10/15/2017: Articles Summaries - Lung & Hematologic Cancers

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 LUNG CANCERS HEMATOLOGY CANCERS

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First-Line Ceritinib Versus Platinum-Based Chemotherapy in Advanced ALK-Rearranged Non-Small-Cell Lung Cancer (ASCEND-4): A Randomised, Open-Label, Phase 3 Study
Soria JC et al., Lancet. 2017 Mar 4;389(10072):917-929.
PubMed ID: 28126333

Introduction:

Certinib is an oral ALK inhibitor with 20x greater potency than crizotinib and was found to have significant anti-tumor activity in ALK-rearranged NSCLC after failure of crizotinib. In a phase III trial, investigators compared the efficacy of ceritinib with platinum-pemetrexed followed by pemetrexed maintenance in treatment-naïve advanced ALK-rearranged NSCLC.

Methods:

  • Patients: histologically or cytologically-proven locally advanced or metastatic ALK-rearranged NSCLC, no previous treatment (except neoadjuvant/adjuvant therapy), ECOG 0-2, asymptomatic/stable brain metastases
  • Study design: open-label, phase III RCT
  • Intervention
    • Experimental: Ceritinib 750 mg PO
    • Control: Cisplatin 75 mg/m2 IV or Carboplatin AUC 5-6, Pemetrexed 500 mg/m2 IV q21d
      * Pemetrexed 500 mg/m2 IV maintenance for patients without progression after 4 cycles of chemotherapy q21d
  • Endpoints
    • Primary: PFS
    • Secondary: OS, PFS investigator), ORR, DOR, DCR, TTR, overall intracranial response, intracranial CBR, patient-reported outcomes, safety

Results:

  • 376 patients randomized to ceritinib (n=189) or chemotherapy (n=187)
  • Baseline patient characteristics: median age 54 yrs., 58% female, 54% Caucasian, 56% ECOG 1, 61% never smokers, 97% adenocarcinoma, 96% stage IV, 42% bone mets, 23% previous surgery, 20% RT, 13% previous brain RT, 5% 1 previous line of chemo, 32% brain metastases
  • 73% in the chemotherapy arm received pemetrexed maintenance
  • Among 73 patients on certinib who progressed, 84% continued to receive ceritinib and 49% continued certinib for at least 2 cycles after progression for clinical benefit.
  • Median duration of treatment exposure: 66.4 wks. vs. 26.9 wks.
  • Median relative dose intensity: 78.4% vs. 93.8-99.2%

Table 1: Efficacy Outcomes
Table 1

 

Table 2: Adverse Events and Treatment Summary

  • Safety:
    • Most common any grade adverse events with certinib: diarrhea (85% vs. 11%), nausea (69% vs. 55%) and vomiting (66% vs. 36%)
    • Most common grade 3-4 adverse events with chemo: neutropenia (11% vs. 1%), anemia (7% vs. 2%), vomiting (6% vs. 5%)
    • Dose modification/interruption was mostly due to GI adverse events. Most diarrhea events resolved with dose interruption and supportive management.
  • QoL
    • Ceritinib significantly improved time to definitive deterioration vs. chemo for lung cancer-specific symptoms (pain, cough shortness of breath) [p=0.0055].
    • 2 scales in the QLQ.C30 instrument related to diarrhea and nausea and vomiting favoured chemotherapy.
    • QLQ-LC-13 symptom scores and EQ-5D-5L index value (p=0∙0006) favoured ceritinib.

Discussion:

  • At a median follow-up of 19.7 mos., first line certinib significantly doubled PFS compared to platinum-pemetrexed in advanced ALK-rearranged NSCLC. This corresponded to a 45% reduction in the risk of disease progression or death.
  • PFS benefit was consistent across all prespecified subgroups. The greatest magnitude of benefit was observed in the subgroup without brain metastases where PFS was prolonged by 18 mos. with ceritinib. OS data was immature at interim analysis.
  • Tumor response rates were almost 3x better with ceritinib compared to chemotherapy; similar intracranial response rate was reported. Moreover, ceritinib provided rapid and durable response.
  • Certinib was associated with higher rates of GI toxicity, particularly diarrhea, nausea and vomiting and elevated liver transaminases. However, most adverse events were low grade and manageable with treatment interruption and supportive management.
  • Patients in the certinib arm were exposed to treatment 2.5x longer than those on chemotherapy. Treatment interruptions and dose modifications as well as grade 3-4 treatment-related adverse events were more common in the certinib group. No treatment-related deaths occurred during the study.
  • Despite more frequent side effects, this did not adversely impact OOL. Ceritinib provided significant improvement QOL especially lung cancer-specific symptoms compared to chemotherapy.
  • Based on this study, ceritinib would be the preferred treatment over platinum doublet in treatment-naive advanced ALK positive NSCLC patients. However, platinum doublet is no longer the standard of care first line systemic therapy and a better comparator would have been crizotinib. Nonetheless, ceritinib is now an option for treatment naive ALK positive patients.
  • In summary, first line ceritinib provided rapid and durable clinical response, with prolonged PFS and better QOL compared to chemotherapy in advanced ALK-rearranged NSCLC.

More Lung Cancer Updates

 

Brentuximab Vedotin or Physician's Choice in CD30-Positive Cutaneous T-cell Lymphoma (ALCANZA): An International, Open-Label, Randomised, Phase 3, Multicentre Trial
Prince HM et al., Lancet. 2017 Aug 5;390(10094):555-566.
PubMed ID: 28600132

Introduction:

Cutaneous T-cell lymphomas are rare forms of non-Hodgkin lymphoma usually presenting as mycosis fungoides and Sézary syndrome. Both are associated with poor quality of life and adverse prognosis in the advanced stage. Mycosis fungoides and primary cutaneous anaplastic large-cell lymphoma (pcALCL) frequently express cell surface antigen CD-30, a potential target for therapy. Investigators conducted the ALCANZA study to determine the efficacy of brentuximab vedotin, an anti-CD30 antibody–drug conjugate vs. physician's choice (methotrexate or bexarotene) in CD30-positive cutaneous T-cell lymphoma, based on promising results from a phase 2 trial (J Clin Oncol 2015; 33: 3750–58).

Methods:

  • Patients: CD30-positive mycosis fungoides or pcALCL, received at least one previous systemic therapy or radiotherapy, Eastern Cooperative Oncology Group [ECOG] performance status 0 to 2
  • Studies included: Phase III open-label RCT
  • Intervention:
    • Experimental: brentuximab vedotin 1.8 mg/kg IV q3 wks. up to 16 cycles
    • Control: (Physician's choice) methotrexate 5-50 mg PO per wk. or bexarotene 300 mg/m2 PO daily up to 48 wks.
  • Outcomes:
    • Primary endpoint: Objective global response lasting (from first to last response) at least 4 mos. (ORR4)
    • Secondary endpoints: Progression-free survival (PFS), complete response (CR), symptom burden, duration of response (DOR), duration of skin response, event-free survival (EFS), quality of life measures, safety

Results:

  • Significant improvement in ORR4 was observed with brentuximab vedotin compared to methotrexate or bexarotene (56.3% vs. 12.5%; p<0.0001) for both mycoses fungoides (50% vs. 10%) and pcALCL (75% vs. 20%) and regardless of level of CD-30 expression.
  • PFS improved by 13.2 mos. (16.7 mos., vs. 3.5 mos., HR 0.270; p<0.0001); EFS similarly favoured brentuximab vedotin. EFS was 9.4 mos. with brentuximab vedotin compared to 2.3 mos. (HR 0.285; p<0.0001) with physician's choice whereas median DOR was 15.1 mos. vs. 18.3 mos., respectively.
  • More patients on brentuximab vedotin achieved an objective response compared to methotrexate or baroxetene (67% vs. 20%; p<-0.0001), with 16% achieving CR compared to 2% with physician's choice (p=0.0046). More than 50% reduction in modified severity weighted assessment tool [mSWAT] was reported in 77% of patients with mycosis fungoides on brentuximab vedotin vs. 41% on methotrexate or baroxetene. Furthermore, 16 patients (63%) with pcALCL had 100% reduction in skin lesions with brentuximab vedotin.
  • Brendtuximab vedotin significantly reduced burden of symptoms (Skindex-29) to a greater extent compared to physician's choice, with a difference in mean maximum score of -18.9 (p<0.0001). However, emotional and functional domains as well as Functional Assessment of Cancer Therapy-General (FACT-G) scores did not differ over time between the two groups.
  • At least a third of patients in each group (30%) developed severe side effects, mostly due to grade 3 fatigue (5%), diarrhea (3%) and skin infection (3%) with brentuximab vedotin, grade 3 fatigue, pyrexia and skin infection (4% each) with methotrexate and grade 3 hypertriglyceridemia (14%), anemia (8%) and pruritus (5%) with bexarotene. Grade 4 asthenia (3%) and hypertriglyceridemia (8%) were reported for becxarotene.
  • Most common any grade adverse events were peripheral sensory neuropathy (45%), nausea (36%), diarrhea (29%) and fatigue (29%) with brentuximab vedotin, pyrexia (28%), fatigue (20%) and nausea (16%) with methotrexate and fatigue (32%), hypertriglyceridemia (30%) and anemia (16%) with baroxetene. Four deaths were reported in the brentuximab vedotin arm, 3 unrelated to study drug while one succumbed to multiorgan failure from tumor lysis syndrome

 Discussion:

  • Brentuximab vedotin provided durable global response rate (at least 4 mos.) compared to methotrexate or bexarotene in CD30 positive cutaneous T-cell lymphoma. EFS and PFS were extended by 7.1 mos., and 13.2 mos., respectively, more than half achieved objective responses and burden of symptoms were significantly reduced with brentuximab compared to methotrexate or bexarotene. Brentuximab vedotin was associated with tolerable side effects.
  • These results support the use of brentuximab vedotin as a novel treatment option for previously treated CD30 positive cutaneous T-cell lymphoma. 

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