ERBB Alteration Linked to Improved PFS With Afatinib in Urothelial Cancer

Peter H. O’Donnell, MD

Five of 6 patients with metastatic urothelial cancer and at least 1 of 2 genetic alterations—multiple copies of HER2, or mutations and multiple copies of ERBB3—demonstrated a marked improvement in 3-month progression free survival (PFS3) of 6.6 months when given afatinib (Gilotrif), compared with patients who lacked these specific genetic abnormalities, according to researchers at the University of Chicago. In the study, 15 patients lacked these specific genetic abnormalities and demonstrated no significant response to the agent. A total of 23 patients were enrolled between November 2013 and May 2015.¹

Researchers targeted the ERBB family of genetic alterations consisting of EGFR, HER2, ERBB3, and ERBB4, a class of tyrosine kinases that have been extensively investigated in other cancers. Afatinib inhibits the activity of proteins in this gene family that promote cancer growth. The occurrence of these alterations in urothelial cancer (UC) is relatively common with EGFR amplifications, at 11%; HER2 amplifications, 7%; and ERBB3 mutations, 11%.

“That’s almost 30% of patients,” said Peter H. O’Donnell, MD, assistant professor of medicine at the University of Chicago and senior author of the study. “We’re in the era where molecularly-directed therapies—precision medicine—are becoming the norm in oncology, and yet bladder cancer hasn’t established that paradigm.”

Historical treatments for chemotherapy-refractory metastatic bladder cancer have resulted in an average time to progression of about 2 months, said O’Donnell. Despite a number of agents investigated over the past 2 to 3 decades, time to progression has not changed. “Platinum-based therapy remains the only standard of care, with no approved second-line therapies in the US,” said O’Donnell. The median PFS for vinflunine, the only approved second-line agent in Europe, is 3.0 months,² and the recently reported median PFS for pembrolizumab in its phase Ib trial was 2.2 months.³

The salient, exploratory endpoint for this trial was whether genomic alterations in EGFR, HER2, ERBB3, and ERBB4, including somatic mutations of all four genes plus copy number analysis of EGFR and HER2, were associated with PFS3 and response or both. “The patients that had the alterations and received afatinib had an average progression time of over 6 months. So that’s a 3-time prolongation, which is a signal that the drug is doing something,” said O’Donnell.

Eligible adults had a histologic diagnosis of UC of the bladder, upper tract, or urethra and had progressed despite receiving prior platinum-based combination chemotherapy in the perioperative or metastatic setting. The median age was 67 years. Patients received continuous therapy with afatinib 40 mg/day until disease progression or intolerability and the primary endpoint was 3-month PFS. Over the course of the trial, patients were carefully monitored for drug-related complications and evaluated with computed tomography or magnetic resonance imaging scans every 6 weeks.

Overall, the researchers observed significant afatinib activity in the predefined subpopulation of patients who had the alteration. O’Donnell noted that all patients received afatinib, but those with alterations had a median PFS of 6.6 months. That was more than 4 times longer than patients without the mutations, who averaged only 1.4 months. There was a stark contrast between the two groups, said O’Donnell. “The findings could be used to define who responds to the agent,” added O’Donnell.

It was hoped that the mechanism of afatinib sensitivity would be further elucidated based on the findings. The researchers were unable to demonstrate that EGFR amplification or protein overexpression identified patients who would benefit from afatinib. The researchers proposed that the EGFR axon 19 and 21 alterations are absent in UC, despite earlier evidence that demonstrated that EGFR alterations could identify UC patients who would benefit from EGFR inhibitors.⁴

The most common treatment-related toxicities of any grade were diarrhea (82.6%), acneiform rash (78.3%), and fatigue (56.5%). The researchers reported that 3 patients underwent dose reductions. In 1 patient, afatinib was discontinued because of an asymptomatic grade 2 reduction in ejection fraction (an on-treatment decrease from 46% to 33% after 10.3 months of treatment, considered possibly related to the drug). This patient’s tumor exhibited alterations of both HER2 and ERBB3. After a short break, however, the patient resumed taking afatanib outside of the trial. The patient’s disease did not progress for another 5.7 months, the researchers reported. There were no treatment-related deaths.

“The next step is to define this signal better,” said O’Donnell. The trial’s significant limitation is its small sample size, he added. The follow-up study, which is in final stages of being activated, would enroll only those patients with the genomic markers.

O’Donnell is hopeful about the role of precision medicine. “I think the excitement of using genetic alterations to identify a treatment for patients is real in bladder cancer. This study speaks to that. These types of investigations might actually inform the treatment that the physician chooses or the trial that a physician enrolls a patient in,” he said, “and that is the future of bladder cancer therapy.”

References

1. Choudhury NJ, Campanile A, Antic T, et al. Afatinib in platinum-refractory metastatic urothelial carcinoma in patients with ERBB alterations. J Clin Oncol. 2016. Published online before print April 4, 2016, doi: 10.1200/JCO.2015.66.3047.
2. Bellmunt J, Theodore C, Demkov T, et al: Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J Clin Oncol 2009;27:4454-4461.
3. Plimack E, Gupta S, Bellmunt J, et al: LBA23—A phase 1b study of pembrolizumab (Pembro; MK-3475) in patients (Pts) with advanced urothelial tract cancer. Ann Oncol 25: 2014 (suppl 4; abstr 1093).
4. Chaux A, Cohen JS, Schultz L, et al. High epidermal growth factor receptor immunohistochemical expression in urothelial carcinoma of the bladder is not associated with EGFR mutations in exons 19 and 21: a study using formalin-fixed, paraffin-embedded archival tissues. Hum Pathol. 2012;43:1590-1595.