Studies Reveal Potential New Targeted Therapies for Common, Hard-to-Treat Cancers

– ASCO Annual Meeting Features Key Advances in Ovarian, Lung and Thyroid Cancers and Leukemia –

Released: 31-May-2014 2:00 PM EDT
Source Newsroom: American Society of Clinical Oncology (ASCO)
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Newswise — CHICAGO – Positive results from four clinical trials of investigational targeted drugs for advanced ovarian, lung, and thyroid cancers, and chronic lymphocytic leukemia were highlighted today at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO). Findings from the mid- and late-stage trials suggest new ways to slow disease progression and improve survival for patients who experience relapses or resistance to available treatments.

"Cancer relapses and treatment resistance have always been among the most daunting challenges in cancer care," said press briefing moderator Gregory Masters, MD, FACP, ASCO Expert and a medical oncologist at the Helen F. Graham Cancer Center in Newark, Delaware. "The good news is that genomic medicine is helping to overcome these challenges by revealing new ways to target a cancer cell’s inner workings. The research highlighted today could lead to new treatment options for patients who, until now, have had none, or for whom the side effects of current drugs outweigh their limited benefits, as we often see with our older patients with leukemia."

Key studies include:
• Second-line treatment with ramucirumab plus standard docetaxel extends survival for patients with advanced non-small cell lung cancer: This phase III clinical trial marks the first time in a decade that a survival benefit has been achieved in second-line therapy for patients with advanced non-small cell lung cancer – findings that could impact the care of 60,000 patients each year in the United States.
• Ibrutinib is highly active, significantly delaying disease progression and extending survival for patients with resistant or relapsed chronic lymphocytic leukemia: Early results from the RESONATE study reveal the first oral agent to improve survival for resistant or relapsed CLL. Treatment was well tolerated, affirming ibrutinib as an important new option for this common adult leukemia, especially for elderly patients who are often unable to tolerate traditional chemotherapy. (Related broadcast quality video available)
• New targeted drug, lenvatinib, yields high response rates, delays progression in patients with radioiodine-resistant, advanced differentiated thyroid cancer: Nearly two-thirds of patients responded to lenvatinib treatment, which also delayed disease progression by 14.7 months over placebo.
• A new targeted drug combination, cediranib plus olaparib, significantly increases progression-free survival in women with recurrent ovarian cancer: A combination of the PARP inhibitor olaparib and the anti-angiogenic drug cediranib delays recurrent ovarian cancer progression by more than eight months compared with olaparib alone. This marks the first time these two types of targeted drugs have ever been combined, and could fill an important gap in treatment of ovarian cancer.
Media Resources:
• Online Annual Meeting Media Resource Center: Visit www.asco.org/AMMRC for press releases, press briefing recordings, the press briefing schedule at-a-glance, embargo policies, high-resolution photos, print-friendly downloads, and the Virtual Press Room, an online repository of corporate and institutional press releases from third-party organizations.
• CancerProgress.Net: The home of ASCO's 50th Anniversary and a timeline detailing the progress made against 18 of the most common cancers.
• Cancer.Net: ASCO's cancer information website, providing doctor-approved information on more than 120 cancer types.
The Annual Meeting Media Resource Center will be updated frequently leading up to and throughout the Annual Meeting.

Lung Cancer (Non-small Cell Metastatic) Oral Abstract Session:
Monday, June 2, 2014: 5:12 - 5:24 PM CDT Location: E Hall D2 Presenting Author: Maurice Perol, MD
Léon-Bérard Cancer Centre,
Lyon, France

Second-Line Treatment With Ramucirumab Plus Standard Docetaxel Extends Survival for Patients With Advanced Non-Small Cell Lung Cancer

Findings from the REVEL phase III study of patients with stage IV non-small cell lung cancer (NSCLC) indicate that a combination of a new anti-angiogenesis drug, ramucirumab, and standard docetaxel chemotherapy extends overall survival for patients who have a relapse after initial treatment compared to docetaxel plus placebo. The median overall survival was 10.5 months in the ramucirumab arm compared to 9.1 months in the placebo arm.
“This is the first treatment in approximately a decade to improve the outcome of patients in the second-line setting,” said lead study author Maurice Pérol, MD, Head of Thoracic Oncology at Cancer Research Center of Lyon in France. “The survival improvement is significant because patients with advanced NSCLC typically have a very short survival time following second-line therapy.”

Ramucirumab is a monoclonal antibody that specifically targets a protein called VEGF receptor 2, blocking growth of new blood vessels in the tumor (angiogenesis). No other approved anti-angiogenesis drugs are available in the second-line setting for advanced NSCLC, and currently ramucirumab is approved only for advanced gastric cancer treatment.
There is a large unmet medical need in the second-line treatment of advanced NSCLC, as all patients eventually experience a relapse following initial therapy. Approved second-line therapies for advanced NSCLC include docetaxel, erlotinib, and pemetrexed (for non-squamous NSCLC only), though clinical outcomes remain poor, with tumor shrinkage rates around 10 percent and median overall survival ranging between seven and nine months.
In the study, 1,253 patients with stage IV NSCLC (26 percent had the squamous subtype) that had progressed despite standard platinum-based therapy were randomly assigned to treatment with ramucirumab plus docetaxel or placebo plus docetaxel.

The addition of ramucirumab improved the efficacy of second-line docetaxel therapy – 22.9 percent of patients experienced tumor shrinkage in the ramucirumab arm compared to 13.6 percent in the placebo arm. The median overall and progression-free survival periods were 10.5 and 4.5 months in the ramucirumab plus docetaxel arm vs. 9.1 and 3 months in the placebo plus docetaxel arm, respectively. The survival benefits were consistent in the major subgroups of patients, including squamous and non-squamous subtypes, suggesting that this therapy could be suitable for all major subtypes of NSCLC. The safety profile was as expected for an anti-VEGFR agent in combination with docetaxel, with no increase in the rate of pulmonary hemorrhage (acute bleeding from the lung).

This research was supported by ImClone, a wholly owned subsidiary of Eli Lilly.

ASCO Perspective:
“This study expands the treatment options for patients with recurrent or refractory non-small cell lung cancer,” said Gregory A. Masters, MD, ASCO Expert. “Ramucirumab is an effective targeted agent when added to chemotherapy, with low toxicity. This will be a significant benefit to those patients whose cancer progresses following initial chemotherapy.”
Relevant links from Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:
• Guide to Lung Cancer
• Targeted Treatments
• When the First Treatment Doesn't Work
• Advanced Cancer Care Planning

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:
• Progress in Targeted Drugs Timeline
• Progress Against Lung Cancer Timeline

Abstract #LBA8006^: REVEL: A randomized, double-blind, phase III study of docetaxel (DOC) and ramucirumab (RAM; IMC-1121B) versus DOC and placebo (PL) in the second-line treatment of stage IV non-small cell lung cancer (NSCLC) following disease progression after one prior platinum-based therapy

Authors: Maurice Perol, Tudor-Eliade Ciuleanu, Oscar Arrieta, Kumar Prabhash, Konstantinos N. Syrigos, Tuncay Göksel, Keunchil Park, Ruben Dario Kowalyszyn, Joanna Pikiel, Grzegorz Czyzewicz, Sergey Orlov, Conrad R. Lewanski, Ekaterine Alexandris, Annamaria Zimmerman, Nadia Chouaki, William J. John, Sergey Yurasov, Edward B. Garon; Léon-Bérard Cancer Centre, Lyon, France; Prof. Dr. I. Chiricuta Institute of Oncology, Cluj County, Romania; Instituto Nacional de Cancerologia - INCAN, Mexico City, Mexico; Tata Memorial Center, Mumbai, India; Section of Medical Oncology, Department of Internal Medicine, Yale Cancer Center, Yale University School of Medicine, New Haven, CT; Ege University, School of Medicine, Izmir, Turkey; Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; Centro de Investigaciones Clínicas, Clínica Viedma, S.A., Argentina; Wojewódzkie Centrum Onkologii, Gdansk, Poland; John Paul II Hospital, Krakow, Poland; Pavlov State Medical University, St. Petersburg, Russia; Charing Cross Hospital, London, United Kingdom; ImClone Systems, a wholly-owned subsidiary of Eli Lilly & Co, Bridgewater, NJ; Eli Lilly & Co., Indianapolis, IN; Eli Lilly and Company, Paris, France; David Geffen School of Medicine, University of California Los Angeles, Translational Research in Oncology-US Network, Los Angeles, CA

Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. Methods: Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m2 in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). Results: Between Dec 2010 and Feb 2013, 1253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P<0.001). The hazard ratio (HR) for PFS was 0.762 (P<0.0001); median PFS was 4.5 months (m) for RAM+DOC vs. 3.0m for DOC. REVEL met its primary endpoint; the OS HR was 0.857 (95% CI 0.751, 0.98; P=0.0235); median OS was 10.5m for RAM+DOC vs. 9.1m for DOC. OS was longer for RAM+DOC in most pt subgroups, including SQ and NSQ histology. Grade ≥3 adverse events (AEs) occurring in >5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). Conclusions: REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. ClinicalTrials.gov identifier: NCT01168973.

Disclosures: Maurice Perol, Consultant or Advisory Role with Pfizer, Roche, Boehringer Ingelheim, Genentech, and Lilly, Honoraria from Pfizer, Roche, Genentech, and Lilly, Other Remuneration from Roche, Genentech, and Lilly, Position as an advisory board member and/or consultant of the trial sponsor; Tudor-Eliade Ciuleanu, Honoraria from Lilly; Tuncay Göksel, Research Funding from Lilly; Keunchil Park, Consultant or Advisory Role with Clovis, AstraZeneca, Roche, Boehringer Ingelheim, Lilly, and Astellas Pharma, Research Funding from AstraZeneca; Conrad R. Lewanski, Honoraria from Lilly, Research Funding from Lilly; Ekaterine Alexandris, Employment/Leadership Position with Lilly, Stock Ownership with Lilly; Annamaria Zimmerman, Employment/Leadership Position with Lilly, Stock Ownership with Lilly; Nadia Chouaki, Employment/Leadership Position with Lilly, Stock Ownership with Lilly; William J. John, Employment/Leadership Position with Lilly, Stock Ownership with Lilly; Sergey Yurasov, Employment/Leadership Position with ImClone Systems; Edward B. Garon, Consultant or Advisory Role with Lilly, Research Funding from Lilly, Position as an advisory board member and/or consultant of the trial sponsor

Research Funding Source: ImClone, a wholly owned subsidiary of Eli Lilly 
Leukemia, Myelodysplasia, and Transplantation Oral Abstract Session:
Tuesday, June 3, 2014: 11:57 AM - 12:09 PM CDT Location: E354a Presenting Author: John C. Byrd, MD
The Ohio State University,
Columbus, OH

Ibrutinib Is Highly Active, Significantly Delaying Disease Progression and Extending Survival for Patients With Resistant or Relapsed Chronic Lymphocytic Leukemia

– Summary contains updated data not included in the abstract –

Early findings from the phase III RESONATE study indicate that ibrutinib yields lasting tumor responses and marked improvement in survival over standard ofatumumab for patients with relapsed chronic lymphocytic leukemia (CLL). This is the first time an oral drug has demonstrated a survival improvement over standard therapy in relapsed CLL. Just as important, the therapy was well tolerated by patients, causing few serious side effects.

CLL is the most common form of leukemia in adults. The standard treatment for CLL is chemo-immunotherapy, a combination of intensive chemotherapy and an antibody such as rituximab. However, elderly patients, who account for the majority of patients with CLL, often cannot tolerate intensive chemotherapy. Ofatumumab is an alternative option for such patients, but studies have shown it is much less effective than intensive chemotherapy.

“With ibrutinib, about 80 percent of patients were still in remission at one year, twice as many as we would expect with standard therapy,” said lead study author John Byrd, MD, a professor of medicine at The Ohio State University Comprehensive Cancer Center in Columbus, Ohio. “Although the follow-up was short in this study, the data definitely support the use of ibrutinib before anything else in this setting.”

Ibrutinib was FDA approved for the treatment of CLL in February of this year, through the FDA’s accelerated review process, less than five years after entering phase I clinical trials.

In the study, 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma (a subtype of CLL) that had progressed after two or more prior therapies were randomly assigned to treatment with ofatumumab or ibrutinib. The median patient age was 67 years, and 40 percent were older than 70 years.

At a median follow-up of 9.4 months, the response rates were dramatically higher in the ibrutinib arm compared to the ofatumumab arm (42 percent vs. 4 percent). An additional 20 percent of patients treated with ibrutinib had a partial response with persistent lymphocytosis (increase in white blood cells called lymphocytes). Ibrutinib was associated with an 80 percent lower risk of disease progression and a 57 percent lower risk of dying compared to ofatumumab; the median progression-free and overall survival have not been reached. Ibrutinib had similarly high activity in two very high-risk groups of patients (17p deletions and purine analog refractory).

Based on these striking early results, patients in the ofatumumab arm were offered the opportunity to cross over to the ibrutinib arm, and patient follow-up continues. According to the researchers, the median overall survival is expected to be in the range of several years.

Overall, both ibrutinib and ofatumumab were well tolerated. Diarrhea, minor bleeding, and atrial fibrillation were more common in the ibrutinib arm, whereas peripheral neuropathy was more common in the ofatumumab arm. This study alleviated concerns about kidney problems that were raised in the phase II ibrutinib study.
This research was supported by Pharmacyclics.

ASCO Perspective:
“This phase III study in relapsed refractory chronic lymphocytic leukemia confirms that ibrutinib, administered orally, has significant efficacy and is well-tolerated," said Olatoyosi Odenike, MD, ASCO Expert. "These results provide a compelling new treatment option for patients with chronic lymphocytic leukemia, including older adults with this disease, and will significantly change practice."
Relevant links from Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:
• Guide to Chronic Lymphocytic Leukemia
• Targeted Treatments
• When the First Treatment Doesn't Work

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:
• Progress in Targeted Drugs Timeline
• Progress Against Leukemia Timeline

Abstract LBA7008: Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial.
Authors: John C. Byrd, Jennifer R. Brown, Susan Mary O'Brien, Jacqueline Claudia Barrientos, Neil E. Kay, Nishitha M. Reddy, Steven E. Coutre, Constantine Tam, Stephen P. Mulligan, Ulrich Jäger, Steve Devereux, Paul M. Barr, Richard R. Furman, Thomas J. Kipps, Florence Cymbalista, Maria Fardis, Jesse S. McGreivy, Fong Clow, Danelle Frances James, Peter Hillmen; The Ohio State University, Columbus, OH; Dana-Farber Cancer Institute, Boston, MA; The University of Texas MD Anderson Cancer Center, Houston, TX; Hofstra North Shore-LIJ School of Medicine, Hempstead, NY; Mayo Clinic, Rochester, MN; Vanderbilt University Medical Center, Nashville, TN; Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA; Peter MacCallum Cancer Centre and St. Vincent's Hospital, Melbourne, Australia; Royal North Shore Hospital, Sydney, Australia; Medical University of Vienna, Vienna, Austria; College Hospital, NHS Foundation Trust Denmark Hill, London, United Kingdom; University of Rochester Cancer Center, Rochester, NY; Presbyterian Hospital/Cornell Medical Center, New York, NY; University of California, San Diego, School of Medicine, San Diego, CA; Hôpital Avicenne, Paris, France; Pharmacyclics, Inc., Sunnyvale, CA; Pharmacyclics, Sunnyvale, CA; Pharmacyclics, Inc, Sunnyvale, CA; The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, United Kingdom
Background: Treatment options for CLL/ SLL patients (pts) who fail chemoimmunotherapy are limited. We report interim results from a phase III randomized study of ibrutinib (ibr), a first in class covalent BTK inhibitor, vs ofatumumab (ofa) in R/R CLL/SLL. The Data Monitoring Committee recommended this analysis be considered final, based on meeting the primary and a key secondary endpoint. Methods: R/R CLL/SLL pts who failed ≥1 therapy received 420 mg oral ibr daily until progression or IV ofa 300/2000mg for 12 doses. Primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). Secondary endpoints included overall survival (OS), IRC assessed overall response rate (ORR) and safety. Results: Of 391 pts enrolled (median age 67 years; 40% ≥70 years; 57% Rai stage III/IV disease; 30% del 17p), 195 were randomized to ibr and 196 to ofa. Ibr pts had median 3 prior therapies vs 2 for ofa. Median follow-up was 9.4 months (m). Ibr significantly lengthened PFS (median not reached vs 8.1 m; HR 0.215, CI 0.146–0.317, p<0.0001; 78.5% risk reduction), and significantly improved OS (median not reached; HR 0.434, CI 0.238–0.789, p=0.0049) compared with ofa. ORR was 42.6 vs 4.1% (p<0.0001) and ORR+PR with lymphocytosis was 62.6 vs 4.1% for ibr vs ofa. Similar effects were seen in del17p and purine analog refractory subsets. In each arm 2 pts had confirmed Richter’s transformation. Most frequent adverse events (AE) for ibr vs ofa were diarrhea (47.7 vs 17.8%) fatigue (27.7 vs 29.8%) and nausea (26.2 vs 18.3%). Atrial fibrillation was more frequent with ibr (5.1 vs 0.5%). Major hemorrhages were reported in 1.0 vs 1.6% for ibr vs ofa. Drug discontinuation due to AE was 4.1 vs 3.6% for ibr vs ofa. 86% of ibr pts were continuing treatment. 57 pts randomized to ofa with confirmed PD had initiated ibr at cross-over. Conclusions: Compared with ofa, ibr significantly improved PFS, OS and ORR in pts with R/R CLL/SLL. The safety profile was comparable with that previously reported (Byrd NEJM 2013). These results support ibr as a beneficial therapy for R/R CLL patients irrespective of del 17p or purine analog refractory disease.
Disclosures: John C. Byrd, Research Funding from Pharmacyclics; Jennifer R. Brown, Consultant or Advisory Role with GlaxoSmithKline and Pharmacyclics, Honoraria from Janssen; Susan Mary O'Brien, Research Funding from Pharmacyclics; Jacqueline Claudia Barrientos, Consultant or Advisory Role with Pharmacyclics, Honoraria from Janssen, Research Funding with Pharmacyclics; Neil E. Kay, Research Funding from Pharmacyclics; Nishitha M. Reddy, Consultant or Advisory Role with Pharmacyclics, Honoraria from Janssen, Research Funding from Pharmacyclics; Steven E. Coutre, Consultant or Advisory Role with Pharmacyclics, Research Funding from Pharmacyclics; Constantine Tam, Consultant or Advisory Role with Pharmacyclics, Expert Testimony for Pharmacyclics; Stephen P. Mulligan, Consultant or Advisory Role with Janssen and Pharmacyclics, Honoraria from Janssen Australia; Ulrich Jäger, Honoraria from Janssen-Cilag; Steve Devereux, Consultant or Advisory Role with Pharmacyclics, Honoraria from Pharmacyclics; Paul M. Barr, Research Funding from Pharmacyclics; Richard R. Furman, Consultant or Advisory Role with Janssen and Pharmacyclics, Honoraria from Janssen; Thomas J. Kipps, Consultant or Advisory Role with Celgene, Pharmacyclics, Genentech, and AbbVie; Florence Cymbalista, Honoraria from Janssen and Pharmacyclics; Maria Fardis, Employment/Leadership Position with Pharmacyclics, Stock Ownership with Pharmacyclics; Jesse S. McGreivy, Employment/Leadership Position with Pharmacyclics, Stock Ownership with Pharmacyclics; Fong Clow, Employment/Leadership Position with Pharmacyclics, Stock Ownership with Pharmacyclics; Danelle Frances James, Employment/Leadership Position with Pharmacyclics, Stock Ownership with Pharmacyclics; Peter Hillmen, Consultant or Advisory Role with Pharmacyclics, Honoraria from Pharmacyclics

Research Funding Source: Pharmacyclics

Head and Neck Cancer Oral Abstract Session: Presenting Author: Martin Schlumberger, MD
Monday, June 2, 2014: 10:28 - 10:40 AM CDT Location: E450 Gustave Roussy and University Paris-Sud
Villejuif, France

New Targeted Drug, Lenvatinib, Yields High Response Rates, Delays Progression in Patients With Radioiodine-Resistant, Advanced Differentiated Thyroid Cancer

Findings from the SELECT phase III study show that lenvatinib is highly effective against differentiated thyroid cancer that is resistant to standard radioiodine (RAI) therapy. The new oral targeted drug delayed disease progression by 14.7 months, and nearly two thirds of patients experienced tumor shrinkage. The median overall survival has not been reached.

“We are confident that, based on our findings, lenvatinib will eventually become a standard treatment for radioiodine-resistant thyroid cancer,” said lead study author Martin Schlumberger, MD, a professor of oncology at the University Paris Sud in Paris, France. “As little as a year ago, this group of patients had no effective treatment options. It’s remarkable that we now have two active drugs in this setting, both of them tyrosine kinase inhibitors.”
Differentiated thyroid cancer is the most common subtype of thyroid cancer, accounting for about 85 percent of the 60,000 thyroid cancer cases diagnosed each year in the United States. Although differentiated thyroid cancer is generally curable with standard treatment – surgery and RAI – roughly 5-15 percent of patients develop RAI resistance. Another targeted drug called sorafenib was approved by the FDA in November 2013 to treat this same population of patients.

Lenvatinib is an oral tyrosine kinase inhibitor that blocks several targets in a cancer cell, including VEGFR1-3, FGFR 1-4, PDGFR-β, KIT, and RET. It is being explored in phase II and phase III clinical trials as a potential treatment for liver, lung, and kidney cancers and other types of solid tumors.

In this study, 392 patients with advanced, RAI-resistant, differentiated thyroid cancer that had progressed within a year were randomly assigned to treatment with either lenvatinib or placebo. Patients on the placebo arm were allowed to cross over to the lenvatinib arm upon disease progression.

Approximately 65 percent of patients experienced tumor shrinkage in the lenvatinib arm, compared to only 3 percent in the placebo arm. The majority of responses occurred within two months of starting treatment. The median progression-free survival was 18.3 months in the lenvatinib arm vs. 3.6 months in the placebo arm. The median overall survival has not been reached.

The five most common side effects of lenvatinib were high blood pressure, diarrhea, decreased appetite, decreased weight, and nausea. Although the side effects necessitated dose reductions in 78.5 percent of patients, the benefit of lenvatinib persisted with decreased dose, Dr. Schlumberger noted.
This research was supported by Eisai Inc.

ASCO Perspective:
“The progress we’re seeing with targeted agents for uncommon cancers is encouraging, said Gregory A. Masters, MD, ASCO Expert. “Patients with differentiated thyroid cancer have historically had limited options when the disease progresses despite radioactive iodine therapy. Now this new drug, lenvatinib, offers an effective option with reasonable side effects and can help patients live longer before the disease worsens.”

Relevant links from Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:
• Guide to Thyroid Cancer
• Targeted Treatments
• When the First Treatment Doesn't Work

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:
• Progress in Targeted Drugs Timeline
• Progress Against Head and Neck Cancer Timeline

Abstract #LBA6008: A phase 3, multicenter, double-blind, placebo-controlled trial of lenvatinib (E7080) in patients with 131I-refractory differentiated thyroid cancer (SELECT).

Authors: Martin Schlumberger, Makoto Tahara, Lori J. Wirth, Bruce Robinson, Marcia S. Brose, Rossella Elisei, Corina E. Dutcus, Begoña de las Heras, Junming Zhu, Mouhammed Amir Habra, Kate Newbold, Manisha H. Shah, Ana O. Hoff, Andrew G Gianoukakis, Naomi Kiyota, Matthew Hiram Taylor, Sung-Bae Kim, Monika K Krzyzanowska, Steven I. Sherman; Department of Nuclear Medicine and Endocrine Oncology,Gustave Roussy and University Paris-Sud, Villejuif, France; Division of Head and Neck Medical Oncology,National Cancer Center Hospital East, Kashiwa, Japan; Department of Medicine, Massachusetts General Hospital, Boston, MA; Kolling Institute of Medical Research, University of Sydney, New South Wales, Australia; Department of Otorhinolaryngology: Head and Neck Surgery,Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA; Department of Endocrinology, University of Pisa, Pisa, Italy; Eisai, Woodcliff Lake, NJ; Eisai, Hatfield, Hertfordshire, United Kingdom; Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX; Royal Marsden Hospital National Health Service Trust, London, United Kingdom; Departments of Internal Medicine,The Ohio State University Comprehensive Cancer Center, Columbus, OH; Instituto do Cancer do Estado de Sao Paulo,Universidade de Sao Paulo, São Paulo, Brazil; Division of Endocrinology and Metabolism,Harbor-UCLA Medical Center, Torrance, CA; Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan; Knight Cancer Institute,Oregon Health and Science University, Portland, OR; Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea; Division of Medical Oncology & Hematology, Princess Margaret Cancer Centre, Toronto, ON

Background: Lenvatinib (LEN) is an oral tyrosine kinase inhibitor of the VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT signaling networks. Based on efficacy results of the phase 2 study of patients (pts) with 131I-refractory differentiated thyroid cancer (RR-DTC), this phase 3 Study of (E7080) Lenvatinib in Differentiated Cancer of the Thyroid (SELECT) was developed. Methods: This randomized, double-blind, placebo (PBO)-controlled study enrolled pts with RR-DTC with documented disease progression within 13 months (mo). Pts were stratified by age (≤65, >65 years), region and ≤1 prior VEGFR-targeted therapies and randomized 2:1 to LEN or PBO (24mg/d, 28-d cycle). Upon progression, pts receiving PBO could crossover to open-label LEN. The primary endpoint was PFS assessed by Independent Radiologic Review; secondary endpoints included overall response rate (ORR; complete response [CR] + PR), overall survival (OS) and safety. Results: 392 pts (63.0 years median age; 51.0% male) were randomized. Pts on LEN had a significantly prolonged PFS vs PBO (hazard ratio 0.21, 95% confidence interval [CI] 0.14–0.31; P <.0001); median PFS was LEN: 18.3 mo (95% CI 15.1–not evaluable), PBO: 3.6 mo (95% CI 2.2–3.7). A LEN PFS benefit was observed in all predefined subgroups; median LEN PFS for pts with prior vs no prior VEGF-therapy was 15.1 mo (n=66) and 18.7 mo (n=195), respectively. Rates (n) of CRs were LEN: 1.5% (4), PBO: 0; PRs were LEN: 63.2% (165), PBO: 1.5% (2). Median exposure duration was LEN: 13.8 mo, PBO: 3.9 mo; median time to LEN response was 2.0 mo. Median OS has not been reached; deaths per arm were LEN: 71 (27.2%), PBO: 47 (35.9%). The 5 most common LEN treatment-related adverse events (TRAEs; any grade) were hypertension (68%), diarrhea (59%), appetite decreased (50%), weight loss (46%), nausea (41%). LEN grade ≥3 TRAEs (≥5%) were hypertension (42%), proteinuria (10%), weight loss (10%), diarrhea (8%), appetite decreased (5%). The dose was reduced in 78.5% of pts and discontinued due to adverse events (AEs) in 14.2% of pts. Conclusions: LEN significantly improved PFS compared with PBO in pts with progressive RR-DTC. There were no unexpected toxicities and AEs were manageable.
Disclosures: Martin Schlumberger, Consultant or Advisory Role with Genzyme/Sanofi, Bayer, Eisai, and AstraZeneca, Honoraria from Genzyme/Sanofi, SOBI, Bayer, Eisai, and AstraZeneca, Research Funding from Genzyme/Sanofi, bayer, Eisai, and AstraZeneca; Makoto Tahara, Consultant or Advisory Role with Merck Serono and Eisai, Honoraria from Merck Serono and Bristol-Myers Squibb, Research Funding from Eisai and Boehringer Ingelheim; Bruce Robinson, Consultant or Advisory Role with Bayer, Eisai, and AstraZeneca, Honoraria from Bayer, Eisai, and AstraZeneca; Marcia S. Brose, Consultant or Advisory Role with Eisai, Research Funding from Eisai; Rossella Elisei, Consultant or Advisory Role with Genzyme, Bayer, and AstraZeneca, Honoraria from Genzyme, Bayer, and AstraZeneca; Corina E. Dutcus, Employment/Leadership Position with Eisai; Begoña de las Heras, Employment/Leadership Position with Eisai; Junming Zhu, Employment/Leadership Position with Eisai; Manisha H. Shah, Consultant or Advisory Role with Exelixis, Research Funding from Exelixis, Bayer, and Eisai; Ana O. Hoff, Research Funding from Eisai; Andrew G Gianoukakis, Research Funding from Eisai; Naomi Kiyota, Honoraria from Eisai, Research Funding from Eisai; Sung-Bae Kim, Consultant or Advisory Role with Novartis, Research Funding from Il Dong Pharmaceuticals and Novartis; Monika K Krzyzanowska, Consultant or Advisory Role with Bayer/Onyx, Honoraria from Novartis, Sanofi, and AstraZeneca, Research Funding from Exelixis, Novartis, Eisai, and AstraZeneca; Steven I. Sherman, Consultant or Advisory Role with Exelixis, Amgen, Bayer, Eisai, Pfizer, Roche, and AstraZeneca, Honoraria from Exelixis and Onyx, Research Funding from Amgen, Other Remuneration from Exelixis

Research Funding Source: Eisai Inc


Gynecologic Cancer Oral Abstract Session: Presenting Author: Joyce Liu, MD, MPH
Saturday, May 31, 2014: 1:15 - 1:27 PM CDT Location: E354a Dana-Farber Cancer Institute,
Boston, MA

A New Targeted Drug Combination, Cediranib Plus Olaparib, Significantly Increases Progression-Free Survival in Women With Recurrent Ovarian Cancer

– Summary contains updated data not included in the abstract –

Findings from a federally funded, NCI-sponsored phase II study suggest that the combination of two investigational oral drugs, the PARP inhibitor olaparib and the anti-angiogenesis drug cediranib, is significantly more active against recurrent, platinum chemotherapy-sensitive disease or ovarian cancer related to mutations in BRCA genes than olaparib alone. The progression-free survival was 17.7 months with the combination treatment vs. nine months with olaparib alone.

“The significant activity that we saw with the combination suggests that this could potentially be an effective alternative to standard chemotherapy,” said lead study author Joyce Liu, MD, MPH, an instructor in medical oncology at Dana-Farber Cancer Institute in Boston, MA. “At the same time, this approach is not yet ready for clinical practice as neither of these drugs is currently FDA approved for ovarian or any other cancer. We also need additional clinical trials to confirm the findings of this study to see how this combination compares to standard treatment.”
This study is the first time a combination of a PARP inhibitor and an anti-angiogenic drug has ever been explored in a clinical trial for ovarian cancer. (PARP is an enzyme involved in many functions in a cell, including repair of DNA damage. Inhibition of PARP may cause cancer cells to die. Anti-angiogenic drugs block the growth of blood vessels in the tumor.) It confirms preclinical research which suggested that olaparib and cediranib synergize, meaning they work together to make each other more active. Dr. Liu and her colleagues designed this trial to confirm, in a clinical setting, that the combination of these two drugs was more active than the single drug olaparib alone.
As many as 80 percent of women with high-grade serous ovarian cancer experience a relapse after initially responding to chemotherapy. When the cancer comes back, it is more difficult to treat, because it will have spread to the pelvis and abdomen, or even the lungs. The current standard treatment for recurrent ovarian cancer is chemotherapy, which often causes significant side effects. Even in the setting of initial response, resistance to chemotherapy eventually develops. Therefore, researchers have been exploring alternate regimens using targeted drugs, with the goal of overcoming such treatment resistance.

Ninety women with recurrent, platinum-sensitive (disease that responds to treatment with platinum-based chemotherapy), high-grade serous or BRCA mutation-related ovarian cancer, were randomly assigned to treatment with olaparib alone or olaparib plus cediranib. The women had no prior treatment with anti-angiogenic drugs in the setting of recurrent ovarian cancer or PARP inhibitors.

Tumor shrinkage rates were markedly higher in the combination arm than in the olaparib arm (80 vs. 48 percent). Five patients in the combination arm and two patients in the olaparib alone arm had a complete remission. The combination treatment substantially delayed disease progression, with a progression-free survival of 17.7 months compared to nine months for olaparib alone. Past trials of standard chemotherapy in the platinum-sensitive setting have demonstrated progression-free survival times between eight and 13 months.
Although certain side effects ─ high blood pressure, fatigue
, and diarrhea ─ occurred more frequently in the combination arm, they were usually controllable by symptom management and dose reductions as needed.
Prior trials have suggested that PARP inhibitors tend to have the most activity in women who have either platinum-sensitive ovarian cancer or BRCA mutations in their tumors. An exploratory analysis from this study suggests that the combination treatment appears to also be active in patients without a known BRCA-mutation. Dr. Liu remarked that it is reasonable to explore whether the combination treatment would be effective in women with platinum-resistant disease as well.

This study was supported by the National Cancer Institute, National Institutes of Health.
*Dr. Liu is the recipient of a 2008 Conquer Cancer Foundation of ASCO Young Investigator Award.

ASCO Perspective:
“The combination of cediranib plus olaparib resulted in a significantly higher response rate, though at the expense of higher toxicity. Whether this response translates into gains in survival needs further follow-up,” said Don S. Dizon MD, FACP, ASCO Expert. “However, this combination represents an oral, non-chemotherapy-based combination treatment option for women with high-grade serous or BRCA-mutation related ovarian cancers and definitely warrants further study.”

Relevant links from Cancer.Net, the oncologist-approved cancer information website from the American Society of Clinical Oncology:
• Guide to Ovarian Cancer
• Hereditary Breast and Ovarian Cancer
• Targeted Treatments

Relevant links from CancerProgress.Net, the home of ASCO's 50th Anniversary and progress made against 18 of the most common cancers:
• Progress in Targeted Drugs Timeline
• Progress Against Ovarian Cancer Timeline

Abstract #LBA5500: A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.

Authors: Joyce Liu, William Thomas Barry, Michael J. Birrer, Jung-min Lee, Ronald J. Buckanovich, Gini F. Fleming, Bj Rimel, Mary K. Buss, Sreenivasa R. Nattam, Jean Hurteau, Weixiu Luo, Philippa Quy, Elizabeth Obermayer, Christin Whalen, Hang Lee, Eric P. Winer, Elise C. Kohn, S. Percy Ivy, Ursula Matulonis; Dana-Farber Cancer Institute, Boston, MA; Massachusetts General Hospital, Boston, MA; National Cancer Institute, National Institutes of Health, Bethesda, MD; University of Michigan, Ann Arbor, MI; University of Chicago Medical Center, Chicago, IL; Cedars Sinai Medical Center, Los Angeles, CA; Beth Israel Deaconess Medical Center, Boston, MA; Fort Wayne Medical Oncology and Hematology, Fort Wayne, IN; Northshore University Health Systems, University of Chicago, Evanston, IL; IBCSG Statistical Center, Dana-Farber Cancer Institute, Boston, MA; Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD

Background: PARP inhibitors and anti-angiogenics are clinically active in recurrent ovarian cancer (OvCa). Pre-clinical studies suggest these agents can synergize, and a phase 1 study showed that the combination of cediranib (ced) and olaparib (olap) is well-tolerated. We therefore compared the activity of olap alone (Olap) to combined ced and olap (Ced/Olap) in treatment of recurrent platinum-sensitive (plat-sens) high-grade serous (HGS) or BRCA-related OvCa (NCT 01116648). Methods: Patients (pts) across 9 centers were randomized 1:1 in this Ph 2 open label study to Olap (olap 400 mg capsules BID) or Ced/Olap (olap 200 mg capsules BID; ced 30 mg daily), stratified by BRCA status and prior anti-angiogenic therapy. Eligibility included pts with recurrent plat-sens HGS or BRCA-related OvCa. Pts had measurable disease by RECIST 1.1, PS 0 or 1, and the ability to take POs. No prior anti-angiogenics in the recurrent setting or prior PARP inhibitor was allowed. Progression-free survival (PFS) was defined as time from randomization to radiographic progression or death. With a target N=90 pts, the study was powered to detect a hazard ratio (HR) of 1.75 (median PFS 6 vs 10.5 mo). Results: Pts were enrolled from Oct 2011 to Jun 2013: 46 to Olap, 44 to Ced/Olap. 48 pts were known BRCA carriers (25 Olap; 23 Ced/Olap). At a planned interim analysis the DSMB recommended release of data. As of Jan 7, 2014, 41 pts had a PFS event. Median PFS was 9.0 mos for Olap and 17.7 mos for Ced/Olap (HR 2.9, 95% CI 1.5-5.6, p = 0.001). There were 2 complete responses (CR) and 21 partial responses (PR) in pts on Olap (56% objective response rate, ORR) and 3 CRs and 33 PRs in pts on Ced/Olap (84% ORR, p = 0.008). The overall rate of Gr3/4 toxicity was higher for pts on Ced/Olap (70%) than on Olap (7%). Differentially occurring toxicities included fatigue (27% Ced/Olap vs 7% Olap), diarrhea (23% vs 0%), and hypertension (39% vs 0%). Updated efficacy and exploratory subgroup analyses will be presented. Conclusions: Combined Ced/Olap significantly extended PFS and ORR compared to Olap in plat-sens OvCa. Further studies of this oral combination in plat-sens OvCa are warranted.

Disclosures: Nothing to disclose

Research Funding Source: NIH

ATTRIBUTION TO THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY ANNUAL MEETING IS REQUESTED IN ALL NEWS COVERAGE.

Click here to view the disclosures for the 2014 ASCO Annual Meeting News Planning Team.

Additional disclosures: TK
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