Cemiplimab-Rwlc for Non-Small Cell Lung Cancer With High PD-L1 Expression
The FDA approved cemiplimab-rwlc for the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC) (locally advanced who are not candidates for surgical resection or definitive chemoradiation or metastatic) whose tumors have high PD-L1 expression (Tumor Proportion Score >50%) as determined by an FDA-approved test, with no EGFR, ALK, or ROS1 aberrations.
Efficacy was evaluated in Study 1624 (NCT03088540), a multicenter, randomized, open-label trial in 710 patients with locally advanced NSCLC who were not candidates for surgical resection or definitive chemoradiation or with metastatic NSCLC. Patients were randomized (1:1) to receive cemiplimab-rwlc 350 mg intravenously every 3 weeks for up to 108 weeks or a platinum-based chemotherapy. The main efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) per blinded independent central review (BICR).
The trial demonstrated statistically significant improvements in OS and PFS for patients receiving cemiplimab-rwlc compared to those treated with platinum-based chemotherapy. Median OS was 22.1 months (95% CI:17.7, NE) for patients in the cemiplimab-rwlc arm compared with 14.3 months (95% CI: 11.7, 19.2) in the chemotherapy arm (HR 0.68; 95%CI: 0.53, 0.87, p=0.0022). Median PFS per BICR was 6.2 months (4.5, 8.3) in the cemiplimab-rwlc arm and 5.6 months (4.5, 6.1) in the chemotherapy arm (HR 0.59; 95% CI: 0.49, 0.72, p<0.0001). Confirmed overall response rate per BICR was 37 percent (95% CI: 32, 42) and 21 percent (95% CI: 17, 25) in the cemiplimab-rwlc and chemotherapy arms, respectively.
The most common adverse reactions (> 10%) with cemiplimab-rlwc as a single agent in Study 1624 were musculoskeletal pain, rash, anemia, fatigue, decreased appetite, pneumonia, and cough. The recommended cemiplimab-rwlc dose for treatment of NSCLC is 350 mg every 3 weeks, intravenously over 30 minutes.
Accelerated Approval of Melphalan Flufenamide for R/R Multiple Myeloma
The FDA granted accelerated approval to melphalan flufenamide in combination with dexamethasone for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy and whose disease is refractory to at least one proteasome inhibitor, one immunomodulatory agent, and one CD38-directed monoclonal antibody.
Efficacy was evaluated in HORIZON (NCT02963493), a multicenter, single-arm trial. Eligible patients were required to have relapsed/refractory multiple myeloma. Patients received melphalan flufenamide 40 mg intravenously on day 1 and dexamethasone 40 mg orally (20 mg for patients >=75 years of age) on day 1, 8, 15, and 22 of each 28-day cycle until disease progression or unacceptable toxicity.
Efficacy was evaluated in a subpopulation of 97 patients who received four or more prior lines of therapy and were refractory to at least one proteasome inhibitor, one immunomodulatory agent, and a CD38-directed antibody. The main efficacy outcome measure was overall response rate (ORR) and duration of response (DOR) assessed by investigators according to the International Myeloma Working Group criteria. The ORR was 23.7 percent (95% CI: 15.7, 33.4) and median DOR 4.2 months (95% CI: 3.2, 7.6).
Common adverse reactions (>20%) were fatigue, nausea, diarrhea, pyrexia, and respiratory tract infection. Common laboratory abnormalities (>=50%) include decreased leukocytes, platelets, lymphocytes, neutrophils, and hemoglobin, as well as increased creatinine.
The safety and efficacy of melphalan flufenamide has not been established for use as a conditioning regimen in patients receiving transplant. The USPI includes a Limitations of Use statement that melphalan flufenamide is not indicated and is not recommended for use as a conditioning regimen for transplant outside of controlled clinical trials. The recommended dose of melphalan flufenamide is 40 mg intravenously over 30 minutes on day 1 of each 28-day treatment cycle, in combination with dexamethasone.
Approval of Lorlatinib for Metastatic ALK-Positive NSCLC
Lorlatinib was granted approval for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive, as detected by an FDA-approved test. In addition, the Ventana ALK (D5F3) CDx assay has been approved as a companion diagnostic for lorlatinib.
Lorlatinib received accelerated approval in November 2018 for the second- or third-line treatment of ALK-positive metastatic NSCLC.
The most-current approval is based on data from Study B7461006 (NCT03052608), a randomized, multicenter, open-label, active-controlled trial conducted in 296 patients with ALK-positive metastatic NSCLC who had not received prior systemic therapy for metastatic disease. Patients were required to have ALK-positive tumors detected by the VENTANA ALK (D5F3) CDx assay. Patients were randomized 1:1 to receive lorlatinib 100 mg orally once daily (n=149) or crizotinib 250 mg orally twice daily (n=147).
Study B7461006 demonstrated an improvement in progression-free survival (PFS) as assessed by blinded independent central review (BICR), with a hazard ratio of 0.28 (95% CI: 0.19, 0.41; p<0.0001). Median PFS was not estimable in the lorlatinib arm and was 9.3 months (95% CI: 7.6, 11.1) for those treated with crizotinib. Overall survival data were immature at the PFS analysis.
Central nervous system (CNS) involvement was assessed in all patients. There were 17 patients in the lorlatinib arm and 13 in the crizotinib arm with measurable CNS lesions based on baseline brain imaging. Among these patients, the intracranial ORR, as assessed by the BICR, was 82 percent (95% CI: 57, 96) in the lorlatinib arm and 23 percent (95% CI: 5, 54) in the crizotinib arm. The duration of intracranial response was >=12 months in 79 percent and 0 percent of patients in the lorlatinib and crizotinib arms, respectively.
The most common adverse reactions (incidence >=20%), including grade 3-4 laboratory abnormalities, in patients receiving lorlatinib were edema, peripheral neuropathy, weight gain, cognitive effects, fatigue, dyspnea, arthralgia, diarrhea, mood effects, hypercholesterolemia, hypertriglyceridemia, and cough. The recommended lorlatinib dose is 100 mg orally once daily.
Axicabtagene Ciloleucel Approved for R/R Follicular Lymphoma
The FDA granted accelerated approval to axicabtagene ciloleucel for the treatment of adult patients with relapsed or refractory follicular lymphoma (FL) after two or more lines of systemic therapy. The approval makes axicabtagene ciloleucel the first chimeric antigen receptor (CAR) T-cell therapy approved for patients with indolent follicular lymphoma.
The approval is based on results from ZUMA-5, an ongoing, single-arm, open-label, multicenter trial. It is evaluating 146 patients (>=18 years old) with relapsed or refractory iNHL who received at least two prior lines of systemic therapy, including the combination of an anti-CD20 monoclonal antibody and an alkylating agent. Efficacy was established on the basis of objective response rate and duration of response (DoR) as assessed by an independent review committee per the 2014 Lugano Classification.
In the study, 91 percent of all FL patients (n=81 evaluable for efficacy analysis) responded to a single infusion of axicabtagene ciloleucel, including 60 percent of patients who achieved a complete remission. Thirteen of the 25 patients who achieved a partial remission met imaging criteria for a complete remission without confirmation by negative bone marrow biopsy after treatment. Median DoR has not yet been reached.
Among the 146 patients evaluable for safety, grade 3 or higher CRS and neurologic toxicities were observed in 8 percent and 21 percent of patients, respectively. Median time to onset of CRS and neurologic toxicities was 4 days (1-20 days) and 6 days (1-79 days), respectively. The most common (>=10%) grade 3 or higher adverse reactions included febrile neutropenia, encephalopathy, and infections with pathogen unspecified.
"Once a follicular lymphoma patient's disease relapses, the duration of response to care shortens with each round of therapy," said Caron A. Jacobson, MD, MMSc, Medical Director of the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute, and Assistant Professor of Medicine at Harvard Medical School.
"Additionally, for follicular patients in the third line of therapy, the 5-year survival rate is only 20 percent, highlighting the urgent need for treatments that offer a real chance for durable remission. Impressively, 91 percent of follicular lymphoma patients in the ZUMA-5 study responded to a single infusion of axicabtagene ciloleucel, including an estimated 74 percent of patients in a continued remission at 18 months, giving these patients much-needed hope and oncologists an important addition to the treatment armamentarium."
The axicabtagene ciloleucel U.S. prescribing information has a boxed warning for the risks of CRS and neurologic toxicities, and it is approved with a risk evaluation and mitigation strategy due to these risks.
Pafolacianine Sodium Injection to Identify Ovarian Cancer
The FDA has accepted a New Drug Application for priority review of pafolacianine sodium injection as an adjunct for identifying ovarian cancer during surgery. Pafolacianine sodium injection is a novel molecule shown to bind to folate receptors and illuminate intraoperatively under near-infrared light, serving as an adjunct to provide greater certainty in a complete resection. It is administered via standard IV. This procedure was investigated for use in ovarian cancer under Special Protocol Agreement and received both Fast Track and Orphan designations from the FDA. Additionally, it is being investigated in lung cancer under Fast Track designation.
Clinical trials for the use of pafolacianine sodium as an intraoperative adjunct to aid in the surgical treatment of ovarian cancer have been conducted in the U.S. and Europe. Phase II results reported surgeons were able to detect additional lesions, regardless of tissue location, in 48.3 percent of patients. Further, pafolacianine sodium injection demonstrated a sensitivity of 97 percent when controlling for detection correlation of multiple lesions within a single patient.
Tipifarnib for Head & Neck Squamous Cell Carcinoma
Tipifarnib has been granted Breakthrough Therapy Designation by the FDA for the treatment of patients with recurrent or metastatic HRAS-mutant head and neck squamous cell carcinoma (HNSCC) with variant allele frequency >=20 percent after disease progression on platinum-based chemotherapy. Tipifarnib is currently being evaluated in an ongoing registration-directed clinical trial (AIM-HN) in this indication of high unmet need.
Despite recent treatment advances, prognosis remains poor, with a 5-year survival rate of less than 40 percent. Second-line treatments provide limited clinical benefit for many patients, with objective response rates (ORR) of 6-16 percent, median progression-free survival (PFS) of 2-3 months, and median overall survival (OS) of 5-8 months.
Tipifarnib's Breakthrough Therapy Designation is based on data from RUN-HN, a Phase II clinical trial evaluating tipifarnib in patients with recurrent or metastatic HRAS-mutant HNSCC. Data showed an ORR of 50 percent, median PFS of 5.9 months, and a median OS of 15.4 months among the 18 evaluable patients. HRAS represents approximately 4-8 percent of HNSCC patients. The HRAS biomarker can be found on most commercially available genomic panels