Rare Drivers Emerge as Successful Targets in NSCLC

Alexander Drilon, MD

Although rare, alterations in MET, RET, and NTRK are showing significant responses to investigational targeted therapies, several of which have already been granted FDA approval or are on track to receive it, explained Alexander E. Drilon, MD.

In May 2018, the FDA granted crizotinib (Xalkori) a breakthrough therapy designation for patients with metastatic non—small cell lung cancer (NSCLC) who harbor MET exon 14 alterations.

Moreover, the investigational agent capmatinib showed a 72% overall response rate (ORR) as frontline therapy in patients with MET exon 14 skipping mutations in the phase II GEOMETRY mono-1 trial.¹ In previously treated patients, the ORR was 39.1%.

“The MET space is moving forward very quickly,” said Drilon. Additionally, LOXO-292 and BLU-667 are 2 potent and specific RET inhibitors that have shown impressive efficacy for patients with RET fusions. In September 2018, LOXO-292 received a breakthrough therapy designation from the FDA for the treatment of patients with RET-fusion—positive NSCLC, RET fusion—positive thyroid cancer who require systemic therapy, or RET-mutant medullary thyroid cancer.² Regarding BLU-667, the agent showed an ORR of 37% in the phase I ARROW trial.³

NTRK is another emerging target of interest, for which there are currently 2 targeted therapies under investigation: larotrectinib and entrectinib. The FDA granted an approval to larotrectinib in November 2018 for adult and pediatric patients with locally advanced or metastatic solid tumors with an NTRK gene fusion. Moreover, a pooled analysis presented at the 2018 ESMO Congress revealed that of 54 evaluable patients with advanced solid tumors harboring a NTRK fusion, 57.4% responded to entrectinib.⁴

OncLive: Beyond EGFR, ALK, and ROS1, what other biomarkers are emerging in the NSCLC space?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Drilon, a medical oncologist at Memorial Sloan Kettering (MSK) Cancer Center, discussed the emerging targetable biomarkers in NSCLC and the investigational therapies designed to target them.Drilon: Several other biomarkers are paired to match targeted therapies. The first group are the MET exon 14 alterations; these are found in about 4% of patients with NSCLC and have a frequency that is very similar to ALK in some series. These mutations result in activation of the MET pathway, and fortunately, they’re amenable to targeted therapy with MET inhibitors. Several MET inhibitors were in development when we detected these exon 14 alterations in clinical samples, so trials evolved very rapidly. Now, we have data on crizotinib, capmatinib, and tepotinib; capmatinib and tepotinib are selective inhibitors, whereas crizotinib is a multikinase inhibitor. Across the board, the response rates are about 30%; these rates are not quite what we’re used to seeing for EGFR, ALK, ROS1, and BRAF combination therapies.

What is the rationale for exploring a MET inhibitor in combination with an EGFR inhibitor?

However, there was a recent report on the use of capmatinib in TKI-naïve patients, which showed a response rate that exceeded 70%. We’re not quite sure how durable those responses are, but it’s something to look forward to. Crizotinib now has a breakthrough designation from the FDA. We hope to see some type of approval for this genomic subset in the future.There are 2 major states for MET activation in cancer. The cancer can either be dependent on MET alone—as is the case with de novo MET amplification or MET exon 14 alterations—or cancers can acquire dependence on MET even when they have another primary driver, such as EGFR. When we used a first- or second-generation EGFR TKI for an EGFR-mutant lung cancer, we saw the emergence of MET amplification. Even osimertinib (Tagrisso) showed a substantial number of patients who had MET amplification.

What is the importance of next-generation sequencing (NGS) in finding these mutations for which there are now targeted therapies?

Several programs have looked at the combination of a MET inhibitor and an EGFR inhibitor. It seems like the combination can work for select subgroups of patients. In the same way that we saw for de novo MET amplification, the higher the degree of amplification, the higher the likelihood of response. It’s a similar trend that you see when you use an EGFR inhibitor and a MET inhibitor: Patients with the highest proclivity for response are those whose cancers are highly amplified. It’s a matter of selecting cases that might benefit from this combination therapy.NGS is certainly much more widely adopted now compared with before. The problem is that those who don’t have a lot of time to reflect on the best possible test will use any NGS test, and these NGS tests can be very different. There are 2 major strategies: amplicon-based testing and hybrid capture. At MSK, we use a hybrid capture-based NGS, which is probably better at detecting a wider variety of actionable alterations.

What is the most important thing to know about these emerging biomarkers?

There are a few NGS tests that are authorized or approved by the FDA. The test that we use at our center is called MSK-IMPACT; that [test] has FDA authorization. Then, there’s the FoundationOne assay, which can also be used as a companion diagnostic to select appropriate patients for a particular targeted therapy. In selecting an NGS assay, you need to be very thoughtful about whether or not it’s poised to detect not just regular mutations, but also fusions. Additionally, [you need to consider whether the assay is] good at [detecting] copy number changes and if it has the breadth to detect any possible alteration, not just in lung cancer but also in other solid tumors where you might find these changes.There are several other emerging biomarkers in addition to MET activation. Some of these fusions are similar to ALK and ROS1. For example, RET fusions are found in up to 2% of patients with NSCLC. We had older multikinase inhibitors that had modest activity, but there were issues with tolerability.

Last year, we saw the entry of more selective RET inhibitors into the clinic. Data on both of those drugs—BLU-667 and LOXO-292—have read out. We’re seeing response rates ranging from 50% up to 70%. Beyond that, we’re also seeing a much- improved tolerability profile. LOXO-292 has already achieved a breakthrough therapy designation by the FDA—not just in lung cancers, but also in thyroid cancers where there is RET activation—not by rearrangement or fusions, but by mutations. There are also NTRK fusions or rearrangements, which have a very interesting distribution. We’re seeing that they’re found at a very high frequency in some rare cancers, such as salivary cancers or breast cancers, but also at a lower frequency across many other solid tumors, like lung cancers. Two major first-generation TRK inhibitors are currently in development: entrectinib and larotrectinib. We heard updated data from both of these drugs at the 2018 ESMO Congress.

With entrectinib, we’re seeing a response rate of about 57% across any solid tumor that harbors an NTRK fusion. With larotrectinib, an updated data set beyond what was published in the New England Journal of Medicine showed an 80% response rate. [Entrectinib has an] FDA breakthrough designation status [and larotrectinib has received approval] for the treatment of any solid tumor that harbors an NTRK fusion; this is similar to the pembrolizumab (Keytruda) approval for any solid tumor that harbors a microsatellite instability—high signature. If 1 of these drugs gets approved soon, it’ll be a landmark approval because it will be the first time a regulatory agency approves a targeted therapy for a molecular signature regardless of what the cancer looks like under the microscope.

References

1. Novartis phase II GEOMETRY mono-1 trial of investigational medicine capma- tinib (INC280) shows positive results in patients with MET mutated advanced NSCLC [news release]. Basel, Switzerland: Novartis; October 19, 2018. https://bit.ly/2CzwAno?rel=0" . Published October 19, 2018. Accessed November 16, 2018.
2. Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin Oncol. 2018;36(suppl; abstr 102). doi: 10.1200/JCO.2018.36.15_suppl.102.
3. Subbiah V, Taylor M, Lin J, et al. Highly potent and selective RET inhibitor, BLU- 667, achieves proof of concept in a phase I study of advanced, RET-altered solid tumors. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, IL. Abstract CT043. doi: 10.1158/1538-7445.AM2018-CT043.
4. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. In: Proceedings from the 2018 ESMO Congress; October 19-23, 2018; Munich, Germany. Abstract LBA17. doi: 10.1093/annonc/ mdy424.017.