On April 22, 2024, the U.S. Food and Drug Administration (FDA) approved nogapendekin alfa inbakicept-pmln in combination with Bacillus Calmette-Guérin (BCG) for the treatment of adult patients with BCG-unresponsive, non-muscle-invasive bladder cancer (NMIBC) and carcinoma in situ (CIS) with or without papilloma. This approval is primarily based on the QUILT-3.032 study.
About the study
The QUILT-3.032 study (NCT0302285) was a single-arm, multicenter clinical trial that enrolled a total of 77 patients with BCG-unresponsive, high-risk NMIBC, and CIS with or without Ta/T1 papillary lesions after transurethral resection. Patients received induction therapy with nogapendekin alfa inbakicept-pmln by intravesical instillation of BCG, followed by maintenance therapy for up to 37 months. Patients underwent cystoscopy and urine cytology every 3 months to assess tumor status, and biopsy examinations were performed within the first 6 months after the start of treatment for up to 2 years. The primary endpoints of the study were complete response (CR) and duration of response (DoR) achieved at any time, with CR defined as negative cystoscopy and negative urine cytology.
The results showed that the CR rate was 62% (95% CI: 51, 73), 58% of patients who achieved CR achieved DOR ≥ 12 months, and 40% of patients who achieved CR achieved DOR ≥ 24 months.
Safety analysis showed that the most common adverse reactions (≥15%) were laboratory abnormalities, including increased creatinine, dysuria, hematuria, urinary frequency, urgency, urinary tract infection, potassium elevation, musculoskeletal pain, chills, and fever.
Recommended dose
The recommended dose of nogapendekin alfa inbakicept-pmln is 400 mcg 1 time a week administered by intravesical instillation of BCG as induction therapy for 6 weeks. If the patient does not achieve CR by the third month, a second induction therapy can be performed. For maintenance therapy after induction therapy, the recommended dose is 400 mcg once a week with intravesical instillation of BCG administered for 3 weeks at months 4, 7, 10, 13, and 19 (15 doses in total). For patients who achieve CR at 25 months or later, BCG maintenance instillations may be given once weekly for 3 weeks at months 25, 31, and 37, up to a maximum of 9 additional instillations. Treatment should be discontinued in patients with disease recurrence or progression or intolerable toxicity after the second induction therapy. The maximum duration of treatment is 37 months.
On April 23, 2024, the FDA granted accelerated approval for tovorafentib in patients with relapsed or refractory pediatric low-grade gliomas (LGGs) who are ≥ 6 months old and harbor BRAF fusion/rearrangement or BRAF V600E mutations. This is the first FDA approval for the systemic treatment of pediatric patients with BRAF fusion/rearrangement LGG, and the application received Priority Review, Breakthrough Designation and Orphan Drug Designation. The approval is primarily based on the FIREFLY-1 study.
About the study
The FIREFLY-1 study is a multicenter, open-label, single-arm trial with inclusion criteria for patients with BRAF-mutant relapsed or refractory pediatric LGG who have received at least one prior line of systemic therapy, and patients with other genetic mutations (eg, IDH1/2 mutations, FGFR mutations) or patients with a known or suspected diagnosis of neurofibromatosis type 1 are excluded. A total of 76 patients were included in the study who were treated with tovorafenib once a week according to body surface area (range 290~476 mg/m², maximum dose of 600 mg) until disease progression or toxicity was intolerable. The primary efficacy endpoint of the study is overall response rate (ORR), defined as the proportion of patients with CR, partial response (PR), or minimal response (MR) as determined by blinded independent central review (BICR) based on pediatric neuro-oncology LGG response assessment (RAPNO-LGG) criteria. Other efficacy endpoints include DoR and others.
The results showed that the patients had an ORR of 51% (95% CI: 40%-63%) and a median DoR of 13.8 months (95% CI: 11.3-not estimable). The most common adverse reactions (≥30%) in the studies were rash, hair color changes, fatigue, viral infections, vomiting, headache, bleeding, fever, dry skin, constipation, nausea, dermatitis acnesiformis, and upper respiratory tract infection. The most common grade 3 to 4 laboratory abnormalities (>2%) include decreased phosphate concentrations, decreased hemoglobin, elevated creatinine phosphokinase, elevated alanine aminotransferase, decreased albumin, lymphopenia, leukopenia, elevated aspartate aminotransferase, decreased serum potassium, and decreased serum sodium.
Recommended dose
The Food and Drug Administration (FDA) recommends tovorafenib based on body surface area at a dose of 380 mg/m² (maximum 600 mg) orally once weekly with or without food until disease progression or toxicity is intolerable. The recommended dose for patients with a body surface area of less than 0.3 m² has not been established.
The FDA also noted that the accelerated approval is based on ORR and DOR data, and that subsequent approval of this indication is subject to validation and evaluation of the clinical benefit of the treatment in confirmatory studies.
On April 23, 2024, the FDA approved lutetium Lu 177 dotatate for the treatment of pediatric patients 12 years of age and older with somatostatin receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), including GEP-NETs in the foregut, midgut, and hindgut. The approval is based on the NETTER-1 study and the NETTER-P study.
About the study
The NETTER-1 study (NCT01578239) is a randomized, multicenter, open-label, active-controlled clinical trial evaluating the safety of lutetium Lu 177 dotatate in 229 adult patients with locally advanced/inoperable or metastatic SSTR-positive midgut GEP-NETs. Based on the data from this study, the FDA approved lutetium Lu 177 dotatate in 2018 for adult patients with GEP-NETs.
The NETTER-P study (NCT04711135) is an international multicenter, open-label, single-arm clinical trial evaluating the safety of lutetium Lu 177 dotatate in adolescent patients aged 12-less years with locally advanced/inoperable or metastatic SSTR-positive GEP-NETs or pheochromocytoma/paraganglioma (PPGL) aged 12 years to younger than 18 years. The primary endpoints of the study were the radiation dose absorbed by the target organ and the incidence of adverse effects after the first cycle of treatment, and the other endpoints included short-term adverse effects after treatment with lutetium Lu 177 dotatate.
Safety analyses of nine pediatric patients (including four patients with GEP-NETs) in the NETTER-P study showed that adverse effects in pediatric patients in the NETTER-P study were similar to those in adult patients in the NETTER-1 study.
Recommended dose
lutetium Lu 177 dotatate的推荐剂量为每8周(±1周)7.4 GBq(200 mCi),共4剂。 术前用药和联合用药均按照推荐剂量使用。 上市后,还需评估lutetium Lu 177 dotatate在青少年患者中的长期安全性。
bibliography
1.FDA approves nogapendekin alfa inbakicept-pmln for BCG-unresponsive non-muscle invasive bladder cancer. April 22, 2024.
2.FDA grants accelerated approval to tovorafenib for patients with relapsed or refractory BRAF-altered pediatric low-grade glioma. FDA. April 23, 2024.
3.FDA approves lutetium Lu 177 dotatate for pediatric patients 12 years and older with GEP-NETS. April 23, 2024.
撰写：Squid、Babel
Typography: Squid
Execution: Squid
Yimaitong is a professional online doctor platform, and the mission of the platform is to "sense the pulse of the world's medicine and help China's clinical decision-making". Yimaitong has a series of products such as "Clinical Guidelines", "Medication Reference", "Medical Literature King", "Yizhiyuan", "eYantong" and "ePulse", which fully meet the needs of medical workers in clinical decision-making, obtaining new knowledge and improving scientific research efficiency.
This platform aims to deliver more medical information to healthcare professionals. The content published on this platform should not be used as a substitute for professional medical guidance in any way, nor should it be regarded as diagnosis and treatment advice. If such information is used for purposes other than understanding medical information, the platform does not assume relevant responsibilities. This platform does not mean that it agrees with its descriptions and views on the published content. If copyright issues are involved, please contact us, and we will deal with it as soon as possible.