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Nivolumab for Resected Esophageal or Gastroesophageal Junction Cancer

The FDA approved nivolumab injection for IV use for the adjuvant treatment of completely resected esophageal or gastroesophageal junction (GEJ) cancer with residual pathologic disease in patients who have received neoadjuvant chemoradiotherapy (CRT). The approval is based on results from the Phase III CheckMate-577 trial that evaluated nivolumab (n=532) compared to placebo (n=262) in esophageal or GEJ cancer patients with residual pathologic disease following neoadjuvant CRT and complete resection.

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In the trial, among patients who received nivolumab, median disease-free survival (DFS) was twice as long as in those who received placebo (22.4 months [95% CI]: 16.6-34.0] compared to 11.0 months [95% CI: 8.3-14.3]). Nivolumab reduced the risk of disease recurrence or death by 31 percent compared to placebo (HR 0.69; 95% CI: 0.56-0.85; P=0.0003).


In an exploratory analysis, among patients with adenocarcinoma (n=563, 70.9%), mDFS was 19.4 months (95% CI: 15.9-29.4) with nivolumab versus 11.1 months (95% CI: 8.3-16.8) with placebo (unstratified HR 0.75; 95% CI: 0.59-0.96), and among squamous cell carcinoma patients (n=230, 29%), mDFS was 29.7 months (95% CI: 14.4-NE) with nivolumab versus 11.0 months (95% CI: 7.6-17.8) with placebo (unstratified HR 0.61; 95% CI: 0.42-0.88).


"Locally advanced esophageal and gastroesophageal junction cancers are aggressive tumor types that often require multiple approaches to address the disease, including chemotherapy, radiation, and surgery," said Ronan J. Kelly MD, MBA, Director of the Baylor Scott & White Charles A. Sammons Cancer Center, and W.W. Caruth Jr. Endowed Chair of Immunology at Baylor University Medical Center.


"Even after neoadjuvant CRT followed by surgery, there may be a high risk of recurrence for patients who do not achieve a pathologic complete response," he noted. "In the CheckMate-577 trial, we saw a doubling in median disease-free survival compared to placebo, which suggests that nivolumab could become a new standard of care for these patients. This is exciting news, providing renewed hope."


Nivolumab is associated with the following warnings and precautions: severe and fatal immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis and hepatotoxicity, endocrinopathies, nephritis and renal dysfunction, dermatologic adverse reactions, and other immune-mediated adverse reactions; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when nivolumab is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.


This application was reviewed under the FDA's Real-Time Oncology Review pilot program, which aims to ensure that safe and effective treatments are available to patients as early as possible. The review was also conducted under the FDA's Project Orbis initiative, which enabled concurrent review by the health authorities in Australia, Canada, and Switzerland.


CheckMate-577 was a Phase III randomized, placebo-controlled, double-blind, multi-center trial, evaluating nivolumab as an adjuvant treatment in patients with esophageal or GEJ cancer with residual pathologic disease following neoadjuvant CRT and complete resection. The trial excluded patients who did not receive CRT prior to surgery, and had stage IV resectable disease, autoimmune disease, or any condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone or equivalent) or other immunosuppressive medications. The primary endpoint of the trial was DFS (investigator assessed).


Following neoadjuvant CRT and complete tumor surgical resection (also known as trimodality therapy), a total of 794 patients were randomized to receive either nivolumab 240 mg (n=532) or placebo (n=262) by intravenous infusion every 2 weeks for 16 weeks, followed by nivolumab 480 mg or placebo by intravenous infusion every 4 weeks beginning at week 17. Treatment was until disease recurrence, unacceptable toxicity, or for up to 1 year in total duration.


The FDA-approved dosing for nivolumab (injection for intravenous use) for adjuvant treatment of patients with resected esophageal or GEJ cancer is 240 mg intravenous infusion over 30 minutes every 2 weeks or 480 mg intravenous infusion over 30 minutes every 4 weeks until disease progression or unacceptable toxicity for a total treatment duration of 1 year.


Nivolumab was discontinued in 12 percent of patients and was delayed in 28 percent of patients for an adverse reaction. Serious adverse reactions occurred in 33 percent of patients receiving nivolumab. A serious adverse reaction reported in >=2 percent of patients who received nivolumab was pneumonitis. A fatal adverse reaction of myocardial infarction occurred in one patient who received nivolumab. The most common adverse reactions reported in 20 percent of patients treated with nivolumab were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%).


Biologics License Application Accepted for Ublituximab + Umbralisib for CLL & SLL

The FDA accepted the Biologics License Application (BLA) for ublituximab, an investigational glycoengineered anti-CD20 monoclonal antibody, in combination with umbralisib, a once-daily, oral inhibitor of PI3K-delta and CK1-epsilon, as a treatment for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). The FDA has set a Prescription Drug User Fee Act (PDUFA) goal date of March 25, 2022.


The BLA submission was based on the results of the UNITY-CLL trial, a global Phase III trial evaluating the combination of ublituximab plus umbralisib compared to obinutuzumab plus chlorambucil in patients with treatment-naive and relapsed or refractory CLL. The FDA previously granted fast track designation to the combination of ublituximab and umbralisib for the treatment of adult patients with CLL and orphan drug designation for ublituximab in combination with umbralisib for the treatment of CLL.


UNITY-CLL is a global Phase III randomized controlled clinical trial comparing the combination of ublituximab plus umbralisib to an active control arm of obinutuzumab plus chlorambucil in patients with both treatment-naive and relapsed or refractory CLL. The trial randomized patients into four treatment arms: ublituximab single agent, umbralisib single agent, ublituximab plus umbralisib, and an active control arm of obinutuzumab plus chlorambucil.


A prespecified interim analysis was conducted to assess the contribution of ublituximab and umbralisib in the combination arm and allowed for the termination of the single agent arms. Accordingly, the UNITY-CLL Phase III trial continued enrollment in a 1:1 ratio into the two combination arms: the investigational arm of umbralisib and the control arm of obinutuzumab plus chlorambucil.


Approximately 420 subjects enrolled to the two combination arms, and approximately 60 percent of patients were treatment-naive and 40 percent were relapsed or refractory. The primary endpoint for this study was superior progression-free survival for the umbralisib combination compared to the control arm. The trial met its primary endpoint and results were presented at the American Society of Hematology Annual Meeting in December 2020. The UNITY-CLL Phase III trial is being conducted under a Special Protocol Assessment agreement with the FDA.


Umbralisib is the first and only oral inhibitor of PI3K-delta and CK1-epsilon. PI3K-delta is known to play an important role in supporting cell proliferation and survival, cell differentiation, intercellular trafficking, and immunity and is expressed in both normal and malignant B cells. CK1-epsilon is a regulator of oncoprotein translation and has been implicated in the pathogenesis of cancer cells, including lymphoid malignancies.


Umbralisib is indicated for the treatment of adult patients with relapsed or refractory marginal zone lymphoma who have received at least one prior anti-CD20-based regimen and for the treatment of adult patients with relapsed or refractory follicular lymphoma who have received at least three prior lines of systemic therapy.


Accelerated Approval of Amivantamab-Vmjw for Metastatic NSCLC

The FDA granted accelerated approval to amivantamab-vmjw, a bispecific antibody directed against epidermal growth factor (EGF) and MET receptors, for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. The FDA also approved the Guardant360 CDx as a companion diagnostic for amivantamab-vmjw.


Approval was based on CHRYSALIS, a multicenter, non-randomized, open-label, multicohort clinical trial (NCT02609776), which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Efficacy was evaluated in 81 patients with advanced NSCLC with EGFR exon 20 insertion mutations whose disease had progressed on or after platinum-based chemotherapy. Patients received amivantamab-vmjw once weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.


The main efficacy outcome measures were overall response rate (ORR) according to RECIST 1.1 as evaluated by blinded independent central review and response duration. The ORR was 40 percent (95% CI: 29%, 51%) with a median response duration of 11.1 months (95% CI: 6.9, not evaluable).


The most common adverse reactions (>= 20%) were rash, infusion-related reactions, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting.


The recommended dose of amivantamab-vmjw is 1,050 mg for patients with baseline body weight < 80 kg, and 1,400 mg for those with body weight >= 80 kg, administered weekly for 4 weeks, then every 2 weeks thereafter until disease progression or unacceptable toxicity.


A Second PSMA-Targeted PET Imaging Drug for Prostate Cancer

FDA has approved piflufolastat F 18-a drug for positron emission tomography (PET) imaging of prostate-specific membrane antigen (PSMA) positive lesions in men with prostate cancer. With the approval of piflufolastat F 18, certain men with prostate cancer will have greater access to PSMA-targeted PET imaging that can aid health care providers in assessing prostate cancer.


Piflufolastat F 18 is indicated for patients with suspected prostate cancer metastasis who are potentially curable by surgery or other therapy. It is also indicated for patients with suspected prostate cancer recurrence based on elevated serum prostate-specific antigen (PSA) levels. Piflufolastat F 18 is a radioactive diagnostic agent that is administered in the form of an intravenous injection.


Prostate cancer is the third most common form of cancer in the U.S. The American Cancer Society estimates in 2021 that prostate cancer will be the most commonly diagnosed cancer in American men, with 248,530 new cases predicted. CT scans, MRI scans, and certain nuclear medicine scans are conventional methods commonly used to image patients with prostate cancer. However, these imaging techniques have limitations in the detection of prostate cancer lesions.


Once administered via injection, piflufolastat F 18 binds to PSMA, which is an important pharmacologic target for prostate cancer imaging because prostate cancer cells usually contain elevated levels of the antigen. As a radioactive drug that emits positrons, it can be imaged by PET to indicate the presence of PSMA-positive prostate cancer lesions in the tissues of the body.


The safety and efficacy of piflufolastat F 18 were evaluated in two prospective clinical trials with a total of 593 men with prostate cancer who each received one injection of the treatment. In the first trial, a cohort of 268 patients with biopsy-proven prostate cancer underwent PET/CT scans performed with piflufolastat F 18. These patients were candidates for surgical removal of the prostate gland and pelvic lymph nodes and were considered at higher risk for metastasis. Among the patients who proceeded to surgery, those with positive readings in the pelvic lymph nodes on piflufolastat F 18 PET had a clinically important rate of metastatic cancer confirmed by surgical pathology. The availability of this information prior to treatment is expected to have important implications for patient care. For example, it may spare certain patients from undergoing unnecessary surgery.


The second trial enrolled 208 patients who had rising serum PSA levels after initial prostate surgery or other definitive therapy, and thus had biochemical evidence of recurrent prostate cancer. Prior to a single piflufolastat F 18 PET/CT scan, all of these patients had baseline conventional imaging performed that did not show definite spread of prostate cancer. Piflufolastat F 18 detected at least one positive lesion in at least one body region (bone, prostate bed, pelvic lymph node, other lymph nodes, or soft tissue) in 60 percent of these patients. In patients with positive piflufolastat F 18 PET readings who had correlative tissue pathology from biopsies, results from baseline or follow-up imaging by conventional methods, or serial PSA levels available for comparison, local recurrence or metastasis of prostate cancer was confirmed in an estimated 85-87 percent of cases, depending on the reader. Thus, the second trial demonstrated that piflufolastat F 18 can detect sites of disease in patients with biochemical evidence of recurrent prostate cancer, thereby providing important information that may impact the approach to therapy.


The most common adverse reactions to treatment were headache, altered taste, and fatigue. There is a risk of hypersensitivity reactions to piflufolastat F 18, particularly in patients with a history of allergy to other drugs and foods. There is a risk for misdiagnosis because piflufolastat F 18 binding may occur in other types of cancer as well as certain non-malignant conditions which may lead to image interpretation errors. There are radiation risks because the therapy contributes to a patient's overall long-term cumulative radiation exposure, which is associated with an increased risk for cancer.