Expanding the Treatment Options in Oncology: 2016 FDA Drug Approvals


In the past decade, significant strides have been made in oncology drug innovation. A better understanding of the biologic underpinnings of cancer has largely fueled oncology drug research and has resulted in the identification of viable targets for therapeutic intervention.

The oncology drug therapy landscape continues to evolve, with several new oncology and oncology supportive care agents approved by the US Food and Drug Administration (FDA) in 2016, and many recently approved drugs are receiving additional or expanded indications for the tumor types or for use in combination with other drugs with different mechanisms of action.

The notable FDA approvals of cancer therapies in 2016 are discussed in this article and are listed in the Table.

Table New Indications and New Cancer Drugs Approved by the FDA through November 2016
Drug name (generic; manufacturer) Mechanism of action Indications FDA approval
Checkpoint inhibitors
Keytruda
(pembrolizumab; Merck)
PD-1 inhibitor Recurrent or metastatic squamous-cell head and neck cancer that progressed during/after platinum-containing chemotherapy August 5, 2016
First-line treatment of metastatic NSCLC that expresses PD-L1, but not EGFR or ALK mutations October 24, 2016
Opdivo
(nivolumab; Bristol-Myers Squibb)
PD-1 inhibitor Resectable/metastatic melanoma, regardless of BRAF mutation status, in combination with ipilimumab; newly diagnosed advanced, BRAF mutation–positive melanoma January 23, 2016
Classic Hodgkin lymphoma after autologous HSCT and posttransplant brentuximab vedotin May 17, 2016
Recurrent/metastatic squamous-cell head and neck cancer November 10, 2016
Tecentriq
(atezolizumab; Genentech)
PD-L1 inhibitor Metastatic urothelial bladder cancer that progressed within 12 months of neoadjuvant or adjuvant treatment during/after platinum-containing chemotherapy May 18, 2016
Metastatic NSCLC that progressed during/after platinum-containing chemotherapy October 18, 2016
Monoclonal antibodies
Arzerra
(ofatumumab; Novartis)
Anti-CD20 monoclonal antibody Recurrent or progressive CLL refractory to fludarabine and alemtuzumab January 19, 2016
Darzalex
(daratumumab; Janssen Biotech)
Anti-CD38 monoclonal antibody Second-line treatment of multiple myeloma, in combination with lenalidomide + dexamethasone or bortezomib + dexamethasone November 21, 2016
Gazyva
(obinutuzumab; Genentech)
Anti-CD20 monoclonal antibody Relapsed/refractory follicular lymphoma, in combination with bendamustine, then Gazyva monotherapy if disease relapses/is refractory to rituximab-containing regimen February 26, 2016
Lartruvo
(olaratumab; Eli Lilly
Anti–PDGFR-α monoclonal antibody Soft-tissue sarcoma in combination with doxorubicin October 19, 2016
Small-molecule inhibitors of signal transduction pathways
Cabometyx
(cabozantinib; Exelixis)
VEGF receptor inhibitor Advanced or metastatic RCC April 25, 2016
Gilotrif
(afatinib; Boehringer Ingelheim)
EGFR inhibitor Advanced squamous-cell carcinoma of the lung that has progressed after platinum-based chemotherapy April 15, 2016
Ibrance
(palbociclib; Pfizer)
CDK4/CDK6 inhibitor HR-positive, HER2-negative advanced or metastatic breast cancer in combination with fulvestrant February 19, 2016
Imbruvica
(ibrutinib; Pharmacyclics)
BTK inhibitor First-line therapy for CLL March 4, 2016
First-line therapy for SLL May 9, 2016
Lenvima
(lenvatinib; Eisai)
VEGF receptor inhibitor Second-line treatment of advanced RCC, in combination with everolimus May 13, 2016
Tarceva
(erlotinib; Genentech)
EGFR inhibitor Now limited to NSCLC with EGFR mutations exon 19 or exon 21 October 18, 2016
Small-molecule inhibitors of signal transduction pathways
Venclexta
(venetoclax; AbbVie/Genentech)
BCL-2 inhibitor Second-line treatment of CLL with 17p deletion April 11, 2016
Xalkori
(crizotinib; Pfizer)
ALK/ROS inhibitor Metastatic NSCLC with ROS1 mutation March 11, 2016
Supportive care drugs
Defitelio
(defibrotide sodium; Jazz Pharmaceuticals)
Anticoagulant Hepatic veno-occlusive disease March 30, 2016
Sustol
(granisetron; Heron Therapeutics)
Serotonin 5-HT3 receptor antagonist CINV, in combination with other antiemetics August 9, 2016
Syndros
(dronabinol; Insys Therapeutics)
Tetrahydrocannabinol CINV in patients who have failed to respond adequately to conventional antiemetic treatments July 5, 2016
Other pathways
Afinitor
(everolimus; Novartis)
mTOR inhibitor Progressive, well-differentiated NETs of GI or lung origin February 26, 2016
Evomela
(melphalan; Spectrum Pharmaceuticals)
Alkylating drug For use as high-dose conditioning before stem-cell transplant in patients with multiple myeloma; for palliative treatment of multiple myeloma in patients who cannot use oral therapy March 10, 2016
Halaven
(eribulin mesylate; Eisai)
Microtubule inhibitor Unresectable or metastatic liposarcoma after anthracycline-containing regimen January 28, 2016
Kyprolis
(carfilzomib; Amgen)
Proteasome inhibitor Relapsed or refractory multiple myeloma with dexamethasone or with lenalidomide plus dexamethasone January 21, 2016
5-HT3 indicates 5-hydroxytryptamine; BTK, Bruton’s tyrosine kinase; CDK, cyclin-dependent kinase; CINV, chemotherapy-induced nausea and vomiting; CLL, chronic lymphocytic leukemia; EGFR, epidermal growth factor receptor; GI, gastrointestinal; HR, hormone receptor; HSCT, hematopoietic stem-cell transplantation; NET, neuroendocrine tumor; NSCLC, non–small-cell lung cancer; PD-1, programmed-cell death receptor-1; PDGFR-α, platelet-derived growth factor receptor alpha; PD-L1, PD-1 ligand 1; RCC, renal-cell carcinoma; SLL, small lymphocytic lymphoma; VEGF, vascular endothelial growth factor.

Immunotherapies

Immunotherapeutic approaches, including those that specifically target checkpoint proteins and those that use targeted monoclonal antibodies, are revolutionizing the treatment of many cancer types, and have led to paradigm shifts in their management and prognoses.

Checkpoint Inhibitors

The advent of checkpoint inhibitors has been the most transformative advancement in oncology in recent times. Inhibition of the immune checkpoint proteins cytotoxic T-lymphocyte–associated protein 4, programmed-cell death receptor-1 (PD-1), and its ligand 1 (PD-L1) has allowed harnessing of the immune system to target tumor cells.

In 2016, several immune checkpoint inhibitors, including the anti–PD-1 inhibitors Opdivo (nivolumab; Bristol-Myers Squibb) and Keytruda (pembrolizumab; Merck), and the PD-L1–blocking antibody Tecentriq (atezolizumab; Genentech) received either new approvals or additional indications.

In January 2016, Opdivo’s indication for melanoma was expanded twice. In May 2016, Opdivo was approved for the treatment of patients with classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem-cell transplantation (HSCT) and posttransplant therapy with Adcetris (brentuximab vedotin; Seattle Genetics).

In September 2016, the FDA modified the dosing regimen for Opdivo by replacing the single-dose regimen (3 mg/kg intravenously [IV] every 2 weeks) with the new recommended regimen of 240 mg IV every 2 weeks until disease progression or intolerable toxicity for renal-cell carcinoma (RCC), metastatic melanoma, and non–small-cell lung cancer (NSCLC).

And in November 2016, Opdivo was approved for the treatment of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck that progresses during or after receiving a platinum-based therapy.

In August 2016, the FDA granted Keytruda a new indication for the treatment of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck that progressed during or after platinum-containing chemotherapy. In October, the FDA approved Keytruda for the first-line treatment of patients with metastatic NSCLC whose tumors express high levels of PD-L1 (tumor proportion score ≥50%) as determined by an FDA-approved test, with no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations, and no previous systemic chemotherapy treatment for metastatic NSCLC. This represents the first approval of a checkpoint inhibitor as first-line treatment in metastatic NSCLC.

In May 2016, the FDA approved Tecentriq for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or after platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

In October 2016, the FDA approved Tecentriq for the treatment of patients with metastatic NSCLC that progressed during or after platinum-containing chemotherapy.

Monoclonal Antibodies

Therapeutic monoclonal antibodies that target various cell surface antigens on lymphoid and myeloid tissues, such as CD20 and CD38, have been successfully used to deplete neoplastic cells in the treatment of hematologic malignancies, including various lymphomas, chronic lymphocytic leukemia (CLL), and multiple myeloma.

Arzerra (ofatumumab; Novartis) is an anti-CD20 monoclonal antibody that was approved in January 2016 for the treatment of patients with CLL that is refractory to fludarabine and alemtuzumab.

In February 2016, another anti-CD20 monoclonal antibody Gazyva (obinutuzumab; Genentech) was approved for use in combination with bendamustine followed by obinutuz­umab monotherapy for the treatment of patients with follicular lymphoma whose disease relapsed after, or is refractory to, a rituximab-containing regimen.

In November 2016, the anti-CD38 antibody Darzalex (daratumumab; Janssen Biotech) received an extended indication for the treatment of patients with multiple myeloma who have received at least 1 previous therapy, in combination with the immunomodulatory drug (IMiD) lenalidomide and dexamethasone, or the proteasome inhibitor bortezomib and dexamethasone. Darzalex was initially approved in 2015 as monotherapy for patients with multiple myeloma who have received at least 3 lines of therapy, including a proteasome inhibitor and an IMiD or whose disease is double refractory to a proteasome inhibitor and an IMiD.

Platelet-derived growth factor receptor alpha (PDGFR-α)–mediated signaling is implicated in the growth and metastatic potential of sarcomas. Lartruvo (olaratumab; Eli Lilly) is a PDGFR-α antagonist that prevents cognate ligand binding and receptor activation. In October 2016, Lartruvo received accelerated approval for use in combination with doxorubicin for the treatment of patients with soft-tissue sarcoma and a histologic subtype for which an anthracycline-containing regimen is appropriate and which is not amenable to curative treatment with radiotherapy or surgery.

Small-Molecule Inhibitors of Signal Transduction Pathways

In 2016, several small-molecule tyrosine kinase inhibitors (TKIs) that blocked signal transduction pathways critical for the pathogenesis of cancer cells were approved by the FDA.

VEGF Pathway Inhibition

Drugs that target the vascular endothelial growth factor (VEGF) receptor pathway have revolutionized the treatment paradigm for patients with metastatic RCC. This year, 2 additional TKIs targeting the VEGF pathway—Lenvima (lenvatinib; Eisai) and Cabometyx (cabozantinib; Exelixis)—were approved for the treatment of patients with advanced or metastatic RCC. In May 2016, Lenvima was approved for use in combination with everolimus for the treatment of patients with advanced RCC after 1 previous anti­angiogenic therapy.

In April 2016, Cabometyx, a multi­kinase TKI with activity against MET, VEGF receptor 2, and RET, was approved for the treatment of patients with advanced RCC who have received previous antiangiogenic therapy.

ALK Inhibition

Nonoverlapping rearrangements of several key genes, including ALK and ROS1, have been identified in NSCLC subtypes. Since the identification of the pathogenic role of ALK fusions in NSCLC, the development and approval of several small-molecule ALK-targeted TKIs, including ceritinib, alectinib, and Xalkori (crizotinib; Pfizer), have transformed the disease course for patients harboring ALK fusions. Xalkori is a multikinase TKI that inhibits ALK, hepatocyte growth factor receptor (c-Met), as well as ROS mutation. In March 2016, the FDA expanded the indication of Xalkori to include patients with metastatic NSCLC with ROS1-positive tumors, in addition to patients with ALK-positive tumors.

EGFR Pathway Inhibition

Several targeted agents that inhibit the oncogenic EGFR pathway are available for the treatment of patients with NSCLC. In October 2016, the FDA modified the indication for Tarceva (erlotinib; Genentech) for lung cancer to limit its use to patients with NSCLC with EGFR mutations exon 19 deletions or exon 21 substitution mutations, as detected by an FDA-approved test, in patients who are receiving first-line, maintenance, or second-­line or later treatment after disease progression with ≥1 chemotherapy regimens. Tarceva has not been shown to improve outcomes in patients with NSCLC without these EGFR mutations.

Gilotrif (afatinib; Boehringer Ingelheim) is another EGFR-directed therapy that received a new indication in April 2016 for patients with advanced squamous-cell carcinoma of the lung that has progressed after treatment with platinum-based chemotherapy, representing a new second-line treatment option for the second largest subtype of NSCLC. It was previously approved as first-line therapy for patients with NSCLC whose tumors have EGFR exon 19 deletions or exon 21 substitution mutations as detected by an FDA-approved test.

Antiapoptotic Strategies

In CLL, the overexpression of the antiapoptotic protein BCL-2 is implicated in treatment resistance; blocking its activity may induce programmed-cell death. The BCL-2 inhibitor Venclexta (venetoclax; AbbVie/Genentech) is a BH3 mimetic that blocks the interaction of BCL-2 with the apoptotic machinery. Venclexta received accelerated approval in April 2016 for the treatment of patients with CLL harboring 17p deletion, as detected by an FDA-approved test, who have received at least 1 previous therapy.

Cell-Cycle Inhibition

Given that cell-cycle regulation is implicated in resistance to endocrine therapy, cyclin-dependent kinase (CDK)4 or 6 inhibition, in combination with endocrine therapy, may be able to overcome this resistance and provide durable tumor responses. In February 2016, Ibrance (palbociclib; Pfizer), a first-in-class inhibitor of CDK4 and CDK6, received approval for expanded use in combination with fulvestrant in women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer who had disease progression after endocrine therapy.

Inhibitors of B-Cell Receptor Signaling

B-cell receptor activation via Bruton’s tyrosine kinase (BTK) signaling is known to play a crucial role in the pathogenesis of CLL and small lymphocytic lymphoma (SLL). In May 2016, the FDA expanded the use of Imbruvica (ibrutinib; Pharmacyclics), a selective BTK inhibitor, to include first-line therapy for SLL.

Other Pathways

Several drugs targeting other pathways were also approved, including Afinitor (everolimus; Novartis), Halaven eribulin mesylate; Eisai), and Kyprolis (carfilzomib; Amgen).

In February 2016, Afinitor, an inhibitor of the PI3K/AKT/mTOR pathway, received expanded approval for the treatment of adults with progressive, well-differentiated, nonfunctional neuroendocrine tumors of gastrointestinal or lung origin with unresectable, locally advanced or metastatic disease.

Previously approved for the treatment of metastatic breast cancer, Halaven, a cytotoxic agent that inhibits microtubule dynamics, received a new indication in January 2016 for the treatment of patients with un­resectable or metastatic liposarcoma who have received a previous anthracycline-containing regimen.

The label for the second-generation proteasome inhibitor Kyprolis is now expanded to include its use in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 to 3 lines of therapy. The FDA also approved Kyprolis as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received 1 or more lines of therapy.

Supportive Care Drugs

Chemotherapy-induced nausea and vomiting (CINV) is a distressing side effect of chemotherapy that can significantly diminish the patient’s health-related quality of life. Two new drugs, Sustol (granisetron; Heron Therapeutics) and Syndros (dronabinol; Insys Therapeutics) were indicated for the treatment of CINV.

On August 9, 2016, the FDA approved Sustol, the first extended-release serotonin receptor antagonist injection, for use in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide combination chemotherapy regimens. Syndros, a pharmaceutical version of tetrahydrocannabinol that acts on cannabinoid receptors, was approved in July 2016 for the treatment of CINV in patients whose disease has failed to respond adequately to conventional antiemetic treatments.

Hepatic veno-occlusive disease, also known as sinusoidal obstruction syndrome, is a rare complication encountered in patients who receive chemotherapy and HSCT, leading to liver damage and frequently to death. In March 2016, the FDA approved Defitelio (defibrotide sodium; Jazz Pharmaceuticals) for the treatment of adults and pediatric patients with hepatic veno-occlusive disease, with renal or pulmonary dysfunction after HSCT. Defitelio is an oligonucleotide mixture with profibrinolytic properties; however, its precise mechanism of action remains to be fully elucidated.

Conclusion

Consistent with the trend of the past few years, 2016 also saw a number of important oncology and supportive care drug approvals by the FDA that included checkpoint inhibitors, monoclonal antibodies, and signal transduction inhibitors, and expanded the current arsenal of oncology treatments.

Notably, checkpoint inhibitors continue to make their mark, cementing their place in the future of anticancer therapy. A plethora of signal transduction inhibitors are now available to combat various cancer types.

The pace of oncology drug innovation is expected to be maintained in the coming years, as many investigational agents are currently in regulatory review or are undergoing early- and late-stage clinical trial testing.