Favorites chosen by Cleveland Clinic’s Hematology and Medical Oncology staff
This year’s theme for the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting was Illumination and Innovation: Transforming Data into Learning. And the abstracts presented certainly did not disappoint.
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Many of our Cleveland Clinic cancer clinicians and researchers attended and presented at ASCO’s May-June session. Since then, we’ve had numerous discussions about which results we think are the most intriguing, or have the greatest potential to change the practice of medical oncology.
While many of the hundreds of studies presented deserve merit, following is our Top 10 list of the ASCO abstracts we believe best match the criteria, as selected by our Cancer Institute’s Department of Hematology and Medical Oncology staff.
Abstract No: 9500
Author(s): Jennifer S. Temel, David Christopher Currow, Kenneth Fearon, Ying Yan, John Friend, Amy Pickar Abernethy; Massachusetts General Hospital, Boston, MA; Flinders University, Adelaide, SA, Australia; Western General Hospital, Edinburgh, United Kingdom; Helsinn Therapeutics (US), Inc., Bridgewater, NJ; Duke University, Durham, NC
Background: Patients with advanced cancers frequently experience anorexia and cachexia, which is associated with decreased functional status and poor tolerance of chemotherapy. ROMANA 1 and 2 were two randomized, double blind trials evaluating the effect of anamorelin, a ghrelin receptor agonist, on cachexia in patients with advanced NSCLC.
Methods: Investigators randomly assigned 484 patients (ROMANA 1) and 495 patients (ROMANA 2) with inoperable stage III or stage IV NSCLC and cachexia ( ≥ 5% weight loss within prior 6 months or BMI < 20 kg/m2) to placebo or anamorelin 100 mg orally once daily. Co-primary efficacy endpoints were the change in lean body mass and handgrip strength from baseline over 12 weeks. Secondary endpoints included change in body weight and symptom burden over 12 weeks and pooled survival from ROMANA 1 and ROMANA 2. Exploratory analyses evaluated change in total body mass and fat mass from baseline to 12 weeks.
Results: Patients assigned to anamorelin experienced an increase in lean body mass compared to those assigned to placebo in ROMANA 1 (1.10 vs -0.44 kg, p < 0.001) and ROMANA 2 (0.75 vs -0.96 kg, p < 0.001), but no difference in handgrip strength. Patients assigned to anamorelin also had a significant increase in body weight (2.2 vs 0.14 kg, p < 0.001) and (0.95 vs -0.57 kg, p < 0.001) and improvement in their anorexia/cachexia symptoms (4.12 vs 1.92, p < 0.001) and (3.48 vs 1.34, p = 0.002) in ROMANA 1 and 2, respectively. Exploratory analysis demonstrated an increase in total body mass (2.87 vs 0.07 kg, p < 0.001) and (2.04 vs -0.59 kg, p < 0.001), and fat mass (1.21 vs -0.13 kg, p < 0.001) and (0.77 vs 0.09 kg, p = 0.012) for anamorelin versus placebo in the two studies, respectively. Anamorelin was well tolerated with hyperglycemia and diabetes as the most frequent drug-related adverse events ( ≤ 5%). Median 1-year survival was not different between study arms.
Conclusions: Anamorelin increased lean body mass, body weight, total body mass and fat mass indicating anabolic activity and restoration of energy balance in patients with advanced NSCLC. Patients also experienced significant improvement in anorexia/cachexia symptoms. Anamorelin was well tolerated, with similar pooled survival between study arms. Clinical trial information: NCT01387269 and NCT01387282
Commentary: Anamorelin, a gherlin analogue has both a peripheral motilin effect and a central appetite stimulating effect. Lung cancer patients present with weight loss and anorexia, anamorelin appears to be target specific for these two symptoms. Future trials need to combine anticachexic agents like omega-3 fatty acids with anamorelin in clinical trials. Single agent therapy is less than optimal in reversing the protean mechanisms on anorexia and cachexia.
Abstract No: 9004
Author(s): F. Stephen Hodi, Michael Andrew Postow, Jason Alan Chesney, Anna C. Pavlick, Caroline Robert, Kenneth F. Grossmann, David F. McDermott, Gerald P. Linette, Nicolas Meyer, Jeffrey K. Giguere, Sanjiv S. Agarwala, Montaser F. Shaheen, Marc S. Ernstoff, David R. Minor, April Salama, Matthew Hiram Taylor, Patrick Alexander Ott, Christine E. Horak, Paul Gagnier, Jedd D. Wolchok; Dana-Farber Cancer Institute, Boston, MA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY; J. Graham Brown Cancer Center, University of Louisville, Louisville, KY; New York University, Perlmutter Cancer Center, New York, NY; Gustave, Roussy and Paris-Sud University, Villejuif-Paris-Sud, France; Huntsman Cancer Institute, Salt Lake City, UT; Beth Israel Deaconess Medical Center, Boston, MA; Washington University, St. Louis, MO; Institut Universitaire du Cancer, Toulouse, France; NCORP of the Carolinas, Greenville, SC; St. Luke’s Cancer Center, Bethlehem, PA; University of New Mexico, Albuquerque, NM; Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH; California Pacific Melanoma Center, San Francisco, CA; Duke University, Durham, NC; Oregon Health & Science University, Portland, OR; Bristol-Myers Squibb, Princeton, NJ; Bristol-Myers Squibb, Wallingford, CT
Background: Combined blockade of T-cell checkpoints by NIVO and IPI demonstrated a high objective response rate (ORR), promising overall survival (OS), and a manageable safety profile in pts with advanced MEL in a phase I study, based on which an appropriate dose was selected for registrational trials. We report efficacy and safety of the NIVO + IPI combination vs IPI alone in treatment-naïve pts with advanced MEL, including pts with poor prognostic factors, in a phase II study.
Methods: Pts (N = 142) with metastatic or unresectable MEL were randomized 2:1 to receive IPI 3 mg/kg combined with either NIVO 1 mg/kg or placebo Q3W × 4, followed by NIVO 3 mg/kg or placebo Q2W until disease progression or unacceptable toxicity. The primary endpoint was ORR in BRAF wild-type (WT) pts. Secondary and exploratory objectives included PFS in BRAF WT pts, ORR and PFS in BRAF V600 mutation-positive (MT) pts, and safety.
Results: In BRAF WT pts (n = 109), ORR was 60% (43/72) for NIVO + IPI; 11% (4/37) for IPI alone (P < 0.0001); complete responses were reported in 12 (17%) and 0 pts, respectively. Median PFS was 8.9 months for the combination vs 4.7 months for IPI alone (P = 0.0012). Higher ORR was observed for NIVO + IPI vs IPI in predefined pt subgroups with poor prognostic factors, such as elevated baseline LDH (53% vs 0%) and M1c stage disease (62% vs 25%). Similar ORR and PFS results were observed in 33 BRAF MT pts. Grade 3–4 drug-related adverse events (AEs) were reported in 51% of pts receiving NIVO + IPI vs 20% for IPI alone. The safety profile of NIVO + IPI was similar across pt subgroups, including age. Select AEs related to the combination regimen were consistent with phase I reports and most resolved with immunosuppressive medication ( > 83% across organ categories) with the exception of endocrinopathies. Updated results from a planned data analysis in March 2015 will be presented.
Conclusions: NIVO + IPI significantly improved ORR and PFS compared with IPI alone and had a manageable safety profile. The efficacy and safety of the combination was similar across pt subgroups and provided a favorable risk-benefit ratio in treatment-naïve pts with advanced MEL. Clinical trial information: NCT01927419
Commentary: The immunotherapy landscape is rapidly changing. The discovery of multiple immune check points and agents to manipulate them has opened new approaches. In CheckMate 069, the combination of anti-CTLA4 (ipilimumab) with anti-PD1 (nivolumab) demonstrated an improved overall response rate, complete response rate and progression free survival compared to ipilimumab alone. Benefit was seen in melanomas with wild type and mutated BRAF. The results also demonstrated a higher rate of serious adverse events. The randomized CheckMate 067 study comparing single agent nivolumab to single agent ipilimumab to the combination confirms these results in part and further suggests that expression of PDL-1 in the tumor may help identify individuals who may benefit from single agent nivolumab single and those who would benefit from combination treatment.
Abstract No: 5001
Author(s): Nicholas David James, Matthew Robert Sydes, Malcolm David Mason, Noel W. Clarke, David Paul Dearnaley, Melissa Ruth Spears, Robin Millman, Chris Parker, Alastair W S Ritchie, J. Martin Russell, John Staffurth, Robert J. Jones, Shaun P. Tolan, John Wagstaff, Andrew Protheroe, Rajaguru Srinivasan, Alison J. Birtle, Joe M. O’Sullivan, Richard Cathomas, Mahesh M K Parmar, STAMPEDE Investigators; University of Warwick, Coventry, United Kingdom; MRC Clinical Trials Unit at UCL, London, United Kingdom; Velindre Hospital, Cardiff, United Kingdom; The Christie and Salford Royal Hospitals, Manchester, United Kingdom; Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom; TBA, UK, United Kingdom; Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; The Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; Clatterbridge Hospital, Wirral, United Kingdom; South West Wales Cancer Institute, Swansea, United Kingdom; University of Oxford Medical Oncology Department, Oxford, United Kingdom; Royal Devon and Exeter NHS Foundation Trust, Exeter, United Kingdom; Lancashire Teaching Hospitals NHS Foundation Trust, Preston, United Kingdom; Belfast City Hospital, Belfast, United Kingdom; Kantonsspital Chur, Chur, Switzerland
Background: STAMPEDE is a randomized controlled trial using a novel multi-arm multi-stage design. It recruits men (pts) with high-risk locally advanced or metastatic prostate cancer (PCa) starting long-term hormone therapy (HT) for the first time. The trial initially assessed adding one or two of three treatment approaches to standard of care (SOC). The report includes primary survival results for three research comparisons that recruited through all their intermediate analyses: docetaxel (D), zoledronic acid (ZA) & the combination (D+ZA).
Methods: SOC was hormone therapy for > = 3yrs; RT was encouraged for N0M0 pts up to Nov-2011, then mandated; RT was optional for N+M0 pts. Stratified randomisation allocated pts 2:1:1:1 to SOC (control), SOC+D, SOC+ZA or SOC+D+ZA. 4mg ZA was given for six 3-weekly cycles then 4-weekly until 2yrs. D was given as 75mg/m2 for six 3-weekly cycles with prednisolone 10mg daily. The primary outcome measure was survival (time from randomisation to death from any cause). Pairwise comparisons to control on survival for each research arm had 90% power at 2.5% 1-sided alpha for a hazard ratio of 0.75 requiring ~400 control arm deaths, accounting for 3 intermediate lack-of-benefit analyses on failure-free survival. Analyses used the Cox model of the logrank test, adjusted for stratification factors.
Results: From Oct-2005 to Mar-2013, 2,962 pts were randomised to the 4 arms. The groups were balanced with median age 65yrs; 61% metastatic, 14% N+/XM0, 22% N0M0; 93% diagnosed within 6m of randomisation; median PSA 65ng/ml. Median follow-up was 42m. Grade 3-5 toxicity was reported for 31% SOC, 50% SOC+D, 32% SOC+ZA and 52% SOC+D+ZA.There were 405 deaths on the control arm (84% from PCa). The hazard ratio was 0.76 (95% CI 0.63, 0.91; p = 0.003) for SOC+D vs SOC; 0.93 (95% CI 0.79, 1.11; p = 0.437) for SOC+ZA vs SOC; and 0.81 (95% CI 0.68, 0.97; p = 0.020) for SOC+D+ZA vs SOC. Median survival was increased by 10m from 67m on SOC to 77m on SOC+D. Results in M0 and M1 disease will be shown.
Conclusions: Survival data from STAMPEDE show a clinically and statistically significant improvement in survival from adding docetaxel but not from adding zoledronic acid in men starting long-term hormone therapy for the first time. Clinical trial information: NCT00268476
Commentary: The results from STAMPEDE strengthen the results from the recently reported US intergroup study – ECOG 3805. The addition of six cycles of up-front Docetaxel to androgen deprivation therapy (ADT) drastically improves the overall survival of men with metastatic hormone naïve/sensitive prostate cancer. This study also demonstrates the lack of survival benefit of the addition of zoledronic acid in this clinical setting. Although questions about disease volume vs. benefit remain, the results of this trial continue to support the new standard of care for men with advanced prostate cancer and settle the question about the utility of early bisphosphonate use for this patient population.
Abstract No: 8009
Author(s): David R. Spigel, Karen L. Reckamp, Naiyer A. Rizvi, Elena Poddubskaya, Howard Jack West, Wilfried Ernst Erich Eberhardt, Paul Baas, Scott Joseph Antonia, Adam Pluzanski, Everett E. Vokes, Esther Holgado, David Michael Waterhouse, Neal Ready, Justin F. Gainor, Osvaldo Rudy Aren, Leora Horn, Luis Paz-Ares, Christine Baudelet, Brian Joseph Lestini, Julie R. Brahmer; Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN; City of Hope National Medical Center, Duarte, CA; Memorial Sloan Kettering Cancer Center, New York, NY; N.N. Blokhin Russian Cancer Research Center, Moscow, Russia; Swedish Cancer Institute, Seattle, WA; Department of Medical Oncology, University Hospital Essen, West German Cancer Centre, Ruhrlandklinik, and University Duisburg-Essen, Essen, Germany; Antoni Van Leeuwenhoek Hospital, Amsterdam, Netherlands; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; Centrum Onkologii – Instytut Im. Marii Sklodowskiej-Curie, Warsaw, Poland; University of Chicago Medical Center, Chicago, IL; Hospital de Madrid, Norte Sanchinarro, Spain; Oncology Hematology Care, Blue Ash, OH; Duke University Medical Center, Durham, NC; Massachusetts General Hospital Cancer Center, Boston, MA; Centro Internacional de Estudios Clinicos, Santiago, Chile; Vanderbilt University Medical Center, Nashville, TN; Hospital Universitario Virgen Del Rocio, Seville, Spain; Bristol-Myers Squibb, Princeton, NJ; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Background: Treatment options are limited for patients (pts) with advanced SQ NSCLC who fail platinum-based doublet chemotherapy (PT-DC). Report discusses results of a randomized, open-label, global phase III study of NIVO, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, vs DOC in pts with SQ NSCLC and with disease progression (PD) during/after one prior PT-DC regimen.
Methods: Pts (N = 272) were randomized 1:1 to receive NIVO 3 mg/kg (n = 135) Q2W or DOC 75 mg/m2(n = 137) Q3W until PD, discontinuation due to toxicity, or other reasons. The primary objective was overall survival (OS). Secondary objectives included investigator-assessed objective response rate (ORR; RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression (PD-L1 testing not required for enrollment), quality of life, and safety.
Results: Superior OS was observed with NIVO vs DOC (HR = 0.59; 95% CI: 0.44, 0.79; p = 0.00025). NIVO improved PFS vs DOC (HR = 0.62; 95% CI: 0.47, 0.81; p = 0.0004). ORR was 20% (27/135) for NIVO and 9% (12/137) for DOC (p = 0.0083). OS HRs favored NIVO regardless of PD-L1 expression (Table). Grade 3–4 drug-related AEs occurred in 7% (9/131) of NIVO and 55% (71/129) of DOC pts. No deaths were related to NIVO vs 3 DOC-related deaths.
Conclusions: CheckMate 017 met its primary objective, demonstrating superior OS of NIVO vs DOC in pts with advanced, previously treated SQ NSCLC and demonstrated PFS and ORR superiority. Tumor PD-L1 status was neither prognostic nor predictive for efficacy endpoints. The safety profile of NIVO 3 mg/kg Q2W is acceptable and favorable vs DOC. NIVO represents a significant improvement in second-line therapy for SQ NSCLC. Clinical trial information: NCT01642004
Abstract Number: LBA109
Author(s): Luis Paz-Ares, Leora Horn, Hossein Borghaei, David R. Spigel, Martin Steins, Neal Ready, Laura Quan Man Chow, Everett E. Vokes, Enriqueta Felip, Esther Holgado, Fabrice Barlesi, Martin Kohlhaeufl, Oscar Rodriguez, Marco Angelo Burgio, Jerome Fayette, Scott N. Gettinger, Christopher Harbison, Cécile Dorange, Friedrich Graf Finckenstein, Julie R. Brahmer; Hospital Universitario Virgen Del Rocio, Sevilla, Spain; Vanderbilt-Ingram Cancer Center, Nashville, TN; Fox Chase Cancer Center, Philadelphia, PA; Sarah Cannon Research Institute, Nashville, TN; Thoraxklinik-Heidelberg gGmbh, Heidelberg, Germany; Duke University Medical Center, Chapel Hill, NC; University of Washington, Seattle, WA; Department of Medicine, University of Chicago, Chicago, IL; Vall d’Hebron University Hospital, Barcelona, Spain; START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain; Aix Marseille University – Assistance Publique Hopitaux De Marseille, Marseille, France; Hospital Schillerhoehe Gerlingen, Gerlingen, Germany; Instituto Nacional de Cancerología, Mexico City, Mexico; IRST-IRCCS, Meldola (FC), Italy; Centre Leon Berard, Lyon, France; Yale School of Medicine, New Haven, CT; Bristol-Myers Squibb, Princeton, NJ; Bristol‐Myers Squibb, Princeton, NJ; Bristol-Myers Squibb Co, Princeton, NJ; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD
Background: Options for advanced non-SQ NSCLC patients (pts) who progress after platinum-based doublet chemotherapy (PT-DC) are limited, with minimal improvement in overall survival (OS). We report results from a randomized, global phase III study of NIVO, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC and tyrosine kinase inhibitor, if eligible.
Methods: Pts were randomized to NIVO 3 mg/kg Q2W (n=292) or DOC 75 mg/m2 Q3W (n=290) until progression or discontinuation due to toxicity/other reasons. Primary objective was OS; Secondary objectives were investigator-assessed objective response rate (ORR; per RECIST v1.1), progression-free survival (PFS), efficacy by PD-L1 expression, quality of life, and safety.
Results: NIVO demonstrated superior OS (HR=0.73; 96% CI: 0.59, 0.89; P=0.00155) and improved ORR (19.2% vs 12.4%; P=0.0235). HR for PFS was 0.92 (95% CI: 0.77, 1.11; P=0.393). PD-L1 expression was associated with benefit from NIVO (Table). In PD-L1+ pts, NIVO showed improved efficacy across all endpoints at predefined 1%, 5%, and 10% cut- points. Grade 3–5 drug-related AEs occurred in 10.5% (30/287) of NIVO and 53.7% (144/268) of DOC pts. No deaths were related to NIVO vs 1 DOC-related death. After discontinuation, 42.1% of NIVO and 49.7% of DOC pts received subsequent systemic therapy.
Conclusions: NIVO demonstrated superior OS vs DOC in pts with advanced non-SQ NSCLC after failure of PT-DC. The safety profile of NIVO 3 mg/kg Q2W was favorable vs DOC. NIVO demonstrated survival benefit across histologies in two randomized phase III trials. Clinical trial information: NCT01673867
Commentary: This year brought a major change in the standard of care for previously treated non-small cell lung cancer (NSCLC) patients. Both the Checkmate 017 trial in squamous cell carcinoma (SCC) of the lung and the Checkmate 057 trial in nonsquamous NSCLC patients showed significantly better overall survival for the PD-1 inhibitor nivolumab compared to docetaxel, the previous standard of care in these populations. Nivolumab is already approved by the FDA for SCC and is likely to be quickly approved for nonsquamous NSCLC as well, becoming the new standard of care treatment for all NSCLC patients who have failed prior chemotherapy.
Abstract No: LBA4
Author(s): Paul D. Brown, Anthony L. Asher, Karla V. Ballman, Elana Farace, Jane H Cerhan, S. Keith Anderson, Xiomara W. Carrero, Frederick G. Barker, Richard L. Deming, Stuart Burri, Cynthia Menard, Caroline Chung, Volker W. Stieber, Bruce E. Pollock, Evanthia Galanis, Jan C. Buckner, Kurt A. Jaeckle; The University of Texas MD Anderson Cancer Center, Houston, TX; Carolinas Healthcare System-Neuroscience Institute, Charlotte, NC; Mayo Clinic, Rochester, MN; Penn State Hershey Medical Center, Hershey, PA; Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN; Massachusetts General Hospital, Boston, MA; Mercy Cancer Ctr, Des Moines, IA; Levine Cancer Institute-Radiation Oncology, Charlotte, NC; Princess Maraget Hospital, Toronto, ON, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada; Novant Health Forsyth Medical Center, Winston Salem, NC; Mayo Clinic Florida, Jacksonville, FL
Background: WBRT significantly improves tumor control in the brain after SRS, yet the role of adjuvant WBRT remains undefined due to concerns regarding neurocognitive risks.
Methods: Patients with 1-3 brain metastases, each < 3 cm by contrast MRI, were randomized to SRS alone or SRS + WBRT and underwent cognitive testing before and after treatment. The primary endpoint was cognitive progression (CP) defined as decline > 1 SD from baseline in any of the 6 cognitive tests at 3 months. Time to CP was estimated using cumulative incidence adjusting for survival as a competing risk.
Results: 213 patients were enrolled with 2 ineligible and 3 cancels prior to receiving treatment. Baseline characteristics were well-balanced between study arms. The median age was 60 and lung primary the most common (68%). CP at 3 months was more frequent after WBRT + SRS vs. SRS alone (88.0% vs. 61.9% respectively, p = 0.002). There was more deterioration in the WBRT + SRS arm in immediate recall (31% vs. 8%, p = 0.007), delayed recall (51% vs. 20%, p = 0.002), and verbal fluency (19% vs. 2%, p = 0.02). Intracranial tumor control at 6 and 12 months were 66.1% and 50.5% with SRS alone vs. 88.3% and 84.9% with SRS+WBRT (p < 0.001). Median OS was 10.7 for SRS alone vs. 7.5 months for SRS+WBRT respectively (HR = 1.02, p = 0.93).
Conclusions: Decline in cognitive function, specifically immediate recall, memory and verbal fluency, was more frequent with the addition of WBRT to SRS. Adjuvant WBRT did not improve OS despite better brain control. Initial treatment with SRS and close monitoring is recommended to better preserve cognitive function in patients with newly diagnosed brain metastases that are amenable to SRS. Clinical trial information: NCT00377156
Commentary: Brain metastasis is a common medical problem. Approximately 300,000 to 400,000 patients are diagnosed each year in the United States with brain metastases. This phase III trial showed that more patients in the whole brain radiation therapy (WBRT) plus radiosurgery (SRS) arm experienced cognitive progression at 3 months compared to patients who were treated with SRS alone. The combination of WBRT and SRS decreased the recurrence of brain metastases compared to SRS alone; however this did not translate into survival benefit. These results support the use of SRS alone as an initial treatment strategy in patients with 1-3 brain metastases. WBRT remains an important therapeutic option for patients with brain metastases and there are ongoing trials to investigate approaches to mitigate its impact on neurocognition (hippocampal sparing strategy and the use of pharmacological agents such as memantine). Future clinical trials will now need to define the role of SRS and WBRT in management of patients with greater than three brain metastases.
Abstract No: 8508
Author(s): Sagar Lonial, Meletios A. Dimopoulos, Antonio Palumbo, Darrell White, Sebastian Grosicki, Ivan Spicka, Adam Walter-Croneck, Philippe Moreau, María-Victoria Mateos, Hila Magen-Nativ, Andrew Belch, Donna Ellen Reece, Meral Beksac, Masafumi Taniwaki, Christoph Röllig, Anil K. Singhal, Jessica Katz, Eric W. Bleickardt, Valerie Poulart, Paul G. Richardson, ELOQUENT-2 Investigators; Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA; National and Kapodistrian University of Athens, Athens, Greece; A. O. U. San Giovanni Battista di Torino – Ospedale Molinette, Torino, Italy; QEII Health Sciences Center, Dalhousie University, Halifax, NS, Canada; Department of Cancer Prevention, Faculty of Public Health, Silesian Medical University, Katowice, Poland; Prague General Hospital, Prague, Czech Republic; Medical University of Lublin, Lublin, Poland; University Hospital, Nantes, France; University Hospital of Salamanca-IBSAL, Salamanca, Spain; Tel Aviv University, Ramat Aviv, Israel; Cross Cancer Institute and University of Alberta, Edmonton, AB, Canada; Princess Margaret Hospital, Toronto, ON, Canada; Ankara University, Ankara, Turkey; Kyoto Prefectural University of Medicine, Kyoto, Japan; Universitatsklinikum der TU, Dresden, Germany; AbbVie Biotherapeutics Inc. (ABR), Redwood City, CA; Bristol-Myers Squibb, Princeton, NJ; Bristol-Myers Squibb, Wallingford, CT; Bristol-Myers Squibb, Braine-l’Alleud, Belgium; Dana-Farber Cancer Institute, Boston, MA
Background: Elo, a monoclonal antibody (mAb) targeting Signaling Lymphocytic Activation Molecule F7 (SLAMF7), kills myeloma cells with minimal effect on normal tissue. Elo showed encouraging activity with Len/dex (Ld) in a phase Ib/II study in pts with RRMM. This phase III study (NCT01239797) compared efficacy and safety of Elo/Len/dex (ELd) vs Ld.
Methods: Patients with RRMM, 1–3 prior therapies (not Len-refractory), were randomized 1:1 to ELd or Ld in 28-day cycles to disease progression/unacceptable toxicity: Elo (10 mg/kg intravenously) weekly cycles 1+2 then biweekly; Len (25 mg) D1–21; dex weekly (40 mg or [Elo wks] 28 mg oral + 8 mg intravenous). Response/progression was assessed by independent review committee by EBMT criteria. Primary endpoints were progression-free survival (PFS) and overall response rate (ORR). Results of an interim analysis are reported.
Results: Six hundred and forty-six pts were randomized (321 ELd, 325 Ld; median age 66; del(17p) 32%; t[4;14] 9%; refractory to last therapy 35%). Median (range) prior therapies: 2 (1–4), including bortezomib 70%, thalidomide 48%, Len 6%. At data cut-off (4 November 2014), 35% (ELd) and 21% (Ld) of pts remained on therapy; discontinuation was mainly for disease progression (42% ELd, 47% Ld). Median follow-up was 24 months; median (95% CI) PFS: ELd 19.4 (16.6, 22.2) months, Ld 14.9 (12.1, 17.2) months (HR [95% CI] 0.70 [0.57, 0.85]; p = 0.0004). 1-year PFS was 68% ELd, 57% Ld; 2-year PFS: 41% ELd, 27% Ld. PFS benefit with ELd was consistent across key subgroups. ORR (95% CI) was 79% (74, 83) ELd, 66% (60, 71) Ld (p = 0.0002). G3–4 adverse events ≥ 15% (ELd vs Ld) were neutropenia (25%, 33%); anemia (15%, 16%). Exposure-adjusted infection rate was the same in both arms (incidence rate/100 person-years of exposure, 197). Infusion reactions (IRs) occurred in 10% of pts with ELd (mostly G1–2). There were 210 deaths (94 ELd, 116 Ld).
Conclusions: A clinically relevant 30% reduction in risk of progression or death was seen with ELd vs Ld. More pts remain on ELd vs Ld and follow-up for long-term outcomes, including survival, is ongoing. IRs were manageable. Elo, a mAb with a novel immunotherapeutic mechanism of action, showed improved PFS, with minimal added toxicity in combination with Ld vs Ld alone, in pts with multiple myeloma. Clinical trial information: NCT01239797
Commentary: Novel immunotherapeutic approaches are not limited to solid tumors. The ELOQUENT-2 study confirms superior efficacy without significant increased toxicity of the addition of elotuzumab to the standard combination of lenalidomide and dexamethasone. This trial should form the basis of a strong application for FDA approval for elotuzumab as a component of therapy in the relapsed and refractory patient population. If approved, elotuzumab will be the first monoclonal antibody approved for patients with myeloma.
Abstract No: LBA500
Author(s): Richard G. Margolese, Reena S. Cecchini, Thomas B. Julian, Patricia A. Ganz, Joseph P. Costantino, Laura Vallow, Kathy S. Albain, Pat W. Whitworth, Mary E. Cianfrocca, Adam Brufsky, Howard M. Gross, Gamini S. Soori, Judith O. Hopkins, Louis Fehrenbacher, Keren Sturtz, Timothy F. Wozniak, Thomas E. Seay, Eleftherios P. Mamounas, Norman Wolmark; NRG Oncology/NSABP, and The Jewish General Hospital, McGill University, Montréal, QC, Canada; NRG Oncology, and the University of Pittsburgh, Pittsburgh, PA; NRG Oncology/NSABP, and The Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA; NRG Oncology/NSABP, and the University of California, Los Angeles, Los Angeles, CA; NRG Oncology/NSABP, ALLIANCE/NCCRT, and Mayo Clinic, Jacksonville, FL, Jacksonville, FL; NRG Oncology/NSABP, SWOG, and Loyola University Chicago Stritch School of Medicine, Maywood, IL; NRG Oncology/NSABP, ALLIANCE/ACOSOG, and Nashville Breast Center, Nashville, TN; ECOG/ACRIN, SWOG, and Banner MD Anderson Cancer Center, Gilbert, AZ; NRG Oncology/NSABP, and Magee Women’s Hospital, Pittsburgh, PA; NRG Oncology/NSABP, and Hem and Onc Div of Dayton Physicians LLC, Dayton, OH; NRG Oncology/NSABP, and Nebraska Cancer Specialists, Omaha, NE; NRG Oncology/NSABP, and SCOR NCORP and the Forsyth Regional Cancer Center, Winston Salem, NC; NRG Oncology/NSABP, and Kaiser Permanente Northern California, Novato, CA; Colorado Cancer Research Program, Denver, CO; NRG Oncology/NSABP, and CCOP, Christiana Care Health Systems, Newark, DE; NRG Oncology/NSABP, and the Atlanta Regional Community Clinical Oncology Program, Atlanta, GA; NRG Oncology/NSABP and UF Cancer Center at Orlando Health, Orlando, FL; NRG Oncology/NSABP, and the Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA
Background: The primary endpoint of NSABP B-35, a phase III trial comparing 1 mg/day anastrozole to 20 mg/day tamoxifen, each given for 5 years, was breast cancer-free interval (BCFI), defined as the time from randomization to any breast cancer (BC) event including local, regional, or distant recurrence or contralateral disease, invasive or DCIS.
Methods: Postmenopausal women with ER-receptor or PgR-receptor positive (by IHC analysis) DCIS and no invasive BC who had undergone a lumpectomy with clear resection margins were randomly assigned to receive either 20 mg/day tam or 1 mg/day A (blinded) for 5 years. Stratification was by age (<60 v ≥60).
Results: From 1/6/2003 to 6/15/2006, 3,104 pts were entered and randomized (1552 in groups tam and A each). As of 2/28/15, follow-up information was available on 3,083 pts for OS and on 3,077 pts for all other disease-free endpoints, with mean time of follow-up of 8.6 years. There were 198 BCFI events, 114 in the tam group and 84 in the A group (HR, 0.73; p=0.03). 10-year point estimates for BCFI were 89.2% for tam and 93.5% for A. A significant time-by-treatment interaction (p=0.02) indicated that the effect was not evident until later in the study. There was a significant interaction between treatment and age group (p=0.04); benefit of A is only in women <60 years old. As to secondary endpoints, there were 495 DFS events, 260 in the tam group and 235 in the A group (HR, 0.89; p=0.21). 10-year point estimates for DFS were 77.9% for tam and 82.7% for A. There were 186 deaths, 88 in the tam group and 98 in the A group (HR, 1.11; p=0.48). 10-year point estimates for OS were 92.1% for tam, 92.5% for A. There were 8 deaths due to breast cancer in the tam group and 5 in the A group. There were 63 cases of invasive breast cancer in the tam group and 39 in the A group (HR, 0.61; p=0.02). There was a non-significant trend for a reduction in breast second primary cancers with A (HR, 0.68; p=0.07).
Conclusions: Anastrozole provided a significant improvement compared to tamoxifen for BCFI, which was seen later in the study, primarily in women <60 years. Support: CA12027, 37377, 69651, 69974; 180868, 180822, 189867 196067, 114732; AstraZeneca Pharmaceuticals LP. Clinical trial information: NCT00053898
Commentary: For patients with DCIS who are going lumpectomy and radiation, tamoxifen is the treatment of choice. But this trial looked at the role of anastrozole versus tamoxifen in this setting. This large randomized study by NSABP study in post-menopausal patients showed that anastrozole improves breast cancer free interval especially in patients under the age of 60. This is a potentially practice changing study and a better option for patients who meet the criteria.
9. PD-1 blockade in tumors with mismatch repair deficiency
Abstract No: LBA100
Author(s): Dung T. Le, Jennifer N. Uram, Hao Wang, Bjarne Bartlett, Holly Kemberling, Aleksandra Eyring, Andrew Skora, Nilofer Saba Azad, Daniel A. Laheru, Ross C. Donehower, Brandon Luber, Todd S. Crocenzi, George A. Fisher, Steve M Duffy, James J. Lee, Minori Koshiji, James R. Eshleman, Robert A Anders, Bert Vogelstein, Luis A. Diaz; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; Johns Hopkins Cancer Ctr, Baltimore, MD; Providence Cancer Center, Portland, OR; Stanford University School of Medicine, Stanford, CA; Bons Secours Cancer Institute, Richmond, VA; University of Pittsburgh, Pittsburgh, PA; Merck & Co., Inc., Kenilworth, NJ; Johns Hopkins University School of Medicine, Baltimore, MD; The Johns Hopkins University School of Medicine, Baltimore, MD; The Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD
Background: Somatic mutations have the potential to be recognized as “non-self” immunogenic antigens. Tumors with genetic defects in mismatch repair (MMR) harbor many more mutations than tumors of the same type without such repair defects. We hypothesized that tumors with mismatch repair defects would therefore be particularly susceptible to immune checkpoint blockade.
Methods: We conducted a phase II study to evaluate the clinical activity of anti-PD-1, pembrolizumab, in 41 patients with previously-treated, progressive metastatic disease with and without MMR-deficiency. Pembrolizumab was administered at 10 mg/kg intravenously every 14 days to three cohorts of patients: those with MMR-deficient colorectal cancers (CRCs) (N = 11); those with MMR-proficient CRCs (N = 21), and those with MMR-deficient cancers of types other than colorectal (N = 9). The co-primary endpoints were immune-related objective response rate (irORR) and immune-related progression-free survival (irPFS) at 20 weeks.
Results: The study met its primary endpoints for both MMR-deficient cohorts. The irORR and irPFS at 20 weeks for MMR-deficient CRC were 40% and 78%, respectively, and for MMR-deficient other cancers were 71% and 67%, respectively. In MMR-proficient CRC, irORR and irPFS at 20 weeks were 0% and 11%, respectively. Response rates and Disease Control Rates (CR+PR+SD) by RECIST criteria were 40% and 90% in MMR-deficient CRC, 0% and 11% in MMR-proficient CRC, and 71% and 71% in MMR-deficient other cancers, respectively. Median PFS and overall survival (OS) were not reached in the MMR-deficient CRC group but was 2.2 and 5.0 months in the MMR-proficient CRC cohort (HR for PFS = 0.103; 95% CI, 0.029 to 0.373; p < 0.001 and HR for OS = 0.216; 95% CI, 0.047 to 1.000; p = 0.05). Whole exome sequencing revealed an average of 1,782 somatic mutations per tumor in MMR-deficient compared to 73 in MMR-proficient tumors (p = 0.0015), and high total somatic mutation loads were associated with PFS (p = 0.02).
Conclusions: MMR status predicts clinical benefit of immune checkpoint blockade with pembrolizumab. Clinical trial information: NCT01876511
Commentary: This is the first study to convincingly demonstrate that immune-based therapies are effective in colorectal cancer. Although only a phase II study, the high rates of response in the MMR-deficient cohort treated with pembrolizumab as well as impressive HR for improvement in disease-free and overall survival are remarkable in this setting. MMR deficiency has the added advantage of being a readily available biomarker that is already widely used to screen for Lynch syndrome. For the subgroup of colorectal and other solid tumor patients with mismatch repair deficiency, this study provides solid proof of substantial benefit from anti-PD-1 approaches.
Authors: Anil D’Cruz, Mitali Dandekar, Richa Vaish, Supreeta Arya, Gouri Pantvaidya, Pankaj Chaturvedi,Devendra Chaukar, P. S. Pai, Anuja Deshmukh, Shubhada Kane, Deepa Nair, Sudhir Vasudevan Nair, Asawari Patil, Rohini W Hawaldar, Manasi Dhopeshwarkar, Jaiprakash Agarwal; Tata Memorial Hospital,Mumbai, India; Tata Memorial Hospital, Navi Mumbai, India; Tata Memorial Centre, Mumbai, India
Background: Management of the neck in early oral cancers has been a matter of debate with clinical equipoise between elective (END) or therapeutic neck dissection (TND).
Methods: This is a prospective phase III RCT (NCT00193765) to test the superiority of END at the time of primary surgery over TND (neck dissection at the time of nodal relapse) in patients with lateralized T1 or T2 squamous carcinoma of oral cavity, amenable to peroral excision. Patients were stratified based on size, site, sex and preoperative neck ultrasound. The primary end point was overall survival (OS) and secondary end-point was disease-free survival (DFS). The trial was planned to demonstrate a 10% superiority (1-sided a 5 0.05 and b 5 0.2) in OS for END vs. TND, assuming 60% 5-year OS in TND arm, with a planned sample size of 710.
Results: This trial was terminated after 596 patients were randomized between January 2004 and June 2014. An interim intent-to-treat analysis of initial 500 patients (255 in TND, 245 END) with a minimum follow-up of 9 months was performed as mandated by Data and Safety Monitoring Committee based on the number of observed deaths in each arm. Both arms were balanced for site and stage. There were 427 tongue, 68 buccal mucosa and 5 floor of mouth tumors; 221 were TI and 279 T2. At a median follow-up of 39 months there were 146 recurrences in TND and 81 in END arms respectively. The 3-year OS was significantly higher in END compared to TND arm (80.0% vs. 67.5%, HR 5 0.63, 95%CI 0.44-0.89, p 5 0.01) as was 3-year DFS (69.5% vs. 45.9%, HR 5 0.44, 95%CI 0.34-0.58, p , 0.001). After adjusting for stratification factors in Cox regression, END continued to be significantly superior to TND for both OS and DFS.
Conclusions: There were 8 excess deaths for every 15 excess recurrences in the TND arm. Elective neck dissection in patients with early oral SCC results in 37% reduction in mortality and should be considered the standard of care. Clinical trial information: NCT00193765.
Commentary: This study reflects a remarkable 10 year, single institution effort to address a long standing issue in the surgical management of oral cavity cancer. It clearly demonstrated that an elective neck dissection should be the standard of care for those patients with early stage tumors and clinically negative necks. Debate still remains, however, about whether there is a very select group of good prognosis patients who can be managed without neck dissection, and how they should best be followed. Future data to emerge from this trial will include information about the potential role of ultrasonographic surveillance for such patients.
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