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Companion Diagnostic Identifies NTRK Fusions in Solid Tumors

The FDA approved the next-generation sequencing (NGS)-based FoundationOne CDx test as a companion diagnostic to identify fusions in neurotrophic receptor tyrosine kinase (NTRK) genes, including NTRK1, NTRK2, and NTRK3. This occurs in DNA isolated from tumor tissue specimens from patients with solid tumors eligible for treatment with larotrectinib.

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Larotrectinib was granted accelerated approval in 2018 for adult and pediatric patients with solid tumors that have a NTRK gene fusion without a known acquired resistance mutation, that are either metastatic or where surgical resection is likely to result in severe morbidity, and who have no satisfactory alternative treatments or their cancer has progressed following treatment.


Approval of larotrectinib was based on data from three multicenter, open-label, single-arm clinical trials: LOXO-TRK-14001, SCOUT, and NAVIGATE. Identification of positive NTRK gene fusion status was prospectively determined in local labs using NGS, fluorescence in situ hybridization (FISH), and reverse transcriptase polymerase chain reaction (RT-PCR) methods. NTRK gene fusions were inferred in three pediatric patients with infantile fibrosarcoma who had a documented ETV6 translocation by FISH. The major efficacy outcome measures were overall response rate and response duration, as determined by a blinded independent review committee according to RECIST 1.1.


The FoundationOne CDx assay (F1CDx) approval as a companion diagnostic for larotrectinib was based on the retrospective testing with F1CDx of available tumor tissue samples from patients enrolled in the three clinical trials that supported the accelerated approval of larotrectinib. Efficacy for larotrectinib was shown to be maintained in patients with confirmed NTRK fusion positive results by the F1CDx. F1CDx is a NGS based in vitro diagnostic device that is capable of detecting several mutations in addition to NTRK gene fusions.


FDA Clearance of IND for Lutetium-177 Labeled Omburtamab Antibody

The FDA has cleared an Investigational New Drug (IND) application for 177Lu-omburtamab-DTPA for the treatment of B7-H3 positive central nervous system (CNS) and leptomeningeal metastasis (LM) from tumors in adult patients.


177Lu-omburtamab-DTPA embodies the naked omburtamab antibody radiolabeled with lutetium-177, using DTPA to chelate the lutetium radioisotope to the antibody. Lutetium-177 is a beta-emitter with a half-life of 6.7 days and a maximum energy of 0.5 MeV, corresponding to a maximum soft-tissue penetration of approximately 1 mm from the binding site.


An international multicenter Phase I/II clinical trial is anticipated for the screening of adult patients with CNS/LM from B7-H3 positive tumors during the fourth quarter of 2020.


Priority Review of Osimertinib for Adjuvant Early-Stage EGFR-Mutated Lung Cancer

Osimertinib was granted Priority Review in the U.S. for the adjuvant treatment of patients with early-stage EGFR-mutated lung cancer. It has received acceptance for its supplemental New Drug Application (sNDA) and has also been granted Priority Review in the U.S. for the adjuvant treatment of patients with early-stage (IB, II, and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumor resection with curative intent.


The sNDA was based on results from the ADAURA Phase III trial showing osimertinib demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) in the primary analysis population of patients with stage II and IIIA EGFRm NSCLC, and also in the overall trial population of patients with stage IB-IIIA disease, a key secondary endpoint.


In April 2020, an Independent Data Monitoring Committee recommended for the trial to be unblinded 2 years early, based on its determination of overwhelming efficacy. Investigators and patients continue to participate in the trial and remain blinded to treatment. The results from the ADAURA trial were presented during the plenary session of the ASCO20 Virtual Scientific Program in May 2020 and were recently published in The New England Journal of Medicine.


Safety information for osimertinib includes the following:


* Interstitial lung disease (ILD)/pneumonitis occurred in patients treated with osimertinib, some of which were fatal. Withhold osimertinib and promptly investigate for ILD in patients who present with worsening respiratory symptoms. Permanently discontinue if confirmed.


* Monitor patients who have a history or predisposition for QTc prolongation or those who are taking medications that are known to prolong the QTc interval. Permanently discontinue osimertinib in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia.


* Cardiomyopathy occurred in osimertinib-treated patients, some of which were fatal. Monitor patients with cardiac risk factors and assess left ventricular ejection fraction in patients who develop symptoms during treatment. Permanently discontinue osimertinib in patients with symptomatic congestive heart failure.


* Promptly refer patients with signs and symptoms of keratitis to an ophthalmologist.


* Withhold osimertinib if Stevens-Johnson syndrome or erythema multiforme major is suspected and permanently discontinue if confirmed.


* Verify pregnancy status of women prior to use. Advise women to use effective contraception during treatment with osimertinib and for 6 weeks after the final dose. Advise men to use effective contraception during treatment with osimertinib and for 4 months after the final dose.


* Most common adverse reactions (>=20%) were diarrhea, rash, dry skin, nail toxicity, stomatitis, fatigue, and decreased appetite.



Osimertinib is indicated for the first-line treatment of patients with metastatic NSCLC whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test. Osimertinib is indicated for the treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor therapy.


FDA Extends Approval of Pembrolizumab for Classical Hodgkin Lymphoma

The FDA extended the approval of pembrolizumab for adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) and pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.


Approval was based on KEYNOTE-204 (NCT02684292), a Phase III, randomized, open-label trial in 304 adult patients with relapsed or refractory cHL after at least one multiagent regimen. Patients were randomized (1:1) to receive either pembrolizumab 200 mg every 3 weeks or brentuximab vedotin (BV) 1.8 mg/kg every 3 weeks for up to 2 years.


Efficacy was based on progression-free survival (PFS) per blinded independent central review assessment. PFS was statistically significantly longer in the pembrolizumab arm. The median PFS was 13.2 months (95% CI: 10.9, 19.4) in the pembrolizumab arm and 8.3 months (95% CI: 5.7, 8.8) in the BV arm, with a hazard ratio of 0.65 (95% CI: 0.48, 0.88; p=0.0027).


Serious adverse reactions occurred in 30 percent of the patients who received pembrolizumab. Serious adverse reactions in >=1 percent of patients included pneumonitis, pneumonia, pyrexia, myocarditis, acute kidney injury, febrile neutropenia, and sepsis.


Adverse reactions in >=20 percent of pembrolizumab recipients included upper respiratory tract infection, musculoskeletal pain, diarrhea, cough, pyrexia, fatigue, and rash. Thirty-eight percent of patients had adverse reactions requiring systemic corticosteroids, including pneumonitis in 11 percent.