PRESS RELEASE
EMBARGOED until 7 October 2016, 8:15 hours (CEST)
Neoadjuvant immunotherapy prior to surgery is safe and feasible in early lung cancer
LUGANO-COPENHAGEN, 7 October, 2016 – Neoadjuvant immunotherapy with the PD-1 inhibitor nivolumab is safe and feasible prior to surgery for early lung cancer, researchers reported at the ESMO 2016 Congress in Copenhagen.1
“Until now nivolumab and the other anti-PD-1 and anti-PD-L1 drug studies have only been reported in metastatic or advanced lung cancer,” said lead author Dr Patrick Forde, Assistant Professor of Oncology, Sidney Kimmel Comprehensive Cancer Centre, Johns Hopkins, Baltimore, US. “This was the first study of neoadjuvant PD-1 blockade in early stage lung cancer.”
The primary objective of the study was to see whether it was safe and feasible to administer neoadjuvant nivolumab to patients with early stage non-small-cell lung cancer (NSCLC) prior to resection of the tumour. Treatment was considered feasible if it did not delay surgery.
Exploratory aims included extensive correlative analyses of the pretreatment biopsy and post-treatment resected tumour including PD-L1 staining, multiplex immunohistochemistry and T cell receptor sequencing. An additional exploratory analysis looked at the degree of pathological regression. This was analysed by a lung cancer pathologist using a method previously reported for use in measuring response to neoadjuvant chemotherapy in NSCLC. Major pathological regression (90% or more) was defined as a resected specimen with less than 10% remaining viable tumour cells.
The study included 20 patients who had a tumour biopsy taken. They then received two doses of nivolumab at four and two weeks prior to surgical resection of the tumour.
The results in the first 16 patients were presented today. The investigators found that there were no significant safety concerns and no delays to surgery with nivolumab.
Six of 15 patients (40%) had major pathological regression of their tumour following nivolumab. All of those tumours had dense infiltration of immune cells and either a complete pathologic response or isolated remaining tumour cells. An additional five patients had some regression of their tumour noted and evidence of immune infiltration. Multiplex IHC demonstrated infiltration of cytotoxic T cells into the tumours and also detection of new T cell clones in the tumour that did not appear to be present in the pre-treatment biopsy.
Forde said: “We found that neoadjuvant administration of nivolumab is safe and feasible in stage I-IIIA NSCLC and also a preliminary signal that anti-PD-1 immunotherapy may have activity in early stage lung cancer. Following these initial results we are expanding the study. One cohort will receive a third dose of nivolumab preoperatively and the other will receive the combination of nivolumab and ipilimumab preoperatively. This expanded study will continue to be conducted in collaboration with investigators at Johns Hopkins University and Memorial Sloan-Kettering Cancer Centre. Others, such as the Lung Cancer Mutation Consortium in the United States, are also conducting larger studies of neoadjuvant immune checkpoint inhibition in NSCLC.”
Commenting on the study, Professor Pieter Postmus, chair of Thoracic Oncology at the University of Liverpool, UK, said: “There is a potential for bias when comparing a small biopsy, which might not represent the whole tumour, with the resected tumour. This is not a validated way to measure response to a treatment. It describes a biological effect but whether that has any clinical impact on survival is unproven.”
“Although we do not know for the time being if a major pathological response is correlated with improved survival, this method could first be validated in a cohort of patients with advanced disease by comparing the percentages of viable tumour cells in tumour biopsies taken before and four to eight weeks after immunotherapy,” continued Postmus. “If in this way regression - as defined in the preoperative study - correlates with survival in patients with advanced cancer, it is likely to hold true in less advanced or resectable patients. Long-term survival data will be the ultimate test for these neoadjuvant immunotherapy strategies."
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Notes to Editors
References
1 Abstract LBA41_PR - ‘Neoadjuvant anti-PD1, nivolumab, in early resectable non-small-cell lung cancer‘ will be presented by Dr Patrick Forde during the Proffered Paper Session, Non-metastatic NSCLC and other thoracic malignancies on Friday, 7 October, 14:00 to 15:30 (CEST) in Room Madrid.
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 LBA41_PR
Neoadjuvant anti-PD1, nivolumab, in early stage resectable non-small-cell lung cancer
P.M. Forde1, K.N. Smith1, J.E. Chaft2, M. Hellmann2, T. Merghoub2, J.D. Wolchok2, S.C. Yang3, R.J. Battafarano3, E. Gabrielson4, C.S. Georgiades5, F. Verde5, G.L. Rosner6, J. Naidoo1, T.R. Cottrell4, J.M. Taube4, V. Anagnostou1, V.E. Velculescu1, S.L. Topalian3, D.M. Pardoll1, J.R. Brahmer1
1Department of Oncology, Johns Hopkins University, Baltimore, MD, USA, 2Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 3Department of Surgery, Johns Hopkins University, Baltimore, MD, USA, 4Department of Pathology, Johns Hopkins University, Baltimore, MD, USA, 5Department of Radiology, Johns Hopkins University, Baltimore, MD, USA, 6Division of Biostatistics, Johns Hopkins University, Baltimore, MD, USA
Background: Nivolumab is a PD-1 inhibitor that has demonstrated durable responses and improved survival in patients (pts) with previously treated, metastatic non-small-cell lung cancer (NSCLC). This is the first report of neoadjuvant PD-1 blockade in pts with early stage NSCLC.
Methods: Pts with untreated, resectable, stage I-IIIA NSCLC underwent pretreatment tumor biopsy and then received two doses of nivolumab 3mg/kg administered at 4 and 2 weeks prior to surgical resection. Postoperatively, standard adjuvant chemotherapy was administered at investigator discretion. The primary endpoints were safety and feasibility of preoperative nivolumab administration. Exploratory endpoints included the degree of pathologic regression, as well as molecular and immunophenotypic changes in tumor and peripheral blood, including T cell repertoire analysis by TCR CDR3 deep sequencing, function, gene expression profiling, and tumor antigen recognition. An initial 6-patient safety run-in cohort was followed by an expansion cohort, with a planned accrual of 16 resected pts.
Results: As of 09/19/2016, 18 pts were enrolled and 16 completed surgical resection (two patients were not ultimately resected). No delays to surgery or surgical complications related to nivolumab occurred. Twelve of 15 resected patients (80%) had pathologic evidence of tumor regression, and 6 (40%) achieved major pathologic responses (MPR; <10% residual viable tumor), at the time of abstract submission final pathology was pending from the 16th resected pt. Of the 6 MPR pts, 3 had no radiographic evidence of response. Surgical specimens in all cases were characterized by substantial T cell infiltration. Among 6 MPRs, 4 tumors have been tested with PD-L1 IHC (28-8 assay) and 3 were positive. Both unique and shared T cell clones were expanded in both tumor and peripheral blood, including new infiltration of T cell clones found only in the post-treatment tumor specimen.
Conclusions: Neoadjuvant nivolumab was feasible and safe. Most pts have pathologic evidence of anti-tumor response, including MPR in 6 of 15 pts. Neoadjuvant anti-PD1 immunotherapy may have substantial anti-tumor activity in early stage NSCLC.
Clinical trial identification: identifier: NCT02259621
Legal entity responsible for the study: Johns Hopkins University School of Medicine
Funding: Stand Up to Cancer, AACR, CRI and LUNGevity BMS pharmaceuticals supplied nivolumab and funding for PD-L1 testing
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Disclosure: |
P.M. Forde: Research grants to my institution for clinical trials of which I am PI from BMS, Novartis, AstraZeneca, Kyowa, outside of this submitted work. Consultant/Advisory Board (uncompensated) - AstraZeneca, Celgene. |
Keywords: early lung cancer, nivolumab, Neoadjuvant, PD1
PRESS RELEASE
EMBARGOED until 7 October 2016, 08:15 hours (CEST)
High response rate in phase I/II paediatric brain cancer trial sets stage for combination therapy with higher response and lower toxicity
LUGANO-COPENHAGEN, 7 October, 2016 – A high response rate with a single drug in a phase I/II trial of paediatric brain tumour has set the stage for combination therapy with higher response and lower toxicity, researchers reported at the ESMO 2016 Congress in Copenhagen.1
“The likelihood of curing a child with a low-grade glioma is very high,” said lead author Dr Mark Kieran, Director, Paediatric Medical Neuro-Oncology, Dana-Farber Boston Children’s, Boston, US. “In fact many children don’t suffer lifelong from the tumour but rather from the cognitive damage and secondary malignancies caused by radiation therapy.”
He continued: “The development of drugs that target the specific causative mutation of the tumour and avoid long-term toxicities may revolutionise the treatment of paediatric brain cancer.”
Up to 10% of paediatric low-grade gliomas have the BRAF V600 mutation. Today researchers reported the phase I and phase II trial results of dabrafenib, a selective inhibitor of mutant protein. The study included 32 patients aged one to 16 years with BRAF V600-mutant low-grade glioma, of whom 15 participated in the phase I trial and 17 were in the phase II trial.
The phase I trial, which focused on determining the recommended phase II dose, did not find any significant dose-limiting toxicities. The recommended dose was therefore based on the pharmacokinetic activity of the drug and was set at 4.5 mg/kg/day for patients aged 12 years and older and 5.25 mg/kg/day for patients under the age of 12.
The phase II trial assessed toxicities with dabrafenib, and whether it could stop tumours from growing or cause them to shrink. “Paediatric low-grade gliomas are a little bit unique in that patients can survive their entire life with a tumour that stops growing, unlike other cancers which need to be completely removed,” said Kieran.
The objective response rate was 72%, with 23 out of 32 patients responding to the drug. In two patients the tumour disappeared and in 11 patients the tumour shrunk by more than half – of these 13 patients eight are still on the therapy. Thirteen patients had stable disease of at least six months’ duration, and 11 of them are still on the therapy.
Regarding adverse events, there were no cases of squamous cell carcinoma, which has been observed in previous trials of dabrafenib in adults with BRAF V600E positive tumours, most of whom have melanoma. One patient had an allergic reaction to the drug. Minor side effects were similar to those seen in adults, including transient fever, upset stomach, fatigue and skin rash.
Studies in adults with BRAF V600E mutations have shown that combining a BRAF inhibitor with a MEK inhibitor reduces toxicity and produces more activity for a longer period of time. The encouraging results with dabrafenib in children have provided the impetus for phase I and II trials with a MEK inhibitor to determine the dose and toxicities, and a trial combining the two drugs is now underway.
Kieran said: “We want to make the response rate with dabrafenib even higher by combining it with a MEK inhibitor since that works in adults. Adding two drugs together normally produces twice as much toxicity. But much of the toxicity from the BRAF drug is inhibited by the MEK drug, so the combination is less toxic than either drug alone, which is unusual.”
Kieran concluded: “The finding that dabrafenib can shrink tumours or stop them growing is exciting and has led to trials with a MEK inhibitor and now the combination of drugs. This combined therapy may completely change the way we treat low-grade gliomas in children with this mutation. The caveat is that these targeted personalised drugs are relatively new so we need to make sure that they don’t have any long-term developmental toxicities in children.”
Commenting on the findings, Professor Michael Weller, chairman, Department of Neurology, University Hospital Zurich, Switzerland, said: “The encouraging thing about this study is that this targeted treatment seems to work. At the moment in neuro-oncology we know almost everything about the molecular make-up of gliomas in adults and in children but we have not really been able to translate all this knowledge into an effective therapeutic agent.”
“These findings will have implications for clinical practice because many parents are willing to travel all around the world to get access to a promising treatment,” he continued. “We have almost no randomised data for brain tumours in children, at least for gliomas, because the tumours are too rare and the trials are difficult for ethical reasons.”
Weller concluded: “We need longer follow up to find out how long the responses last and whether we get long-term survival. And then of course in children we want to know if there is any long-term toxicity.”
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Notes to Editors
References
1 Abstract LBA19_PR “The first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas” will be presented by Dr Mark Kieran during the Proffered Paper Session, CNS tumours, on Friday, 7 October 2016, 16:00 to 17:30 (CEST) in Room Bern.
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 LBA19_PR
The first study of dabrafenib in pediatric patients with BRAF V600–mutant relapsed or refractory low-grade gliomas
M.W. Kieran1, E. Bouffet2, U. Tabori3, A. Broniscer4, K. Cohen5, J. Hansford6, B. Geoerger7, P. Hingorani8, I. Dunkel9, M. Russo10, L. Tseng10, Q. Liu10, N. Nebot10, J. Whitlock2, D. Hargrave11
1Pediatric Medical Neuro-Oncology, Harvard Medical School, Boston Children’s Hospital, Dana-Farber Cancer Institute, Boston, MA, USA, 2Haematology/Oncology, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada, 3Division of Haematology/Oncology, Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada, 4Oncology Department, St. Jude Children’s Research Hospital, Memphis, TN, USA, 5Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA, 6Children's Cancer Centre, The Royal Children’s Hospital, University of Melbourne, Murdoch Children’s Research Institute, Melbourne, Australia, 7Department of Pediatric and Adolescent Oncology, Gustave Roussy, Villejuif, France, 8Hematology/Oncology, Phoenix Children’s Hospital, Phoenix, AZ, USA, 9Pediatric Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA, 10Global Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 11Haematology and Oncology, Great Ormond Street Hospital, London, UK
Background: BRAF V600 mutations are present in 15%-20% patients (pts) with pediatric low-grade gliomas (pLGG). Relative to pts with BRAF V600–wild type pLGG, pts with BRAF V600E–mutant pLGG had poor survival and lower objective response rates (ORR) to initial (29%) and 2nd-line (11%) chemotherapy (Lassaletta A, ASCO 2016). There remains a need for improved treatment options for this pLGG subgroup. Dabrafenib is a potent and selective inhibitor of the V600–mutant form of the BRAF kinase. We report the results of the first study of dabrafenib in pediatric pts with BRAF V600–mutant recurrent or progressive LGG.
Methods: Thirty-two pts aged 2-17 y with BRAF V600–mutant relapsed or refractory LGG were enrolled Dec 2013 to Jul 2015 across 4 dose levels of dabrafenib monotherapy up to and including the recommended phase 2 dose (RP2D; 4.5 mg/kg/day in pts ≥ 12 y, 5.25 mg/kg/day in pts < 12 y, divided into 2 equal doses per day [Kieran MW, ASCO 2015]). The results presented are from all 32 pts with pLGG (15 pts enrolled into the dose-finding and 17 pts treated after determination of the RP2D). Overall, 24 pts were treated at the RP2D.
Results: Twenty-two of the 32 pts remained on study as of April 2016. Adverse events were generally similar to those observed in adults, with frequent low-grade pyrexia, vomiting, fatigue, headache and rash. There have been no reports of cutaneous squamous cell carcinoma. The most frequent grade 3 or 4 AE was pneumonia, in 3 pts. 1 pt experienced a significant allergic reaction on day 2 of dosing and again upon rechallenge and was discontinued from study. Independent confirmed overall response by RANO criteria was 2 CRs and 11 PRs in this 2nd-line setting (N=32, ORR 41% [95% CI, 24%-59%]), with a median duration of response of 11 months (8 responders ongoing). There were an additional 13 pts (41%) with SD of 6 months or greater duration (11 ongoing). Investigator confirmed overall response was 1 CR and 22 PRs (ORR 72% [95% CI, 53%-86%]).
Conclusions: Targeted therapy using dabrafenib showed promising activity, with an independently confirmed ORR of 41%, and was well tolerated in this population with recurrent or progressive BRAF V600–mutant pLGG, comparing favorably to historical data.
Clinical trial identification: Regulatory Agency Identifying Number(s): IND No.: 117,989. EudraCT Number: 2012-001499-12. Release date: 24 July, 2012.
Legal entity responsible for the study: Supported by GlaxoSmithKline. Dabrafenib is an asset of Novartis AG as of 2 March 2015.
Funding: Supported by GlaxoSmithKline. Dabrafenib is an asset of Novartis AG as of 2 March 2015.
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Disclosure: |
M.W. Kieran: Membership on Board of Directors or Advisory Committee: Novartis. |
Keywords: pediatric cancer, BRAF, dabrafenib, low grade glioma