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Pembrolizumab for BCG-Unresponsive, High-Risk Non-Muscle Invasive Bladder Cancer

The FDA approved pembrolizumab for the treatment of patients with bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

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Efficacy was investigated in KEYNOTE-057, a multi-center, single-arm trial that enrolled 148 patients with high-risk NMIBC, 96 of whom had BCG-unresponsive CIS with or without papillary tumors. Patients received pembrolizumab 200 mg every 3 weeks until unacceptable toxicity, persistent or recurrent high-risk NMIBC or progressive disease, or up to 24 months of therapy without disease progression.


The major efficacy outcome measures were complete response (as defined by negative results for cystoscopy [with TURBT/biopsies as applicable], urine cytology, and CT urography imaging) and duration of response. The complete response rate in the 96 patients with high-risk BCG-unresponsive NMIBC with CIS was 41 percent (95% CI: 31, 51) and median response duration was 16.2 months (0.0+, 30.4+). Forty-six percent (46%) of responding patients experienced a complete response lasting at least 12 months.


The most common adverse reactions (incidence >=10%) in patients who received pembrolizumab in KEYNOTE-057 were fatigue, diarrhea, rash, pruritis, musculoskeletal pain, hematuria, cough, arthralgia, nausea, constipation, urinary tract infection, peripheral edema, hypothyroidism, and nasopharyngitis


The recommended pembrolizumab dose is 200 mg every 3 weeks.


"For patients with high-risk, non-muscle invasive bladder cancer that has become unresponsive to BCG treatment, the most effective treatment option is a radical cystectomy, which includes removing the entire bladder and a prostatectomy for men or total hysterectomy in women," said Arjun V. Balar, MD, Associate Professor of Medicine and Director of Genitourinary Medical Oncology at NYU Langone Health's Perlmutter Cancer Center. "This surgery carries a substantial risk for morbidity and mortality and can negatively impact quality of life. In fact, many patients are not medically eligible for a radical cystectomy. This approval provides a new approach for treating patients with BCG unresponsive high-risk non-muscle invasive bladder cancer, and moreover highlights the continued impact that systemic immunotherapies have had in the management of this disease."


Balar was the lead investigator of the phase II KEYNOTE-057 trial. The main finding was 40 percent of patients had a complete response (clinically meaningful); half of those (20%) still had a complete response after 1 year.


"The study demonstrates local activity in the bladder from a systemically administered treatment," Balar noted. "This is promising since systemic immune activation is what ultimately leads to long-term durable remissions of cancer."


Gary D. Steinberg, MD, a member of the faculty of NYU Langone urology and Director of Perlmutter Cancer Center's Urology Bladder Cancer Program, joined NYU Langone in 2019 to complement ongoing efforts in the care of patients with bladder cancer. Steinberg was a scientific advisor on the KEYNOTE-057 trial and is principal investigator for the KEYNOTE-676 phase III study of BCG with or without pembrolizumab for high-risk NMIBC that is persistent or recurrent following BCG induction.


"The approval of pembrolizumab is paradigm-changing and offers patients a possible therapy to preserve their native bladder function while eliminating their cancer," said Steinberg. "This a breakthrough for some patients and most likely will lead to new combinations of therapy for this aggressive form of localized bladder cancer that will hopefully benefit additional patients. This will lead to further research and innovative treatments for the bladder cancer community and clearly is a significant advance."


Estimates are about 80,000 people are diagnosed with bladder cancer each year in the U.S. Seventy-five percent of these diagnosed bladder cancer cases are NMIBC.


First Targeted Therapy Approved for Rare Mutation in Gastrointestinal Stromal Tumors

Avapritinib has been approved for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation. This approval includes GIST that harbors a PDGFRA D842V mutation, which is the most common exon 18 mutation.


"GISTs harboring a PDGFRA exon 18 mutation do not respond to standard therapies for GIST. However, today's approval provides patients with the first drug specifically approved for GIST harboring this mutation," 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. "Clinical trials showed a high response rate with almost 85 percent of patients experiencing tumor shrinkage with this targeted drug."


GISTs arise from specialized nerve cells found in the walls of the gastrointestinal tract. One or more mutations in the DNA of one of these cells may lead to the development of GIST. These cells aid in the movement of food through the intestines and control various digestive processes. More than half of GISTs start in the stomach. Most of the others start in the small intestine, but GISTs can start anywhere along the gastrointestinal tract. The activating mutations in PDGFRA have been linked to the development of GISTs, and up to approximately 10 percent of GIST cases involve mutations of this gene.


The FDA approved avapritinib based on the results of a clinical trial involving 43 patients with GIST harboring a PDGFRA exon 18 mutation, including 38 patients with PDGFRA D842V mutation. Patients received avapritinib 300 mg or 400 mg orally once daily until disease progression or they experienced unacceptable toxicity. The recommended dose was determined to be 300 mg once daily. The trial measured how many patients experienced complete or partial shrinkage (by a certain amount) of their tumors during treatment (overall response rate).


For patients harboring a PDGFRA exon 18 mutation, the overall response rate was 84 percent, with 7 percent having a complete response and 77 percent having a partial response. For the subgroup of patients with PDGFRA D842V mutations, the overall response rate was 89 percent, with 8 percent having a complete response and 82 percent having a partial response. While the median duration of response was not reached, 61 percent of the responding patients with exon 18 mutations had a response lasting 6 months or longer (31% of patients with an ongoing response were followed for less than 6 months).


Common side effects for patients taking avapritinib were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash, and dizziness. Avapritinib can cause intracranial hemorrhage in which case the dose should be reduced, or the drug should be discontinued. Avapritinib can also cause central nervous system effects including cognitive impairment, dizziness, sleep disorders, mood disorders, speech disorders, and hallucinations. If this happens, depending on the severity, avapritinib should be withheld and then resumed at the same or reduced dose upon improvement or permanently discontinued.


Health care professionals should advise pregnant women that avapritinib may cause harm to a developing fetus or newborn baby. Additionally, the FDA advises health care professionals to tell females of reproductive potential, and males with female partners of reproductive potential, to use effective contraception during treatment with avapritinib and for 6 weeks after the final dose.


The FDA granted this application Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition, when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies. Avapritinib was also granted Fast Track designation, which expedites the review of drugs to treat serious conditions and fill an unmet medical need. Avapritinib received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.


FDA Granted Orphan Drug Designation for CLR 131 in Lymphoplasmacytic Lymphoma

The FDA Office of Orphan Products Development has granted Orphan Drug Designation to CLR 131 in lymphoplasmacytic lymphoma (LPL). CLR 131 is a phospholipid drug conjugate product candidate currently in a phase II clinical study in relapsed or refractory select B-cell lymphomas, including LPL. CLR 131 has previously been granted Orphan Drug Designation for the treatment of multiple myeloma by both the U.S. and the European Commission and Rare Pediatric Disease and Orphan Drug designations for the treatments of neuroblastoma, rhabdomyosarcoma, osteosarcoma, and Ewing's sarcoma.


CLOVER-1 is a phase II study of CLR 131 being conducted in approximately 10 leading cancer centers in the U.S. in patients with relapsed or refractory B-cell hematologic cancers. The hematologic cancers being studied in the trial include multiple myeloma, chronic lymphocytic leukemia/small lymphocytic lymphoma, LPL, marginal zone lymphoma, mantle cell lymphoma, and diffuse large B-cell lymphoma.


The study will enroll up to 80 patients. Its primary endpoint is clinical benefit response, with additional endpoints of overall response rate, progression-free survival, median overall survival, and other markers of efficacy following a fractionated dose of 37.5mCi/m2 of CLR 131 administered in two 30-minute infusions of 18.75mCi/m2 of CLR 131 administered on day 1 and day 7 (+/- 1), with the option for a second dose cycle approximately 75-180 days later.


Orphan Drug Designation to HSB-1216 for Treatment of Small Cell Lung Cancer

Orphan drug designation (ODD) was granted to salinomycin based on nonclinical pharmacology data from HSB-1216, a new chemical entity for the treatment of small cell lung cancer. The ODD designation provides 7 years of market exclusivity post-approval for the HSB-1216.


HSB-1216 is a novel formulation of salinomycin, a potent cancer stem cell inhibitor, encapsulated within HSB-1216 delivery technology. Salinomycin kills cancer stem cells (CSCs) by ferroptosis when iron is sequestered in the lysosomes. CSCs represent an elusive population of tumor stem cells believed to reproduce and sustain cancer. HSB-1216 has shown strong effect on eliminating CSCs. The HSB-1216 salinomycin concentrates within the tumor and is a highly efficacious inhibitor of lung cancer cells. The encapsulation within the HSB-1216 enables may increase tolerability to salinomycin.


FDA Approves Olaparib for gBRCAm Metastatic Pancreatic Adenocarcinoma

The FDA approved olaparib for the maintenance treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) metastatic pancreatic adenocarcinoma, as detected by an FDA-approved test, whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen.


The FDA also approved the BRACAnalysis CDx test as a companion diagnostic for the selection of patients with pancreatic cancer for treatment with olaparib based upon the identification of deleterious or suspected deleterious germline mutations in BRCA1 or BRCA2 genes.


Efficacy was investigated in POLO (NCT02184195), a double-blind, placebo-controlled, multi-center clinical trial that randomized (3:2) 154 patients with gBRCAm metastatic pancreatic adenocarcinoma to olaparib 300 mg orally twice daily or placebo until disease progression or unacceptable toxicity.


The main efficacy outcome measure was progression-free survival (PFS) by blinded independent central review using RECIST 1.1. Additional efficacy outcome measures were overall survival (OS) and overall response rate (ORR).


Median PFS was 7.4 months (95% CI: 4.1, 11.0) for patients who received olaparib compared with 3.8 months (95% CI: 3.5, 4.9) for patients who received placebo (HR 0.53; 95% CI: 0.35, 0.81; p=0.0035). Median OS for olaparib and placebo was 18.9 months (95% CI: 14.9, 26.2) and 18.1 months (95% CI: 12.6, 26.1), respectively (HR 0.91; 95% CI: 0.56, 1.46; p=0.683). ORR among patients who had measurable disease at baseline was 23 percent and 12 percent, respectively.


In general, the adverse reaction profile of olaparib observed in POLO is consistent with the known safety profile of olaparib. The most common adverse reactions to olaparib (>=10%) in clinical trials include nausea, fatigue, vomiting, abdominal pain, anemia, diarrhea, dizziness, neutropenia, leukopenia, nasopharyngitis/upper respiratory tract infection/influenza, respiratory tract infection, arthralgia/myalgia, dysgeusia, headache, dyspepsia, decreased appetite, constipation, stomatitis, dyspnea, and thrombocytopenia.


The recommended olaparib dose is 300 mg taken orally twice daily with or without food.


Orphan Drug Designation for PRGN-3006 UltraCAR-T in Acute Myeloid Leukemia

The FDA granted orphan drug designation to PRGN-3006, a first-in-class investigational therapy using the non-viral UltraCAR-T therapeutic platform for patients with relapsed or refractory acute myeloid leukemia (AML) (clinical trial identifier: NCT03927261).


PRGN-3006 utilizes the UltraCAR-T therapeutic platform, which eliminates ex vivo expansion, reduces manufacturing time, and provides the ability to administer CAR-T therapy to patients only 1 day after non-viral gene transfer at the cancer center. PRGN-3006 UltraCAR-T is a multigenic CAR T-cell treatment utilizing a non-viral gene delivery system to co-express a chimeric antigen receptor, membrane-bound interleukin 15 (mbIL15), and a kill switch for better precision and control in targeting relapsed or refractory AML and higher risk MDS.