In a randomized trial involving patients with
ALK
-rearranged lung cancer, brigatinib was associated with longer progression-free survival and more activity against central nervous system disease ...than crizotinib.
Immune checkpoint blockade has been a pivotal development in the management of advanced non–small-cell lung cancer (NSCLC). Although durable antitumour activity and improved survival have been ...observed in a subset of patients, there is a need for additional predictive biomarkers to improve patient selection and avoid toxicity in potential non-responders. This review will address the use and limitations of tumour programmed death-ligand 1 expression as a predictive biomarker and review emerging biomarker strategies specifically related to NSCLC including genetic alterations (tumour mutation burden, loss and gain activated mutations), tumour-related factors (tumour microenvironment) and factors related to the host immune system. Novel approaches in biomarker detection such as peripheral blood monitoring will also be reviewed.
•At present, tumour PD-L1 expression is the only approved biomarker, albeit imperfect, used in clinical practice for PD-(L)1 blockade in NSCLC.•Tumour Mutational Burden may enter clinical practice as a biomarker to select patients who are potential candidates for dual immune blockade.•Several biomarker strategies specifically related to NSCLC are under investigation.•Tumour-related factors such as genetic alterations and tumour microenvironment play a crucial role and are relevant for a prediction role.•Factors related to the host immune system (peripheral blood biomarkers etc.) and their combination with other biomarkers will be the next future.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in ...advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events).
Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected.
Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio HR, 0.49 95% CI, 0.35 to 0.68; log-rank
< .0001; median, 24.0
11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4
9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 95% CI, 0.49 to 1.00; log-rank
= .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 95% CI, 0.98 to 1.031;
= .69).
Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.
In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited ...superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results.
Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy.
A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio HR = 0.48, 95% confidence interval CI: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed.
In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study.
The incidence of melanoma is increasing worldwide. Advances in targeted agents and immunotherapy have improved outcomes in metastatic disease, but biomarkers are required to optimize treatment. We ...determined the prevalence of circulating tumor cells (CTCs) and explored their utility as prognostic and pharmacodynamic biomarkers. A total of 101 patients with metastatic cutaneous melanoma were recruited prospectively. CTC number was determined using the CellSearch platform and melanoma kits in samples taken at baseline and serially during treatment. CTC numbers ranged between 0 and 36 per 7.5ml blood; 26% of patients had ≥2 CTCs. Baseline CTC number was prognostic for median overall survival (OS) in univariate analysis (2.6 vs. 7.2 months (P<0.011) for patients with ≥2 CTCs vs. <2 CTCs, respectively). In multivariate analysis, CTC number was an independent prognostic biomarker of OS (hazard ratio (HR) 2.403, 95% confidence interval (CI) 1.303–4.430, P=0.005). Patients receiving treatment in whom CTC number remained ≥2 CTCs during treatment had shorter median OS than those who maintained <2 CTCs (7 vs. 10 months, HR 0.34, 95% CI 0.14–0.81, log-rank test P=0.015). In conclusion, CTC number in metastatic cutaneous melanoma patients is prognostic for OS with a cutoff of 2 CTCs per 7.5ml blood. CTC number measured before and throughout treatment provided additional prognostic information. Larger studies are warranted to confirm CTC biomarker utility in melanoma patients.
Epidermal growth factor receptor (EGFR) activating mutations and anaplastic lymphoma kinase (ALK) gene rearrangement in advanced non-small cell lung cancer (NSCLC) represent the two oncogenic events ...with an impact on current clinical practice. EGFR tyrosine kinase inhibitors (TKIs) and crizotinib are the standard of care for the treatment of EGFR mutant and ALK gene rearranged advanced NSCLC patients. Unfortunately, despite initial clinical benefit, acquired resistance to EGFR-TKIs or crizotinib usually develops after an average of 10–12 months of treatment. The aim of this review is to describe the mechanisms of resistance to first/second generation EGFR-TKIs and crizotinib. In particular, we focus on strategies to overcome resistance due to secondary EGFR T790M mutation and mutations of the ALK domain.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent the standard of care for advanced non-small cell lung cancer (NSCLC) patients whose tumor harbors an activating ...EGFR mutation. The vast majority of patients will experience disease control with an EGFR-TKI but inevitably all patients will progress, often within a year of treatment. There is no current standard of care for this scenario but, in clinical practice, most of the patients will be offered platinum-based doublet chemotherapy. In some situations, continuation of the EGFR-TKI beyond radiological progression, with or without use of local treatments in case of oligo-progressive disease, represents a reasonable therapeutic option. The aim of this review is to describe the different treatment strategies that have been developed to tackle progression on EGFR-TKIs, including specific clinical scenarios and novel agents designed to tackle the common T790M resistance mutation.
The use of patient-reported outcomes (PROs) has been shown to enhance the accuracy of symptom collection and improve overall survival and quality of life. This is the first study comparing ...concordance and patient preference for two PRO tools: Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE
) and the adapted-REQUITE Lung Questionnaire.
Patients with lung cancer were recruited to the study while attending outpatient clinics at a tertiary cancer centre. Clinician-reported outcomes were generated through initial patient assessment with CTCAE v4.03. Participants then completed the PRO-CTCAE
and adapted-REQUITE questionnaires. Concordance between the 2 questionnaires was assessed by calculating Pearson correlation coefficient. PRO-CTCAE
and CTCAE concordance was demonstrated by calculating Pearson correlation coefficient from the linear predictors of an ordinal logistic regression. P-values were also calculated.
Out of 74 patients approached, 65 provided written informed consent to participate in the study. 63 (96.9%) patients completed both PRO-CTCAE
and adapted-REQUITE questionnaires. Pearson correlation coefficient between PRO tools was 0.8-0.83 (p <.001). Correlation between CTCAE and PRO-CTCAE
ranged between 0.66-0.82 (p <.001). Adapted-REQUITE and CTCAE correlation was higher for all symptoms ranging between 0.79-0.91 (p <.001). Acceptable discrepancies within one grade were present in 96.8%-100% of symptom domains for REQUITE and in 92.1%-96.8% for all domains in the PRO-CTCAE
. 54% of the total participant cohort favored the adapted-REQUITE questionnaire due to reduced subjectivity in the questions and ease of use.
The adapted-REQUITE questionnaire has shown a superior correlation to clinician-reported outcomes and higher patient preference than the PRO-CTCAE
. The results of this study suggest the use of the REQUITE questionnaire for patients with lung cancer in routine clinical practice.
PDF
