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Pembrolizumab for Advanced Esophageal Squamous Cell Cancer

The FDA approved pembrolizumab for patients with recurrent, locally advanced, or metastatic squamous cell carcinoma of the esophagus (ESCC) whose tumors express PD-L1 (combined positive score [CPS] >=10), as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

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The FDA also approved a new use for the PD-L1 IHC 22C3 pharmDx kit as a companion diagnostic device for selecting patients for the above indication.


Efficacy was investigated in two clinical trials, KEYNOTE-181 (NCT02564263) and KEYNOTE-180 (NCT02559687). KEYNOTE-181 was a randomized, open-label, active-controlled trial that enrolled 628 patients with recurrent locally advanced or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced or metastatic disease. Patients were randomized (1:1) to receive either pembrolizumab 200 mg intravenously (IV) every 3 weeks or the investigator's choice of the following regimens: paclitaxel 80-100 mg/m2 IV on days 1, 8, and 15 of every 4-week cycle; docetaxel 75 mg/m2 IV every 3 weeks; or irinotecan 180 mg/m2 IV every 2 weeks (control arm). Randomization was stratified by geographic region and histologic subtype (squamous vs. adenocarcinoma). PD-L1 status was determined using the PD-L1 IHC 22C3 pharmDx kit.


The primary efficacy outcome measure of KEYNOTE-181 was overall survival (OS) in patients with ESCC, patients with tumors expressing PD-L1 CPS >=10, and all randomized patients. Additional efficacy outcome measures were progression-free survival, overall response rate (ORR), and response duration. The hazard ratio for OS in patients with ESCC whose tumors expressed PD-L1 CPS >=10 was 0.64 (95% CI: 0.46, 0.90). Median OS was 10.3 months (95% CI: 7.0, 13.5) and 6.7 months (95% CI: 4.8, 8.6) in the pembrolizumab and control arms, respectively.


KEYNOTE-180 was a single-arm, open-label trial that enrolled 121 patients with locally advanced or metastatic esophageal cancer who progressed on or after at least 2 prior systemic treatments for advanced disease. With the exception of the number of prior lines of treatment, the eligibility criteria were similar to and the dosage regimen identical to KEYNOTE-181.


The major efficacy outcome measures of KEYNOTE-180 were ORR and response duration. In the 35 patients with ESCC expressing PD-L1 CPS >=10, ORR was 20 percent (95% CI: 8, 37) and response durations ranged from 4.2 to 25.1+ months, with 71 percent (five patients) having responses of 6 months or longer and 57 percent (three patients) having responses of 12 months or longer.


Adverse reactions in patients with esophageal cancer were similar to those in 2,799 patients with melanoma or NSCLC treated with single-agent pembrolizumab. Common adverse reactions reported in at least 20 percent of patients receiving pembrolizumab include fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.


The recommended pembrolizumab dose for esophageal cancer is 200 mg every 3 weeks.


Darolutamide for Non-Metastatic Castration-Resistant Prostate Cancer

The FDA approved darolutamide, an androgen receptor inhibitor, for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). The approval is based on the phase III ARAMIS trial evaluating darolutamide plus androgen deprivation therapy (ADT), which demonstrated a highly significant improvement in the primary efficacy endpoint of metastasis-free survival (MFS), with a median of 40.4 months versus 18.4 months for placebo plus ADT (p<0.0001). Darolutamide was approved under the FDA's Priority Review designation, which is reserved for medicines that may provide significant improvements in the safety or effectiveness of the treatment for serious conditions.


"Patients at this stage of prostate cancer typically don't have symptoms of the disease. The overarching goals of treatment in this setting are to delay the spread of prostate cancer and limit the burdensome side effects of therapy," said Matthew Smith, MD, PhD, Director of the Genitourinary Malignancies Program at Massachusetts General Hospital Cancer Center. "This approval marks an important new option for the prostate cancer community."


In the ARAMIS trial, both arms showed a 9 percent discontinuation rate due to adverse reactions. The most frequent adverse reactions requiring discontinuation in patients who received darolutamide included cardiac failure (0.4%) and death (0.4%). Adverse reactions occurring more frequently in the darolutamide arm (>=2% over placebo) were fatigue (16% vs. 11%), pain in extremity (6% vs. 3%), and rash (3% vs. 1%). Darolutamide was not studied in women and there is a warning and precaution for embryo-fetal toxicity.


Overall survival (OS) and time to pain progression were additional secondary efficacy endpoints. OS data were not yet mature at the time of final MFS analysis. The MFS result was supported by a delay in time to pain progression, defined as at least a 2-point worsening from baseline of the pain score on Brief Pain Inventory-Short Form or initiation of opioids, in patients treated with darolutamide as compared to placebo. Pain progression was reported in 28 percent of all patients on study.


FDA Accepts IND Application for huMNC2-CAR44 T Cells to Treat Solid Tumors

The FDA has approved an IND application to conduct clinical trials with huMNC2-CAR44, an autologous CAR T-cell therapy for solid tumors. huMNC2-CAR44 targets MUC1* (muk one star), a cleaved form of MUC1 present on over 75 percent of solid tumor cancer cells. Unlike the normal full-length MUC1, MUC1* is a potent growth factor receptor that is rendered constitutively active when onco-embryonic growth factor NME7ABbinds to and dimerizes its truncated extracellular domain.


The chimeric antigen receptor (CAR) technology genetically engineers the patient's own immune cells to recognize and kill specific types of cancer cells. The homing device on the CAR is an antibody that can distinguish the tumor-associated cleavage product, MUC1*, from the normal, full-length MUC1. Previous attempts to make cancer therapeutics that target MUC1 have failed because they have targeted the a portion of full-length MUC1, which on tumor cells is cleaved, then shed and released form the cancer cell surface.


FDA Approves First Therapy for Rare Joint Tumor

The FDA granted approval to pexidartinib capsules for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) associated with severe morbidity or functional limitations and not responsive to improvement with surgery.


"TGCT can cause debilitating symptoms for patients such as pain, stiffness and limitation of movement. The tumor can significantly affect a patient's quality of life and cause severe disability," said Richard Pazdur, MD, Director of the FDA's Oncology Center of Excellence and Acting Director of the Office of Hematology and Oncology Products in the FDA's Center for Drug Evaluation and Research. "Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure. Today's approval is the first FDA-approved therapy to treat this rare disease."


TGCT is a rare tumor that affects the synovium and tendon sheaths. The tumor is rarely malignant but causes the synovium and tendon sheaths to thicken and overgrow, causing damage to surrounding tissue.


The approval of pexidartinib was based on the results of a multi-center international clinical trial of 120 patients, 59 of whom received placebo. The primary efficacy endpoint was the overall response rate (ORR) analyzed after 25 weeks of treatment. The clinical trial demonstrated a statistically significant improvement in ORR in patients who received pexidartinib, with an ORR of 38 percent, compared to no responses in patients who received placebo. The complete response rate was 15 percent and the partial response rate was 23 percent. A total of 22 out of 23 responders who had been followed for a minimum of 6 months following the initial response maintained their response for 6 or more months, and a total of 13 out of 13 responders who had been followed for a minimum of 12 months following the initial response maintained their response for 12 or more months.


The prescribing information for pexidartinib includes a Boxed Warning to advise health care professionals and patients about the risk of serious and potentially fatal liver injury. Health care professionals should monitor liver tests prior to beginning treatment and at specified intervals during treatment. If liver tests become abnormal, pexidartinib may need to be withheld, the dose reduced, or permanently discontinued, depending on the severity of the liver injury. Pexidartinib is available only through the pexidartinib Risk Evaluation and Mitigation Strategy (REMS) Program.


Common side effects for patients taking pexidartinib were increased lactate dehydrogenase, increased aspartate aminotransferase, loss of hair color, increased alanine aminotransferase, and increased cholesterol. Additional side effects included neutropenia, increased alkaline phosphatase, decreased lymphocytes, eye edema, decreased hemoglobin, rash, dysgeusia, and decreased phosphate.


The FDA advises health care professionals to tell females of reproductive age and males with a female partner of reproductive potential to use effective contraception during treatment with pexidartinib. Women who are pregnant or breastfeeding should not take pexidartinib because it may cause harm to a developing fetus or newborn baby. Pexidartinib must be dispensed with a patient Medication Guide that describes important information about the drug's uses and risks.


The FDA granted this application Breakthrough Therapy designation and Priority Review designation. Pexidartinib also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.