Only a few weeks until the start of the 2016 annual meeting of the American Society of Clinical Oncology (ASCO). This year’s ASCO, taking place in the McCormick Place convention center in Chicago, Illinois, June 3-7, is expected to attract as many as 30,000 oncology professionals from the United States and around the world.
The theme of the annual meeting is Collective Wisdom: The Future of Patient-Centered Care and Research, emphasizing that the combined knowledge from various disciplines, cancer types, treatment approaches, and big data technologies is essential to progress. The theme is noticeable throughout the entire annual meeting and reinforces the inextricable link – a necessity – between ongoing research and advances in patient-centered care. The 2016 theme is also evident as the latest, most exciting discoveries, based on a better understanding of cancer biology and chemistry, will be presented.
In preparation of the meeting, the program coordinators have accepted more than 5,200 abstracts to the ASCO Annual Meeting. Additional Late-Breaking Abstracts (LBAs), including Plenary abstracts, will be released on-site throughout the Annual Meeting.
Quality and access to care
Improving quality as well as access to appropriate care is a key subject being discussed during the 2016 annual meeting. Care may come in different forms, and researchers will discuss a phase III trial exploring whether using a mobile device-friendly web application for symptom monitoring improves survival of patients with lung cancer (Abstract LBA9006). Another study discusses a large analysis examining use of aggressive medical care and hospice for patients younger than age 65 in the last 30 days of life (Abstract LBA10033). Another study exploring racial disparities in receipt of breast and ovarian cancer risk-reducing procedures among younger breast cancer survivors with BRCA mutations (Abstract LBA1504). Cost of novel cancer therapeutics plays a role in access to these drugs. An analysis of cancer drug prices around the world (Abstract LBA6500) is expected to shine some light on the discrepancy in the availability of care.
Immunotherapy
One of the exciting development in the treatment of cancer includes immunotherapy. During the upcoming annual meeting, researchers will highlight studies representing the range of research topics, discuss survival data from early pre-clinical to phase III trials with a number of (novel) antibody-drug conjugates (ADCs) and other targeted therapies, include PD-1’s and BiTe’s.
Antibody-drug conjugates have, over the last decade, revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumor-associated target antigens and deliver a highly potent cytotoxic agent.[1]
Today there are multiple ADCs in clinical trials, targeting varied antigens using different linker chemistries and cytotoxic payloads. In the development novel ADCs, scientists have met a number of challenges including how to improve the therapeutic index, the selection of the optimal target, a better understanding of mechanism of action (MOA), how to manage and understand off-target toxicities, as well as the selection of appropriate clinical settings where these novel drugs may have the highest clinical benefit. [2]
Optimal target selection
The identification of optimal target is key to the clinical advancement of new antibody-drug conjugates. The possibilities of these novel targeted drugs used in the treatment of a wide range of solid cancers and hematological malignancies is limited by the discovery of suitable targets. Optimal targets are highly expressed on cancer cells and not, or minimally, on normal, healthy, tissues.[1]
On Sunday morning, June 5, Howard A. Burris, MD (Sarah Cannon Research Institute) will be discussing the importance of the discovery of unique targets for antibody-drug conjugates designed to “make chemotherapy great again.”
Brentuximab vedotin
Brentuximab vedotin (also known as SGN-035; Adcetris® by Seattle Genetics Inc.) is an antibody-drug conjugate (ADC) or immunoconjugate directed to CD30, which is expressed in classical hodgkin lymphoma and systemic anaplastic large cell lymphoma.
This year, as part of ASCO’s oral abstract session “Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia,” on Saturday June 4, Steven I. Park, MD (University of North Carolina Lineberger Comprehensive Cancer Center) will present data from phase II trial of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by brentuximab vedotin consolidation in limited stage non-bulky Hodgkin lymphoma (Abstract 7508).
During the poster discussion session on Monday, June 6, Anas Younes, MD (Memorial Sloan Kettering Cancer Center) will discuss results from Checkmate 205, a phase II study comparing safety and efficacy of nivolumab (Opdivo®; Bristol-Myers Squibb), a programmed death-1 (or PD-1) inhibitor approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of melanoma and advanced non-small cell lung cancer, in classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and brentuximab vedotin. (Abstract 7535, Poster Board: #91).
On Monday, Philippe Armand, MD, PhD (Dana-Farber Cancer Institute) will share an update of a phase I/II study to evaluate safety and efficacy of nivolumab plus brentuximab vedotin in patients with CD30-expressing relapsed/refractory non-Hodgkin lymphomas. (Abstract TPS7576; Poster Board: #130a).
Another poster, presented by Somali C. Gavane, MBBS (Memorial Sloan Kettering Cancer Center) on Monday, includes an update of metabolic tumor volume to predict event-free survival in patients with relapsed/refractory Hodgkin lymphomas treated with brentuximab vedotin-based salvage therapy (Abstract 11566, Poster Board: #263).
Ado-trastuzumab emtansine
Ado-trastuzumab emtansine, also know all T-DM1 (Kadcyla®; Genentech/Roche) is an antibody-drug conjugate consisting of the recombinant anti-epidermal growth factor receptor 2 (HER2) antibody trastuzumab conjugated to the maytansinoid DM1 via a nonreducible thioether linkage (MCC). The trastuzumab moiety binds to HER2 on tumor cell surface surfaces. Following internalization, the DM1 is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2.
The linkage of antibody and drug through a nonreducible linker has shown to contribute to the improved efficacy and reduced toxicity of ado-trastuzumab emtansine compared to similar ADCs constructed with reducible linkers.
During the 2016 annual meeting, results from a large number of studies with ado-trastuzumab emtansine will be presented:
- On Sunday, June 5, Carlos H. Barrios (PUCRS School of Medicine) will present a poster covering patient-reported outcomes from MARIANNE: A phase III study of trastuzumab emtansine (T-DM1) +/- pertuzumab vs. trastuzumab + taxane for the treatment of HER2-positive advanced breast cancer (Abstract 593, Poster Board: #81);
- The same day Audrey Mailliez, MD (Centre Oscar Lambert) will present response to ado-trastuzumab emtansine according to RANO criteria in central nervous system metastases of HER2 positive breast cancers (Abstract 605, Poster Board: #93);
- Sunil S. Badve, MD (Indiana University) will present an update from the EMILIA trial discussing the role of tumor infiltrating lymphocytes (TILs) in HER2+ metastatic breast cancers (MBC) treated with ado-trastuzumab emtansine (T-DM1) or lapatinib plus capecitabine (Abstract 607, Poster Board: #95);
- During the same poster session, Rachel A. Freedman, MD, MPH (Dana-Farber Cancer Institute) will present data about adjuvant ado-trastuzumab emtansine (T-DM1) for older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. (Abstract TPS629, Poster Board: #109a).
- Finally, Kathy Miller, MD (Indiana University Melvin and Bren Simon Cancer Center) will present results from the HERMIONE-trial, a phase II randomized, open label trial comparing MM-302 + trastuzumab with chemotherapy of physician’s choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine. (Abstract TPS631, Poster Board: #110a)
During an oral abstract session on Monday, June 6 (breast cancer—HER2/ER), Sara A. Hurvitz (David Geffen School of Medicine, University of California Los Angeles) will discuss pathologic complete response (pCR) rates after neoadjuvant ado-trastuzumab emtansine + pertuzumab vs. docetaxel + carboplatin + trastuzumab + pertuzumab (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (KRISTINE). (Abstract 500)
Sacituzumab govitecan
The anti-Trop-2-SN-38 antibody-drug conjugate (ADC) sacituzumab govitecan (IMMU-132), being developed by Immunomedics (Morris Plains, NJ 07950), is designed to deliver the moderately-toxic conventional chemotherapeutic drug, SN-38, the active metabolite of irinotecan (Camptosar®, Pfizer), site-specifically and at a high drug to antibody ratio (DAR), to a humanized antibody that targets the Trop-2 receptor, expressed by many solid cancers, while reducing overall toxic effects that are usually found with conventional administration of these chemotherapeutic agents.
During the clinical science symposium “Future directions in breast cancer treatment: new drugs, new markers,” on Friday, June 3, Aditya Bardia, MD, MPH (Massachusetts General Hospital Cancer Center) will present results from a phase II study of sacituzumab govitecan, for the treatment relapsed/refractory metastatic triple-negative breast cancer (mTNBC) (Abstract LBA509).
Results with the first-in-class antibody-drug conjugate sacituzumab govitecan in patients with previously treated metastatic small-cell lung cancer (mSCLC) will be presented in a poster session by Alexander Starodub, MD, PhD (Indiana University Health Goshen Center for Cancer Care) on Saturday, June 4, discussing “Lung Cancer—Non-Small Cell Local-Regional, Small Cell and Other Thoracic Cancers” (Abstract 8559; Poster Board: #187)
On Monday, June 6, during the clinical science symposium “Raising the bar for targeted therapies for lung cancers,” D. Ross Camidge, MD, PhD (University of Colorado), will present new approaches to the treatment of metastatic, non-small cell lung cancer (mNSCLC) with sacituzumab govitecan (Abstract 9011).
In early 2016 sacituzumab govitecan received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with triple-negative breast cancer or TNBC who have failed at least 2 prior therapies for metastatic disease.
Rovalpituzumab tesirine
Rovalpituzumab tesirine combines a novel targeted drug (anti-DLL3 antibody) with a toxin, D6.5 pyrrolobenzodiazepine (PBD), which is conjugated to cysteine residues on the SC16 antibody via a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with a mean drug-to-antibody ratio (DAR) of 2. [3]
On Sunday, June 5, Charles M. Rudin, MD, PhD (Memorial Sloan Kettering Cancer Center) will present results from a phase I/II study investigating the safety and efficacy of antibody-drug conjugate rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate, for the treatment of recurrent or refractory small cell lung cancer (SCLC) (Abstract LBA8505).
New indication of rovalpituzumab tesirine also include the potential treatment of metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas (NECs). Initial results are presented in a poster presentation on June 6 by Stemcentrx‘s Stanford L. Peng, MD, PhD will present (Abstract 11611, Poster Board: #308).
PSMA ADC
Prostrate-specific membrane antigen or PSMA is a protein that is highly expressed on most of the tumor cells in prostate cancer. The protein is also expressed on the (neo)vasculature that supplies blood to many other tumors. Researchers at Ambrx (La Jolla, CA 92037) have developed a site specific antibody-drug conjugate using the company’s proprietary drug payload. The trial drug, which is being evaluating for efficacy and overall toxicity compared with conventional antibody-drug conjugates, may have the potential to demonstrate increased potency in cancer patients while decreasing the toxicity that is usually seen in other antibody-drug conjugates due to the heterogeneity of the random conjugation approach used to generate these molecules. The anti-PSMA ADC is being developed for the treatment of patients with prostate cancer and glioblastoma multiforme.
On Saturday, June 4, Heinrich Elinzano, MD (Rhode Island Hospital) will present results of the Phase II Brown University Oncology Research Group Study investigation the novel PSMA ADC in patients with progressive glioblastoma (Abstract 2065; Poster Board: #252)
The potential treatment of glioblastoma (GBM), the most common malignant primary brain tumor, is also presented by Martin J. Van Den Bent, MD (Erasmus MC Cancer Center) in a poster presentation reviewing the efficacy of ABT-414 (AbbVie), composed of the antibody ABT-806 targeting active EGFR/mutant EGFRvIII linked to the anti-microtubule agent monomethyl auristatin F, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (Abstract 2542; Poster Board: #242).
Scientists have identified aberrant EGFR expression and signaling as a hallmark of cancer growth and survival. In several EGFR-overexpressing tumor xenografts ABT-414 has shown potent anti tumor activity.
Enfortumab vedotin
The antibody-drug conjugates enfortumab vedotin comprises the human anti-nectin-4 antibody conjugated to the highly potent microtubule disrupting agent monomethyl auristatin E (MMAE). Scientists at Agensys (Santa Monica, CA, 90404) prepared hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME). They were able to bind the the versions of enfortumab vedotin to cell surface expressed nectin-4, a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules and reported high affinity and induced cell death in vitro in a dose-dependent manner. [4]
Using mouse xenograft models of human breast, bladder, pancreatic, and lung cancers, scientists found that treatment with enfortumab vedotin significantly inhibited the growth these tumor types. They also noted tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors, and support further clinical development, investigation, and application of nectin-4-targeting ADCs.[4]
On Monday, June 6, during a poster session covering genitourinary (non-prostate) cancers, Jonathan E. Rosenberg, MD (Memorial Sloan Kettering Cancer Center) will present data of the anti-tumor activity, safety and pharmacokinetics of ASG-22CE (ASG-22ME; enfortumab vedotin) in a phase I dose escalation trial in patients with metastatic urothelial cancer. (Abstract 4533, Poster Board: #156).
Inotuzumab ozogamicin
Inotuzumab ozogamicin is an investigational ADC comprised of a humanized IgG4 anti-CD22 antibody targeting CD22, a cell surface antigen expressed on approximately 90% of B-cell malignancies, covalently linked to N-acetyl-gamma-calicheamicin dimethyl hydrazine or calichDMH, a derivative of gamma calicheamicin, a cytotoxic antibiotic produced by the bacterium Micromonospora echinospora, with potential antineoplastic activity.
When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is rapidly internalized, delivering the conjugated CalichDMH intracellularly. The CalichDMH moiety then binds to the minor groove of DNA in a sequence-specific manner, resulting in double-strand DNA breaks and apoptosis.
The trial drug originates from a collaboration between Pfizer and Celltech (now part of UCB).
During the poster session “Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant” on Monday, June 6, a total of 3 posters with trial updates covering inotuzumab ozogamicin will be presented:
- Hagop M Kantarjian, MD (The University of Texas MD Anderson Cancer Center, Department of Leukemia) will present patient-reported outcomes from a global phase III randomized controlled trial of inotuzumab ozogamicin vs. standard care for relapsed/refractory (R/R) acute lymphoblastic leukemia or ALL. (Abstract 7027, Poster Board: #19);
- Daniel J. DeAngelo, MD, PhD (Dana-Farber Cancer Institute) will present the efficacy and safety by prior therapy of inotuzumab ozogamicin for the treatment of patients with relapsed/refractory acute lymphoblastic leukemia in the phase III INO-VATE trial.(Abstract 7028, Poster Board: #20), and
- Elias Jabbour, MD (The University of Texas MD Anderson Cancer Center) will follow with data of the efficacy and safety of inotuzumab ozogamicin in older patients with relapsed/refractory acute lymphoblastic leukemia (ALL) who were enrolled in the phase III INO-VATE trial.(Abstract 7029,Poster Board: #21).
The presented results stem from the INO-VATE trial, is an open-label, randomized, Phase III study evaluating the safety and efficacy of inotuzumab ozogamicin as compared with a defined set of chemotherapy choices in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).
The two primary endpoints in this trial are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Secondary endpoints include progression-free survival, volume of distribution and systemic clearance for inotuzumab ozogamicin in serum, duration of response, rate of stem-cell transplantation, minimal residual disease, cytogenetics, safety and quality of life based on the EORTC’s Quality of Life Questionnaire.
More studies
A (poster) presentation by George R. Blumenschein, M.D., Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, presents the results of a phase I study of anti-mesothelin antibody drug conjugate anetumab ravtansine, also known as BAY 94-9343, being developed by Bayer HealthCare under an agreement with ImmunoGen, consists of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker (Abstract 2509; Poster Board: #209). [5]
Upon internalization, the DM4 moiety in anetumab ravtansine binds to tubulin and disrupts microtubule assembly/disassembly dynamics, resulting in inhibition of cell division and cell growth of mesothelin-expressing tumor cells. Mesothelin is overexpressed on all mesotheliomas as well as many ovarian and pancreatic cancers while minimally expressed on normal tissue. [6]
Results from a number of studies with antibody-drug conjugates presented during ASCO include:
- Results from a phase I, open-label, dose-escalation and expansion study of ABBV-399 (AbbVie), an antibody drug conjugate targeting c-Met, in patients with advanced solid tumors. (Abstract 2510; Poster Board: #210), presented by John H. Strickler, MD (Duke University Medical Center)[7]
- A poster presentation by Carlos Alberto Gomez-Roca, MD (Institut Universitaire du Cancer de Toulouse) detailing the results of a phase I study of SAR566658, an anti CA6-antibody-drug conjugate created by ImmunoGen and licensed preclinically to Sanofi, in patients with CA6-positive advanced solid tumors (STs)(NCT01156870). SAR566658 comprises of ImmunoGen’s huDS6 CA6-targeting antibody conjugated to DM4 via one of the compansy’s engineered linkers (SPDB). (Abstract 2511; Poster Board: #211)[8]
- Results from mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate in clinical trials as single agent activity in platinum-resistant epithelial ovarian cancer patients will be presented by Kathleen N. Moore, MD (University of Oklahoma Health Sciences Center) (Abstract 5567; Poster Board: #390)
- Data from a randomized, open-label, phase II study of the anti-NaPi2b antibody-drug conjugate Lifastuzumab (Lifa) Vedotin, also known as DNIB0600A and RG-7599, being developed by Genentech/Roche, compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer, will be presented by Susana N. Banerjee, MBBS, MA, PhD, MRCP (Royal Marsden Hospital). (Abstract 5569; Poster Board: #392).[9]
Nanoparticle-drug conjugate
Nanotechnology is a multidisciplinary field opening the door to a new generation of devices for cancer diagnosis, treatment and prevention. Drug-loaded nanoparticles offer considerable potential to provide a potentially ideal solution to solve some of the problems seen with traditional chemotherapy.
Although nanoparticles can become concentrated preferentially to tumors by virtue of the enhanced permeability and retention (EPR) effect of the vasculature, the low selectivity of nanoparticles towards the cancer cells hinders the advantages of the nanoparticle formulation for efficient chemotherapy. One reason is that a therapeutic agents such as docetaxel, a commercially successful oncology drug that suffers from a poor safety profile limiting its clinical utility, also kills healthy cells. To solve this problem, scientist have been working on the development of novel drugs containing docetaxel.
CRLX301 is a novel nanoparticle-drug conjugate (NDC) containing a docetaxel payload being developed by Cerulean Pharma (Waltham, MA 02451) for the treatment of patients with refractory solid tumors. The trial drug is expected to be differentiated from standard docetaxel because it is designed to concentrate more docetaxel in tumor cells and spare healthy tissue. Preclinical data show that CRLX301 had lower toxicity than has been reported with docetaxel in preclinical studies.
Ben Markman, MBBS, FRACP (Monash Cancer Center) will presents phase I trial results of CRLX301. (Abstract 2526; Poster Board: #226).
ASCO’s iPlanner
It’s just a few more weeks until the start of the 2016 annual meeting of American Society of Clinical Oncology. To help attendees plan their meeting, ASCO has developed a a new scheduling tool – the iPlanner – to browse abstract titles, search for sessions, or create a customized schedule. In addition, the organizers have developed a new ‘Insiders Guide‘ designed to help meeting attendees navigate the ASCO and make the best of their time during the 2016 annual meeting.
Every year, in addition to offering a forum to share clinical updates in all areas of oncology, ASCO offers it’s audience a valuable opportunity to actively participate in discussions with colleagues, conforming it’s standing among the leading oncology meetings around the globe.
Last Editorial Review: May 7, 2016
Last Editorial update: May 8, 2016
Featured Image: Escalators in the McCormick Place convention center in Chicago, Illinois during the 51st annual meeting of the American Society of Clinical Oncology. Courtesy: © ASCO/Rodney White 2015 . Used with permission. Photo 1.0: Howard A. Burris, M.D., during the Annual Business Meeting at the American Society for Clinical Oncology (ASCO) Annual Meeting , Monday June 3, 2013. Courtesy © ASCO/Phil McCarten. Used with permission.
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