Therapies Moving Though Pipeline for Rare Mutations in NSCLC

Caroline Seymour

Dr. Sai-Hong Ignatius Ou

Sai-Hong Ignatius Ou, MD, PhD

In non–small cell lung cancer (NSCLC), KRAS G12 mutations have been historically difficult to target, and research efforts dedicated to the development of effective targeted therapies for NRG1 fusions have not been successful. However, several biopharmaceutical companies are in the early stages of addressing that challenge, explained Sai-Hong I. Ou, MD, PhD.

KRAS has been a mutation that we have had difficulty targeting for the last 30 to 40 years. In the last half year, however, 2 companies have made a direct KRAS G12C inhibitor,” said Ou. “On average, NRG1 fusions occur in about 0.2% to 0.3% of cancers. They’re [extremely] rare, but given the success of targeting NTRK fusions, we'll overcome the challenge of finding these NRG1 fusions.”

In addition to these alterations, Ou explained that EGFR exon 20 insertions and HER2 transmembrane domain mutations, albeit rare, are likely to gain therapeutic traction in the coming years as well. 

In an interview during the 2019 OncLive® State of the Science Summit™ on Non–Small Cell Lung Cancer, Ou, professor, Division of Hematology/Oncology, Department of Medicine, University of California Irvine School of Medicine, discussed the status of these mutations in lung cancer and the work being done to bring clinically meaningful treatments to the space.

OncLive®: What is known about KRAS mutations?

Ou: Now, we have 2 direct KRAS G12C inhibitors. One is from Amgen and is called AMG 510. The other is from Mirati Therapeutics, and the compound is called MRTX849. Both compounds are covalent KRAS inhibitors; they bind to the mutated glycine cystine and they only target G12C mutations at this point. By binding to G12C, the compounds try to shift the active form of KRAS to the inactive form. We may hear some data on these agents at the 2019 ASCO Annual Meeting; we'll definitely hear data by the end of 2019. Those agents are very exciting. This is one of the first times we're trying to target KRAS, and we may be successful.

There is also a SHIP2 inhibitor that is targeting the GDP and GTP exchange factors. Those [inhibitors] are not specific to KRAS G12C; they can target all the G12 mutations, including G12A, which is also in lung cancer, as well as G12D, and other mutations. KRAS is not limited to lung cancer. Even the KRAS G12 [mutations] are not limited to lung cancer. The SHIP2 inhibitor is even broader for all the KRAS mutations. G12D mutations are usually found in invasive mucinous adenocarcinoma, the primary [site] of gastrointestinal origin. There are 2 SHIP2 inhibitors that I'm aware of that are in clinical trials. One is from Novartis called TNO155 and the other is from REVOLUTION Medicines called RMC-4630. We may also hear of some clinical activity regarding these SHIP2 inhibitors by the end of 2019.

Going forward, the strategy will be to combine a direct KRAS G12C inhibitor with a SHIP2 inhibitor. Osimertinib (Tagrisso) is a covalent binder to the EGFR protein, and the resistance mutation—usually the mutation of the cystine residue—is what is required for osimertinib to bind. Therefore, I anticipate that the mutation for the direct KRAS inhibitor will also be in the cystine residue; that would knock out the binding through the KRAS protein itself. A combination approach will be the key of immunotherapy with other downstream TKIs or SHIP2 inhibitors. There will be many variations down the road, but it's important to see single-agent activity so that [researchers] are confident to go ahead with combination trials. 2019 is an exciting time. We anticipate great results by the end of the year. 

You also spoke about NRG1 fusions in your presentation at the State of the Science Summit. What is the work that is being done with these?

NRG1 stands for neuregulin; it's a transmembrane protein that is cleaved at the very end of the production of the protein and it contains an EGF motif. It binds to the HER3 receptor and activates the HER3 receptor. NRG1 fusions were first reported in lung cancer in 2014 by Roman Thomas of the University of Cologne along with his colleagues in Germany.

Since then, Steven Liu, MD, of MedStar Health, and colleagues, published a paper in April 2019 in Clinical Cancer Research. They did a survey of the prevalence of NRG fusions in solid tumors. They looked at the Claris database which has been [recording] RNA sequencing for the last few years. They looked at more than 20,000 tumor samples and the incidence of NRG fusions in all the major solid tumors from head and neck cancer, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, renal cell carcinoma, and even sarcoma.

NTRK fusions are also rare in incidence, but we now have 1 NTRK inhibitor that's FDA approved. We should have another coming very soon, and the next-generation NTRK inhibitors are already in clinical development. I anticipate that we’ll be able to target NRG fusions [in the future]. Additionally, Rain Therapeutics already has a compound called tarloxotinib (TH-4000), and they’re opening up a cohort specifically for patients with NRG fusions independent of tumor type very soon.

Are there any other potentially targetable alterations to be aware of?

We published a survey of the Foundation Medicine database and found HER2 transmembrane domain mutations. These mutations can act as driver mutations and are very rare, occurring in 0.15% of all lung adenocarcinomas. The paper was published in 2007 in General Forensic Oncology. We're updating the data at the 2019 World Conference on Lung Cancer in Barcelona, Spain, in September. There are now more cases of HER2 transmembrane domain mutations. We actually found some other HER3 mutations in the same coexistence that will increase the binding efficacy or the dimerization efficacy of the HER2 and HER3 protein, so stay tuned.

One of the other targets that was not described at this summit due to time constraints is EGFR exon 20 insertions. We will see some data with some of the inhibitors at the 2019 ASCO Annual Meeting, including Takeda’s compound TAK-788. There are other EGFR exon 20 insertion inhibitors such as poziotinib, for which we will have data for soon. EGFR exon 20 is an exciting target; they constitute about 5 to 10% of all EGFR mutations. For a long time, we have not had success targeting that subgroup of insertions, but this year, and going forward in 2020, [I believe] a few compounds will be FDA approved for EGFR exon 20 insertions. 
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