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