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Fast Track Designation for First-in-Class NBTXR3 in Head & Neck Cancer

The FDA has granted Fast Track designation for the investigation of NBTXR3 activated by radiation therapy, with or without cetuximab, for the treatment of patients with locally advanced head and neck squamous cell cancer who are not eligible for platinum-based chemotherapy.

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NBTXR3 is a first-in-class product designed to destroy tumors through physical cell death when activated by radiotherapy. It has a high degree of biocompatibility, requires one single administration before the first radiotherapy treatment session, and has the ability to fit into current worldwide radiation therapy standards of care. The physical mode of action of NBTXR3 makes it applicable across solid tumors such as lung, prostate, liver, glioblastoma, and breast cancers.


NBTXR3 is actively being evaluated for locally advanced head and neck squamous cell carcinoma of the oral cavity or oropharynx in elderly and frail patients unable to receive chemotherapy or cetuximab with limited therapeutic options. Promising results have been observed in the phase I trial regarding local control.


The other ongoing NBTXR3 trials are treating patients with hepatocellular carcinoma or liver metastases, locally advanced or unresectable rectal cancer in combination with chemotherapy, head and neck cancer in combination with concurrent chemotherapy, and prostate adenocarcinoma.


MET Inhibitor Capmatinib for METex14 Mutated Advanced Non-Small Cell Lung Cancer

The FDA accepted and granted Priority Review to capmatinib's (INC280) New Drug Application (NDA). Capmatinib is a MET inhibitor being evaluated as a treatment for first-line and previously treated patients with locally advanced or metastatic MET exon 14 skipping (METex14) mutated non-small cell lung cancer. If approved, capmatinib will be the first therapy to specifically target METex14 mutated advanced lung cancer that has a particularly poor prognosis.


The NDA submission for capmatinib is supported by results from the GEOMETRY mono-1 phase II study, which demonstrated an overall response rate of 67.9 percent (95% CI, 47.6-84.1) and 40.6 percent (95% CI, 28.9-53.1) among treatment-naive and previously treated patients, respectively, based on the Blinded Independent Review Committee (BIRC) assessment per RECIST v1.1 (ASCO 2019; Abstract 9004). The study also demonstrated that capmatinib provided durable responses among all patients: median duration of response was 11.14 months (95% CI, 5.55-NE) in treatment-naive patients and 9.72 months (95% CI, 5.55-12.98) in previously treated patients.


All results were based on independent assessment by the BIRC, and all tumor CT scans were evaluated in parallel by two radiologists to confirm the response. The most common treatment-related adverse events (AE) (>= 10% all grades) across all cohorts (N=334), were peripheral edema (42%), nausea (33%), creatinine increase (20%), vomiting (19%), fatigue (14%), decreased appetite (13%), and diarrhea (11%). The majority of the AEs were grades 1/2.


Priority Review to Atezolizumab Monotherapy as First-Line Therapy in Advanced NSCLC

The FDA has accepted the company's supplemental Biologics License Application (sBLA) and granted Priority Review for atezolizumab as a first-line monotherapy for people with advanced non-squamous and squamous non-small cell lung cancer (NSCLC) without EGFR or ALK mutations with high PD-L1 expression (TC3/IC3 wild-type [WT]), as determined by PD-L1 biomarker testing. The FDA is expected to make a decision on approval by June 19, 2020.


This sBLA is based on results from the phase III IMpower110 study, a randomized, open-label study to evaluate the efficacy and safety of atezolizumab monotherapy compared with cisplatin or carboplatin and pemetrexed or gemcitabine (chemotherapy) in PD-L1-selected, chemotherapy-naive participants with advanced non-squamous or squamous NSCLC without ALK or EGFR mutations (WT). A total of 572 people (555 WT) were enrolled and were randomized 1:1 to receive:


* atezolizumab monotherapy, until loss of clinical benefit (as assessed by the investigator), unacceptable toxicity or death; or


* cisplatin or carboplatin (per investigator discretion) combined with either pemetrexed (non-squamous) or gemcitabine (squamous), followed by maintenance therapy with pemetrexed alone (non-squamous) or best supportive care (squamous) until disease progression, unacceptable toxicity, or death.



The primary efficacy endpoint is overall survival (OS) by PD-L1 subgroup (TC3/IC3-WT; TC2/3/IC2/3-WT; and TC1,2,3/IC1,2,3-WT), as determined by the SP142 assay test. Key secondary endpoints include investigator-assessed progression-free survival, objective response rate, and duration of response.


The study showed that atezolizumab monotherapy improved overall survival by 7.1 months compared with chemotherapy (median OS=20.2 vs. 13.1 months; HR=0.595, 95% CI: 0.398-0.890; p=0.0106) in people with high PD-L1 expression (TC3/IC3-WT). Safety for atezolizumab appeared to be consistent with its known safety profile, and no new safety signals were identified. Grade 3/4 treatment-related adverse events were reported in 12.9 percent of people receiving atezolizumab compared with 44.1 percent of people receiving chemotherapy.


FDA Accepts Supplemental New Drug Application for Selinexor to Treat R/R DLBCL

The FDA has accepted for filing a supplemental New Drug Application seeking accelerated approval for oral selinexor tablets, a first-in-class, selective inhibitor of nuclear export (SINE) compound, for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, who have received at least two prior therapies. The FDA also granted a request for Priority Review and assigned a user fee goal date of June 23, 2020, under the Prescription Drug User Fee Act.


Selinexor functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). Selinexor blocks the nuclear export of tumor suppressor, growth regulatory, and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion.


Selinexor has received Fast Track and Orphan designations from the FDA for the patient population evaluated in the SADAL study. It is also being evaluated in several other mid- and later-phase clinical trials across multiple cancer indications, including multiple myeloma in a pivotal, randomized phase III study in combination with bortezomib and low-dose dexamethasone (BOSTON), as a potential backbone therapy in combination with approved therapies (STOMP), in liposarcoma (SEAL) and in endometrial cancer (SIENDO), among others. Additional phase I, phase II, and phase III studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform clinical development priorities for selinexor.


Enfortumab Vedotin-Ejfv + Pembrolizumab in First-Line Advanced Bladder Cancer

The FDA has granted Breakthrough Therapy designation for enfortumab vedotin-ejfv in combination with pembrolizumab for the treatment of patients with unresectable locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy in the first-line setting.


The Breakthrough Therapy designation was granted based on results from the dose-escalation cohort and expansion cohort A of the phase Ib/II trial, EV-103 (NCT03288545), evaluating patients with locally advanced or metastatic urothelial cancer who are unable to receive cisplatin-based chemotherapy treated in the first-line setting with enfortumab vedotin-ejfv in combination with pembrolizumab.


Initial results from the trial were presented at the European Society of Medical Oncology (ESMO) 2019 Congress, and updated findings at the 2020 Genitourinary Cancers Symposium. EV-103 is an ongoing, multi-cohort, open-label, multicenter, phase Ib/II trial of enfortumab vedotin-ejfv alone or in combination, evaluating safety, tolerability and efficacy in muscle invasive, locally advanced, and first- and second-line metastatic urothelial cancer.


FDA Approves Neratinib for Metastatic HER2-Positive Breast Cancer

On Feb. 25, 2020, the FDA approved neratinib in combination with capecitabine for adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting.


Efficacy of neratinib with capecitabine was investigated in NALA (NCT01808573), a randomized, multicenter, open-label clinical trial in 621 patients with metastatic HER2-positive breast cancer who received two or more prior anti-HER2 based regimens in the metastatic setting. Patients were randomized (1:1) to receive neratinib 240 mg orally once daily on days 1-21 with capecitabine 750 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (n=307) or lapatinib 1,250 mg orally once daily on days 1-21 with capecitabine 1,000 mg/m2 given orally twice daily on days 1-14 for each 21-day cycle (n=314). Patients were treated until disease progression or unacceptable toxicity.


The primary efficacy outcome measures were progression-free survival (PFS), assessed by a blinded independent central review per RECIST v1.1, and overall survival (OS). Key secondary outcome measures were objective response rate (ORR) and response duration. Median PFS was 5.6 months (95% CI: 4.9, 6.9) for patients who received neratinib with capecitabine and 5.5 months (95% CI: 4.3, 5.6) for those receiving lapatinib with capecitabine (HR 0.76; 95% CI: 0.63, 0.93; p=0.0059). The PFS rate at 12 months was 29 percent (95% CI: 23, 35) versus 15 percent (95% CI: 10, 20), respectively.


Median OS was 21 months (95% CI: 17.7, 23.8) for patients receiving neratinib with capecitabine compared to 18.7 months (95% CI: 15.5, 21.2) for those receiving lapatinib plus capecitabine (HR 0.88; 95% CI: 0.72, 1.07; p=0.2086). The ORR was 32.8 percent (95% CI: 27.1, 38.9) versus 26.7 percent (95% CI: 21.5, 32.4), respectively. Median response duration was 8.5 (95% CI: 5.6, 11.2) versus 5.6 months (95% CI: 4.2, 6.4), respectively.


The most common adverse reactions of any grade (>5%) in the neratinib plus capecitabine arm were diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms. The most frequently reported grade 3 or 4 adverse reactions were diarrhea, nausea, vomiting, fatigue, and decreased appetite.


The recommended neratinib dose for advanced or metastatic breast cancer is 240 mg (6 tablets) given orally once daily with food on days 1-21 of a 21-day cycle plus capecitabine (750 mg/m2 given orally twice daily) on days 1-14 of a 21-day cycle until disease progression or unacceptable toxicities.