., afatinib) or a third-generation (i.e., osimertinib) EGFR-TKI is used.

Treatment-naïve EGFR -mutant non-small-cell lung cancer patients are unlikely to benefit from the addition of cetuximab to afatinib, results suggest.

medwireNews : The US FDA has expanded the indication for afatinib to include patients with first-line non-small-cell lung cancer (NSCLC) and non-resistant epidermal growth factor receptor ( EGFR ) mutations.

The analysis included data on 168 patients (89 with NSCLC, 79 with melanoma) who received first-line TKI therapy with dabrafenib, vemurafenib, gefitinib, afatinib, or erlotinib between January 2015 and April 2017 at The Christie NHS Foundation Trust.

Specifically, median PFS was longest with afatinib, at 12.0 months, and shortest with erlotinib, at 3.8 months.

The current analysis – published as a research letter in JAMA Oncology – included 133 diabetes-free participants of a Mexican phase 2 study that investigated the addition of metformin 500 mg twice a day to an EGFR–TKI (erlotinib, afatinib, or gefitinib) for the treatment of stage IIIB–IV NSCLC with an activating EGFR mutation.

Noting that the participant with the EGFR G719A mutation had an ongoing response to dacomitinib at 17 months, which exceeded the response duration of 11 months with osimertinib, the team writes: “Further investigation is needed to determine whether upfront treatment with a second-generation TKI such as dacomitinib or afatinib may be superior to osimertinib for patients with atypical EGFR alterations.”

All patients included in the current report had previously been treated with EGFR– or pan-HER–TKIs (such as gefitinib, osimertinib, and afatinib), and three had a single G719X mutation, while the remaining seven patients additionally harbored at least one other EGFR mutation, such as S768I and T790M.

Their phase I trial enrolled individuals who had developed resistance to erlotinib, gefitinib, or afatinib – but were negative for the EGFR T790M mutation – or had progressed on osimertinib.

And only 18% of the first-line EGFR–TKI cohort went on to receive a second-line therapy, most commonly pemetrexed-based chemotherapy (45%), with the second-generation EGFR–TKI afatinib and the third-generation EGFR–TKI osimertinib, which targets the EGFR T790M mutation, given to just 16% of patients each.

Of the treatments included, osimertinib offered the greatest PFS benefit, with significant differences versus dacomitinib (hazard ratio [HR] for progression or death=0.74), afatinib (HR=0.52), erlotinib (HR=0.48), gefitinib (HR=0.44), icotinib (HR=0.39), pemetrexed-based chemotherapy (HR=0.24), pemetrexed-free chemotherapy (HR=0.16), afatinib plus cetuximab (HR=0.44), and gefitinib plus pemetrexed (HR=0.65).

All 139 study participants received standard doses of EGFR–TKIs – erlotinib, afatinib, or gefitinib – and 69 individuals additionally received the repurposed anti-cancer drug metformin hydrochloride 500 mg twice daily.

The most commonly used EGFR–TKI was gefitinib (n=95), followed by erlotinib (n=79), afatinib (n=47), and osimertinib (n=17), report Liao and co-authors in the European Journal of Cancer .

The team also highlights that the interaction between PD-1/PD-L1 blockade and osimertinib appears to be drug-specific rather than a class effect, as there were no cases of severe irAEs among patients who received the EGFR–TKIs erlotinib (n=20) or afatinib (n=7) after immune checkpoint inhibitor therapy.

We now have five EGFR-targeted, FDA-approved agents for this subset alone: first-generation TKIs erlotinib and gefitinib, second-generation TKI afatinib, third-generation TKI osimertinib, and most recently, another second-generation TKI dacomitinib.

The third-generation EGFR tyrosine kinase inhibitor (EGFR–TKI) was initially granted conditional marketing approval in 2015 for use in patients who had developed the EGFR resistance mutation T790M on or after treatment with a first- or second-generation EGFR–TKI, such as gefitinib or afatinib, respectively.

Acknowledging that even moderately severe side effects become a “real burden” to patients using treatment for a year or longer, he continued: “Both the trial-based data and clinical experience in the real world have shown […] that patients have a far easier time with osimertinib than [with] options like erlotinib or afatinib.”

Of 20,156 cases of non-small-cell lung cancer (NSCLC) registered between 2015 and 2017, 5777 individuals received an EGFR–TKI (afatinib, gefitinib, erlotinib, or osimertinib), 5178 were treated with the anti-PD-1 agent nivolumab, while 70 received both.