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  • Opdivo has a brief opportunity to CheckMate other immunotherapies in head and neck cancer

    By: Arnold DuBell, Ph.D., M.B.A., Consultant, Clinical & Scientific Assessment, Kantar Health

    Patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) have few treatment prospects and a poor prognosis. In the first-line setting, patients are primarily treated with Erbitux® (cetuximab, Merck KGaA/Bristol-Myers Squibb/Eli Lilly) plus chemotherapy and in later lines of therapy may be treated with Erbitux monotherapy or a variety of other single-agent systemic therapies. No new targeted therapies have been approved since 2011, which was Erbitux’s frontline approval in combination with 5-fluorouracil and platinum agents. The unmet need for this indication is illustrated by the fact that only one-half of patients will receive second-line treatment, while even fewer patients will receive third-line therapy or beyond.1

    Patients with head and neck cancer will be cheered that the gains achieved by the new immunotherapies in indications such as melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) should soon be available for them and, moreover, that there will be options. The first late-stage data for this class of agents was presented today at the American Association of Cancer Research (AACR) as Dr. Maura Gillison presented results from the CheckMate-141 trial.2

    CheckMate-141 randomized (2:1) 361 patients with R/M SCCHN to treatment with Opdivo® (nivolumab, Bristol-Myers Squibb) 3 mg/kg every two weeks or the investigator’s choice of chemotherapy (methotrexate, docetaxel or Erbitux). Although most patients (45%) received only one prior line of therapy, almost 20% of patients were treated with three or more prior lines of systemic therapy. CheckMate-141 was stopped at its interim endpoint in January after crossing the defined threshold for meeting its overall survival (OS) primary endpoint, a 30% reduction in the risk of death. As reported at today’s session, patients treated with Opdivo enjoyed a 2.4-month OS improvement compared with patients treated in the control arm (7.5 months versus 5.1 months, HR 0.70, p=0.0101). Notably, at one year patients treated with Opdivo had twice the probability of remaining alive than patients on the control arm (one-year OS rate: 36.0% versus 16.6%). Moreover, the OS benefit may increase as 17.4% of patients are continuing Opdivo therapy compared with only 2.7% of patients on the control arm.

    Biomarker analysis was performed to determine the predictive value for PD-L1 positivity (defined as staining ≥ 1% and seen in 57.3% of the total sample) and p16 status (a marker for HPV positivity). Although PD-L1-positive patients saw a greater benefit for Opdivo than PD-L1-negative patients did (Table 1), PD-L1 negative patients did see a trend to benefit with Opdivo (11% reduction in risk of death); however, the Kaplan-Meyer curve separated dramatically at the tail end and provides some hope for this subgroup.  HPV positivity, as measured through p16 positivity, was not predictive of benefit.

    Table 1: Efficacy Data from CheckMate-141

    Opdivo Investigator’s Choice
    N mOS, mos N mOS, mos HR
    All patients 240 7.5 121 5.1 0.70
    PD-L1 ≥ 1% 88 8.7 61 4.6 0.55
    PD-L1 < 1% 73 5.7 38 5.8 0.89
    p16-positive 63 9.1 29 4.4 0.56
    p16-negative 50 7.5 36 5.8 0.73
    Source: Gillison, Abstract CT-099, AACR 2016


    As might be expected from this class of inhibitors, Opdivo was better tolerated than the controls. Only 13.1% of patients reported Grade 3-4 adverse events on Opdivo compared with 35.1% of patients on the control arm. Noteworthy primary toxicities of all grades for Opdivo included endocrine abnormalities (7.6% versus 0.9%) and pneumonitis (2.1% versus 0.9%).

    Bristol-Myers Squibb publically stated at the time of the early trial closure that it is in discussions with regulatory officials regarding filing. When Opdivo is approved, it will most likely need to immediately compete with Merck’s Keytruda® (pembrolizumab). Merck announced in early April that the U.S. Food and Drug Administration (FDA) granted priority review of its application for accelerated approval of Keytruda with a target action date of August 9, 2016. This application was based on updated results of the Phase Ib KEYNOTE-012 trial, which reported an overall response rate of 24.8%, median progression-free survival (PFS) of 2.2 months, and median OS of 9.6 months in head and neck cancer patients.3,4 Physicians will undoubtedly try to tease out efficacy and tolerability differences between the two agents, but generally the agents seem to be equally effective.

    Merck has ongoing Phase III trials for Keytruda in first-line (KEYNOTE-048, NCT02358031 and more on this below) and relapsed (KEYNOTE-040; NCT02252042) treatment as well as a Phase II trial (KEYNOTE-055; NCT02255097). Although the data for KEYNOTE-055 has not been publically reported, it may be included in Merck’s application for accelerated approval. The data for Opdivo suggests that it could be an effective option in frontline: The one-year OS rate (36.0%) reported in CheckMate-141 in pretreated patients compares favorably with data from the first-line EXTREME study,5 which reported a 40% one-year OS rate for Erbitux in combination with a platinum agent and 5-fluorouracil. However, Opdivo might have difficulties once the frontline KEYNOTE-048 trial reports. Unlike other Keytruda trials, KEYNOTE-048 does not require patients to be PD-L1-positive, so physicians could treat all of their patients with this agent once approved. If that wasn’t enough competition, MedImmune and AstraZeneca have two ongoing combination trials for their PD-L1 inhibitor durvalumab with their CTLA-4 inhibitor tremelimumab: the frontline KESTREL trial (NCT02551159) and the relapsed EAGLE trial (NCT02369874).

    As with other indications that immunotherapies have entered, increased competition means increased options for patients. Opdivo should enjoy its well-earned spotlight with the release of CheckMate-141 data. It will be interesting to see which new options – new immunotherapies or combinations with existing immunotherapies – patients can look forward to tomorrow.


    1. Kantar Health, CancerMPact® Future Trends and Insights; accessed April 19, 2016.
    2. Gillison, Abstract CT099, AACR 2016
    3. Seiwert, Abstract LBA 6008, ASCO 2015
    4. Chow, Abstract 2866, ESMO 2015
    5. Vermorken, NEJM, 2008

    The Immuno-Oncology 360° Meeting: Stakeholders Discuss the Future of IO

    “No single player can do this alone.”
    – Axel Hoos, Head, Immuno-Oncology, GSK

    By Neil Canavan

    New York – Stakeholders of every stripe in the cancer immunotherapy space gathered at the New York Academy of Medicine, February 2nd and 3rd, for the second annual Immuno-Oncology 360° meeting. The FDA was there, as was Wall Street, big pharma, and small biotech, academia sent several top clinical researchers, and, most poignantly, the very first successfully treated CAR-T patient also found time to attend (Emily Whitehead, age 10).

    This remarkable group of people had gathered to discuss a remarkable thing: the possibility of actually curing cancer.

    “I’m using the word ‘cure’ now,” said Axel Hoos, MD, PhD, senior vice president, Oncology Research and Development, GlaxoSmithKline. “It’s a word we have been shying away from for a long time in oncology, but now – we may actually have an opportunity to cure patients of metastatic disease.”

    Dr. Hoos, a co-organizer of the IO 360° meeting along with James Gully of the NCI, played a significant role in the clinical development of the drug that kicked off the IO revolution: ipilimumab. Improvements in overall survival seen with this drug in patients with metastatic melanoma were without precedent; some patients are so far out in time from their last treatment (over 10 years) as to be considered effectively cured.

    Ipilimumab (Ipi), the first “checkpoint inhibitor,” was approved in 2011. And since then the field has exploded.

    In 2015, a second checkpoint was approved (pembrolizumab), and then a third (nivolumab), and there are many checkpoints in the near-term pipeline. Beyond that there are the so-called CARs, the first CD19 flavored, and now a whole menu, and now also, the first oncolytic virus treatment has been approved (T-Vec), and bi-specific antibodies are in late stage development, and vaccines – yes, vaccines – vaccines are back and it is all getting to be just a bit too much…

    “The pace of progress has been so amazing,” said Dr. Hoos. “We’re almost not able to catch up in terms of even doing events that report on that progress.” Yet with each advance, each new opportunity, there are new questions, such as: How to safely use these drugs; who is more likely to respond; what combinations should be tried; how are IO trials different from targeted therapies; what is the FDA thinking about all this… How do you set a price on cure?

    “The purpose of this event is to try to address some of the needs of all stakeholders,” said Dr. Hoos. “From the business angle to the bedside, all the way to the last basic aspects of science.”

    On to Business
    Topics presented at IO 360° ran the gamut from regulatory perspectives to imaging software. However, the focus here will be on aspects of business development in cancer immunotherapy, and certain themes that emerged during the meeting regarding: Combinations, Collaborations, Contractions, and Cost.

    Peter Thompson, of the healthcare hedge fund, Orbimed, led off the business discussions. “There is no question that (IO) is really different,” he said. “The results from the (pivotal ipilimumab/nivolumab) Checkmate studies… This is dramatically different than what we’ve seen before.” And there are a lot of implications.

    One of the top concerns is with the FDA, though Thompson insists that, given the complexity of IO, the FDA is doing a pretty good job. “There’s been a lot of (IO) approvals, and relatively quickly. The FDA has been working very hard to try to adapt the regulatory space at a pace that is commensurate with the evolution of our understanding of the science.”

    More than ever, it’s critical that IO players be in constant communication with the FDA concerning trial design, in particular, having clearly defined endpoints according to the science.

    “Recall that the initial results for Ipi were a bit challenging to interpret,” said Thompson. “The overall response rate wasn’t really much to go on, in fact, Ipi and (tremelimumab) had similar data sets, yet one organization walked away from the one drug, and the other continued.”

    The problem wasn’t a lack of efficacy, it was a lack of understanding of how IO works. Simply put, immunotherapy takes longer, and works in different ways than targeted treatments. Responses to IO therapies are so different in fact that a new response criteria is now recognized as the standard for IO investigations (irRC; Immune-Related Response Criteria).

    One of the many open questions going forward is how to design a trial for the multitude of upcoming IO/targeted therapy combinations. Think of all the opportunities for different trial designs: IO versus targeted treatment; IO/targeted versus targeted/targeted; novel/novel IO agents versus IO approved agent/novel IO…

    Moreover, is an overall survival endpoint even valid for a drug that is potentially curative?

    As GSK’s Dr. Hoos suggests, “With the increasing survival rates we’re seeing with these drugs you may not be able to use overall survival as a primary endpoint if you need to wait ten years for the data. It is not realistic—it requires us to rethink the way we measure activity.”

    As these novel therapeutic trails continue to be blazed, the only and best advice for now is to talk to the FDA early, and often.

    Gobble gobble
    While the FDA grasps for an understanding of utterly novel technologies, pharma has been trying to figure out how to either become competitive, or vault ahead of the competition. To wit, a spate of recent deals:

    • Merck buys IOmet Pharma (January 2016; IDO inhibitor asset)
    • Merck buys cCAM Biotherapeutics (July 2015; checkpoint asset)
    • BMS buys Flexus Biosciences (February 2015; IDO asset)
    • Novartis buys CoStim Pharmaceuticals (February 2014; PD-1 asset)
    • AstraZeneca buys Amplimmune (August 2013; PD-1 asset)

    Note that all five transactions involved checkpoint inhibitors.

    “Checkpoints will be the foundational components of IO regimens going forward,” said Jeff Bockman, of the healthcare consultancy, Defined Health. “It’s like taxanes in the chemotherapy arena – it’s always a taxane plus something else.”

    So does everyone need a checkpoint? Business trends seem to suggest so. For example, the acquisition of Bionovion (checkpoint asset) in late 2015 by Aduro: “It’s a real advantage if you bring something like this in to your franchise and have the ability to control, say, anti-PD-1 and to combine it with whatever novel agents you have, rather than go outside,” said Bockman.

    Michael King, senior biotech analyst at JMP Securities agrees. “PD-1 is such an axis—it would be like treating HIV without having a nuke backbone—it’s a foundational therapy.” King believes that in the checkpoints setting, and in the field overall, smaller players will be snapped up. “When you think about the technical complexity, the capital allocation needed to be directed toward developing follow-on therapies, the ability to go in and negotiate with payer groups, be it US or elsewhere… there will be more upward consolidation.”

    Diversify or die
    Smaller players can take heart in the example of Agenus, under the leadership of Robert Stein.

    “As soon as I got involved in this space it became clear that combinations would be required,” said Stein. “And it won’t be the same combination for every patient—not like in HIV or HCV—for cancer you have to know the mutational landscape of neoepitopes (mutations that are likely to be unique to a given patient).”

    “It was also clear that we need to shape the immune response, or disarm the tumor if it has deployed a defense mechanism—that’s the reason to get into the checkpoint modulator space.” To that end, Agenus is in checkpoint partnerships with Incyte, and Merck, and to help mine for neoepitopes Agenus just acquired Phosimmune.

    At GSK (they of the deep pockets) the admonition that “we can’t do this alone” is interpreted as “no modality can do this alone,” and in recognition of that understanding, GSK is developing potentially overlapping assets and recognizing what it already has in-house.

    “There are so many new technologies pushing out,” said Dr. Hoos. “Bispecific antibodies, oncolytic virus, vaccines, and CARs, are all just the part of the story. To be successful in the long run we need to integrate all this information and recognize the modalities we have available so we maximize their potential.”

    Furthermore, maximizing potential does not mean getting really good at one thing – that won’t fly after your IO IPO:

    “Not that many companies, after they go public, use their funding to make other M&A and BD decisions,” said Mark Simon, Torreya Partners. And in the IO space that’s a problem. “If you look, for example, at Bellicum, and some of the other CAR-T companies like Juno, they were very aggressive in bringing in other technologies. Others were more complacent,” he said. “Time will tell which approach is better, but history has shown that the ones who get out there and realize that there are good technologies outside their walls generally do better.”

    “Vaccines are being reevaluated,” said Defined Health’s Bockman. “Single epitope, whole cell tumor lysates, tumor RNA, DNA, peptides, danger signals, costims, adjuvants… it’s a very diverse space.” Yet, there is no small amount of trepidation from investors when presented with vaccine opportunities. “There’s still a lot of misperception and baggage from the past,” but going forward the writing on the wall is clear: vaccines failed for lack of understanding about the immune system, and the checkpoints, and now with that knowledge in hand…

    “I don’t see pulses raging just yet for cancer vaccines companies,” said JMP’s Mike King, “but I don’t think it would take a whole lot of data to move that needle.”

    A few end notes, consensus observations, and advice on overcoming boredom:

    • The therapeutic potential for CAR-T programs is difficult to estimate—suffice it to say it is extreme. Marketability, however, is an open question. How many CAR-T manufacturing facilities will be needed? Will Novartis have one, and Juno another, or, if technology allows, will each company have one at the patient’s bedside? What about off-the-shelf CAR-T cells, does that make more sense? Will allogenic CAR-T cells be as effective?

    • How are investigations with IO/targeted combinations going to be prioritized? There are literally hundreds of potential combinations, and there is not enough money, nor are there enough patients to test them all. Deep knowledge of your drug’s mechanism will be critical in making the right choices.

    • For IO drugs there may not be a maximum tolerated dose. As IO expert, Dr. Jedd Wolchok of Memorial Sloan Kettering Cancer Center stated, “We’re still figuring out how to use these drugs.” For instance, the dose of PD-1 for lung cancer is much less than that used in melanoma patients. Trial designs will have to take this into account.

    • Cost. How do you price cure? Or, perversely, as one panelist pointed out, how do you adjust for the lost revenue from patients in the relapsed/refractory disease setting if those patients are being cured instead?

    • In the case of Emily Whitehead, what do you do when you’re with your parents? You play Candy Crush on your iPhone just like any other perfectly healthy 10-year-old would do.

    For more information on the IO 360° conference:


    Five Things You Should Know About the Oncology Care Model

    By Gena Cook, CEO, Navigating Cancer

    2016 promises to be a transformative year for cancer care delivery, with the roll out of the Oncology Care Model (OCM). In a few short months, the Center for Medicare and Medicaid Innovation (CMMI) is expected to announce the 100 participants from the pool of OCM applicants that were submitted last June.

    What do cancer centers need to understand about OCM now?

    OCM is a payment reform model designed to improve episodes of care for patients undergoing chemotherapy. The goal of this payment model is to promote care delivery at the lowest cost, in the most medically-appropriate setting. An OCM episode of care begins with the initiation of chemotherapy treatment and extends over the following six-month period, but one beneficiary may undergo multiple OCM episodes of care during the five-year OCM performance period. Provider participants will consist of physician group practices, as well as practitioners in solo practice. One key feature of OCM is that it places the medical oncologist in the lead role of managing care quality, delivery and cost. In exchange, providers will earn a management fee of $160 per beneficiary per month. That’s $960 per 6-month episode.

    In addition, practices will have the potential of earning an average of 12% shared savings through semi-annual performance-based payments – a figure which could amount to $16,000 per beneficiary per year.

    Both of these OCM payments are in addition to practices continuing to bill traditional Medicare fee-for-service claims, including reimbursement for Part B drugs administered during OCM episodes at ASP plus a 4% to 6% margin.

    While some of the OCM rules and specifications will remain vague pending the official start, here are five over-arching trends we can begin to consider now:

    1. The program is designed to impact cancer care nationwide.. Whether your practice applied or not, your hospital may be impacted. Participating practices will engage in practice transformation and this will be a valuable learning opportunity for cancer programs everywhere. OCM is a multi-payer model and many national payers applied. The practice of oncology is shifting quickly to value-based payment models, and just as early-adopters of medical homes will more easily qualify for OCM, early-adopters of OCM will be better poised to meet the next wave of value-based payment requirements.
    1. Coordination of integrated care teams will be crucial. One of the core tenets of OCM is the creation and use of a comprehensive care plan and as part of the care plan, an integrated care team will be designated. This is how responsibility for each aspect of the patient’s care will be made explicitly clear (e.g., the cancer care team, the primary care/geriatrics care team, etc.). As this type of cross-functional integration becomes the norm, conversations between providers and payers will revolve increasingly around care coordination and management fees.
    1. Data sharing is a must. Another core tenet of OCM is the use of data for continuous improvement in patient care management and quality. OCM data sources will include practice-reported data, patient-reported data and Medicare claims data. Even before the program begins, you can expect the collection and distribution of baseline data on designated measures to inform initial evaluations. While CMMI will provide data feedback reports, practices that push for broader interoperability of their health IT solutions will be best positioned for success in the OCM landscape. Practices can do this now by asking their current EMR vendors to provide the necessary interfaces to make all of the practice’s IT systems interoperable, and by taking steps in future IT contracting processes to protect themselves from potential information blocking by ensuring they have the necessary interfaces specified in their contracts. The goal is to use the wealth of data that is amassing now to better understand medical practice at the national scale, improve outcomes, realize risk-stratified care delivery, and meet the requirements of alternative payment models. To achieve this, practices will need all of their IT vendors (not just their EMR) to support data interoperability.
    1. Patient-reported outcomes (PROs) will be mission-critical. The use of PROs in care delivery is on the rise. This is because data shows that people who are engaged and involved in their own healthcare feel more than just greater satisfaction with their experience; they actually realize better outcomes. Only through the productive PROs that come from effective patient engagement will providers be able to deliver the proactive quality of cost-efficient care that OCM is all about. When patients are motivated to communicate their symptoms or side effects early on, providers can intervene before things escalate into emergency situations. This is why there is an increased focus on the use of patient engagement tools and quality performance reporting in the Merit-based Incentive Payment System (MIPS) which, like OCM, will also shape how physicians are paid in healthcare’s value-based future.
    1. New technology solutions are needed. To most cancer programs, more than a few OCM quality measures will be completely novel. Only through the right combination of people, processes and new technical capabilities will programs be able to transform clinic workflow to meet and report on these new quality measures. For example, beyond attesting to Meaningful Use Stage 1 by the end of the first model performance year, OCM practices will need to support the electronic availability of patient-centered, integrated care plans. Also needed are user-friendly tools for collecting and reporting PROs, for assessing satisfaction and psychosocial distress, and for connecting patients with local support services as appropriate. New health information technology will be required beyond the standard clinical EHR systems, and the ability for these systems to readily interoperate with the EMR will be mandatory.

    Putting these features in place now won’t just set practices up for success in advance of the inflection point in cancer care delivery that OCM will bring; they will improve experiences, and outcomes, for cancer patients. And that, ultimately, is the point.

    Continued Expansion of Immuno-Oncology – GI Malignancies Are Not Immune

    By: Arnold DuBell, Ph.D., M.B.A., Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health 

    It seems impossible to attend an oncology conference these days without immuno-oncology being a significant focus, and it’s starting to become passé. Well, not quite. Two years ago the idea of this treatment class playing a role in gastrointestinal (GI) cancers seemed unlikely. However, as we learned yesterday at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium, these tumors might be immune-sensitive after all. Updated data and new results were reported for several checkpoint inhibitors, which collectively support the continued development of these drugs in GI cancers.

    In gastric cancer, first results of the CheckMate-032 trial were presented for Opdivo® (nivolumab, Bristol-Myers Squib/Ono Pharmaceuticals).1  In a heavily pretreated population of 59 patients with gastric or gastroesophageal junction (GEJ) cancer, single-agent Opdivo (at a dose of 3 mg/kg) resulted in a 14% objective response rate (ORR), which included one patient with a complete response. Among the responding patients, median duration of response was 7.1 months. Across all patients, the median progression-free survival (PFS) was 1.4 months, the median overall survival (OS) was 5.0 months, the six-month OS rate was 49%, and encouragingly 36% of patients were alive at one year. There was a slight correlation between ORR and PD-L1 expression, with higher ORR observed in PD-L1-positive patients compared with PD-L1–negative patients (27% versus 12%, using expression in 1% or more of the tumor cells as the definition of PD-L1-positivity). Consistent with studies in other tumor types, Opdivo was well tolerated, with only 17% of patients experiencing a Grade 3 or 4 adverse event. The efficacy data for Opdivo appear, at first glance, to be in line with the activity previously reported for Keytruda® (pembrolizumab, Merck & Co.): 22% ORR, 1.9-month median PFS, and 69% six-month OS in heavily pretreated PD-L1-positive gastric cancer.2

    Also debuting data in gastric/GEJ cancer at ASCO GI 2016 was avelumab (MSB0010718C, Merck KGaA/Pfizer). The gastric cancer cohort of the JAVELIN Solid Tumor trial enrolled 75 patients and treated them with avelumab monotherapy in either the second-line setting (n=20) or as maintenance therapy following first-line chemotherapy (n=55).3  In second-line, avelumab produced a 15% ORR and 2.7-month PFS among all patients, and like the Opdivo results there was a suggested correlation between ORR and PD-L1 expression, with higher ORR observed in PD-L1-positive patients compared with PD-L1–negative patients (20% versus 0%, using 1% or more as the definition of PD-L1 positivity along with caution due to small sample sizes). Similar outcomes were reported in the JAVELIN Solid Tumor Japan trial’s gastric cancer cohort: 15% ORR in all patients and suggested correlation with PD-L1 expression (40% in PD-L1-positive versus 7% in PD-L1-negative patients, using 1% or more as the definition of PD-L1 positivity and caution due to small sample sizes).4

    Although these study data are all preliminary, they serve collectively to provide evidence that checkpoint inhibition has clinical activity in metastatic gastric cancer and support the multiple Phase III trials that are already underway for all three of these drugs. While these data also suggest PD-L1 overexpression might correlate with improved ORR, the data are reminiscent of outcomes observed in other tumors and further perpetuate ideas that PD-L1 might not be the best biomarker to select patients for treatment with a checkpoint inhibitor.

    Results were also reported for this class in metastatic esophageal cancer. The Ono Pharmaceuticals-sponsored Phase II ONO‐4538‐07 study enrolled 65 squamous cell carcinoma esophageal cancer patients and treated them with single-agent Opdivo (3 mg/kg q2w). In this heavily pretreated population, Opdivo produced a 17% ORR by central review, with 1.5-month median PFS and 10.8-month median OS.5  Among those patients who achieved a response, the duration is quite long (median was not reached, but all responding patients seemed to remain in response for at least eight months based on a review of the spider plot). This trial did not provide an analysis of outcomes according to patient PD-L1 status or other biomarker.

    The KEYNOTE-028 trial evaluated Keytruda (10 mg/kg q2w) in relapsed/refractory metastatic esophageal cancer patients, specifically enrolling only PD-L1-positive patients, defined as expression in 1% or more of tumor or inflammatory cells or positive bands in the stroma. In  patients with predominantly squamous cell carcinoma treated in the third-line or later, the observed ORR of 30% among evaluable patients (n=23) was quite encouraging.6 These efficacy data were a reprisal of data originally presented at ASCO 2015,7 but of particular interest was new data presented on a gene expression signature composed of six genes that play a role in adaptive immune response. In tumors with a high inflamed signature score, there was a propensity toward higher likelihood of prolonged PFS compared with patients with a low score. Even among patients with a high signature score, there still appeared to be a subpopulation with greater benefit, so more work is needed to fully understand how to identify the most responsive patients with PD-1 inhibition, but this data was an intriguing step in the move beyond PD-L1 immunohistochemistry assays.

    As in gastric cancer, development of PD-1 inhibitors is advancing quickly in esophageal cancer. Opdivo and Keytruda have recently initiated Phase III trials in this disease, with both targeting the relapsed/refractory setting.

    The data for checkpoint inhibitors as reported at ASCO GI 2016 is focused within gastric, GEJ and esophageal cancers. However, previously reported data for Keytruda in colorectal cancer (CRC) was discussed, especially within the context of patient selection for use of checkpoint inhibitors. As reported originally at ASCO 2015, CRC and other GI tumors with high microsatellite instability (MSI-H) or that are deficient in mismatch repair (dMMR) have demonstrated high ORR and prolonged PFS when treated with Keytruda.8 Confirmation of this activity is ongoing in Phase II and Phase III studies. Clinical trials are also currently ongoing with Keytruda and Opdivo in pancreatic cancer and hepatocellular carcinoma.  Although we won’t see clinical data in these indications at ASCO GI 2016, today’s Keynote address by Dr. Robert Vonderheide presented intriguing in vitro and in vivo data that supports pursuit of immunotherapy in pancreatic cancer through a combination approach of immune response activation (using chemotherapy, radiotherapy, and/or vaccination) and immune response maintenance (using checkpoint inhibition).9 For now, checkpoint inhibitors continue to garner significant attention across a range of cancer indications, and gastrointestinal cancers can no longer be considered immuno-insensitive.


    1. Le DT, Bendell JC, Calvo E, et al.; “Safety and activity of nivolumab monotherapy in advanced and metastatic (A/M) gastric or gastroesophageal junction cancer (GC/GEC): Results from the CheckMate-032 study;” J Clin Oncol 34, 2016 (suppl 4S; abstr 6).
    2. Muro K, Bang Y-J, Shankaran V, et al.; “Relationship between PD-L1 expression and clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012;” J Clin Oncol 33, 2015 (suppl 3; abstr 3).
    3. Chung HC, Arkenau HT, Wyrwicz L, et al.; “Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with advanced gastric or gastroesophageal junction cancer;” J Clin Oncol 34, 2016 (suppl 4S; abstr 167).
    4. Nashina T, Shitara K, Iwasa S, et al.; “Safety, PD-L1 expression, and clinical activity of avelumab (MSB0010718C), an anti-PD-L1 antibody, in Japanese patients with advanced gastric or gastroesophageal junction cancer;” J Clin Oncol 34, 2016 (suppl 4S; abstr 168).
    5. Kojima T, Hara H, Yamaguchi K, et al.; “Phase II study of nivolumab (ONO-4538/BMS-936558) in patients with esophageal cancer: Preliminary report of overall survival;” J Clin Oncol 34, 2016 (suppl 4S; abstr TPS175).
    6. Doi T, Piha-Paul SA, Jalal SI, et al.; “Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475);” J Clin Oncol 34, 2016 (suppl 4S; abstr 7).
    7.  Doi T, Piha-Paul SA, Jalal SI, et al.; “Pembrolizumab (MK-3475) for patients (pts) with advanced esophageal carcinoma: Preliminary results from KEYNOTE-028;” J Clin Oncol 33, 2015 (suppl; abstr 4010).
    8. Le DT, Uram JN, Wang H, et al.; “PD-1 blockade in tumors with mismatch repair deficiency;” J Clin Oncol 33, 2015 (suppl; abstr LBA100).
    9. Vonderheide RH, “Inflammatory networks and cancer immune surveillance;” Keynote address; American Society of Clinical Oncology Gastrointestinal Cancers Symposium; San Francisco, California; February 22, 2016.

    2016 ASCO Gastrointestinal Cancers Symposium Kicks Off; NETs in the Spotlight

    The 2016 Gastrointestinal Cancers Symposium, being held January 21-23 in San Francisco, will attract cancer researchers and clinicians from around the world to hear the latest in colorectal, pancreatic, liver, esophageal, gastric and other GI malignancies. Three studies were previewed ahead of the meeting in a presscast.

    Two support new treatments for neuroendocrine tumors (NETs) of the GI tract. NETs are a group of cancers that originate in hormone-producing (ie, neuroendocrine) cells of various organs in the body, with 60% being gastrointestinal. While they are diagnosed in the US each year in only about 8,000 people, their incidence is increasing and there are few treatment options after patients progress on somatostatin analogs (SSAs), according to presscast moderator and ASCO Spokesperson Smitha Krishnamurthi MD, of Seidman Cancer Center and the Case Comprehensive Cancer Center in Cleveland, Ohio.

    Results of a third study suggest that preoperative treatment of locally advanced rectal cancer can be delivered more conveniently.

    Everolimus Effective in NETs of GI Origin

    The mTOR inhibitor everolimus, which is approved for the treatment of pancreatic NETs, has demonstrated efficacy against NETs in the GI tract and those of unknown origin, according to a subgroup analysis of the international phase IIII RADIANT-4 trial (Abstract 315).

    Patients randomized to receive everolimus (10 mg/day) had approximately a doubling in progression-free survival (PFS) versus placebo in this post-hoc analysis. In the primary analysis of RADIANT-4, presented at the European Cancer Congress, everolimus reduced the risk of progression by 52% among patients with advanced GI and lung NETs (P < 0.00001).

    “This was quite a stunning finding—a 7-month improvement in PFS. We are now looking in detail at the GI subgroup,” said Simron Singh, MD, MPH of Sunnybrook’s Odette Cancer Centre in Toronto, Canada, who presented the latest findings to the media.

    The current analysis included 175 patients with previously treated advanced GI NETs and 36 patients with NETs from an unknown site. All patients had non-functional tumors, meaning the tumors were causing few or no symptoms initially.

    In the overall population of this subanalysis, everolimus reduced the risk of disease progression by 40% or more, compared to placebo. Median PFS was 13.1 months versus 5.4 months among patients with GI tumors (HR =0.56) and 13.6 versus 7.5 months, respectively, among those with tumors of unknown origin (HR = 0.60).

    “This was clearly a significant improvement in stopping tumors from growing with everolimus,” Dr. Singh commented.

    When the researchers examined the findings in the midgut (ileum, jejunum, cecum, duodenum, appendix and small intestine) versus non-midgut (stomach, colon, rectum) locations, they found relative risk reductions of 29% and 73%, respectively, favoring everolimus, he said.

    Additionally, prior treatment with an SSA did not reduce the benefit of everolimus, as the relative risk reduction was approximately 50% in groups with and without prior treatment. “Patients appeared to benefit from everolimus across the board,” he said.

    The most common adverse effects with everolimus were those familiar to the drug—stomatitis, diarrhea, peripheral edema, and fatigue.

    “This study in advanced progressive NETs suggests everolimus is a new, effective, exciting treatment option,” Dr. Singh concluded.

    Dr. Krishnamurthi commented on the results. “While everolimus is already approved for treating pancreatic NETs, these results demonstrate that it may also be effective for a broader group of patients. The findings are important, showing an improvement in the risk of progression by more than 40%, without severe toxicity. This is a welcomed finding for patients with limited systemic treatment options.”

    NETs in Midgut Benefit from Radiolabeled SSA

    A novel radiolabeled SSA, 177Lu-DOTA0-Tyr3-Octreotate (177Lu-Dotatate) (Lutathera), reduced the risk of disease progression or death by 79% in an international phase III study of previously treated, advanced NETs of midgut origin (Abstract 194).

    177Lu-Dotatate belongs to a fairly new therapeutic class known as peptide receptor radionuclide therapy (PRRT). With 177Lu-Dotatate, an SSA is attached to a radioactive molecule, enabling targeted delivery of radiation to tumors, explained Jonathan R. Strosberg, MD, of Moffitt Cancer Center, Tampa, Florida.

    “There have been several generations of PRRTs. 177Lu-Dotatate is the latest, and it has a relatively favorable therapeutic index compared to previous generations,” Dr. Strosberg indicated.

    “NETTER-1 is the first trial to test a PRRT in a randomized, prospective fashion,” he said.

    NETTER-1 randomized 230 patients who progressed after SSA therapy to 177Lu-Dotatate or to more SSA treatment with high-dose octreotide LAR 60 mg. Patients in the experimental arm were treated once every 8 weeks for a total of 4 administrations of 177Lu-Dotatate.

    At the time of analysis, 23 patients in the experimental group had disease progression, compared to 67 in the octreotide group. Median PFS was not reached with 177Lu-Dotatate but was 8 months with octreotide LAR (HR = 0.21; P < 0.0001).

    “The study met its primary endpoint in extremely impressive fashion,” Dr. Strosberg commented in the presscast. “With roughly a year and a half of follow-up, the expected median PFS is likely to be longer than 3 years.”

    Response rates were also higher with 177Lu-Dotatate, 19% versus 3% (P < 0.0004). While this rate may sound low, he explained that NET patients are very resistant to systemic therapy, and response rates to other treatments “are in the single digits.”

    “This is the only large study showing double-digit response rates in midgut NETs, and the difference is highly significant,” he said.

    Serious adverse events were reported in 26% of the experimental arm and 24% of the control arm. At the Symposium, Dr. Strosberg will provide more detail on these.

    To date, 13 patients in the experimental arm have died, versus 22 in the control arm (P < 0.019), a numerical trend that does not yet meet statistical significance for this interim analysis, he said, “but is suggestive of an improvement” in overall survival.

    Dr. Krishnamurthi commented that NETTER-1 shows 177Lu-Dotatate to have “an impressive ability to slow the growth of midgut tumors progressing on an SSA.” She was further impressed with the response rate in a population typically unresponsive to systemic treatments. “It’s exciting to see this novel therapy,” she said.

    Shorter Radiation Course Benefits Locally Advanced Rectal Cancer

    For preoperative treatment of locally advanced rectal cancer, a short, 5-day course of radiation followed by chemotherapy may be as effective as standard chemoradiation, which delivers radiation over about 5 weeks, with concurrent chemotherapy typically given in the 1st and 5th weeks, Polish investigators are reporting at the Symposium (Abstract 489).

    The phase III study by the Polish Colorectal Study Group found that 5 days of radiation followed by 3 cycles of chemotherapy prior to surgery achieved similar outcomes with less toxicity.

    “The new regimen has similar efficacy but causes fewer side effects and is more convenient for patients. It is also less costly compared to standard chemoradiation, so it may be especially valuable in limited-resource settings,” said Lucjan Wyrwicz, MD, PhD, of the Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology in Warsaw.

    The study enrolled 515 patients with stage cT3 or cT4 rectal cancer, assigning them to standard chemoradiation or to the short-course radiation regimen. All patients received FOLFOX4 (5-FU, leucovorin, oxaliplatin). In the experimental arm, 3 cycles of chemotherapy followed 5 days of radiation (5 x 500 cGy), while in the control arm chemotherapy was given concurrently with radiation, which was delivered over about 5 weeks. The protocol was amended partway through the study to state that the use of oxaliplatin (which is relatively toxic) was by physician discretion and was not mandated. Both groups underwent surgery approximately 12 weeks after starting radiotherapy.

    The short-course approach achieved outcomes that were as good as, or better than, those of the conventional arm. The treatments conveyed the same ability to perform radical surgery and achieved similar disease-free survival, but the short-course was associated with less toxicity, Dr. Wyrwicz reported.

    R0 resection (negative surgical margins), the primary endpoint, was achieved in 77% of the experimental arm and 71% of the control arm (P = 0.081), indicating a trend in favor of the short-course approach. Pathologic complete responses were achieved by 16% and 12%, respectively (P = 0.17).

    Rates of disease-free survival and local failure at 3 years were, for the experimental and control arms respectively, 53% versus 52% (P = 0.85) ad 22% versus 21% (P = 0.82). Acute toxicities were observed in 75% and 83%, respectively (P = 0006), though rates of grade 3+ toxicities were similar at 23% and 21%, he reported.

    While those endpoints were not significantly different, the Kaplan-Meier curves for overall survival separated at about 2 years and plateaued afterward, with 3-year survival rates of 73% with the short-course radiation modality and 65% with chemoradiation (P = 0.046).

    This preliminary observation of an 8% absolute survival benefit warrants a closer look for factors that may be contributing to a survival benefit, he added.

    “Despite the fact that the trial was negative—it did not show superiority of the short-course for radical resection rate—we showed for the first time that there is an alternative to standard chemoradiation lasting more than 5 weeks,” Dr. Wyrwicz commented.

    According to Dr. Krishnamurthi, short-course radiotherapy has been more widely used in Europe than in the US, largely because of conflicting results of studies that have compared it to standard treatment. “But these results may lead to increased use of this method here,” she said. “We’re trying to fine-tune how we deliver treatment to patients prior to surgery, to maximize efficacy and convenience and minimize side effects.”

    by Caroline Helwick

    Highlights of 2016 ASCO Genitourinary Cancers Symposium

    The 2016 Genitourinary Cancers Symposium will kick off this coming Thursday in San Francisco. At a pre-meeting press cast, investigators were enthusiastic about the meeting, which will focus on “patient-centric” care. They spoke about 3 separate studies: two related to prostate cancer and one in advanced kidney cancer.

    Another Benefit of Aspirin?

    [Abstract 306]

    Regular use of aspirin appears to lower the risk of developing and dying from lethal prostate cancer, according to a large observational study. Regular aspirin use did not, however, lead to a reduction in the overall incidence of prostate cancer.

    Lead study author, Christopher Brian Allard, MD, Urologic Oncology Fellow at Brigham and Women’s Hospital and Massachusetts General Hospital in Boston said: “It is premature to recommend aspirin to prevent lethal prostate cancer, but men with prostate cancer who may already benefit from aspirin’s cardiovascular effects could have one more reason to consider regular aspirin use.” He added that discussions with patients about aspirin should include bleeding risks versus benefits.

    Previous studies of aspirin and prostate cancer have been equivocal. Dr. Allard said his is the first study to focus specifically on prevention of lethal prostate cancer and to clarify the potential role of aspirin in prevention of advanced disease.

    The study was based on data from 22,071 men enrolled in the Physician’s Health Study. Over 27 years of follow up, 3193 men were diagnosed with prostate cancer and 403 developed lethal prostate cancer, defined as metastatic disease or prostate cancer-specific death. Regular aspirin use was defined as 3 or more tablets per week (of any dosage).

    A multivariate analysis adjusted for age, race, body mass index, and smoking status showed that regular aspirin use was protective in the overall trial, resulting in a 24% reduced risk of developing lethal prostate cancer versus no regular aspirin use. Among men with a diagnosis of prostate cancer, regular aspirin use after diagnosis was associated with a 39% reduced risk of dying of prostate cancer.

    Regular aspirin use did not protect against developing prostate cancer, high-grade prostate cancer, or locally-advanced prostate cancer.

    Dr. Allard and colleagues will study mechanisms by which aspirin reduces the risk of prostate cancer death. More research is needed to select subsets of men that would benefit from regular aspirin use and to determine the optimal dose.

    Sumanta Pal, MD, ASCO spokesperson and moderator of the presscast pointed out that there may be one more benefit of aspirin beyond that seen in colorectal cancer and cardiovascular disease. “….It’s thought-provoking that this low-cost medication may lower the risk from prostate cancer,” he said.

    New Blood Test May Guide Treatment Decisions

    (Abstract 163)

    A preliminary study suggests that an experimental blood test based on a “liquid biopsy” may be useful for individualizing treatment decisions for men with advanced prostate cancer. The non-invasive assay scans a patient’s blood for cancer cells (i.e., circulating tumor cells [CTC]), analyzing their shape and size as well as genetic makeup to predict whether patients can benefit from hormone-directed therapies such as abiraterone and enzalutamide

    A “liquid biopsy” based on easily-obtained blood samples is much more convenient and comfortable for patients than invasive tumor biopsy. Also, this assay allows for earlier adjustments in therapy compared with an invasive tumor biopsy.

    “Not all men respond equally to either enzalutamide or abiraterone, and some men don’t respond at all. If this test is validated, it could be used to help select the treatment to which a patient is more likely to respond, sparing the toxicities that may result from an ineffective treatment,” explained lead author Howard I. Scher, MD, chief of the Genitourinary Oncology Service at Memorial Sloan-Kettering Cancer Center in New York City.

    For the test, a blood specimen is stained with dyes to distinguish normal blood cells from CTCs, and then the cells are scanned for morphology, “much like facial recognition software used at airport security,” said Dr. Scher. “The software can quickly identify a cell by examining its features.” The cells of interest can then be analyzed for genetic abnormalities.

    In the study, 221 blood specimens were obtained from 179 patients with metastatic prostate cancer slated for treatment with either enzalutamide or abiraterone. Patients with a higher heterogeneity score (i.e., more variation in CTC appearance and genetic composition) had a poor response to hormone therapy. Compared with those with a low heterogeneity score, patients with high heterogeneity score had shorter median progression-free survival (5 months vs 17 months) and overall survival (9 months vs not yet reached).

    Heterogeneity score was not associated with response to taxane chemotherapy.

    Before this assay can be used in clinical practice, it needs to be validated in larger sample sizes. Then clinical studies are required to determine if results predict outcomes.

    “Tumors change over time, and prostate cancer appears to become especially complex over time. This exciting preliminary study suggests a method that may help us profile individual cancers in real time… Eventually, we may be able to offer the right treatment to the right patient and personalize our selection of therapy,” said Dr. Pal.

    Cabozantinib Beats Everolimus in Advanced Kidney Cancer

    (Abstract 499)

    Cabozantinib achieved greater benefit than everolimus, the standard of care, in patients with previously treated advanced kidney cancer, according to an updated analysis of the phase III METEOR trial. Results showed that progression-free survival (PFS) was significantly improved with cabozantinib across all subgroups. Cabozantinib’s superiority was independent of risk category, metastatic sites, and number and types of prior treatments.

    An interesting hypothesis-generating finding was that patients who failed on second-line checkpoint inhibitor therapy did especially well on cabozantinib versus everolimus. But this included only a small number of patients (n=32) and needs further study.

    Although current treatments can help patients with advanced kidney cancer, more effective treatments are needed, according to lead study author Bernard Escudier, MD, Institut Gustave Roussy, Villejuif, France. “Our preliminary results suggest that cabozantinib may help overcome treatment resistance and provide new hope for patients with this aggressive cancer,” he said.

    Cabozantinib is approved for the treatment of thyroid cancer and is investigational in kidney cancer.

    The study randomized 658 patients with advanced kidney cancer previously treatment with VEGFR inhibitor therapy (and 32 with previous immunotherapy) to receive cabozantinib or everolimus. Analysis of the first 375 patients found that cabozantinib improved median PFS versus everolimus: 7.4 months versus 3.8 months, respectively.

    At the GU Cancers Symposium, Dr. Escudier will present results on all 658 patients enrolled in the trial, which basically replicate the findings in the first 375 patients, with a 48% reduction in risk of progression for those treated with cabozantinib versus everolimus.

    Final overall survival results are expected to be presented at ASCO 2016.

    An exploratory subgroup analysis found that cabozantinib was especially effective in patients with bone metastasis (considered difficult to treat), patients previously on sunitinib, and those who failed on prior checkpoint inhibitor therapy.

    Common side effects with cabozantinib included diarrhea, fatigue, nausea and vomiting, decreased appetite, and hand-foot syndrome; the most common side effects with everolimus were fatigue, anemia, decreased appetite, cough, and dispend.

    “These results exceed what we have seen in this setting. Virtually all patients derive benefit from cabozantinib. These striking early signs of success exemplify how precision medicine is paying off for patents,” said Dr. Pal.

    By Alice Goodman

    Buparlisib May be a BELLE Only for Select Patients

    by Arnold DuBell; co-authored by Stephanie Hawthorne

    In the past, patients with hormone receptor-positive (HR+), HER2-negative metastatic breast cancer were treated with single-agent hormonal agents – either tamoxifen if the patient is premenopausal or an aromatase inhibitor (AI) if she is postmenopausal. This old paradigm was shattered in 2012 with the publication of the Phase III BOLERO-2 results, which showed the benefit of adding the mTOR inhibitor Afinitor® (everolimus, Novartis) to exemestane in patients whose disease was refractory to either letrozole or anastrozole.1 This result was followed in 2014 with the presentation of final analysis of the Phase II PALOMA-1/TRIO-18 data, which showed a strong progression-free survival (PFS) benefit of adding the CDK4/6 inhibitor Ibrance® (palbociclib, Pfizer) to letrozole as a first-line treatment option.2 Based on these data, Afinitor was approved by the U.S. Food and Drug Administration (FDA) in 2012, and Ibrance was granted accelerated approval in 2015.

    Other agents are in development in this treatment setting, making the HR+ metastatic breast cancer clinical space very competitive: other CDK4/6 inhibitors in late-stage development include ribociclib (Novartis) and abemaciclib (Eli Lilly); Syndax is currently running a trial for the HDAC inhibitor entinostat; and Roche and Novartis are developing their PI3K inhibitors (Roche’s taselisib and Novartis’s alpelisib and buparlisib) in this space as well.  This last agent was the subject of a presentation at the last oral general session at the 2015 San Antonio Breast Cancer Symposium, as Dr. Jose Baselga from Memorial Sloan Kettering presented the results of the BELLE-2 trial.3

    BELLE-2 randomized 1,147 postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer who progressed on or after aromatase inhibitor therapy to 500 mg/day Faslodex®(fulvestrant, AstraZeneca) plus placebo or buparlisib 100 mg/day. Dr. Baselga noted that the treatment arms were not completely balanced, as the placebo arm included slightly more chemotherapy-pretreated patients (24.5% versus 31.0%). This trial had three primary endpoints: PFS in the full patient population, PFS in the main population (which excluded patients with unknown PI3K activation status) and PFS in patients whose tumors had “activated” PI3K. This last group included only those patients with PIK3CAmutations and/or PTEN loss. This screening was based on archival tumor tissues. Additionally, a prospective yet exploratory endpoint was PFS in those patients who had PIK3CA mutations from blood circulating tumor cell DNA (ctDNA) as assessed by BEAMing technology.4

    BELLE-2 met some but not all its co-primary endpoints. In the full patient population, buparlisib modestly but significantly improved median PFS by 1.9 months (6.9 months versus 5.0 months, HR 0.78, one-sided p<0.001). A similar benefit for buparlisib was seen in the “main” population (HR 0.80, one-sided p=0.003; median values not provided). However, in the PI3K-activated group of patients, buparlisib only showed a trend of a PFS benefit (6.8 months versus 4.0 months, HR 0.76, one-sided p=0.014).* Buparlisib non-significantly improved response rates in both the full population (11.8% versus 7.7%) as well as in patients with PI3K-activated tumors (10.6% versus 8.2%). Overall survival (OS) data were not presented.

    The exploratory endpoint analysis was the most interesting. In the 200 patients with ctDNA PIK3CAmutations, the addition of buparlisib significantly improved PFS by 3.8 months (7.0 months versus 3.2 months, HR 0.56, one sided p<0.001). The presence of these mutations appeared to be predictive for benefit, as there was no added benefit of buparlisib in the 387 patients with PIK3CA WT ctDNA (6.8 months versus 6.8 months, HR 1.05, one-sided p=0.642). This predictive nature for ctDNA PIK3CAmutations was extended to response rate as well (Mutant: 18.4% versus 3.5%; WT: 11.6% versus 10.6%).

    One of the possible explanations for buparlisib’s modest benefit in the full population was an increased treatment discontinuation rate due to adverse events (13.2% versus 1.8%), resulting in a reduction in the median duration of treatment (4.2 months versus 5.0 months). Grade 3-4 adverse events of note increased in the buparlisib arm included elevated ALT (25.5% versus 1.1%), elevated AST (18.0% versus 2.8%), hyperglycemia (15.4% versus 0.2%), rash (7.9% versus 0%) and depression (4.4% versus 0.4%).

    Although the trial did achieve some of its primary endpoints, the modest nature of the improvements in two of these endpoints as well as inability to meet a third co-primary endpoint throws some doubt into the future prospects for buparlisib. This is in light of the strong benefit seen with Ibrance. Both the Phase II first-line PALOMA-1 trial (HR 0.488)2 and the Phase III 2L+ PALOMA-3 trial (HR 0.422)5 may have set a high bar for expectations regarding the degree of benefit required for novel targeted therapeutics in combination with hormone therapy in this setting. Moreover – and as noted above – there is such a large competitive set of agents for this setting that further leads one to question what will happen next for buparlisib. Also, Novartis has another ongoing late-stage trial for buparlisib: the BELLE-3 trial (NCT01633060) is randomizing patients to Faslodex with or without buparlisib. BELLE-3 differs in that enrolled patients will have had to have progressed on an mTOR inhibitor (likely Afinitor) in addition to a prior aromatase inhibitor. These data are expected next year.

    Although exciting, the exploratory data based on PIK3CA mutations in ctDNA need to be confirmed in further prospective studies. One notable question that needs to be addressed in future studies is why the cohort of patients with PI3K-activated tumors as assessed through archived tissue samples failed to meet its endpoint. During the question period following the presentation, Dr. Baselga suggested that this result was not simply due to the presence of patients with PTEN loss in the PI3K-activated tumor group; he seemed to believe the use of BEAMing technology on the ctDNA samples was a more sensitive measure for the presence of a predictive biomarker. If Novartis chooses to pursue this approach, it will be moving to reinforce an idea heard repeatedly at this year’s conference. The individualized nature for breast cancer is more than just the three different groupings currently used to decide treatment approach (HR+, HER2+, triple-negative) but will be further segmented so that individual patients will receive the best treatment.

    * It should be noted that due to the use of three co-primary endpoints, the one-sided α was split using a gate-keeping approach to keep the overall type-1 error at α=0.025.  Therefore, the p-value required for meeting the endpoint in the PI3K activated group was 0.01.


    1. Baselga J, NEJM, 366: 520, 2012
    2. Finn RS, Lancet Oncology, 16:25, 2014
    3. Baselga, Proc of the San Antonio Breast Cancer Symposium, Abstract S6-01, 2015
    4. Higgins M, Clin Cancer Res, 18:3462, 2012.
    5. Turner, NEJM, 373: 209, 2015.

    Veni, Vedi, Vene? Venetoclax Hopes to Conquer CLL

    by Stephanie Hawthorne; co-authored by Len Kusdra

    Treatment of chronic lymphocytic leukemia (CLL) has enjoyed somewhat of a renaissance in the past couple of years. Until recently, therapy for both front-line and relapsed disease usually consisted of a Rituxan® (rituximab, Genentech)-based regimen often in combination with chemotherapy agents such as fludarabine or Treanda® (bendamustine, Teva). While CLL is a rather indolent disease and is usually sensitive to chemotherapy, curative outcomes are rare and the disease is associated with multiple relapses and multiple lines of treatment; about 70% of patients will go on to receive second-line therapy, and about 50% will receive third-line therapy.1 The lack of clinical development of more effective agents that can induce a more durable response has remained a high unmet need. This has changed recently with the approvals of novel agents such as Gazyva® (obinutuzumab, Roche/Genentech), Imbruvica®(ibrutinib, Pharmacyclics/Janssen) and Zydelig® (idelalisib, Gilead), which have begun to shift the landscape of front-line and relapsed disease, offering physicians more options to treat CLL. The various cytogenetic subpopulations exhibit differing responses for therapy and present a challenge on how to best treat them. One such population in CLL has been those patients carrying a del17p mutation, which has been shown to be associated with poor response to chemotherapy.

    Venetoclax (ABT-199/GDC-0199, AbbVie, in collaboration with Genentech) is a small molecule inhibitor of Bcl-2, a protein that promotes cell survival; its overexpression is characteristic of CLL, thus representing a tantalizing target. Venetoclax monotherapy showed impressive activity in its dose-finding Phase I trial, demonstrating objective response rates (ORR) in over 70% of patients with CLL.2 This encouraged AbbVie to push venetoclax into late-stage clinical development with the initiation of two pivotal trials: a Phase II trial (NCTO1889186) evaluating venetoclax monotherapy in relapsed patients with del17p mutation and the Phase III MURANO trial (NCT02005471) evaluating venetoclax plus Rituxan versus Rituxan plus Treanda in a broader relapsed patient population.

    Results from the Phase II trial were presented at a plenary session on Monday at the 57th American Society of Hematology (ASH) Annual Meeting, and the data continue to support the robust activity of venetoclax.3 Patients (n=107) were initially treated with venetoclax on a weekly dose ramp-up schedule (20, 50, 100, 200 and 400 mg) followed by a continual dose of 400 mg until disease progression or discontinuation for other reasons; this ramp-up dosing schedule along with risk-based prophylaxis was implemented to reduce the incidence of tumor lysis syndrome (TLS), a serious adverse event that was observed in early trials with venetoclax. The primary endpoint was ORR as determined by an independent review committee (IRC) as well as by investigator review. Secondary objectives included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. As determined by IRC, the ORR was 79.4% (95% CI: 70.5%–86.6%), the complete remission with incomplete marrow recovery (CR/CRi) rate was 7.5%, and the nodular partial remission (nPR) rate was 2.8%. Of note, 52% of patients had no CLL in the bone marrow and 40% were minimal-residual disease (MRD)-negative in the peripheral blood, suggesting deep responses with venetoclax treatment. Median time to normalization of absolute lymphocyte count was 22 days, and only four out of 87 patients evaluated did not have normalization of absolute lymphocyte counts. In measuring tumor lesion diameter, 92% of patients (89/96) had a 50% of greater reduction in their largest nodal lesion diameter from baseline measurements. There were also very encouraging signals in durability of response. Estimates showed that responses continued at one year in 84.7% of patients who exhibited any kind of response, in 100% of patients exhibiting a CRi/nPR, and in 94.4% of patients who achieved MRD-negativity. The 12-month estimate of PFS was 72.0% (95% CI: 61.8-79.8) and 12-month estimated OS was 86.7% (95% CI: 78.6-91.9). The most common Grade 3-4 adverse events were neutropenia (17% Grade 3, 23% Grade 4), anemia (18%), thrombocytopenia (15%) and infection (20%, most common being upper respiratory tract). Laboratory signs for TLS occurred during the ramp-up period in five patients with no clinical consequence and were managed through dose interruption and electrolyte management.

    Based on these promising data in relapsed/refractory del17p CLL, AbbVie has submitted an application for regulatory approval with the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).4 Given the efficacy results and coupled with the breakthrough status awarded to venetoclax in May 2015 for this same treatment setting, approval of venetoclax seems likely to occur in the near future. In this context, the MURANO trial will serve as the confirmatory study, as well as expanding utilization options for venetoclax to include combination regimens. Excitement for this agent will be high, particularly in light of its strong efficacy in a patient population that is particularly difficult to treat (second-line, del17p). The remission rate is impressive on its own, but more important is the durability of the responses, since del17p patients have historically lost their responses to chemotherapy quickly.  The PFS rate observed in this study with venetoclax (in patients treated with a median of two prior lines of therapy) appears superior to the PFS historically reported for del17p CLL patients in the first-line setting.

    Venetoclax will have to compete with both Zydelig and Imbruvica. Imbruvica is approved for relapsed/refractory CLL (and has U.S. approval specifically in del17p patients without a line of therapy designation), and Zydelig was approved in combination with Rituxan in the relapsed setting (although its European label specifies use in first-line del17p patients and the National Comprehensive Cancer Network (NCCN) also recommends its use in relapsed del17p patients5). Imbruvica and Zydelig are heavily entrenched in the CLL market,1 and new data and indications are expanding their use rapidly (including impressive results from Study 115 for Zydelig in combination with Treanda and Rituxan in relapsed CLL that were presented immediately prior to the venetoclax results6). Venetoclax may have difficulty penetrating the treatment paradigm, although its clinical data suggests it may be superior to these two agents in the del17p subset. The pivotal RESONATE trial for Imbruvica enrolled 127 patients with del17p, and in that subset Imbruvica produced a 48% ORR and six-month PFS was 83%.7 In the pivotal Study 116, Zydelig plus Rituxan produced an 80% ORR in the subset of 20 del17p patients enrolled in the trial, with a six-month PFS of more than 80% and 12-month PFS of over 60%.8 In comparison, venetoclax seems superior to Imbruvica (nearly double ORR) and possibly comparable to Zydelig (although the sample size in which Zydelig was studied was very small to draw sweeping conclusions). These comparisons will work in venetoclax’s favor and could make it the go-to drug in del17p patients. A significant concern for venetoclax may be the incidence of TLS. While the new dosing scheme utilized to minimize the risk is encouraging, the prolonged “step-up” dosing protocol and the necessary patient monitoring and potential hospitalization in high-risk groups could prove difficult to implement into regular clinical practice upon launch. Certainly the high response rates are difficult to ignore, but if the administration is viewed as cumbersome, physicians may be hesitant to adopt venetoclax into their treatment algorithm, particularly in certain patient populations such as the elderly, who are at an increased risk of TLS and are associated with comorbidities.

    Despite these concerns, one must keep things in perspective: In a disease that once suffered from a lack of significant clinical advancement, the current battle among multiple highly active and novel therapies is certainly better than a stalemate of none.


    1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed December 8th, 2015.
    2. Roberts AW, Davids MS, Pagel JM et. al. “Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.” NEJM, Dec 6, [Epub ahead of print], 2015.
    3. Stilgenbauer S, Eichhorst BF, Schetelig, J, et al. Venetoclax (ABT-199/GDC-0199) Monotherapy Induces Deep Remissions, Including Complete Remission and Undetectable MRD, in Ultra-High Risk Relapsed/Refractory Chronic Lymphocytic Leukemia with 17p Deletion: Results of the Pivotal International Phase 2 Study. Abstract LBA6, American Society of Hematology Annual Meeting, December 2015.
    4. Abbvie, Press Release, December 6, 2015
    5. National Comprehensive Cancer Network (NCCN) guidelines, accessed December 8, 2015.
    6. Zelenetz AD, Robak T, Coiffier B, et al. “Idelalisib plus bendamustine and rituximab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: Results of a Phase 3 randomized, double blind placebo-controlled study.” Abstract LBA5, American Society of Hematology Annual meeting, December 2015
    7. Byrd JC, Brown JR, O’Brien S, et al. “Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid Leukemia.” N Engl J Med 2014;371:213-23.
    8. Sharman JP, Coutre SE, Furman RR, et al. “Efficacy of idelalisib in CLL subpopulations harboring del(17p) and other adverse prognostic factors: Results from a phase 3, randomized, double-blind, placebo-controlled trial.”  J Clin Oncol 32:5s, 2014 (suppl; abstr 7011^)

    Checkpoint Inhibitors in Multiple Myeloma: Knocking at the Door of a Crowded Market

    by Stephanie Hawthorne; co-authored by Elizabeth Clarke

    The field of immunotherapy in oncology has exploded in the last few years, particularly in the case of immune checkpoint inhibitors, which block the immune system’s “brakes” by inhibiting either CTLA-4, PD-L1, PD-L2 or PD-1 (although inhibitors of other immune checkpoint molecules are also in early stages of development). Since the original FDA approval of Yervoy® (ipilimumab, BMS/Ono Pharmaceuticals), development of this field has accelerated rapidly. Currently, two PD-1 inhibitors are marketed ‒ Opdivo®(nivolumab, BMS/Ono Pharmaceuticals) in melanoma, non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) and Keytruda® (pembrolizumab, Merck & Co.) in melanoma and NSCLC ‒ and there is considerable Phase III development of these and several PD-L1 inhibitors in other solid tumor and hematologic indications, making the market for these highly efficacious agents increasingly crowded.

    At the 57th American Society of Hematology (ASH) Annual Meeting in Orlando this week, Merck reported the results from both a single-arm Phase I and a single-arm Phase II trial, evaluating the efficacy and safety of two different combinations of Keytruda in relapsed/refractory multiple myeloma. There is a strong rationale for targeting the PD-L1/PD-1 axis in multiple myeloma, as PD-L1 expression is naturally high across all stages of the disease, and T-cell expression of the molecule is increased in relapsed/refractory patients.1

    First, an open-label, Phase I, multicenter, non-randomized, dose-escalation trial (NCT02036502, KEYNOTE-023) evaluated the safety, tolerability and efficacy of Keytruda plus Revlimid® (lenalidomide, Celgene) and low-dose dexamethasone (RevDex) in the relapsed/refractory setting (median of four prior lines of treatment). With a median follow-up of 296 days, the objective response rate (ORR) was 76% (nine of the 17 patients achieved a partial response and four of the 17 achieved a very good partial response). In addition, a whopping 94% of patients experienced reduction in M protein or free light chains (which are biomarkers of active disease) with a median of 50% reduction in levels. The median duration of response was 9.6 months and the median time to first response was rapid, at 1.2 months. The combination was well-tolerated, with only three patients experiencing a dose-limiting toxicity (DLT): neutropenia (Grade 3/4), infectious pneumonia (Grade 3) and tumor lysis syndrome (Grade 3) with hyperuricemia (Grade 4). Based upon these data, the maximum tolerated dose/maximum administered dose (MTD/MAD) was established as Keytruda 200 mg fixed dose in combination with standard dose RevDex (Revlimid 25 mg and low-dose dexamethasone 40 mg). What is so remarkable about the “promising preliminary activity” observed with Keytruda in this study, as aptly stated by the discussant Dr. Jesus San Miguel, is that many of the patients included in the trial were refractory to Revlimid.2 Indeed, the preliminary results of KEYNOTE-023 demonstrate that PD-1 blockade with Keytruda in combination with RevDex is associated with promising disease-targeted activity and a tolerable safety profile in heavily pretreated relapsed/refractory multiple myeloma patients.

    In addition to the Phase I results, interim data were reported from an ongoing single-arm, Phase II trial (NCT02289222, conducted at the University of Maryland and partially sponsored by Merck) evaluating the efficacy and safety of Keytruda in combination with Pomalyst® (pomalidomide, Celgene) and dexamethasone in relapsed/refractory patients. In the study, relapsed/refractory multiple myeloma patients (median of three prior lines of treatment) received 28-day cycles of Keytruda (200 mg IV every two weeks) plus Pomalyst (4 mg daily x 21 days) and dexamethasone (40 mg weekly). Hematologic toxicities (Grade 3 or higher) were neutropenia (29%), lymphopenia (17%) and thrombocytopenia (8%). The most common non-hematologic adverse events included (Grade ≤2; ≥3): fatigue (n=12; 1), constipation (n=10; 0), dyspnea (n=9; 2), itching (n=6; 0), muscle spasms (n=6; 0) and hyperglycemia (n=5; 0). Objective responses were observed in 16 of 27 (60%) evaluable patients, including stringent complete response (n=1), very good partial response (n=4) and partial response (n=11); additionally, eight patients had stable disease. The time to best response (as in KEYNOTE-023) was rapid, with a median value of 2.0 months. Data on survival and progression-free survival (PFS) is very preliminary (only 7.4 months’ follow-up), but looking at the Kaplan-Meier curves suggests the six-month overall survival exceeds 80% and six-month PFS exceeds 60%.3 Overall, the data demonstrate that Keytruda in combination with Pomalyst and dexamethasone has favorable therapeutic activity and an acceptable safety profile in heavily pretreated multiple myeloma and thus may represent an efficacious combination regimen for this indication (similar to the results seen above with Keytruda + RevDex).

    Presumably based on early readout of these data, Merck initiated two Phase III trials of Keytruda in multiple myeloma in October 2015. At the time, the data prompting those trial initiations was unknown, so the readout of these two studies at ASH sheds light on the rationale for their initiation. KEYNOTE-183 (NCT02576977) will randomize patients to treatment with Pomalyst/dexamethasone with or without Keytruda as third-line or later treatment (prior therapy with an immunomodulatory and proteasome inhibitor is required). KEYNOTE-185 (NCT02579863) will randomize newly diagnosed patients to treatment with Revlimid/dexamethasone with or without Keytruda. In addition to Keytruda, the checkpoint inhibitors Opdivo (with or without lirilumab; NCT01592370), atezolizumab (with or without Revlimid; NCT02431208), and durvalumab (with or without Pomalyst; NCT02616640) are being evaluated in this space (Phase I trials), putting Keytruda well ahead of the competition in this indication. However, the market in relapsed/refractory multiple myeloma is already quite crowded. In November 2015 alone, this space has seen three new approvals ‒ the anti-CD38 antibody Darzalex™ (daratumumab, Genmab), the next-generation proteasome inhibitor Ninlaro® (ixazomib, Millennium/Takeda) and the SLAMF7-directed antibody Empliciti™ (elotuzumab, BMS/AbbVie) ‒ in addition to the numerous other agents that have been previously approved for this disease (Kyprolis® (carfilzomib, Amgen), Farydak® (panobinostat, Novartis), Pomalyst, Revlimid, and Velcade® (bortezomib, Takeda)).

    Is there room in the relapsed/refractory space for immune checkpoint inhibitors? The early-stage Keytruda trials described here evaluate the agent in the context of established backbone therapies (e.g., RevDex), which should bolster the efficacy of the therapy and more easily incorporate it into the treatment paradigm. By initiating two Phase III trials at nearly identical times, Merck is positioning Keytruda well for incorporation into practice. Ultimately, given what we know about the efficacy of checkpoint inhibitors in other tumor types, the KEYNOTE-185 trial in first-line may be where Keytruda ultimately fits into practice; however, that trial will likely take longer to read out, which positions the KEYNOTE-183 trial as the first opportunity for Keytruda to enter the myeloma market in the relapsed/refractory setting. This is the first Phase III trial seeking to add a novel targeted agent onto a Pomalyst/dexamethasone backbone regimen, so this strategy is diving into unknown waters but comes with the advantage of distinguishing Keytruda from the other targeted agents seeking development in combination with doublet regimens. If Keytruda ends up being as successful in multiple myeloma as it is in a host of other tumor types, it could present a fair challenge to these already-existing therapies.


    1. Paiva, B, et al.  PD-L1/PD-1 presence in the tumor microenvironment and activity of PD-1 blockade in multiple myeloma. Leukemia. 2015 Oct;29(10):2110-3.
    2. Miguel, JS et al., ASH 2015 (Abstract 505).
    3. Plesner T et al., ASH 2015 (Abstract 506).

    RATIFYing a novel agent in the treatment of AML: Midostaurin shows efficacy in front-line therapy

    by Stephanie Hawthorne; co-authored by Len Kusdra

    Cytarabine-based intensive chemotherapy remains standard of care for patients with acute myeloid leukemia (AML); however, about 70% of patients will relapse within five years of initial therapy, thus highlighting the need for development of more efficacious regimens.1 While therapy has traditionally consisted of a “one-size-fits-all” concept, it is better appreciated that AML is a rather heterogeneous disease comprising various subtypes with complex genetic and chromosomal changes. Some of these genetic aberrations have been identified in AML, but it is unclear whether these changes represent viable therapeutic targets. Perhaps the only one that has been the focus of clinical development has been FLT3, a tyrosine kinase that plays a role in hematopoiesis; mutations in this gene are believed to play a role in the development of AML. Two major classes of mutations have been identified: point mutations in the tyrosine kinase domain (FLT3-TKD) or the presence of internal tandem repeats (FLT3-ITD). Of the two classes, FLT3-ITD is the more common aberration, occurring in about 30% of AML patients, and has been associated with poor prognosis and shorter overall survival.2 Despite the promise of FLT3-ITD as a target, its history has been turbulent, as evidenced by the failure of lestaurtinib (Cephalon), a FLT3-targeted agent that failed in its pivotal trial and called into question the rationale of inhibiting FLT3-ITD and threatening further clinical development on this target.

    Novartis hopes to change that with its development of midostaurin, an oral multitargeted kinase inhibitor with activity against FLT3. In early-stage trials, midostaurin showed promising activity both as monotherapy and in combination with induction therapy in patients with FLT3 mutated AML compared with FLT3 wildtype AML. Encouraged by these data, Novartis initiated the RATIFY trial in collaboration with Cancer and Leukemia Group B (CALGB-10603; NCT00651261), a Phase III double-blind study evaluating midostaurin versus placebo, both in combination with standard first-line systemic therapy, in AML patients younger than 60. Only patients with FLT3 mutations were enrolled and stratified according to whether they had had a high FLT3 allelic fraction (≥0.7) or a low FLT3 allelic fraction (<0.7); a third cohort consisted of patients with mutations in the kinase domain (FLT-3 TKD). As part of induction therapy, patients received the 7+3 regimen (daunorubicin 60 mg/m2 IV d1-3 and cytarabine 200mg/m2 d1-7 IV) plus midostaurin (50mg oral daily) or placebo. Patients who achieved a complete remission after one or two cycles of induction went on to receive consolidation (four cycles of cytarabine (3g/m2 on days 1, 3, 5) plus midostaurin (50mg oral, daily) or placebo), followed by 12 months of maintenance with midostaurin or placebo at the same dose used during induction and consolidation.  There was no prespecified mandate on the use or not of stem cell transplantation, but the details presented at the 57th American Society of Hematology (ASH) Annual Meeting suggest that midostaurin (or placebo) was not continued for patients who received a stem cell transplantation (less than 50% of patients who received consolidation went on to receive maintenance). The primary endpoint of the trial was overall survival (OS), and secondary endpoints included event-free survival (EFS). While analysis of the results was set to occur at 509 deaths, the slow rate of events led the investigators to amend the protocol to allow for primary analysis at 357 events. With the shadow of lestaurtinib’s failure in its own clinical trial and the challenge in recruitment in RATIFY, many asked: Would midostaurin live up to its potential?

    At the ASH annual meeting held in Orlando, that question was answered, with midostaurin demonstrating significant activity in FLT3+ AML patients.3 In total, 717 patients were enrolled, with 360 enrolled in the midostaurin arm and 357 receiving placebo. Evaluation of toxicity revealed no significant safety signals in the midostaurin arm. The most common Grade 3+ adverse events in the placebo versus midostaurin arms were febrile neutropenia (82% versus 81%), infection (38% versus 40%), diarrhea (16% versus 15%), and rash/desquamation (13% versus 8%). The rate of Grade 5 events was also similar between both arms (5.3% in the placebo arm and 5% in the midostaurin arm).

    Addition of midostaurin to initial therapy led to a statistically significant improvement in OS and EFS. Patients receiving midostaurin had an OS of 74.7 months (95% CI: 31.5 months-not reached) versus 25.6 months in the placebo group (95% CI: 18.5-42.9 months) (HR=0.77, p=0.007). The four-year survival rate in the midostaurin arm was 51.4% and 44.2% in the placebo group. The benefit in OS was seen across all three subgroups, although it was strongest in patients carrying the FLT3-TKD mutation (HR=0.65, p=0.05), compared with patients with FLT3-ITD high (HR=0.8, p=0.09) and FLT3-ITD low (HR=0.8, p=0.08). The complete response (CR) rates at day 60 were similar between patients receiving midostaurin (59%) and placebo (53%) (p=0.15). Censoring of OS data at the time of transplant (57% of patients received a transplant at some time during their treatment) maintained the OS benefit achieved in patients in the midostaurin arm compared with placebo (four-year OS 63.8% versus 55.7%; HR=0.75, p=0.04). EFS also was significantly improved in patients receiving midostaurin versus placebo (8.0 months versus 3.0 months; HR=0.79, p=0.0.0025), and once again the greater level of benefit was achieved in FLT3-TKD patients (HR 0.75, p=0.02) compared with FLT3-ITD high (HR 0.77, p=0.04) or FLT3-ITD low patients (HR 0.85, p=0.10). Among all patients achieving a CR during induction or consolidation, the EFS benefit achieved with midostaurin was still significant (11.3 months versus 6.1 months, HR 0.73, p=0.0002).

    Novartis has guided that it plans to submit regulatory applications in 2016,4 and results from the RATIFY trial should support approval. If approved, what will physicians’ reception to midostaurin be? The dearth of novel agents in this disease will certainly favor its utilization. While Mylotarg® (gemtuzumab ozogamicin, Pfizer) also is being studied in newly diagnosed patients, its troubled history may hinder its utilization, which would help midostaurin be the first novel agent to be approved in for newly diagnosed patients.  However, midostaurin faces challenges of its own. RATIFY was initiated almost eight years ago, and since then the standard of care in AML has changed with respect to utilization of stem-cell transplantation increasing as part of initial therapy. This poses problems for the interpretation of the OS data from RATIFY and whether the survival data presented here will translate into long-term benefits for both transplanted and non-transplanted patients. However, that analysis would extend the trial even longer. Indeed, the investigators noted that in 2014 and 2015 the rates of events plateaued down to six events and three events, respectively, thus providing rationale for the trial amendment to shorten the time for primary analysis. Even so, physicians may hesitate to adopt midostaurin without clear longer-term results. Adding to this hesitation is the decision as to which patient population to administer midostaurin. Elderly patients are less likely to receive an intensive chemotherapeutic regimen such as 7+3, and indeed patients older than 60 years were excluded from eligibility in RATIFY.  The limitation of enrollment to ages 18-60 narrows the eligible population to only one-quarter of newly diagnosed AML patients, and layering on the 30% incidence rate of FLT3+ disease (assuming incidence does not vary by age) leaves less than 10% of AML patients eligible for treatment with midostaurin. Another challenge is midostaurin’s mechanism of action as a FLT3 inhibitor.

    Other FLT3-targeted agents ‒ quizartinib (Daiichi-Sankyo Inc.; previously Ambit Biosciences), crenolanib (Arog Pharmaceuticals) and ASP-2215 (Astellas) ‒ are being evaluated in the relapsed setting, and encouraging data has been reported for sorafenib in this setting (when used in combination with azacitidine), which has led to its recommended use in relapsed FLT3+ patients  by the National Comprehensive Cancer Network (NCCN).  Midostaurin will be unchallenged initially in newly diagnosed FLT3+ patients, but should any of these competitors move into first-line testing they could pose a direct threat to midostaurin. For now, midostaurin represents a move forward in the right direction in a disease that has historically suffered from a lack of significant innovation.


    1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed December 6, 2015.
    2. Frohling S, Schelnk RF, Breitruck J, et al. Prognostic significance of activating FLT3 mutations in younger adults (16 to 60 years) with acute myeloid leukemia and normal cytogenetics: a study of the AML Study Group Ulm. Blood. 2002;100(13):4372-4380.
    3. Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance]). Plenary session, Abstract 6, American Society of Hematology Meeting, December, 2015
    4. Novartis, press release, December 6, 2015