 fusions occur in low frequency across solid tumors, and because these alterations can evade traditional sequencing modalities, RNA-based next-generation sequencing (NGS) is imperative, said Stephen Liu, MD. Among those in whom these fusions are identified, afatinib (Gilotrif) has shown notable antitumor activity.

 in which the use of afatinib, a pan-ErbB inhibitor, showed very rapid, very dramatic, and in some cases, very durable responses lasting 2 years or longer. These are all of the [boxes] we're looking [to check] with targeted therapy,” said Liu.

However, due to the limited generalizability of case series, more data are needed to characterize the true activity of afatinib. To that end, ASCO’s TAPUR trial is treating patients whose tumors express 

 fusions with afatinib to prospectively assess the safety and activity of the drug.

, Liu, associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center, discussed the known incidence of 

 fusion—positive cancers and the work being done to match targeted treatments with this patient subset.

fusions are transforming oncogenic events that occur at a very low incidence across tumor types. These fusions can be seen in non—small cell lung cancer (NSCLC), breast cancer, colon cancer, pancreatic cancer, and cholangiocarcinoma—really, a multitude of tumor types. They are detected in less than 1% [of cancers]; approximately 0.2% or 0.3% of all tumors will have an 

 fusions do have transforming potential. When we target that pathway, we see pretty dramatic results.

 portion, which contains an EGFR-like ligand, and the fusion partner, which is responsible for tethering the ligand to the plasma membrane. When localized to the plasma membrane, the ligand will interact with HER3 or HER4, which will then heterodimerize, induce phosphorylation, and signal transduction through the MAPK and PI3K pathways. That leads to [malignant] cell proliferation and survival. If we can interrupt that pathway in these fusion—positive tumors, we can induce an antitumor effect, and that's what we're seeing.

 is a true target; it’s a target we can go after and exploit therapeutically with drugs like afatinib. Moreover, other drugs are targeting the HER3 pathway, including monoclonal antibodies, bispecific [T-cell engagers], and antibody—drug conjugates; a whole multitude of strategies are being examined in an effort to target these fusions. Our suspicion is that [

 fusions] don’t respond as well to strategies such as immunotherapy or other standard options.

 is a new [target] that needs to be identified in order to be managed appropriately. In order to identify all of these cases, you need to use RNA-based NGS. You’ll often miss [

 fusions] with DNA-based sequencing. Once identified, you should try to identify a trial to match [the patient with an appropriate targeted therapy]. 

 will be the next big target throughout oncology. 

What is the current prognosis of these patients?

We don't really know many of those details yet. Patients with 

 fusion—positive lung cancer generally fit the phenotype that we look for with targeted therapy. [Patients are generally] nonsmokers, younger, and have nonsquamous histology. We need to identify the natural history of the disease and determine how patients respond to current standards so we can figure out how to improve upon that with additional targeted therapies. We still have a lot to learn regarding what a patient with an 

 fusion looks like. Without any good phenotypic clues, we need to do RNA sequencing in order to identify these patients.

Could you speak to the efficacy of afatinib in this patient subset?

We’ve added 7 more case reports to the 7 that had been published previously, and we showed pretty rapid [and durable] responses with afatinib. One patient had a response lasting 2 years. At progression, they were treated with other systemic therapies and then retreated with afatinib. We saw a response that was very similar to [that achieved with] other targeted agents. [At the 2019 ESMO Congress], we reported on 4 cases of NSCLC. [

] fusions seem to be a little more frequent in invasive mucinous adenocarcinoma, but we do see them in other tumor types. We also reported [the first incidence of an 

 fusion] in colorectal cancer, as well as 2 cases in 

The NRG portion seems to be fairly constant, but the fusion partner can be quite variable. While the most common partner is CD74, there are many different fusion partners and splice variants.

Could you discuss the goal of the ongoing TAPUR trial?

The TAPUR trial is ASCO’s first clinical trial; it’s a prospective study that’s using genomic information to assign patients to various treatments. It’s a precision medicine basket study. As we learn more about these targets, identify new targets and new drugs, the study will evolve. One of the arms in TAPUR is for patients with

 fusions, and they’ll receive afatinib. [With this trial, we hope to learn] the true response rate, progression-free survival, and overall survival of these patients on afatinib. 

What are the next steps for this research?

We've seen that afatinib can be an effective treatment in patients with 

fusion—positive cancer, but we don’t know what the true response rate is [with this agent in this population]. With case reports, there’s no denominator. We’re only seeing positive cases. We don't know how frequently afatinib works, so we need more prospective studies like TAPUR. With these data, we’ll be able to characterize responses to afatinib in a more comprehensive and methodic way. Prospective studies are really what's needed to determine afatinib’s true place in the management of these tumors.

In NSCLC, we're already past the tipping point [of personalized medicine]. We know NGS is the proper testing method to detect multiple alterations rather than doing parallel testing or sequential testing for 

, and so forth. If you do RNA-based NGS, you could find 

, and other important alterations in addition to 

Liu SV, Duruisseaux M, Tolba K, et al. Targeting NRG1—fusions in multiple tumour types: afatinib as a novel potential treatment option. 

. 2019;30(5 suppl, abstr 1969P). doi: 10.1093/annonc/mdz268.096.

Articles

NRG1 fusions occur in low frequency across solid tumors, and because these alterations can evade traditional sequencing modalities, RNA-based next-generation sequencing is imperative.

Expert Hails NRG1 Fusions as the "Next Big Target" in Oncology

Michaël Duruisseaux, MD, a medical oncologist at Lyon Cancer Institute, discusses the incidence of 

 is an actionable target that was first discovered in 2014, says Duruisseaux; it has been found in patients with 

negative invasive mucinous adenocarcinoma. According to data presented at the 2019 ASCO Annual Meeting, the fusion has also been identified in select cases of nonmucinous lung adenocarcinoma and squamous lung carcinoma. The fusion can also be detected in up to half of all 

 wild-type pancreatic cancers, as well as select cases of cholangiocarcinoma, ovarian cancer, and sarcoma, adds Duruisseaux.

 fusions has not been well established but is thought to comprise less than 1% of these tumors overall. 

 fusions are believed to function as oncogenic drivers through activation of ErbB signaling pathways. As such, the irreversible pan-ErbB inhibitor, afatinib (Gilotrif) has shown deep and durable responses in patients with 

 wild-type pancreatic cancer, and cholangiocarcinoma, he concludes.

Videos

Michaël Duruisseaux, MD, a medical oncologist at Lyon Cancer Institute in France, discusses the incidence of NRG1 fusions in solid tumors.

Dr. Duruisseaux on the Incidence of NRG1 Fusions in Solid Tumors

Stephen Liu, MD, associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center, discusses the prevalence of 

 fusions are rare oncogenic drivers that occur across tumor types, including non—small cell lung cancer, breast cancer, colon cancer, pancreatic cancer, and cholangiocarcinoma. However, inhibition of the pathway that is responsible for the development of the 

 fusion can result in significant antitumor effects. Several case reports have shown that afatinib (Gilotrif), a pan-ERBB inhibitor, can induce rapid and durable responses, says Liu.

 fusions are a viable target in oncology. In order to accurately identify an 

 fusion, RNA-based sequencing is necessary. Once identified, patients with an

 fusion can enroll in the TAPUR trial to gain access to afatinib. However, this is not the only agent that is under evaluation, adds Liu. Notably, agents targeting HER3, monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates are also under investigation. Research exploring such strategies is necessary as current approaches may be insufficient, he concludes.

Stephen Liu, MD, associate professor of medicine, Division of Hematology and Oncology, Georgetown University Medical Center, discusses the prevalence of NRG1 fusions in oncology.

Dr. Liu on NRG1 Fusions in Oncology

Afatinib (Gilotrif) is a potential treatment option for patients with 

-positive tumors across multiple cancer types. At the ESMO 2019 Congress, Stephen Liu, MD, and colleagues described a series of 7 pretreated patients with 

-positive tumors who were treated with afatinib with varying degrees of success.

Of the 7 patients treated in the series, 4 patients had lung cancer, 2 had pancreatic cancer, and 1 had colon cancer. One patient with lung adenocarcinoma received 14 lines of therapy prior to afatinib, which included chemotherapy and erlotinib (Tarceva) plus gefitinib (Iressa). The longest duration of response was a partial response (PR) that lasted 24 months, said Liu, director of Developmental Therapeutics, Georgetown University.

“We know from previous work that this fusion event can occur in many different types of tumors, including cholangiocarcinoma and breast cancer. It’s a tumor-agnostic fusion event. Although it’s rare, it’s something you would pick up with next-generation sequencing, primarily through RNA sequencing.”

 fusion leads to the constitutive activation of the HER3/HER4 pathway, which in turn, leads to activation of the PI3 kinase and the MAP kinase pathways, promoting cell proliferation, survival, and growth. “Agents [such as afatinib] that target HER3/HER4 would be agents that could have efficacy in the presence of an 

 fusion,” he said. “This series shows us that when you block the HER pathway with a drug like afatinib in the presence of an NRG1 fusion, you can induce responses and in some cases, durable responses.”

Multiple drugs, including monoclonal antibodies and bispecific antibodies, are in development that target 

 fusions, he added. Prospective trials with afatinib in patients with NRG1-positive tumors are ongoing and others are about to be launched. One prospective study is ongoing in the Drug Rediscovery Protocol trial. One soon to be launched is through the Targeted Agent and Profiling Utilization Registry (TAPUR), which is a multiarm basket protocol being run by ASCO.

The 7 patients treated in this series were as follows:

A 70-year-old female, never-smoker with pan-wildtype, nonmucinous lung adenocarcinoma who received afatinib, 40 mg/day, for 24 months as her fifteenth line. She discontinued after 24 months due to progressive disease. An NRG1 fusion was then identified and she was rechallenged with afatinib, 30 mg/day, with a PR, for 3 months, before switching to atezolizumab (Tecentriq).

A 66-year-old female, never-smoker with nonmucinous lung adenocarcinoma and multiple lung and lymph node metastases  at diagnosis. A 

 fusion was identified and afatinib as fifth-line treatment was initiated. Several dose adjustments were made (down to 20 mg/day) due to diarrhea and malaise. After 19 months, afatinib treatment is ongoing, with PR.

A 68-year-old male with a >20 pack-year smoking history with nonmucinous lung adenocarcinoma. A 

 fusion was identified and afatinib, 30 mg/day, was started in the second line. Best response was stable disease (SD) with a duration of 4 months.

A nonsmoking 43-year old female with advanced invasive mucinous lung adenocarcinoma. A 

 fusion was identified and afatinib was started in the third line. Best overall response on afatinib (40 mg/day) was a PR, and the duration of best response is 18+ months and ongoing.

-mutated colorectal cancer with multiple liver and lung metastases at diagnosis. The patient received 2 lines of treatment prior to afatinib, neither of which were tolerated. Following a right hemicolectomy and liver/lung metastasectomies, a novel 

 fusion was detected and afatinib (30 mg/day) was initiated. Best overall response on afatinib was SD, with treatment ongoing at 9+ months.

wild-type, metastatic pancreatic cancers. Following progressive disease on chemotherapy, 

 fusions, respectively, were detected and afatinib at 30 mg/day and 40 mg/day, respectively, was initiated. The dosage was reduced to 30 mg/day in the 59-year-old due to diarrhea. Best overall response in both patients was a PR with a duration of best response of 8 months and 5.5 months, respectively.

Together with other published case reports, the findings solidify the identity of

 fusions as an actionable alteration, said Liu. “When we use a targeted agent here, we can see dramatic, rapid, and durable responses,” he said. “What we don’t know is the response rate because these are case series, and people typically only report when there are good outcomes.

“The key is because the introns are so large, DNA-based sequencing will miss many of the 

 fusions, so the best test is an RNA-based approach to identify those more reliably, and when found, it’s important to identify trials for these patients.”

Liu SV, Duruisseaux M, Tolba K, et al. Targeting NRG1-fusions in multiple tumour types: Afatinib as a novel potential treatment option. Presented at ESMO 2019; September 27-October 1, 2019; Barcelona, Spain. Abstract 1969P.

NRG1 is a growth factor that binds HER3/4 and activates ErbB signaling pathways. 

 fusions are transforming genomic events, Liu explained. 

 is fused to various partners, most commonly CD74. As a result of this fusion, the EGF-like domain of NRG1 is tethered to the plasma membrane. “The signaling is through the EGF-like domain, which acts as a ligand for HER3/HER4 heterodimers, so the actual signaling that leads to the oncogenic event is through the HER3/HER4 pathway,” he said.

A case series presented at the 2019 ESMO Congress highlighted the activity of afatinib in patients with NRG1-positive tumors.

Case Series Highlights Afatinib Activity in NRG1+ Cancers

Khaled A. Tolba, MD, MBBCh, assistant professor of medicine, School of Medicine, Oregon Health & Science University, discusses the use of afatinib (Gilotrif) in 

The TAPUR study is an umbrella trial aimed at matching patients with specific gene mutations, chromosomal transformations or driver mutations with personalized treatment, explains Tolba.

Recently, afatinib has been added to the TAPUR trial for use in 

-mutant lung cancer because it appears there is activity with this treatment, says Tolba. This is particularly important because there are no FDA-approved therapies for this disease,nor any targeted agents for patients with 

Pan-ERBB TKIs like afatinib are aimed downstream by targeting ERBB3 and ERBB4. The hope is to target the active ligand and ultimately benefit this particular patient population.


Khaled A. Tolba, MD, MBBCh, discusses the use of afatinib in NRG1 fusion–positive lung adenocarcinoma.
 

Dr. Tolba on the Use of Afatinib in NRG1-Mutated in Lung Adenocarcinoma

Khaled A. Tolba MD, MBBCh, assistant professor of medicine, School of Medicine, Oregon Health & Science University, discusses the potential to target 

 fusion—positive lung adenocarcinoma with afatinib (Gilotrif).

Approximately 17 cases of patients harboring a 

 chromosomal translocation treated with afatinib have been reported in the literature, says Tolba. At the 2019 World Conference on Lung Cancer, findings from a small case series showed that 4 patients with lung adenocarcinoma harboring an NRG1 fusion achieved a response or disease stabilization with afatinib.

Afatinib is a TKI that is commonly used to treat 

-mutant non—small cell lung cancer, says Tolba. As such, there is a lot of comfort in using the drug and managing any adverse events (AEs) that may result. Common AEs include skin rash and gastrointestinal toxicity, which can manifest as mouth sores and diarrhea. However, these toxicities can generally be managed with dose reductions, antibiotics, and skin care products, concludes Tolba.

Khaled A. Tolba MD, MBBCh, assistant professor of medicine, School of Medicine, Oregon Health & Science University, discusses the potential to target NRG1 fusion–positive lung adenocarcinoma with afatinib (Gilotrif).

Dr. Tolba on Targeting NRG1 Fusions With Afatinib

Early data suggest that afatinib (Gilotrif) is a potentially effective treatment option for patients with lung adenocarcinoma who have 

 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 

 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 

 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 

 fusion—positive lung cancer treated with afatinib.

, Tolba, an assistant professor of medical oncology at Oregon Health and Science University, discussed 

 chromosomal translocations, the promise of afatinib in the treatment of patients with these fusions, and next steps for future research.

 and the importance of targeting it in lung cancer?

 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), 

 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 

, 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. [

 gene fusions are] a little bit less common than some of the recently discovered chromosomal translocations, such as 

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 

 chromosomal translocations, since they’re not present in several of the gene fusion panels.

What data have seen with afatinib in patients with 

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 

To the best of my knowledge, there are 17 cases in the literature of patients with 

 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 

-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 

 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 

 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 

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 

 chromosomal translocation, because there is currently no FDA approval for afatinib in patients with 

 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, 

 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 

 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 

-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 

, 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.

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

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

Findings from a small case series of patients with lung cancer added to evidence that afatinib (Gilotrif) is a potentially effective treatment in patients with lung adenocarcinoma who have 

 fusions, according to a poster presentation during the 2019 World Conference on Lung Cancer.

Results of the analysis showed that 4 patients with lung adenocarcinoma associated with 

 gene fusions all had some degree of response or tumor stabilization when treated with the EGFR inhibitor.

“These findings add to a growing body of evidence suggesting afatinib activity in 

 fusion—positive non–small cell lung cancer (NSCLC),” Michael Duruisseaux, MD, of the Lyon Cancer Institute in France, and colleagues reported in a poster presentation during the meeting. “Mutational testing of patients with solid tumors may help to identify potentially targetable genomic aberrations, such as NRG1 fusions. This may be particularly important in lung invasive mucinous adenocarcinoma, where 

 fusion prevalence is relatively high.”

 is a growth factor containing an epidermal growth factor-like domain that binds to ERBB3 or ERBB4 to activate ERBB signaling pathways. Clinically actionable 

 gene fusions that may function as oncogenic drivers have been identified in multiple tumor types, including NSCLC, the investigators noted.

 fusions have an estimated prevalence of about 0.2% in various solid tumors, but the prevalence in lung invasive mucinous adenocarcinoma could be as high as 31%.

Afatinib, an irreversible pan-ERBB inhibitor, may represent a viable therapeutic option for 

-associated lung adenocarcinoma, a theory supported by several case reports, Duruisseaux and colleagues continued. They described four new cases of 

 fusion—positive lung adenocarcinoma treated with afatinib.

A 70-year-old nonsmoking Caucasian female patient had a diagnosis of pan-wildtype, nonmucinous lung adenocarcinoma in 2004 and received 14 prior lines of therapy prior to afatinib, including chemotherapy and targeted agents. The patient initiated afatinib in February 2015, had a rapid initial response, and remained on treatment until March 2017, when she developed progressive disease.

 fusion was identified in October 2017 by NanoString analysis, and the patient reinitiated afatinib at 30 mg daily, which led to regression of lung condensations. The patient discontinued afatinib after 3 months because of cough and fever, but reinitiated afatinib in April 2018. Treatment continued until August 2018, when disease progression occurred.

The second case involved a 66-year-old nonsmoking Asian female patient with low body weight. In June 2015, the patient had diagnosis of metastatic nonmucinous lung adenocarcinoma, with multiple lung and lymph node metastases at diagnosis. The patient had received 4 prior lines of therapy, including chemotherapy and targeted agents—specifically nivolumab (Opdivo) and docetaxel/ramucirumab (Cyramza).

Afatinib treatment at 40 mg daily began in December 2017 after detection of a 

fusion. After several dose adjustments because of diarrhea and malaise, the patient attained a partial response (PR), which was ongoing after 19 months of follow-up. Afatinib is being administered at 20 mg daily.

The third patient was a 68-year-old Caucasian man with a ≥20 pack-year history of smoking. He had a diagnosis of nonmucinous invasive lung adenocarcinoma in January 2016. He received 2 prior lines of therapy: cisplatin/pemetrexed chemotherapy, which led to progressive disease as best response, and nivolumab, which resulted in a PR. The patient remained on the PD-1 inhibitor from September 2016 to March 2017, when the treatment was discontinued because of progressive disease associated with immune hepatitis.

 fusion, the patient initiated afatinib at 30 mg daily in August 2018 and attained stable disease for 4 months. At disease progression, that patient chose not to have further treatment.

A diagnosis of invasive mucinous adenocarcinoma of the lung in August 2016 formed the basis for the fourth case, a 43-year-old nonsmoking Caucasian woman. Her treatment history consisted of pemetrexed/cisplatin chemotherapy plus bevacizumab (Avastin), followed by bevacizumab/pemetrexed maintenance until July 2017. She then received nivolumab until September 2017, when RNA sequencing identified a 

The patient initiated treatment with afatinib at 40 mg daily, which led to a major PR, and treatment is ongoing.

“A prospective study of a larger cohort of patients with 

 fusion—positive NSCLC treated with afatinib is warranted to better evaluate its potential activity,” the investigators concluded in their poster.

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 to 10, 2019; Barcelona, Spain; Abstract P1.14-25.

Findings from a small case series of patients with lung cancer added to evidence that afatinib is a potentially effective treatment in patients with lung adenocarcinoma who have NRG1 fusions. 

Afatinib Continues to Showcase Activity in NRG1 Fusions in Lung Cancer

New case reports show that afatinib (Gilotrif) may be a potential treatment option for patients with rare 

 fusion—positive gastrointestinal (GI) cancers, said Benjamin Weinberg, MD, especially if given earlier on in the treatment course.

“Afatinib is an oral ErbB family-blocker; it is FDA approved for use in subsets of patients with advanced non—small cell lung cancer (NSCLC),” added Weinberg. “The idea is that these 

 fusions lead to overactivation of the ErbB pathway, which then leads to activation of cellular proliferation signaling pathways. By blocking this fusion product on the cell surface and preventing homo- or heterodimerization of the ErbB dimer, you are blocking the downstream signal that leads to cellular growth.”

Weinberg and colleagues reported findings from 3 new cases of afatinib treatment in patients with 

 fusion—positive GI cancers at the 2019 World Congress on Gastrointestinal Cancer. Of the 3 cases, 1 patient had 

-mutant metastatic colorectal cancer (CRC), while the other 2 patients had 

 fusions across all solid tumor tumors is only about 0.2%, their prevalence can rise as high as 30% in certain subgroups of patients, according to Weinberg. As such, the oncology community must be aware of its existence—the fact that it’s a potentially actionable target&mdash;and that comprehensive genomic profiling is critical in order to detect them early.

“The more targets we find, the more we have to test for,” said Weinberg. “It’s important for our patients that even if we find a ‘needle in the haystack,’ it could be a ‘silver bullet’ and that really could impact their treatment course.”

, Weinberg, an assistant professor of medicine, Division of Hematology and Oncology, in the Lombardi Comprehensive Cancer Center at Georgetown University, Medstar Health, provided insight into NRG1 fusions, the effectiveness of afatinib in patients harboring these fusions, and future research being done in this area.

: What is known thus far about the rare gene fusion 

: NRG1 encodes for neuregulin 1, a growth factor that binds to receptor pathways known as the HER or ErbB pathway. It specifically binds to HER3 and HER4 and activates downstream signaling pathways that lead to cellular growth and proliferation. Gene fusions occur when 

 basically combines with another gene that allows it to be activated.

 fusions have been implicated rarely but can play a role in a variety of solid tumors. They’re very rare; their overall frequency is about 0.2% across all solid tumors. However, in some select subgroups of solid tumors, their prevalence can jump as high as 30%. [This target] is of special interest because there is a series of drugs in development, like afatinib, that are panHER-blocking drugs that can theoretically work in these cancer types.

Could you discuss the data with afatinib in patients with GI cancers harboring NRG1 fusions?

Our interest was specifically in GI tumors. We wanted to see if [these patients] have the 

 fusion and if we can target it with a drug such as afatinib. At the 2019 World Congress of Gastrointestinal Cancers, Meeting, we presented 3 cases. One of them was my patient, a gentleman with metastatic 

-mutated CRC, and the other 2 were patients with metastatic pancreatic cancer who were 

 wild-type, which is a rarer form of metastatic pancreatic adenocarcinoma.

-mutated CRC is an older gentleman who initially presented with a right-sided colon cancer that was bleeding. He underwent surgical resection, despite multiple liver lesions being present at the time of diagnosis. He did not tolerate chemotherapy very well and ultimately had a liver resection followed by low-dose chemotherapy, and then, ultimately, lung resections for metastatic cancer.

Around that time, he was discovered to have a novel 

 molecular profile. Afatinib was initiated in [this patient] September of last year and he remains on the drug, 10 months later. He had stable disease, initially declined in his carcinoembryonic antigen blood tumor marker—which subsequently uptrended&mdash;and then he got local radiation therapy to a couple of metastatic sites with improvement in his scan and numbers. He remains on the drug with overall stable disease following isolated areas of progression. He’s tolerating the drug better than any chemotherapy he received.

wild-type metastatic pancreatic cancer, was a younger gentleman who had liver metastases at diagnosis, had 1 line of chemotherapy that he stopped for intolerance—gemcitabine and nab-paclitaxel (Abraxane)&mdash;and then was started on afatinib for an 

 fusion that was identified. He had tumor shrinkage, a significant radiological response, and he remains on afatinib 7 months later with an ongoing response.

And the other patient, a similar middle-aged gentleman with metastatic 

wild-type pancreatic cancer with liver metastases at diagnosis, received 2 lines of standard chemotherapy—FOLFIRINOX and then gemcitabine. He also had a partial response on 40 mg of afatinib. His dose was then reduced and he had disease progression following 5.5 months. He ultimately died of progressive disease thereafter.

[Afatinib] seems to be a little [more effective] if it’s given earlier on in the treatment schema, if we can identify these 

 fusions earlier. In order to find these [fusions] you really have to do whole-genome transcriptome analysis or pretty broad next-generation sequencing on solid tumor tissue; it’s not something that’s easily picked up in liquid biopsies and the like. This especially needs to be done in order to detect these novel fusion partners—such as my patient who had the 

 fusion—that fusion product hasn’t been seen before or since. Without doing whole-transcriptome sequencing, you are probably going to miss those types of findings.

He’s also the only patient with CRC in the 1700 patients that were tested who had an 

 fusion of any type, so [this fusion] is pretty rare, but it obviously is a potentially clinically actionable [target].

Were there any notable associated toxicities with afatinib? How did you manage them?

The big ones with afatinib are diarrhea and then a rash. However, I find that at the 30-mg daily dose, the agent is actually very tolerable. The 40-mg daily dose can be harder to tolerate. The second patient with pancreatic cancer [that I described] had to have a dose reduction from 40 mg daily to 30 mg daily due to diarrhea. [The first patient described], my patient, has always had some degree of baseline diarrhea and he did have a mild rash on the drug, but we never had to hold the drug or decrease the dose. Therefore, I believe that the 30-mg daily dose is tolerable, and I don’t think that there is a big difference in terms of efficacy between the 2 dose levels, although that is always a question.

Benjamin Weinberg, MD, provides insight into NRG1 fusions, the effectiveness of afatinib in patients harboring these fusions, and future research being done in NRG1 fusion–positive gastrointestinal cancers.

Developments in NRG1 Fusion+ Cancers | Special Issues