CAR T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma
The FDA approved axicabtagene ciloleucel, a CAR T-cell therapy for adult patients with large B-cell lymphoma (LBCL) that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy.
Axicabtagene ciloleucel demonstrated a clinically meaningful and statistically significant improvement in event-free survival (EFS) (HR=0.398; P<0.0001) over the current standard of care (SOC) that has been in place for decades. EFS was determined by blinded central review and defined as the time from randomization to the earliest date of disease progression, commencement of new lymphoma therapy, or death from any cause.
Additionally, 2.5 times more patients receiving axicabtagene ciloleucel (40.5%) were alive at 2 years without disease progression or need for additional cancer treatment, after their one-time infusion of axicabtagene ciloleucel versus SOC (16.3%), and the median EFS was four-fold greater (8.3 months vs. 2.0 months) with axicabtagene ciloleucel versus SOC. Axicabtagene ciloleucel is also being reviewed by global regulatory authorities for additional indications inclusive of the ZUMA-7 patient population. ZUMA-7 is considered a landmark trial for being the first and largest trial of its kind, with the longest follow-up.
Earlier this month, the National Comprehensive Cancer Network (NCCN) updated its Clinical Practice Guidelines in Oncology for B-cell Lymphomas to include axicabtagene ciloleucel for "relapsed disease <12 months or primary refractory disease" under Diffuse Large B-cell Lymphoma as a Category 1 recommendation. Axicabtagene ciloleucel is the first CAR T-cell therapy to receive a NCCN Category 1 recommendation. NCCN defines Category 1 as recommendations based upon high-level evidence with uniform NCCN consensus that the intervention is appropriate.
Axicabtagene ciloleucel was initially approved by the FDA in 2017 based on the ZUMA-1 trial for a smaller population of LBCL patients who failed two or more lines of therapy. The ZUMA-1 trial has recently reported durable 5-year survival results, with axicabtagene ciloleucel showing 42.6 percent of study patients alive at 5 years with 92 percent of those patients needing no additional cancer treatment at this important milestone.
ZUMA-7 is a randomized, open-label, global, multicenter, Phase III study evaluating the safety and efficacy of axicabtagene ciloleucel versus current SOC for second-line therapy (platinum-based salvage combination chemoimmunotherapy regimen followed by high-dose therapy [HDT] and ASCT in those who respond to salvage chemotherapy) in adult patients with relapsed or refractory LBCL within 12 months of first-line therapy.
In the study, 359 patients in 77 centers around the world were randomized (1:1) to receive a single infusion of axicabtagene ciloleucel or current SOC second-line therapy. The primary endpoint is EFS as determined by blinded central review and defined as the time from randomization to the earliest date of disease progression per Lugano Classification, commencement of new lymphoma therapy, or death from any cause. Key secondary endpoints include objective response rate (ORR) and overall survival (OS). Additional secondary endpoints include patient-reported outcomes and safety.
Axicabtagene ciloleucel demonstrated a 2.5-fold increase in patients who were alive at 2 years and did not experience cancer progression or require the need for additional cancer treatment (40.5% vs. 16.3%) and a four-fold greater median EFS (8.3 months vs. 2.0 months) compared to SOC (HR=0.398; 95% CI: 0.308-0.514, P<0.0001). In addition to being the largest and longest study of its kind, ZUMA-7 study participants on the axicabtagene ciloleucel arm did not receive additional bridging chemotherapy that could have potentially confounded results.
Nearly 3 times as many patients randomized to axicabtagene ciloleucel ultimately received the definitive CAR T-cell therapy treatment (94%) versus those randomized to SOC (35%) who received on-protocol HDT+ASCT. More patients responded to axicabtagene ciloleucel (ORR: 83% vs. 50%, OR: 5.31 [95% CI: 3.1-8.9; P<0.0001]) and achieved a complete response (CR) with axicabtagene ciloleucel (CR rate: 65% vs. 32%) than with SOC. At a pre-specified interim analysis at the time of the primary EFS analysis, OS has not met the criteria for statistical significance, but favored axicabtagene ciloleucel. Fifty-five percent of patients in the SOC arm subsequently received CD19-directed CAR T-cell therapy off study.
In the study, axicabtagene ciloleucel had a safety profile that was consistent with previous studies. Among the 168 axicabtagene ciloleucel-treated patients evaluable for safety, Grade >=3 cytokine release syndrome and neurologic events were observed in 7 percent and 25 percent of patients, respectively. In the SOC arm, 83 percent of patients had high grade events, mostly cytopenias.
Lutetium Lu 177 Vipivotide Tetraxetan for Metastatic Castration-Resistant Prostate Cancer
The FDA approved lutetium Lu 177 vipivotide tetraxetan for the treatment of adult patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer (PSMA-positive mCRPC) that has metastasized. These patients have already been treated with other anticancer treatments, including androgen receptor pathway inhibition and taxane-based chemotherapy.
"The approval of Lutetium Lu 177 vipivotide tetraxetan is an important clinical advancement for people with progressing mCRPC, as it can significantly improve survival rates for those who have limited treatment options," said Oliver Sartor, MD, Medical Director at Tulane Cancer Center. "Lutetium Lu 177 vipivotide tetraxetan is a step forward in the evolution of precision medicine for prostate cancer."
Lutetium Lu 177 vipivotide tetraxetan is the first FDA-approved targeted radioligand therapy for eligible patients with mCRPC that combines a targeting compound with a therapeutic radioisotope.
The FDA has also approved a kit for the preparation of gallium Ga 68 gozetotide injection. After radiolabeling, this imaging agent may be used to identify PSMA-positive lesions in adult patients with mCRPC through a positron emission tomography (PET) scan. The gallium-68 labeled kit can identify tumor lesions expressing the PSMA biomarker and locate where in the body tumors may have spread, identifying patients eligible for targeted treatment with Lutetium Lu 177 vipivotide tetraxetan. PSMA is highly expressed in more than 80 percent of patients with prostate cancer, making it an important phenotypic biomarker for assessing the progression of metastatic prostate cancer.
FDA approval of Lutetium Lu 177 vipivotide tetraxetan is based on the results of the Phase III VISION trial which demonstrated that PSMA-positive mCRPC patients previously treated with androgen receptor pathway inhibition and taxane-based chemotherapy who received Lutetium Lu 177 vipivotide tetraxetan plus standard of care (SOC) had improved overall survival compared to SOC alone. They also had a 38 percent reduction in risk of death and a statistically significant reduction in the risk of radiographic disease progression or death (rPFS) compared to SOC alone. Interpretation of the magnitude of the rPFS effect was limited due to a high degree of censoring from early drop out in the control arm.
In addition, about a third (30%) of patients with evaluable disease at baseline demonstrated an overall response (per RECIST 1.1) with Lutetium Lu 177 vipivotide tetraxetan plus SOC, compared to 2 percent in the SOC alone arm. The most common adverse events (all grades) in the Lutetium Lu 177 vipivotide tetraxetan arm of the study were fatigue (43%), dry mouth (39%), nausea (35%), anemia (32%), decreased appetite (21%), and constipation (20%).
177Lu-rhPSMA-10.1 for Prostate Cancer
The FDA has cleared an Investigational New Drug Application for 177Lu-rhPSMA-10.1. This will initiate a Phase I/II clinical study to evaluate the safety, tolerability, dosimetry, and anti-tumor activity of 177Lu-rhPSMA-10.1 in men with metastatic castrate-resistant prostate cancer (mCRPC).
Phase I will investigate the safety, tolerability, and dosimetry of multiple cycles of 177Lu-rhPSMA-10.1 in subjects with PSMA-positive mCRPC which has progressed following prior therapy. Results from Phase I will be used to determine the recommended treatment regimen to be tested in Phase II. The Phase I study will be conducted at clinical sites in the U.S., with further sites added for the Phase II component of the trial in both the U.S. and Europe.
Approval of Alpelisib for PIK3CA-Related Overgrowth Spectrum
The FDA granted accelerated approval to alpelisib for adult and pediatric patients 2 years and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data from EPIK-P1, a single-arm clinical study in patients 2 years of age and older with PROS who received alpelisib as part of an expanded access program for compassionate use.
Eligible patients had clinical manifestations of PROS that were assessed by the treating physicians as severe or life-threatening and necessitating systemic treatment, as well as having documented evidence of mutation in the PIK3CA gene. The efficacy of alpelisib was evaluated in a total of 37 patients with at least one target lesion identified on imaging performed within 24 weeks prior to receipt of the first dose.
The major efficacy outcome measure was the proportion of patients with radiological response at week 24 as determined by blinded independent central radiology review, defined as a >=20 percent reduction from baseline in the sum of measurable target lesion volume in up to three lesions confirmed by at least one subsequent imaging assessment. Duration of response was an additional efficacy outcome measure.
Of the 37 patients included in the efficacy population, 27 percent (95% CI: 14, 44) had a radiological response at Week 24. Among responding patients, 60 percent had a response lasting 12 months or longer. The most common (>=10%) adverse reactions occurring in patients were diarrhea, stomatitis, and hyperglycemia.
The recommended alpelisib dosage for pediatric patients (2 to less than 18 years of age) is 50 mg taken orally once daily with food; for pediatric patients 6 years of age and older, the dose can be increased to 125 mg after 24 weeks if clinically indicated. The recommended dosage for adult patients (>=18 years) is 250 mg taken orally once daily with food.
Fast Track Approval for Targeted Breast Cancer Immunotherapy
The FDA granted Fast Track status to Bria-IMT for the treatment of metastatic breast cancer. It is a cell-based immunotherapy designed to selectively destroy tumor cells without harming the normal cells. The trial is currently enrolling and dosing advanced breast cancer patients in its Phase I/IIa combination study of Bria-IMT with the checkpoint inhibitor, retifanlimab, and an immunomodulator, epacadostat.
Initial data on patient survival in this study was first presented at the San Antonio Breast Cancer Symposium in December 2021 and was over 12 months (average of nine prior regimens) compared with 7-10 months in a study in third-line breast cancer patients (those who failed two prior regimens for metastatic breast cancer). Other patient subsets with possible survival benefit included those who match Bria-IMT at one or more HLA type and those with Grade 1 (well-differentiated) or Grade 2 (moderately differentiated) breast cancer.
PRGN-3006 UltraCAR-T for Relapsed or Refractory Acute Myeloid Leukemia
The FDA has granted Fast Track designation for PRGN-3006 UltraCAR-T in patients with relapsed or refractory acute myeloid leukemia (AML). The treatment was previously granted FDA Orphan Drug Designation.
PRGN-3006 UltraCAR-T is a multigenic autologous chimeric antigen receptor (CAR) T-cell treatment utilizing the non-viral Sleeping Beauty system to simultaneously express a CAR specifically targeting CD33, which is over expressed on AML blasts; membrane bound IL-15 for enhanced in vivo expansion and persistence; and a kill switch to conditionally eliminate CAR-T cells for an improved safety profile.
The UltraCAR-T platform is designed to overcome limitations of currently available CAR-T therapies by utilizing an advanced overnight non-viral gene delivery manufacturing process at a medical center's cGMP facility without the need for ex vivo expansion. Current CAR T-cell therapies are limited due to, inter alia, the prolonged interval between apheresis to product infusion and an exhausted phenotype of T cells resulting from lengthy ex vivo expansion.