“Gene fusions” are not exactly a household term, and still fly under the radar of many even in the precision medicine space due to their rarity. However, with the recent FDA approvals of targeted therapies for NTRK, ROS1, and RET fusions, and growing recognition of NRG1 fusions as a new emerging target, awareness of this class of genomic alterations is gaining momentum.
While gene fusions may sound like a new, emerging field of study, it has actually been 20 years since the first FDA approval of a therapeutic targeting a gene fusion product! As of 2021, over a dozen therapies have since been approved for tumors driven by various gene fusions.
Here we’ll take a look back at the proven history of gene fusions in oncology, and our evolving understanding of their potential as promising therapeutic targets.
The path to approvals
Gene fusions are genomic alterations resulting from the chimeric combination of two unrelated genes. If a tumor suppressor gene or oncogene is involved, the resulting fusion proteins can lead to unregulated cell growth and proliferation, and ultimately tumorigenesis.
The identification of the BCR-ABL gene fusion as a genomic alteration in chronic myelogenous leukemia (CML) kicked off a new era of research and drug development for hematologic cancers. The first BCR-ABL inhibitor, imatinib, was approved by the FDA in 2001 and quickly became the standard of care for front line therapy in CML.
After a decade of research in hematologic malignancies, the ALK inhibitor, crizotinib, became the first approved targeted therapy for a gene fusion in a solid tumor in 2011. Though not commonly referred to as “fusions”, the well-known class of ALK inhibitors for non-small cell lung cancer (NSCLC) in fact target ALK fusions. The approval of crizotinib was quickly followed by a number of second and third generation ALK inhibitors (Figure 1), firmly establishing the importance of genomic testing and matched targeted therapeutics for patients with NSCLC.
In these 20 years of active research and development, significant progress has been made not only in the sophistication of inhibitor design for gene fusions, but also in the genomic testing technologies necessary for identification of gene fusions. As a result, we’re now able to uncover new gene fusions that are likely to be driver alterations, design therapies to target them, and identify the patients that are most likely to benefit more quickly and efficiently than ever. Clinical trials can now be designed and efficiently enrolled for these specific, genomically defined patient populations. By matching the right patient with the right therapeutic, we are now improving the low probability of technical success, historically associated with oncology clinical trials.
The result is a compelling string of advancements in targeted therapies. Since 2018, we’ve seen the accelerated approvals for therapies targeting NTRK fusions, ROS1 fusions, and RET fusions. When I consider these approvals in terms of the new patient populations that now have the potential to benefit from precision medicines specifically matched to their tumor type, it is incredibly uplifting and inspiring.
The promise of precision medicines
The growing momentum behind gene fusions as promising therapeutic targets is supported not only by the number of recent accelerated approvals, but by clinically meaningful data.
Of note, these recent approvals have been characterized by high objective response rates (ORR), the proportion of patients who have a partial or complete response to therapy. For example, selpercatinib demonstrated a 64% ORR in previously treated patients, and 85% ORR in treatment-naïve patients with advanced RET-fusion positive NSCLC.1 Entrectinib demonstrated a 78% ORR in ROS1 fusion-positive NSCLC patients.2 In patients with any NTRK fusion-positive solid tumor, entrectinib and larotrectinib achieved an ORR of 57% and 75%, respectively.2,3
Not only are we seeing clinical responses in the majority of patients treated, the responses appear to be durable. While data continues to mature and median duration of response has not yet been reported for many of these studies, the available data suggests that the majority of responses last over 9 months, with some continuing past 2 years.1,2,3
These trends are exciting. Importantly, they suggest that as an industry we are getting increasingly better at identifying the “right” biomarkers that uniquely define a patient’s tumor, and at using them to match patients with the drugs from which they’re most likely to benefit. This is the promise of precision medicine in oncology, and gene fusions appear to be targets at the leading edge.
Improving patient outcomes is critical and unquestionably job number one. However, the advancements gained from studying gene fusions haven’t stopped there.
In 2017, pembrolizumab received the first tumor-agnostic approval ever using the aggregate biomarker measure of microsatellite instability (MSI). This marked the beginning of a potentially groundbreaking paradigm shift towards clinical treatment decisions based on a tumor’s genomic signature rather than tissue of origin or histology.
With the 2018 and 2019 approvals of larotrectinib and entrectinib for any solid tumor with an NTRK fusion, the single data point became a trend. Not only that, the NTRK inhibitors represent the first tumor-agnostic approvalsever granted in a population defined by a single biomarker.
This ability to achieve high response rates and durable responses across multiple tumor types defined by a single biomarker supports the hypothesis that gene fusions, though relatively rare, may be true oncogenic drivers whenever they are found. More than ever, gene fusions appear to be critical targets for precision medicines in oncology.
The next summit: NRG1 fusions
NRG1 fusions have emerged as another druggable gene fusion that carries that hallmark of a true oncogenic driver across multiple solid tumors.4,5,6,7,8 Importantly, when NRG1 fusions are found, they appear to be mutually exclusive with other known driver alterations.8,9 This increases the likelihood for NRG1 fusions to be another biomarker that can uniquely define a patient’s tumor in a tumor-agnostic way.
At Elevation Oncology, we are excited to build on the proven history of gene fusions in oncology and the growing potential for tumor-agnostic development (Figure 2). We are currently developing the investigational anti-HER3 mAb seribantumab for solid tumors driven by an NRG1 fusion in the Phase 2 CRESTONE study, now open and enrolling patients across the US.
Therapies targeting gene fusions have repeatedly changed the treatment landscape in oncology over the last 20 years, and our industry understanding of the oncogenic potential of gene fusions only continues to grow. At Elevation Oncology, we believe that collaboration between drug developers and diagnostic providers is key to continuing to unlock opportunities in targeting genomic driver alterations. Our partnerships today power patient enrollment in our ongoing Phase 2 CRESTONE study targeting the NRG1 fusion, and we look forward to many more opportunities for collaboration to come.
While gene fusions may be rare, it seems clear that they deserve the attention of researchers in the precision medicine space. We look forward to what the next 20 years of study will bring as genomic testing continues to grow and we unlock therapeutics that make genomic testing results actionable!
1. FDA, RETEVMO™ (selpercatinib) Package Insert, 05/2020
2. FDA, ROZLYTREK™ (entrectinib) Package Insert, 08/2019
3. FDA, VITRAKVI®(larotrectinib) Package Insert, 11/2018
4. Muscarella, L. A. & Rossi, A. NRG1: a cinderella fusion in lung cancer? “. Lung Cancer Manag 6, 121–123 (2018).
5. Russo, A. et al. NTRK and NRG1 gene fusions in advanced non-small cell lung cancer (NSCLC). Precision Cancer Medicine 3, 14–14 (2020).
6. Fernandez-Cuesta, L. & Thomas, R. K. Molecular pathways: Targeting nrg1 fusions in lung cancer. Clinical Cancer Research 21, 1989–1994 (2015).
7. NRG1 Fusions Hold Promise as Pan-tumor Target. https://www.onclive.com/view/nrg1-fusions-hold-promise-as-pan-tumor-target.
8. Jonna et al., Detection of NRG1 Gene Fusions in Solid Tumors. Clin Cancer Res. 2019 Aug 15;25(16):4966-4972.
9. Jones et al., NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma. Clin Cancer Res. 2019 Aug 1;25(15):4674-4681.
|ALK||anaplastic lymphoma kinase|
|BCR-ABL1||breakpoint cluster region protein-abelson murine leukemia|
|COL1A1-PDGFRB||collagen type I alpha 1-platelet-derived growth factor beta chain|
|FIP1L1-PDGFRA||factor interacting with PAPOLA And CPSF1- platelet-derived growth factor receptor-alpha|
|NTRK||neurotrophic tyrosine receptor kinase|
|PDGFR||platelet-derived growth factor receptors|
|RET||REarranged during Transfection|
|ROS1||ROS Proto-Oncogene 1|