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Afatinib benefits extend to NSCLC patients with rare mutations

Afatinib shows promising clinical activity in patients with a difficult-to-treat form of non-small cell lung cancer (NSCLC), according to a new study published in The Oncologist. These findings suggest a potential therapeutic role for afatinib in NSCLC patients with few treatment options.

Two types of epidermal growth factor receptor () mutations – deletions in exon 19 (Del19) and a point mutation in exon 21 (L858R) – account for approximately 90% of all cases of mutation-positive NSCLC. Patients with common mutations typically respond well to upfront treatment with -targeted therapies such as erlotinib or gefitinib. However, treatment with standard reversible anti- therapy is less effective in NSCLC patients with rare mutations. Furthermore, the benefit of subsequent anti- therapy for NSCLC in patients previously treated with erlotinib or gefitinib is not well understood.

Afatinib is an irreversible, second-generation anti-EGFR agent that is currently approved for the first-line treatment of patients with NSCLC who harbor common EGFR mutations. In contrast to erlotinib and gefitinib, afatinib has also shown activity in NSCLC patients with rare EGFR mutations.

In the current study, a team of researchers led by David F. Heigener, MD, of LungenClinic Grosshansdorf in Grosshansdorf, Germany, examined the safety and effectiveness of afatinib in patients with heavily pretreated NSCLC and rare EGFR mutations.

“Patients with uncommon EGFR mutations can derive benefit from treatment with afatinib, even in some cases of tumors harboring rare mutations associated with resistance to standard anti-EGFR therapy,” Dr. Heigener said.

The study included 60 patients with advanced or metastatic NSCLC who were treated with afatinib as part of a compassionate use program prior to its approval in Europe. All patients had been previously treated with at least one line of chemotherapy and one line of anti-EGFR therapy (erlotinib or gefitinib). Two thirds of the patients (67%) received afatinib as third- or fourth-line treatment.

An analysis of NSCLC tumor samples revealed 66 different types of uncommon EGFR mutations. This included 30 uncommon EGFR mutations associated with resistance to standard EGFR-targeted therapy.

The median duration of afatinib treatment was 10 months. The median time to treatment failure (TTF) was 3.8 months for all patients with uncommon EGFR mutations. Afatinib appeared to be particularly active in patients with a rare mutation called E709X. In these patients, the median TTF exceeded 12 months.

As part of the afatinib compassionate use program, 165 patients with common EGFR mutations also received afatinib. In this group, the median TTF was 5.1 months (p = 0.244), suggesting similar activity with afatinib regardless of the presence of common or rare EGFR mutations.

Diarrhea and skin-related reactions were the most commonly reported side effects of afatinib treatment. The study found no new safety signals in patients with heavily pretreated NSCLC.

“While the ideal treatment approach to patients with EGFR mutations would include mutation-specific inhibitors, our findings suggest that afatinib may be an effective treatment option for patients with rare EGFR mutations who progress on standard, reversible EGFR-targeted therapy,” Dr. Heigener said.

Nathan Pennell, MD, a medical oncologist at the Cleveland Clinic and an Editor of The Oncologist, commented, “With mutation testing now becoming routine, patients with uncommon EGFR mutations are being identified on a regular basis, and there is very little information out there to help oncologists decide what to do with this information. This study could be very helpful for physicians and patients in deciding whether to try afatinib for an uncommon mutation or to move on to other treatment choices.”

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