03/25/2018: Articles Summaries - Lung & Hematologic Cancers

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 LUNG CANCERS HEMATOLOGY

LUNG CANCERS

Dacomitinib versus gefitinib as first-line treatment forpatients with EGFR-mutation- positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial
Wu YL et al., Lancet Oncol. 2017 Nov;18(11):1454-1466.
PubMed ID: 28958502

 

Introduction:

Dacomitinib is a 2nd generation, irreversible TKI with activity against not only EGFR/HER1 but also to HER2, and HER4 that distinguishes it from 1st generation EGFR TKIs gefitinib and erlotinib. As first line treatment in advanced NSCLC, dacomitinib resulted in objective response in 76.5% of patients with activating EGFR mutations and a median PFS of 18.2 mos. (Lancet Oncol 2014; 15: 1433–41).

The ARCHER 1050 study was designed as a head to head trial to compare the efficacy of first line dacomitinib vs gefitinib in advanced EGFR-mutation-positive NSCLC.

 

Methods:

  • Patients: Histologically or cytologically confirmed newly diagnosed stage IIIB/IV or recurrent NSCLC (minimum 12 mos. disease-free interval between completion of adjuvant/neoadjuvant therapy and recurrence of NSCLC), at least 1 documented EGFR mutation, no brain or leptomeningeal metatasis.
  • Study design: Phase III, open-label RCT
  • Intervention
    • Experimental: Dacomitinib 45mg PO daily q28 days
    • Control: Gefitinib 250mg PO q28 days
  • Endpoints
    • Primary: PFS (IRC)
    • Secondary: PFS (investigator), ORR, DOR, OS, OS at 30 mos., time to treatment failure, safety, patient-reported outcomes

 

Results:

  • N=452 randomized and analyzed by ITT, dacomitinib N=227, gefitinib N=225
     
  • Baseline patient characteristics: median age 62 yrs., 60% female, 77% Asians (51% Chinese), 70% ECOG 1, 81% stage IV, 64% never smokers, 59% Exon 19 deletion mutation
     
  • Post-progression systemic treatment: 41% vs 56
     
  • Most common post-progression systemic treatment: pemetrexed, carboplatin, cisplatin, and osimertinib

 

TABLE 1: Efficacy Endpoints

  • Safety
    • Most common adverse events with dacomitinib: diarrhea (87%), paronychia (62%), dermatitis acneiform (49%), stomatitis (44%)
       
    • Most common adverse events with gefitinib: diarrhea (56%), elevated ALT (39%), elevated AST (36%)
       
    • Most common grade 3-4 adverse events: dermatitis acneiform (14% vs 0), diarrhea (8% vs 1%), elevated ALT (1% vs 8%)
       
    • Treatment-related serious adverse events: GI disorders (4% vs 0), skin and subcutaneous disorders (1% vs 0), respiratory disorders (1% vs 1%), hepatobiliary disorders (1% vs 1%), elevated liver enzymes (0 vs 1%), metabolism and nutrition disorders (1% vs 0), infections (1% vs <1%), keratitis (<1% vs 0), acute kidney injury (<1% vs 0), CML (<1 vs 0)
       
    • Most common cause of treatment discontinuation with dacomitinib: skin and subcutaneous tissue disorders (n=7), GI disorders (n=4), interstitial lung disease or pneumonitis (n=3)
       
    • Most common cause of treatment discontinuation with gefitinib: elevated ALT/AST aspartate aminotransferase (n=6), interstitial lung disease or pneumonitis (n=3)
       
    • Lowest dose reductions in the dacomitinib group: 38% received 30 mg/day, 28% received 15 mg/day
       
    • Patient-reported outcomes
      • Improvement from baseline in the symptoms of chest pain (mean-10.24 vs. -7.44; p=0.0235) was significantly higher with dacomitinib.
      • Improvement in dyspnea (–4.89 vs –4.81; p=0.9411), cough (–13.61 vs –12.28; p=0.3440), pain in arm or shoulder (–5.58 vs –4.34; p=0.2854) and pain in other parts (–4.05 vs –5.09; p=0.3288) was similar in both arms.
      • Greater increase from baseline in diarrhea (19.88 vs 7.32; p<0.0001) and sore mouth (15.09 vs 3.51;p<0.0001 was observed with dacomitinib.
      • Global QOL significantly favored gefitinib over dacomitinib (0.20 vs. 4.94; p-=0.0002)
      • Time to deterioration of chest, arm or shoulder pain, dyspnea, fatigue and cough was similar in both arms.

 

Discussion:

  • Treatment with first line dacomitinib was associated with significant improvement in PFS compared to gefitinib in patients with advanced EGFR-mutation-positive NSCLC. Dacomitinib extended PFS by 5.5 mos. and reduced the risk of disease progression and death by 41%.
     
  • Subgroup analyses suggested a consistent PFS treatment benefit across major subgroups. The non-Asian subgroup seemed to derive less benefit with dacomitinib compared to the Asian subgroup. A posthoc analysis suggested benefit in favor of dacromitinib for non-Asian patients (68%) with treatment response (CR or PR).
     
  • Although DOR and TTF were significantly better with dacomitinib compared to gefitinib, ORR was similar in both arms. Patients on dacomitinib were treated for a longer duration compared to gefitinib (median duration 15.3 mos. vs 12 mos.).
     
  • Diarrhea was a significant dose-limiting side effect, moreso with dacomitinib compared to gefiitinib (87% vs 56%). Adverse events resulted in temporary treatment discontinuation in 78% and dose reduction in 66% compared to 54% and 8%, respectively.
     
  • Chest pain improved more with dacomitinib compared to gefitinib. However, patients on dacomitinib experienced more diarrhea and sore mouth. Overall, gefitinib resulted in better global QOL, although QOL was maintained in the dacomitinib arm.
     
  • The advantage of irreversible binding and activity against all three ErbB kinase-active members with 2nd generation TKIs over 1st generation TKIs was similarly demonstrated in the LUX-lung 7 trial that compared afatinib with gefitinib (Lancet Oncol 2016; 17: 577–89). Afatinib significantly improved PFS (11 vs. 10.9 mos.; HR 0.73; p=0.0165), TTF (13.7 vs 11.5 mos., HR 0.73; p=0.0073) and DOR (10.1 vs 8.4 mos.) compared to gefitinib as first line treatment in EGFR-mutation-positive advanced NSCLC. Higher toxicity rates were observed with afatinib, particularly grade 3 diarrhea, rash and stomatitis. However, rates of treatment discontinuation were similar between the 2 arms.
     
  • The ARCHER 1050 trial revealed greater efficacy with dacomitinib as first line treatment in advanced EGFR-mutation-positive NSCLC compared to gefitinib. This advantage however, was offset by considerable toxicity. Almost 90% of patients experienced diarrhea (any grade) and 66% required dose reductions, for an average of 11 mos. This is a potential limitation in clinical practice where elderly patients with multiple comorbidities are at higher risk for treatment-related complications and deterioration in QOL. Longer follow-up will reveal whether the impressive PFS advantage will translate to OS benefit with dacomitinib. Perhaps a trial looking at a lower dacomitinib dose will provide better insight on its efficacy with a more tolerable safety profile
More Lung Cancer Updates

 

HEMATOLOGY CANCERS

Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma
Neelapu SS et al., N Engl J Med. 2017 Dec 28;377(26):2531-2544.
PubMed ID: 29226797

 

Introduction:

Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy where T cells removed from a patient are genetically engineered to express anti-CD19 CARs and then injected back to the patient. In the ZUMA-1 study, 5 out of 7 patients with refractory large B-cell lymphoma achieved overall response while 4 had complete response (Mol Ther 2017; 25: 285-95). Results from the phase 2 study and updated analysis are presented below.

 

Methods:

  • Patients: Histologically confirmed large B-cell lymphoma, including diffuse large
    B-cell lymphoma (cohort 1) and primary mediastinal B-cell lymphoma or transformed follicular lymphoma (cohort 2), progressive or stable disease as the best response to the most recent chemotherapy regimen or disease progression or
    relapse within 12 months after autologous stem cell transplantation (ASCT).
  • Study design: Phase I-II RCT
  • Intervention
    • After leukapheresis and axi-cel manufacturing, patients received fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 on days -5, -4 and -3 followed by axi-cel at 2x106 CAR T cells/kg on day 0. Systemic bridging therapy was not allowed after leukapheresis and before axi-cel.
  • Endpoints
    • Primary: Overall response rate (ORR)
    • Secondary: duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, blood levels of CAR T cells and serum cytokines.

 

Results:

  • For the primary analysis, ORR was achieved in 82% of patients, 54% had complete response (CR) at a minimum follow-up of 6 months compared to historical controls (20%, p<0.001). Responses were achieved as early as 1 month and were sustained for at least 8.1 months. In patients with primary refractory disease, the response rate was 88% and among those who received ASCT, it was 76%. Treatment effects were consistent across the prespecified patient subgroups, regardless of age, disease stage and burden, subtype and previous medication.
  • Updated analysis at a minimum follow-up of 1 year revealed similar outcomes, with ORR of 82% and CR in 58%. Among patients who did not achieve CR a month after axi-cel infusion, 23 patients (11/35 with partial response, 12/25 with stable disease) had CR without additional therapies up to 15 months after treatment. 
  • Median DOR was 11.1 months while median duration of PFS was 5.8 months. PFS rates at 6, 12 and 15 months were 49%, 44% and 41%, respectively. Median OS was not reached and corresponding OS rates were 78%, 59% and 52% at 6, 12 and 15 months. 
  • Among 11 patients with disease progression, 27% who were CD19 positive at baseline had CD19 negative disease upon disease progression.
  • For the primary analysis, at least 95% of patients had grade ≥ 3 adverse events, the most common being neutropenia (78%), anemia (43%) and thrombocytopenia (38%). Cytokine release syndrome occurred in 93%, most of them low grade. Grade ≥ 3 cytokine syndromes were pyrexia (11%), hypoxia (9%) and hypotension (9%); 17% required vasopressors and symptoms resolved within 8 days except for one case of grade 5 hemophagocytic lymphohistiocytosis. Neurologic events were reported in 64% (28% grade ≥ 3) and resolved within 17 days.
  • Safety report for the updated analysis showed serious adverse events in 10 patients (8 with infection) but no new cytokine release syndrome or neurologic events. Three patients died from adverse events. Replication-competent retrovirus or axi-cel treatment-related secondary cancers did not occur.
     
  • CAR T cell blood levels peaked within 14 days after infusion and were detectable at 180 days in most patients. Three patients who remained on complete remission at 24 months had detectable levels of CAR T cells. Expansion was significantly associated with response (p<0.001). Area under the curve (first 28 days after treatment) for responders was almost 5.4x as high as nonresponders. Grade ≥ 3 neurologic events were significantly associated with peak expansion and area under the curve. Interleukin-6, -10, -15, and -2Rα and granzyme B were significantly associated with grade ≥ 3 neurologic events.

 

Discussion:

  • Updated analysis of the ZUMA-1 study at a median follow-up of 15.4 months revealed early and durable tumor responses in up to 82% and no late-onset adverse events with the use of axicabtagene ciloleucel (axi-cel) in refractory large B-cell lymphoma.
     
  • Axi-cel is a highly effective treatment that can induce prolonged remission in refractory large B-cell lymphoma. However, studies are needed to provide insights on the management of cytokine release syndrome and its feasibility, given the complexity of the treatment regimen. 

More Hematologic Cancer Updates