||Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-Cell Lung Cancer
Soria JC et al., N Engl J Med. 2018 Jan 11;378(2):113-125.
PubMed ID: 29151359
Osimertinib is a 3rd generation EGFR TKI approved for the treatment of metastatic T790M-positive NSCLC with disease progression during or after EGFR TKI therapy. This was based on the AURA trial program that demonstrated anti-tumor activity of osimertinib in this subgroup of patients. Preclinical studies revealed the ability of osimetinib to cross the blood-brain barrier. Osimertinib has also shown activity in tumours harbouring EGFR activating mutations Exon 19 deletion (Ex19del) and Exon 21 L858R (L858R). Hence, Soria and colleagues conducted the phase III FLAURA trial to investigate its efficacy and safety in treatment naïve EGFR mutated advanced NSCLC, irrespective of T790M status.
- Patients: Locally advanced or metastatic NSCLC, no previous treatment for advanced disease, eligible to receive gefitinib or erlotinib, positive EGFR Ex19del or L858R mutation, alone or co-occurring with other EGFR mutations, neurologically stable CNS metastases.
- Study design: Phase III, double-blind placebo-controlled RCT
- Osimertinib 80 mg PO daily
- Control (Standard TKI):
- Gefitinib 250 mg PO daily or Erlotinib 150 mg PO daily
- Primary: PFS
- Secondary: OS, ORR, DCR, DOR, depth of response, safety
- 556 patients randomized to osimertinib (n=279) v standard TKI (277)
- Standard TKI: 66% gefitinib, 34% erlotinib
- Baseline patient characteristics: median age 64 yrs., 37% male, 36% white, 64% never smokers, 59% PS 1, 99% adenocarcinoma, 95% metastatic disease, 35% visceral metastases, 21% CNS metastases, 63% Exon 19 deletion mutation
- Treatment beyond RECIST disease progression: 67% (osimertinib) v 70% (standard TKIs)
- Subsequent anticancer therapy: 29% v 47%; 43% in the standard TKI group crossed over to receive osimertinib (n=48); 7 patients received outside study treatment therapy
Table 1: Efficacy Outcomes
Table 2: Response by CNS Metastases
- Most common adverse events: rash/acne (58% v 78%), diarrhea (58% v 57%), dry skin (36% each)
- Most common Grade ≥3 adverse event osimertinib: decreased appetite (3%), pneumonia (2%), diarrhea (2), prolonged QT interval (2%)
- Most common grade ≥3 adverse events with standard TKIs: increased ALT (9%), rashes/acne (7%), increased AST 94%
- No fatal torsades des pointes or QT prolongation was reported in either treatment group.
Table 3: Adverse events and treatment summary
- One patient on osimertinib reported serious adverse event of prolonged QT interval.
- No fatal adverse event was deemed to be related to osimertinib; one fatal diarrhea was deemed to be possibly related to standard TKI.
- Pneumonia was the most common serious adverse event in both treatment arms (3% each).
- The FLAURA trial met its primary endpoint, demonstrating that first line treatment with osimertinib significantly prolonged PFS by 8.7 mos. compared to standard TKI and reduced the risk of disease progression or death by 54% in patients with advanced EGFR-mutated NSCLC. This advantage occurred as early as 6 weeks was consistently observed across all treatment subgroups. OS was similar in both treatment arms at interim analysis.
- Osimertinib provided slightly better tumor response compared to standard TKI. This was reflected in greater reduction in target lesion size compared to standard TKIs. DOR was 2x longer with osimertinib v standard TKIs.
- When patients were grouped by CNS metastases status at baseline, osimertinib consistently provided better clinical outcomes compared to standard TKIs, although the magnitude of benefit was higher in the subgroup without known/treated CNS metastases. Osimertinib appeared to delay CNS progression in patients with known/treated CNS metastases at baseline. The study however did not assess for asymptomatic brain metastases because brain MRI were not mandatory.
- Osimertinib had a more favourable safety profile compared with standard TKIs. Adverse events were mostly low grade and there were less incidences of grade 3/4 toxciity. Six patients on osimertinib died from pneumonia, respiratory tract infection, cerebral infarction, myocardial infarction, pulmonary embolism, and intestinal ischemia. None were attributed to osimertinib.
- Osimertinib showed consistent advantage in terms of PFS and provided rapid and durable tumor response over standard 1st generation EGFR TKI, with a tolerable safety profile. The FLAURA study has the potential to change clinical practice based on this compelling evidence. Longer follow-up will determine whether osimertinib can prolong OS.
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Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma
Connors JM et al., N Engl J Med. 2018 Jan 25;378(4):331-344.
PubMed ID: 29224502
Brentuximab vedotin is an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to the microtubule-disrupting agent monomethyl auristatin E. In a phase 1 dose escalation study, 96% of patients with Hodgkin's lymphoma who received brentuximab vedotin with doxorubicin, bleomycin, vinblastine, and dacarbazine (A+ABVD) or A+AVD achieved complete response (Lancet Oncol 2013; 14: 1348-56). 5-year failure-free survival (FFS) rate was 92%, with 100% overall survival (OS) [Blood 2017; 130:1375-7].
To further investigate the efficacy of brentuximab vedotin, researchers conducted the ECHELON-1 trial to determine the efficacy and safety of A+AVD vs ABVD in treatment-naïve stage III or IV classic Hodgkin's lymphoma.
- Patients: Histologically confirmed advanced classic Hodgkin's lymphoma (Ann Arbor stage III or IV), no prior systemic therapy, Eastern Cooperative Oncology
Group (ECOG) performance status 0-2, no cerebral or meningeal disease and not nodular lymphocyte predominant subtype.
- Study design: Phase III, open-label RCT
- Intervention (chemotherapy on day 1 and 15, q28 days x 6 cycles)
- Brentuximab Vedotin 1.2 mg/kg,Doxorubicin 25 mg/m2, Vinblastine 6 mg/m2, Dacarbazine 375 mg/m2
- Doxorubicin 25 mg/m2, Bleomycin 10 u/m2, Vinblastine 6 mg/m2, Dacarbazine 375 mg/m2 IV
- Primary: modified progression-free survival (mPFS) - time to disease progression, death, or modified progression (evidence of noncomplete
response after completion of frontline therapy)
- Secondary: OS, event-free survival (EFS), disease-free survival (DFS), objective response rate (ORR), duration of response (DOR), duration of
complete remission (DCOR), health-related quality of life (HRQoL), safety
- A+AVD significantly improved mPFS compared to ABVD, with 23% reduction in the risk of disease progression, modified progression or death (2-yr. mPFS 82.1% vs. 77.2%, HR 0.77; p=0.03) as first line treatment for advanced classic Hodgkin's lymphoma. PFS benefit was more evident in patients from North America, those with >1 extranodal site involvement, International Prognostic Score (IPS) 4-7, males, stage IV disease, age <60 yrs.
- OS at interim analysis did not significantly differ between the two treatment arms. 2-yr. OS was 96.6% vs. 94.9% (HR 0.72; p=0.19).
- At least 73% of patients on A+AVD achieved a complete response vs. 70% with ABVD. ORR was 86% vs. 83%; complete response at the end of frontline therapy was 73% vs. 71%, respectively.
- Fewer patients on A+AVD had a positive positron-emission tomography (PET) scan and subsequent treatment (8% vs. 15%) as well as radiation (22% vs. 32%) and other subsequent anticancer therapies compared to ABVD. PET2 (Deauville score 1-3) negativity rates were 89% and 86%, respectively.
- The most common grade 3 or higher side effect with A+AVD was neutropenia (54% vs. 39%), which was the most common cause of death (no primary G-CSF prophylaxis was given). Other common (any grade) adverse events with A+AVD were constipation, vomiting, fatigue, peripheral sensory neuropathy and diarrhea. Rates of infection were similar in both arms and neuropathy resolved/improved to grade 1 in at least two-thirds of the patients. A+AVD was associated with higher rates of grade ≥3 adverse events (83% vs. 66%), severe adverse events (43% vs. 27%) and hospitalizations (37% vs. 28%). Deaths due to treatment were reported in 1% vs. 2%, respectively. Pulmonary toxicity was the most common cause of death in the ABVD group.
- At a median follow-up of 24.9 mos., ECHELON-1 trial met its primary endpoint, with patients receiving brentuximab vedotin in combination with AVD having a significantly longer mPFS compared to standard ABVD in advanced classic Hodgkin's lymphoma.
- Tumor responses and subsequent anticancer therapy all favored A+AVD over ABVD. However, neutropenia was a significant adverse event that was mitigated with prophylactic G-CSF.
- Results from this study provide compelling evidence on the superiority of combination therapy vs. ABVD in reducing the risk of failure after first line therapy for advanced classic Hodgkin's lymphoma. Although A+AVD has a less favorable safety profile, toxicities are manageable with aggressive supportive therapy
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