in Yervoy-treated melanoma in a Phase III randomized trial – is its efficacy superior to the already approved Keytruda?

    (Weber, Abstract LBA3)

    Past oncology meetings have highlighted the promise of Opdivo™ (nivolumab, Bristol-Myers Squibb) in melanoma. Opdivo demonstrated impressive early clinical data that suggested improved overall response rate (ORR) with fewer toxicities when compared with historical data for Yervoy® (ipilimumab, Bristol-Myers Squibb), a CTLA-4 immune checkpoint inhibitor. At ASCO 2014, another anti-PD-1 monoclonal antibody, Keytruda® (pembrolizumab, Merck), took center stage with impressive Phase II data that ultimately led to its approval in the U.S. in September 2014 as therapy for Yervoy-treated melanoma patients.

    Recognizing the urgency of getting to market as soon as possible, BMS submitted U.S./EU regulatory applications for Opdivo for Yervoy-treated melanoma, with expected U.S. approval in March 2015. Once Opdivo becomes approved, physicians will look to efficacy and safety data to drive their decision when choosing between the two agents. At ESMO, highly anticipated data from a randomized Phase III study (Opdivo versus chemotherapy of choice) were presented for 405 previously treated (including Yervoy) unresectable Stage III/IV melanoma patients.

    The ORR was 32% for Opdivo versus 11% for chemotherapy, with benefit observed across all subgroups, including PD-L1 negative patients. Grade 3/4 toxicities were reported in 9% of patients in the Opdivo arm versus 31% in the chemotherapy arm, with no new safety signals reported. Unfortunately, the progression-free survival (PFS) and overall survival (OS) data were not yet available at the time of analysis, but duration of response among responding patients suggests prolonged benefit (3.6 months in the chemotherapy arm versus median not reached in the Opdivo arm but with 95% of responders still benefiting at six months). So how does Opdivo compare to Keytruda in this patient population? As shown below, the activity appears very similar between the drugs, and no dramatic differences exist in their safety profiles.

    Efficacy in Previously-Treated Metastatic Melanoma

    Drug ORR CR mPFS
    Opdivo (n=120) 32% 3% ND
    Chemotherapy (47) 11% 0% ND
    Keytruda (n=197)1 28% 2% 5.6 mos

    1Ribas, Abstract LBA9000, ASCO 2014

    While response rate is a valid and informative endpoint about the drug’s efficacy, PFS and OS data ultimately might help decide which of the two will become the winner. This is especially important for Opdivo’s trial, in which OS was the co-primary endpoint. Will the improved response rates translate into a statistically significant OS benefit that supports the regulatory applications? The expected answer is yes, although due to immature data we now continue to wait with bated breath for this data. While Keytruda already demonstrated that PD-1 inhibitor works in Yervoy-treated melanoma patients, the results from the Opdivo trial were significant in that it presented, for the first time, data from a randomized Phase III study. Commercially, Keytruda will have a six-month time-to-market advantage over Opdivo and will likely amass a strong foothold in the Yervoy-pretreated setting by the time Opdivo launches. Will having overall survival data from a randomized study (assuming it is available by the time of launch) sway physicians to forgo Keytruda in favor of Opdivo, or will physicians interpret a positive survival benefit for Opdivo to be a surrogate for similar expectations with Keytruda?

    Is Keytruda leading the PD-1 pack in NSCLC?

    (Garon, Abstract LBA43)

    Safety and efficacy data for Keytruda were reported for previously treated and treatment-naive NSCLC patients enrolled in Phase I study expansion cohorts. In 262 patients, treatment-related adverse events included (any grade; Grade 3/4) fatigue (20%; <1%), pruritus (9%; 0%) and pneumonitis (4%, 2%). In 236 evaluable patients, the ORR was 21% (26% in treatment-naïve and 20% in previously treated patients).  Curiously, current/former smokers appeared to achieve a better response compared to never smokers (27% vs 9%), although the underlying reasons for this observation remain unknown. Median PFS and OS also appeared better for treatment-naïve versus previously treated patients (mPFS: 27 weeks vs. 10 weeks; mOS: not reached vs. 8.2 months).

    The study evaluated whether the expression of PD-L1 biomarker correlates with outcomes. Strong PD-L1 expression was defined as 50% or higher membrane staining in tumor cells and weak expression as 1-49%. The ORR correlated with the level of PD-L1 expression (37% for strong positive, 17% for weak positive and 10% for negative). PFS was also longer for patients with strong versus weak PD-L1 expression (HR 0.52), as was OS (HR 0.59). While the efficacy certainly appears better for PD-L1 positive patients, it is not a black-and-white scenario, and many unresolved issues remain. Namely, differences exist in how the PD-L1 biomarker is measured in the different assays that the various manufactures are developing (what antibody is used), how tissue is collected (old, frozen tissue versus fresh biopsy), where it is measured (tumor cells versus tumor-infiltrating immune cells) and which cutoff threshold is used (1% versus 5% versus others). More importantly, a subset of PD-L1 negative patients still derive a benefit from these inhibitors, yet many of the pivotal trials in NSCLC are conducted in PD-L1 positive tumors. How will that affect the real-world patients, and will the biomarker-negative patients be denied treatment if the drugs receive PD-L1 positive labels (especially outside of the U.S., where payers tend to impose stricter rules)? Keytruda is exclusively targeting PD-L1 positive patients in its pivotal NSCLC trials, while BMS chose to target both PD-L1 positive patients as well as all-comers (including squamous and non-squamous histologies). If those trials are positive, perhaps the inclusion of these patients will enable BMS to have a competitive marketing edge over Keytruda.

    While the data presented for Keytruda was certainly very encouraging, how does it compare with the other key competitors that are also vying to win the NSCLC space? At a first glance, it appears that the agents have similar levels of activity in terms of response rates and survival. But the data are still premature, and the efficacy and safety could start differentiating as more patients are enrolled and longer follow-up becomes available. For now, there is no clear winner in NSCLC, and it has yet to be determined whether targeting the receptor versus ligand may prove to be a more efficacious or safer strategy.

    Drug NSCLC ORR



    (1st line)

    NSCLC ORR (pretreated) mPFS mOS
    MPDL3280A1 23% (n=53) ND 23% (n=53) ND ND
    MEDI-47362 16% (n=58) ND 16% (n=58) ND ND
    Opdivo3 17% (n=129) 30% (n=20) 17% (n=129) 2.3 mos 9.9 mos
    Keytruda4 21% (n=236) 26% (n=42) 20% (n=194) 2.5 mos 8.2 mos

    1Soria, 1322P, ESMO 2014

    2Brahmer, Abstract 8021, ASCO 2014

    3Gettinger, Abstract 8024, ASCO 2014

    4Garon, LBA43, ESMO 2014

    In terms of approval timelines in NSCLC, BMS has an advantage over the other agents as it already submitted a regulatory application in the EU and a rolling submission in the U.S. for Opdivo as a third-line therapy in squamous NSCLC. The submissions were based on data from a Phase II study, and the drug could be approved in both regions next year.

    Keytruda shows promising activity in gastric and urothelial cancers

    Like BMS, Merck is also pursuing an aggressive development strategy for Keytruda that spans multiple tumor types. Promising preliminary results were reported at ESMO for the gastric cancer (Muro, Abstract LBA15) and urothelial cancer (Plimack, Abstract LBA23) cohorts from the KEYNOTE-012 Phase Ib study. In the gastric cancer presentation, 162 patients with recurrent or metastatic adenocarcinoma of the stomach or gastroesophageal junction (GEJ) were screened to identify 65 (40%) patients with PD-L1 positive tumors, who were then treated with 10 mg/kg Keytruda every two weeks. Keytruda showed an acceptable safety profile in 39 evaluable patients, although there was one incidence each of Grade 4 pneumonitis and Grade 5 (fatal) hypoxia. Keytruda achieved 30.8% ORR (no complete responses) and reduction in tumor size in 41% of patients. Efficacy was similar in Asian and non-Asian patients, and responses were durable. Based on these results, initiation of a Phase II trial in advanced gastric cancer is expected in in the first quarter of 2015.

    In the urothelial cancer cohort, 95 patients with recurrent or metastatic cancer of the renal pelvis, ureter, bladder or urethra were screened to identify 61 (64.2%) patients with PD-L1 positive tumors. Thirty-three patients with PD-L1 positive tumors were treated with 10 mg/kg Keytruda every two weeks. Grade 3 or higher adverse events were observed in four patients and included AST increase, dehydration, neuromyopathy, macropapular rash, pruritic rash, rhabdomyolysis, thrombocytopenia, and toxic encephalopathy (n=1 for each, some patients had multiple Grade ≥3 adverse events). The ORR was 24.1% (including three complete responses), and a reduction in tumor size was observed in 64% of patients. Six of the seven responses were ongoing, and median duration of response was not reached at a median follow-up of 11 months. These promising results served as the impetus for the Phase III KEYNOTE-045 trial scheduled to begin by the end of 2014.

    MPDL3280A shows promising activity in monotherapy activity in bladder, and activity in RCC in combination with Avastin, but will it succeed in CRC?

    Roche/Genentech was awarded breakthrough therapy status for its MPDL3280A in urothelial bladder cancer (UBC) in May 2014. Unlike Opdivo and Keytruda, this antibody targets the ligand (PD-L1) rather than receptor, but it is too early to tell whether this strategy will translate into better efficacy and/or a better safety profile.  Perhaps recognizing the increasing crowdedness and being too late to the melanoma market, Roche’s clinical development strategy has focused on other tumor types, including NSCLC and RCC as well as the less commercially attractive (in the eyes of big pharma) urothelial/bladder space. Its first potential approved indication is likely to be bladder, in which they could file for an accelerated approval based on data from the ongoing Phase II study, thus potentially beating Keytruda to the market in the urothelial space. It would certainly give physicians the chance to become familiar with the agent in the real-world setting so that by the time the agent is approved (if successful) in larger indications, it may ease the adoption process by clinicians; being approved on the market could also aid in off-label utilization following positive Phase III data in other tumor types, bypassing a delay for supplemental regulatory approval. In terms of its activity in metastatic RCC as monotherapy, data were presented from a Phase I expansion cohort that included 69 patients (McDermott, Abstract 809O). MPDL3280A was very well-tolerated in these patients with Grade 3 or higher fatigue reported in two patients; all other adverse events were Grade 1/2.  In 62 evaluable patients,  the ORR was 20% in patients with PD-L1 expression of IHC1+/2+/3+ (including one complete and six partial responses) and 10% in patients who were PD-L1 negative (IHC0).

    While the inhibitors have been primarily tested as monotherapy, the next wave of trials will examine their efficacy in combination with other regimens, such as chemotherapy, targeted therapy and other immune modulators. Not surprisingly, Roche has already begun the clinical development of MPDL3280A in combination with Avastin® (bevacizumab) and reported preliminary data from a Phase Ib study (Lieu, Abstract 1049O). The study had two arms: Arm A (n=35) evaluated MPDL3280A IV every three weeks plus Avastin 15mg/kg IV every three weeks; Arm B (n=36) evaluated MPDL3280A IV every two weeks plus Avastin 10mg/kg every two weeks and FOLFOX. Dose expansion cohorts in Arm A included patients with colorectal cancer (CRC) and other solid tumors, including breast, melanoma, NSCLC and RCC; Arm B included oxaliplatin-naïve CRC (with or without liver lesions) as well as other solid tumors, including RCC and breast cancer. In Arm A, the combination with Avastin achieved 40% ORR in the first-line RCC cohort (n=10) and 8% ORR in CRC patients. In Arm B, the combination with Avastin plus chemotherapy achieved 36% ORR in CRC.

    Avastin plus chemotherapy has been a blockbuster regimen in the treatment of CRC, so it is not surprising that Roche is pushing the combination with its PD-L1 inhibitor. Notably, initial data from Opdivo’s Phase I trial did not show activity in CRC (or prostate cancer), so CRC has not been on the forefront of pivotal studies for other PD-1 inhibitors. While the 36% ORR is certainly encouraging, one must question how much of it was contributed by Avastin plus chemotherapy alone. The response rate appears similar to that observed in pivotal trials for Avastin plus chemotherapy, so the early readout seemed perhaps a bit underwhelming.

    But the response rate may not be the best endpoint to evaluate the efficacy of the combination regimen as immunotherapy does not always follow the standard response kinetics and can be associated with delayed responses. So it is still possible that longer follow-up might show improved survival, but will it produce truly stellar results as we have seen so far for the combination of two checkpoint inhibitors in melanoma (Sznol, Abstract LBA9003, ASCO 2014)? In the absence of randomized data, it is difficult to say whether this combination will pan out in CRC. The data in RCC, on the other hand, appear much more promising for the Avastin combination, although the number of patients was small. Avastin has shown efficacy as monotherapy in frontline RCC by achieving approximately 13% ORR, so the reported 40% ORR when combined with PD-L1 inhibitor provides encouraging evidence that the improved efficacy is driven by the addition of MPDL3280A. The activity of the combination regimen certainly appears higher compared to MPDL3280A alone, as discussed above, and might be the strategy going forward, although no such plans have been announced yet. It certainly would help Avastin garner greater utilization in RCC, where it is approved but not a key competitor. However, MPDL3280A plus Avastin will find itself competing with Opdivo, which is currently being studied in combination with Yervoy as first-line therapy for RCC in a head-to-head trial versus Sutent® (sunitinib, Pfizer).

    The amount of data presented at ESMO on the role of immune checkpoint inhibitors was impressive and quite overwhelming. It has become very clear that PD-1 targeted drugs are considered a major breakthrough in oncology with the promise to make a meaningful impact in the lives of patients with various malignancies. To date, data has focused on their activity in solid tumors, but we expect to see the first sets of data for these agents in hemtatologic malignancies at the upcoming American Society of Hematology (ASH) conference. It is the beginning of exciting times in oncology and we can all sit back and enjoy the fight for the PD-1 space spanning multiple tumors.

    CLEOPATRA: Overall survival data makes Perjeta the unmistakable queen in first-line HER2+ metastatic breast cancer

    By: Len Kusdra, Analyst, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health

    The introduction of Herceptin® (trastuzumab, Roche/Genentech) over a decade ago turned HER2+ metastatic breast cancer (MBC) from what was once a patient population with poor prognosis to one with a vastly improved outlook and led the way for an influx of targeted therapies for this population. Now, the armamentarium against HER2+ MBC has expanded and includes several HER2-targeted agents: Tykerb® (lapatinib, GSK), Perjeta® (pertuzumab, Roche/Genentech) and Kadcyla® (ado-trastuzumab, Roche/Genentech). Updated overall survival (OS) data from the CLEOPATRA (NCT00567190) trial were presented at the Presidential Symposium at ESMO on September 28, 20141, and the results will serve to further solidify Roche as the dominant player in HER2-targeted treatment in MBC, if there was any doubt before now. The CLEOPATRA trial was designed to test whether the combination of Herceptin, Perjeta and docetaxel improved outcomes in first-line HER2+ MBC patients. The study randomized 808 patients to receive Hercpetin plus docetaxel plus either placebo or Perjeta. The primary endpoint was progression-free survival (PFS), and secondary endpoints included OS, PFS as assessed by the investigator, overall response rate and safety.

    The initially published results2 in 2012 showed an improvement in PFS from 12.4 months in the control group to 18.5 months in the Perjeta group (HR=0.62; 95% confidence interval (CI), 0.51-0.75; P<0.001). The objective response rate was 69.3% in the control group and 80.2% in the Perjeta group (95% CI, 4.2-17.5; P = 0.001). These significant positive results led to FDA approval in 2012 and European approval in 2013 for Perjeta in combination with Herceptin and docetaxel as first-line treatment in HER2+ MBC. At the time, however, the data was not yet mature to determine OS, and many were left wondering whether the impressive improvement in the primary endpoint of PFS would translate into an equally significant improvement in OS.

    Final results of CLEOPATRA did not disappoint. With a median follow-up of 50 months (range 0-70 months), addition of Perjeta to Herceptin plus docetaxel provided a 15.7-month improvement in OS compared with patients who received Herceptin, docetaxel and placebo (mOS: 56.5 months in the Perjeta arm vs. 40.8 months in the placebo arm; HR=0.68, 95% CI 0.56-0.84, p=0.0002). Updated PFS data were similar to what was published in 2012, with a slight increase in PFS in the Perjeta arm (18.7 months vs. 12.4 months, HR=0.68, p<0.0001). The toxicity profiles between the arms were similar and manageable, with the Perjeta arm experiencing a higher rate of Grade 3 febrile neutropenia (13.7% vs. 7.6%) and diarrhea (9.3% vs. 5.1%). The significant improvement in OS now solidifies Perjeta plus Herceptin and docetaxel as the new standard care in first-line MBC patients.

    So what is next? According to Kantar Health’s CancerMPact® Treatment Architecture, Perjeta has already benefited from a significant penetration into the first line setting, with use in one-third of U.S. patients in the year after its launch.3 The question that arises is, can we improve even further on these results, and can we do it by eliminating chemotherapy altogether? One intriguing piece of data presented  was the duration of study treatment: While the number of cycles of docetaxel remained the same at eight cycles (range: 1-42 cycles for the placebo arm and 1-52 cycles for the Perjeta arm), the duration of study treatment was extended with the addition of Perjeta from 11.4 months (range: 0.1-66.3 months) in the placebo arm to 17.4 months (range: 0.1-67.7 months) in the Perjeta arm, raising the possibility of prolonged Perjeta and Herceptin combination even after ending the docetaxel portion of the study treatment. The possibility of removing chemotherapy and replacing it with targeted therapy alone has been the Holy Grail in the oncology field ever since Herceptin revolutionized the way MBC is treated. In that vein, the MARIANNE (NCT01120184) study is looking to do just that by examining whether Perjeta and Kadcyla are more efficacious than Herceptin plus Perjeta and a taxane (paclitaxel or docetaxel). In essence, Kadcyla would provide both the targeted therapy and the microtubule-disrupting activity provided by taxanes. Results from this study would certainly provide further impetus for a paradigm shift of complete elimination of chemotherapy in first-line MBC. Results from MARIANNE are expected before the end of this year. Until then, the results from the CLEOPATRA trial provide great hope for patients in a disease that had few options over a decade ago and opens the door for the development of novel and more potent combination therapies in what was once an intractable disease. These are exciting times indeed.


    1. Swain et al. Abstract 350O ESMO 2014
    2. Baselga et al. NEJM 2012
    3. Kantar Health, CancerMPact, Treatment Architecture United States, accessed September 28, 2014

    Gilotrif improves PFS in platinum-pretreated head and neck cancer, but is that enough?

    By: Mara Jeffress, Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Senior Director, Clinical & Scientific Assessment, Kantar Health

    Head and neck cancer patients tend to receive chemotherapy doublets with or without the only approved targeted agent, the EGFR antibody Erbitux® (cetuximab, Bristol-Myers Squibb/Lilly/Merck Serono) as first-line therapy. Up to 90% of squamous cell carcinoma of the head and neck (SCCHN) patients have a tumor with EGFR aberrations, and according to Kantar Health’s CancerMPact® Treatment Architecture United States, in 2013 38% of chemotherapy-naïve SCCHN patients received Erbitux as part of their first-line therapy for advanced disease. Erbitux may also be used in second-line, with approximately one-fifth of patients receiving Erbitux monotherapy and another one-fifth receiving Erbitux in combination with chemotherapy.

    The use of Erbitux in multiple lines belies the large unmet need for relapsed or refractory patients, whose median overall survival ranges from three to six months (Machiels, Abstract LBA29, ESMO 2014). In addition, less than half of patients who receive a first-line therapy go on to receive a second line of therapy.1 Several other EGFR-directed agents have been tested in SCCHN, including Vectibix® (panitumumab, Amgen), zalutumumab (Genmab), Iressa® (gefitinib, AstraZeneca), and Tykerb® (lapatinib, GlaxoSmithKline). All have failed to improve survival in Phase III trials. Gilotrif® (Giotrif® in Europe, afatinib, Boehringer Ingelheim), an oral small molecule that inhibits EGFR, HER2 and HER4, is currently approved in non-small cell lung cancer (NSCLC) and is vying for a spot in SCCHN.

    The LUX-Head & Neck 1 trial of Gilotrif in 474 second-line SCCHN patients who had progressed on platinum treatment advanced the field at this year’s European Society for Medical Oncology (ESMO) meeting2 by being the first positive trial of a novel targeted agent since the pivotal Erbitux EXTREME trial.3 The LUX-Head & Neck 1 trial stratified patients 2:1 to receive either Gilotrif (40 mg daily, oral) or methotrexate (40 mg/m2, IV weekly), and patients were stratified by ECOG status (0 vs. 1) and prior EGFR inhibitor use. Median progression-free survival (PFS) was significantly improved in the Gilotrif arm (2.6 vs. 1.7 months, HR=0.80, p=0.030), as was overall response rate (ORR; 10.2 vs. 5.6%) and disease control rate (DCR; 49.1 vs. 38.5%). There was no significant difference in overall survival (median OS 6.8 vs. 6.0 months, HR=0.96, p=0.7). Patient-reported outcomes and quality-of-life measures favored Gilotrif. In addition, Gilotrif was less toxic with fewer dose reductions (32% vs. 42%), discontinuations (7% vs. 16%) and fatal events (0.6% vs. 3%). As expected, adverse events characteristic of EGFR inhibitors were higher in the Gilotrif arm (all grade rash 74% vs. 8%; Grade 3/4 rash 10% vs. 0%; all grade diarrhea 72% vs. 12%; Grade 3/4 diarrhea 10% vs. 2%). In the methotrexate arm stomatitis (39% vs. 43%), fatigue (25% vs. 32%) and neutropenia (<1% vs. 19%) were higher.

    Subgroup analysis from LUX-Head & Neck 1 suggests that patients who are HPV p16-negative and who have not received prior Erbitux are more likely to respond to Gilotrif, and prior Erbitux in 60% of the enrolled patients may have negatively biased the trial. How much better would the efficacy outcomes have been if patients had been preselected to be HPV-negative? With such a high number of patients being treated with Erbitux in front-line, would it have been possible to quickly enroll such a trial? Perhaps, as was suggested by the discussant, Dr. Seiwert, there are other biomarkers that might help refine which patients benefit the most from Gilotrif?

    The suggestion that prior treatment with Erbitux negatively biased overall survival outcomes in this trial may be a biologically sound rationale, but it is clinically irrelevant since Erbitux is an approved drug used in a large proportion of patients with advanced disease. This outcome may speak to acquired resistance to EGFR inhibition, which is an inherent risk to developing a drug with a similar mechanism of action in the relapsed/refractory setting. That PFS was significantly improved despite the majority of patients having received prior Erbitux suggests they were not completely resistant, that Gilotrif remains active in Erbitux-resistant clones, or that the mechanisms of action of these two drugs (monoclonal antibody vs. tyrosine kinase inhibitor) differ sufficiently to confer response when used in sequence.

    Similar outcomes have been observed with other EGFR inhibitors studied in the platinum-pretreated advanced SCCHN setting: Zalutumumab significantly improved PFS but not overall survival compared with best supportive care,4 and Iressa improved response rate but not PFS or overall survival when compared with methotrexate.5 The lack of overall survival benefit in LUX-Head & Neck 1 is concerning since there are so few effective options in this disease; one would expect that an active agent could have an impact on overall survival. The FDA may take a similar stance, requiring an overall survival benefit for approval, although other regulatory authorities (such as the European Medicines Agency) may be more willing to approve a drug with a PFS benefit alone.

    If approved, Gilotrif will compete directly with Erbitux in platinum-pretreated patients in the U.S., although ex-U.S. it will be largely unchallenged due to lack of approval of Erbitux in second-line. In the U.S., Erbitux will have nearly a decade head start over Gilotrif, although Gilotrif could have the advantage of being the first marketed drug to show a PFS benefit in a randomized trial in this setting (Erbitux was approved in the U.S. based on a single-arm study). A comparison of the available data suggests that Gilotrif has similar efficacy in second-line as Erbitux; in 103 platinum-resistant second-line patients, Erbitux demonstrated a 2.3-month time to progression and a 12.6% response rate.6 With physicians being so familiar with Erbitux, would they be willing to switch to Gilotrif given the available data? The fact that Gilotrif is an oral agent will help it differentiate itself. However, given the higher co-pays required for oral agents in the United States, patients’ pocketbooks may disagree. At this time, no head-to-head trials of Erbitux vs. Gilotrif are planned.

    The LUX-Head & Neck 1 trial results are the first to report as part of the larger LUX-Head & Neck program, which includes a companion trial of similar design conducted in Asian patients (LUX-Head & Neck 3), as well as two studies evaluating Gilotrif as post-remission therapy in locally advanced SCCHN (LUX-Head & Neck 2 and 4). It’s encouraging that PFS was improved in this first trial to report, and confirmation of activity in these other trials could go a long way to establish the degree of clinical benefit that Gilotrif confers in SCCHN and form a foundation upon which it may become adopted into clinical practice for this disease.


    1. Kantar Health, CancerMPact® Treatment Architecture US, accessed September 28, 2014
    2. Machiels, Abstract LBA29, ESMO 2014
    3. Vermorken, NEJM, 2008
    4. Machiels, LBA5506, ASCO 2010
    5. Stuart, JCO, 2009
    6. Vermorken, JCO, 2007


    SAN FRANCISO, CA – The 56th Annual Meeting of the American Society for Radiation Oncology (ASTRO) was in high gear this week. A record number of abstracts were submitted (n=2874); 2370 abstracts were presented, among these were 364 oral scientific sessions. More than 10,000 people from around the world attended the meeting, according to 2014 ASTRO President, Bruce T. Haffty, MD.

    At the opening press conference, Dr. Haffty highlighted three important initiatives of ASTRO – participation in the ABIM’s Choosing Wisely® campaign, the Stereotactic Radiosurgery (SRS) patient registry, and the Radiation Oncology Incident Learning System (RO-ILS).

    ASTRO unveiled its second list of 5 radiation treatments to question for routine use as part of Choosing Wisely®; these treatments/procedures should be thoroughly discussed by physicians with their patients to ensure appropriate use.

    In 2013, ASTRO issued its first list of 5 such treatments, and the good news is that this effort is beginning to pay off in clinical practice, conserving resources for appropriate use, informed Dr. Haffty.

    To find all 10 treatments that should be questioned before prescribing them go to: www.choosingwisely.com.

    The Stereotactic Radiosurgery (SRS) patient registry is a partnership between ASTRO and the American Association of Neurologic Surgeons (AANS). SRS purports to gather data from 30 diverse high-volume sites, with data specific to SRS, over the next 3 years. This national registry will define patterns of care in radiosurgery, and hopefully support informed decision-making to improve outcomes and possibly lower the costs of care for patients.

    The RO-ILS program sponsored jointly by ASTRO and the American Association of Physicists in Medicine (AAPM) is a patient-safety initiative that is the centerpiece of ASTRO’s Target Safely plan.  Radiologists are invited to submit data on radiation mishaps anonymously to give the radiation community a heads-up about potential problems and enable detection of patterns of safety.

    “The anonymity provides confidentiality and creates a secure environment,” Dr. Haffty said. “Radiation is an extremely safe modality. Nonetheless, we want to strive for zero errors and review mistakes.”

    Selected highlights from the Clinical Trials session include the following:

    • A study showing that radiation therapy was as effective as chemoradiation in reducing the incidence of dysphagia for patients with advanced esophageal cancer in the palliative setting (Abstract CT-03). This finding suggests that this patient population can avoid chemotherapy, its side effects and costs.
    • Convincing evidence showed that adding thoracic radiotherapy to prophylactic whole brain irradiation extends survival and reduces local recurrence in patients with advanced small-cell lung cancer (Abstract CT-05).
    • A very large study of more than 41,000 patients found that radiation improves 10-year survival by 50% in patients with early stage Hodgkin’s disease, yet radiation remains highly under utilized in this population in the U.S. (Abstract CT-08).  Medical oncologists are apparently not suggesting radiation because of perceived fears about long-term side effects.
    • Hypofractionated whole breast irradiation reduces acute toxicity and long-term fatigue compared with conventional fractionation in patients with stage 0-II breast cancer undergoing breast conserving therapy (Abstract LBA 3). Again, fears of side effects with a more concentrated dose of radiation delivered over a shorter time period have limited adoption of hypofractionated regimens.

    Highlights of the Plenary Session

    This included a talk centered on the ability of radiotherapy to induce antigen-specific immune responses when combined with anti-PD-1 blockade (Abstract PL-01). These preclinical data were selected for prime time presentation because of the intense interest in immunotherapy in the oncologic community with the recent successes in advanced melanoma.

    Another Plenary Session talk showed that 28 months of androgen deprivation therapy (ADT) combined with high-dose radiation therapy improved biochemical control rates and survival compared with only 4 months of ADT plus high-dose radiation in patients with intermediate and high-risk localized prostate cancer. (Abstract PL-02). The benefit of prolonged ADT was seen mainly in high-risk patients.

    This study adds to evidence that longer than 6 months or 1 year of ADT is needed to reap the survival benefits of this difficult-to-tolerate therapy.  A separate study, not presented at the plenary, showed that 18 months of ADT was just as effective as 36 months and improved quality of life when combined with radiation in this setting (Abstract 24). The optimal duration of ADT plus radiation remains to be established with certainty, but for now, longer than 12 months is better.

    A separate Plenary Session presentation demonstrated that one high-dose of radiation therapy was as effective as more frequent lower doses of radiation in preserving mobility in patients with malignant spinal cord compression who cannot undergo decompression surgery (Abstract LBA 2). These patients have a miserable prognosis, with a neurological deterioration-free survival time of 1.4 months and an overall survival of just 4 months.

    Other news of note is the development of a 10-gene signature to predict radiation sensitivity in a variety of solid tumors. This signature is treatment-specific rather than disease-specific, as distinct from genetic signatures for OncotypeDX or MammaPrint assays.

    The signature was the subject of 10 presentations at ASTRO, and featured at a Panel Discussion (Abstracts 2463 2224, 2615, 1246, 2649, 2899, 3633, 3916, 1420, 1031, and 2873).

    So far, the genetic signature has been tested and correlated with clinical outcomes in rectal, lung, esophageal, and brain cancer, as well as and metastatic colorectal and prostate cancers.

    The signature is the brainchild of Javier Torres-Roca, MD, Moffitt Cancer Center in Tampa, FL, and it took 11 years to develop, he said. He believes the signature will be clinically actionable – showing that higher doses of radiation are needed in resistant patients (according to the signature) and reducing radiation doses in sensitive patients.

    The signature is a joint venture with the NCI, Moffitt Cancer Center, and the Asan Medical Center in Korea. A company called CvergenX, founded by Dr. Torres-Roca and colleague Stephen Eschrish, PhD, has the license to market it, once it is CLIA or FDA approved.

    By John McCleery

    Five “Picks” Featured at Pre-Meeting Presscast for 2014 Breast Cancer Symposium

    September 2, 2014 — The 2014 Breast Cancer Symposium got a jump start at a pre-meeting Presscast highlighting 5 newsworthy studies to be presented in San Francisco later this week. Three studies focus on issues related to  preventive mastectomy and breast reconstruction surgery, and two other studies explore methods of encouraging repeat screening mammography and factors that predict loco-regional breast cancer recurrence in higher-risk breast cancer.

    Genetic counseling and prophylactic double mastectomy

    Celebrity publicity about health matters appears to pay off, according to a retrospective study. During the 6 months following Angelina Jolie’s announcement of her BRCA mutation status and subsequent prophylactic double mastectomy, there was a huge increase in requests for genetic counseling and testing at an academic cancer center in Ontario, Canada.  Moreover, this increase was observed among women with a positive family history of breast cancer – the population most at risk.

    During the 6-month period after Angelina Jolie’s revelation, referrals for genetic counseling increased from 487 to 816 — 90% — and the number of women who qualified for genetic testing increased from 213 to 437 (about 105%). The number of BRCA carriers identified increased by about 100% (from 29 before her announcement to 61 after).

    “This is a real triumph for public disclosure,” stated Presscast moderator Harold Burstein, MD, Dana-Farber Cancer Institute, Boston, MA.

    “Early detection of mutational status will help lower the incidence of breast cancer and ovarian cancer diagnosis, with preventive surgeries like mastectomy and oophorectomy. For women who already have breast cancer, a finding of BRCA positivity can increase the uptake of preventive treatments to reduce the risk of a second breast cancer,” said study author Jacques Raphael, MD, clinical fellow at Sunnybrook Odette Cancer Center in Toronto, Canada.

    Double mastectomy versus single mastectomy

    Over the past decade, there has been a trend toward increased use of double mastectomy in women diagnosed with breast cancer, even in women with single-sided breast cancer. Many women who opt for double mastectomy are average risk and will not derive additional survival benefit from double mastectomy versus single mastectomy. Thus, there is a need for more data on the risks of single versus double mastectomy. At the Presscast, Mark Sisco, MD, University of Chicago Pritzker School of Medicine, presented results of the largest series of analysis to date that examined 30-day complication rates of single versus double mastectomy with reconstruction.

    The analysis included 18,000-plus women diagnosed with breast cancer who participated in the American College of Surgeons national Surgical Quality Improvement Program. Results showed that although complications are rare for either type of surgery (overall rate, 5.3%), double mastectomy is associated with higher rates of implant loss and reoperation, need for transfusion, and longer hospital stays, compared with single mastectomy.

    In the study, almost two-thirds of women underwent single mastectomy, and slightly more than one-third, double mastectomy with reconstruction.  In both groups, 15,000 women received implant-based reconstruction rather than autologous-based reconstruction: 88.6% of the bilateral surgery group and 79.4% of the unilateral surgery group.

    “These findings are reassuring for women who are considering mastectomy with reconstruction and provide additional information that may inform their choice of surgery,” Dr. Sisco said. The information should aid in decision-making between single and double mastectomy, he added.

    Commenting on this study, Dr. Burstein said: “The take-home points are that complications are infrequent and medical complications are unaffected by the choice of double versus single mastectomy with reconstruction. But three complications are higher with double mastectomy: implant loss, reoperation, and bleeding requiring transfusion.  These are some of the first data we have seen that allow surgeons to quantify these risks for patients.”

    A separate study related to the growing use of double mastectomy focused on factors influencing choice of preventive double mastectomy versus single mastectomy among 150 women newly diagnosed with breast cancer. This is one of the first studies to look at women’s surgical preferences prospectively, prior to undergoing surgery. The study found that women with higher anxiety levels and less knowledge about breast cancer recurrence and survival were more likely to choose double mastectomy than single mastectomy.

    “There is so much information out there and patients can become easily overwhelmed. It is our job as doctors to be aware of each patient’s level of knowledge and concerns. We need to do a better job of educating patients that the risk of developing contralateral breast cancer is actually low, and that breast cancer can come back in other parts of the body regardless of the type of surgery they have,” said lead author Katharine Yao, MD, Director of the Breast Surgical Program at NorthShore University HealthSystem, Evanston, IL, and clinical associate professor of surgery at the Pritzker School of Medicine, University of Chicago.

    The survey included 55 questions related to knowledge about breast cancer recurrence and survival, general anxiety and depression, and surgery preference. Overall, 59% of respondents chose lumpectomy, 32% single mastectomy, and 9% double mastectomy. Twenty-four percent of women said they did not want to consider double mastectomy, 11% said they did not think it was an option, and none of these two groups chose double mastectomy. Fifty-eight percent (83 women) considered double mastectomy, and twenty-one percent (12 women) underwent double mastectomy.

    “Almost all women diagnosed with breast cancer think about double mastectomy,” Dr. Burstein commented. “The anxiety is understandable. We can address the knowledge gap with a multi-disciplinary effort. Personal preference remains important.”

    Adding the personal touch to increase repeat screening

    A study from the British Columbia Cancer Agency, in BC, Canada, showed that a low-tech intervention –family physician-signed reminder letters – boosted uptake of screening mammography in women who were overdue for screening. These personalized reminders were added to the standard schedule of postcard reminders for medical appointments. Over a 6-month period, the rate of return mammography screening was 22% among women overdue for screening who received only postcard reminders, and the rate rose to 33% if they received a personalized letter from their physicians.

    This good news reminds us that technology advances are not the only way to increase screening uptake. Lead author Elisa Chan, MD, formerly with the BC Cancer Agency and now a radiation oncologist at Saint John Regional Hospital in New Brunswick, Canada, and Assistant Professor at Dalhousie University, said “A very simple intervention from a family physician can make a big difference in improving the overall screening mammography return rate.”

    “A simple human touch increased rescreening rates by about 70%. This is tribute to the power of personal connection. Oncologists need to work with their primary care networks to improve rescreening rates,” Dr. Burstein commented.

    Predicting loco-regional recurrence following neoadjuvant therapy

    The fifth study featured at the Presscast identified 2 factors that can predict loco-regional recurrence (LRR) following neoadjuvant therapy in patients with stage I to III breast cancer: pathological complete response to neoadjuvant therapy (pCR, meaning no residual cancer) and tumor subtype. This study is preliminary and more research is needed to substantiate these findings; however, both factors should be considered when trying to select the best treatment options after neoadjuvant therapy, said lead author Eleftherios Mamounas, MD, Medical Director of the Comprehensive Breast Program at the UF Health Center in Orlando, FL, and Professor of Surgery at the University of Central Florida.

    The study was an analysis of 12 large clinical trials that included a total of 11,995 women with stage I to III breast cancer who received neoadjuvant chemotherapy prior to surgery. At a median follow-up of 5.4 years, the overall rate of LRR was 8.3%. The study showed that having a pCR to neoadjuvant chemotherapy was protective against loco-regional recurrence.  Women who had residual disease in the breast after neoadjuvant chemotherapy were 1.6 times more likely to recur compared to those with pCR; and those with residual disease in both the breast and the axillary lymph nodes were 2.8 times more likely to recur than those with pCR. The effect of pCR was seen in patients who went on to mastectomy as well as those treated with lumpectomy plus radiation.

    Tumor subtype was also a predictive factor. The lowest recurrence rate was in women with hormone-receptor-positive (HR+)/HER2-negative, Grade 1 and 2 tumors; at 5 years, these patients had an LRR rate of 4.2%. All other tumor subtypes had an elevated risk of LRR. For example, women with HR+/HER2-negative, Grade 3 breast cancer had a 9.2% risk of LRR; triple-negative breast cancer patients had a 12.2% LRR rate; HR+/HER2-positive breast cancer had an LRR rate of 9.7%; and women with HR-negative/HER2-positive breast cancer had an LRR rate of 14.8%.

    “These data add to our knowledge base and provide a complicated matrix that helps us understand the risk of LRR. This is ‘insider baseball’ data that set the table for deciding which patients require more aggressive therapy and which ones need less,” Dr. Burstein said.

    By Alice Goodman

    Beyond KRAS exon 2: Research at ASCO and Important Treatment Implications for Metastatic Colorectal Cancer

    New biomarker data in metastatic colorectal cancer (mCRC) presented at ASCO 2014 showed clinical implications of RAS mutations. The influence of RAS mutations on testing and treatment patterns of mCRC has profound implications on a tumor’s behavior throughout the course of the disease.

    The EGFR monoclonal antibodies, Erbitux® (cetuximab, Eli Lilly/Bristol-Myers Squibb/Merck KGaA) and Vectibix® (panitumumab, Amgen), have been shown to benefit patients with wild-type KRAS, but not patients with mutant KRAS exon 2. In Europe, both drugs’ labels were restricted to KRAS wild-type patients. The FDA recommended in 2009 that both drugs be used only in patients with wild-type KRAS.

    To understand the implications of some KRAS exon 2 wild-type patients not benefiting from anti-EGFR therapy, a retrospective analysis of the PRIME study evaluated the benefit of increasing the definition of a KRAS mutation. PRIME randomized 1,183 previously untreated patients to FOLFOX or FOLFOX plus Vectibix. Vectibix’s benefit was seen only in patients with KRAS exon 2 wild-type. (Douillard, J  Clin Oncol, 2010). PRIME followed patients forward, studying all RAS mutations, other mutations in KRAS, and mutations in NRAS. Expanding the definition of RAS wildtype to include other KRAS mutational sites as well as NRAS improved the HR for progression or death with combination therapy from 0.80 to 0.72. Progression-free survival was not improved by Vectibix in KRAS exon 2 wild-type patients who had other KRAS mutations in other exons (HR 1.28); (Douillard, NEJM, 2013).

    The PEAK Study, presented at ASCO 2013, evaluated Vectibix in mCRC patients with wild-type KRAS exon 2 and in patients wild-type for exons 3 and 4 of KRAS, and in exons 2, 3 or 4 of NRAS. Comparing Vectibix plus mFOLFOX6 or Avastin plus mFOLFOX6, 285 patients were randomized. In the KRAS exon 2 wild-type intent-to-treat group, progression-free survival was not significantly different between the two arms (HR 0.62, p=0.353). In the extended RAS wild-type subgroup,[1] patients on the Vectibix arm had a progression-free survival benefit (HR 0.65, p=0.029) compared to patients treated with the Avastin combination (Schwartzberg, J Clin Oncol, 2014).

    Retrospective RAS mutation status tumor sample analyses were performed from the OPUS and CRYSTAL studies and presented at ASCO 2014.  In the OPUS study, which evaluated FOLFOX4 plus Erbitux versus FOLFOX4 alone, Erbitux improved progression-free survival in KRAS exon 2 wild-type patients (Bokemeyer, Ann Oncol, 2011). Extended RAS mutations, beyond those in exon 2, were detected in 26% of patients. Extending this to consider both KRAS exon 2 and the extra possible mutation sites indicated further Erbitux benefit, as Erbitux had no benefit in KRAS exon 2 wild-type patients who possessed other KRAS mutations (median PFS: 7.5 months vs. 7.4 months, HR 0.77, p=0.60; Bokemeyer, Abstract 3505, ASCO 2014).

    The CRYSTAL study, Erbitux and FOLFIRI was associated with a significantly improved progression-free survival benefit compared to FOLFIRI in patients with the KRAS exon 2 wild-type phenotype (Van Cutsem, NEJM, 2009). Extended RAS mutations beyond that of KRAS exon 2 were detected in 15% of KRAS exon 2 wild-type patients. In these extended RAS wild-type patients, a significant benefit was associated Erbitux and FOLFIRI; mean progression-free survival: 11.4 months versus 8.4 months, HR 0.56, p=0.0002.  In patients with wild-type KRAS exon 2 but with mutations in other locations in KRAS or NRAS, there was no benefit from adding Erbitux to FOLFIRI in progression-free survival (7.2 months versus 6.9 months, HR 0.81, p=0.56; Ciardiello, Abstract 3506, ASCO 2014).

    Kantar Health’s CancerMPact® Biomarker Analysis Report reports approximately 36% of US CRC patients possess KRAS exon 2 mutations. Nearly 18,000 mCRC patients in 2014 are ineligible for first-line treatment with an anti-EGFR monoclonal antibody. These trials’ retrospective analyses suggest that 15-26% of patients who are seemingly wild-type for KRAS exon 2 actually possess other RAS mutations. For a common tumor like CRC, the percentage of patients not benefiting from targeted therapy is considerable.

    Also, discordance among tumor lesions has important testing implications. An ASCO 2014 presentation examined whether KRAS biomarker status was consistent between various lesions in mCRC patients. In 115 pairs of sequenced primary and metastatic tissue, the KRAS mutation concordance rate was 89%. Chemotherapy was associated with 3.5-times higher odds of discordance compared to patients who did not receive therapy between resection of primary and metastatic tumors (P = 0.008; Kopetz, Abstract 3509, ASCO 2014). A cohort of 10 patients showed that KRAS variant allele frequency differed between primary and metastases based on treatment.  (Graham, Abstract 3510, ASCO 2014). RAS mutation testing will likely be subject to mutation status discordance between the primary tumor and metastasis in mCRC, with important treatment and prognostic ramifications.

    Data at ASCO 2014 showed that anti-EGFR monoclonal antibodies are inactive in patients with KRAS exon 2 mutations and in patients with a mutation in any part of KRAS or other RAS genes. Retrospective analyses indicate that it is not sufficient to test mCRC patients for only KRAS exon 2 mutational status, but that all RAS mutations should be considered during pathological evaluation. Only patients who are wild-type for all RAS genes should be treated with EGFR-inhibitors. While the European Medicines Agency has already modified its authorization for Erbitux and Vectibix to exclude patients with any RAS mutations, the FDA still labels these agents for patients without KRAS exon 2 mutations. Discussions to expand the FDA label are presumed to be under way.

    Submitted by Julie Katz, MPH, M.Phil., Associate Consultant, Global Oncology Epidemiology, Kantar Health and Arnold DuBell, Ph.D., Consultant, Kantar Health

    [1] KRAS having no mutations in exons 2, 3 and 4 as well as being NRAS wild-type