Dabrafenib, Afatinib Trials Demonstrate Activity In NSCLC Mutation Patients

Dabrafenib may be efficacious in non-small-cell lung cancer patients with BRAF mutations, while first-line afatinib may be more effective than gefitinib for those with EGFR mutations

medwireNews: Results from two clinical trials published in The Lancet Oncology shed light on potential treatment options for non-small-cell lung cancer (NSCLC) patients with a BRAFV600E or EGFR mutation.

The first report, by Bruce Johnson, from Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and co-workers, gives preliminary findings from the open-label phase II study of the BRAF inhibitor dabrafenib 150 mg, given orally twice daily, in patients with stage IV metastatic disease positive for the BRAFV600E mutation.

The primary endpoint of investigator-assessed overall response, defined as the proportion of patients with a confirmed complete or partial response to treatment, was 33% for the 78 previously treated patients and 67% for six treatment-naïve patients.

Serious adverse events were reported in 42% of the patients, including one fatal intracranial haemorrhage attributed to dabrafenib treatment. The most common grade 3 or more severe side effects were cutaneous squamous cell carcinoma (12%), asthenia (5%) and basal cell carcinoma (5%).

“Dabrafenib showed substantial antitumour activity leading to durable clinical responses in a substantial proportion of patients with BRAFV600E-positive NSCLC and had an acceptable safety profile”, the researchers write.

Noting that the majority of trial participants were former or current smokers, they add: “Our results highlight the importance of screening for BRAF genetic alterations in patients with advanced NSCLC, particularly in patients with tumours negative for EGFR mutations and ALK rearrangements.”

The second report gives early results from the phase IIb LUX-Lung 7 trial comparing afatinib with gefitinib for patients with treatment-naïve, stage IIIB or IV NSCLC with a EGFR exon 19 deletion or Leu858Arg mutation.

After a median follow-up of 27.3 months, the 160 patients randomly assigned to receive afatinib 40 mg/day until disease progression or beyond had longer median progression-free survival (PFS) than the 159 given gefitinib 250 mg/day, at 11.0 versus 10.9 months and a hazard ratio (HR) of 0.73.

Indeed, afatinib was associated with significantly higher PFS rates at the 12-, 18- and 24-month checkpoints, and this benefit was independent of EGFR mutation type, say Keunchil Park, from Sungkyunkwan University in Seoul, South Korea, and co-investigators.

The time to treatment failure was also significantly longer with afatinib than gefitinib, at a median of 13.7 versus 11.5 months and an HR of 0.73, as was the rate of objective tumour response (70 vs 56%, odds ratio=1.87).

And while overall survival data are not yet mature, the team notes that there was a trend towards higher median values for afatinib than gefitinib therapy, at 27.9 versus 25.0 months.

Grade 3 and 4 treatment-related side effects in the afatinib and gefitinib patients included diarrhoea (13 vs 1%), rash or acne (9 vs 3%) and liver enzyme elevations (0 vs 9%). Serious adverse events occurred in 11% and 4% of the afatinib and gefitinib treatment groups, respectively, with side effects resulting in discontinuation in 6% of patients in both trial arms.

“LUX-Lung 7 indicates that irreversible ErbB blockade with afatinib could be more effective than reversible EGFR inhibition in the treatment of EGFR mutation-positive NSCLC”, Keunchil Park et al comment.

“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 tumour control.”

References

Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAFV600E-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label phase 2 trial. Lancet Oncol 2016; Advance online publication 11 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)00077-2

Park K, Tan E-H, O’Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol 2016; Advance online publication 11 April. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30033-X

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