FDA Updates Highlighting the Latest Cancer Treatments

Accelerated Approval of Tepotinib for and killing of the lymphoma cells. Once the cells are modified, they Metastatic Non-Small Cell Lung Cancer are infused back into the patient. The FDA granted accelerated approval to tepotinib for adult pa- The safety and efficacy of lisocabtagene maraleucel were estab- tients with metastatic non-small cell lung cancer (NSCLC) harbor- lished in a multicenter clinical trial of more than 250 adults with ing mesenchymal-epithelial transition (MET) exon 14 skipping refractory or relapsed large B-cell lymphoma. The complete re- alterations. mission rate after treatment with lisocabtagene maraleucel was 54 Efficacy was demonstrated in the VISION trial (NCT02864992), a percent. multicenter, non-randomized, open-label, multicohort study enrolling Treatment with lisocabtagene maraleucel has the potential to 152 patients with advanced or metastatic NSCLC with MET exon 14 cause severe side effects. The labeling carries a boxed warning for skipping alterations. Patients received tepotinib 450 mg orally once cytokine release syndrome (CRS), which is a systemic response to daily until disease progression or unacceptable toxicity. the activation and proliferation of CAR-T cells, causing high fe- The main efficacy outcome measures were overall response rate ver, flu-like symptoms, and neurologic toxicities. Both CRS and (ORR) determined by a blinded independent review committee us- neurological events can be life-threatening. Other side effects in- ing RECIST 1.1 and response duration. Among the 69 treatment-naïve clude hypersensitivity reactions, serious infections, low blood cell patients, the ORR was 43 percent (95% CI: 32%, 56%) with a median counts, and a weakened immune system. Side effects generally ap- response duration of 10.8 months (95% CI: 6.9, not estimable). Among pear within the first 1-2 weeks following treatment, but some side the 83 previously treated patients, the ORR was 43 percent (95% CI: effects may occur later. 33%, 55%) with a median response duration of 11.1 months (95% CI: Because of the risk of CRS and neurologic toxicities, lisocabta- 9.5, 18.5). gene maraleucel is being approved with a risk evaluation and miti- The most common adverse reactions (≥ 20% of patients) were gation strategy (REMS) which includes elements to assure safe use edema, fatigue, nausea, diarrhea, musculoskeletal pain, and dyspnea. (ETASU). The FDA is requiring, among other things, that health Tepotinib can also cause interstitial lung disease, hepatotoxicity, and care facilities that dispense lisocabtagene maraleucel be specially embryo-fetal toxicity. The recommended tepotinib dose is 450 mg certified. As part of that certification, staff involved in the pre- orally once daily with food. scribing, dispensing, or administering of lisocabtagene maraleucel are required to be trained to recognize and manage the risks of Uttroside-B Receives Orphan Drug CRS and neurologic toxicities. The REMS program specifies that Designation for Treating Liver Cancer patients be informed of the signs and symptoms of CRS and neu- The FDA Office of Orphan Products Development has granted rological toxicities following infusion—and of the importance of Orphan Drug Designation to Uttroside-B, a small molecule chemo- promptly returning to the treatment site if they develop fever or therapeutic for the treatment of hepatocellular carcinoma (HCC), the other adverse reactions after receiving treatment with lisocabta- most common form of liver cancer. In preclinical studies, Uttroside-B gene maraleucel. was up to 10-times more potent against HCC cells than sorafenib, the To further evaluate the long-term safety, the FDA is also requir- standard of care drug at the time. ing the manufacturer to conduct a post-marketing observational As an orphan drug, Uttroside-B may benefit from a 7-year market study involving patients treated with lisocabtagene maraleucel. exclusively following marketing approval, grant funding for clinical Lisocabtagene maraleucel is the first regenerative medicine trials that contribute to marketing approval, protocol assistance, and therapy with RMAT designation to be licensed by the FDA. tax credits. Preclinical testing is now underway to support an FDA Orphan Drug designation provides incentives to assist and Investigational New Drug application expected this year. encourage the development of drugs for rare diseases. The With very limited approved first-line pharmaceutical therapies for lisocabtagene maraleucel application was reviewed using a co- HCC available today, challenges include drug resistance, adverse side ordinated, cross-agency approach, including both the Center effects, and high costs. An estimated 700,000 people are diagnosed for Biologics Evaluation and Research and FDA’s Oncology with HCC each year, with the global market for liver cancer drugs Center of Excellence. expected to grow to $3.9 billion by 2027. TH1902 Receives Fast Track Designation New Treatment for Adults with Relapsed or for Sortilin-Expressing Cancers Refractory Large B-Cell Lymphoma The FDA has granted Fast Track designation to TH1902 as a single The FDA approved lisocabtagene maraleucel, a cell-based gene therapy agent for the treatment of patients with sortilin-positive recurrent ad- to treat adult patients with certain types of large B-cell lymphoma who vanced solid tumors that are refractory to standard therapy. have not responded to, or who have relapsed after, at least two other The proposed Phase I TH1902 clinical trial design includes a types of systemic treatment. Lisocabtagene maraleucel, a chimeric an- dose-escalation study to evaluate the safety, pharmacokinetics, maxi- tigen receptor (CAR) T-cell therapy, is the third gene therapy approved mum tolerated dose (MTD), and preliminary anti-tumor activity of by the FDA for certain types of non-Hodgkin lymphoma, including TH1902 administered once every 3 weeks in patients with advanced diffuse large B-cell lymphoma (DLBCL). Lisocabtagene maraleucel is solid tumors refractory to available anti-cancer therapies. Once the not indicated for the treatment of patients with primary central ner- MTD is determined, it is planned that a total of 40 additional pa- vous system lymphoma. tients will be enrolled to evaluate the potential anti-tumor activity of “Today’s approval represents another milestone in the rapidly TH1902 in patients with endometrial, ovarian, colorectal, pancreatic, progressing field of gene therapy by providing an additional treat- and triple-negative breast cancers where it has been estimated that ment option for adults with certain types of cancer affecting the the sortilin receptor is expressed in 40-90 percent of cases. The Phase blood, bone marrow, and lymph nodes,” said Peter Marks, MD, I trial is expected to be initiated in the second quarter of calendar PhD, Director of the FDA’s Center for Biologics Evaluation and year 2021 and is designed to identify a recommended dose for Phase Research. “Gene and cell therapies have evolved from promising II development. concepts to practical cancer treatment regimens.” Funda Meric-Bernstam, MD, Chair of the Department of Each dose of lisocabtagene maraleucel is a customized treatment Investigational Cancer Therapeutics at The University of Texas created using a patient’s own T cells, a type of white blood cell, to MD Anderson Cancer Center, is lead principal investigator of the help fight the lymphoma. The patient’s T cells are collected and Phase I trial for TH1902. The detailed study protocol is available at genetically modified to include a new gene that facilitates targeting ClinicalTrials.gov under the identifier number NCT04706962. 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