Dear colleague,
Please find below five Press Releases relating to late breaking trials being presented at ESMO 2016 today:
- Cabozantinib improves progression-free survival in metastatic renal cell carcinoma
- Custirsen shows no survival benefits in metastatic prostate cancer
- Significant survival gains from neoadjuvant chemotherapy for high-risk soft tissue sarcoma
- MEK inhibition in KRAS-mutant NSCLC did not improve survival
- Longer disease-free survival in phase III trial of sunitinib as adjuvant treatment for kidney cancer
Kind regards
ESMO Press Office
PRESS RELEASE
EMBARGOED until 10 October 2016, 8:15 hours (CEST)
Cabozantinib improves progression-free survival in metastatic renal cell carcinoma
LUGANO-COPENHAGEN, 10 October, 2016 – Cabozantinib significantly improves progression-free survival and response rate in patients with metastatic renal cell carcinoma compared to sunitinib, according to research presented today at the ESMO 2016 Congress in Copenhagen1.
Cabozantinib targets a class of enzymes called tyrosine kinases but, unlike sunitinib which targets the vascular endothelial growth factor receptors (VEGFR), cabozantinib additionally inhibits the action of MET and AXL.
“Both MET and AXL seem to be associated with tumour progression but more importantly, animal models showed that the development of resistance to VEGFR inhibitors like sunitinib can be mediated through AXL and MET,” said principal investigator Dr. Toni Choueiri, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, US.
In this phase II multicenter trial, 157 patients with untreated clear-cell metastatic renal cell carcinoma of intermediate or poor risk, were randomized either to oral cabozantinib (60mg once daily) or sunitinib (50mg once daily, 4 weeks on, 2 weeks off).
Patients treated with cabozantinib showed a 31% reduction in the median rate of progression or death compared to those treated with sunitinib (8.2 months vs. 5.6 months, p = 0.012). The objective response rate was also significantly higher in the cabozantinib arm compared to the sunitinib arm (46% vs.18%).
Researchers observed a similar rate of adverse events between the two arms of the study, with the incidence of grade 3 or higher adverse events being 70.5% in the cabozantinib arm and 72.2% in the sunitinib arm. The most common adverse events for both treatments included diarrhoea, fatigue, hypertension, palmar-plantar erythrodysesthesia, hematological events, and 16 patients in each arm terminated their treatment early due to toxicity.
The study did not include good-risk patients, but Choueiri said there was no biological or clinical rationale to think that cabozantinib would not be equally effective in that population.
“Cabozantinib is currently approved for second or later lines of therapies, after patients have progressed on a VEGFR tyrosine kinase inhibitor, but this data shows that cabozantinib has the potential to become a first-line standard treatment,” Choueiri said.
Commenting on the study, Dr Bernard Escudier, chairman of the renal cancer unit at Institut Gustave-Roussy, France, said, “For many years, sunitinib has been the most commonly used standard of care for first line metastatic renal cell carcinoma, and recently, cabozantinib was proven to be active in second line, especially after sunitinib failure.”
“Obviously, this study will raise a lot of questions, such as whether these results are expandable to all metastatic renal cell carcinoma patients, including the good prognosis group; whether cabozantinib should become a new standard of care in the first line setting; and how we should interprete all the ongoing phase III first-line studies which selected sunitinib as the control arm.”
“While more mature data and additional studies using cabozantinib in the first line setting will be required, this study raises a lot of new expectations for the treatment of metastatic renal cell carcinoma,” Escudier concluded.
-END-
Notes to Editors
References
1 LBA30_PR - CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial, presented by Dr Toni Choueiri during Presidential Symposium 3 on Monday, 10 October, 16:30 to 18:10 (CEST).
Disclaimer
This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO and ESMO cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct .
About the European Society for Medical Oncology
ESMO is the leading professional organisation for medical oncology. Comprising more than 13,000 oncology professionals from over 130 countries, we are the society of reference for oncology education and information. We are committed to supporting our members to develop and advance in a fast-evolving professional environment.
Founded in 1975, ESMO has European roots and a global reach: we welcome oncology professionals from around the world. We are a home for all oncology stakeholders, connecting professionals with diverse expertise and experience. Our educational and information resources support an integrated, multi-professional approach to cancer treatment. We seek to erase boundaries in cancer care as we pursue our mission across oncology, worldwide.
Abstract for LBA30_PR
CABOzantinib versus SUNitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma (mRCC) of poor and intermediate risk groups: Results from ALLIANCE A031203 trial
T.K. Choueiri1, S. Halabi2, B. Sanford2, O. Hahn3, M.D. Michaelson4, M. Walsh1, T. Olencki5, J. Picus6, E.J. Small7, S. Dakhil8, D. George9, M.J. Morris10
1Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA, 2Biostatistics & Bioinformatics, Duke University, Durham, NC, USA, 3Medical Oncology, The University of Chicago Medical Centre, Chicago, IL, USA, 4Medical Oncology, Massachusetts General Hospital, Boston, MA, USA, 5Medical Oncology, Ohio State Univ Medical Center, Columbus, OH, USA, 6Medical Oncology, Washington University School of Medicine, St Louis, MO, USA, 7Medical Oncology, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA, 8Hematology, Cancer Center of Kansas, Wichita, KS, USA, 9Medical Oncology, Duke University, Durham, NC, USA, 10Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Background: Cabozantinib (Cabo) is an oral, potent inhibitor of MET, AXL and VEGFR2 that increases progression free-survival (PFS) and overall survival (OS) in mRCC patients (pts) after VEGF-targeted therapy. This randomized phase II multicenter trial compared the PFS of Cabo to Sunitinib (Sun) as front-line targeted therapy in pts with mRCC.
Methods: Eligible pts had untreated clear-cell mRCC, ECOG performance status 0-2, and were intermediate or poor risk, per the International mRCC Database Consortium Criteria (IMDC, Heng JCO 2009). Pts were randomized 1:1 to Cabo (60 mg QD) or Sun (50 mg QD, 4 weeks on/2 weeks off). Pts were stratified by IMDC risk groups (intermediate vs. poor risk) and bone metastasis (yes, no). With 123 events (progression or deaths), the log-rank statistic has 85% power to detect a hazard ratio of 0.67 for PFS assuming a one-sided type I error of 0.12.
Results: From July 2013 to April 2015, 157 pts were randomized (79 to Cabo and 78 to Sun). Median follow up was 20.8 months (mo). 13 (16.46%) pts remained on therapy in the Cabo arm vs. 2 (2.56%) pts in the Sun arm. 80.9% of pts were IMDC intermediate risk and 36.3% had bone metastases and were equally distributed across arms. Median PFS was significantly increased at 8.2 mo (95% CI=6.2-8.8) for Cabo vs. 5.6 mo (95% CI=3.4-8.2) for Sun, with 31% reduction in rate of progression or death (adjusted HR 0.69, 95% CI 0.48 to 0.98, one-sided P=0.012). ORR was 46% (95% CI 34-57%) for Cabo vs. 18% (95% CI 10-28%) for Sun. Median OS was 26.4 mo. for Cabo vs. 23.5 mo for Sun (adjusted HR 0.87, 95% CI 0.55-1.4). All-causality grade 3 or higher adverse events were 70.5% for Cabo and for 72.2% for Sun, and included diarrhea (Cabo 10%, Sun 11%), fatigue (Cabo 6%, Sun 15%), hypertension (Cabo 28%, Sun 22%), palmar-plantar erythrodysesthesia (Cabo 8%, Sun 4%) and hematological (Cabo 2.6%, Sun 22.2%). In each arm, 16 pts ended treatment due to toxicity.
Conclusions: Cabozantinib demonstrated a significant benefit in PFS and ORR over standard sunitinib in untreated intermediate and poor risk mRCC pts.
Clinical trial identification: NCT01835158
Legal entity responsible for the study: Alliance/CTEP
Funding: Exelixis
|
Disclosure: |
T.K. Choueiri: Institutional funds from Exelixis and Pfizer. Advisory board compensation from Pfizer. |
Keywords: metastatic renal cell carcinoma, VEGF, sunitinib, resistance to treatment
PRESS RELEASE
EMBARGOED until 10 October 2016, 8:15 hours (CEST)
Custirsen shows no survival benefits in metastatic prostate cancer
LUGANO-COPENHAGEN, 10 October, 2016 – A phase III randomized controlled trial of custirsen in combination with cabazitaxel/prednisone in patients with previously-treated metastatic, castration-resistant prostate cancer has shown no significant survival gains compared to cabazitaxel/prednisone alone, according to data presented at the ESMO 2016 Congress in Copenhagen1.
“Despite the negative outcome of the trial, the evaluation of custirsen in prostate cancer was conducted on the basis of solid preclinical and clinical evidence supporting anti-tumour activity,” said principal investigator Professor Karim Fizazi, head of the Department of Cancer Medicine at the Institut Gustave Roussy, Villejuif, France.
Custirsen blocks production of the protein clusterin, which is known to be involved in carcinogenesis and tumour growth, as well as contributing to treatment resistance.
A previous phase II trial of custirsen combined with chemotherapy in men with metastatic castration-resistant prostate cancer suggested inhibition of clusterin may lead to improved clinical outcome, and an earlier phase III trial of custirsen in combination with docetaxel suggested patients with more aggressive cancers may benefit from the combination.
In the AFFINITY trial, 635 patients with metastatic, castration-resistant prostate cancer – who had previously been treated with docetaxel - were randomized to 21-day cycles of custirsen plus cabazitaxel/prednisone or cabazitaxel/prednisone plus placebo, until disease progression, unacceptable toxicity, or ten cycles.
Researchers saw no significant difference in overall survival between the custirsen and placebo arms of the study, with a median overall survival of 14.2 months in the custirsen arm and 13.4 months in the placebo arm (p = 0.529).
The same was observed in the 62% of patients who met the criteria for poor prognosis, where median overall survival was 11.1 months among those taking custirsen and 10.9 months in those in the placebo group.
Similar numbers of patients in each arm discontinued due to progressive disease – 28.9% in the custirsen arm and 25% in the placebo arm – while 21.9% of patients treated with custirsen and 18.9% of patients in the placebo arm discontinued due to adverse events.
The most frequently reported serious adverse events were neutropenia, anemia, fatigue, asthenia, bone pain, and febrile neutropenia.
“I am obviously disappointed with the results but am proud to have been involved in this program, and we will take the learnings of this trial to advance our knowledge of the disease in the hope to further advance care,” Fizazi said.
“Custirsen remains a viable candidate currently being evaluated for the treatment of non-small cell lung cancer, as failure in one tumour type does not predict the outcome of trials in other indications,” said Fizazi.
Commenting on the study, Dr Cora Sternberg, Chief of the Department of Medical Oncology at
San Camillo Forlanini Hospital in Rome, Italy, said “A number of approaches have been investigated to overcome resistance in prostate cancer, including the use of novel taxanes and tubulin inhibitors, and the inhibition of cell survival pathways.”
“Given the results observed using a taxane as either first-line or second-line chemotherapy in castration resistant prostate cancer, the hypothesis was that combination with custirsen may decrease taxane resistance and enhance the survival benefit of taxane therapy,” Sternberg said.
“There was a strong rationale for adding custirsen to chemotherapy to overcome resistance but unfortunately the final results were negative. We likely need even more robust biological molecular stratification before launching phase III trials,” concluded Sternberg.
-END-
Notes to Editors
References
1 Abstract LBA9_PR “Final overall survival (OS) from the AFFINITY phase 3 trial of custirsen and cabazitaxel/prednisone in men with previously treated metastatic castration-resistant prostate cancer (mCRPC)” presented by Professor Karim Fizazi during the Presidential Symposium 3, on Monday 10 October 2016, 16:30 to 18:10 (CEST) in Room Copenhagen.
Disclaimer
This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO and ESMO cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct .
About the European Society for Medical Oncology
ESMO is the leading professional organisation for medical oncology. Comprising more than 13,000 oncology professionals from over 130 countries, we are the society of reference for oncology education and information. We are committed to supporting our members to develop and advance in a fast-evolving professional environment.
Founded in 1975, ESMO has European roots and a global reach: we welcome oncology professionals from around the world. We are a home for all oncology stakeholders, connecting professionals with diverse expertise and experience. Our educational and information resources support an integrated, multi-professional approach to cancer treatment. We seek to erase boundaries in cancer care as we pursue our mission across oncology, worldwide.
Abstract for LBA9_PR
Final overall survival (OS) from the AFFINITY phase 3 trial of custirsen and cabazitaxel/prednisone in men with previously treated metastatic castration-resistant prostate cancer (mCRPC)
K. Fizazi1, S.J. Hotte2, F. Saad3, B. Alekseev4, V.B. Matveev5, A. Flechon6, G. Gravis7, F. Joly8, K.N. Chi9, Z. Malik10, P. Stewart11, C. Jacobs12, T.M. Beer13
1Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France, 2Oncology, Juravinski Cancer Centre, Hamilton, ON, Canada, 3Urology, CRCUM-Universite de Montreal, Montreal, QC, Canada, 4Urology/Oncology, N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, 5Research, N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation, 6Medical Oncology, Centre Léon Bérard, Lyon, France, 7Medical Oncology, Institute Paoli Calmettes, Marseille, France, 8Medical Oncology, Centre Francois Baclesse, Caen, France, 9Medical Oncology, BC Cancer Agency, Vancouver General Hospital University of British Columbia, Vancouver, BC, Canada, 10Clinical Oncology, Clatterbridge Centre for Oncology NHS Foundation Trust, Wirral, UK, 11Clinical Development, OncoGenex Pharmaceuticals, Inc., Bothell, WA, USA, 12Clinical Research, OncoGenex Pharmaceuticals, Inc., Bothell, WA, USA, 13Knight Cancer Institute, Oregon Health Science University, Portland, OR, USA
Background: Treatment failure is the major barrier to extending survival in patients (pts) with advanced cancer. Clusterin (CLU) is a cytoprotective protein upregulated by chemotherapy in cancer cells. Custirsen (C) inhibits CLU production in vivo. This international phase 3 study (AFFINITY; Clinicaltrials.gov NCT01578655) evaluated C in combination with cabazitaxel/prednisone (Cbz/P) in pts with mCRPC. Co-primary objectives were to evaluate overall survival (OS) in pts receiving Cbz/P/C compared to pts receiving Cbz/P alone for all randomized (ITT) pts and a poor prognosis subgroup.
Methods: Pts with progressive disease after docetaxel, adequate organ function, and Karnofsky score ≥70% were randomized to Cbz/P/C or Cbz/P. Treatment consisted of 21-day cycles of 25 mg/m2 IV Cbz on day 1 with 10 mg oral P daily with or without 640 mg IV C on days 1, 8, and 15 (plus 3 prior loading doses) until disease progression, unacceptable toxicity, or 10 cycles. Overall type I error probability (alpha) was one-sided 0.025, allocated as 0.01 and 0.015 for ITT and poor prognosis final analyses, respectively, with 85% power. Hypothesized HR for ITT was 0.75 at 547 events. Hypothesized HR for poor prognosis was 0.69 assuming 299 events.
Results: 635 men were randomized: median age 68 yrs, Karnofsky score ≤80% in 50%. Demographics and exposure to Cbz/P were similar for both arms. In ITT population (n=635), median OS was 14.2 mo on Cbz/P/C and 13.4 mo on Cbz/P (two-sided p=0.529; HR 0.946, 95% CI 0.796 – 1.124). 62% of pts (n=392) met criteria for poor prognosis; OS was 11.1 mo on Cbz/P/C (n=195) and 10.9 mo on Cbz/P (n=197) in this subset (p=0.470; HR 0.918, 95% CI 0.727 – 1.158). 28.9% of pts on Cbz/P/C and 25% on Cbz/P discontinued due to progressive disease, and 21.9% and 18.9% due to adverse events (AEs). Arms were comparable in ≥Grade 3 AEs (75.9% vs 66.3%) and SAEs (49.2% vs 42.3%). The most frequently reported ≥Gr3 AEs were neutropenia, anemia, fatigue, asthenia, bone pain, and febrile neutropenia.
Conclusions: In this phase 3 study, no survival benefit was seen in pts receiving Cbz/P/C compared to Cbz/P in both ITT population and poor prognosis subset.
Clinical trial identification: NCT01578655
Legal entity responsible for the study: OncoGenex Pharmaceuticals, Inc.
Funding: OncoGenex Pharmaceuticals, Inc.
|
Disclosure: |
K. Fizazi: The author declares participation on advisory boards and honoraria from Orion, Bayer, Sanofi, Amgen, Genentech, Janssen, Astellas, and Takeda. |
Keywords: custirsen, mCRPC, cabazitaxel, second-line treatment
PRESS RELEASE
EMBARGOED until 10 October 2016, 8:15 hours (CEST)
Significant survival gains from neoadjuvant chemotherapy for high-risk soft tissue sarcoma
LUGANO-COPENHAGEN, 10 October 2016. Neoadjuvant chemotherapy with an anthracycline plus ifosfamide was associated with significant survival gains in patients with soft tissue sarcoma of the trunk or extremities who are at high-risk of recurrence, in an interim analysis that led to the early discontinuation of a trial presented today at the ESMO 2016 Congress in Copenhagen.
The study compared this chemotherapy with tailoring chemotherapy regimens to histology sub-types.
“The benefit of adjuvant chemotherapy in soft tissue sarcoma has been debated a lot over recent years because of contradictory study outcomes,” said principal investigator Dr Alessandro Gronchi, Chair of the Sarcoma Surgery at the National Cancer Institute, Milan, Italy.
In this multi-center study, researchers recruited 287 patients with high-risk soft tissue sarcoma of the trunk or extremities, from five histological subtypes which represent around 80% of all soft tissue sarcomas arising in an extremity or trunk wall.
Patients were randomized 1:1 either to three cycles of epirubicin (120 mg/sqm) plus ifosfamide (9 g/sqm), or three cycles of one of five histologically-tailored regimens: gemcitabine+docetaxel in undifferentiated pleomorphic sarcoma; trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma; etoposide+ifosfamide in malignant peripheral nerve sheath tumors; or gemcitabine+dacarbazine in leiomyosarcoma. All regimens were given pre-operatively.
After a median follow-up of 12.3 months, patients randomized to epirubicin plus ifosfamide showed significantly higher probability of relapse-free survival at 46 months compared to patients randomized to a histology-driven regiment (0.62 vs. 0.38, p=0.004), and of overall survival (0.89 vs. 0.64, p=0.033).
“In this 80% of patients who have a high-risk soft tissue sarcoma of the trunk or extremeties, it is worthwhile considering chemotherapy with epirubicin plus ifosfamide because their prognosis is improved by 20%,” Gronchi said. “We look forward to further follow-up of this trial to provide confirmation of this interim analysis as this is the first time that convincing evidence favoring the use of neoadjuvant chemotherapy is provided.”
While the study failed to show any benefit from histologically-tailored regimens, sub-group analysis did suggest that patients with high-grade myxoid liposarcoma who were treated with trabectedin had similar progression-free and overall survival to those treated with epirubicin plus ifosfamide.
“Trabectedin is far less toxic than conventional chemotherapy, so we will now expand this subgroup to assess if there is no difference between the two in terms of outcomes,” Gronchi said, pointing out that histology-driven therapy was not associated with any detrimental effects.
Commenting on the study, Professor Thomas Brodowicz, Program Director of the Bone and Soft Tissue-Sarcoma Unit at the Medical University Vienna, Austria, said, “Investigators wanted to show a one-third reduction in the relapse risk in favour of histology-driven therapy, so that means the trial did not meet the primary objective.”
“What we can conclude out of this is that the neoadjuvant anthracycline plus ifosfamide is better than the histology-driven regimens, but the question still is, is it better in comparison to no treatment?” Dr Brodowicz asked. “Furthermore, are three cycles of histology-driven therapy enough and is the neoadjuvant approach the right approach for all high risk patients?”
Brodowicz commented that there had been a lot of interest in histology-driven regimens for metastatic disease, and that while the results of this study in localised disease were negative, the conclusions could not be extended to metastatic disease.
“As it was not apparent that the histology-driven therapy could have been associated with any detrimental effect per se, the main interest of these findings (if confirmed by a longer follow-up) is proof that using a neo-adjuvant therapy in patients affected by high risk soft tissue sarcoma of the extremities or trunk wall, is associated with a clear-cut overall and relapse-free survival advantage, as compared with any other available strategy, including no treatment,“ Gronchi concluded.
-END-
Notes to Editors
References
1Abstract LBA6_PR Full-dose neoadjuvant anthracycline+ifosfamide chemotherapy is associated with a relapse-free survival and overall surviva benefit in localized high-risk adult soft tissue sarcom of the extremities and trunk wall: interim analysis of a prospective randomized trial, ‘will be presented by Dr. Alessandro Gronchi during Presidential Symposium 3 on Monday 10.10.2016 at 16:30(CEST).
Disclaimer
This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO and ESMO cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct .
About the European Society for Medical Oncology
ESMO is the leading professional organisation for medical oncology. Comprising more than 13,000 oncology professionals from over 130 countries, we are the society of reference for oncology education and information. We are committed to supporting our members to develop and advance in a fast-evolving professional environment.
Founded in 1975, ESMO has European roots and a global reach: we welcome oncology professionals from around the world. We are a home for all oncology stakeholders, connecting professionals with diverse expertise and experience. Our educational and information resources support an integrated, multi-professional approach to cancer treatment. We seek to erase boundaries in cancer care as we pursue our mission across oncology, worldwide.
LBA6_PR Full-dose neoadjuvant anthracycline + ifosfamide chemotherapy is associated with a relapse free survival (RFS) and overall survival (OS) benefit in localized high-risk adult soft tissue sarcomas (STS) of the extremities and trunk wall: Interim analysis of a prospective randomized trial
A. Gronchi1, S. Ferrari2, V. Quagliuolo3, J. Martin Broto4, A. Lopez-Pousa5, G. Grignani6, V. Ferraresi7, J-Y. Blay8, P. Rutkowski9, F.D. Merlo10, E. Marchesi11, P. Ledesma12, A.P. Dei Tos13, S. Bague Rosell14, J-M. Coindre15, C. Morosi16, S. Stacchiotti17, P. Picci18, P. Bruzzi19, P.G. Casali20
1Surgery, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 2Medical Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy, 3Surgery, Istituto Clinico Humanitas, Rozzano, Italy, 4Medical Oncology, Hospital Universitario Virgen del Rocio, Seville, Spain, 5Research, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 6Medical Oncology, Istituto di Candiolo-IRCCS-Fondazione Piemontese per la Ricerca sul Cancro-Onlus, Candiolo, Italy, 7Istituti Fisioterapici Ospedalieri, U.O. Oncologia Medica 1, Regina Elena National Cancer Institute, Rome, Italy, 8Medical Oncology, Centre Léon Bérard, Lyon, France, 9Soft Tissue/Bone Sarcoma and Melanoma, MSC Memorial Cancer Centre and Institute Maria Sklodowska-Curie, Warsaw, Poland, 10Biostatistics, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, 11Laboratorio di Oncologia Sperimentale, Istituto Ortopedico Rizzoli, Bologna, Italy, 12None, Sofpromed Investigacion Clinica, Palma de Mallorca, Spain, 13Department of Pathology, Ospedale Regionale Ca' Foncello, Treviso, Italy, 14Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain, 15Pathology, Institute Bergonié, Bordeaux, France, 16Radiology, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 17Department of Cancer Medicine, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy, 18Muscoloskeletal Oncology, Istituto Ortopedico Rizzoli, Bologna, Italy, 19Epidemiology, IRCCS AOU San Martino - IST-Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy, 20Adult Sarcoma Medical Oncology Unit, Istituto Nazionale Tumori, Milan, Italy
Background: An Italian Sarcoma Group randomized trial versus no chemotherapy was indicative of an OS benefit with 5 cycles of adjuvant full-dose epirubicin+ifosfamide in localized high-risk STS (JCO 2001;19:1238). A subsequent randomized trial showed no difference between 3 vs 5 cycles of the same neo-adjuvant regimen (JCO 2012;30:850).
Methods: This multicenter European randomized trial compared epirubicin 120 mg/sqm + ifosfamide 9 g/sqm versus an histology-driven regimen: gemcitabine+docetaxel in undifferentiated pleomorphic sarcoma (UPS); trabectedin in high-grade myxoid liposarcoma; high-dose prolonged-infusion ifosfamide in synovial sarcoma (SS); etoposide + ifosfamide in malignant peripheral nerve sheath tumors (MPNST); gemcitabine+dacarbazine in leiomyosarcoma (LMS). Patients had localized high-risk STS (grade = 3; size >5 cm; deep site) of extremities or trunk wall. Primary end-point was RFS. With an expected accrual of 350 randomized patients, the trial was powered to show a 1/3 reduction in the hazard risk of relapse in favor of histology-driven therapy (with 80% power at the 5% [1-sided] significance level). Yearly futility analyses were conducted.
Results: From May 2011 to May 2016, 287 patients were randomized (97 = UPS; 65 = myxoid liposarcoma; 70 = SS; 27 = MPNST; 28 = LMS). At the third futility analysis, with a median follow-up of 12.3 months, the RFS probability at 46 months was 0.62 and 0.38 (log rank p=0.004; figure 1) and OS probability at 46 months was 0.89 and 0.64 (log rank p=0.033; figure 2), in the standard and in the histology-driven arm, respectively. In agreement with the Independent Reviewing Committee, the study was closed in advance. The analysis is being updated and subgroup analyses will be reported.
Conclusions: This trial provides randomized evidence that a neo-adjuvant chemotherapy with 3 full-dose courses of an anthracycline plus ifosfamide full-dose regimen can be associated with an absolute benefit averaging 20% for both RFS and OS over a different chemotherapy regimen, in a population of STS patients selected by a risk of relapse averaging 60-70%.
Clinical trial identification: NCT01710176; EUDRACT 2010 – 023484 – 17
Legal entity responsible for the study: Italian Sarcoma Group
Funding: Eurosarc FP7 278472
Disclosure: All authors have declared no conflicts of interest.
Keywords: extremities, sarcoma, Adjuvant chemotherapy, survival
PRESS RELEASE
EMBARGOED until 10 October 2016, 8:15:00 hours (CEST)
MEK inhibition in KRAS-mutant NSCLC did not improve survival
LUGANO-COPENHAGEN, 10 October, 2016 – MEK inhibitor selumetinib in combination with docetaxel does not improve progression free or overall survival in individuals with KRAS-mutant non-small-cell lung cancer (NSCLC), according to data presented at the ESMO 2016 Congress in Copenhagen1.
“KRAS-mutant lung cancer is the largest genomically defined subset of lung cancer where we do not have effective targeted therapies,” said principal investigator Dr Pasi Jänne, from the Dana-Farber Cancer Institute in Boston, US.
Selumetinib inhibits an effector protein immediately downstream from KRAS, which was thought to turn off KRAS-mediated signalling in KRAS-mutant cancers.
An earlier phase II trial in KRAS-mutant NSCLC had shown significant improvements in progression-free survival and objective response rate in patients treated with selumetinib plus docetaxel compared to docetaxel alone.
In the phase III, double-blind, randomized SELECT-1 trial, 510 patients with KRAS-mutant non-small-cell lung cancer were randomized either to oral selumetinib (75mg, twice daily) plus intravenous docetaxel (75mg/m2 on day 1 of a 21 day-cycle), or docetaxel plus placebo.
At data cut-off, median progression-free survival was not significantly different between the selumetinib arm and placebo arm (3.9 months vs. 2.8 months, HR 0.93, p=0.44), nor was there a significant difference in median overall survival (8.7 months vs. 7.9 months, HR 1.05, p=0.64).
There was a trend towards a higher objective response rate in the selumetinib group compared to the placebo group (20.1% vs. 13.7%, OR 1.61, p=0.051).
Serious adverse events occurred more frequently in patients treated with the selumetinib plus docetaxel combination compared to placebo (49% vs. 32%), as did adverse events leading to hospitalisation (46% vs. 30%).
“The results of the phase III trial demonstrate that the addition of selumetinib to docetaxel, in patients with advanced KRAS mutant lung cancer, does not provide clinical benefit in terms of improving progression free or overall survival,” Jänne said.
“Hence it is not a treatment approach that should be adapted moving forward, and there remains a desperate need and an opportunity to develop new treatments for this subset of NSCLC patients.”
Commenting on the study, Dr Alex Adjei, director of the Early Cancer Therapeutics Program and Global Oncology at the Mayo Clinic in Rochester, US, said “Dr Jänne and colleagues should be congratulated for performing a well-designed genotype-driven trial, however the preclinical rationale for studying this combination specifically in KRAS mutant NSCLC was weak, at best.”
“Selumetinib and other MEK inhibitors are not effective in KRAS mutant NSCLC cell lines and, while there are preclinical data that demonstrate cytotoxic synergy between selumetinib and other MEK inhibitors combined with docetaxel in a number of tumor types, including NSCLC, such synergy is independent of KRAS status,” Adjei said.
“A randomized phase II trial of the combination of another MEK inhibitor, trametinib and docetaxel failed to show any difference in efficacy between KRAS mutant and wild-type NSCLC. Furthermore, the phase II study on which this phase III trial design was based had a very small sample size and historically, such small randomized phase II studies have led to negative phase III trials,” concluded Adjei.
-END-
Notes to Editors
References
1 LBA47_PR “Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: Results from the phase III SELECT-1 trial” will be presented by Prof Pasi Jänne during the Proffered Paper session, NSCLC, metastatic 2 on Monday, 10 October 2016, 09:15 to 10:15 CEST in Room Vienna.
Disclaimer
This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO and ESMO cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct .
About the European Society for Medical Oncology
ESMO is the leading professional organisation for medical oncology. Comprising more than 13,000 oncology professionals from over 130 countries, we are the society of reference for oncology education and information. We are committed to supporting our members to develop and advance in a fast-evolving professional environment.
Founded in 1975, ESMO has European roots and a global reach: we welcome oncology professionals from around the world. We are a home for all oncology stakeholders, connecting professionals with diverse expertise and experience. Our educational and information resources support an integrated, multi-professional approach to cancer treatment. We seek to erase boundaries in cancer care as we pursue our mission across oncology, worldwide.
Abstract for LBA47_PR Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: Results from the phase III SELECT-1 trial
P.A. Jänne1, M. van den Heuvel2, F. Barlesi3, M. Cobo4, J. Mazieres5, L. Crinò6, S. Orlov7, F. Blackhall8, J. Wolf9, P. Garrido10, A. Poltoratskiy11, G. Mariani12, D. Ghiorghiu12, E. Kilgour13, P. Smith14, A. Kohlmann15, D. Carlile16, D. Lawrence17, K. Bowen18, J.F. Vansteenkiste19
1Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA, 2Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, Netherlands, 3Multidisciplinary Oncology and Therapeutic Innovations Department, Aix Marseille University APHM, Marseille, France, 4Department of Medical Oncology, Hospital Clinico Carlos Haya, Málaga, Spain, 5Pulmonology Department, Toulouse University Hospital, Toulouse, France, 6Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy, 7Department of Medicine, Pavlov Medical University, St. Petersburg, Russian Federation, 8Medical Oncology, Manchester University and The Christie Hospital NHS Foundation Trust, Manchester, UK, 9Department of Internal Medicine, Center for Integrated Oncology, University Hospital of Cologne, Cologne, Germany, 10Medical Oncology Department, University Hospital Ramon y Cajal, Madrid, Spain, 11Department for Clinical and Pre-Clinical Trials, Petrov Research Institute of Oncology, St. Petersburg, Russian Federation, 12Global Medicines Development, Oncology, AstraZeneca, Cambridge, UK, 13Oncology, AstraZeneca, Macclesfield, UK, 14Cancer Biosciences, AstraZeneca, Cambridge, UK,15Personalised Healthcare and Biomarkers, IMED, AstraZeneca, Cambridge, UK, 16Innovative Medicines, AstraZeneca, Cambridge, UK, 17Biostatistics and Information Sciences, AstraZeneca, Cambridge, UK, 18Global Medicines Development, AstraZeneca, Gaithersburg, MD, USA, 19Respiratory Oncology Unit, Department of Respiraory Diseases, University Hospital KU Leuven, Leuven, Belgium
Background: KRAS-mutant (KRASm) NSCLC is the largest molecular genomic NSCLC subset. Selumetinib (SEL; AZD6244, ARRY-142886) is an oral, potent and selective MEK1/2 inhibitor with a short half-life. In a Phase II KRASm advanced NSCLC trial (n=87), 2L SEL + docetaxel (DOC) significantly improved PFS (median 5.3 vs 2.1 mo) and ORR (37 vs 0%), and numerically improved OS (median 9.4 vs 5.2 mo; primary endpoint) compared with DOC. SELECT-1 (NCT01933932), a Phase III, double-blind, randomised trial aimed to confirm the clinical benefit of SEL + DOC for pts with locally advanced or metastatic KRASm NSCLC.
Methods: Enrolment completed in January 2016 with 3323 pts screened at 202 sites in 25 countries. 510 pts with a centrally confirmed KRAS mutation (cobas® KRAS Mutation Test, Roche Molecular Systems) were randomised 1:1 to SEL 75 mg BID, PO + DOC 75 mg/m2 IV on day 1 of every 21-day cycle (n=254), or placebo (PBO) + DOC (n=256); pts also received prophylactic G-CSF. Primary objective was PFS by investigator assessment (RECIST 1.1). Secondary objectives included OS, ORR (RECIST 1.1) and safety and tolerability. The trial was powered to characterise differences in both PFS and OS.
Results: At data cut-off, 447 pts (88%) had progressed; 346 pts (68%) had died. Median PFS was 3.9 mo with SEL + DOC and 2.8 mo with PBO + DOC; HR for PFS was 0.93 (95% CI 0.77, 1.12; 2-sided p=0.44). Median OS was 8.7 mo with SEL + DOC and 7.9 mo with PBO + DOC (HR 1.05, 95% CI: 0.85, 1.30; 2-sided p=0.64). ORR was 20.1% with SEL + DOC and 13.7% with PBO + DOC (odds ratio: 1.61; 95% CI: 1.00, 2.62; 2-sided p=0.051). AEs (all causality) were reported by 99% and 95% pts in the SEL + DOC and PBO + DOC groups, respectively; ≥G3 AEs were more frequent in the SEL + DOC group (67 vs 45% pts). SAEs (49 vs 32%) and AEs leading to hospitalisation (46 vs 30%) were also more frequent in the SEL + DOC group than the PBO + DOC group. Mean (SD) actual dose intensity relative to intended dose intensity of DOC over 6 cycles was similar between groups: 86.7% (15.90) with SEL+DOC and 90.3% (15.01) with PBO + DOC.
Conclusions: SELECT-1 was the first prospective Phase III trial in KRASm NSCLC. SEL + DOC did not significantly improve PFS, OS or ORR vs PBO + DOC. The safety profile was consistent with historical data.
Clinical trial identification: NCT01933932 August 29, 2013
Legal entity responsible for the study: AstraZeneca
Funding: AstraZeneca
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Disclosure: |
P.A. Jänne: Grants and fees from AstraZeneca. Fees from Roche and Chugai. Grant from Astellas. Fees from Merrimack, Ariad and Boehringer Ingelheim. Stock ownership in Gatekeeper Pharmaceuticals. |
Keywords: Phase III, selumetinib, non-small cell lung cancer (NSCLC), metastatic disease
PRESS RELEASE
EMBARGOED until 10 October 2016, 8:15 hours (CEST)
Longer disease-free survival in phase III trial of sunitinib as adjuvant treatment for kidney cancer
LUGANO-COPENHAGEN, 10 October, 2016 – A phase III trial of sunitinib has met its primary endpoint of disease-free survival for adjuvant treatment of high-risk renal cell carcinoma after nephrectomy, researchers report at the ESMO 2016 Congress in Copenhagen.1
“The recurrence rate of kidney cancer after nephrectomy, where part or all of a kidney is removed, is up to 50% in some subgroups of patients,” said lead author Professor Alain Ravaud, head of medical oncology, University Hospital of Bordeaux, France. “This distinguishes it from other tumours such as breast cancer where in general there is a low chance of the cancer coming back.”
“We have good drugs to control disease in patients with metastatic kidney cancer but there are no standard adjuvant treatments,” he added.
This phase III trial tested the ability of adjuvant treatment with sunitinib, a receptor tyrosine kinase inhibitor, to improve disease-free survival in a type of kidney cancer called clear cell renal carcinoma. The study included 615 post-nephrectomy patients at high risk of their cancer recurring. Patients were randomised to placebo or sunitinib for one year. Sunitinib was administered at 50 mg per day in a four weeks on / two weeks off schedule, and one dose reduction to 37.5 mg per day was allowed. Patients with suspected metastases in an independent central review were excluded from the study.
The primary endpoint was disease-free survival. It was assessed by an independent central review committee of radiologists who examined CT scans and ruled whether an event had occurred or not. Events could be recurrence in the remaining kidney or in local lymph nodes, metastases, or a second malignancy. In cases of disagreement between the independent central review and the study investigators a decision was reached by obtaining a biopsy or surgery sample of the tumour – if it contained cancer this was ruled as a recurrence.
The primary endpoint of the trial was met with a significantly longer disease-free survival of 6.8 years with sunitinib compared to 5.6 years with placebo (hazard ratio 0.761, p=0.03). Adverse events of grade 3 or higher were more frequent with sunitinib (62.1%) compared to placebo (21.1%). There were no deaths due to treatment toxicity.
Ravaud said: “Sunitinib is a potential new option for adjuvant therapy in renal cell carcinoma, given the increase in disease-free survival and the manageable safety profile. The results of this trial could change practice because there is currently no standard treatment in this setting.”
He concluded: “We hope sunitinib will be approved by regulators for adjuvant therapy in renal cell carcinoma. Clinicians should then use the drug according to the trial. In other words, in patients with predominant clear cell renal cell carcinoma without metastases and at high risk of recurrence, at a starting dose of 50 mg and a minimum dose of 37.5 mg per day and with the same dosing schedule. This is particularly important since sunitinib was not beneficial in another trial using a different methodology.”
Commenting on the results, Professor Thomas Powles, professor of urology cancer, Barts Cancer Institute, London, UK, said: “This positive trial should be taken in the context of a previous larger adjuvant study (ASSURE) with a very similar design. ASSURE showed no difference in disease-free survival or overall survival. This generates a lot of uncertainty. I suspect a meta-analysis of progression-free survival would be negative and at this point it would be premature to change practice. Both studies show that adjuvant sunitinib is assocated with toxicity.”
He continued: “Disease-free survival is a useful surrogate endpoint, but the results from different studies have been contradictory. It does not necessarily translate to overall survival, which is the gold standard. Preliminary results in this setting do not point towards a survival benefit. There are a number of other trials ongoing in this area and I would like to see one of these being positive to tip the balance towards benefit.”
Powles concluded: “Without a consistently positive disease-free survival signal it would be premature for me to recommend sunitinib as adjuvant therapy for my patients, particularly when one considers the toxicity. A positive survival signal, or meta-analysis for disease-free survival, would be needed. Other studies in this area are awaited.”
-END-
Notes to Editors
References
1 Abstract LBA11_PR ‘Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC)‘ will be presented by Professor Alain Ravaud during the Presidential Symposium 3 on Monday, 10 October 2016, 16:30 to 18:10 (CEST) in Room Copenhagen.
Disclaimer
This press release contains information provided by the authors of the highlighted abstracts and reflects the content of those abstracts. It does not necessarily reflect the views or opinions of ESMO and ESMO cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct .
About the European Society for Medical Oncology
ESMO is the leading professional organisation for medical oncology. Comprising more than 13,000 oncology professionals from over 130 countries, we are the society of reference for oncology education and information. We are committed to supporting our members to develop and advance in a fast-evolving professional environment.
Founded in 1975, ESMO has European roots and a global reach: we welcome oncology professionals from around the world. We are a home for all oncology stakeholders, connecting professionals with diverse expertise and experience. Our educational and information resources support an integrated, multi-professional approach to cancer treatment. We seek to erase boundaries in cancer care as we pursue our mission across oncology, worldwide.
Abstract for LBA11_PR
Phase III trial of sunitinib (SU) vs placebo (PBO) as adjuvant treatment for high-risk renal cell carcinoma (RCC) after nephrectomy (S-TRAC)
Ravaud1, R.J. Motzer2, H.S. Pandha3, M. Staehler4, D. George5, A.J. Pantuck6, A. Patel7, Y-H. Chang8, B. Escudier9, F. Donskov10, A. Magheli11, G. Carteni12, B. Laguerre13, P. Tomczak14, J. Breza15, P. Gerletti16, X. Lin17, M. Lechuga16, J-F. Martini17, J-J. Patard18
1Service d'Oncologie & Radiotherapie, CHU Bordeaux Hopital St. André, Bordeaux, France, 2Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3Department of Microbial Sciences, University of Surrey, Surrey, UK, 4Department of Urology, University Hospital of Munich, Munich, Germany, 5Medical Oncology, Duke University, Durham, NC, USA, 6Department of Urology, Ronald Reagan UCLA Medical Center, Los Angeles, CA, USA,7Oncology, Spire Roding Hospital, London, UK, 8Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, 9Medical Oncology, Institut Gustave Roussy, Villejuif, France, 10Department of Oncology, Aarhus University, Aarhus, Denmark, 11Department of Urology, Charité Universitaetsmedizin Berlin, Berlin, Germany, 12Division of Oncology and Division of Urology, 11Azienda Ospedaliera di Rilievo Nazionale A. Cardarelli, Naples, Italy, 13Medical Oncology, Centre Eugene - Marquis, Rennes, France, 14Oncology, Klinika Onkologii Oddzial Chemioterapii, Poznań, Poland, 15Department of Urology, Slovak Medical University in Bratislava, Bratislava, Slovak Republic, 16Oncology, Pfizer S.r.L, Milan, Italy, 17Oncology, Pfizer Inc, San Diego, CA, USA, 18Department of Urology, Bicêtre Hospital, Paris-Saclay University, Le Kremlin Bicetre, France
Background: This randomized, double-blind phase 3 trial examined the efficacy and safety of SU vs PBO in post-nephrectomy patients (pts) with locoregional RCC at high risk (per modified UISS criteria) of tumor recurrence.
Methods: Treatment-naïve pts (n=615) with locoregional RCC (≥T3 and/or N1–2) received 50 mg/d SU or PBO in a 4-wks-on/2-wks-off schedule for 1 yr until disease recurrence, occurrence of secondary malignancy, significant toxicity, or consent withdrawal. One dose reduction to 37.5 mg/d was allowed. Baseline imaging was centrally reviewed to exclude pts with suspicion of metastases. Primary endpoint was disease-free survival (DFS) assessed by central review. Secondary endpoints included investigator-assessed DFS, overall survival (OS), safety, and pt-reported outcomes.
Results: Baseline characteristics were balanced between the SU (n=309) and PBO (n=306) arms. Median (m) number of cycles and relative dose intensity (SU) were 9 and 88.4%, respectively. Fewer DFS events were seen with SU (113; 36.6%) vs PBO (144; 47.1%). The trial met its primary endpoint: DFS by central review was significantly longer for SU vs PBO (HR, 0.761; P=0.030), and these results were supported by secondary DFS analyses in all randomized pts and a higher-risk subgroup (Table 1). OS data were immature at data cutoff (mOS not reached in either arm). Grade ≥3 adverse events (AEs) were more frequent with SU (62.1%) vs PBO (21.1%), but serious AE incidence was similar (21.9% vs 17.1%); no death occurred due to treatment toxicity.
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Table: DFS analyses |
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|
SU |
PBO |
HR (95% CI) SU vs. PBO |
P |
|
|
mDFS (95% CI) (yr) |
|
|
|
|
Central Review |
|
|
|
|
|
All randomized |
6.8 (5.8–NR) |
5.6 (3.8–6.6) |
0.761 (0.594–0.975) |
0.030 |
|
Higher-risk* |
6.2 (4.9–NR) |
4.0 (2.6–6.0) |
0.737 (0.548-0.993) |
0.044 |
|
Investigator review |
|
|
|
|
|
All randomized |
6.5 (4.7–7.0) |
4.5 (3.8–5.9) |
0.811 (0.643–1.023) |
0.077 |
|
Higher-risk* |
5.9 (4.4–7.0) |
3.9 (2.8–5.6) |
0.763 (0.577–1.009) |
0.056 |
* T3, N0 or NX, M0, Fuhrman’s grade ≥2, ECOG PS ≥1 and T4 and/or N1–2
Conclusions: SU prolonged DFS in pts with locoregional RCC at high risk for recurrence. Given the increase in DFS and the manageable safety profile, SU represents a potential new treatment option as adjuvant therapy in RCC.
Clinical trial identification: NCT00375674 (Release date: July 2016)
Legal entity responsible for the study: Pfizer, Inc.
Funding: Pfizer, Inc.
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Disclosure: |
A. Ravaud: Member of advisory boards in RCC for Pfizer, Novartis, GSK, Roche, and BMS, and received institutional support grants from Pfizer and Novartis, and housing and transportation for meetings and speeches by Pfizer, Novartis, and BMS. |