This section provides a brief overview of new cancer drugs or new indications approved by the FDA between November 5 and December 3, 2019.
- Tazverik First FDA-Approved Drug for Advanced Epithelioid Sarcoma Ineligible for Resection
- Ayvakit First Targeted Therapy Approved for Gastrointestinal Stromal Tumors with PDGFRA Mutations
- Enhertu a Novel Dual-Targeted Therapy Approved for Metastatic HER2-Positive Breast Cancer
- Padcev First-in-Class Targeted Therapy FDA Approved for Advanced or Metastatic Urothelial Carcinoma
- Keytruda Indicated for BCG-Unresponsive High-Risk, Non–Muscle Invasive Bladder Cancer
- Lynparza Indicated for Maintenance Treatment of Metastatic Pancreatic Cancer with BRCA Mutation
- Xtandi Now Approved for Metastatic Castration-Sensitive Prostate Cancer
Tazverik First FDA-Approved Drug for Advanced Epithelioid Sarcoma Ineligible for Resection
On January 23, 2020, the FDA accelerated the approval of tazemetostat (Tazverik; Epizyme Inc), an EZH2 methyltransferase blocker, for the treatment of patients aged ≥16 years with metastatic or locally advanced epithelioid sarcoma (a subtype of soft-tissue sarcoma) that is not eligible for complete resection. Tazemetostat received an orphan drug designation for this indication.
“Epithelioid sarcoma accounts for less than one percent of all soft-tissue sarcomas,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Until today, there were no treatment options specifically for patients with epithelioid sarcoma. The approval of Tazverik provides a treatment option that specifically targets this disease.”
Epithelioid sarcoma usually begins in the soft-tissue area under the skin of an extremity, although it can start in other areas of the body. For patients with localized disease, surgery is the standard treatment; chemotherapy or radiation may also be used, but the likelihood of progression to metastatic disease is high with these treatments; approximately 50% of people have metastatic disease at the time of diagnosis.
The approval of tazemetostat was based on a clinical trial of 62 patients with metastatic or locally advanced epithelioid sarcoma. Patients received 800 mg of tazemetostat twice daily until disease progression or unacceptable toxicity. The primary end point was overall response rate (ORR).
The ORR was 15%, consisting of 1.6% complete responses and 13% partial responses. Of the 9 patients who had a response, 6 (67%) patients had a response lasting >6 months.
The most common adverse events were pain, fatigue, nausea, decreased appetite, vomiting, and constipation. Tazemetostat therapy is associated with an increased risk for secondary malignancies, including T-cell lymphoblastic lymphoma, myelodysplastic syndrome, and acute myeloid leukemia, and the drug can also cause harm to a fetus.
Ayvakit First Targeted Therapy Approved for Gastrointestinal Stromal Tumors with PDGFRA Mutations
On January 9, 2020, the FDA accelerated the approval of avapritinib (Ayvakit; Blueprint Medicines Corporation), a kinase inhibitor, for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. This approval includes GIST that harbors a PDGFRA D842V mutation, which is the most common exon 18 mutation. The FDA granted breakthrough therapy and orphan drug designations to avapritinib.
“GIST harboring a PDGFRA exon 18 mutation do not respond to standard therapies for GIST. However, today’s approval provides patients with the first drug specifically approved for GIST harboring this mutation,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Clinical trials showed a high response rate with almost 85% of patients experiencing tumor shrinkage with this targeted drug.”
The activating mutations in PDGFRA have been linked to the development of GIST, and up to approximately 10% of patients with GIST have this type of gene mutation.
The approval of avapritinib was based on a clinical trial of 43 patients with GIST associated with a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutation. Patients received avapritinib 300 mg or 400 mg orally once daily until disease progression or until unacceptable toxicity. Based on the study’s results, the recommended dose of avapritinib is 300 mg once daily.
The primary end point was overall response rate (ORR). Among patients with a PDGFRA exon 18 mutation, the ORR was 84%, consisting of 7% complete responses and 77% partial responses. For patients with PDGFRA D842V mutation, the ORR was 89%, including 8% with a complete response and 82% with a partial response.
The median duration of response was not yet reached, but in the 61% of the patients with exon 18 mutations who had a response, the response lasted ≥6 months (31% of patients with an ongoing response were followed for <6 months).
The common side effects with avapritinib were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased tearing (lacrimation), abdominal pain, constipation, rash, and dizziness. Avapritinib can cause intracranial hemorrhage and central nervous system effects, and this drug may cause harm to a fetus.
Enhertu a Novel Dual-Targeted Therapy Approved for Metastatic HER2-Positive Breast Cancer
On December 23, 2019, the FDA accelerated the approval of fam-trastuzumab deruxtecan-nxki (Enhertu; Daiichi Sankyo), a HER2-directed antibody and topoisomerase inhibitor conjugate, for the treatment of adults with unresectable or metastatic HER2-positive breast cancer after ≥2 previous anti-HER2–based regimens in the metastatic setting. The FDA granted fam-trastuzumab deruxtecan-nxki a breakthrough therapy designation.
“There have been many advances in the development of drugs for HER2-positive breast cancer since the introduction of Herceptin (trastuzumab) in 1998. The approval of Enhertu represents the newest treatment option for patients who have progressed on available HER2-directed therapies,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Drug development in the area of targeted therapies builds on our scientific understanding of malignant diseases not only in breast cancer, but in multiple other diseases.”
Approximately 1 of 5 breast cancers is associated with the HER2 gene mutation, an aggressive type of breast cancer.
Enhertu’s approval was based on the results of a clinical trial of 184 female patients with HER2-positive, unresectable and/or metastatic breast cancer who had received ≥2 previous anti-HER2 therapies in the metastatic setting. Patients were heavily pretreated in the metastatic setting, receiving from 2 to 17 previous therapies. In the study, patients received fam-trastuzumab deruxtecan-nxki every 3 weeks, and tumor imaging was obtained every 6 weeks. The overall response rate was 60.3%, with a median duration of response of 14.8 months.
The most common adverse events with fam-trastuzumab deruxtecan-nxki were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, decreased neutrophil count, diarrhea, leukopenia, cough, and decreased platelet count. This drug may increase the risk for ventricular dysfunction.
Fam-trastuzumab deruxtecan-nxki is associated with a risk for interstitial lung disease and embryo-fetal toxicity. Pregnant women should not take this medication.
Padcev First-in-Class Targeted Therapy FDA Approved for Advanced or Metastatic Urothelial Carcinoma
On December 18, 2019, the FDA accelerated the approval of enfortumab vedotin-ejfv (Padcev; Astellas Pharma), a Nectin-4–directed antibody and microtubule inhibitor conjugate, for the treatment of adults with locally advanced or metastatic urothelial carcinoma after immunotherapy with a PD-1 or PD-L1 inhibitor and a platinum-containing chemotherapy. These are the current standard treatments for patients with bladder cancer, the sixth most common cancer in the United States. Urothelial cancer accounts for >90% of bladder cancers.
Enfortumab vedotin-ejfv represents a new type of therapy for patients with advanced urothelial cancer whose disease progressed during chemotherapy and immunotherapy. The FDA granted a breakthrough therapy designation to this therapy.
“Antibody-drug conjugates are strategic tools in the targeted treatment of cancer. These conjugates combine the ability of monoclonal antibodies to target specific receptors on cancer cells and then deliver a drug to the cancer cell,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “Padcev is an antibody-drug conjugate that targets Nectin-4, a cell surface protein expressed on bladder cancer cells and a cell-killing agent, monomethyl auristatin E.”
Enfortumab vedotin-ejfv was approved based on the results of a clinical trial of 125 patients with locally advanced or metastatic urothelial cancer who have received a PD-1 or PD-L1 inhibitor therapy and platinum-based chemotherapy.
The overall response rate was 44%, including 12% complete responses and 32% partial responses. The median duration of response to therapy with enfortumab vedotin-ejfv was 7.6 months.
The most common adverse events with enfortumab vedotin-ejfv were fatigue, peripheral neuropathy, decreased appetite, rash, alopecia, nausea, altered taste, diarrhea, dry eye, pruritis, and dry skin. Patients receiving this drug may have hyperglycemia, regardless of the presence of diabetes, as well as eye disorders, and the drug may cause harm to a fetus.
Keytruda Indicated for BCG-Unresponsive High-Risk, Non–Muscle Invasive Bladder Cancer
On January 8, 2020, the FDA accelerated the approval of a new indication for pembrolizumab (Keytruda; Merck & Co) for the treatment of Bacillus Calmette-Guérin (BCG)-unresponsive, high-risk, non–muscle invasive bladder cancer and carcinoma in situ, with or without papillary tumors, in patients who are ineligible for or who have elected not to undergo cystectomy. Pembrolizumab has been previously approved for many indications.
The approval was based on efficacy results from the KEYNOTE-057 clinical trial, a multicenter, single-arm study involving 148 patients with high-risk non–muscle invasive bladder cancer, of whom 96 had BCGunresponsive carcinoma in situ with or without papillary tumors. Patients received pembrolizumab 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk disease, or progressive disease, or up to 24 months of therapy without disease progression.
The major efficacy outcomes were complete response, urine cytology, computed tomography urography, and duration of response. The complete response rate in the 96 patients with high-risk BCG-unresponsive disease with carcinoma in situ was 41% (95% confidence interval, 31-51), and the median response duration was 16.2 months. Overall, 46% of responding patients had a complete response lasting ≥12 months.
The most common (≥10%) adverse reactions with pembrolizumab in this study were fatigue, diarrhea, rash, pruritis, musculoskeletal pain, hematuria, cough, arthralgia, nausea, constipation, urinary tract infection, peripheral edema, hypothyroidism, and nasopharyngitis.
Lynparza Indicated for Maintenance Treatment of Metastatic Pancreatic Cancer with BRCA Mutation
On December 27, 2019, the FDA accelerated the approval of a new indication for olaparib (Lynparza; AstraZeneca) for the maintenance treatment of adults with metastatic pancreatic adenocarcinoma associated with a deleterious or suspected deleterious germline BRCA mutation, as detected by an FDA-approved test, and whose disease did not progress during ≥16 weeks of a first-line platinum-based chemotherapy regimen. Olaparib was previously approved for ovarian cancer and for breast cancer associated with BRAF mutation.
At the same time, the FDA approved the BRACAnalysis CDx test (Myriad Genetic Laboratories) as a companion diagnostic for the selection of patients with pancreatic cancer for treatment with olaparib based on the identification of deleterious or suspected deleterious germline BRCA1 or BRCA2 mutations.
This approval was based on results from the POLO clinical trial, a doubleblind, placebo-controlled, multicenter study that randomized (3:2) 154 patients with metastatic pancreatic adenocarcinoma associated with a deleterious or suspected deleterious germline BRCA mutation to olaparib 300 mg orally twice daily or to placebo until disease progression or unacceptable toxicity.
The main efficacy measure was progression-free survival (PFS). Additional outcome measures included overall survival (OS) and overall response rate (ORR). The median PFS was 7.4 months (95% confidence interval [CI], 4.1-11) with olaparib compared with 3.8 months (95% CI, 3.5-4.9) with placebo (hazard ratio [HR], 0.53; 95% CI, 0.35-0.81; P = .0035). The median OS was 18.9 months (95% CI, 14.9-26.2) with olaparib versus 18.1 months (95% CI, 12.6-26.1) with placebo (HR, 0.91; 95% CI, 0.56-1.46; P = .683); the ORRs in patients with measurable disease at baseline were 23% versus 12%, respectively.
The adverse reactions with olaparib in the POLO study were consistent with the safety profile of olaparib.
Xtandi Now Approved for Metastatic Castration-Sensitive Prostate Cancer
On December 16, 2019, the FDA approved a new indication for enzalutamide (Xtandi; Astellas Pharma) for the treatment of patients with metastatic castration-sensitive prostate cancer (CSPC). Enzalutamide was previously approved for patients with castration-resistant prostate cancer.
The approval was based on efficacy results from the ARCHES clinical trial of 1150 patients with metastatic CSPC who were randomized (1:1) to oral enzalutamide 160 mg once daily (N = 574) or to oral placebo once daily (N = 576). All patients received a gonadotropin-releasing hormone analog or had previous bilateral orchiectomy.
The main efficacy measure was radiographic progression-free survival (PFS), which was defined as the time from randomization to radiographic disease progression at any time or death within 24 weeks after drug discontinuation. Radiographic disease progression was defined by the identification of ≥2 new bone lesions on a bone scan with confirmation and/or progression in soft-tissue disease. The time to new antineoplastic therapy was an additional end point.
The median radiographic PFS was not reached in the enzalutamide arm versus 19.4 months (95% confidence interval, 16.6-not reached) in the placebo arm (P <.0001). A significant improvement was also seen with enzalutamide versus placebo in the time to initiation of a new antineoplastic therapy (P <.0001). The overall survival data were not mature at the time of the analysis.
The most common (≥5%) adverse reactions occurring more frequently (≥2% vs placebo) with enzalutamide in this study were hot flush, asthenia/fatigue, hypertension, fractures, and musculoskeletal pain.