Accelerated Approval of Naxitamab for High-Risk Neuroblastoma
The FDA granted accelerated approval to naxitamab in combination with granulocyte-macrophage colony-stimulating factor 0(GM-CSF) for pediatric patients one year of age and older and adult patients with relapsed or refractory high-risk neuroblastoma in the bone or bone marrow demonstrating a partial response, minor response, or stable disease to prior therapy.
Efficacy was evaluated in patients with relapsed or refractory neuroblastoma in the bone or bone marrow enrolled in two single-arm, open-label trials: Study 201 (NCT 03363373) and Study 12-230 (NCT 01757626). Patients with progressive disease following their most recent therapy were excluded.
Patients received 3 mg/kg naxitamab administered as an intravenous infusion on days 1, 3, and 5 of each 4-week cycle in combination with GM-CSF subcutaneously at 250 [mu]g/m2/day on days -4 to 0 and at 500 [mu]g/m2/day on days 1 to 5. At the investigator's discretion, patients were permitted to receive pre-planned radiation to the primary disease site in Study 201 and radiation therapy to non-target bony lesions or soft tissue disease in Study 12-230.
The main efficacy outcome measures were confirmed overall response rate (ORR) per the revised International Neuroblastoma Response Criteria and duration of response (DOR). Among 22 patients treated in the multicenter Study 201, the ORR was 45 percent (95% CI: 24%, 68%) and 30 percent of responders had a DOR greater or equal to 6 months. Among 38 patients treated in the single-center Study 12-230, the ORR was 34 percent (95% CI: 20%, 51%) with 23 percent of patients having a DOR greater or equal to 6 months. For both trials, responses were observed in either the bone, bone marrow or both.
The prescribing information contains a Boxed Warning stating that naxitamab can cause serious infusion-related reactions and neurotoxicity, including severe neuropathic pain, transverse myelitis and reversible posterior leukoencephalopathy syndrome. To mitigate these risks, patients should receive premedication prior to each naxitamab infusion and be closely monitored during and for at least 2 hours following completion of each infusion.
The most common adverse reactions (incidence >=25% in either trial) in patients receiving naxitamab were infusion-related reactions, pain, tachycardia, vomiting, cough, nausea, diarrhea, decreased appetite, hypertension, fatigue, erythema multiforme, peripheral neuropathy, urticaria, pyrexia, headache, injection site reaction, edema, anxiety, localized edema, and irritability. The most common grade 3 or 4 laboratory abnormalities (>=5% in either trial) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased platelet count, decreased potassium, increased alanine aminotransferase, decreased glucose, decreased calcium, decreased albumin, decreased sodium, and decreased phosphate.
The recommended naxitamab dose is 3 mg/kg/day (up to 150 mg/day) on days 1, 3, and 5 of each treatment cycle, administered after dilution as an intravenous infusion in combination with GM-CSF, subcutaneously at 250 [mu]g/m2/day on days -4 to 0 and at 500 [mu]g/m2/day on days 1 to 5. Treatment cycles are repeated every 4-8 weeks.
FDA Approves Device for Treatment of Osteoid Osteoma in the Extremities
The FDA approved the Sonalleve MR-HIFU system for the treatment of osteoid osteoma in the extremities. MR-guided high-intensity focused ultrasound (MR-HIFU) treatment is an image-guided technique combining high-intensity focused ultrasound ablation with real-time monitoring of temperature change during the sonication.
The clinical results support the probable benefit of Sonalleve MR-HIFU system for the ablation of painful osteoid osteoma. Efficacy was evaluated in a study of nine patients treated with MR-HIFU, without technical difficulties or serious adverse events. There was a statistically significant decrease in their pain scores within 4 weeks of treatment. No pain medication usage was achieved in 8 of 9 patients after 4 weeks.
Pralsetinib for RET-Altered Thyroid Cancers
The FDA approved pralsetinib for adult and pediatric patients 12 years of age and older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who require systemic therapy or RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).
Efficacy was investigated in a multicenter, open-label, multi-cohort clinical trial (ARROW, NCT03037385) in patients whose tumors had RET gene alterations. Identification of RET gene alterations was prospectively determined in local laboratories using either next-generation sequencing, fluorescence in situ hybridization, or other tests.
The main efficacy outcome measures were overall response rate (ORR) and response duration determined by a blinded independent review committee using RECIST 1.1. Efficacy for advanced or metastatic RET-mutant MTC was evaluated in 55 patients who received prior cabozantinib or vandetanib. The ORR for these patients was 60 percent (95% CI: 46%, 73%); 79 percent of responding patients had responses lasting 6 months or longer. Efficacy was also evaluated in 29 patients with RET-mutant MTC who did not receive prior cabozantinib or vandetanib. The ORR was 66 percent (95% CI: 46%, 82%); 84 percent of patients had responses lasting 6 months or longer. Efficacy for patients with RET fusion-positive thyroid cancer was evaluated in nine patients who were radioactive iodine-refractory. The ORR was 89 percent (95% CI: 52%, 100%); all responding patients had responses lasting 6 months or longer.
The most common adverse reactions (>=25%) were constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea. The most common grade 3-4 laboratory abnormalities (>=2%) were decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased calcium (corrected), decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased platelets, and increased alkaline phosphatase.
The recommended pralsetinib dose in adults and pediatric patients 12 years and older is 400 mg orally once daily on an empty stomach with no food intake for at least 2 hours before and at least 1 hour after taking pralsetinib.
First Approved PSMA-Targeted PET Imaging Drug for Prostate Cancer
The FDA approved Gallium 68 PSMA-11 (Ga 68 PSMA-11), the first drug for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) positive lesions in patients with prostate cancer.
Ga 68 PSMA-11 is indicated for patients with suspected prostate cancer metastasis (when cancer cells spread from the place where they first formed to another part of the body) who are potentially curable by surgery or radiation therapy. Ga 68 PSMA-11 is also indicated for patients with suspected prostate cancer recurrence based on elevated serum prostate-specific antigen (PSA) levels. Ga 68 PSMA-11 is a radioactive diagnostic agent that is administered in the form of an intravenous injection.
"Ga 68 PSMA-11 is an important tool that can aid health care providers in assessing prostate cancer," said Alex Gorovets, MD, Acting Deputy Director of the Office of Specialty Medicine in FDA's Center for Drug Evaluation and Research. "With this first approval of a PSMA-targeted PET imaging drug for men with prostate cancer, providers now have a new imaging approach to detect whether or not the cancer has spread to other parts of the body."
Once administered via injection, Ga 68 PSMA-11 binds to PSMA, which is an important pharmacologic target for prostate cancer imaging because prostate cancer cells usually contain elevated levels of the antigen. As a radioactive drug that emits positrons, Ga 68 PSMA-11 can be imaged by PET to indicate the presence of PSMA-positive prostate cancer lesions in the tissues of the body.
The safety and efficacy of Ga 68 PSMA-11 were evaluated in two prospective clinical trials with a total of 960 men with prostate cancer who each received one injection of Ga 68 PSMA-11. In the first trial, 325 patients with biopsy-proven prostate cancer underwent PET/CT or PET/MRI scans performed with Ga 68 PSMA-11. These patients were candidates for surgical removal of the prostate gland and pelvic lymph nodes and were considered at higher risk for metastasis. Among the patients who proceeded to surgery, those with positive readings in the pelvic lymph nodes on Ga 68 PSMA-11 PET had a clinically important rate of metastatic cancer confirmed by surgical pathology. The availability of this information prior to treatment is expected to have important implications for patient care. For example, it may spare certain patients from undergoing unnecessary surgery.
The second trial enrolled 635 patients who had rising serum PSA levels after initial prostate surgery or radiotherapy, and thus had biochemical evidence of recurrent prostate cancer. All of these patients received a single Ga 68 PSMA-11 PET/CT scan or PET/MR scan. Based on the scans, 74 percent of these patients had at least one positive lesion detected by Ga 68 PSMA-11 PET in at least one body region (bone, prostate bed, pelvic lymph node, or extra-pelvic soft tissue). In patients with positive Ga 68 PSMA-11 PET readings who had correlative tissue pathology from biopsies, results from baseline or follow-up imaging by conventional methods, and serial PSA levels available for comparison, local recurrence or metastasis of prostate cancer was confirmed in an estimated 91 percent of cases. Thus, the second trial demonstrated that Ga 68 PSMA-11 PET can detect sites of disease in patients with biochemical evidence of recurrent prostate cancer, thereby providing important information that may impact the approach to therapy.
No serious adverse reactions were attributed to Ga 68 PSMA-11. The most common adverse reactions to Ga 68 PSMA-11 were nausea, diarrhea and dizziness. There is a risk for misdiagnosis because Ga 68 PSMA-11 binding may occur in other types of cancer as well as certain non-malignant processes which may lead to image interpretation errors. There are radiation risks because Ga 68 PSMA-11 contributes to a patient's overall long-term cumulative radiation exposure, which is associated with an increased risk for cancer.
Key Regulatory Designations of PTC596 for Rare Oncology Indications
The FDA has granted PTC596 both Orphan Drug Designation and Fast Track designation for the potential treatment of leiomyosarcoma (LMS), a rare type of cancer that affects smooth muscle tissue. Furthermore, the FDA has also granted PTC596 a Rare Pediatric Disease designation and Orphan Drug Designation for the potential treatment of Diffuse Intrinsic Pontine Glioma (DIPG), an ultra-rare childhood glioma. PTC596 is currently being studied in clinical trials in LMS and DIPG.
PTC596 is an orally bioavailable small molecule tubulin binding agent that arrests tumor cells in G2/M phase, including cancer stem cells, through the action of inhibiting tubulin polymerization. It is currently in a Phase Ib study for LMS, which accounts for approximately 10-28 percent of all soft tissue sarcomas.
Approximately 4,000 patients are diagnosed with LMS annually in the U.S., the risk of developing metastases is approximately 40 percent, and the 5-year survival rate is estimated to be 13.6 percent for metastatic LMS.2 PTC596 is also currently in a clinical study for DIPG, an ultra-rare glioma arising in the brainstem that makes up 10 to 15 percent of all brain tumors in children. Approximately 300 patients are diagnosed with DIPG annually in the U.S., and the median overall survival with the current standard of care of radiation therapy, is approximately 9 months with a two-year overall survival rate of less than 10 percent.