09/24/2017: Articles Summaries - Lung Cancer

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 LUNG CANCERS 

 LUNG CANCERS

Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomised phase 3 trial
Hida T et al., Lancet. 2017 Jul 1;390(10089):29-39.
PubMed ID: 28501140

Introduction:

Patients with ALK positive NSCLC achieve good clinical response with alectinib in the second line setting after failure of crizotinib. However, acquired resistance develops due to multiple mechanisms. Alectinib is an ALK inhibitor found to have antitumor activity against secondary mutations and with CNS penetration (Lancet Oncol 2014;15: 1119–28). Based on encouraging results from trials of alectinib in ALK positive NSCLC, Japanese researchers conducted a head to head comparison of alectinib with crizotinib as first line treatment. 

Methods:

  • Patients: Japanese patients with histologically or cytologically confirmed ALK-positive advanced NSCLC, chemotherapy/ALK inhibitor-naïve or received one line of chemotherapy, ECOG 0-2, asymptomatic meningeal/brain metastases not requiring treatment
  • Study design: phase III open-label RCT
  • Intervention:
    • Experimental: Alectinib 300 mg PO 2x/day
    • Control: Crizotinib 250 mg PO 2x/day
  • Endpoints:
    • Primary: PFS by independent review facility (IRF)
    • Secondary: investigator-assessed PFS, ORR, DOR, TTR, OS, time to onset of brain metastases, TTP of brain metastases, HRQOL, safety

Results:

  • 207 patients randomized to alectinib (n=103) and crizotinib (n-=104)
  • Baseline patient characteristics: median age 60 yrs., 60% female, 49% ECOG 0, 73% stage IV, 64% first line treatment, 57% never smokers
  • More patients in the crizotinib arm had baseline brain metastases (14% vs. 28%

TABLE 1: EFFICACY OUTCOMES
Lung Table 1

  • PFS consistently favoured alectinib for first or second line treatment, postoperative treatment, stage III or IV
  • TTP for brain metastases/death with and without brain metastases at baseline appeared to favour alectinib (HR 0.16 and HR 0.41, respectively).
  • Preplanned analysis showed decreased risk of progression in CNS and non CNS lesions with alectinib.
  • Safety
    • Most common adverse events with crizotinib (>20%): nausea (74%), diarrhea (73%), vomiting (58%), visual disturbances (55%), dysgeusia (52%), constipation (44%), increased ALT (32%), increased AST (31%), nasopharyngitis (23%), pyrexia (20%), decreased appetite (20%)
    • Most frequent adverse events with alectinib (>20%): constipation (35%), nasopharyngitis (20%)

TABLE 2: ADVERSE EVENTS AND TREATMENT SUMMARY
Lung Table 1

  • Most common cause of treatment discontinuation: grade 1-2 interstitial lung disease (8% vs. 8%), grade 3-4 abnormal hepatic function (0 vs. 5%), grade 3-4 increased ALT (0 vs. 4%).
  • Alectinib mean plasma trough concentrations were similar on day 57 and day 133

Discussion:

  • In Japanese patients with ALK positive advanced NSCLC, alectinib significantly prolonged PFS and provided durable tumor responses compared to crizotinib. Survival advantage was consistent regardless of line of treatment and tumor stage.
  • Tumor responses were marginally better with alectinib while TTP for brain metastases appeared to favour alectinib, thereby demonstrating CNS penetration compared to crizotinib. More patients on crizotinib had brain metastases at baseline (28% vs. 14%).
  • Adverse event profile favoured alectiib over criztonib. Alectinib was associated with less frequent gastrointestinal disorders, grade 3-4 adverse events, dose interruption and treatment discontinuation.
  • In summary, J-ALEX trial demonstrated superiority of first line alectinib over crizotinib in ALK positive advanced NSCLC. The safety profile of alectinib makes it a more attractive treatment option with the potential to change clinical practice. However, the dose of alectinib in the study is lower than approved dose elsewhere in the world, thus limiting the generalizability of study results.
  • A limitation of this study was the restriction to a Japanese population. The ALEX study, an international study with similar design, was recently presented showing an improvement in PFS compared to crizotinib at the 600 mg bid dosing..

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Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer
Peters et al., N Engl J Med. 2017 Aug 31;377(9):829-838.
PubMed ID: 28586279

Introduction:

Alectinib is a potent TKI with activity against ALK mutations that cause resistance to crizotinib. Its ability to penetrate the blood brain barrier was observed in phase 2 studies and provides a potential advantage. Researchers investigated the efficacy of alectinib vs. crizotinib in treatment-naïve ALK positive NSCLC, including asymptomatic CNS disease in the phase III ALEX trial. Study results are summarized below.

Methods:

  • Patients: cytologically or histologically proven ALK positive advanced NSCLC, no previous treatment for advanced disease, asymptomatic brain metastases or leptomeningeal disease, ECOG 0-2, previous CNS RT allowed if at least 14 days prior to enrollment. Patients with asymtomatic brain metastases without treatment were eligible for the study.
  • Study design: phase III open-label RCT
  • Intervention
    • Experimental: Alectinib 600 mg PO 2x/day
    • Control: Crizotinib 250 mg PO 2x/day
  • Endpoints:
    • Primary: PFS (investigator-assessed)
    • Secondary: PFS (IRC), OS, time to CNS progression, ORR, DOR, duration of CNS response, rate of CNS response, safety

Results:

  • 303 patients were randomized to alectinib (n=152) and crizotinib (n=151)
  • Baseline patient characteristics: median age 56 yrs., 57% female, 46% Asian, 93% ECOG 0 or 1, 32% former smokers, 63% nonsmokers, 97% stage IV, 92% adenocarcinoma, 40% CNS metastases, 68% WBRT, 16% previous brain RT
  • Alectinib significant delayed progression in the cns  at 12 months (9 percent vs 41 percent)

TABLE 1: EFFICACY OUTCOMES
GI Table 1

  • Safety
    • Adverse events more frequently reported with alectinib: anemia (20% vs. 5%), myalgia (16% vs. 2%), increased blood bilirubin (15% vs. 1%), increased weight (10% vs.0%), musculoskeletal pain (7% vs. 2%), photosensitivity reaction (5% vs. 0%)
    • Adverse events more common with crizotinib: nausea (48% vs. 14%), diarrhea (45% vs. 12%), vomiting (38% vs. 7%)
    • Fatalities in the alectinib arm were deemed to be not related to the study drug.

TABLE 2: TREATMENT SUMMARY & ADVERSE EVENTS
GI Table 2

 Discussion:

  • In the ALEX trial, alectinib demonstrated superiority over crizotinib as first line treatment for ALK positive advanced NSCLC. At a median follow-up of around 18 mos., alectinib significantly extended PFS and reduced the risk of death or disease progression by 53%. This was consistent with PFS assessment by independent review. However, no difference in OS was observed in both arms. OS data was immature at the time of analysis.
  • In the subgroup of patients with CNS metastases (n=43 with measurable disease, n=122 with measurable and nonmeasurable disease), alectinib provided better clinical outcomes compared to crizotinib in terms of time to CNS progression, CNS response and duration of CNS response. The ability of alectinib to penetrate CNS has proven to be beneficial in these patients.
  • Alectinib had a comparable safety profile with crizotinib, although side effects were different. Anemia, myalagia and elevated bilirubin levels were common with alectinib while nausea, diarrhea and vomiting were more prevalent with crizotinib
  • These findings are similar to results from the J-ALEX trial (Hida et al, Lancet 2017) where a similar population of Japanese patients was randomized to alectinib or crizotinib. PFS in the first and 2nd line setting, ORR and DOR all favored alectinib, especially in the subgroup with brain metastases. However, constipation and nasopharyngitis were the most common side effects reported and the dose used in the study was 300mg 2x/day compared to 600mg/day in ALEX trial.
  • Results from the ALUR trial were presented (Abstract 12990PR at the ESMO conference. Patients with ALK positive NSCLC who progressed on previous platinum-based chemotherapy and crizotinib were randomized to alectinib or chemotherapy. Alectenib extended PFS by 8.2 mos. (absolute difference), with 85% reduction in the risk of disease progression or death (HR 0.15; p<0.001). Moreover, at least half of the patients with measurable CNS disease achieved a response (ORR 54.2% vs. 0; p<0.001).
  • In summary, ALEX trial provided evidence on the superiority of alectinib over crizotinib as first line treatment in ALK positive advanced NSCLC. Despite longer treatment duration with alectinib compared to crizotinib, toxicities were comparable in both arms. Alectinib was CNS protective and delayed progression by 4 -fold at one year, and may provide a new standard of care.
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