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  • Melanoma and Other Skin Cancers: Immediate Impact of 2016 ASCO Presentations on Clinical Practice

    Introduction

    In an effort to provide you with timely market feedback from the 2016 ASCO Annual Meeting, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ conducted immediately after the meeting. This report explores skin cancer (melanoma and merkel cell carcinoma) presentations concerning the use of checkpoint inhibitors and the combination of BRAF and MEK inhibitors.

    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 genitourinary cancers utilizing targeting parameters within the proprietary MDoutlook® global cancer treater panel
    • Timing: June 2016. Launched 1 day after close of 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL, June 3-7, 2016
    • Fielding to proprietary panel of cancer treaters, targeted by clinical interest
    • Data capture 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: 90
    • Responses are from 14 countries: Austria, Belgium, Brazil, Canada, France, Germany, Hungary, Italy, Romania, Spain, Sweden, Switzerland, United Kingdom and US

    OncoPoll_Melanoma_Figure1

     

    OncoPoll_Melanoma_Figure2

     

    OncoPoll_Melanoma_Figure3

    Key Conclusions

    • On a 0 – 5 scale of 0 = no awareness to 5 = very aware, clinicians have an above average awareness of these presentations
      • A slightly higher level of awareness is seen by those outside of the US
      • Attendees of the conference showed a higher level of awareness (not shown)
      • The awareness about avelumab in merkel cell carcinoma was somewhat lacking compared to the other antibodies in melanoma
    • Clinical impact, also rated on a 0 – 5 scale of 0 = no impact at all to 5 = very important, for these agents in general are seen as very clinically meaningful
      • US oncologists rate the merkel cell abstract as less clinically important
      • For most of these abstracts, importance assigned is slightly higher by those who did not attend the meeting, although the differences are never very large

    OncoPoll_Melanoma_Figure4

    Key Conclusions

    • On the same 0 – 5 scale, there is an above average level awareness about this presentation outside of the US, while awareness in the US is slightly lower
      • Higher level of awareness among the attendees compared to those who did not attend (not shown)
    • Oncologists view this as an important presentation, with those outside the US rating it as very clinically important
      • Attendance at the meeting does not impact the rating of clinical importance (not shown)
    • Oncologists view this as an important presentation, with those outside the US rating it as very clinically important
      • Attendance at the meeting does not impact the rating of clinical importance (not shown)
      • Even with the clinical importance of this abstract, expected usage of the BRAF + MEK inhibitor combination as 1st line therapy for BRAF V600E/K-mutant melanoma is expected to loose favor to the use of checkpoint inhibitors (not shown)

    Conclusions: Immediate Impact of 2016 ASCO Presentations on Clinical Practice for Melanoma and Merkel Cell Carcinoma

    • All of these studies highlight the importance of the ASCO Annual Meeting to the entire global oncology community – awareness of these presentations are high and can occur quite quickly even for those who did not attend
    • The importance of these presentations suggest that integration of these results into clinical practice will happen in relatively short order, especially since most of these agents are already widely available and in use

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

    Submitted by Robert Stephan, VP, Research and Physician Society, and Jan Heybroek, President MDoutlook.

     

    Genitourinary Cancers: Immediate Impact of 2016 ASCO Presentations on Clinical Practice

    Introduction

    In an effort to provide you with timely market feedback from the 2016 ASCO Annual Meeting, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ conducted immediately after the meeting. This report explores genitourinary (non-prostate) presentations concerning the use of checkpoint inhibitors as therapy for bladder cancer and new overall survival data for agents in kidney cancer.

    OncoPoll™ Methodology

    • Primary research phase involved a global survey to verified and validated medical oncologists and multi-disciplinary physicians with an identified clinical interest in genitourinary cancers utilizing targeting parameters within the proprietary MDoutlook® global cancer treater panel
    • Timing: June 2016. Launched 4 days after close of 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL, June 3-7, 2016
    • Fielding to proprietary panel of cancer treaters, targeted by clinical interest
    • Data capture 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: 89
    • Responses are from 20 countries: Argentina, Austria, Belgium, Brazil, Canada, Chile, France, Germany, Israel, Italy, Netherlands, Norway, Pakistan, Poland, South Africa, Spain, Sweden, Turkey, United Kingdom and US

    OncoPoll_GU_Figure1

    OncoPoll_GU_Figure2

    OncoPoll_GU_Figure3

    Key Conclusions

    • On a 0 – 5 scale of 0 = no awareness to 5 = very aware, clinicians have an above average awareness of these presentations
      • A general higher level of awareness is seen by those in the US (~0.5-0.7 higher ratings)
      • The awareness about durvalumab was somewhat lacking compared to the other antibodies
    • Clinical impact, also rated on a 0 – 5 scale of 0 = no impact at all to 5 = very important, for these agents in general are seen as very clinically meaningful
      • US oncologists assign a higher importance to these agents than those outside of the US
      • In total, a slightly higher level of importance is seen for 2nd+ line than in 1st line
      • Both awareness and assigned importance is greater for those who attended the meeting than those who did not (not shown)
    • In a follow-up question, we asked if participants had used atezolizumab for urinary cancer in their practices yet (outside of clinical trials); 40% of US respondents say they had, compared to 11% of those outside of the US

    OncoPoll_GU_Figure4

    OncoPoll_GU_Figure5

    Key Conclusions

    • On the same 0 – 5 scale, there is an above average level awareness about these presentations in the US, while awareness outside of the US is about average
      • No meaningful differences in awareness between these two abstracts
      • Much higher level of awareness among the attendees (3.8-3.9) compared to those who did not attend (2.7-2.8)
    • US oncologists view both of these presentations as very clinically important. Those outside of the US view these as less important and the nivolumab data as more important than the Meteor data
      • More importance (over a full point difference) was assigned to both presentations by the attendees than with the non-attendees (not shown)

    Conclusions: Immediate Impact of 2016 ASCO Presentations on Clinical Practice for Bladder and Kidney Cancer

    • All of these studies highlight the importance of the ASCO Annual Meeting to the entire global oncology community – awareness of these presentations are high and can occur quite quickly even for those who did not attend
    • The importance of these presentations suggest that integration of these results into clinical practice will happen in relatively short order, especially since most of these agents are already widely available and in use

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

    Submitted by Robert Stephan, VP, Research and Physician Society, and Jan Heybroek, President MDoutlook.

    Biomarkers for Immunotherapy: Results from ASCO 2016

    By Gena Kanas, M.P.H., Ph.D., Consultant, Clinical & Scientific Assessment, Kantar Health

    At ASCO 2016, new data was presented on potential biomarkers that could predict response to immunotherapy in the treatment of a variety of cancers. Current U.S. Food and Drug Administration (FDA)-approved PD-1/-L1 checkpoint inhibitor immunotherapy approvals include the use of Keytruda® (pembrolizumab, Merck & Co.) or Opdivo® (nivolumab, Bristol Myers-Squibb/Ono Pharmaceuticals) in advanced melanoma and advanced non-small cell lung cancer (NSCLC); Opdivo for use in advanced renal cell carcinoma and Hodgkin’s lymphoma; and most recently approved Tecentriq™ (atezolizumab, Genentech/Roche) in advanced urothelial carcinoma.

    One goal for the choice of biomarkers is their utility to select only those patients who will respond to a given treatment. Current immunotherapies target the interaction between PD-1 and PD-L1, and the inhibition of this interaction leads to antitumor activity. Unfortunately, over half of patients treated with immunotherapy do not show a clinical response, which has led to further investigation into possible immunotherapy combination strategies and to identify potential biomarkers to better predict those patients who best respond to immunotherapy.

    The use of tumor mutation burden, mismatch repair deficiency and PD-L1 expression as possible biomarkers were discussed at this year’s ASCO conference.

    PD-L1 Expression

    Two abstracts from the KEYNOTE-010 and KEYNOTE-021 studies focused on PD-L1 expression as a potential predictive biomarker for response in NSCLC patients. KEYNOTE-010 reported a general correlation between improved efficacy with increasing PD-L1 expression, as defined by a tumor proportion score (TPS), in Keytruda-treated NSCLC patients compared to docetaxel.1 However, since PD-L1-negative patients were not included in the study, KEYNOTE-010 was unable to evaluate PD-L1 status as a biomarker for Keytruda. KEYNOTE-021 reported improved efficacy of Keytruda combined with different chemotherapy regimens regardless of PD-L1 status in three cohorts of advanced NSCLC patients .2 Across all three cohorts, the overall response rate (ORR) did not significantly differ between patients with TPS of 1% or greater and those with TPS less than 1%. These studies suggest that PD-L1 expression is weakly correlated with clinical response to immunotherapy.

    Tumor Mutation Burden

    Three abstracts reported on tumor mutation burden (TMB) as a possible predictor of immunotherapy response in NSCLC, melanoma, and urothelial carcinoma patients. Each study used the same set of genes for the analysis of TMB (calculated as the number of synonymous and nonsynonymous variants from a series of 236-315 genes).

    The first study reported a correlation between TMB and longer immunotherapy (Keytruda, Opdivo, or avelumab (Pfizer)) treatment duration in 64 NSCLC cases.3 Patients with TMB of 15 mutations/Mb or more had a longer immunotherapy treatment duration compared to those with TMB of less than 15 mutations/Mb (p=0.010). However, the authors did not report data on efficacy of immunotherapy treatment by level of TMB.

    The authors of the second analysis reported a correlation between increasing TMB and higher progression free survival (p<0.001) and overall survival (p<0.001) in melanoma patients treated with immunotherapy (Opdivo, Keytruda or Tecentriq).4 A high TMB in this study was defined as more than 23.1 mutations/Mb. TMB was not predictive for survival for patients not treated with immunotherapy.

    The third study reported the results of an analysis of predictors of metastatic urothelial carcinoma patients’ response to Tecentriq in the IMvigor 210 Phase II trial.5 The patients within the highest quartile of median mutational load (more than 16 mutations/Mb for platinum treated and more than 13.5 mutations/Mb for first line cisplatin-ineligible) had higher overall survival (p=0.0012 and p=0.0079, respectively) than patients in the lower quartiles. The authors also reported an improved efficacy among patients with higher PD-L1 expression. When included in a multivariable model, both PD-L1 and TMB were independent and significant predictors of response to Tecentriq (p=0.0109 and p<0.0001, respectively).

    The results of these three studies suggest that a high TMB is correlated with clinical response to immunotherapy; however, each study provided a different definition of “high” TMB. While assessing TMB as a potential biomarker, the threshold to be used to identify those patients who would benefit most from immunotherapy treatment will need to be determined via consensus.

    Mismatch Repair Deficiency

    Two abstracts reported updated results that included more patients from the same study6 that focused on mismatch repair (MMR) deficiency or microsatellite instability (MSI) as markers of immunotherapy response.7, 8

    In the first analysis,7 30 patients with MMR-deficient metastatic or locally advanced non-colorectal cancers who had received at least one prior therapy were treated with Keytruda. After a 10-month median follow-up, 53% of the patients had an objective response, and responses were observed in all of the cancer types evaluated with durable disease control. Unfortunately, patients with MMR-proficient cancers were not included in this analysis, thus this study is unable to determine the utility of testing for MMR as a biomarker for Keytruda. The second analysis8 focused on metastatic colorectal cancer patients treated with Keytruda and included both MMR-deficient (n=28) and MMR-proficient (n=25) patients. In contrast to the previous results for PD-L1 and TMB, there were no responses to Keytruda in MMR-proficient colorectal tumors, highlighting the selective nature for this biomarker.

    Future studies will be necessary to confirm the utility of MMR deficiency as a biomarker as well as the relationship for MMR deficiency with PD-L1 expression and/or TMB. Several Phase III and Phase II trials are currently recruiting in patients with MSI-high or MMR-deficient advanced or metastatic colorectal cancer.

    Conclusions

    Among the FDA-approved indications for the three approved PD-1/-L1 inhibitors, only Keytruda has a label currently limiting use to a biomarker-defined patient subtype (Keytruda in PD-L1-positive NSCLC). Nevertheless, as the development of these agents is rapidly expanding across tumor types, there remains strong interest to identify predictive biomarkers of response.

    Of the three possible biomarkers discussed above, MMR deficiency has the strongest evidence supporting its predictive behavior to PD-1 inhibitors. PD-L1 status and TMB may ultimately be most effective as predictive biomarkers when combined with each other and potentially other tumor-specific factors. Thus, the current oncology model of using a single biomarker to select patients for treatment may not be the best approach in the era of immunotherapy.

    References

    1. Bass P, et al. J Clin Oncol. 2016; 34(suppl); abstr 9015.
    2. Gadgeel SM, et al. J Clin Oncol. 2016; 34(suppl); abstr 9016.
    3. Spigel DR, et al. J Clin Oncol. 2016; 34(suppl); abstr 9017.
    4. Johnson DB, et al. J Clin Oncol. 2016; 34(suppl); abstr 105.
    5. Rosenberg JE, et al. J Clin Oncol. 2016; 34(suppl); abstr 104.
    6. Le DT, et al. N Engl J Med. 2015; 372(26):2509-20.
    7. Diaz LA, et al. J Clin Oncol. 2016; 34(suppl); abstr 3003.
    8. Le DT, et al. J Clin Oncol. 2016; 34(suppl); abstr 103.

     

    Non-Small Cell and Small Cell Lung Cancers: Immediate Impact of 2016 ASCO Presentations on Clinical Practice

    Introduction

    In an effort to provide you with timely market feedback from the 2016 ASCO Annual Meeting, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ conducted immediately after the meeting. This report explores presentations concerning the treatment of ALK+ non-small cell lung cancer (NSCLC) and the use of checkpoint inhibitors as therapy for small cell lung cancer (SCLC).

    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 2016. Launched 2 days after close of 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL, June 3-7, 2016
    • Fielding to proprietary panel of cancer treaters, targeted by clinical interest
    • Data capture 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: 146
    • Responses are from 14 countries: Austria, Belgium, Brazil, Canada, France, Germany, Italy, Japan, Poland, Spain, Switzerland, Turkey, United Kingdom and US

    OncoPoll_NSCLC_Figure1

     

    OncoPoll_NSCLC_Figure2v2

    Key Conclusions

    • On a 0 – 5 scale of 0 = no awareness to 5 = very aware, clinicians have an above average awareness
      • Higher level of awareness was seen by those outside of the US (~3.8 vs. 3.3)
      • Much higher level of awareness (nearly a full point) was seen among the attendees compared to those who did not attend (not shown)
    • Clinical impact, also rated on a 0 – 5 scale of 0 = no impact at all to 5 = very important, oncologists see this new information as very clinically meaningful, with average rating of ~3.7
      • Only small differences in importance was seen between US and Ex-US and between attendees and non-attendees (not shown)
      • There is some concern that these results were from a single country (Japan) and thus may not be entirely reproducible to all patients (not shown). Large scale integration of these results into clinical practice may wait until the results of the global ALEX trial are available.

     

    OncoPoll_NSCLC_Figure3v2

    Key Conclusions

    • On the same 0 – 5 scale, there is an above average level awareness about this brigatinib presentation in the US, while awareness outside of the US is well above average
      • Much higher level of awareness among the attendees (3.7) compared to those who did not attend (2.2)
    • The 2nd generation ALK inhibitor brigatinib is seen as welcome addition to the oncologists’ armamentarium for ALK+ NSCLC, as seen by the clinically important ratings
      • The clinical importance averaged ~3.5, regardless of region
      • With the higher level of awareness, more importance was seen by the attendees than with the non-attendees (not shown)

    OncoPoll_NSCLC_Figure4v2

    Key Conclusions

    • Treaters of SCLC are aware about this new clinical data combining nivolumab (anti-PD-1) with ipilimumab (anti-CTLA-4) with level of awareness of ~3.7
      • Very high level of awareness among the attendees (4.1) compared to those who did not attend (3.0); highest level of awareness among these lung cancer abstracts by non-attendees (not shown)
    • The use of the dual checkpoint inhibition in SCLC is seen as clinically important
      • US oncologists assign slightly more importance to this information, average rating of 4.0 vs. 3.6 for ex-US respondents
        • Over 1/4 of respondents rated the importance as a “5” (not shown)
      • Even with the higher level of awareness by the attendees, both attendees and non-attendees have similar views as to its importance, upon learning about this new data (not shown)

    Conclusions: Immediate Impact of 2016 ASCO Presentations on Clinical Practice for ALK+ NSCLC and SCLC

    • All of these studies highlight the importance of the ASCO Annual Meeting to the entire global oncology community – awareness of these presentations are high and can occur quite quickly even for those who did not attend
    • The importance of these presentations suggest that integration of these results into clinical practice will happen in relatively short order, especially since most of these agents are already widely available and in use

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

    Submitted by Robert Stephan, VP, Research and Physician Society, and Jan Heybroek, President MDoutlook.

    Gastrointestinal Cancers: Immediate Impact of 2016 ASCO Presentations on Clinical Practice

    Introduction

    In an effort to provide you with timely market feedback from the 2016 ASCO Annual Meeting, OBR and MDoutlook are pleased to share results from MDoutlook’s OncoPolls™ conducted immediately after the meeting. This report explores presentations concerning the sidedness of the primary tumor in metastatic colorectal cancer(mCRC) and the potential use of gemcitabine + capecitabine (GEMCAP) as adjuvant therapy in resected pancreatic cancer patients.

    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 GI cancers utilizing targeting parameters within the proprietary MDoutlook® global cancer treater panel
    • Timing: June 2016. Launched 3 days after close of 2016 American Society of Clinical Oncology (ASCO) Annual Meeting, held in Chicago, IL., June 3-7, 2016
    • Fielding to proprietary panel of cancer treaters, targeted by clinical interest.
    • Data capture 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: 134
    • Responses are from 17 countries: Austria, Belgium, Brazil, Canada, France, Germany, Greece, Hungary, Ireland, Italy, Poland, Slovakia, Spain, Sweden, Switzerland, United Kingdom and US

    Geographic Distribution and Attendance of Respondents

    OncoPoll_GI_Figure1

    Primary Tumor Sidedness in mCRC:

    Awareness & Importance of Abstracts #3504, 3405 and 3406

     OncoPoll_GI_Figure2

    Key Conclusions

    • On a 0 – 5 scale of 0 = no awareness to 5 = very aware, clinicians have an above average awareness of ~3.3
      • No difference seen between US and ex-US respondents
      • Higher level of awareness was seen among the attendees compared to those who did not attend (not shown)
    • Clinical impact, also rated on a 0 – 5 scale of 0 = no impact at all to 5 = very important, oncologists see this new information as clinically meaningful, with average rating of ~3.3
      • Those outside of the US assign slightly more importance to this information
      • Only small differences in importance was seen between attendees and non-attendees (not shown)
      • Changes in treatment selections will primarily occur only for left-sided tumors, with a 38% increase in the use of FOLFOX or FOLFIRI + cetuximab, with a 9% decrease in the use of bevacizumab in these patients (not shown)

    Adjuvant Therapy for Pancreatic Cancer:

    Awareness and Importance of Abst. #LBA4006

    OncoPoll_GI_Figure3

    Key Conclusions

    • On the same 0 – 5 scale, treaters of pancreatic cancer are aware about this new clinical data, with level of awareness ranging between ~3.5-3.7
      • Much higher level of awareness among the attendees (3.8) compared to those who did not attend (2.9)
    • The addition of capecitabine to gemcitabine (GEMCAP) as an adjuvant therapy for pancreatic cancer is seen as very clinically important
      • Those outside of the US assign slightly more importance to this information, average rating of 4.0 vs. 3.8 for US respondents
      • With the higher level of awareness, more importance was seen by the attendees than with the non-attendees (not shown)
      • While these results will not have much impact on the overall use of adjuvant therapy in general, GEMCAP usage will experience a very large growth in usage and will be considered the standard of care in the adjuvant setting (not shown)

    Conclusions: Immediate Impact of 2016 ASCO Presentations on Clinical Practice for mCRC and Pancreatic Cancers

    • Both of these studies highlight the importance of the ASCO Annual meeting to the entire global oncology community – awareness of these presentations are high and can occur quite quickly even for those who did not attend
    • Integration of these results into clinical practice are going to happen in relatively short order, especially since agents are already widely available and in use

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

    Submitted by Robert Stephan, VP, Research and Physician Society, and Jan Heybroek, President MDoutlook

    PALOMA Soars!

    By: Tari Awipi, Ph.D. Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Arnold DuBell, Ph.D., M.B.A., Senior Consultant, Clinical & Scientific Assessment, Kantar Health 

    The CDK 4/6 inhibitor Ibrance® (palbociclib, Pfizer) burst onto the scene in February 2015 with its original approval from the U.S. Food and Drug Administration (FDA) for treatment of newly diagnosed HR+/HER2- breast cancer. This accelerated approval, based on the Phase II PALOMA-1 trial, was contingent on a post-marketing Phase III trial, PALOMA-2. Yesterday the positive results of PALOMA-2 were presented at the American Society for Clinical Oncology (ASCO) annual meeting and confirmed the 10-month improvement in progression-free survival (PFS) (10.2 months versus 20.2 months, HR 0.49, p=0.0004) in patients with HR+/HER2- advanced breast cancer reported in PALOMA-1.1,2

    As it was partly confirmatory, PALOMA-2 had a similar design. In PALOMA-2, 666 previously untreated HR+/HER2- breast cancer patients were randomized to Ibrance or Ibrance plus letrozole. Similar to PALOMA-1, the addition of Ibrance was associated with a 10.3-month improvement in PFS (investigator-assessed medians: 24.8 months versus 14.5 months; HR 0.58, p=0.0004). Independent central review suggested a similar benefit (30.5 months versus 19.3 months, HR 0.65, p=0.0005). In the intent-to-treat population, Ibrance improved the objective response (42% versus 35%, OR 1.40, p=0.031) and the clinical benefit rate (85% versus 70%, OR 2.39, p<0.0001). Overall survival data were not presented. Ibrance primarily increased the incidence of Grade 3-4 neutropenia (66% versus 1%) and leucopenia (25% versus 0%). This is represented in the minor increase in the adverse event-associated treatment discontinuation rate (9.7% versus 5.9%). One factor that was highlighted in both the presentation and the discussion was that the data from the Phase III PALOMA-2 trial were strongly consistent with the data from the Phase II PALOMA-1 trial (see table below). This consistency confirms not only the statistically significant efficacy benefit for Ibrance but also the strong clinical relevance of this efficacy benefit.

    PALOMA-11 PALOMA-22
    Trial Design Phase II, open-label Phase III, placebo control
    Patients on Study 165 666
    PFS, HR 0.49 0.58
    Median PFS (months) 20.2 versus 10.2 months

    (10 month improvement)

    24.8 versus 14.5 months

    (10.3 month improvement)

    ORR (ITT) 43% versus33% 42% versus 35%
    CBR (ITT) 81% versus 58% 85% versus 70%
    Source: (1) Finn, Lancet Oncol, 2015; (2) Finn, Abstract 507, ASCO 2016

     

    A third study, PALOMA-3, compared Ibrance in combination with Faslodex® (fulvestrant, AstraZeneca) in patients who had already progressed on endocrine therapy and also published strong positive safety and efficacy data.3 The results of this trial were the basis for Ibrance’s FDA label extension to include the treatment of patients in the second-line setting in February 2016. In all three trials, neutropenia was affected the most by the addition of Ibrance.

    Since its 2015 accelerated approval, Ibrance has already gained strong utilization in the U.S. and is already the most utilized regimen as first-line therapy for postmenopausal HR+ metastatic breast cancer patients, with approximately 30% utilization.4 These strong new data will support conversion of accelerated approval in the United States and regulatory filings for Ibrance in the first-line setting elsewhere. While Ibrance currently enjoys first-in-class status (at least in the first-line setting) it may soon face more competition from two other CDK 4/6 inhibitors in this space. The first is Eli Lilly’s abemaciclib. It has two ongoing Phase III trials: MONARCH 2 (NCT02107703), which is comparing Faslodex with or without abemaciclib in 630 HR+/HER2- patients, and MONARCH 3 (NCT02246621), which is comparing the activity of non-steroidal aromatase inhibitors with or without abemaciclib in 450 HR+/HER2- patients. Abemaciclib received a boost at this year’s ASCO annual meeting with presentation of positive results from its MONARCH 1 Phase II trial. MONARCH-1 found that single-agent abemaciclib was active in refractory metastatic HR+/HER2- patients with a 19.7% objective response rate (ORR), a six-month median PFS and a 17.7-month median overall survival (OS). Toxicities were more of a concern, with diarrhea (19.7%), fatigue (12.9%), neutropenia (26.9%) and leucopenia (27.7%) being common Grade 3-4 toxicities.5 Eli Lilly’s agent had already received Breakthrough Therapy Status in October 2015. The second competitor in the first-line setting is Novartis’ ribociclib, which is being evaluated in three trials: MONALEESA-2 (NCT01958021; letrozole with or without ribociclib in 667 HR+ postmenopausal patients), MONALEESA-3 (NCT02422615; Faslodex with or without ribociclib in 660 HR+ men or postmenopausal women) and MONALEESA-7 (NCT02278120; hormone therapy with or without ribociclib in 660 premenopausal patients).

    Moreover, Afinitor® (everolimus, Novartis) is currently approved for use in postmenopausal women with advanced HR+ breast cancer in combination with exemestane after relapse on letrozole or anastrozole, based on the results of the BOLERO-2 trial.6 Novartis had attempted other trials in both the first-line and relapsed settings. BOLERO-1, which evaluated Afinitor plus Herceptin and paclitaxel in HR+/HER2+ patients, failed to reach its PFS primary endpoint.7 Afinitor did meet the primary endpoint in the BOLERO-3 trial,8 which evaluated the efficacy of adding Afinitor to Herceptin and vinorelbine to Herceptin pretreated patients; however, the PFS benefit was small (HR 0.78), and Novartis has not yet filed for regulatory approval since the trial’s 2014 data publication. Other agents are being evaluated in late-stage trials for relapsed patients. These include buparlisib (PI3K inhibitor, Novartis), alpelisib (PI3Kα inhibitor, Novartis), taselisib (PI3Kα inhibitor, Genentech/Roche) and entinostat (histone deacetylase inhibitor, Syndax). If successful in the relapsed setting, these agents could also become competition to Ibrance in the first-line setting.

    In spite of the future competition, Ibrance solidified its current position for use as a first-line treatment option with the results from PALOMA-2 and made it harder for competitors to dislodge its preferential status in this setting. With the extremely positive data presented at ASCO 2016, Ibrance can truly spread its wings and soar.

    References:

    1. Finn, Lancet Oncol, 2015.
    2. Finn, Abstract 507, ASCO 2016
    3. Christofanilli, Lancet Oncol, 2016.
    4. Kantar Health, CancerMPact® Treatment Architecture 2015 US, accessed June 6, 2016.
    5. Dickler, Abstract 510, ASCO 2016.
    6. Baselga, NEJM, 2012.
    7. Hurvitz, Lancet Oncol, 2015
    8. André, Lancet Oncol, 2014

    PD-1 Inhibitors Running Neck-and-Neck in Head and Neck

    By: Haris Vikis, Ph.D. Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health

    Patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) who are refractory to platinum-based therapy have a poor prognosis with a median overall survival of  six months or less.1,2 While Erbitux® (cetuximab, Eli Lilly/Bristol-Myers Squibb/Merck KGaA) and platinum-based regimens are most commonly used in locally advanced and metastatic disease, immunotherapies are about to take center stage, offering significantly improved therapeutic options based on today’s findings at the American Society for Clinical Oncology (ASCO) annual meeting. Within the last two years, the PD-1 checkpoint inhibitors Keytruda® (pembrolizumab, Merck & Co.) and Opdivo™ (nivolumab, Bristol-Myers Squibb/Ono Pharmaceuticals) have garnered approvals in several tumor types, including melanoma, non-small cell lung cancer, and more recently renal cell carcinoma and Hodgkin’s lymphoma for Opdivo. Data presented at ASCO 2016 now have single-agent Keytruda and Opdivo racing for approval in HNSCC.

    Over the last 12 months Opdivo and Keytruda have each reported promising topline efficacy and safety data in the R/M setting for HNSCC.3-5 This prompted regulatory filing for accelerated approval for Keytruda in April 2016 based on data from the KEYNOTE-012 Phase I study.3,4 A U.S. Food and Drug Administration (FDA) action date of August 9, 2016, has been set, and it is anticipated to result in the first immunotherapy approval in HNSCC, likely subject to confirmation of the ongoing randomized Phase III KEYNOTE-040 trial. Hot on the heels of Keytruda is Opdivo, which recently reported positive data at the 2016 American Association of Cancer Research (AACR) annual meeting based on a planned interim analysis of the CHECKMATE-141 Phase III study.3 The FDA quickly granted Breakthrough Therapy designation, and a regulatory filing is highly anticipated in the near future. Given the high unmet needs within HNSCC and the enthusiasm for immunotherapy that has penetrated oncology over the last few years across multiple tumor types, these agents are likely to be approved and adopted quickly. Today at the ASCO 2016 annual meeting, four oral abstracts were presented6-9 detailing updated efficacy and safety data that strongly support the registration programs for both Keytruda and Opdivo, further prompting cross-trial comparative analyses.

    Today’s presentation on CHECKMATE-141, a randomized (2:1) Phase III trial of 361 patients testing Opdivo versus investigator’s choice therapy in R/M platinum refractory patients,4 was largely a reprisal of data presented at AACR in April 2016. In the ASCO presentation, Opdivo demonstrated a median overall survival (mOS) of 7.5 months (HR: 0.70, P=0.01 when compared with the control arm). More benefit was observed in the PD-L1 ≥ 1% subgroup with a mOS of 8.7 months (HR: 0.55, 0.36-0.83) and an objective response rate (ORR) of 17%. Benefit in the PD-L1 ≤ 1% population exhibited an ORR of 12% and a mOS of 5.7 months (HR: 0.89, 0.54-1.45), which were similar to the control arm. However, as first described at AACR there is some divergence in the Kaplan-Meier curve at eight to nine months, suggesting some long-term benefit with Opdivo in this patient subgroup. Nevertheless, these data largely dismiss PD-L1 status as an effective biomarker of response, as all patients benefit regardless of PD-L1 status. The updated data presented today continue to support this. The same story holds true for HPV positivity as a biomarker of response, as both HPV-positive and HPV-negative patients continue to derive benefit. The Opdivo arm yielded superior safety. Treatment-related adverse events (TRAEs) totaled 59% (Grade 3-4 = 13%) versus 78% (35% Grade 3-4) in the control arm, and no new safety signals were reported. These data are generally consistent with the improved safety profiles in other tumor types and in the KEYNOTE trials discussed below. Finally, newly released data showed that Opdivo stabilized measures of patient-reported outcomes (PROs), while patients on investigator’s choice had declines in function and worsening of symptoms, adding another reason to support Opdivo as a new standard-of-care option in R/M HNSCC.

    Merck has an aggressive development strategy for Keytruda in HNSCC, which was evident in the three abstracts reported on two Keytruda trials in the R/M setting. Long-term follow-up of expansion cohorts in HNSCC (n=192) as part of KEYNOTE-012 was presented at ASCO 2016.7 Updated data revealed an ORR that was largely maintained at 18%, with observations of significant durable responses as 85% of responses lasted six months or longer. The median OS was slightly reduced to eight months from previous reporting.3,4 A companion abstract reported in-depth biomarker analysis for PD-L1, which consistently showed increased ORR, OS and progression-free survival (PFS) in PD-L1-positive versus PD-L1-negative tumors.8 Interestingly, when tumor and inflammatory cells were included as part of a PD-L1 biomarker score, the ORR increased to 21% in PD-L1-positive versus only 6% in PD-L1 negative tumors, indicating a significantly increased ability to predict response, which may be an important consideration in the future. Biomarkers beyond PD-L1, including PD-L2 and an IFN-γ gene signature, were also strongly correlated with response, PFS and OS.

    And finally newly released data from KEYNOTE-055, a large, single-arm Phase II study in platinum- and Erbitux-refractory patients, also were presented and largely confirmed the findings of KEYNOTE-012. This study was performed in a more heavily pretreated population (84% with two or more prior regimens) and reported an ORR of 17% in the total and PD-L1-positive population. TRAEs were reported at 60% (12% Grade 3-4) and agreed well with safety signals observed in the KEYNOTE-012 trial and CHECKMATE-141 trials.

    How will data from these three trials be viewed in cross-trial comparisons? While the patient populations are largely similar (with the exception of the KEYNOTE-055, which was conducted in a more heavily pretreated population), the efficacy and safety data are remarkably similar between Keytruda and Opdivo (see table). Efficacy is consistently in the 18% range for ORR, two months for PFS and eight months for OS at the median. All measures of efficacy were independent of HPV status, and PD-L1 status was  largely predictive of those who may benefit more but could not exclude those patients who may benefit regardless even among the PD-L1–negative population.

    6CHECKMATE-141 7,9KEYNOTE-012 8KEYNOTE-055
    Patient Setting

    (≥2 prior lines)

    56%

    prior plat

    61%

    91% had prior plat

    84%

    prior plat and cetuximab

    mOS 7.5 mos

    8.7 mo (PD-L1³1%)

    8 mos 8 mos
    mPFS 2.0 mos 2.2 mos 2.1 mos
    ORR 17% (PD-L1³1%) 18% (PD-L1³1%) 17% (PD-L1³1%)
    Any TRAEs 59% 64% 60%
    Grade 3/4 TRAEs 13% 13% 12%

     

    Based on the filing in April, Keytruda is set to become the first immunotherapy approved for HNSCC. While Opdivo has the virtues of a larger and randomized study, Keytruda now has confirmatory evidence from the Phase II KEYNOTE-055 study, and it remains to be seen whether the data presented at ASCO are included as part of the Keytruda regulatory filing. If the FDA follows suit as it did in melanoma and lung, it will grant Keytruda accelerated approval and await data from a randomized Phase III trial (KEYNOTE-040) before granting full approval. However, Keytruda will need to compete in this setting with Opdivo, which has comparable data in a randomized Phase III trial, and durvalumab (AstraZeneca), whose ongoing EAGLE Phase III trial has yet to report. As Merck did with Keytruda, AstraZeneca has also guided for possible accelerated filings based on Phase II data.

    As single-agent therapies, there is little evidence to suggest a difference between Keytruda and Opdivo PD-1/-L1 inhibitors in terms of efficacy and safety. These agents may be able to distinguish themselves by the additional development strategies being employed ‒ durvalumab and Keytruda are also exploring use of the PD-L1 biomarker to select patients; Opdivo is focusing strictly on an all-comers population; and durvalumab is also being developed in combination with tremelimumab. While refinement of biomarker populations based on PD-L1, PD-L2 and IFN-γ gene signatures have been presented, little evidence to date suggests that PD-L1 is the appropriate biomarker to distinguish responders from non-responders. Success of one PD-1 inhibitor over the other may come down to physician preference.

    It is clear that single-agent Keytruda and Opdivo significantly improve the treatment armamentarium in R/M HNSCC for a patient population with limited options. Responses are durable, and the agents are well tolerated with distinct and manageable toxicity profiles. While the race for the first immunotherapy in HNSCC may be neck-and-neck, future developmental activity continues and undoubtedly is moving toward evaluation of combination therapies and integration of immunotherapy into earlier lines of therapy.

    References:

    1. Machiels JP et al., Lancet Oncol. 2015 May;16(5):583-94
    2. Kushwaha VS et al., Cancer Biol Ther. 2015;16(2):346-51
    3. Seiwert, Abstract LBA 6008, ASCO 2015
    4. Chow, Abstract 2866, ESMO 2015
    5. Gillison, Abstract CT099, AACR 2016
    6. Ferris, Abstract 6009, ASCO 2016
    7. Mehra, Abstract 6012, ASCO 2016
    8. Bauml, Abstract 6011, ASCO 2016
    9. Chow, Abstract 6010, ASCO 2016

    Finding NEMO: NRAS-mutant melanoma patients finally have an effective treatment option

    By: Len Kusdra, Ph.D., Analyst, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

    The pace of treatment in metastatic melanoma has significantly accelerated in the past couple of years. What was once a disease beset by toxic and largely ineffective treatments now enjoys a number of effective agents that have reduced the mortality of this aggressive disease. Yervoy® (ipilimumab, Bristol-Myers Squibb), a CTLA-4 antagonist, was the first of these effective immunotherapy agents that showed a significant and clinically relevant improvement in survival and led to its approval by the U.S. Food and Drug Administration (FDA) in 2011 for both first- and second-line metastatic melanoma. With the pervasive excitement of immunotherapy in the field of oncology (for which Yervoy provided proof-of-concept in melanoma), it was only a matter of time that more of these agents would make their way into melanoma. As a result, Opdivo® (nivolumab, Bristol-Myers Squibb) and Keytruda (pembrolizumab, Merck) have been added to the armamentarium for physicians in treating metastatic melanoma. The age of targeted therapy further emerged between 2012 and 2015 with approval of four agents that target the RAS-BRAF-MAPK pathway: Zelboraf® (vemurafenib, Roche/Genentech), Tafinlar® (dabrafenib, Novartis), Mekinist® (trametinib, Novartis) and Cotellic® (cobimetinib, Roche/Genentech/Exelixis, in combination with Zelboraf). All four agents are indicated for use in metastatic melanoma patients whose tumors harbor BRAF mutations.

    For BRAF-mutant patients, the approval of BRAF and MEK inhibitors ushered in an era of patient segmentation and the resulting personalized medicine in melanoma; however, it is now appreciated (as is the case with other tumor types) that other mutations exist that provide niche opportunities for development of novel agents. One such mutation type is in NRAS, which occurs in about 15% of patients and is associated with more aggressive disease and poorer prognosis.1,2 Until recently, no active clinical development existed for this population, representing a major unmet need in the treatment of metastatic melanoma. This has changed with the development of binimetinib (Array Biopharma), a novel MEK inhibitor that showed promising clinical activity in a Phase II trial (NCT01320085) in patients demonstrating a 20% response rate in patients with NRAS mutations and in 20% of BRAF-mutant patients.3 Based on these promising results, Novartis decided to move binimetinib forward into late-stage development with the initiation of the NEMO clinical trial.

    NEMO (NCT01763164) is an open-label, Phase III trial evaluating binimetinib versus dacarbazine in patients with advanced, unresectable (Stage IIIC) or metastatic NRAS melanoma who were either untreated or who had progressed on or after immunotherapy. Patients were randomized 2:1 to receive either 45 mg twice a day or dacarbazine at 1000 mg/m2 intravenously every three weeks. The primary endpoint is progression-free survival (PFS) with secondary endpoints including overall survival (OS), response rates, and disease control rate. In December 2015, Array Biopharma announced top-line results from NEMO demonstrating that the trial had met the primary endpoint of improving PFS (HR = 0.62, p<0.001). The median PFS for patients in the binimetinib arm was 2.8 months versus 1.5 with dacarbazine (Array BioPharma, press release, December 2015).

    Today at the American Society of Clinical Oncology annual meeting, attendees were presented with more detailed findings from NEMO.3 At this interim analysis, 269 patients had received binimetinib and 133 patients had received dacarbazine. The PFS did not change from that announced in the press release, and, at this interim analysis, there was no improvement in OS (11.0 months in the binimetinib arm versus 10.1 in the dacarbazine arm); however, the data is not mature and longer-term follow-up is required before final assessment. The confirmed overall response rate was 15% (95% CI: 11% to 20%) and disease control rate was 58% (95% CI: 52%-64%) for binimetinib, respectively, compared with 7% (95% CI: 3%-13%) and 25% (18%-33%) for dacarbazine (p-value for response=0.015; p-value for the disease control rate <0.001). An intriguing piece of data arises in the prespecified subset analysis between patients who had received prior immunotherapy versus patients who had received no prior immunotherapy, although the data should be interpreted with caution given the small patient population in the prior immunotherapy arm (n=57 and 28 in the binimetinib and dacarbazine cohort, respectively). While the PFS benefit was seen in both subgroups, the benefit appeared to be greater in patients who had received prior immunotherapy (5.5 months in the binimetinib arm versus 1.6 months in the dacarbazine arm in patients who had prior immunotherapy, HR=0.46; 2.8 months in the binimetinib arm versus 1.5 months in the dacarbazine arm in patients with no prior immunotherapy). The trend favoring binimetinib in patients who had received prior immunotherapy was observed regardless of whether patients received Yervoy or a PD-1 agent. Of some concern is the side effect profile: 21% of patients discontinued treatment due to adverse events in the binimetinib group and 6% discontinued treatment in the dacarbazine arm due to side effects. Overall, binimetinib was associated with increased incidence of Grade 3/4 adverse events (68% binimetinib versus 46% dacarbazine). The most common Grade 3-4 adverse event was elevation of blood CPK (19% with binimetinib versus 0% with dacarbazine), hypertension (7% with binimetinib versus 2% with dacarbazine), and rash (4% with binimetinib versus 0% with dacarbazine).

    Data from NEMO paves the way for regulatory approval of binimetinib in NRAS-mutant melanoma patients, a population with a high unmet need, making it first to market in this niche setting. While not being evaluated directly in this patient population, Keytruda, Opdivo and Yervoy may pose a competition for binimetinib. The activity seen with checkpoint inhibitors in both BRAF-mutant and BRAF-wildtype patients has raised the debate on whether to administer immunotherapy as first-line therapy in all subtypes regardless of mutational status or whether to reserve immunotherapy for the relapsed setting following failure of BRAF inhibitors in BRAF-mutant patients. Indeed, while the majority of BRAF-mutant patients will receive Zelboraf or Tafinlar with or without Mekinist, physicians also will administer Opdivo with or without Yervoy in a fraction of patients.5 With the subset analysis showing a greater efficacy benefit in patients with prior immunotherapy treatment, physicians may push binimetinib treatment to the second line, preferring to utilize immunotherapy upfront as a treatment paradigm for NRAS patients. In addition, while the PFS improvement in the entire population is significant, physicians may question the benefit-to-cost ratio given the increased rate of Grade 3/4 adverse events, thus posing a challenge to uptake. Countering that viewpoint is that NRAS patients suffer from a lack of effective clinical options, and the unmet need justifies binimetinib’s use.

    Another question that inevitably arises is whether combination therapy will yield improved outcomes as seen with Tafinlar and Mekinist. As such, Array has initiated a Phase III trial evaluating binimetinib in combination with their BRAF inhibitor encorafenib (NCT01909453; COLUMBUS). This trial recently completed enrollment, and initial data readout and regulatory filing are expected to occur sometime in 2016 (Array BioPharma Investor Report, January 13, 2016).

    Despite the challenges discussed, binimetinib represents the first major therapeutic option for NRAS-mutant melanoma and has offered a ray of hope in the dark muddy waters of this deadly and aggressive disease.

    References:

    1. Colombino, M, Capone M, Lissia A et al. “BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma.” J Clin Oncol, 30(20): 2522-2529, 2012.
    2. Devitt B, Liu W, Salemi et al.; “Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma;” Pigment Cell Melanoma Res, 24(5):666-672, 2011.
    3. Ascierto PA, Schadendorf D, Berking C, et al.; “MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study;” Lancet Oncol, 14(3):249-256, 2013.
    4. Dummer, Schadendorf D, Ascierto, PA, “Results of NEMO: A phase III trial of binimetinib (BINI) vs dacarbazine (DTIC) in NRAS-mutant cutaneous melanoma.” J Clin Oncol 34, 2016 (suppl; abstr 9500)
    5. Kantar Health, CancerMPact® Treatment Architecture, accessed June 6, 2016

    CASTOR Shines in Relapsed/Refractory Multiple Myeloma

    By: Greg Wolfe, Ph.D., Senior Consultant, Clinical & Scientific Assessment, Kantar Health and Jay Grisolano, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health

    The armamentarium of treatment options available for patients with multiple myeloma continues to grow as the result of several recent, successful novel therapeutic agents in development. In November 2015, three novel agents received approval from the U.S. Food and Drug Administration (FDA) for treatment of relapsed/refractory disease: Darzalex® (daratumumab, HuMax-CD38; Genmab/Janssen Biotech), a human monoclonal antibody directed against CD38 that is highly expressed on the surface of multiple myeloma cells and indicated for patients who have received at least three prior lines of therapy;  Empliciti™ (elotuzumab; Bristol-Myers Squibb/Abbvie), a SLAMF7-directed immunostimulatory antibody indicated in combination with Revlimid® (lenalidomide, Celgene) and dexamethasone for the treatment of patients who have received one to three prior lines of therapy; and Ninlaro® (ixazomib, Takeda) an orally administered proteasome inhibitor (PI) indicated in combination with Revlimid and dexamethasone for the treatment of patients who have received at least one prior line of therapy.

    Darzalex targets and mediates destruction of CD38+ immunosuppressive regulatory cells and promotes T-cell expansion and activation. This agent has multiple mechanisms of action, including complement-dependent cytotoxicity, antibody-dependent, cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis. Darzalex received accelerated approval for use as a single agent in the United States in November 2015 for the treatment of patients with multiple myeloma who have received at least three prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent. In April 2016, Darzalex was also granted conditional marketing approval by the Europe Commission as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a PI and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. The design of the clinical trial upon which Darzalex’s approval is based relegates Darzalex utilization to later lines of therapy.

    In March 2016, Johnson & Johnson announced that the randomized Phase III CASTOR trial (NCT02136134) achieved its primary endpoint and was stopped early as recommended by the Independent Data Monitoring Committee. Today at the annual meeting of the American Society for Clinical Oncology (ASCO), data were presented from the prespecified interim analysis of the CASTOR trial that compared the safety and efficacy of Darzalex, Velcade (bortezomib; Takeda) and dexamethasone (DVd) versus Velcade and dexamethasone (Vd) in subjects with relapsed or refractory multiple myeloma.1 Patients (n=498) with progressive disease after at least one prior line of therapy were randomized (1:1) to receive Darzalex (16 mg/kg IV QW in cycles 1-3, Q3W in cycles 4-8, Q4W thereafter), Velcade ( 1.3 mg/m2 SC on Days 1, 4, 8 and 11 of cycles 1-8) and dexamethasone (20 mg PO on Days 1, 2, 4, 5, 8, 9, 11 and 12 of cycles 1-8) or VelDex (1.3 mg/m2 Velcade SC on Days 1, 4, 8 and 11 of cycles 1-8; 20 mg dexamethasone PO on Days 1, 2, 4, 5, 8, 9, 11 and 12 of cycles 1-8) alone. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints included time to progression, overall survival (OS), overall response rate, very good partial response and complete response rates, and percentage of patients with minimal residual disease. Patients in the trial had received a median of two prior therapies.

    Treatment with DVd yielded superior clinical activity compared with treatment with VelDex alone. Darzalex significantly improved PFS with the median not reached in DVd treated patients and a median PFS of 7.2 months in the Vd arm (HR=0.31; p<0.0001). PFS at one year was 60.7% for DVd versus 26.9% for Vd, and for patients who received just one prior line of therapy PFS at one year was 77.5% versus 29.4%, respectively. Treatment with DVd also improved median time to progression: not reached for DVd versus 7.3 months for Vd (HR=0.30; p<0.0001). Darzalex improved objective response rate to 83% from 63% for Vd (p<0.0001), and treatment with DVd doubled rates of complete responses or better (19% versus 9%) and very good partial responses or better (59% versus 29%) compared with Vd alone. Just 3% of Vd patients were MRD-negative compared with 14% MRD-negative for DVd. Median OS data are immature as the median follow-up was only 7.4 months. Darzalex was well tolerated and was not associated with additional cumulative toxicity.

    Darzalex utilization is currently reserved for fourth-line; however, results from the CASTOR trial are practice changing, and these data suggest that DVd should be considered a new standard of care for relapsed/refractory multiple myeloma patients currently receiving Vd alone. The 78% PFS at one year for patients who had received only one prior therapy supports early Darzalex utilization.

    While impressive results from the CASTOR trial bode well for Darzalex VelDex combination, a triplet combination of Darzalex plus a PI and an immunomodulatory agent such as Revlimid (lenalidomide, Celgene) may be an even more important regimen to evaluate in the future. More imminent are the results of the randomized Phase III POLLUX trial comparing Darzalex, Revlimid, and dexamethasone (DRd) versus Revlimid and dexamethasone (Rd) in relapsed/refractory multiple myeloma patients that will be reported next week at the 21st Congress of the European Hematology Association (EHA). Preliminary data from this trial (Genmab press release, May 18, 2016) reported a significant improvement in mPFS, which was not reached for DRd versus 18.4 months for Rd (HR = 0.37, p < 0.0001). Notably, the mPFS in the Rd control arm of POLLUX is longer than the Vd control arm in CASTOR.  It will be interesting to see whether this is a result of a difference in median number of prior therapies for patients between the two trials. Potential future competition for Darzalex is on the horizon from isatuximab (Sanofi), another CD38-directed monoclonal antibody, and from checkpoint inhibitor-based combinations such as Keytruda plus Revlimid. Nonetheless, the results of CASTOR clearly suggest DVd provides a highly efficacious option for relapsed/refractory patients, further increasing the crowdedness of the multiple myeloma landscape.

    References:

    1. Palumbo A, Chanan-Khan AAA, Weisel K, et al.; “Phase III randomized controlled study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study;” J Clin Oncol 34, 2016 (suppl; abstr LBA4).

    VYXEOS scores a 10 over 7+3

    By: Madelyn Hanson, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health and Stephanie Hawthorne, Ph.D., Vice President, Clinical & Scientific Assessment, Kantar Health

    Therapeutic approaches for acute myeloid leukemia (AML) have gone unchanged for several years. Most newly diagnosed patients achieve complete remission (CR) with a combination regimen of cytarabine plus an anthracycline (7+3 most commonly). However, the high rate of CR comes at the cost of a high level of toxicities with this regimen. This poses a significant problem for the multiple subsegments within AML that have a poor prognosis, such as elderly patients, those with specific molecular aberrations, and patients with various comorbidities. Often these patients cannot tolerate the high toxicities that accompany the 7+3 regimen, which leaves only less efficacious treatment options for these patient subsegments. Hypomethylating agents (HMAs) that are approved for the treatment of myelodysplastic syndromes (MDS) ‒ such as Dacogen® (decitabine, Eisai/Janssen) and azacitidine ‒ are often used to treat these patients.

    More recently, these patients with high unmet need have become a hotbed for new therapy development. Exciting results presented at the 2015 annual meeting of the American Society of Hematology (ASH) demonstrated that the FLT3 inhibitor midostaurin (Novartis) combined with 7+3 was able to triple overall survival (OS) in newly diagnosed FLT3+ AML patients.1 Other agents currently being evaluated in Phase III trials for relapsed/refractory FLT3+ AML include quizartinib (Daiichi Sankyo) and enasidenib (AG-221, Agios/Celgene). While these agents have created a great deal of excitement for FLT3+ patients, even more development is ongoing for the treatment of elderly patients with AML. While the definition of “elderly” is not based strictly on chronological age but more often biologic age (which takes into account patient “fitness”), more than half of AML patients are still considered to be “elderly” (according to surveyed U.S. physicians2), signifying that this is a large patient population with a high unmet need. VYXEOS (CPX-351, Celator), ganetespib (Synta Pharmaceuticals), guadecitabine (SGI-110, Otsuka/Astex), sapacitabine (Cyclacel), vadastuximab talirine (SGN-CD33A, Seattle Genetics), and volasertib (Boehringer Ingelheim) are all in late-stage development for newly diagnosed, elderly patients.

    Today at the annual meeting of the American Society for Clinical Oncology (ASCO), final results were presented from a Phase III trial (NCT01696084) evaluating VYXEOS in untreated, elderly AML patients considered at high risk for recurrence.3 VYXEOS is a liposomal formulation of cytarabine and daunorubicin in a 5:1 molar ratio. This formulation is administered intravenously at 100 u/m2 on days 1, 3 and 5 by approximately 90-minute infusion compared with the standard 7+3 regimen, which requires continuous infusion of cytarabine (100 mg/m2/day) for seven days as well as of daunorubicin (60 mg/m2) on days 1, 2 and 3.

    In the trial, VYXEOS was compared with the standard 7+3 regimen of cytarabine and daunorubicin as first induction in untreated elderly patients with high-risk or secondary AML. The study enrolled 309 patients and OS was the primary endpoint. VYXEOS met its primary endpoint with mOS of 9.56 months compared with 5.95 months for patients receiving 7+3 therapy (HR=0.69, p=0.005). A 1.22-month improvement in event-free survival (EFS) also was observed in the VYXEOS arm (2.53 vs. 1.51 months, HR=0.74, p=0.021). VYXEOS was shown to improve the overall response rate (CR+CRi of 47.7% vs. 33.3%; p=0.016), with a significant improvement in CR (37.7% vs. 5.6%, p=0.040) and EFS (HR= 0.74, p=0.021).

    Subanalysis of OS in patients with or without transplant was also performed. Although the sample was small (n=91), the mOS of patients who went on to receive a stem cell transplant following induction was significantly improved in the VYXEOS arm compared with the 7+3 arm (not reached vs. 10.25 months, HR=0.46, p=0.0046).

    To begin to evaluate tolerability of VYXEOS, 60-day mortality favored VYXEOS versus 7+3 (13.7% vs. 21.2%). However, the presenter noted that while there was a significant reduction in deaths due to progressive AML (3.3% vs. 11.3%), there was no difference in deaths due to adverse events between the two arms (10.4% with VYXEOS vs. 9.9% with 7+3). Thus, the 60-day mortality improvement likely reflects the improvement in efficacy and not a difference in safety signals between the two regimens. In fact, there was no difference in Grade 3-5 adverse events between the two arms of the study. In addition, in patients achieving a CR after one induction, patients in the VYXEOS arm had a median six-day delay in absolute neutrophil count recovery compared with the 7+3 arm and a 7.5-day delay in platelet count recovery.

    VYXEOS was awarded the U.S. Food and Drug Administration (FDA) Breakthrough Therapy designation in May 2016, and Celator intends to submit a new drug application with the FDA later this year based on the data reported. Efficacy results from this study suggest that VYXEOS could quickly change the treatment approach for newly diagnosed, elderly AML patients that are deemed high risk. The fact that VYXEOS is a liposomal formulation of two agents (cytarabine and daunorubicin) that are currently standard of care for AML also supports rapid uptake by physicians. However, the issues of tolerability with the 7+3 regimen in elderly patients remain with VYXEOS. Physicians will have to decide whether the efficacy achieved along with the adverse-event profile warrants use of VYXEOS in individual patients. Although not discussed, additional subanalyses from this trial could provide physicians the information they need to select the patients most likely to benefit from VYXEOS. Although this trial was not performed in low-risk or younger patients, there may be a desire among physicians to use VYXEOS in these other patient types to improve the ability to reach stem cell transplant and improve OS, although such use would be considered off-label.

    Thus, while VYXEOS sets a high survival benchmark in elderly, high-risk AML patients, this cytotoxic agent still leaves some room for targeted agents such as volasertib (which targets polo-like kinase), ganetespib (which targets heat-shock protein 90), and vadastuximab talirine (which targets CD33) with potentially less toxicity to enter into the same space if they too can demonstrate significant survival benefits, although notably these drugs are all being compared with low-intensity, single-agent therapies in their ongoing pivotal trials.

    References:

    1. 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
    2. Kantar Health, CancerMPact® Treatment Architecture U.S., accessed June 6, 2016.
    3. Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. J Clin Oncol 34, 2016 (suppl; abstr 7000).