Sacituzumab Govitecan for Advanced Urothelial Cancer
The FDA granted accelerated approval to sacituzumab govitecan for patients with locally advanced or metastatic urothelial cancer (mUC) who previously received a platinum-containing chemotherapy and either a programmed death receptor-1 (PD-1) or a programmed death-ligand 1 (PD-L1) inhibitor.
Efficacy and safety were evaluated in TROPHY (IMMU-132-06; NCT03547973), a single-arm, multicenter trial that enrolled 112 patients with locally advanced or mUC who received prior treatment with a platinum-containing chemotherapy and either a PD-1 or PD-L1 inhibitor. Patients received sacituzumab govitecan, 10 mg/kg intravenously, on days 1 and 8 of a 21-day treatment cycle.
The main efficacy endpoints were objective response rate (ORR) and duration of response (DOR), evaluated by independent review using RECIST 1.1 criteria. The confirmed ORR was 27.7 percent (95% CI:19.6, 36.9) with 5.4 percent complete responses and 22.3 percent partial responses. The median DOR was 7.2 months (n=31; 95% CI: 4.7, 8.6; range 1.4+, 13.7).
Most common adverse reactions (incidence >25%) in patients receiving sacituzumab govitecan are neutropenia, nausea, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, decreased appetite, rash, and abdominal pain.
The recommended sacituzumab govitecan dose is 10 mg/kg once weekly on days 1 and 8 of 21-day treatment cycles until disease progression or unacceptable toxicity.
Nivolumab + Chemotherapy for Metastatic Gastric Cancer & Esophageal Adenocarcinoma
Nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy has been FDA-approved for advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
Efficacy was evaluated in CHECKMATE-649 (NCT02872116), a randomized, multicenter, open-label trial that enrolled 1,581 patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma. PD-L1 combined positive score (CPS) was determined centrally using the PD-L1 IHC 28-8 pharmDx test. Patients received nivolumab in combination with chemotherapy (n=789) or chemotherapy alone (n=792); study treatment was administered as follows:
* nivolumab 240 mg with mFOLFOX6 (5-fluorouracil, leucovorin and oxaliplatin) every 2 weeks, or mFOLFOX6 every 2 weeks.
* nivolumab 360 mg with CapeOX (capecitabine and oxaliplatin) every 3 weeks, or CapeOX every 3 weeks.
The main efficacy outcome measures, assessed in patients with PD-L1 CPS >=5 (n=955), were progression-free survival (PFS) assessed by blinded independent central review and overall survival (OS). CHECKMATE-649 demonstrated a statistically significant improvement in PFS and OS for patients with PD-L1 CPS >=5. Median OS was 14.4 months (95% CI: 13.1, 16.2) in the nivolumab plus chemotherapy arm versus 11.1 months (95% CI: 10.0, 12.1) in the chemotherapy alone arm (HR 0.71; 95% CI: 0.61, 0.83; p<0.0001). Median PFS was 7.7 months (95% CI: 7.0, 9.2) in the nivolumab plus chemotherapy arm versus 6.0 months (95% CI: 5.6, 6.9) in the chemotherapy alone arm (HR 0.68; 95% CI: 0.58, 0.79; p<0.0001).
As an additional efficacy outcome measure, a statistically significant improvement in OS was also demonstrated for all randomized patients (n=1,581) irrespective of CPS, with a median OS of 13.8 months (95% CI: 12.6, 14.6) in the nivolumab plus chemotherapy arm versus 11.6 months (95% CI: 10.9, 12.5) in the chemotherapy alone arm (HR 0.80; 95% CI: 0.71, 0.90; p=0.0002).
The most common adverse reactions (incidence >=20%) observed in patients receiving nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy were peripheral neuropathy, nausea, fatigue, diarrhea, vomiting, decreased appetite, abdominal pain, constipation, and musculoskeletal pain.
The recommended nivolumab dosages are:
* 360 mg every 3 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every 3 weeks.
* 240 mg every 2 weeks in combination with fluoropyrimidine- and platinum-containing chemotherapy every 2 weeks.
Dostarlimab-Gxly for dMMR Endometrial Cancer
The FDA granted accelerated approval to dostarlimab-gxly for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by an FDA-approved test, that has progressed on or following a prior platinum-containing regimen.
Efficacy was evaluated based on cohort A1 in the GARNET Trial (NCT02715284), a multicenter, multicohort, open-label trial in patients with advanced solid tumors. The efficacy population consisted of 71 patients with dMMR recurrent or advanced endometrial cancer who progressed on or after a platinum-containing regimen. Patients received dostarlimab-gxly, 500 mg intravenously, every 3 weeks for 4 doses followed by 1,000 mg intravenously every 6 weeks.
The main efficacy endpoints were overall response rate (ORR) and duration of response (DOR), as assessed by blinded independent central review according to RECIST 1.1. Confirmed ORR was 42.3 percent (95% CI: 30.6%, 54.6%). The complete response rate was 12.7 percent and partial response rate was 29.6 percent. Median DOR was not reached, with 93.3 percent of patients having durations >=6 months (range: 2.6 to 22.4 months, ongoing at last assessment).
Serious adverse reactions occurred in 34 percent of patients receiving dostarlimab-gxly. Serious adverse reactions in >2 percent of patients included sepsis, acute kidney injury, urinary tract infection, abdominal pain, and pyrexia . The most common adverse reactions (>=20%) were fatigue/asthenia, nausea, diarrhea, anemia, and constipation. The most common grade 3 or 4 adverse reactions (>=2%) were anemia and elevated transaminases. Immune-mediated adverse reactions can occur including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
The recommended dostarlimab-gxly dose and schedule (doses 1 through 4) is 500 mg every 3 weeks. Subsequent dosing, beginning 3 weeks after dose 4, is 1,000 mg every 6 weeks until disease progression or unacceptable toxicity. Dostarlimab-gxly should be administered as an intravenous infusion over 30 minutes.
Natural Killer Cell Therapy CYNK-001 in Malignant Gliomas
The FDA has granted Orphan Drug Designation to a non-genetically modified cryopreserved human placental hematopoietic stem cell-derived natural killer (NK) cell therapy, CYNK-001, for the treatment of patients with malignant gliomas. CYNK-001 is currently being investigated in a Phase I clinical trial (NCT04489420) for the treatment of patients with glioblastoma multiforme, an indication within the scope of this orphan designation. The therapeutic program is based on its placental-derived unmodified NK cell type is CYNK-001, an allogeneic unmodified NK cell being developed as a treatment for hematologic malignancies, solid tumors, and infectious diseases.
Evaluating Safety & Efficacy of PVSRIPO in Advanced Solid Tumors
The FDA has cleared the Investigational New Drug application (IND) for PVSRIPO in patients with solid tumors. LUMINOS-103 (NCT04690699) is a Phase I/II open-label, multicenter, single-arm basket trial evaluating the administration of PVSRIPO with or without PD-1/L1 inhibitors in adult subjects with solid tumor cancers.
The trial will begin with two bladder cancer cohorts and is expected to initiate enrollment mid-2021. PVSRIPO is a novel intratumoral viral immunotherapy that activates a patient's innate and adaptive immune system to facilitate a systemic anti-tumor immune response. The immunotherapy enters solid tumor cells and antigen presenting cells in the tumor microenvironment via CD155 (the poliovirus receptor). Because CD155 is expressed on virtually all solid tumors, PVSRIPO has the potential to treat many different cancers.
This is the third IND clearance for PVSRIPO following other recent clinical trial progress, including the initiation of LUMINOS-101 (NCT04479241) in recurrent glioblastoma and LUMINOS-102 (NCT04577807) in anti-PD-1/L1 refractory melanoma.
Immunotherapy for Endometrial Cancer With Specific Biomarker
The FDA granted accelerated approval to dostarlimab for treating patients with recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing chemotherapy and whose cancers have a specific genetic feature known as dMMR (which contain abnormalities that affect the proper repair of DNA inside the cell), as determined by an FDA-approved test.
"Today's approval of [dostarlimab] is evidence of the FDA's progress in applying precision medicine to expand treatment options for patients with cancer," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA's Center for Drug Evaluation and Research. "This immunotherapy was specifically studied to target dMMR endometrial cancer and leverages scientific knowledge surrounding the mechanism of immunotherapy response in this unmet medical need population."
Dostarlimab works by targeting the cellular pathway known as PD-1/PD-L1. Dostarlimab helps the body's immune system in its fight against cancer cells by blocking this pathway. The safety and efficacy of fostarlimab was studied in a single-arm, multi-cohort clinical trial. Of the 71 patients with dMMR recurrent or advanced endometrial cancer who received dostarlimab in the trial, 42.3 percent had a complete response or partial response to treatment. For 93 percent of responders, the response lasted for 6 months or more.
Common side effects of dostarlimab include fatigue, nausea, diarrhea, anemia, and constipation. Dostarlimab can cause serious conditions known as immune-mediated side effects, including pneumonitis, colitis, hepatitis, endocrinopathies, and nephritis.
Patients who experience severe or life-threatening infusion-related reactions should stop taking dostarlimab. Women who are pregnant or breastfeeding should not take dostarlimab because it may cause harm to a developing fetus or newborn baby. The safety and effectiveness of dostarlimab in pediatric patients are not known.
Dostarlimab received Priority Review designation and Breakthrough Therapy designation for this indication. Priority Review designation directs overall attention and resources to the evaluation of applications for drugs that, if approved, would be significant improvements in the safety or effectiveness of the treatment, diagnosis or prevention of serious conditions when compared to standard applications. Breakthrough Therapy designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).
Dostarlimab was approved for this new indication using the Accelerated Approval pathway, under which the FDA may approve drugs for serious conditions where there is unmet medical need and a drug is shown to have certain effects that are reasonably likely to predict a clinical benefit to patients. Further clinical trials may be required to verify and describe anticipated clinical benefits of dostarlimab and the sponsor is currently conducting these trials in additional patients with dMMR endometrial tumors.