Recent FDA News Advancing Treatments in Oncology

Oncology Drug Targeting a Key Genetic and AST liver tests every 2 weeks during the first month of treatment, Driver of Cancer Approved then monthly and as clinically indicated. Women who are pregnant or The FDA granted Accelerated Approval to larotrectinib, a treatment for breastfeeding should not take larotrectinib because it may cause harm adult and pediatric patients whose cancers have a specific biomarker. to a developing fetus or newborn baby. Patients should report signs of This is the second time the agency has approved a cancer treat- neurologic reactions such as dizziness. ment based on a common biomarker across different types of tumors The FDA granted this application Priority Review and Breakthrough rather than the location in the body where the tumor originated. The Therapy designation. Larotrectinib also received Orphan Drug desig- approval marks a new paradigm in the development of cancer drugs nation, which provides incentives to assist and encourage the develop- that are “tissue agnostic.” It follows the policies that the FDA developed ment of drugs for rare diseases. in a guidance document released earlier this year. Larotrectinib is indicated for the treatment of adult and pediatric Venetoclax Combination Approved for Adult patients with solid tumors that have a neurotrophic receptor tyrosine AML Patients kinase (NTRK) gene fusion without a known acquired resistance mu- The FDA recently granted Accelerated Approval to venetoclax in com- tation, are metastatic, or where surgical resection is likely to result in bination with azacitidine or decitabine or low-dose cytarabine for severe morbidity and have no satisfactory alternative treatments or the treatment of newly diagnosed acute myeloid leukemia (AML) in that have progressed following treatment. adults who are age 75 years or older, or who have comorbidities that “[This] approval marks another step in an important shift toward preclude use of intensive induction chemotherapy. treating cancers based on their tumor genetics rather than their site of Approval was based on two open-label, non-randomized trials in origin in the body,” said FDA Commissioner Scott Gottlieb, MD. “This patients with newly diagnosed AML who were >75 years of age or had new site-agnostic oncology therapy isn’t specific to a cancer arising in comorbidities that precluded the use of intensive induction chemo- a particular body organ, such as breast or colon cancer. Its approval therapy. Efficacy was established based on the rate of complete remis- reflects advances in the use of biomarkers to guide drug development sion (CR) and CR duration. and the more targeted delivery of medicine. Study M14-358 (NCT02203773) was a non-randomized, open- “We now have the ability to make sure that the right patients get label clinical trial of venetoclax in combination with azacitidine the right treatment at the right time. This type of drug development (n=67) or decitabine (n=13) in newly diagnosed patients with AML. program, which enrolled patients with different tumors but a common In combination with azacitidine, 25 patients achieved a CR (37%, 95% gene mutation, wouldn’t have been possible a decade ago because we CI: 26, 50) with a median observed time in remission of 5.5 months knew a lot less about such cancer mutations,” he continued. “Using our (range: 0.4-30 months). In combination with decitabine, seven pa- breakthrough therapy designation and accelerated approval processes, tients achieved a CR (54%, 95% CI: 25, 81) with a median observed we support innovation in precision oncology drug development and time in remission of 4.7 months (range: 1.0-18 months). The observed the evolution of more targeted and effective treatments for cancer pa- time in remission is the time from start of CR to data cut-off date or tients. This is especially true when it comes to pediatric cancers. relapse from CR. “We’re committed to continuing to advance a more modern frame- Study M14-387 (NCT02287233) was a non-randomized, open- work of clinical trial designs that support more targeted innovations label trial of venetoclax in combination with low-dose cytarabine across disease types based on our growing understanding of the un- (n=61) in newly diagnosed patients with AML, including patients derlying biology of diseases like cancer.” with previous exposure to a hypomethylating agent for an antecedent Research has shown that the NTRK genes, which encode for TRK pro- hematologic disorder. In combination with low-dose cytarabine, 13 teins, can become fused to other genes abnormally, resulting in growth patients achieved a CR (21%, 95% CI: 12, 34) with a median observed signals that support the growth of tumors. NTRK fusions are rare but time in remission of 6 months (range: 0.03-25 months). occur in cancers arising in many sites of the body. Prior to this approval, The most common adverse reactions (≥30%) to venetoclax in com- there had been no treatment for cancers that frequently express this mu- bination with azacitidine or decitabine or low-dose cytarabine were tation, like mammary analogue secretory carcinoma, cellular or mixed nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile congenital mesoblastic nephroma, and infantile fibrosarcoma. neutropenia, fatigue, vomiting, peripheral edema, pneumonia, dyspnea, The efficacy of larotrectinib was studied in three clinical trials that hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, included 55 pediatric and adult patients with solid tumors that had an dizziness, cough, oropharyngeal pain, pyrexia, and hypotension. identified NTRK gene fusion without a resistance mutation and were The recommended venetoclax dose depends upon the combination metastatic or where surgical resection was likely to result in severe regimen. morbidity. These patients had no satisfactory alternative treatments This indication is approved under Accelerated Approval and con- or had cancer that progressed following treatment. tinued approval for this indication may be contingent upon verifica- Larotrectinib demonstrated a 75 percent overall response rate tion and description of clinical benefit in confirmatory trials. FDA across different types of solid tumors. These responses were durable, granted this application Priority Review, Breakthrough Therapy with 73 percent of responses lasting at least 6 months, and 39 percent Designation, and Orphan Product Designation. lasting a year or more at the time results were analyzed. Examples of The ongoing phase III studies, VIALE-A (NCT02993523) and tumor types with an NTRK fusion that responded to larotrectinib in- VIALE-C (NCT03069352), evaluate venetoclax in combination with clude soft tissue sarcoma, salivary gland cancer, infantile fibrosarcoma, azacitidine or low-dose cytarabine with overall survival as the primary thyroid cancer, and lung cancer. endpoint and are intended as the confirmatory trials. Larotrectinib received an accelerated approval, which enables the FDA to approve drugs for serious conditions to fill an unmet med- Atezolizumab With Chemo & Bevacizumab ical need using clinical trial data that is thought to predict a clini- for Metastatic Non-Squamous NSCLC cal benefit to patients. Further clinical trials are required to confirm The FDA recently approved atezolizumab in combination with larotrectinib’s clinical benefit and the sponsor is conducting or plans ­bevacizumab, paclitaxel, and carboplatin for the first-line treatment to conduct these studies. of patients with metastatic non-squamous, non-small cell lung cancer Common side effects reported by patients receiving larotrectinib (NSq NSCLC) with no EGFR or ALK genomic tumor aberrations. in clinical trials include fatigue, nausea, cough, constipation, diarrhea, Approval was based on the IMpower150 trial (NCT02366143), an dizziness, vomiting, and increased AST and ALT enzyme blood levels open-label, randomized (1:1:1), three-arm trial enrolling 1,202 pa- in the liver. Health care providers are advised to monitor patient ALT Continued on page 34 oncology-times.com Oncology Times 33 The NCI estimates that approximately 19,520 people will be diag- FDA UPDATES nosed with AML this year; approximately 10,670 patients with AML continued from page 33 will die of the disease in 2018. The efficiency of gilteritinib was studied in a clinical trial of 138 patients with relapsed or refractory AML having a confirmed FLT3 tients receiving first-line treatment for metastatic NSq NSCLC. Eighty- mutation. Twenty-one percent of patients achieved complete remis- seven percent (1,045 patients) were identified as not having EGFR or sion or complete remission with partial hematologic recovery with ALK tumor mutations. The trial was designed to conduct comparisons treatment. Of the 106 patients who required red blood cell or platelet between each of the atezolizumab-containing arms with the control transfusions at the start of treatment with gilteritinib, 31 percent be- arm. Patients were randomized to receive the following: came transfusion-free for at least 56 days. • atezolizumab, carboplatin, paclitaxel, and bevacizumab (4-drug Common side effects reported by patients in clinical trials were regimen); myalgia/arthralgia, fatigue, and liver transaminase. Health care pro- • atezolizumab, carboplatin, and paclitaxel (3-drug regimen); or viders are advised to monitor patients for posterior reversible en- • carboplatin, paclitaxel, and bevacizumab (control arm). cephalopathy syndrome, prolonged QT interval, and pancreatitis. Following completion of 4 or 6 cycles of carboplatin and paclitaxel, pa- Rare cases of differentiation syndrome have been seen in patients tients continued to receive bevacizumab in the four-drug arm and the con- taking gilteritinib. Women who are pregnant or breastfeeding should trol arm and continued to receive atezolizumab in the two experimental not take gilteritinib­ because it may cause harm to a developing fetus arms until disease progression or unacceptable toxicity. The major efficacy or newborn baby. measures were overall survival (OS) and progression-free survival (PFS). The FDA granted this application Fast Track and Priority Among patients with NSq NSCLC without an EGFR or ALK muta- Review designation. Gilteritinib also received Orphan Drug designa- tion, the estimated median OS was 19.2 months for patients receiving tion, which provides incentives to assist and encourage the develop- the four-drug regimen and 14.7 months for those receiving carboplatin, ment of drugs for rare diseases. paclitaxel, and bevacizumab (HR 0.78; 95% CI: 0.64, 0.96; p=0.016). The estimated median PFS was 8.5 months for patients receiving the Glasdegib Plus LDAC Approved for Patients four-drug regimen and 7.0 months for those in the control arm (HR With Acute Myeloid Leukemia 0.71; 95% CI 0.59, 0.85; p=0.0002). The overall response rates were 55 The FDA recently approved glasdegib tablets to be used in combina- percent in the four-drug arm and 42 percent in the control arm. No sig- tion with low-dose cytarabine (LDAC) for the treatment of newly nificant differences in interim OS or final PFS were observed between ­diagnosed acute myeloid leukemia (AML) in adults who are 75 years the three-drug arm and the control arm. of age or older or who have comorbidities that may preclude the use The most common adverse reactions (reported in ≥ 20% of pa- of intensive chemotherapy. tients) with atezolizumab administered with carboplatin, paclitaxel, “Intensive chemotherapy is usually used to control AML, but many and bevacizumab were fatigue/asthenia, alopecia, nausea, diarrhea, adults with AML are unable to have intensive chemotherapy because constipation, decreased appetite, arthralgia, hypertension, and neu- of its toxicities. [This] approval gives health care providers another ropathy. Atezolizumab was discontinued for adverse reactions in 15 tool to use in the treatment of AML patients with various, unique percent of patients; the most common adverse reaction resulting in needs. Clinical trials showed that overall survival was improved using discontinuation of atezolizumab was pneumonitis (1.8%). glasdegib in combination with LDAC compared to LDAC alone for The incidence of development antibodies to atezolizumab (anti- patients who would not tolerate intensive chemotherapy,” said Richard drug antibodies, ADA) ranges from 30 percent to 42 percent across Pazdur, MD, Director of the FDA’s Oncology Center of Excellence and clinical studies supporting the approved indications. Among 364 Acting Director of the Office of Hematology and Oncology Products patients with NSCLC who received the four-drug regimen in the in the FDA’s Center for Drug Evaluation and Research. IMpower150 study, 36 percent (n=132) had treatment-emergent an- NCI estimates that in 2018, approximately 19,520 people will be tibodies against atezolizumab with the majority (83% of these 132 diagnosed with AML and approximately 10,670 patients with AML patients) having ADA prior to receiving the second atezolizumab will die of the disease. Almost half of the adults diagnosed with AML dose. Patients who tested positive for treatment-emergent ADA had are not treated with intensive chemotherapy because of comorbidities lower systemic atezolizumab exposure compared to those who were and chemotherapy related toxicities. ADA-negative. In an exploratory analysis, the HR for OS was similar The efficacy of glasdegib was studied in a randomized clinical trial in the ADA-positive (0.69; 95% CI: 0.44, 1.07) and the ADA-negative in which 111 adult patients with newly diagnosed AML were treated subgroups (0.64; 95% CI: 0.46, 0.90). The presence of ADA neither in- with either glasdegib in combination with LDAC or LDAC alone. The creased the incidence nor severity of adverse reactions. Given the high trial measured overall survival (OS) from the date of randomization rate of ADA, analyses across the atezolizumab development program to death from any cause. Results demonstrated a significant improve- will be conducted to evaluate the effects of ADA on efficacy, safety, ment in OS in patients treated with glasdegib. The median OS was 8.3 and pharmacokinetics. FDA granted this application Priority Review. months for patients treated with glasdegib plus LDAC compared with 4.3 months for patients treated with LDAC only. Treatment Approved for Adult R/R AML Common side effects reported by patients receiving glasdegib in Patients With FLT3 Mutation clinical trials include anemia, fatigue, hemorrhage, febrile neutro- Gilteritinib tablets have been approved by the FDA for the treatment of penia, muscle pain, nausea, edema, thrombocytopenia, dyspnea, de- adult patients who have relapsed or refractory acute myeloid leukemia creased appetite, dysgeusia, mucositis, constipation, and rash. (AML) with a FLT3 mutation as detected by an FDA-approved test. The The prescribing information for glasdegib includes a Boxed FDA also approved an expanded indication for a companion diagnostic Warning to advise health care professionals and patients about the to include use with gilteritinib. The LeukoStrat CDx FLT3 Mutation risk of embryo-fetal death or severe birth defects. It should not be used Assay is used to detect the FLT3 mutation in patients with AML. during pregnancy or while breastfeeding. Pregnancy testing should be “Approximately 25-30 percent of patients with AML have a mu- conducted in females of reproductive age prior to initiation of glas- tation in the FLT3 gene. These mutations are associated with a par- degib treatment and effective contraception should be used during ticularly aggressive form of the disease and a higher risk of relapse,” treatment and for at least 30 days after the last dose. said Richard Pazdur, MD, Director of the FDA’s Oncology Center Glasdegib must be dispensed with a patient Medication Guide of Excellence and Acting Director of the Office of Hematology and that describes important information about the drug’s uses and risks. Oncology Products in the FDA’s Center for Drug Evaluation and Patients should also be advised not to donate blood or blood products Research. “[Gilteritinib] targets this gene and is the first drug to be during treatment. Health care providers should also monitor patients approved that can be used alone in treating patients with AML having for changes in the electrical activity of the heart, called QT prolongation. a FLT3 mutation who have relapsed or who don’t respond to initial The FDA granted this application Priority Review designation. treatment.” Glasdegib also received Orphan Drug Designation. OT

34 Oncology Times January 5, 2019