FDA Updates Highlighting the Latest Cancer Treatments

First Cellular Therapy for Unresectable or Metastatic MelanomaFDA Updates: FDA UpdatesThe FDA approved lifileucel, the first cellular therapy indicated for the treatment of adult patients with melanoma that is unresectable or has spread to other parts of the body that previously has been treated with other therapies (a PD-1 blocking antibody and, if BRAF V600 mutation-positive, a BRAF inhibitor with or without a MEK inhibitor). “Unresectable or metastatic melanoma is an aggressive form of cancer that can be fatal,” said Peter Marks, MD, PhD, Director of the FDA's Center for Biologics Evaluation and Research (CBER). “The approval of [lifileucel] represents the culmination of scientific and clinical research efforts leading to a novel T-cell immunotherapy for patients with limited treatment options.” Treatment for unresectable or metastatic melanoma may include immunotherapy using PD-1 inhibitors, which are antibodies targeting certain proteins in the body to help the immune system fight off cancer cells. In addition, drugs targeting the BRAF gene, which helps manage the growth and functioning of cells, may be used for treating melanoma associated with BRAF gene mutations. Those patients whose melanoma has progressed with these therapies have a high unmet medical need. Lifileucel is a tumor-derived autologous T-cell immunotherapy composed of a patient's own T cells, a type of cell that helps the immune system fight cancer. A portion of the patient's tumor tissue is removed during a surgical procedure prior to treatment. The patient's T cells are separated from the tumor tissue, further manufactured, and then returned to the same patient as a single dose for infusion. This is the first FDA-approved tumor-derived T-cell immunotherapy. “Melanoma is a life-threatening cancer that can cause devastating impacts to affected individuals with a significant risk of metastasizing and spreading to other areas in the body,” said Nicole Verdun, MD, Director of the Office of Therapeutic Products in CBER. “[This] approval reflects the FDA's dedication and commitment to the development of innovative, safe, and effective treatment options for cancer patients.” Lifileucel was approved through the Accelerated Approval pathway, under which the FDA may approve drugs for serious or life-threatening illnesses or conditions where there is an unmet medical need and the drug has an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients (e.g., improving how patients feel or function, or whether they survive longer). This pathway generally gives patients the opportunity for earlier access to a promising therapy while the company conducts further trials to verify the predicted clinical benefit. A confirmatory trial is ongoing to verify the clinical benefit of lifileucel. The safety and effectiveness of lifileucel was evaluated in a global, multicenter, multicohort clinical study of adult patients with unresectable or metastatic melanoma who had previously been treated with at least one systemic therapy, including a PD-1 blocking antibody, and if positive for the BRAF V600 mutation, a BRAF inhibitor or BRAF inhibitor with an MEK inhibitor. Effectiveness was established based on objective response rate to treatment and duration of response, which was measured from the date of confirmed initial objective response to the date of progression, death from any cause, starting a new anti-cancer treatment, or discontinuation from follow-up, whichever came first. Among the 73 patients treated with lifileucel at the recommended dose, the objective response rate was 31.5 percent, including three (4.1%) patients with a complete response and 20 (27.4%) patients with a partial response. Among patients who were responsive to the treatment, 56.5 percent, 47.8 percent, and 43.5 percent continued to maintain responses without tumor progression or death at 6, 9, and 12 months, respectively. Patients treated with lifileucel may exhibit prolonged severe low blood count, severe infection, and cardiac disorder. They can also develop worsened respiratory or renal function or have fatal treatment-related complications. A Boxed Warning is included in the label containing information about these risks. Patients receiving this product should be closely monitored before and after infusion for signs and symptoms of adverse reactions. Treatment should be withheld or discontinued in the presence of these symptoms as indicated. The most common adverse reactions associated with lifileucel included chills, fever, fatigue, tachycardia, diarrhea, febrile neutropenia, edema, rash, hypotension, hair loss, infection, hypoxia, and feeling short of breath. Approval of Osimertinib + Chemotherapy for EGFR-Mutated NSCLC Osimertinib with platinum-based chemotherapy has received FDA approval for patients with locally advanced or metastatic non-small cell lung cancer (la/mNSCLC) whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations as detected by an FDA-approved test. Efficacy was evaluated in FLAURA 2 (NCT04035486), an open-label, randomized trial of 557 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive la/mNSCLC and no prior systemic therapy for advanced disease. Patients were randomized 1:1 to receive either osimertinib with platinum-based chemotherapy or osimertinib monotherapy. The major efficacy outcome measure was progression-free survival (PFS), as assessed by the investigator, with overall survival (OS) as a key secondary outcome measure. Osimertinib plus platinum-based chemotherapy demonstrated a statistically significant improvement in PFS compared to osimertinib monotherapy with a hazard ratio of 0.62 (95% CI: 0.49, 0.79; two-sided p<0.0001). The median PFS was 25.5 months (95% CI: 24.7, not estimable [NE]) and 16.7 months (95% CI: 14.1, 21.3) in the respective arms. While OS results were immature at the current analysis with 45 percent of pre-specified deaths for the final analysis reported, no trend toward a detriment was observed. The most common adverse reactions (≥20% incidence) in patients receiving osimertinib plus platinum-based chemotherapy were leukopenia, thrombocytopenia, neutropenia, lymphopenia, rash, diarrhea, stomatitis, nail toxicity, dry skin, and increased blood creatinine. The recommended osimertinib dose is 80 mg orally once daily, with or without food, until disease progression or unacceptable toxicity. Refer to the prescribing information for pemetrexed and cisplatin or carboplatin for the respective dosing information. FDA Approves Tepotinib for Metastatic Non-Small Cell Lung Cancer The FDA granted traditional approval to tepotinib for adult patients with metastatic non-small cell lung cancer (NSCLC) harboring mesenchymal-epithelial transition (MET) exon 14 skipping alterations. Tepotinib was previously granted accelerated approval for this indication on February 3, 2021, based on initial overall response rate (ORR) and duration of response (DOR) in the VISION trial (NCT02864992), a multicenter, non-randomized, open-label, multicohort study. The conversion to traditional approval was based on an additional 161 patients and an added 28 months of follow-up time to assess DOR. Efficacy was demonstrated in a total of 313 patients with metastatic NSCLC harboring MET exon skipping alterations. Patients received tepotinib 450 mg once daily until disease progression or unacceptable toxicity. The primary efficacy measures were ORR and DOR, determined by a Blinded Independent Review Committee. Among 164 treatment-naïve patients, ORR was 57 percent (95% CI: 49, 65) with 40 percent of responders having a DOR ≥12 months. Among 149 previously treated patients, ORR was 45 percent (95% CI: 37, 53) with 36 percent of responders having a DOR ≥12 months. The most common adverse reactions (≥20%) were edema, nausea, fatigue, musculoskeletal pain, diarrhea, dyspnea, decreased appetite, and rash. The recommended tepotinib dose is 450 mg orally once daily with food.