In the Literature - June 2016

VBCC - June 2016, Vol 7, No 5 - In the Literature

In This Article

Afatinib Superior to Gefitinib as First-Line Treatment for EGFR Mutation–Positive NSCLC

The EGFR targeting tyrosine kinase inhibitors (TKIs) gefitinib (Iressa), erlotinib (Tarceva), and afatinib (Gilotrif) are approved by the FDA for the first-line treatment of EGFR mutation–positive non–small-cell lung cancer (NSCLC). Data show that all 3 drugs are superior to standard chemotherapy in terms of progression-free survival (PFS), objective responses, and safety profiles. However, head-to-head clinical trials comparing the safety and efficacy of approved TKIs are needed to help clinicians select the most appropriate first-line treatment in this patient population.

A prospective, multicenter, international, open-label, exploratory, randomized controlled phase 2b study (LUX Lung 7) was conducted to compare the efficacy and safety of afatinib, a first-generation, irreversible ErbB family blocker, versus gefitinib, a second-generation, reversible EGFR TKI, in treatment-naïve patients with EGFR mutation–positive NSCLC (Park K, et al. Lancet. 2016 Apr 12. Epub ahead of print).

A total of 319 patients with stage IIIB or IV EGFR mutation–positive NSCLC were randomly assigned to receive afatinib 40 mg (N = 160) or gefitinib 250 mg (N = 159) until disease progression or beyond, if deemed beneficial. The primary end points included PFS, time to treatment failure, and overall survival.

Patients receiving afatinib had a median PFS of 11 months versus 10.9 months in patients taking gefitinib (P = .017). The objective response rate was 70% among patients taking afatinib versus 56% among patients taking gefit­inib. Furthermore, the time to treatment failure was 13.7 months with afatinib versus 11.5 months with gefitinib (P = .0073). Overall survival data were not mature at the time of this analysis.

Serious treatment-related adverse events occurred in 11% of patients taking afatinib and 4% of patients taking gefitinib. In addition, fatal events occurred in 9% of patients taking afatinib versus 6% of patients taking gefitinib; all but 1 death was considered unrelated to treatment.

Afatinib’s superior efficacy over gefitinib may be explained by its mechanism of action and has an important clinical implication–irreversible ErbB blockade with afatinib could be more effective than reversible EGFR inhibition during treatment for EGFR mutation–positive NSCLC. “The results suggest that first-generation and second-generation tyrosine kinase inhibitors are not interchangeable and imply that the broader and irreversible mechanism of action of afatinib compared with gefitinib could have led to better tumor control,” concluded the authors.

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Combination Chemotherapy plus Radiation Prolongs Survival in Low-Grade Glioma

Low-grade gliomas account for 5% to 10% of all primary brain tumors and are associated with premature death. Initial data from a phase 3 study published in 2012 indicated that treating grade 2 gliomas with combination chemotherapy comprising procarbazine, lomustine (also called CCNU), and vincristine plus radiation therapy resulted in longer progression-free survival (PFS) than radiation therapy alone. However, combination chemotherapy plus radiation did not result in improved overall survival (OS) compared with radiation therapy alone.

Long-term follow-up of this clinical trial investigated whether combination chemotherapy plus radiation therapy resulted in better PRS and OS than radiation therapy alone in patients with grade 2 glioma (Buckner JC, et al. N Engl J Med. 2016;374:1344-1355).

A total of 251 patients with grade 2 astrocytoma, oligoastrocytoma, or oligodendroglioma aged <40 years and who had undergone subtotal resection or biopsy, or who were aged ≥40 years and had undergone biopsy or resection of any of the tumor were randomized to receive combination chemotherapy plus radiation or radiation therapy alone, with a median follow-up of 11.9 years.

OS among patients who received combination chemotherapy plus radiation was 13.3 years versus 7.8 years with radiation therapy alone (P = .003). The estimated PFS at 10 years was 51% with combination chemotherapy plus radiation versus 21% with radiation therapy alone. In addition, the estimated OS at 10 years was 60% with combination chemotherapy plus radiation versus 40% with radiation therapy alone.

Patients who received radiation plus combination chemotherapy experienced more adverse events than those who received radiation therapy alone; the majority of adverse events were grade 1 or 2 in severity, with grade 3 or 4 adverse events being rare.

Patients with IDH1 R132H mutations derived the most benefit from combination chemotherapy plus radiation. This finding is consistent with results from 2 phase 3 studies that showed patients with newly diagnosed anaplastic oligodendroglioma with 1p/19q codeletion, IDH mutations, or both, had longer PFS and OS with radiation therapy plus chemotherapy than with radiation therapy alone.

Because IDH mutations are associated with the CpG island methylator phenotype, “it is plausible that DNA-repair enzymes that repair alkylator damage, such as O6-methylguanine-DNA methyltransferase, are silenced by promotor methylation, which results in greater sensitivity to alkylating agents,” the authors noted.

The use of combination chemotherapy with radiation therapy in patients with low-grade gliomas is a promising treatment option but is associated with more frequent adverse events than radiation therapy alone. “Patients and their physicians will have to weigh whether the longer survival justifies the more toxic therapeutic approach,” the authors advised.

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Less Frequent Lung Cancer Screening Warranted in Individuals with Negative Initial Screening

Although annual lung cancer screening with low-dose computed tomography (CT) is recommended in high-risk individuals, it is associated with an increased rate of false-positive results, necessitating further testing that adds risks and costs. Modifications in lung cancer screening guidelines are warranted to improve the efficiency and cost-effectiveness of population-based screening programs. A new study examined the rates of lung cancer in participants who had a negative prevalence low-dose CT screening to assess whether yearly low-dose CT screening is necessary in these individuals (Patz EF Jr, et al. Lancet Oncol. 2016 March 18. Epub ahead of print).

Using a retrospective cohort analysis of 26,231 participants in the National Lung Screening Trial, a randomized, multicenter screening study for the early detection of lung cancer in high-risk individuals, investigators identified 19,066 individuals with a negative low-dose CT prevalence screening.

Per 100,000 person-years, participants with a negative initial screening had an incidence of lung cancer of 371 compared with 661 among participants with a positive initial screening. In addition, individuals with a negative initial screening had lung cancer–related mortality of 185 per 100,000 person-years compared with 277 per 100,000 person-years. At the 1-year screening, 34% of participants with a negative initial CT screening had lung cancer versus 1% among all participants.

Overall, the investigators estimated that if lung cancer screening had not been performed at 1 year among individuals with a negative initial screening, no more than 28 additional participants would have died in this subgroup of patients. In addition, participants with 3 negative annual low-dose CT screens had lower incidence and mortality than participants with an initial negative CT screen.

The investigators stated that these results question the necessity for annual screening after an initial negative result and annual screenings after subsequent negative low-dose CT screenings may not be obligatory. They noted that although the use of annual low-dose CT screening can detect lung cancers at earlier stages, its use should be weighed against its risks and costs.

“Future risk prediction and cost-effectiveness models can incorporate our data to optimise screening guidelines. Improving efficiency of low-dose CT screening for lung cancer could substantially reduce the number of annual screens required, which would have a meaningful impact on population-based screening programmes,” concluded the researchers.

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Last modified: June 24, 2016
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