Expert Discusses Potential Breakthroughs in ROS1+ and BRAF+ NSCLC

Sai-Hong Ignatius Ou, MD, PhD, discusses the current landscapes of ROS1-positive and BRAF-mutant non–small cell lung cancer.

Sai-Hong Ignatius Ou, MD, PhD

The treatment of patients with non—small cell lung cancer (NSCLC) was revolutionized with the discovery of targetable mutations more than a decade ago. Although many agents have been approved in the ALK-positive NSCLC landscape since then, other targets, such as ROS1 and BRAF, are under investigation in a new age of targeted therapies, said Sai-Hong Ignatius Ou, MD, PhD.

In a presentation during the 2018 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, broke down the current landscapes of ROS1-positive and BRAF-mutant NSCLC.

Approximately 2% of all patients with NSCLC have a ROS1 alteration, and about 1% to 3% of patients are positive for the BRAF V600E mutation. Historically, each of these subtypes have been considered to have a poor prognosis.

ROS1-Rearranged NSCLC

Currently, the only FDA-approved next-generation sequencing (NGS) test to detect both ROS1 and BRAF mutations is the Oncomine Dx Target Test. This assay was approved in June 2017 for detection of BRAF, EGFR, and ROS1 alterations. Although it is a 23-gene panel, it can only be used to test for these 3 alterations, based on the FDA’s indication, explained Ou.The ROS1-rearrangement was discovered in lung cancer around the same time as ALK in 2007. This receptor tyrosine kinase fusion is also seen in other tumor types such as brain, breast, soft tissue, skin, stomach, and ovarian cancer. All receptor tyrosine kinase fusions have fusion partners, said Ou, adding that there are about 13 fusions partners established for ROS1.

“We all figured that not all [of] the fusion partners will be the same; they locate differently in the cells and they may have different functions. It is a heterogeneous disease, and in the next decade, through NGS, we can understand the fusion partners much closer than just calling it ROS1-positive NSCLC,” said Ou.

ROS1 can be targeted through a few inhibitors. The agents that have been tested in phase II clinical trials include ropotrectinib (TPX-0005), lorlatinib, DS-6051b, entrectinib, crizotinib (Xalkori), and ceritinib (Zykadia). Cabozantinib (Cabometyx) and brigatinib (Alunbrig) have been evaluated in phase I studies. Crizotinib is the only ROS1 kinase inhibitor that is FDA approved for this population.

Crizotinib was approved in March 2016 based on data from a 50-patient experience. Findings of this phase I study demonstrated on overall response rate (ORR) of 72%, with more than a 17-month median duration of response, as determined by independent review.1

Ou explained that patients with ROS1-rearranged lung cancer do very well on crizotinib compared with patients who have ALK-positive NSCLC.

ROS1 is a very good prognostic biomarker, but eventually patients do progress. We do not have as many inhibitors for ROS1 as there are for ALK, in terms of second- and third-generation [agents]. However, [they are] coming in a few years,” Ou said. Although crizotinib is currently the only FDA-approved agent for the treatment of patients with ROS1-positive NSCLC, there are several drugs under evaluation, with data coming out later this year.

In data presented at the 2018 ASCO Annual Meeting, ropotrectinib, a next-generation ROS1 inhibitor, was found to be well tolerated and exhibited both intra- and extracranial clinical activity in tyrosine kinase inhibitor-refractory ROS1-positive and NTRK-positive patients with solvent front mutation— containing tumors.2

Additionally, there is a cohort of patients with ROS1-positive disease in a trial of lorlatinib, and both ceritinib and brigatinib have data impending. Ou noted that entrectinib may be approaching FDA approval as well.

Lorlatinib data were presented at the 2017 IASLC World Conference on Lung Cancer. There were 47 patients enrolled in the ROS1 cohort. Regardless of prior treatment, the ORR for ROS1-positive patients was 36% (17/47; 95% CI, 23%-52%) and the intracranial ORR was 56% (14/25; 95% CI, 35%-76%).3

Ou said that the problems with this study are that it was only in 47 patients and the agent does not have a fast track designation. “We will see what the path of getting lorlatinib is when its approved; it will probably be an off-label use.”

Ceritinib is another inhibitor under investigation in this patient population. In a Korean study of 30 TKI-naïve patients, there was a promising response rate (62%), with a median progressionfree survival of 19.3 months.4 Ou said that since this study was smaller, he is unsure if it will be enough data for an FDA approval.

Brigatinib has been tested in a small study of patients with ROS1-rearranged NSCLC, and the results showed 1 partial response, 1 patient with stable disease, and 1 with progressive disease.5 Ou said he is not convinced that brigatinib will move forward in development.

Data from entrectinib were also presented at the 2017 IASLC World Conference on Lung Cancer. By blinded independent central review, the ORR was 68.8%, which included 2 complete responses (6.3%).6 There was also activity demonstrated in the central nervous system (CNS), investigators noted. For those with measurable CNS lesions at baseline, the intracranial ORR was 83.3%.

“[Entrectinib] has better CNS penetration than crizotinib. It will most likely be approved by the FDA later this year or next year,” said Ou.

BRAF V600E Mutations

Updated data for DS-6051b, TPX-0005, ensartinib, and brigatinib are expected to come out in 2018. “The field will hopefully be a little clearer in the future,” said Ou.BRAF V600E mutations are not fully understood yet, Ou explained. Although, the June 2017 FDA approval of the combination of dabrafenib (Tafinlar) and trametinib (Mekinist) in patients with advanced and metastatic disease signifies a step forward.

This combination showed significant clinical activity in previously treated patients with BRAF V600E-positive NSCLC, said Ou. However, not much is known about the resistance mechanism. The ORR was 61.1% (95% CI, 43.5%-76.9%) in the treatment-naïve group, and 68% of patients did not show progression at a median follow-up of 9 months.7 In the previously treated cohort, the ORR was 63% (95% CI, 49%-76%).

“The FDA approval of dabrafenib plus trametinib is independent of line of therapy. The response rates are very similar in the frontline and second-line [settings],” said Ou. “Resistance is harder to understand. It may be chemotherapy [plus] immunotherapy down the road for these patients, like everything else.”

Like ROS1, Oncomine Dx is approved for the detection for BRAF V600E mutations. However, the FDA approved FoundationOne CDx in November 2017 for the detection of BRAF V600E mutations, in addition to EGFR and ALK mutations and 19 deletions.

Although these 2 molecular aberrations tend to have a poorer prognosis, Ou said he is confident that upcoming data will uncover more about how to treat patients with ROS1 rearrangements and BRAF V600E mutations.


  1. Shaw AT, Ou S-HI, Bang Y-J, et al. Crizotinib in ROS1-rearranged non—small-cell lung cancer. N Engl J Med. 2014;371(21):1963-1971. doi:10.1056/NEJMoa1406766.
  2. Drilon AE, Ou S-H I, Cho BC, et al. A phase 1 study of the next-generation ALK/ ROS1/TRK inhibitor ropotrectinib (TPX-0005) in patients with advanced ALK/ROS1/ NTRK+ cancers (TRIDENT-1). J Clin Oncol. 2018;36(suppl; abstr 2513). abstracts.asco. org/214/AbstView_214_214997.html.
  3. Solomon BJ, Shaw A, Ignatius Ou S-H, et al. Phase 2 study of lorlatinib in patients with advanced ALK+/ROS1+ non-small-cell lung cancer. In: Proceedings from the the IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8573.
  4. Lim SM, Kim HR, Lee JS, et al. Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement. J Clin Oncol. 2017;35(23):2613-2618. doi: 10.1200/JCO.2016.71.3701.
  5. Gettinger SN, Bazhenova LA, Langer CJ, et al. Activity and safety of brigatinib in ALK-rearranged non-small-cell lung cancer and other malignancies: a single-arm, open-label, phase 1/2 trial. Lancet Oncol. 2016;17(12):1683-1696. doi: 10.1016/S1470-2045(16)30392-8.
  6. Ahn M-J, Cho BC, Siena S, et al. Entrectinib in patients with locally advanced or metastatic ROS1 fusion-positive non-small cell lung cancer (NSCLC). In: Proceedings from the IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8564. final-slides_v2.pdf.
  7. 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; abstr 107).