Targeted Therapies Continue to Show Potential for Less Common Drivers in NSCLC

Josephine L. Feliciano, MD, discusses established and emerging therapeutic developments for patients with non–small cell lung cancer with less common driver mutations.

Josephine L. Feliciano, MD

Clinical familiarity with driver mutations, including BRAF V600 and ROS1, continues to grow as seen with FDA approvals of novel therapies, according to Josephine L. Feliciano, MD, an assistant professor of oncology at Johns Hopkins Medicine. Other molecular targets, including RET, MET, and NTRK, continue to be explored with new agents.

For example, patients with BRAF V600—positive advanced or metastatic non–small cell lung cancer (NSCLC) are eligible to receive the combination of dabrafenib (Tafinlar) and trametinib (Mekinist). In a phase II study, both treatment-naïve (n = 36; 95% CI, 43.5%-76.9%) and previously treated patients (n = 57; 95% CI, 49%-76%) with BRAF V600 positivity demonstrated equally impressive overall response rates of 61.1% and 63.0%, respectively, at a median follow-up of 9 months. Additionally, durable responses were seen, with a median duration of 12.6 months (95% CI, 6.9-16.0).1 Based on these data, the FDA approved the combination in June 2017.

Following suit are tyrosine kinase inhibitors (TKIs) such as crizotinib (Xalkori) and ceritinib (Zykadia), which have demonstrated success in patients with both ALK translocations and ROS1 mutations. Moreover, in May 2018, the FDA granted crizotinib a breakthrough therapy designation for the treatment of patients with metastatic NSCLC with MET exon 14 alterations who progress after receiving platinum-based chemotherapy. For those who develop resistance, Feliciano noted that lorlatinib seems to hold the most promise. In a phase I doseescalation study, patients with ALK- or ROS1-positive NSCLC were given doses of lorlatinib ranging from 10 mg to 200 mg once daily or 35 mg to 100 mg twice daily. Of the 12 patients with ROS1-positive NSCLC, 6 demonstrated an objective response.2

Although patients with RET mutations do not yet have an FDA-approved therapy, impressive data were presented at the 2018 ASCO Annual Meeting on the highly selective RET inhibitor LOXO-292. Data from the phase I LIBRETTO-001 study indicated an objective response rate (ORR) of 77% (95% CI, 58%-90%) for patients with RET fusion—positive NSCLC. No patients had progressed at the April 2018 cutoff, and all patients with measurable intracranial lesions responded to therapy.3 In September 2018, the FDA granted LOXO-292 a breakthrough therapy designation for the treatment of patients with RET fusion—positive NSCLC or RET-mutant medullary thyroid cancer.

Another selective RET inhibitor, BLU-667, demonstrated promise in the phase I ARROW trial.4 Results of the trial showed an ORR of 50% in patients with NSCLC (n = 14), consisting of 5 confirmed partial responses (PRs) and 2 unconfirmed PRs.

Another target is NTRK. In May 2018, the FDA granted a priority review to a new drug application for larotrectinib for the treatment of adult and pediatric patients with locally advanced or metastatic solid tumors with an NTRK gene fusion.

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What options are available for those with ROS1 fusions?

Ongoing research continues to foster the development of novel therapies, and in an interview during the 2018 OncLive® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Feliciano spoke about both established and emerging therapeutic developments for patients with less common driver mutations, also acknowledging the importance of rebiopsying in directing therapy decisions.Feliciano: BRAF V600 [is a] mutation that is also found in other cancers, such as melanoma and cholangiocarcinoma. The study I focused on [in my presentation] included both a BRAF and MEK inhibitor—dabrafenib and trametinib for patients with BRAF V600—positive NSCLC. Essentially, that combination was approved by the FDA for patients with BRAF V600 mutations based on very high response rates.Yes. What we are also seeing is that many of these drugs and trials are starting to become less cancer-specific. They’re starting to incorporate broader categories of malignancies, but with the same driver mutation.ROS1 is a mutation similar to an ALK translocation. It has a similar configuration in the receptor. Many of the TKIs that are effective for ALK are similarly effective for ROS1. Crizotinib is approved for patients with ROS1 mutations. It’s effective, has high response rates, and has long durations of response for NSCLC. This mutation occurs in about 1% of NSCLC and tends to be mutually exclusive of ALK translocations.

Are there emerging therapies for RET?

What research exists for patients with MET abnormalities?

Are there agents for patients with NTRK mutations?

Is there potential for combinations of targeted therapy and immunotherapy?

What is the biggest challenge in practice?

Other ALK inhibitors, such as ceritinib, have been studied and show high response rates. Those aren’t the only 2 [showing promise]. Lorlatinib is a later-generation TKI that has been shown to be effective in tumors that have become resistant to crizotinib. Common secondary mutations can develop [while patients are] on most of these drugs; therefore, we’re now starting to develop regimens for resistance mutations.RET does not have an FDA-approved regimen yet. However, 2 drugs were presented recently: LOXO-292 and BLU-667. Both of those have also shown efficacy in RET-mutated tumors with significant response rates, including in the brain. In lung cancer, many patients have progression in the brain, so the ones with central nervous system penetration have been of interest.For MET, there can be MET amplification or MET exon 14 skipping mutation. At the 2016 ASCO Annual Meeting, they presented the data from a study called PROFILE 1001. It looked at patients with MET exon 14 mutations as well as MET amplifications. Essentially, they found that crizotinib was an effective therapy in patients with a skipping mutation. Then, a separate analysis based on MET amplification also demonstrated efficacy in patients who overexpressed MET.NTRK is another mutation, and there are a couple of drugs that are being studied. The one that I briefly spoke about is entrectinib. It also has activity against ROS1 and ALK. NTRK fusions are rare, but they can be found not just in adenocarcinomas but in other histologies. Entrectinib showed efficacy in a few patients with NTRK mutations in a study looking at patients with NTRK, ALK, or ROS1. [Patients with NTRK were] the minority, but there were some patients with NSCLC who did respond to the drug.That is probably a potential [strategy] to be studied in the future. Right now, targeted therapy is the preferred regimen prior to currently approved regimens for immunotherapy for those patients with driver mutations.Although we have made a significant amount of progress in the last decade for targeted therapies and identifying driver mutations with potential targets, [only] a minority of patients have an actionable mutation. Many patients, even if they do have a driver mutation, develop resistance.

Why are molecular profiling and rebiopsy important?

Even before that, a big challenge is identifying those patients. An unmet need is looking at how to better diagnose these patients. It can be challenging because not all institutions and testing mechanisms can necessarily identify these mutations. There is an increasing awareness of the need to rebiopsy patients and to remember to think of these possibilities when diagnosing the patient.Molecular profiling has become standard of care, particularly in NSCLC. We are seeing an increased understanding that perhaps this will also extend to every histology of NSCLC. We also have to recognize the importance of adequacy of tissue, which can be difficult with these patients. We frequently don’t have enough tissue to perform these tests.

In terms of rebiopsy, we’re learning that many patients can develop secondary mutations to currently approved targeted therapies and that some of these secondary resistance mechanisms are also potentially targetable.


  1. Planchard D, Besse B, Groen HJM, et al. An open-label phase II trial of dabrafenib (D) in combination with trametinib (T) in patients (pts) with previously treated BRAF V600E—mutant advanced non-small cell lung cancer (NSCLC; BRF113928). J Clin Oncol. 2016;34(suppl 15; abstr 107). doi: 10.1200/JCO.2016.34.15_suppl.107.
  2. Shaw AT, Felip E, Bauer TM, et al. Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial. Lancet Oncol. 2017;18(12):1590-1599. doi: 10.1016/S1470- 2045(17)30680-0.
  3. 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).
  4. 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, Illinois. Abstract CT043.