Afatinib Generates Excitement in NRG1 Fusion+ Lung Cancer, But Challenges Remain

Khaled A. Tolba, MD, MBBCh

Early data suggest that afatinib (Gilotrif) is a potentially effective treatment option for patients with lung adenocarcinoma who have NRG1 fusions, said Khaled A. Tolba, MD, MBBCh, but the identification of these fusions continues to pose a challenge.

“Many of the gene fusion panels do not contain the NRG1 chromosomal translocation. We hope that as the medical oncology community becomes more aware of the incidence or the presence of these translocations, they will be included in more gene fusion panels,” said Tolba. “That way, we'll be able to identify these patients at the time of diagnosis and then assign them to receive the appropriate targeted therapy early on rather than after they have exhausted all other options.”

Findings from a small case series presented at the 2019 World Conference on Lung Cancer showed that 4 patients with lung adenocarcinoma associated with NRG1 gene fusions all achieved some degree of response or tumor stabilization when treated with afatinib. The data are encouraging, warranting a prospective study of a larger cohort of patients with NRG1 fusion—positive lung cancer treated with afatinib.

In an interview with OncLive, Tolba, an assistant professor of medical oncology at Oregon Health and Science University, discussed NRG1 chromosomal translocations, the promise of afatinib in the treatment of patients with these fusions, and next steps for future research.

OncLive: Could you discuss NRG1 and the importance of targeting it in lung cancer?

Tolba: NRG1 is one of the myriads of chromosomal translocations that has recently been identified in lung cancer, many other adenocarcinomas, and solid tumors. This translocation was first discovered about 5 or 6 years ago in patients with invasive mucinous adenocarcinoma and it was thought to be one of the oncogenic chromosomal translocations that are unique to adenocarcinoma. Later on, with the widespread use of comprehensive genomic profiling and next-generation sequencing (NGS), NRG chromosomal translocations have been identified in multiple other cancer types beyond lung adenocarcinoma; it is found in bladder cancer, biliary adenocarcinomas, ovarian cancer, colorectal cancer, pancreatic cancer that is negative for KRAS, and several other solid tumors. Two recent large data sets showed the incidence of these translocations are [present in] about 0.2% to 0.3% of all solid tumors. [NRG1 gene fusions are] a little bit less common than some of the recently discovered chromosomal translocations, such as NTRK, for example.

What treatment options are available to patients with these fusions?

In lung cancer, most of these patients, because the immunohistochemistry is of mucinous adenocarcinoma, would receive a platinum doublet—most commonly, carboplatin plus pemetrexed. Most recently, with the introduction of immunotherapy plus chemotherapy, the combination of carboplatin, pemetrexed, and pembrolizumab (Keytruda) has been commonly used in these patients. As is common with most adenocarcinomas, the treatment is mostly palliative with survival [ranging from] 1 to 2 years. We hope to extend that [survival] with the use of appropriate targeted therapy, but the main detriment to that goal is the difficulty of identifying NRG1 chromosomal translocations, since they’re not present in several of the gene fusion panels.

What data have seen with afatinib in patients with NRG1 fusion—positive lung cancer?

The data are fairly in their infancy right now, and that's partly because the translocation itself is fairly rare. However, more importantly is the difficulty in identifying these patients because, as I mentioned earlier, many of the gene fusion panels do not contain the NRG1 chromosomal translocation.

To the best of my knowledge, there are 17 cases in the literature of patients with NRG1 chromosomal translocations who have been treated with afatinib. Afatinib, as we all know, is a drug that has been available for about 10 or 12 years, and has been used almost exclusively in EGFR-mutated adenocarcinoma of the lung; this is where we had fairly extensive experience with the drug. The adverse events (AEs) [seen with the agent] are mostly skin rash and gastrointestinal (GI) toxicity in the form of mouth sores and diarrhea. Most are currently fairly familiar with these AEs; there are ways to manage these toxicities, mostly through dose reductions and the use of antibiotics and skin care products to minimize the incidence of skin rash and manage GI toxicities.

What are the next steps that should be taken with afatinib?

At this point, we are fairly confident and capable of managing the [associated] toxicities. The main issue in using afatinib to treat NRG1 chromosomal translocations is to be able to identify these patients in the frontline setting, where they are more likely to respond to treatment, as opposed to running through a litany of less effective treatments before we use the agent. The incorporation of NRG1 gene fusions into NGS panels will be a necessary step to achieve that goal.

How might the ongoing TAPUR study (NCT02693535) help to incorporate targeting NRG1?

The TAPUR study, which is sponsored by ASCO, is one of several umbrella trials that are trying to match patients who have various forms of driver mutations with the appropriate targeted therapies or immunotherapies in the hope of making these drugs more accessible and generating additional data that will help to expand the use of these drugs.

Recently, the TAPUR study incorporated the use of afatinib for patients with NRG1 chromosomal translocation, because there is currently no FDA approval for afatinib in patients with NRG chromosomal translocation. Therefore, we hope that umbrella trials, such as TAPUR, will generate necessary data to allow for the expanded access of drugs like afatinib. As we know, NRG1 is a growth factor containing an epidermal growth factor—like domain that binds to ERBB3 and ERBB4. Since we do not have specific treatment to inhibit the NRG itself, we target downstream from the NRG by focusing on the ERBB3 and ERBB4. We do not have a specific inhibitor, so we tend to use pan-ERBB inhibitors like afatinib, which has shown activity in that setting.

What are some key challenges that remain with afatinib and NRG1 gene fusions?

There are 2 key ones that pertain to NRG1 chromosomal translocations and NRG1-driven adenocarcinomas in general, whether it's lung, pancreatic, colorectal, gallbladder. The number one [step] is identifying these chromosomal translocations. That particular translocation is not incorporated in several gene fusion panels, so we hope that as more and more panels incorporate NRG1, we'll be able to identify these patients with increasing frequency.

The next question is, “What is the most appropriate way to inhibit signaling from ERBB3 and ERBB4?” There is at least one publication showing that monoclonal antibodies against ERBB3 are highly effective; however, this class of drugs is not widely available, so pan-ERBB inhibitors such as afatinib become our default, because it is a reasonably studied and well-understood compound that can be used for these chromosomal translocations.

Duruisseaux M, Laskin JJ, Tolba K, et al. Targeting NRG1-fusions in lung adenocarcinoma: afatinib as a novel potential treatment strategy. Presented at: 2019 International Association for the Study of Lung Cancer World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract P1.14-25.