||Nivolumab in Patients With Advanced Gastric or Gastro-Oesophageal Junction Cancer Refractory to, or Intolerant of, at Least Two Previous Chemotherapy Regimens (ONO-4538-12, ATTRACTION-2): a Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial
Kang, YK et al. Lancet. 2017 Dec 2;390(10111):2461-2471.
PubMed ID: 28993052
Immune checkpoint inhibitors have proven anti-tumor activity in several solid malignancies such as breast and lung cancer, as revealed in several trials. In gastric cancer, PD-L1 expression is associated with depth of invasion, tumor size, lymph node metastasis and shorter median survival. Because advanced gastric and gastro-oesophageal cancers are characterized by a high mutational burden and overexpression of immune checkpoint proteins, the use of an immune checkpoint inhibitor like nivolumab is a potential therapy to target this disease.
Based on preliminary data from the phase I/II CHECKMATE 032 trial on anti-PD-1 therapy in advanced gastric and gastro-oesophageal junction cancer, investigators further examined the efficacy and safety of nivolumab in a heavily pretreated population unselected for PD-L1 tumor expression.
- Patients: Histologically confirmed advanced unresectable or recurrent gastric or gastro-oesophageal junction adocarcinoma refractory to, or intolerant of, standard therapy, ECOG 0-1; patients with symptomatic brain metastases or requiring treatment were ineligible.
- Study design: phase III, double-blind placebo-controlled RCT
- Experimental: Nivolumab 3mg/kg IV q2 wks. (6 wks.=1 cycle)
- Control: Placebo
- Primary: OS
- Secondary: ORR, DCR, DOR, best overall response, maximum percentage change from baseline in the sum of diameters of target lesions, PFS, safety
- 493 patients randomized 2:1 to nivolumab (n=330) and placebo (n=163)
- Baseline patient characteristics: 71% male, median age 61 yrs., 46% Japanese, 45% Korean, 71% ECOG 1, 74% with ≥ 2 organs with metastases, 86% lymph node metastases, 22% peritoneal metastases, 41% ≥ 4 previous treatment regimens, 62% previous gastrectomy
- Previous therapies: pyrimidine analogues (100%), platinum (95%), taxane (86%), irinotecan (75%), ramuirumab (12%)
- Subsequent anticancer therapy: 47% vs 44.2%
Table 1: Efficacy Outcomes
- Serious treatment-related adverse events with nivolumab (≥ 2 patients): interstitial lung disease (n=3) and colitis, pyrexia, pneumonia, urinary tract infection, diabetic ketoacidosis (n=2 each)
- Most common any grade adverse events: pruritus (9% vs 6%), diarrhea (7% vs 2%), rash (7% vs 3%), fatigue (5% vs 6%)
- Adverse events (any grade) of special interest: interstitial lung disease (2% vs 0), maculopapular rash (1% vs 1%), colitis (1% vs 0), hyperthyroidism (1% vs 0)
Table 2: Adverse events and treatment summary
- In heavily pretreated advanced gastric and gastro-oesophageal junction cancer, nivolumab provided marginal improvement in OS compared to placebo. Nivolumab improved OS by 1.1 mos. and the estimated 18-mo. OS was 3x longer than placebo. The risk of disease progression or death was reduced by 40% with nivolumab and at 6 mos., 20% were free from disease progression.
- In a posthoc analysis, patients on nivolumab derived almost similar benefit regardless of PD-L1 status. However, only 26 patients were PD-L1 positive. Hence, these results should be interpreted with caution. Patients previously treated with ramucirumab (11%) likewise had better clinical outcomes compared to placebo.
- Partial response was achieved in at least 11% on nivolumab and tumor responses were durable whereas none of the patients on placebo achieved PR.
- The safety profile of nivolumab was similar to that previously reported in the literature. Adverse events were more frequently observed in the nivolumab arm, particularly pruritus, diarrhea and rash. Immune-related adverse events occurred in <3% of patients on nivolumab and were mostly low grade.
- Patients were not preselected based on PD-L1 status and only 40% had archival tissue samples available for testing. Hence, an association between nivolumab and PD-L1 expression was not established in this trial, unlike studies in NSCLC which revealed greater magnitude of benefit with nivolumab in tumors with higher PD-L1 expression. QOL, which is an important outcome especially in heavily treated patients was not assessed in the study.
- This is the first phase III trial to demonstrate improvement in survival for patients with advanced gastric and gastro-esophageal junction cancer previously treated with 2 or more chemotherapy regimens. While there was a 37% relative reduction in the risk of death the absolute improvement in survival was a modest 1.1 months. While nivolumab treatment can be considered in this patient population, further clinical trials of immune checkpoint inhibitors in non-Asian advanced gastric cancer patients should be considered.
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Bosutinib Versus Imatinib for Newly Diagnosed Chronic Myeloid Leukemia: Results From the Randomized BFORE Trial
Cortes JE et al., J Clin Oncol. 2018 Jan 20;36(3):231-237.
PubMed ID: 29091516
Bosutinib is a 2nd generation dual SRC/ABL kinase inhibitor with efficacy in Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) and is currently approved as 2nd or subsequent line therapy. In a study that compared bosutinib with imatinib in newly diagnosed Ph chromosome-positive chronic phase CML (CP CML), no difference was observed in complete cytogenetic response (CCyR) at 12 mos., despite improvement in major molecular response (MMR) at 12 mos. and a lower rate of transformation to accelerated phase (AP) or blast phase (BP) with bosutinib (J Clin Oncol 30:3486-3492, 2012). These results prompted Cortes and colleagues to further investigate the efficacy and safety of bosutinib at a lower initial dose (400 mg daily) compared with imatinib in a similar population.
- Patients: CP CML diagnosed within 6 mos. prior to the study, Ph positive or Ph-negative/BCR-ABL1–positive, Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Ph-positive patients with typical BCR-ABL1 transcript types (e13a2 and/or e14a2); Ph-negative patients (ie, 0 out of ≥10 to 99 metaphases at baseline) and those with unknown Ph status and/or atypical transcript type were excluded from this population but included in the safety analyses and analyses of the ITT population of all patients randomly assigned.
- Study design: Phase III, double-blind RCT
- Experimental: Bosutinib 400 mg PO daily
- Control: Imatinib 400 mg PO daily
- Primary: MMR at 12 mos.
- Secondary: CCyR by 12 mos., MMR by 18 mos., duration of CCyR and MMR, event-free survival (EFS), overall survival (OS), safety
- Treatment with bosutinib provided significantly better rate of MMR at 12 mos. compared to imatinib (47.2% v 36.9%; P=0.200 [mITT]). This advantage with bosutinib was consistently observed at 3, 6 and 9 mos., with a shorter time to response compared to imatinib.
- Deeper molecular responses were achieved with bosutinib compared to imatinib at 3, 6, 9 and 12 mos. More patients on bosutinib achieved BCR-ABL1 transcripts ≤ 10% at 3 mos. Furthermore, CCyR rate at 12 mos. was significantly higher with bosutinib (77.2% v 66.4%; P = 0.0075).
- Dose escalation due to suboptimal response was less common in the bosutinib arm (17.2% v 27.5%). CCyR was achieved by 7.11% on bosutinib v 15.8% on imatinib. The corresponding MMR rates were 3.4% and 10.6%, respectively.
- Disease progression to AP or BP occurred in 1.6% (bosutinib) v 2.5% (imatinib). Five patients (bosutinib n=3, imatinib n=2) continued to receive treatment during AP and four patients achieved MMR. 12-mo. EFS (cumulative incidence) was 2x higher with bosutinib compared to imatinib (3.7% v 6.4%). 12-mo. OS was 99.6% v 97.9%, respectively.
- Diarrhea and liver function abnormalities were the most common side effects with bosutinib, although diarrhea was transient and mostly low grade. Dose reductions (34.7% v 17.%), dose interruptions (56.3% v 35.8%) and treatment discontinuation (14.2% v 10.6%) due to adverse events were more frequent with bosutinib. The most common grade 3 or higher adverse events with bosutinib were elevated ALT (19%), thrombocytopenia (13.8%), elevated AST and lipase (9.7% each) and diarrhea (7.8%). Grade ≥ 3 liver function events were 6x higher with bosutinib (24.3% v 4.2%) and were the most common cause of treatment discontinuation.
- Cardiac events (5.2% v 5.3%) were mostly low grade; grade 3 or higher events were reported in 0.7% and 0.4%, respectively. Peripheral vascular events were reported in <2% of patients (1.5% v 1.1%) while cardiovascular events occurred in 3% v 0.4%. (2.2% v 0.4% in the first year). One patient on imatinib died from a cerebrovascular event
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