publication date: Apr. 20, 2018
Drugs and Targets
FDA approves Tagrisso for front-line metastatic NSCLC with common EGFR mutations
FDA has approved Tagrisso (osimertinib) for the first-line treatment of patients with metastatic non-small cell lung cancer whose tumors have epidermal growth factor receptor exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.
The drug is sponsored by AstraZeneca Pharmaceuticals LP.
Approval was based on a multicenter, international, randomized, double-blind, active-controlled trial (FLAURA, NCT02296125) conducted in 556 patients with EGFR exon 19 deletion or exon 21 L858R mutation-positive, unresectable or metastatic NSCLC who had not received previous systemic treatment for advanced disease.
The trial results were presented at the European Society of Medical Oncology 2017 Congress and published in the New England Journal of Medicine.
Patients were randomized (1:1) to receive osimertinib 80 mg orally once daily or “standard-of-care” treatment of gefitinib 250 mg or erlotinib 150 mg orally once daily. Of those randomized to SOC, 20% received osimertinib as the next line of antineoplastic therapy.
The estimated median progression-free survival was 18.9 months (95% CI: 15.2, 21.4) in the osimertinib arm and 10.2 months (95% CI: 9.6, 11.1) in the SOC arm (hazard ratio 0.46 (95% CI: 0.37, 0.57), p<0.0001). The confirmed overall response rate was 77% for the osimertinib arm and 69% for the SOC arm. The estimated median response durations for the osimertinib and SOC arms were 17.6 and 9.6 months, respectively. At the time of the primary PFS analysis, there were too few deaths to estimate or compare survival outcomes.
The recommended dose of osimertinib is 80mg orally once daily, with or without food.
In the US, Tagrisso is already approved for the 2nd-line treatment of patients with metastatic EGFRm NSCLC, whose disease has progressed on or after a 1st-line EGFR-TKI therapy and who have developed the secondary T790M mutation, as detected by an FDA-approved test.
In 2017, Tagrisso was granted Breakthrough Therapy and Priority Review designations by the FDA in the first-line treatment setting. Tagrisso is under regulatory review in the European Union and Japan for use in the 1st-line treatment setting with regulatory decisions anticipated in the second half of 2018.
Full prescribing information is available here.
FDA approves Opdivo and Yervoy for front-line advanced RCC
FDA has granted approvals to nivolumab and ipilimumab (Opdivo and Yervoy, Bristol-Myers Squibb Co.) in combination for the treatment of intermediate or poor risk, previously untreated advanced renal cell carcinoma.
The approvals were based on CheckMate 214 (NCT02231749), a randomized open-label trial. Patients with previously untreated advanced RCC received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for 4 doses followed by nivolumab monotherapy (3 mg/kg) every 2 weeks, or sunitinib 50 mg daily for 4 weeks followed by 2 weeks off every cycle.
Efficacy was evaluated in intermediate or poor-risk patients (n=847). The trial demonstrated statistically significant improvements in overall survival and objective response rate for patients receiving the combination (n=425) compared with those receiving sunitinib (n=422).
Estimated median OS was not estimable in the combination arm compared with 25.9 months in the sunitinib arm (hazard ratio 0.63, 95% CI: 0.44, 0.89; p<0.0001). The ORR was 41.6% (95% CI: 36.9, 46.5) for the combination versus 26.5% (95% CI: 22.4, 31) in the sunitinib arm (p<0.0001). The efficacy of the combination in patients with previously untreated renal cell carcinoma with favorable-risk disease was not established.
The recommended schedule and dose for this combination is nivolumab, 3 mg/kg, followed by ipilimumab, 1 mg/kg, on the same day every 3 weeks for 4 doses, then nivolumab, 240 mg, every 2 weeks or 480 mg every 4 weeks.
Prescribing information for both nivolumab and ipilimumab have been updated with these results. Full prescribing information is available online: Nivolumab PI and Ipilimumab PI.
FDA approves Tavalisse for ITP
FDA approved Tavalisse (fostamatinib disodium hexahydrate tablets) for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia who have had an insufficient response to a previous treatment.
The agent is sponsored by Rigel Pharmaceuticals Inc.
Approval was based on two identical, double-blind, placebo-controlled trials, FIT-1 (NCT02076399) and FIT-2 (NCT02076412) that enrolled a total of 150 patients with persistent or chronic ITP who had an insufficient response to previous treatment, which included corticosteroids, immunoglobulins, splenectomy, and/or a thrombopoietin receptor agonist.
Patients were randomized 2:1 to fostamatinib (100 mg orally twice daily) or placebo for 24 weeks. Dose could be escalated to 150 mg orally twice daily after one month.
Efficacy was based on stable platelet response (at least 50 x109/L on at least 4 of the 6 visits between Weeks 14 to 24). In FIT-1, stable platelet response was demonstrated in 18% (n=9) of patients receiving fostamatinib compared with 0% (n=0) of patients receiving placebo (p=0.03). In FIT-2, stable platelet response was seen in 16% (n=8) and 4% (n=1) of patients, respectively (p=0.26).
In the FIT-3 (NCT 02077192) extension study, a stable response was observed in 23% (n=10) of patients newly exposed to fostamatinib. Durable platelet responses were seen in the FIT-1, FIT-2 trials and the FIT-3 extension study.
The recommended dose initially is 100 mg administered orally twice daily. After a month, if platelet count has not increased to at least 50×109/L, increase dose to 150 mg twice a day.
Full prescribing information is available here.
FDA issues guidance on investigational in vitro diagnostics in oncology trials
FDA has issued a draft guidance, “Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination,” to describe for sponsors of certain oncology trials an optional streamlined submission process to determine whether use of an investigational in vitro diagnostic in a trial of investigational cancer drug or biological products is considered significant risk, non-significant risk, or exempt from further pre-market review.
This guidance, which is posted here, will be open for public comment until June 15.
The draft guidance outlines criteria under which sponsors may include information about an investigational IVD in the Investigational New Drug application submission to the FDA center responsible for the therapeutic product (Center for Drug Evaluation and Research or Center for Biologics Evaluation and Research).
This would allow the pre-market information related to the investigational drug and the investigational IVD to be contained in a single IND application. Currently, separate applications are required for the therapeutic product and the IVD.
Consolidating the information about the investigational drug and device into the same application enables more efficient review and assist in establishing the scientific relationship between the drug and the diagnostic used to select patients.
CDER or CBER would then coordinate with the FDA’s Center for Devices and Radiological Health to determine whether use of the investigational IVD in the trial is considered significant risk, non-significant risk, or exempt.