OBR Journal

Receive OBR green
OBR green is our dynamic, eco-friendly digital journal featuring all of our original content. Register to begin receiving OBR green today. View the Most Recent Issue»



Archives

  • Links

  • Recent Posts

  • Advances in Immunotherapy Stand Out During a Highly Influential ASCO 2015

    Nearly half the oncologists surveyed on the impact of this year’s American Society of Clinical Oncology meeting said they were likely to make changes in patient treatment based on what they learned during the five-day conference.  Forty-nine percent of oncologists said they were very likely or extremely likely to alter treatment strategies, as compared to 24% surveyed last year.

    For the fourth consecutive year, Encuity Research surveyed oncologists immediately after ASCO and received responses from more than 100 clinicians, 90% of whom are engaged in direct patient care. With so much information offered at ASCO that directly impacts treatment decisions, and with four immunotherapy drugs now on the market, it is little wonder that the oncologists found this year’s event to be significantly more valuable than prior years. Sixty-six percent of physicians rated the 2015 conference as very or extremely valuable, 13 points higher than the 53% in 2014.

    For the pharmaceutical and biotech companies developing and commercializing oncology products, the perceptions oncologists take away from ASCO are important, as they help shape prescribing behavior for the coming year. Burrowing down into the details of oncologists’ experience yields other interesting data.

    There was growing, palpable excitement in the meeting rooms and hallways at ASCO around the development of novel immunotherapies and the promise they hold in future treatment. In the survey, oncologists reported plans to expand their use of immunotherapies, particularly in non-small cell lung carcinoma (NSCLC) and melanoma, for which there have been few treatment options. Respondents said that advances in PD-1 and PD-L1 pathways were the most important pieces of new clinical information presented at this year’s conference, followed closely by clinical information on immunotherapies.

    A great many pharmaceutical and biotech companies presented their research at ASCO in both standing-room-only presentations and poster sessions, but Bristol-Myers Squibb stood out from the pack. When asked which companies provided the most valuable information at ASCO, 72% of oncologists cited Bristol-Myers Squibb, more than twice as many as in 2014. Genentech/Roche was ranked second, cited by 60% of oncologists, with Merck seeing a similarly large increase in ratings over last year and ranking third in terms of overall value provided.

    Opdivo (nivolumab) from BMS/Ono was cited by 75% of oncologists (unaided) as the most valuable product-related information at ASCO. The company presented data from three clinical trials, with the highest ranking information from a trial of Opdivo in patients with previously treated advanced or metastatic squamous cell and non-small cell lung carcinoma. Merck’s Keytruda (pembrolizumab) also was ranked as among the most valuable product information. Seventy percent of oncologists rated as valuable Merck’s presentation of data on the combination of Keytruda with low-dose Yervoy (ipilimumab) in the treatment of melanoma and kidney cancer. Oncologists also valued highly valued information presented by Merck on the study of Keytruda plus Yervoy as a second-line therapy for treating non-small cell lung cancer.

    Clinical trial data and perspective presented on Johnson & Johnson and Genmab’s daratumumab monotherapy followed BMS and Merck, with two-thirds of physicians rating the information as very or extremely valuable.

    Another important topic at ASCO this year was molecular diagnostics. In 2016, the National Institutes of Health will be introducing the Precision Medicine Initiative, a program with a goal of developing better prevention and treatment strategies tailored to the individual. Encuity asked ASCO attendees about their views on the emerging topic of molecular diagnostics and found that close to 40% of oncologists report that they are familiar with the Precision Medicine Initiative and three-quarters of respondents report familiarity with the use of molecular diagnostics in cancer treatment. We will delve into the opinions and experiences ASCO attendees have around molecular diagnostics in a future article.

    For a cost-conscious industry research such as this helps measure and refines the effectiveness of communications at critical venues like ASCO. Such research allows companies to understand the impact of the clinical information presented and the relative return on promotional efforts designed to educate physicians’ and influence perceptions, understanding, and intent to prescribe.

    by Dave Johnson, Vice President, Encuity Research.

    For a full version the ASCO Impact Report, please visit http://www.encuity.com/asco

    Immune Checkpoint Inhibitors for Lung Cancer: Immediate Impact of 2015 ASCO Presentations on Clinical Practice

    Introduction

    In an effort to provide you with timely market feedback from ASCO 2015, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ from the meeting. This first report explored presentations concerning the anti-PD-1 / PD-L1 antibody-based Immune Checkpoint Inhibitors in non-small cell lung cancer (NSCLC).

    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 lung cancers utilizing targeting parameters within the proprietary MDoutlook® global cancer treater panel
    • Timing: June 2015. Launched 1 week after close of 2015 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL., May 29-June 2, 2015
    • Fielding via interactive web-based survey instrument, utilizing proven MDoutlook methodology and proprietary technology
    • Links to discussed abstracts on the ASCO website were provided within the survey
    • Reponses at data collection: 125

    Geographic Distribution of Respondents

    Attendance at 2014 ASCO Annual Meeting

    Key Conclusions

    • Three-fifths of survey respondents attended this year’s ASCO annual meeting
    • Almost all (97%) who attended ASCO went to at least one Lung cancer session
      • 1/3 attended 6 or more sessions on lung cancer


    Survey Participants’ NSCLC Cancer Patient Flow:
    Average Nearly 20 Cases Each Month

    Key Conclusions

    • Survey participants* averaged 57 cases of NSCLC last 3 months
      • Majority of cases involved metastatic disease
    • Non-mutated, Non-squamous NSCLC was the predominate subtype of NSCLC seen

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


    Expected Usage of Immune Checkpoint Blockade Antibodies in Non-Mutated NSCLC

    Key Conclusions

    • Physicians expect to use immune checkpoint inhibitors in more than half of 2nd line treatment decisions for non-squamous NSCLC. Even higher usage (~2/3) for squamous NSCLC
      • Only 8% of physicians will not use at all in 2nd line for non-squamous NSCLC; only 2% will never use for squamous histology (data not shown)
    • Strong usage of this approach will persist in later lines as well


    Expected Usage of Immune Checkpoint Blockade Antibodies in NSCLC with Driver Mutations

    Key Conclusions

    • Primary usage of the immune checkpoint inhibitors in NSCLC with driver mutations will be in the 3rd line or later
      • Approximately 1 line later than in NSCLC without the driver mutations
    • Only 5% of physicians will never use this approach with these NSCLC subtypes

    Dual Immune Checkpoint Blockade in NSCLC

    Key Conclusions

    • Overall calculated average of 6.35
    • More than 1/3 of respondents (38%) rate the clinical impact of these anti-bodies as high / very high


    Perceived Value of Immune Checkpoint Blockade Antibodies in NSCLC

    Key Conclusions

    • Overall calculated average of 4.74
    • Over ¼ of physicians (27%) perceive the value of these antibodies, at current prices, as being high / very high

    Conclusions: Impact of ASCO 2015 on Immune Checkpoint Inhibitors for Lung Cancer

    • The immune checkpoint inhibitors (anti-PD-1/PD-L1) are going to have a very significant impact on the treatment landscape for NSCLC
    • For cases of NSCLC without driver mutations, treatment with these antibodies is expected to become the primary 2nd line treatment option
      • Nearly 2/3 of squamous NSCLC patients will receive an anti-PD-1/PD-L1 antibodies in the 2nd line
      • About half of non-squamous NSCLC will receive this therapeutic approach in the 2nd line
      • Usage declines in later lines but still remains at respectable levels (20-30% of patients)
    • For cases of NSCLC with driver mutations (ALK+ or mutated EGFR), usage of the anti-PD-1/PD-L1 antibodies will still occur, albeit in 1 later line of therapy (primarily starting in 3rd line)
    • Combining the anti-PD-1/PD-L1 antibodies with the anti-CTLA-4 antibody ipilimumab is seen as a promising approach that will further impact treatment paradigms in the future
    • At today’s prices, physicians see good value in using the anti-PD-1/PD-L1 antibodies for NSCLC
      • 27% of respondents rate their value in NSCLC as high or very high
      • 38% of respondents rate their clinical impact in NSCLC as high or very high

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

    Submitted by Robert Stephan, Sr. Director Medical Services and Strategy, and Jan Heybroek, President MDoutlook.

    Crowd surfing: Competition in myeloma continues to rage on

    By Mara Jeffress, Ph.D., Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

    The number of agents available to treat relapsed/refractory myeloma has expanded rapidly over the past three years, with the launch of next-generation proteasome inhibitor Kyprolis® (carfilzomib, Onyx /Amgen, accelerated FDA approval July 2012) and the next-generation immunomodulator Pomalyst® (pomalidomide, Celgene, FDA approved February 2013) as monotherapies, and the HDAC inhibitor Farydak® (panobinostat, Novartis, accelerated FDA approval February 2015) for use in combination with bortezomib + dexamethasone (VelDex). These three agents add to the long-established standards of care, Velcade® (bortezomib, Millennium/Takeda) and Revlimid® (lenalidomide, Celgene), which are used in both newly diagnosed and relapsed/refractory patients. Pivotal data for Kyprolis and two new agents ― elotuzumab (AbbVie/Bristol-Myers Squibb) and daratumumab (Genmab/Janssen) ― were presented on Tuesday at the Myeloma Oral Session of the American Society of Clinical Oncology (ASCO) annual meeting.

    Based on the results of a large Phase II program, Kyprolis was granted FDA accelerated approval as a monotherapy for myeloma patients who have received prior therapy with an immunomodulatory agent and proteasome inhibitor. It is now the most commonly used third-line agent, used in one-third of patients.1 As a second-generation proteasome inhibitor, the ability of Kyprolis to gain use in earlier lines of therapy will hinge on demonstrating benefit in comparison with the entrenched first-generation proteasome inhibitor, Velcade. The Phase III ENDEAVOR trial compared Kyprolis (at a dose of 56 mg/m2, twice the currently approved monotherapy dose of 27 mg/m2) plus dexamethasone (KypDex) versus VelDex in 929 patients who have received one to three prior lines of therapy (50% were second-line, 33% were third-line and 17% were fourth-line). Progression-free survival (PFS) was significantly improved, with the KypDex arm doubling PFS at the median compared to VelDex (median PFS 18.7 versus 9.4 months, HR=0.53, p< 0.0001).2 Overall survival (OS) data were immature; however, a slight trend to benefit was suggested in the data presented (HR=0.79, p=0.66). Overall response rates (ORR) also favored Kyprolis: 77% versus 63% (p< 0.0001); 54% versus 29% had a very good partial response or better, and 13% versus 6% of patients had a complete response. Responses were robust even in patients treated with prior Velcade. Treatment discontinuation (14.0% vs. 15.7%) and on study death (3.9% vs. 3.4%) due to an adverse event (AE) occurred at similar frequencies in each arm. Grade 3/4 hypertension (8.9% vs. 2.6%), dyspnea (5.6% vs. 2.2%), cardiac failure (4.8% vs. 1.8%) and acute renal failure (4.1% vs. 2.6%) were all increased in the KypDex arm. Considering the fact that patients in this trial were receiving double the approved monotherapy dose, the AEs perhaps aren’t unexpected, although they are still concerning when considering the use of this regimen in the general population of myeloma patients outside of a highly selected clinical trial. These increased toxicities were balanced by a significant decrease in Grade 2 or higher peripheral neuropathy (6.3% vs. 32.0%, p< .0001), which is all the more encouraging considering that the majority (79%) of patients in the control arm received subcutaneous (SC) Velcade, which has lower rates of neuropathy compared to the intravenous (IV) formulation.

    The near doubling of PFS over VelDex will establish KypDex as a new standard of care, especially if OS data is positive. The positive results from ENDEAVOR should only serve to strengthen Kyprolis’ share in third-line and help it gain share in second-line, where VelDex is currently utilized in one-third of patients.1 The positive results of ENDEAVOR come just six months after another positive Phase III trial for Kyprolis – the ASPIRE trial, which showed that patients receiving Kyprolis combined with lenalidomide + dexamethasone (RevDex) had a median PFS of 26.3 months compared to a median PFS of 17.6 months for patients treated with RevDex alone (HR=0.69; p=0.0001).3 Together, these two trials raise questions about where Kyprolis will fit in the treatment paradigm – as a doublet or a triplet, and in which line of therapy?

    While Kyprolis, at least in ENDEAVOR, is challenging Velcade head-to-head, elotuzumab is choosing to combine with one of the current standard-of-care treatment regimens, RevDex. Elotuzumab is an anti-SLAMF7 monoclonal antibody that has FDA Breakthrough Therapy Designation for relapsed/refractory multiple myeloma and is being studied in two Phase III trials, both in combination with RevDex, in the front-line and relapsed/refractory settings. In the relapsed setting, the results of the ELOQUENT-2 trial compared elotuzumab in combination with RevDex versus RevDex alone in 646 patients who had received a median of two prior therapies, including Velcade (70%), thalidomide (48%) and Revlimid (6%). Revlimid-refractory patients were excluded from enrollment. Elotuzumab given with RevDex extended PFS by a median of 4.5 months compared with RevDex alone (median PFS 19.4 vs. 14.9 months, HR = 0.70, p = 0.0004). In addition, one-year PFS was 68% versus 57% and two-year PFS was 41% versus 27%. ORR also favored the addition of elotuzumab (79% vs. 66%, p = 0.0002).4 OS is still immature and was not reported, but the presenter, Dr. Lonial, suggested the results, which will be available in the fourth quarter of 2015, were trending toward the positive. There were no significant increases in toxicity except for Grade 3/4 lymphopenia (77% vs. 49%) and increased incidence of Grade 1-3 infusion reactions (10% vs. 0%); Grade 3/4 neutropenia was lower in the elotuzumab arm (34% vs. 44%). A large number of high-risk patients were enrolled in the trial (32% del17p and 10% t(4;14)), and subgroup analysis showed that PFS was robust even in these subgroups (HR=0.65 for del17p and HR=0.53 for t(4;14)). While important to understand that the regimen provides benefit in these subsets, it does create difficulties for cross-trial comparisons.

    Acknowledging the trial demographic differences, a comparison of ELOQUENT-2 with outcomes for KypDex and Kyprolis + RevDex suggests that elotuzumab + RevDex might provide a comparable median PFS and ORR as is achieved with KypDex (although the Hazard Ratio was better for KypDex), and inferior median PFS and ORR compared to KypRevDex (comparison is difficult here as fewer patients (12.6%) in ASPIRE were high-risk, which may have boosted the mPFS); however, the AE profile appears most benign for elotuzumab in combination with RevDex. A key advantage of elotuzumab is its novel mechanism of action and its combinability with other agents due to its relative mild toxicity profile. While these advantages may give elotuzumab a strong positioning stance in newly diagnosed patients, competitive pressures are stronger in relapsed myeloma. Most significant may be the changing backbone of care across the lines of therapy (choice of immunomodulator or proteasome inhibitor or both), which may leave fewer opportunities for use of elotuzumab if its approval in the relapsed/refractory setting is tied to the RevDex combination.

    Elotuzumab is aiming to be the first monoclonal antibody used to treat multiple myeloma. Competition will come quickly from another antibody known as daratumumab. Daratumumab is a human monoclonal antibody directed against CD38, which is highly expressed on the surface of multiple myeloma cells. Daratumumab has multiple mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis. Based on promising early data, the FDA granted Breakthrough Therapy Status to daratumumab for treatment of double-refractory multiple myeloma.

    Daratumumab, at least initially, is taking a slightly different development tactic than either Kyprolis or elotuzumab and is hoping to enter the myeloma market initially by targeting fourth-line or later patients.5 An open-label, two-part Phase II study (Sirius, MMY2002, NCT01985126) evaluated daratumumab monotherapy in its FDA breakthrough therapy designation population: double-refractory myeloma patients with at least three prior lines of therapy. In part 1, 34 patients were randomized to daratumumab 8 mg/kg (n = 18) or 16 mg/kg (n = 16) to determine the most effective dose. In part 2, 90 additional patients were given the 16 mg/kg dose. Data for 106 heavily pretreated (median five prior lines, including 95% double refractory and 66% refractory to three of four approved agents (Revlimid, Velcade, Pomalyst and/or Kyprolis)) patients were reported. After a median follow-up of 9.3 months, 29% of patients responded to daratumumab, including three complete responses, 10 very good partial responses, and 18 partial responses. Responses to daratumumab were rapid and durable, lasting on average 7.4 months. Response was consistent across all subgroups including the most refractory patients. Median PFS was 3.7 months. Median OS has not been reached, and the estimated one-year OS rate is 65%, which is remarkable in such a refractory population. Common all-grade AE (≥ 20%) were fatigue (39.6%), anemia (33.0%), nausea (29.2%), thrombocytopenia (25.5%), back pain (22.6%), neutropenia (22.6%) and cough (20.8%). Infusion-related reactions were common (43%) but mainly Grade 1/2 (5% Grade 3; 0% Grade 4). J&J intends to seek accelerated approval for daratumumab later this year6 and already has plans to enter the ranks of emerging triplet therapies in myeloma, by initiating two Phase III trials in relapsed/refractory patients combining daratumumab with VelDex (NCT02136134) or with RevDex (NCT02076009). The discussant, Dr. Lentzsch, enthusiastically reviewed the Phase I/II data showing that daratumumab plus RevDex had an impressive 87% ORR with responses that deepened over time.

    Given the increasingly crowded relapsed/refractory setting, companies that plan to bring more agents to multiple myeloma will need to go head-to-head against or combine with RevDex, VelDex, KypDex or the various established and emerging triplet regimens. As we have seen in other crowded markets such as renal cell carcinoma, even existing approved agents may be forced into head-to-head trials to establish dominance and win a significant portion of the market. As of now, there is no clear winner, and the influx of new agents will only confuse matters more with the lack of understanding of whether triplets are better than doublets, if quadruplets are better than triplets (this is sure to be explored in the near future), which regimen is superior and how to sequence the drugs. Furthermore, across all scenarios also exists the question of cost of care. Can the market (and patients) afford combination therapies that continue to push the boundaries of affordability? The price may be justified if the new combination therapies can provide a long-term survival benefit, but for now the regimens reported here have only firmly established a PFS benefit.

    References:

    1. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed June 1, 2015.

    2. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): Results from the phase III study ENDEAVOR. J Clin Oncol. 2015;33(suppl; abstr 8509)

    3. Stuart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma. NEJM, 372(2): 142-52, 2015.

    4. Lonial S, Dimopoulos MA, Palumbo A, et al. ELOQUENT-2: A phase III, randomized, open-label study of lenalidomide (Len)/dexamethasone (dex) with/without elotuzumab (Elo) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2015;33(suppl; abstr 8508)

    5. Lonial S, Weiss BM, Usmani SZ et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (Sirius). J Clin Oncol. 2015;33(suppl; abstr LBA8512)

    6. Johnson & Johnson press release, May 20, 2015.

    Immunotherapy continues to grow; the question may soon become where this class of agents won’t have a strong impact

    By Arnold DuBell, Ph.D., M.B.A., Consultant; Elizabeth Clarke, Ph.D., M.P.H., Analyst; Stephanie Hawthorne, Ph.D., Senior Director; Len Kusdra, Ph.D., Analyst; and Gregory Wolfe, Ph.D., Senior Consultant – Clinical & Scientific Assessment, Kantar Health

    Immunotherapy has dominated the conversation in oncology for the past several years, and the excitement still hasn’t waned at all — in fact, it continues to grow. New drugs have entered development in this space, new mechanisms of action have emerged, and new tumor types have become the focus of our attention. We have previously seen various levels of evidence to support the activity of checkpoint inhibitors in melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancer, breast cancer, gastric cancer, head and neck cancer and Hodgkin’s lymphoma. At this year’s annual meeting of the American Society of Clinical Oncology (ASCO), we observed first reports of the activity of several PD-1 and PD-L1 inhibitors in multiple new tumor indications, adding to the growing body of evidence that suggests immunotherapy is closely approaching panacea status.

    Hepatocellular carcinoma

    Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) was studied in a global Phase I/II trial in patients with advanced hepatocellular carcinoma (HCC).1 This was a dose-escalation study, and it also stratified patients according to their hepatitis B/C viral (HBV, HCV) infection status (uninfected vs. HCV-infected vs. HBV-infected). The majority of patients (75%) had received prior systemic therapy for their disease, with most (68%) having received prior Nexavar® (sorafenib, Onyx/ Amgen/Bayer). At this interim analysis of 42 evaluable patients, single-agent Opdivo produced a 19% objective response rate (ORR; which was measured across all dose cohorts), including two patients (5%) with a complete response; an additional 48% of patients had stable disease. Responses were seen in all patient cohorts, but the response rate was higher in those with HCV infections (36%). It was postulated that perhaps patients with higher viral load/disease burden are more sensitive to PD-1 inhibition and speculated that HCV T-cells may naturally express higher levels of PD-L1, making them more sensitive to PD-1 inhibition; both of these observations are very preliminary in nature, however, and need more data to fully understand whether there is a correlation with activity and, if so, why. The duration of responses were very encouraging (out to one year in some patients) and the one-year overall survival (OS) rate was 62% — unheard of in metastatic, relapsed HCC! These are exciting data in a tumor of very high unmet need, and we’re looking forward to following this trial for the final results and monitor for future clinical development in this indication.

    Esophageal

    There has been little development of targeted therapies for esophageal cancer, making it a tumor of small incidence but large unmet need. Immunotherapy agents have already shown promise in gastric and gastroesophageal junction adenocarcinoma, so it was nice to see a presentation describing the first data for this class in patients with metastatic esophageal cancer. An expansion cohort of the Phase Ib KEYNOTE-028 trial enrolled 23 patients with primarily PD-L1-positive, heavily pretreated esophageal cancer (a few patients had gastroesophageal carcinoma).1 Treatment with single-agent Keytruda® (pembrolizumab, Merck & Co.) was associated with a 30.4% partial response rate (29.4% in the 17 patients with squamous cell carcinoma and 40.0% for the five patients with adenocarcinoma). Responses are very durable, with an average duration of response of 40 weeks. More than half of patients showed some degree of tumor shrinkage. These are excellent outcomes, especially considering that a 30% response rate isn’t much different than that usually seen in the first-line setting for gastroesophageal cancer. However, the discussant, Dr. Fuchs, emphasized slight caution due to the lack of central review in this trial. Similar to other trials for Keytruda, adverse events (AEs) were very limited, with only four patients (17.4%) experiencing Grade 3 toxicities. During the discussion, Dr. Fuchs hypothesized on why these patients seemed to respond so well to Keytruda. Although the patients with the Epstein-Barr virus (EBV)-positive and microsatellite instability (MSI)-positive2 adenocarcinoma subtypes might be responding to increased immune activity due to association of these subtypes with increased PD-L1 expression, the responses in patients with squamous cell carcinoma may be associated with the high degree of DNA focal copy number alterations. Further research is warranted to evaluate these hypotheses as well as confirm the encouraging activity of Keytruda in these patients.

    Ovarian Cancer

    Today results were presented from two separate Phase Ib studies that are evaluating safety and efficacy of PD-1 checkpoint inhibitors in patients with relapsed/refractory ovarian cancer. In the first of the two trials,3 75 heavily pretreated ovarian cancer patients enrolled in an expansion cohort were treated with the PD-L1 inhibitor avelumab (Merck KGaA/Pfizer). Patients were not selected based on PD-L1 status. There were no complete responses, and eight patients achieved partial responses for an ORR of 10.7%. Stable disease was the best response in 33 patients, for a clinical benefit rate of 54.7%. Responses were ongoing in five of eight patients, and the median duration of response was nine weeks. Grade 3/4 adverse events were reported in six patients (8%), and the most common treatment-related AEs of any grade included fatigue (16.0%), chills (12.0%), nausea (10.7%) and diarrhea (10.7%). The author noted that a Phase III trial of avelumab is currently being planned. The second presentation reported results from the ovarian cancer cohort (n=26) of the Phase 1b KEYNOTE-028 trial.4 Heavily pretreated, PD-L1-positive patients were enrolled in KEYNOTE-028 and received the anti-PD-1 antibody Keytruda, and they were treated for 24 months or until disease progression. The ORR was 11.5% and included one complete response and two partial responses. Another six patients achieved stable disease for a disease-control rate of 34.6%. Median duration of response was not reached. Grade 3/4 AEs were reported in 3.8% of the patients, and the most common treatment-related AEs included arthralgia (23.1%), diarrhea (11.5%) and nausea (11.5%). The authors are further analyzing their data to discern whether there is a relationship between PD-L1 expression and activity. These two studies demonstrate that both anti-PD-1 and anti-PD-L1 antibodies are well-tolerated and active in heavily pretreated ovarian cancer patients. Interestingly, the ORR was similar between the two trials; therefore, as with other indications, physicians may need to wait for follow-up data to determine the ultimate choice of immunotherapy option.

    Glioblastoma

    Another example where immunotherapies may make an impact is in recurrent glioblastoma multiforme (GBM), which has a poor prognosis when treated with current therapies and thus represents a considerable unmet need. PD-L1 expression has been associated with high-grade but not low-grade gliomas.5 Also, antitumor activity using a non-commercial anti-PD-1 monoclonal antibody was observed in mouse glioma models.6 Given this preliminary data, Bristol-Myers Squibb (BMS) initiated the Phase III CheckMate-143 trial, which will randomize patients to Opdivo or Avastin® (bevacizumab, Genentech/Roche/Chugai) after progression following surgical resection, radiation and temozolomide. The design of CheckMate-143 included a safety run-in phase evaluating Opdivo with or without Yervoy® (ipilimumab, BMS), which reportedly helped influence the Phase III trial design; some of this data from 20 patients were presented in a poster session at ASCO 2015.7 Note that the arms containing Yervoy were included based on activity observed for Yervoy in patients with melanoma and brain metastases.8 In the data just presented, treatment-related serious AEs occurred in two patients in the monotherapy arm and seven patients treated with the combination. Moreover, as might be expected, the combination regimen had more treatment-related discontinuations (40% vs. 0%). With this said, Opdivo monotherapy was very well tolerated. Opdivo monotherapy was associated with a 10% partial response (PR) rate and a 50% clinical benefit rate; six- and nine-month OS rates were 70% and 60%, respectively. In contrast, Opdivo plus Yervoy was associated with no PRs and a 40% stable disease rate; six- and nine-month OS rates were 80% and 60%, respectively. Given this data, Opdivo monotherapy was chosen to be evaluated in the Phase III trial initiated last year. With the limited options currently available for GBM patients, there should be a high level of enthusiasm to quickly see the outcome from this trial.

    Small Cell Lung Cancer

    Checkpoint inhibitors are active in other thoracic tumors. Opdivo is already approved for use in non-small cell lung cancer (NSCLC) patients with squamous histology and recently excited ASCO attendees with the CheckMate-057 data in patients with non-squamous histology. Keytruda also showed strong promise in both NSCLC in the KEYNOTE-001 trial and malignant pleural mesothelioma in an expansion cohort of the Phase Ib KEYNOTE-028 trial. Given the level of competition between the two molecules in these other thoracic tumors, it is not surprising to see data for both agents in small cell lung cancer (SCLC). A different cohort from Keynote-028 examined the safety and preliminary efficacy of Keytruda in 20 patients with PD-L1-positive relapsed SCLC.9 The toxicity profile was mild, with 10% of patients having Grade 3 or greater AEs; one fatality occurred due to Grade 5 colitis. There was promising evidence of efficacy, with seven (35%) evaluable patients achieving a partial response. Median time to response was 8.6 weeks, with six of seven responses ongoing at the time of data cutoff; one patient has exhibited a response of at least 32 weeks. Opdivo was evaluated in the CheckMate-032 trial, a Phase I/II trial randomizing 90 heavily pretreated SCLC patients to Opdivo with or without Yervoy.10 The combination was evaluated at two dose levels: Yervoy dosed at 1 mg/kg or 3 mg/kg. The most common Grade 3/4 side effects in patients receiving Opdivo plus Yervoy included diarrhea (8.5%), increase in lipase (6.4%), rash (4.3%) and vomiting (4.3%); the total incidence of Grade 3/4 toxicities was 15% for the monotherapy and 34% for the combinations. The initial ORR for Opdivo monotherapy was 18% (CR 0%) and for both combinations was 17% (CR 2%). The ORR for the combination increased with continued treatment, as seven patients with initial stable disease were upgraded to confirmed partial responses, resulting in an ORR of 32.6%. Subgroup analysis showed that this level of response was found in both platinum-sensitive and platinum-resistant patients. Median duration of response was 6.9 months for the combination and was not reported for the monotherapy. Median OS was 4.4 months for Opdivo monotherapy and 8.2 months for the combination. Neither trial showed evidence of a linkage between increased PD-L1 expression and activity. Although Keytruda showed a higher level of activity than Opdivo monotherapy (35% versus 18%), the numbers of patients and the inability at this stage to assess how similar the patient populations are will force physicians to wait for further data in this indication to help them make choices as to which immunotherapy to offer their SCLC patients.

    Colorectal

    In the original Phase I trial for Opdivo presented at ASCO 2012,11 no responses were observed among 19 patients with colorectal cancer (CRC). At ASCO 2015, however, data presented from a new Phase I trial suggests a subset of these patients may actually benefit from PD-1 inhibition. In a multicohort Phase II trial, patients with pretreated CRC were enrolled into two cohorts – those with tumors proficient for mismatch repair (MMR; n=25, n=25 evaluable) and those with MMR-deficient tumors (n=25; n=13 evaluable); a third cohort enrolled patients with MMR-deficient non-colorectal pretreated solid tumors (n=21; n=10 evaluable). Activity was strikingly different among these cohorts of patients following treatment with Keytruda. The ORR was 62% in MMR-deficient CRC patients and 60% ORR in MMR-deficient non-colorectal cancers, but the ORR was 0% in patients with MMR-proficient CRC. The difference can’t be blamed on the depth of response, because disease control including stable disease was equally different: 92% in MMR-deficient CRC, 70% in MMR-deficient non-colorectal cancers, and only 16% in MMR-proficient CRC. Progression-free survival and OS were also longer in patients with MMR-deficient CRC or other cancer compared to patients with CRC-proficient tumors. Although the sample sizes of MMR-deficient CRC and MMR-deficient non-CRC cohorts were small, and there was a slight imbalance in patient demographics between the cohorts (MMR-proficient CRC patients were older and slightly more pretreated), the degree of differential efficacy seems large enough to suggest the correlations may be real. Additional analysis shows that MMR-deficient tumors have greater density of invasive CD8+ T-cells, greater density of PD-L1-positive invasive CD8+ T-cells, and more somatic mutations per tumor than MMR-proficient tumors. Together, these data point to a possible mechanistic explanation for the differential activity of Keytruda, wherein higher tumor mutational burden leads to greater immune system recognition and tumor infiltration, leading to improved activity of PD-1 inhibitors.

    This theory explains the exquisite activity of checkpoint inhibitors that has been observed in melanoma, NSCLC, bladder cancer, SCLC, gastric cancer, esophageal cancer and head and neck cancer: These tumors have the highest somatic mutational burden according to data from the Cancer Genome Project.12 Although mutational load is unlikely to be the only factor that influences likelihood of response to checkpoint blockade, new data from ASCO 2015 suggest it certainly plays a role and may need to be considered for future development plans and eventually patient selection across a number of solid tumor types.

    References:

    1. El-Khouery AB, Melero I, Crocenzi TS, et al.; “Phase I/II safety and antitumor activity of nivolumab in patients with advanced hepatocellular carcinoma (HCC): CA209-040;” J Clin Oncol 33, 2015 (suppl; abstr LBA101).

    2. MSI: microsatellite instability; EBV: Epstein-Barr Virus

    3. Disis ML, Patel MR, Pant S, et al.; “Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory: a phase Ib open label expansion trial;” J Clin Oncol, 33 (suppl., abstr 5509), 2015.

    4. Varga A, Piha-Paul SA, Ott PA, et al.; “Antitumor activity and safety of pembrolizumab in patients with PD-L1 positive ovarian cancer: interim results for a phase 1b study;” J Clin Oncol, 33 (suppl., abstr 5510), 2015

    5. Yao Y, Tao R, Wang X, et al.; “B7-H1 is correlated with malignancy-grade gliomas but is not expressed exclusively on tumor stem-like cells;” Neuro Oncol, 11:757–766, 2009.

    6. Zeng J, See AP, Phallen J, et al.; Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas;” Int J Radiat Oncol Biol Phys, 86: 343-349, 2013.

    7. Sampson JH, Vlahovic G, Sahebjam S, et al.; “Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CheckMate-143; J Clin Oncol, 33 (15_supp), Abst 3010, 2015.

    8. Margolin K, Ernstoff MS, Hamid O, et al.; “Ipilimumab in patients with melanoma and brain metastases: an open-label phase 2 trial;” Lancet Oncol, 13:459-465.

    9. Ott PA, Fernandez MEE, Hiret S, et al.; “Pembrolizumab in patients with extensive-stage small cell lung cancer: Preliminary safety and efficacy results from KEYNOTE-028;” J Clin Oncol. 33 (suppl. Abstr 7502), 2015.

    10. Antonio SJ, Bendell JC, Taylor MH, et al.; “Phase I/II study of nivolumab with or without ipilimumab for treatment of recurrent small cell lung cancer: CA209-032;” J Clin Oncol. 33 (suppl. Abstr 7503), 2015.

    11. Le D, Uram J, Wang H, et al.; “PD-1 blockade in tumors with mismatch repair deficiency;” J Clin Oncol 33, 2015 (suppl; abstr LBA100).

    12. Alexandrov LB, Nik-Zainal S, Wedge DC, et al.; “Signatures of mutational processes in human cancer;” Nature 2013, 500: 415-421.

    Baby, can you drive my CAR-T? Great potential and excitement, but questions remain

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

    In several B-cell malignancies, physicians have a number of new options for their patients, allowing these patients the promise of being treated for several lines of therapy. For chronic lymphocytic leukemia (CLL) and indolent lymphoma patients, physicians now have the option to use kinase inhibitors such as Imbruvica® (ibrutinib, Pharmacyclics/Janssen) or Zydelig® (idelalisib, Gilead). For multiple myeloma patients, physicians now have the option to utilize Kyprolis® (carfilzomib, Amgen/Onyx) or Pomalyst® (pomalidomide, Celgene). However, patients do ultimately progress even after being treated with these new agents. A Clinical Science Symposium held during the annual meeting of the American Society of Clinical Oncology (ASCO) presented early-stage data for a set of agents that give hope that this gap might be filled: chimeric antigen receptor (CAR) T-cell therapies. The fact that three abstracts on early-phase data were reviewed in a symposium dedicated to this novel mechanistic class of therapies speaks to the level of excitement this mechanism of action (MOA) is eliciting from the oncology and hematology communities.

    CARs are synthetic, engineered receptors that can target cell surface antigens expressed by tumor cells. For many B-cell malignancies, a target has been most studied with this class of agents is CD19. These engineered receptors can be stably expressed on primary T-cells, allowing the engineered T-cell to dock with and kill tumor cells containing the antigen target of interest. Moreover, second and third generations of CAR-T therapies are being developed, including CD3ζ (to improve cytotoxicity), CD28 (to improve proliferation and cytokine production) and motifs such as 4-1BB or OX40 (for co-stimulatory functionality). As Dr. Ansell suggested as part of his “CAR-T 101” presentation, these “super T-cells” (not his words) will hopefully provide better responses than normal T-cells through enhanced tumor cell recognition, forced T-cell activation and increased T-cell persistence.

    There were three clinical presentations during this session: two evaluating CAR-T therapies in patients with B-cell lymphomas and one evaluating a CAR-T therapy in patients with multiple myeloma. In the first presentation,1 a CAR-T therapy with only CD-28 and CD3ζ motifs (19-28z, Memorial Sloan Kettering/Juno Therapeutics) was used to treat 11 patients with relapsed/refractory aggressive B-cell non-Hodgkin’s lymphoma (NHL) after high-dose therapy and autologous stem cell transplantation (ASCT). This study was primarily designed to determine a safe dose to use for Phase II trials. The primary toxicity for this therapy was cytokine release syndrome (CRS), reported in seven patients, and this toxicity was dose-limiting in one patient. Although the post-ASCT design of this trial makes it difficult to firmly evaluate the efficacy contribution of 19-28z CAR-T, it is quite encouraging to note that four of 10 evaluable patients remain in complete remission (40%) for durations of at least 13 to 21 months.

    The second presentation evaluated a different CAR-T construct in 22 heavily pretreated CD19+ lymphoma patients (13 DLBCL, 7 FL, 2 MCL).2 The construct used to generate the CAR-T therapy (CTL019; Novartis/University of Pennsylvania) contained CD-28, CD3ζ and 4-1BB motifs. The activity of the therapy was very promising in diffuse large B-cell lymphoma (DLBCL) patients: the best response rate (at three months) was 50%, with five out of six patients remaining in CR for at least six months and two responses lasting longer than a year. Of the seven evaluable follicular lymphoma patients treated with CTL019, the response rate was 100%, includingsix patients in CR at six months. To date, only two mantle cell lymphoma (MCL) patients have been enrolled, so efficacy data is very immature. Among all patients, the primary Grade 3 or higher toxicities were lymphopenia (18 patients), neutropenia (nine patients) and leucopenia (five patients). Two patients had Grade 3 or higher cytokine release syndrome (CRS), while delirium and encephalopathy occurred in one patient each.

    The final abstract evaluated CTL019 in 10 patients with advanced multiple myeloma.3 This tumor type is an interesting choice for a CD19-derived CAR-T, as the majority of myeloma cells are CD19-negative. The presenter (Dr. Garfall) speculated on several rationales for this Phase I pilot study: the presence of clonotypic CD19+ B-cells or a subset of drug-resistant CD19+ cells, as well as a few cells in the dominant CD19 population with diminished copy number of cell-surface CD19 (CD19-dim). The 10 patients were already treated with ASCT and multiple lines of chemotherapy, and then treated with ASCT again along with administration of CTL019. With more than 100 days of follow-up, evidence of clinical benefit was observed in three of four evaluable patients. Moreover, two of these patients had longer and deeper responses than what they had experienced with their prior ASCT, suggesting efficacy contribution attributable to CTL019.

    Although this technology is very promising, several technical hurdles remain to be solved. The two hurdles noted most often by the speakers were the persistence of the engineered T-cells and reducing the CRS and central nervous system toxicities. The last speaker (Dr. Avigen) provided current pre-clinical research – for example, addition of suicide genes within the CAR cassette to abrogate CAR-mediated toxicity, or the co-administration of select interleukins to increase persistence – that may solve some of these issues. However, the real question is whether CAR-T therapies are ready to make an impact within the next few years. In certain cases the answer appears to be a resounding “yes,” as there have been other promising data in other disease types, most notably acute lymphoblastic leukemia as well as the promising data presented at ASCO 2015 in B-cell lymphomas. However, the data presented at the ASCO Clinical Science Symposium also suggest that for other tumors types, such as multiple myeloma, the technology is not ready to let oncologists “drive your CAR-T therapy.”

    References:

    1. Sauter, Abstract 8515, ASCO 2015

    2. Schuster, Abstract 8516, ASCO 2015

    3. Garfall, Abstract 8517, ASCO 2015

    Gaga over Gazyva? GADOLIN shows clinical benefit in Rituxan-refractory indolent NHL

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

    Rituxan® (rituximab, Roche/Genentech) forms the backbone of virtually every aspect of therapeutic management for B-cell non-Hodgkin’s lymphoma (NHL); however, while clinically effective, approximately 20% of patients with indolent NHL (iNHL) are considered Rituxan-refractory. This poses an unmet need for patients, leaving them historically with only chemotherapy as a treatment option, although with the July 2014 approval of Zydelig® (idelalisib, Gilead) in relapsed/refractory follicular lymphoma there is now a new option for these patients. In addition to the clinical unmet need in these patients, Genentech and Roche have their own need to consider. With the approaching U.S. patent expiration of Rituxan, the companies are hoping to leapfrog ahead of potential biosimilar competitors with the next-generation anti-CD20 antibody, Gazyva® (obinutuzumab) as Rituxan’s heir apparent.

    Gazyva is a third-generation, humanized anti-CD20 IgG1 monoclonal antibody that has been glycoengineered to enhance its antibody-dependent cellular cytotoxicity (ADCC). It has been shown to bind with high affinity to the CD20 type II epitope, resulting in the induction of ADCC that is five- to 100-fold greater than observed with Rituxan and shown to be more potent at inducing cell death.1 This in vitro data translated into clinically meaningful benefit in patients with newly diagnosed chronic lymphocytic leukemia (CLL) when the CLL11 trial showed superiority of Gazyva with chlorambucil in prolonging progression-free survival (PFS) compared to Rituxan plus chlorambucil,2 which led to its approval in CLL in 2013 and its “debut” appearance into B-cell malignancies. Roche and Genentech are hoping to expand Gazyva’s use in other B-cell malignancies and have initiated concurrent trials in iNHL and diffuse large B-cell lymphoma (DLBCL).

    GADOLIN (NCT01059630) was an open-label, randomized Phase III study investigating the efficacy and safety of Gazyva in combination with Treanda® (bendamustine, Teva/MundiPharma/Symbio) compared with Treanda alone in 396 patients with Rituxan-refractory iNHL. Patients who had progressed within six months following Rituxan-based therapy were randomized to receive Treanda + Gazyva for six cycles or Treanda alone for six cycles; patients in the Treanda + Gazyva arm who had not progressed after six cycles were given Gazyva monotherapy as maintenance every two months for up to two years. Enrolled patients in this trial had received a median of two prior lines of therapy. At the 2015 American Society of Clinical Oncology (ASCO) annual meeting, initial response and survival results were presented that showed the trial had met its primary endpoint of significantly prolonging PFS.3 According to independent review, the median PFS was 14.9 months in the Treanda arm, and the median was not yet reached in the Gazyva + Treanda arm, with an associated hazard ratio (HR) of 0.55 (p = 0.00011). Subgroup analysis of PFS suggested two patient types in which the benefit with Gazyva was less convincing: patients with non-follicular indolent NHL (HR 0.94; 95% CI 0.45-1.90) and patients who had received more than two prior lines of therapy (HR 0.80; 95% CI 0.43-1.48), although in both of these subsets the patient sample size was relatively small. There were no significant differences in objective response rate (ORR: 63.0% Treanda vs. 69.1% Gazyva + Treanda) or complete response rate (CR: 12.2% Treanda vs. 11.2% Gazyva + Treanda) at the end of induction as determined by independent review. In looking at the Kaplan-Meier plots, one question that arises is how much of the PFS improvement was conferred by Gazyva maintenance as opposed to Gazyva + Treanda given the lack of difference in ORR and by the fact that that the PFS curves overlap initially and only begin to separate at approximately the time induction is completed. No differences in OS have yet been observed ― median OS is not reached in either arm ― the data are not mature enough to make any conclusions; longer-term data will be required to make final assessment.

    The toxicity of the combination was relatively mild with no significant differences in adverse events between the arms. Grade 3 or higher adverse events were seen in 62% and 67% of patients receiving Treanda or Gazyva + Treanda, respectively, the most notable being neutropenia (26.3% vs. 33.0%, respectively) and infusion-related reactions (3.5% vs. 8.8%, respectively). Interestingly, more Grade 3 or higher thrombocytopenia (16.2% vs. 10.8%), anemia (10.1% vs. 7.7%) and pneumonia (5.6% vs. 2.6%) were seen in the Treanda-alone arm. As evidenced by the relatively tolerable safety profile, 90% and 80% of patients received at least 90% of the dose intensity of Gazyva and Treanda, respectively, in the combination arm; 77% received at least 90% of the dose intensity in the Treanda monotherapy arm.

    These impressive results led to the independent data monitoring committee (IDMC) stopping the trial due to the high level of benefit.4 In the press release, the companies guided filing for regulatory approval with the Food and Drug Administration (FDA) and European Medicines Agency (EMA), and with these results regulatory approval is not far off. While GADOLIN will support approval, how Gazyva will fare in its uptake is unclear. Potentially impinging on physician enthusiasm is the use of Treanda monotherapy as the comparator arm, a choice of therapy that, while commonly utilized when the trial was initiated, does not currently reflect clinical practice. Zydelig is now the currently preferred treatment regimen in Rituxan-refractory follicular lymphoma, used in about one-quarter of patients.5 Zydelig thus represents Gazyva’s closest competitor in indolent NHL at the moment.

    Will the level of PFS improvement in GADOLIN be convincing enough for physicians to adopt a next-generation anti-CD20 antibody in Rituxan-refractory patients, or will physicians prefer an agent with a novel mechanism of action (e.g., PI3K inhibitor Zydelig) before trying Gazyva? The compelling 28-month PFS that Gazyva plus Treanda confers in these patients is indeed hard to ignore, especially in a patient population that has relapsed following first-line standard of care and for which no cure exists. Zydelig’s current approval in follicular lymphoma is based on a single-arm study in Rituxan-refractory patients who had received a median of four prior lines of therapy. In that study, single-agent Zydelig produced a 57% ORR .6 While the ORR may be arguably similar (given the difference in patient pretreatment in the two studies), the fact that Gazyva has been shown to significantly improve PFS in a randomized study may represent a more clinically relevant metric and physicians may be sufficiently convinced to switch their treatment practice. Additionally, the subgroup analysis showing less benefit in more heavily pretreated patients could spur use of Gazyva in earlier lines to maximize benefit.

    Making landfall in the relapsed setting, Roche’s goal to replace Rituxan appears to be on track. A supportive Phase II trial (GAUSS, NCT00576758) is comparing Gazyva head-to-head with Rituxan, and the Phase III GALLIUM trial (BO21223, NCT01332968) is comparing Gazyva + chemotherapy versus Rituxan + chemotherapy in previously untreated iNHL. In addition to Zydelig, Imbruvica® (ibrutinib, Pharmacyclics/Janssen), Revlimid® (lenalidomide, Celgene) and duvelisib (AbbVie/Infinity) are also vying for a piece of the NHL space, with multiple Phase III trials ongoing.

    For now, though, Gazyva is well-poised to shift the sands once more in the ever-changing and exciting iNHL landscape.

    References:

    1. Robak T. GA-101, a third-generation, humanized and glyco-engineered anti-CD20 mAb for the treatment of B-cell lymphoid malignancies. Curr Opin Investig Drugs. 2009;10(6):588-96.

    2. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-10.

    3. Sehn LH, Chua NS, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;33(suppl; abstr LBA8502)

    4. Genentech press release. 3 Feb 2015.

    5. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed June 1, 2015.

    6. Gopal AK, Kahl BS, de Vos S, et al. PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med. 2014;370(11):1008-18.

    Dual checkpoint blockade in metastatic melanoma: PFS makes a strong case, but overall survival impact still an unknown

    By Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

    The treatment armamentarium available for patients with advanced melanoma has become quite well stocked as recent progress in the development of novel therapeutic agents has been tremendous. Immune checkpoint inhibition and targeted inhibition of BRAF and MEK are two therapeutic approaches that have significantly improved survival for patients with advanced melanoma. Since 2011, the Food and Drug Administration(FDA) has approved three checkpoint inhibitors, starting with the cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) inhibitor Yervoy® (ipilimumab, Bristol-Myers Squibb/Ono Pharmaceuticals), followed by subsequent approvals of programmed death-1 (PD-1) receptor inhibitors Keytruda® (pembrolizumab, Merck & Co.) and Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals); for patients whose tumors harbor a BRAF mutation, the BRAF inhibitors Zelboraf® (vemurafenib, Roche/Plexxikon/Daiichi-Sankyo) and Tafinlar (dabrafenib, Novartis) and the MEK inhibitor Mekinist (trametinib, Novartis) round out the armamentarium.

    Opdivo holds the title of the first PD-1 inhibitor to gain global regulatory approval when it was approved in Japan in July 2014 for metastatic melanoma. In September 2014, Keytruda became the first PD-1 inhibitor to gain approval in the U.S. when the FDA awarded it accelerated approval for treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy and, if BRAF V600 mutation positive, a BRAF inhibitor. However, the race to the U.S. market was tight as Opdivo received accelerated approval from the FDA in December 2014 for a similar indication.

    With both Keytruda and Opdivo approved for refractory melanoma, the battle has shifted to treatment-naïve advanced melanoma, where Yervoy has ruled as the only approved checkpoint inhibitor in the U.S. since 2011. However, recent data from the Phase III KEYNOTE-006 trial demonstrated the superiority of Keytruda over Yervoy with regard to significant progression-free survival (PFS) and overall survival (OS).1 Thus, it is evident that the dominance of Yervoy monotherapy as front-line treatment for BRAF-wildtype patients will soon fade away.

    The next logical step to consider is combinations of checkpoint inhibitors. Immune checkpoints play critical roles in balancing co-stimulatory and co-inhibitory signals that regulate human self-tolerance and control the amplitude and duration of T-cell responses. CTLA-4 and PD-1 are distinct yet complementary pathways that inhibit antitumor immunity. Published Phase I and II data already suggest that simultaneous blockade of both pathways with Yervoy and Opdivo may be more active than either monotherapy alone.2,3

    Today, preliminary results from the phase III CheckMate-067 trial were reported in the Plenary Session of the annual meeting of the American Society for Clinical Oncology (ASCO).4,5 This trial is evaluating the impact of combining two immunotherapies, Opdivo and Yervoy, versus either single agent in treatment-naïve patients with Stage III (unresectable) or Stage IV melanoma. Patients were randomized (1:1:1) to receive Opdivo alone (3 mg/kg every two weeks, plus a Yervoy-matched placebo), versus Opdivo (1 mg/kg) in combination with Yervoy (3 mg/kg) administered every three weeks for four doses followed by Opdivo alone (3 mg/kg every two weeks) until disease progression, versus Yervoy alone (3 mg/kg every three weeks for a total of four doses, plus an Opdivo-matched placebo). OS and PFS are co-primary endpoints.

    Treatment with the combination of Opdivo plus Yervoy or with Opdivo monotherapy yielded superior clinical activity compared to treatment with Yervoy alone. Median PFS were 11.5 months (Opdivo + Yervoy; HR 0.42 and p<0.00001 vs. Yervoy), 6.9 months (Opdivo; HR 0.57 and p<0.00001 vs. Yervoy) and 2.9 months (Yervoy). Objective response rates were 57.6% (Opdivo + Yervoy; p<0.00001 vs. Yervoy), 43.7% (Opdivo; p<0.00001 vs. Yervoy) and 19.0% (Yervoy). Quite disappointingly, OS data are immature and were not presented. PFS was also analyzed in prespecified subgroups of patients according to PD-L1 expression. Among patients with PD-L1-positive tumors (defined as ≥1% PD-L1-positive tumor cells) the median PFS was 12.4 months for both the Opdivo + Yervoy arm and the Opdivo-alone arm, which was strongly improved compared to the 3.9–month median PFS for patients treated with Yervoy alone. Patients with PD-L1-negative tumors (<1% PD-L1-positive tumor cells) had median PFS of 11.2 months (Opdivo + Yervoy), versus 2.8 months (Opdivo alone) versus 2.8 months (Yervoy alone). Improved clinical efficacy of the combination comes at a cost, however. Drug-related Grade 3/4 adverse events were reported in 55% of patients in the combination arm versus 16.3% in the Opdivo-alone arm and 27.3% in the Yervoy-alone arm. Approximately 36% of patients in the combination arm discontinued treatment due to toxicity, compared to only 8% of patients treated with Opdivo monotherapy and 15% of patients treated with Yervoy monotherapy. Interestingly, a majority of patients who required a treatment discontinuation actually developed an objective tumor response after drug discontinuation.

    Results from this trial are practice changing, and now either Opdivo + Yervoy or a PD-1 checkpoint inhibitor alone (Keytruda or Opdivo) should be considered standard of care for front-line BRAF wildtype melanoma. Although the efficacy of dual checkpoint pathway blockade is impressive, management of toxicity and patient selection remain challenges. Greater effort is needed to develop biomarkers/assays that will identify those patients who are likely to respond and those who are not. PD-L1 expression is a weak biomarker, and current assays are technically difficult and imperfect, especially for patients with low PD-L1 expression. The need for a better biomarker assay is particularly important when considering that Yervoy + Opdivo is associated with Grade 3/4 toxicity in 55% of patients. In patients where tolerance of toxicity is a key consideration, a PD-1 checkpoint inhibitor monotherapy may be the appropriate choice. Furthermore, appropriate patient selection is critical with regard to cost of therapy. Opdivo + Yervoy has an annual price tag in excess of $180,000, further necessitating the development of an assay to differentiate between potential responders and non-responders to contain costs (although Dr. Jedd D. Wolchok made a point at the end of his presentation to advertise a BMS-sponsored expanded access program now available for this combination, which may alleviate the financial burden in the short term ahead of FDA approval). Other alternatives may also help ease the disadvantages of this regimen. Could a lower dose of Yervoy (such as two doses rather than four) be equally efficacious but help reduce both toxicity and the cost of dual checkpoint inhibitor therapy?  We also don’t yet know if the observed PFS benefit will also translate into an OS benefit. While hope is high that dual checkpoint blockade will raise the survival curve plateau (how high can it go?), would we achieve the same OS outcomes if both drugs are combined in first-line compared with their use in sequential lines of therapy? Unfortunately, this remains a blackbox since not even a hint of OS outcomes were reported at today’s Plenary Session.

    While development of checkpoint inhibitors has revolutionized melanoma treatment and dual checkpoint therapy appears very promising, balancing safety, efficacy and cost requires further consideration, and there is a long way to go toward identification of patients who are best suited to this combination therapy.

    References:

    1. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumb in advanced melanoma. New Engl J Med. 2015; DOI: 10.1056/NEJMoa1503093.
    2. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced Melanoma. N Engl J Med. 2013;369:122-133.
    3. Postow MA, Chesney J, Pavlick AC, et al.; “Nivolumab and ipilimumab versus ipilimumab in untreated melanoma.” N Eng J Med, 2015; 372 (21): 2006-2017.
    4. Larkin J, Chiarion-Sileni V, Gonzalez R, et al.; “Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.” N Eng J Med, 2015; DOI: 10.1056/NEJMoa1504030.
    5. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al., “Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alnoe in treatment-naïve patients (pts) with advanced melanoma.” J Clin Oncol, 33, 2015 (suppl; abstr LBA1).

    HELIOS: God of the sun in Greek mythology also lights the way for patients with CLL

    By Linda Zhao, Ph.D., Director, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

    Two important drugs obtained approval from the Food and Drug Administration (FDA) last year for use in relapsed/refractory chronic lymphocytic leukemia (CLL): Imbruvica® (ibrutinib, Pharmacyclics/Janssen) as a single agent in February 2014 and Zydelig® (idelalisib, Gilead) in combination with Rituxan® (rituximab, Genentech/Roche) in July 2014. Still, better treatment options with greater therapeutic outcomes are strongly needed in CLL treatment to prolong survival in these patients.

    Imbruvica is a covalent inhibitor of Bruton’s tyrosine kinase (BTK), which is involved in the maturation and activation of B-cells and is implicated as a driver of B-cell related lymphomas and leukemias. Pharmacyclics and Janssen are aggressively developing Imbruvica in CLL across multiple lines of therapy and are looking beyond its recent approval as monotherapy and hoping that combining Imbruvica with the standard-of-care chemotherapy backbone in second-line – Rituxan plus Treanda (bendamustine, Teva/MundiPharma/Eisai), the BR regimen – will yield stronger clinical benefits over R-Treanda alone in the relapsed/refractory setting.

    In September 2012, Janssen initiated the Phase III placebo-controlled HELIOS trial (NCT01611090) to evaluate the safety and efficacy of BR (up to six cycles) with or without Imbruvica (given until disease progression) in relapsed or refractory CLL or small lymphocytic lymphoma (SLL) patients; patients with del17p (> 20% of cells) were excluded. The trial completed enrollment of 578 patients in February 2014. The primary endpoint of the study is progression-free survival (PFS), and secondary endpoints include objective response rate (ORR), overall survival (OS), rate of minimal residual disease (MRD)-negative remissions, quality of life, and adverse events. In March 2015, Janssen announced that the independent data monitoring committee (IDMC) unanimously recommended unblinding the HELIOS trial, citing that the study met its primary endpoint by demonstrating a significant improvement in PFS in favor of the Imbruvica arm. Today, the much anticipated results from this trial were reported in Chicago at the American Society for Clinical Oncology (ASCO) annual meeting by Dr. Asher Alban Akmal Chanan-Khan as a Late Breakthrough Abstract oral presentation.1

    The pre-planned interim analysis reported today confirmed the positive news as stated in the company’s news release. Enrolled patients had received a median of two prior lines of therapy and had a median age was 64 years old, and 38% of patients were Rai Stage III/IV. At a median follow-up of 17.2 months, the IDMC-assessed median PFS in the Imbruvica + BR arm was significantly longer than the control arm (not reached in the Imbruvica + BR arm vs. 13.3 months in the BR arm, HR: 0.203p< 0.0001). The PFS results were consistent across all subgroups analyzed. The ORR and complete remission (CR/CRi) rates were also significantly improved in the Imbruvica arm: 82.7% versus 67.8% and 10.4% versus 2.8%, respectively. Even though the median OS were not reached in either arm at the time of interim analysis, the survival curves suggest a benefit in favor of the Imbruvica + BR arm (HR 0.628, p=0.0598). This trend to OS benefit is all the more encouraging considering that patients with confirmed progressive disease in the BR + placebo arm were allowed per protocol to cross over to receive Imbruvica (a fact that may ultimately confound the ability to reach statistical significance).

    Most adverse events (AEs) were similar between the two arms. The most common all-grade AEs were neutropenia (58.2% in the Imbruvica + BR arm vs. 54.7% in the placebo + BR arm) and nausea (36.9% in vs. 35.2%); the most common Grade 3/4 AEs were neutropenia, also similar in the two arms (53.7% vs. 50.5%), and thrombocytopenia (15.0% each arm). Rates of Grade 3/4 atrial fibrillation were 2.8% and 0.7%, and major hemorrhages occurred in 2.1% and 1.7% of patients, respectively.

    The BR regimen is commonly used in second-line CLL (among patients who don’t receive single-agent Imbruvica) and is the most commonly used regimen used in the first-line setting. The addition of Imbruvica to this standard backbone regimen reduced the risk of progression or death by 80%, with few additional AEs (although with a slight increase in Grade 3/4 atrial fibrillation). The results reported here strongly confirm Imbruvica as an important treatment option for patients with previously treated CLL/SLL  and pave the way to significantly expanded use of Imbruvica in relapsed/refractory disease and may even support the use of the Imbruvica + BR regimen in front-line. The excitement driven by the efficacy benefit seen in HELIOS is heightened by the fact that the safety profile with Imbruvica + BR is not worse than the safety profiles from Imbruvica or BR alone; this could alleviate physician concern regarding exacerbated side effects usually seen when two drugs are combined. Overall, the success of the HELIOS trial will significantly expand the commercial opportunity for Imbruvica in CLL, and it’s just the beginning: HELIOS is just one of the six pivotal trials of Imbruvica ongoing for CLL treatments. Ultimately it will maximize the commercial opportunities for Imbruvica if its use in combination with the BR regimens will displace the use of traditional chemotherapy in the second-line setting or expand its use into front-line.

    The question raised by the discussant, Professor Lloyd Damon from the University of California San Francisco, was whether the HELIOS trial has asked the best question for CLL treatment. Dr. Damon compared the results of HELIOS with several other single-arm studies: an earlier Phase II trial of Imbruvica + BR2  and a combined analysis of several single-agent Imbruvica studies,3 citing the similarities between patient baseline features, prior regimens, ORR, CR, as well as the median PFS between these three studies. Dr. Damon suggested that the implication of the HELIOS trial may lie in whether chemotherapy can be omitted as first treatment for CLL/SLL. This issue is being explored in the ongoing Phase III ECOG E1912 study (which compares R-Imbruvica versus the historical R-FC (fludarabine and cyclophosphamide) regimen in previously treated patients) and the ALLIANCE A041202 trial (which compares Imbruvica versus R-Imbruvica versus BR alone in previously untreated elderly patients). Success in these trials could lead to a revolutionary change in CLL treatment. Of course, Gilead is also seeking to expand the role of Zydelig in CLL and has several ongoing randomized studies that will keep it in direct competition with Imbruvica across all lines of therapy.

    With the recent introductions of Imbruvica, Zydelig, and Gazyva® (obinutuzumab, Genentech/Roche), the CLL treatment landscape has already changed drastically from just 15 months ago. The results from HELIOS today will support even further change, and with the number of ongoing Phase III trials for these agents as well as several other promising new drugs, outcomes for patients with CLL are beginning to look very bright.

    References:

    1. Chanan-Khan AAA, Cramer P, Demirkan F, et al.“Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): First results from a randomized, double-blind, placebo-controlled, phase III study; J Clin Oncol. 2015;33(suppl; abstr LBA7005).
    2. Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125(19):2915-2922.
    3. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506.

    CheckMate? The rules of the game may be changing

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

    Non-small cell lung cancer (NSCLC) is one of the tumor types with the highest unmet need, representing the most commonly diagnosed cancer globally1 and one that is frequently diagnosed at an advanced stage,2 where prognosis is most dire. As such, NSCLC has long been a focus of significant clinical development and currently is a poster child for personalized medicine; treatment varies significantly depending on a patient’s tumor histology and their biomarker status (EGFR mutation and ALK translocation are currently the key biomarkers guiding clinical decision making, although many others are under study).

    The most recently approved agent for the treatment of NSCLC is Opdivo® (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals), which was approved by the FDA in March 2015 for squamous metastatic NSCLC patients who have previously received a platinum-based therapy. This approval was based largely on a single-arm Phase II trial, supplemented by randomized Phase III data (the CheckMate-017 trial) that will be reported publicly for the first time at the American Society for Clinical Oncology (ASCO) annual meeting tomorrow. The approval in squamous histology is the first targeted therapy approved for this subset of patients, representing a major advance in their disease management. However, squamous NSCLC represents only a fraction (approximately 25%) of all NSCLC, leaving the majority of NSCLC patients who have non-squamous disease with an unknown level of benefit from this PD-1 inhibitor.

    One of the most anticipated data from ASCO 2015 are the results of CheckMate-057, the Phase III trial that compares Opdivo versus docetaxel as second-line therapy for patients with non-squamous metastatic NSCLC.3 This trial randomized 582 patients to treatment with 3 mg/kg q2w Opdivo or 75 mg/m2 q3w docetaxel, both administered until disease progression or unacceptable toxicity. In the intent-to-treat (ITT) population, Opdivo significantly improved overall survival (OS) compared to docetaxel. OS is the gold standard by which to judge activity, and Opdivo resulted in a 27% reduction in the risk of death, which amounted to a 2.8-month difference at the median (12.2 months vs. 9.4 months, HR 0.73, p=0.0015). Importantly, the survival curve plateaued, with the one-year OS rates significantly differing between the two treatment arms (51% vs. 39%) and the curves continuing to separate even at later time points (18-month OS is approximately 40% vs. 20%, although there are still a large number of censored patients at this time point). No new safety signals were observed, and no single adverse event occurred in more than 1% of patients. However, the ITT population showed no progression-free survival (PFS) benefit (median PFS 2.3 months vs. 4.2 months, HR 0.92, p=0.3932). Interestingly, both the PFS and OS curves crossed, and the Opdivo arm eventually showed more patients progression-free at one year than those treated with docetaxel (19% vs. 8%). These results in the ITT population appear to be slightly less robust than the data for Opdivo in squamous patients, as reported for the CheckMate-017 trial to be presented later during ASCO.4

    While it was exciting to see an OS benefit in the broad population of non-squamous NSCLC patients, the real story was the secondary endpoint of outcomes according to PD-L1 biomarker status. Patients were not required to overexpress the ligand for study entry but were required to have tissue available for secondary analysis and stratification. The majority (78%) of enrolled patients had tumor samples with quantifiable PD-L1 expression. When OS was evaluated by PD-L1 expression status, a clear and large benefit was associated with biomarker overexpression, and no OS benefit was seen in patients with less than 1% PD-L1 expression. Additionally, the magnitude of OS benefit (measured as the Hazard ratio; please refer to the table below) appeared to gain significance when higher thresholds of PD-L1 positivity were assessed. A similar association between activity and threshold of PD-L1 positivity was observed with regard to PFS and response rate outcomes.

    These results present a bit of a conundrum. In one sense, the trial met its primary endpoint in the ITT population, showing a significant OS benefit for pretreated non-squamous NSCLC patients regardless of biomarker status. This could support FDA approval in such a broad population, and indeed its current approval in squamous NSCLC is not limited by biomarker (we hope to learn at tomorrow’s presentation of CheckMate-017 whether a correlation exists with biomarker status in that patient population). Use of Opdivo in the ITT population without limitation by PD-L1 status was supported by Dr. Roy Herbst, who discussed the CheckMate-057 data. He argued that the biomarker isn’t ready for prime time, for a number of reasons. On the other hand, the lack of any benefit in patients with less than 1% PD-L1 expression makes a strong case for not using Opdivo in these patients, especially given the high cost of this therapy (in and of itself, but also when compared to generic docetaxel).

    Two clear arguments emerge in favor of using Opdivo regardless of biomarker status. First, it is clearly better tolerated than docetaxel, with very few Grade 3/4 adverse events observed with Opdivo, and docetaxel is characteristically associated with myelosuppression. Therefore, even in a patient with no PD-L1 expression, Opdivo could be viewed as an equally effective and better tolerated treatment option. The second argument, and the one that is the subject of the most debate, is the reliability of the PD-L1 diagnostic assay and how and when it is evaluated. The majority of patients in CheckMate-057 had archival tumor tissue that was evaluated for the biomarker. Knowing that tumors evolve over time, how accurate is it to categorize a patient’s biomarker status for treatment in second-line based on an assay that was performed on tumor tissue collected potentially much earlier in the course of their disease? Additionally, tumors are notoriously heterogeneous, both within the same lesion as well as comparing primary and metastatic lesions. Can we be sure a patient is truly PD-L1-negative based on lack of overexpression in a single tumor sample? Although Dr. Herbst was particularly vocal about this point during his discussion, this same argument can be made about most biomarkers used in oncology today, and yet we don’t argue that EGFR wildtype NSCLC or KRAS-mutant colorectal cancer patients should be treated with Tarceva® (erlotinib, OSI/Astellas/Roche) or Erbitux® (cetuximab, Eli Lilly/Merck KGaA), respectively. Why should we treat the PD-L1 biomarker any differently? One reason to offer Opdivo to PD-L1-negative patients may be the potential lost long-term OS benefit if an active drug is withheld from a patient based on the results of an imperfect assay.

    Clearly the issue of PD-L1 as a necessary biomarker in NSCLC continues to be a subject of debate. Data to be presented later at this conference for other checkpoint inhibitors will add to the body of data for this, but the final answer is unlikely to emerge before the conference concludes. However, the data will add complexity to the treatment paradigm and has the potential to change the rules of the game when it comes to PD-1 and PD-L1 inhibitors. The results of CheckMate-057 clearly establish Opdivo as a new standard of care for second-line NSCLC. What remains to be determined is for how many of those patients?

    References:

    1) Globocan 2012, available from globocan.iarc.fr; accessed May 30, 2015.

    2) Kantar Health, CancerMPact Patient Metrics, available from www.cancermpact.com; accessed May 30, 2015.

    3) Paz-Ares L, Horn L, Borghaei H, et al. Phase III, randomized trial (CheckMate 057) of nivolumab (NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(suppl; abstr LBA109).

    4) Spigel DR, Reckamp KL, Rizvi NA, et al. A phase III study (CheckMate 017) of nivolumab (NIVO; anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated advanced or metastatic squamous (SQ) cell non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33: (suppl; abstr 8009).

    A New Partnership Between Varian and Flatiron Signifies Change in the Digital Oncology Marketplace

    The new partnership announced today between Varian Medical Systems and Flatiron Health hits on many of the keywords in the digital space these days, including cloud-based technology, EHR, data analytics, and decision-support software. Varian is known as a market leader in radiation oncology software and Flatiron acquired Altos who makes the leading web-based oncology-focused EMR, called OncoEMR. But with the pairing of these two companies, we wondered if it is all about strength in marketing, big data, or is it about synergies to help provide oncologists with new tools and improve quality cancer care? OBR talked to Sukhveer Singh, Vice President, Oncology Continuum Solutions, Varian Medical Systems and Zach Weinberg, Co-Founder, President, and COO at Flatiron to see if we could better understand the underpinnings of the alliance.

    Both companies consider themselves market leaders in their respective specialties: Varian in radiation oncology and Flatiron in oncology-specific EMRs. Varian publicly states that the ARIA platform is used in more than 3,400 radiation oncology centers worldwide, while Flatiron states that there are over 220 community oncology practices and/or cancer centers using OncoEMR. By partnering, they hope to build upon their respective areas of expertise and provide a comprehensive suite of products that encompass radiation oncology, medical oncology, and data analytics. “We want to leverage the complementary nature of our products” said Mr. Singh.

    According to Singh, “the ARIA software platform provides solutions for managing patient care and treatments. Historically, we have been responsible for most of the innovations in radiation oncology software. That is what we want to build upon now.”

    Regarding the partnership, Mr. Weinberg told us, “we offer two different products for the oncology provider – a cloud-based oncology EHR called OncoEMR, and a data analytic tool called OncoAnalytics, which helps providers with their day-to-day decision making. Both companies are addressing provider-facing problems in any setting, whether academic or community based, and are hoping the partnership will address problems across the continuum of care in radiation and medical oncology.”

    What are those problems that the partnership hopes to solve?

    Mr. Weinberg describes the silos in oncology as radiation oncology, surgical oncology, medical oncology, and other care providers that are not easily sharing information. The hope is that this partnership will allow cross-communication and breakthrough each of those silos resulting in improved care.

    How, specifically, do they intend to help physicians break down the silos?

    “The partnership is about product integration, about making OncoEMR interoperable with all the products in the ARIA software suite. We want to make all of these ‘best of breed’ services work together seamlessly,” said Weinberg.

    “The most exciting thing is where we want to go together. We believe that software, informatics, and analytics, can become the backbone of a patient’s journey from diagnosis to survivorship,” said Singh.

    Weinberg agrees, “you can see both the depth and breadth from this partnership – breadth in terms of the number of customers that the combined offering will cover, and depth because we will now start to see data across the continuum, and not just medical or radiation oncology data.”

    Adding value to the continuum of care
    Cancer patients are treated by more than one specialty, meaning medical oncologists, radiation oncologists, and surgical oncologists, in addition to a psychiatrist, dietician and other members of the treatment team. Varian and Flatiron feel the value in this partnership is in care coordination.

    According to Weinberg, the value in this integration from the medical oncology standpoint can be as basic as “did my patient receive the radiation treatment they were scheduled to receive?” to the seamless workflow across the patient care continuum which benefits both providers and patients.

    Regarding analytics, Weinberg says, “the key with analytics is having a full picture of the patient… Over time, all of the medical oncology and radiation oncology data will flow into a central place. And then both companies will be offering different analytic solutions depending on the problem at hand. In that way, analytics will become enhanced regardless of which company is offering them because the two systems are interoperable.”

    Singh noted that “this is a unique value proposition because we are making decision support accessible at the point of care. We are working toward a rapid cycle of gathering high-quality data, converting that data into insights, and making those insights available to the physicians at point of care when the patient is being treated.”

    Physicians will still be able to purchase ARIA and/or OncoEMR separately, depending on what is best for the customer. The brand names will stay the same. Initially, the focus will be in the United States, but all of the product enhancements will be offered internationally as well.

    by Don Sharpe