The year 2015 marked a noteworthy 12-month period for oncology drugs approved by the US Food and Drug Administration (FDA). The Center for Drug Evaluation and Research, which reviews the approval of antibodies and small molecules, approved a total of 45 new drugs in 2015; 15 of which are indicated for the treatment of cancer.1
According to the FDA’s drug approval database, there were 34 new FDA-approved indications in the general field of hematology/oncology in 2015.2 Although many of these indications are expansions on previously approved therapeutics,2 17 represent new molecular entities (NMEs) containing active drug moieties not previously approved by the FDA.3
In particular, disease states for which multiple NMEs were approved included non−small-cell lung cancer (NSCLC), with 3 new drug approvals (alectinib, necitumumab, osimertinib), as well as multiple myeloma, with 4 new drug approvals (elotuzumab, daratumumab, ixazomib, panobinostat).1,2,4 Also included in this list of 2015 FDA approvals were filgrastim-sndx (Zarxio injection), the first biosimilar approved in the United States, and talimogene laherparepvec (Imlygic), the first US-approved oncolytic viral therapy.2
Dominance of Immunotherapy Approvals
The subspecialty of oncology that has dominated the list of recently approved therapeutics is immuno-oncology.4 Medicines for this subfield work by activating T-cells to target cancer, or inhibiting tumor antigens that allow cancer cells to evade the immune system (eg, checkpoint inhibitors).4
Two of the unique aspects of immunotherapies include their ability to achieve relatively high response rates in pretreated patients, as well as the potential for durable remissions in patients who respond to therapy. Currently, several of these agents have achieved FDA approval for use in patients with metastatic melanoma or NSCLC.4 In addition, there are a multitude of ongoing clinical trials evaluating the activity of checkpoint inhibitors in a variety of different malignancies.4,5
The 17 hematology/oncology NMEs approved in 2015 represent a significant upward trajectory from the 2 previous years—9 oncology NMEs were approved in 2014, and 7 were approved in 2013.1,4,6 Although it may seem that this accelerated rate of drug approvals is unsustainable, there is reason to believe that this trend will continue. The American Association for Cancer Research (AACR) estimates that there are more than 836 vaccines and medications for targeting cancer currently being tested in clinical trials, or awaiting FDA approval.7 In addition, the AACR estimates that approximately 80% of these medicines in the pipeline have the potential to become first-in-class therapies, and 73% will potentially be personalized medicines.
Although the AACR has continued to invest heavily in the research and development of innovative oncology drugs, recent legislation indicates that Congress has also recognized the need for additional cancer research funding. In December 2015, Congress passed a bill to increase the budget of the National Institutes of Health by 6.6%; this amounts to a total of $32.1 billion, $5.2 billion of which is designated for the National Cancer Institute.4,8
In the first 3 months of 2016, the FDA already approved 3 hematology/oncology NMEs (Table 1), and 6 new indications for previously approved drugs.2,9-11 In addition to these approvals, we estimate that there could be ≤18 new NMEs and 1 new biosimilar approved during the remainder of 2016 (Table 2).12-40 Below we provide a brief review of select agents with potential for FDA approval in 2016.
Andexanet alfa is an intravenous recombinant being developed by Portola Pharmaceuticals, Inc, to reverse bleeding in patients anticoagulated with factor Xa inhibitors.12,13 Currently, there are no FDA-approved medications specifically indicated for the reversal of factor Xa inhibitors; thus, andexanet alfa would represent a first-in-class medication for this indication.
Investigators from 2 randomized, double-blind, placebo-controlled trials (ANNEXA-R and ANNEXA-A) have reviewed the safety and efficacy of andexanet alfa use in healthy volunteers. The results, published in the New England Journal of Medicine, demonstrated that andexanet alfa reversed the anticoagulant effects of apixaban and rivaroxaban within minutes of administration, without causing adverse events.13
Portola Pharmaceuticals, Inc, submitted a rolling biologics license application (BLA) to the FDA in early 2016, which was accepted under the accelerated approval pathway. Currently, andexanet alfa has a goal date of August 17, 2016, for the FDA to complete its review of the BLA.12
Genentech, Inc, is currently in the late stages of developing an immunotherapy agent for patients with previously treated metastatic urothelial bladder cancer.15 Atezolizumab, an intravenous monoclonal antibody designed to directly bind with the programmed death-ligand 1 (PD-L1), has a slightly different mechanism of action than the previously approved checkpoint inhibitor, because it targets the PD-L1 tumor antigen rather than the PD-1 receptor on T-cells.15 Advanced bladder cancer is a disease with limited treatment options, and atezolizumab would represent a first-in-class PD-L1 inhibitor for the treatment of this disease.
In a phase 2, open-label, single-arm study (IMvigor 210), atezolizumab demonstrated an objective response rate of 27% in patients with metastatic urothelial carcinoma whose disease had medium/high levels of PD-L1 expression.16 Importantly, responses were still ongoing during interim data analysis, and median duration of response has not yet been established.16 In addition to this study, Genentech, Inc, is currently conducting a phase 3 clinical trial comparing atezolizumab to standard-of-care chemotherapy in patients with metastatic urothelial carcinoma that worsened after treatment with ≥1 platinum-containing regimens.
Genentech, Inc’s BLA submission for atezolizumab was granted priority review in March 2016; the company has a goal date of September 12, 2016, for the FDA’s decision on approval of the drug.15
Clovis Oncology, headquartered in Boulder, CO, is a biopharmaceutical company with several cancer treatments in their pipeline. Their most advanced-stage product is rociletinib, which is being developed for the treatment of NSCLC in patients with initial activating epidermal growth factor receptor (EGFR) mutations, including the T790M mutation.41 Rociletinib is a novel, oral, mutation-selective inhibitor of EGFR forms known to be present in 15% to 35% of white and East Asian patients with NSCLC.
Last year, the first therapy (osimertinib) was approved for treatment of patients with T790M gatekeeper mutation, which can result in patients developing resistance to first- and second-line EGFR inhibitors. Updated results from Clovis Oncology’s phase 2 trial demonstrated that rociletinib produced an objective response rate in 60% of patients with the T790M mutation, 37% with T790M-negative disease, and was relatively well-tolerated.42,43
In May 2014, rociletinib was granted breakthrough therapy designation by the FDA for the treatment of patients with NSCLC and the T790M mutation, after their disease progressed on EGFR-directed therapy.41 Most recently, the FDA has extended the review period for rociletinib by 3 months, and the company’s current goal date for FDA review is June 28, 2016.
In partnership with AbbVie Inc, F. Hoffmann-La Roche Ltd is developing venetoclax, a new, targeted agent for the treatment of patients with relapsed or refractory chronic lymphocytic leukemia (CLL).31 Venetoclax is an oral, bioavailable, highly selective inhibitor of the B-cell lymphoma 2 (BCL-2) protein. BCL-2, which is expressed in various types of leukemia and lymphoma, confers that an antiapoptotic signal when constitutively active leads to long-lived malignant lymphocytes that are highly resistant to apoptosis.31
Results from a phase 1, dose-escalation study demonstrated that venetoclax was highly active against CLL, and that it was able to produce an overall response rate of ≥71%, with 20% of patients achieving complete remissions.38 Venetoclax was granted breakthrough therapy designation in April 2015 for the treatment of patients with previously treated (relapsed or refractory) CLL, including those with 17p deletion.
In January 2016, the FDA granted venetoclax priority review; the companies anticipate a final decision on approval of the drug in mid-to-late 2016.
The information provided in this pipeline preview sheds light on some of the unique characteristics of select emergent therapies expected to receive approval in 2016. The advancement in our understanding of tumor biology has paved the way for future cancer treatments that are more effective, less toxic, and personalized to each patient’s specific disease state. In projecting the 2016 hematology/oncology drug pipeline, we can clearly see continued trends in targeted therapies, as well as immunotherapy. Along with these potential new drug approvals will come continued emphasis on identifying patients who will benefit most from these emerging therapies, as well as determination of where these drugs fit into existing oncology treatment pathways. Although there remain many unanswered questions about the state of cancer treatment, we anticipate that the current pipeline of oncology therapeutics will provide evidence-based solutions that will continue to advance the standard of care across all types of cancers.
Author Disclosure Statement
Dr Beechinor reported no conflicts of interest. Dr Valgus is on the Advisory Boards for Genentech, Inc, Sandoz, and Taiho Oncology, Inc.
- Mullard A. 2015 FDA drug approvals. Nat Rev Drug Discov. 2016;15:73-76.
- US Food and Drug Administration. Hematology/oncology (cancer) approvals & safety notification. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm. Updated March 30, 2016. Accessed April 6, 2016.
- US Food and Drug Administration. Novel drug approvals for 2015. www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm430302.htm. Updated April 1, 2016. Accessed April 6, 2016.
- Dizon DS, Krilov L, Cohen E, et al. Clinical cancer advances 2016: annual report on progress against cancer from the American Society of Clinical Oncology. J Clin Oncol. 2016;34:987-1011.
- Hoos A. Development of immuno-oncology drugs - from CTLA4 to PD1 to the next generations. Nat Rev Drug Discov. 2016;15:235-247.
- American Cancer Society. Cancer factors & figures 2015. www.cancer.org/acs/groups/content/@editorial/documents/document/acspc-044552.pdf. Published 2015. Accessed April 6, 2016.
- American Association for Cancer Research. Medicines in development for cancer. http://phrma.org/sites/default/files/pdf/oncology-report-2015.pdf. Accessed April 6, 2016.
- Kelly N. What’s next for the National Institutes of Health? www.theatlantic.com/politics/archive/2016/01/national-institutes-of-health-congress-budget/423837. The Atlantic. Published January 13, 2016. Accessed April 4, 2016.
- Kovaltry [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc; 2016.
- Idelvion [package insert]. King of Prussia, PA: CSL Behring; 2016.
- Defitelio [package insert]. Palo Alto, CA: Jazz Pharmaceuticals Inc; 2016.
- Portola Pharmaceuticals, Inc. Andexanet alfa: FXa inhibitor antidote. www.portola.com/clinical-development/andexanet-alfa-fxa-inhibitor-antidote. Accessed April 6, 2016.
- Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373:2413-2424.
- Portola Pharmaceuticals announces biologics license application for andexanet alfa accepted for review by FDA [news release]. South San Francisco, CA: Portola Pharmaceuticals, Inc; February 17, 2016. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=2140255. Accessed April 6, 2016.
- FDA grants Genentech’s cancer immunotherapy Atezolizumab priority review for advanced bladder cancer [news release]. South San Francisco, CA: Genentech, Inc; March 14, 2016. www.gene.com/media/press-releases/14621/2016-03-14/fda-grants-genentechs-cancer-immunothera. Accessed April 6, 2016.
- Hoffman-Censits JH, Grivas P, Van Der Heijden MS, et al. IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC). Presented at: 2016 Genitourinary Cancers Symposium; January 7-9, 2016; San Francisco, CA. http://meetinglibrary.asco.org/content/158128-172. Accessed April 6, 2016.
- Lilly receives FDA breakthrough therapy designation for abemaciclib – a CDK 4 and 6 inhibitor – in advanced breast cancer [news release]. Indianapolis, IN: Eli Lilly and Company; October, 8 2015. https://investor.lilly.com/releasedetail.cfm?releaseid=935735. Accessed April 6, 2016.
- Abemaciclib – Lilly’s oral CDK 4/6 inhibitor – shows single-agent activity in a phase I study for patients with a specific type of lung cancer [news release]. Indianapolis, IN: Eli Lilly and Company; May 14, 2014. https://investor.lilly.com/releasedetail.cfm?ReleaseID=848054. Accessed April 6, 2016.
- Array BioPharma. Binimetinib (MEK162). www.arraybiopharma.com/product-pipeline/binimetinib. Accessed April 6, 2016.
- Center for Health Policy at Brookings. Breakthrough therapy designation: exploring the qualifying criteria. www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM447165.pdf. Published April 24, 2015. Accessed April 7, 2016.
- Cerulean announces data at the 2015 AACR-NCI-EORTC international conference on molecular targets and cancer therapeutics [news release]. Cambridge, MA: Cerulean Pharma Inc; November 9, 2015. http://ir.ceruleanrx.com/releasedetail.cfm?releaseid=941459. Accessed April 6, 2016.
- Cerulean’s CRLX101 receives orphan drug designation from the FDA for the treatment of ovarian cancer [news release]. Cambridge, MA: Cerulean Pharma Inc; May 26, 2015. www.businesswire.com/news/home/20150526005442/en/Cerulean%E2%80%99s-CRLX101-Receives-Orphan-Drug-Designation-FDA. Accessed April 6, 2016.
- Threshold Pharmaceuticals’ partner Merck KGaA, Darmstadt, Germany, receives FDA fast track designation for evofosfamide for the treatment of patients living with advanced pancreatic cancer [news release]. South San Francisco, CA: Threshold Pharmaceuticals, Inc; May 12, 2015. http://investor.thresholdpharm.com/releasedetail.cfm?ReleaseID=912471. Accessed April 7, 2016.
- Rigel granted orphan drug designation for fostamatinib in ITP [news release]. South San Francisco, CA: Rigel Pharmaceuticals, Inc; September 8, 2015. http://ir.rigel.com/phoenix.zhtml?c=120936&p=irol-newsArticle&ID=2085860. Accessed April 6, 2016.
- Cellceutix Corporation. Kevetrin. http://cellceutix.com/kevetrin/#sthash.0fDQEeoV.dpbs. Accessed April 6, 2016.
- Puma Biotechnology, Inc. PB272 (Neratinib). www.pumabiotechnology.com/pb272_neratinib.html. Accessed April 6, 2016.
- Campbell T. A big year could be on tap for Puma Biotechnology in 2016. www.fool.com/investing/general/2015/12/19/a-big-year-could-be-on-tap-for-puma-biotechnology.aspx. Published December 19, 2015. Accessed April 6, 2016.
- Regulatory submission for Sanoz’ proposed biosimilar pegfilgrastim accepted by the FDA [news release]. Holzkirchen, Upper Bavaria, Germany: Sandoz Inc; November 18, 2015. www.novartis.com/news/media-releases/regulatory-submission-sandoz-proposed-biosimilar-pegfilgrastim-accepted-fda. Accessed April 6, 2016.
- Novartis drug PKC412 (midostaurin) receives breakthrough therapy designation from the FDA for newly-diagnosed FLT3-mutated acute myeloid leukemia (AML) [news release]. Basel, Switzerland: Novartis AG; February 19, 2016. www.novartis.com/news/media-releases/novartis-drug-pkc412-midostaurin-receives-breakthrough-therapy-designation-fda. Accessed April 6, 2016.
- MEI Pharma receives orphan status for lead drug candidate pracinostat for treatment of acute myeloid leukemia [news release]. San Diego, CA: MEI Pharma, Inc; February 28, 2014. http://investor.meipharma.com/2014-02-28-MEI-Pharma-Receives-Orphan-Status-For-Lead-Drug-Candidate-Pracinostat-For-Treatment-Of-Acute-Myeloid-Leukemia. Published February 28, 2014. Accessed April 6, 2016.
- F. Hoffmann-La Roche Ltd. FDA grants priority review for venetoclax new drug application. www.roche.com/investors/updates/inv-update-2016-01-12.htm. Published January 12, 2016. Accessed April 6, 2016.
- Epizyme announces tazemetostat granted orphan drug designation for malignant rhabdoid tumors by U.S. FDA [news release]. Cambridge, MA: Epizyme, Inc; February 8, 2016. www.businesswire.com/news/home/20160208005579/en/Epizyme-Announces-Tazemetostat-Granted-Orphan-Drug-Designation. Accessed April 6, 2016 .
- Epizyme presents updated data from ongoing phase 1 study of tazemetostat showing objective, durable responses in relapsed or refractory non-hodgkin lymphoma [news release]. Orlando, FL: Epizyme, Inc; December 7, 2015. www.businesswire.com/news/home/20151207005478/en/Epizyme-Presents-Updated-Data-Ongoing-Phase-1. Accessed April 6, 2016.
- TRACON announces FDA orphan drug designation for TRC105 in soft tissue sarcoma [news release]. San Diego, CA: TRACON Pharmaceuticals, Inc; January 25, 2016. http://ir.traconpharma.com/phoenix.zhtml?c=253885&p=irol-newsArticle&ID=2131824. Accessed April 6, 2016.
- Rosen LS, Hurwitz HI, Wong MK, et al. A phase I first-in-human study of TRC105 (Anti-Endoglin Antibody) in patients with advanced cancer. Clin Cancer Res. 2012;18:4820-4829.
- FDA grants second orphan designation for VAL-083 [news release]. Vancouver, British Columbia and Menlo Park, CA: DelMar Pharmaceuticals, Inc; March 15, 2016. www.prnewswire.com/news-releases/fda-grants-second-orphan-designation-for-val-083-300236008.html. Accessed April 6, 2016.
- DelMar Pharmaceuticals, Inc. VAL-083: GBM historical review & strategy for product development. www.delmarpharma.com/VAL-083%20GBM%201502.pdf. Updated February 2015. Accessed April 6, 2016.
- Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:311-322.
- Celator Pharmaceuticals, Inc. Vyxeos pivotal study. www.celatorpharma.com/#!clinical-trials/c1ckq. Accessed April 6, 2016.
- Celator announces phase 3 trial for vyxeos (CPX-351) in patients with high-risk acute myeloid leukemia demonstrates statistically significant improvement in overall survival [news release]. Ewing, NJ: Celator Pharmaceuticals, Inc; March 14, 2016. www.prnewswire.com/news-releases/celator-announces-phase-3-trial-for-vyxeos-cpx-351-in-patients-with-high-risk-acute-myeloid-leukemia-demonstrates-statistically-significant-improvement-in-overall-survival-300235620.html. Accessed April 7, 2016.
- Clovis Oncology. Rociletinib. http://clovisoncology.com/products-companion-diagnostics/rociletinib. Accessed April 6, 2106.
- Sequist LV, Goldman JW, Wakelee HA, et al. Efficacy of rociletinib (CO-1686) in plasma-genotyped T790M-positive non-small cell lung cancer (NSCLC) patients (pts). Presented at: 2015 ASCO Annual Meeting; May 29-June 2, 2015; Chicago, IL. http://meetinglibrary.asco.org/content/152181-156. Accessed April 6, 2016.
- Clovis Oncology’s rociletinib (CO-1686) phase 2 study results demonstrate consistent and promising clinical activity and disease control in very advanced patients with EGFR-mutant non-small cell lung cancer (NSCLC) [news release]. Chicago, IL: Clovis Oncology, Inc; May 31, 2015. www.businesswire.com/news/home/20150531005040/en/Clovis-Oncology%E2%80%99s-Rociletinib-CO-1686-Phase-2-Study. Accessed April 6, 2016.