Afatinib shows promise for genetically mutated urothelial cancer

The oral tyrosine kinase inhibitor afatinib exhibited significant activity in patients with metastatic, platinum-refractory urothelial cancer who harbor HER-2 or ERBB3 alterations, according to the results of a phase 2 study.

“Compared to other drugs which have been tried for refractory metastatic bladder cancer, including immune therapies which will likely be approved, the time to disease progression is significantly lower with afatinib [Gilotrif, Boehringer Ingelheim] in patients carrying genetic alterations,” Peter H. O’Donnell, MD, assistant professor of medicine at University of Chicago, said in a press release. “There have been no other drugs approved in the United States in decades in this disease setting.”

Urothelial cancer is the fourth most common cancer in men and the eighth leading cause of cancer death in the United States, according to study background. Platinum-based therapy remains the only standard of care.

Because somatic mutations and copy number variations in the ERBB gene family are commonly seen in urothelial cancer, O’Donnell and colleagues surmised that afatinib — an irreversible inhibitor of this gene family — may have activity in patients who harbor ERBB mutations.

The researchers conducted a phase 2 study of 23 patients (median age, 67 years; range, 36-82; 78% men) who received continuous daily afatinib (40 mg) until progression or intolerance.

All patients had an ECOG performance status of 0 or 1. The median time from prior chemotherapy was 3.6 months. Seven patients (30%) had liver metastases.

O’Donnell and colleagues conducted prespecified tumor analyses for alteration in epidermal growth factor receptor, HER-2, ERBB3 and ERBB4.

PFS at 3 months served as the primary endpoint.

Five patients (21.7%) met the PFS threshold (partial response, n = 2; stable disease, n = 3).

The researchers noted that of all tumors analyzed (n = 21), 83.3% of patients (n = 5 of 6) with HER-2 and/or ERBB3 alterations achieved 3-month PFS, with PFS ranging from 5 months to 10.3 months. In contrast, no patients without genetic alterations achieved 3-month PFS (P < .001).

Three out of four patients with HER-2 amplification and all three patients with ERBB3 somatic mutations (G284R, V104M and R103G) achieved 3-month PFS.

One patient with both HER-2 amplification and an ERBB3 mutation did not experience disease progression, but discontinued treatment after 10.3 months due to depressed ejection fraction.

Patients with genetic alterations had a median time to progression or discontinuation of 6.6 months, compared with 1.4 months in patients without alterations (P < .001).

The most common any-grade adverse events included diarrhea (82.6%), acneiform rash (78.3%) and fatigue (56.5%). Three patients required dose reductions due to grade 3 fatigue, grade 3 rash and grade 2 cardiotoxicity.

The researchers acknowledged the small sample size and single-arm study design as limitations.

“The connections linking afatinib with a better response to treatment for this group of patients are encouraging,” O’Donnell said. “Our next step is to organize a follow-up trial focused entirely on patients with at least one of these mutations.” – by Cameron Kelsall

Disclosure: Boehringer Ingelheim funded this study. O’Donnell reports institutional research funding from Boehringer Ingelheim, as well as other financial relationships with numerous pharmaceutical companies. Please see the full study for a list of all other researchers’ relevant financial disclosures.