AZ’s Tagrisso, Roche’s Rozyltrek & Diagnostic Breakthroughs: Big month for Lung Cancer

August 13, 20200

This year witnessed an upsurge in approvals by regulatory authorities for lung cancer treatmentThis is very encouraging given the substantial level unmet need in the indication that is confounded by anexpansive level of late diagnosis and consequently poor clinical outcomes. Combination therapy iscommonly used to address various aspects of the disease due to the various causative mutations 

Astra Zeneca’s TagrissoRecently, Astra Zeneca announced that the US Food and Drug Administration(FDA) has granted Breakthrough Therapy Designation (BTD) Status for Tagrisso 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) post complete tumor resection with curative intent.Adjuvant treatment, also known as an adjunct therapy is administered to maximize the effectiveness of the main form of treatment. This approval is based on Phase III ADAURA trial conducted among 682 patients (with Stage IB, II, IIIA EGFRm NSCLC after complete tumor resection and adjuvant chemotherapy) across 20 countries. The trial showed statistically significant clinical improvement in Disease-Free Survival (DFS), a secondary endpoint, on the administration of these oral tablets daily, andthe risk of recurrence or death reduced by 79%. Though trial results were originally to be readout by 2022, the Independent Data Monitoring Committee recommended it to be unblinded due to exceptional efficacy outcomes. This add-on therapy is an exciting development as 30 % of patients diagnosed in early-stage NSCLC, eligible for surgery, face recurrence of the disease. Also, 50% of patients with Stage IB and 75% of Stage IIIA patients experience recurrence of the disease within five years. 

Tagrisso is also approved for the treatment of locally advanced or metastatic EGFR T790M mutation-positive NSCLC as well as for the 1st-line treatment of patients with locally advanced or metastaticEGFRm NSCLC in the US, China, Japan, the EU, and many other countries around the world. This indication expansion also holds substantial revenue potential for Astra Zeneca. 

Roche’s RozyltrekAdding to the momentum, Roche’s first ever tumor-agnostic therapy was approvedin Europe, Rozlytrek® (entrectinib), an oral once-daily tyrosine kinase inhibitor. Tumoragnostic therapyis a form of treatment that focuses on mutation rather than the disease and hence can be used formultiple diseases with the same mutation. It was approved for treatment of patients with neurotrophic tyrosine receptor kinase (NTRK) fusion-positive solid tumors and for people with ROS1-positive advanced non-small cell lung cancer (NSCLC). European Commission granted conditional Marketing authorization following recommendation by European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) in May. Japan was the first nation to approve Rozlytrek in June 2019followed by an accelerated FDA (Food and Drug Administration) approval in August. It was also granted Priority Medicines (PRIME) designation by the EMA due to the rare nature of these mutations. 

The treatment is approved for: (a) patient expressing NTRK gene fusion, with a locally advanced, metastatic disease or in which surgical resection would result in severe morbidity, with no priortreatment involving NTRK inhibitor and is of ages 12 and above; (b) patient with ROS1-positive, advanced NSCLC and is an adult. The approval is based on integrated analysis of phase I ALKA-372-001 trials, phase I STARTRK-1 and pivotal phase II STARTRK-2 along with data from the phase I/II STARTRK-NG study. 

Results were as follows: 

Disease targeted  Results  Participants 
NTRK fusion-positive, locally advanced, or metastatic solid tumors  Overall response rate63.5%  74 
Children and adolescents with NTRK gene fusions   Overall response rate: 100%  5 
Complete response: 40% 
ROS1-positive, advanced NSCLC (minimum of 6 months of follow up); (includes 29% of patients with central nervous system (CNS) metastases at baseline)  Overall response rate: 67.1%  161 
ROS1-positive, advanced NSCLC  Overall response rate: 73.4%  94 


NTRK and ROS1 populations with CNS metastases at baseline, when Rozlytrek was administeredintracranial overall response rate of 62.5% and 79.2% was seen. 

Breakthrough in companion diagnostics and robot assisted bronchoscopy: The recent development in the lung cancer therapeutics needs to be backed by progress in diagnostics so, as to support patients fully, catering both diagnosis and prognosis of the medical condition. Adding to the momentum in lung cancer treatment are important development in robot assisted bronchoscopy and liquid biopsy. 

Transbronchial microwave ablation using robotassisted bronchoscopyU.S. FDA granted Ethicon, unit of Johnson & Johnson Medical Device Company Breakthrough Device Designation for its currently under development, transbronchial microwave ablation technology using robot-assisted bronchoscopy. The device covers technologies acquired by Ethicon through acquisition of NeuWaveMedical in 2016. It offers a minimally invasive alternative for soft tissue lesions. This deal was followed by the addition of lung focused robotic surgery platform of Auris Healthcare though USD 3.4 billion deallast year. The robotassisted bronchoscopy system was introduced for the first time in the United Statesand represents innovation trends in safer alternatives for invasive diagnostics and treatment options.  

Liquid biopsy as companion diagnostic for Astra Zeneca’s Tagrisso: As the use of personalized cancer therapies have expanded, companion diagnostics for profiling genetic biomarkers have been an important enabler. FDA’s recent approval of Guardant Health’s companion diagnostifor AstraZeneca’sTagrissois a critical milestone. This novel test combines liquid biopsy along with Next GenerationSequencing and is capable of detecting mutations in 55 tumor genes. Guardant360CDx will be able to offer complete tumor profile information, including various solid tumor biomarkers along with the identification of patients with EGFR mutations, who can benefit from treatment with Tagrisso. Clinical and analytical validation was performed over 5000 samples, data from phase III clinical trials FLAURA and AURA3 indicated that the NSCLC patients were selected for treatment using the diagnostic device.  

Guardant Health has also partnered with other pharma companies including AmgenJanssen Biotech,and Radius Health Inc., to develop companion diagnostics for personalizing oncology therapeutics under development. Especially in the context of Tagrisso and lung cancer, such non-invasive companion diagnostics are very encouraging given the high risk of pneumothorax (collapse of the lungs) associated with biopsies. This is also highly relevant in the current pandemic context where this test can negate the need for in-hospital biopsy procedures as a precursor to clinical decision making on the of drug. 

Overall, we are enthused by regulatory momentum during the current year in lung cancer treatments,especially for NSCLCs which is the most common form of lung canceraffecting 84% lung cancerpatients. 

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