Treatment Options Expand for ROS1, BRAF, and NTRK Alterations in NSCLC

Christina S. Baik, MD, MPH

The scope of targeted therapies has extended more in non—small cell lung cancer (NSCLC), especially with the recent FDA approval of larotrectinib (Vitrakvi) for patients with NTRK gene fusions irrespective of the primary tumor type. A growing focus on smaller oncogenic drivers in lung cancer has opened up new treatment options and many potential drugs in development for patients with less common alterations.

ROS1-Targeted Therapy

During a presentation at the 16th Annual Winter Lung Cancer Conference, Christina S. Baik, MD, MPH, discussed several existing and emerging treatment options for ROS1, BRAF, and NTRK genetic aberrations.ROS1 translocations or rearrangements occur in about 1% to 2% of patients with NSCLC, and usually only in those with a nonsquamous histology. Baik explained that ROS1-rearranged NSCLC usually occurs in younger patients who are never smokers.

Currently, only crizotinib (Xalkori) is FDA-approved for the treatment of patients with ROS1-positive NSCLC. However, Baik said that patients with ROS1 will eventually develop resistance to crizotinib and progress, requiring further treatment. The reasons for disease progression on crizotinib are typically either central nervous system (CNS) failure or acquired resistance, which develops in about 50% to 60% of patients.

A phase II East Asian study looking at the efficacy of crizotinib in patients with ROS1-altered NSCLC demonstrated an overall median progression-free survival (PFS) of 15.9 months. When PFS was reviewed in patients with and without CNS disease at baseline, the median PFS was 18.8 months in those without CNS disease and 10.2 months in patients with CNS disease.¹

Several next-generation TKIs are in development for treating patients with ROS1-altered NSCLC. Baik pointed out 2 agents that are active against CNS disease but are not reliably active against resistance mutations: ceritinib (Zykadia) and entrectinib. Ceritinib has already been approved for the treatment of patients with ALK alterations and also shows activity against ROS1.

In a phase II study of 32 patients with ROS1 rearrangements performed in Korea, ceritinib induced an objective response rate (ORR) of 67% in patients who did not receive prior treatment with crizotinib.² The study had previously looked at patients who had received prior treatment with crizotinib but no responses were seen in pretreated patients, Baik explained. The median PFS in the overall population was 9.3 months, but in crizotinib-naïve patients, the median PFS was 19.3 months.

“That’s one more important distinction that you should keep in mind, that ceritinib is active after crizotinib in ALK-positive patients, but not in ROS1-positive patients,” Baik said. “The situation where I can think about using this drug are those patients who are crizotinib naïve who have enough CNS disease where we might be thinking about whole brain radiation unless the patient wants to postpone whole brain radiation.”

Entrectinib is a TKI that is active against ALK, ROS1, and NTRK, while it is not yet FDA approved, Baik noted that it will likely be approved in the near future.

In the cohort of patients with ROS1-positive NSCLC, entrectinib demonstrated a median PFS of 19.0 months (95% CI, 12.2-36.6). Patients with CNS disease at baseline had a median PFS of 13.6 months (95% CI, 4.5-not evaluable) and those without CNS disease had a median PFS of 26.3 months (95% CI, 15.7-36.6). The ORR was 77% with an ORR in CNS disease of 55%.³

Lorlatinib, a third-generation ALK/ROS1 inhibitor with broad activity against resistance mutations, was recently FDA approved for the treatment of patients with ALK-positive NSCLC who have previously received treatment with a second-generation ALK TKI. Baik noted that in ROS1-rearranged NSCLC, lorlatinib is active against both CNS disease and resistance mutations.

In the ROS1 cohort of a phase II trial, lorlatinib induced an ORR of 26.5% (95% CI, 12.9%-44.4%) among 34 crizotinib-pretreated patients, with stable disease also seen in 47.1% of patients.⁴ The median PFS was 8.5 months (95% CI, 4.4-18.0), and the median duration of response was not yet reached. Additionally, the intracranial ORR was 52.6% among 19 patients with CNS disease. Baik also pointed to repotrectinib, DS-6051b, brigatinib (Alunbrig), and cabozantinib (Cabometyx), all of which have shown preclinical activity for treating patients with ROS1 rearrangements.

“There are a number of drugs that are showing very compelling preclinical data but we really don’t have enough clinical data for us to really comment at this point, from a clinical practice standpoint,” Baik noted. She said that as of now, she treats patients with ROS1 rearrangements in the first line with crizotinib as it is well tolerated and most patients will have long disease control with this agent.

BRAF-Targeted Therapy

“When patients progress, I generally try to get them access to lorlatinib,” she said. However, when she is unable to get access to lorlatinib for the patient, she said that she will give ceritinib if they have CNS-only progressive disease.Although the proportion of BRAF mutations in NSCLC is approximately 3% to 5% overall, there are only clinical trial data available in NSCLC for BRAF V600E mutations, which make up approximately 1% to 2% of NSCLCs. Baik noted that while BRAF V600E mutations are mostly seen in adenocarcinomas, there are no further associations with clinical characteristics such as age or smoking history. “I think that this is a patient population where we really do need to make an effort to test everyone, regardless of smoking history,” she said.

Unlike with most other oncogene-driven lung cancers, BRAF V600E requires a combination approach of both BRAF and MEK inhibition, Baik said. Treatment with dabrafenib (Tafinlar) monotherapy for patients with BRAF V600E—mutant advanced NSCLC showed a modest ORR of 33% (95% CI, 23%-45%) and a median PFS of 5.5 months (95% CI, 3.4-7.3) in a phase II trial of 84 patients.⁵ “There is efficacy [with BRAF inhibitor monotherapy], but not at the level that we’ve come to expect from our targeted therapies,” she commented.

Alternatively, dabrafenib in combination with trametinib (Mekinist) demonstrated an ORR of 63% (95% CI, 49%-76%) and a median PFS of 9.7 months (95% CI, 7-20) in previously treated patients with BRAF V600E—mutated NSCLC.5 The rates were similar among treatment-naïve patients with an ORR of 64% (95% CI, 46%-79%) and a median PFS of 10.4 months by investigator assessment.⁶

NTRK-Targeted Therapy

The combination was approved for the treatment of patients with BRAF V600—positive advanced or metastatic NSCLC in June 2017. Yet, Baik noted that the toxicity profile is a bit more challenging with this combination with a notable rate of grade 1/2 pyrexia seen in 53% of patients, which is more difficult to manage.Baik called NTRK the “newest kid on the block” in terms of oncogenic drivers in NSCLC. She explained that there can be NTRK alterations and NTRK fusions, and the fusions are the really important oncogenic alterations that oncologists should care about. In NSCLC, the frequency of NTRK fusions is approximately 1% to 3%.

Larotrectinib was FDA approved in November 2018 for the treatment of adult and pediatric patients with an NTRK genetic fusion without a known acquired resistance mutation. The approval was based on data from 3 phase I/II clinical trials which collectively demonstrated an ORR of 80% (95% CI, 67%-90%) by investigator assessment.⁷ There were 4 patients with lung cancer in the published study, and each of these patients achieved at least stable disease, Baik said.

She said that larotrectinib is a “very active drug that is quite durable in terms of disease control, and it is very well tolerated.” There were very few grade 3/4 treatment-related adverse events recorded in the study, including most frequently increased AST/ALT levels.

Other NTRK inhibitors currently in development include entrectinib, repotrectinib, and DS-6051b. “Now that we have 5 targets [with approved targeted therapies in lung cancer], and more to come, I think this really underscores the importance of comprehensive tumor genomic testing,” Baik concluded.

References

1. Wu YL, Yang JC, Kim DW, et al. Phase II study of crizotinib in east asian patients with ROS1-positive advanced non-small-cell lung cancer. J Clin Oncol. 2018;36(14):1405-1411. doi: 10.1200/JCO.2017.75.5587.
2. 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.
3. Doebele R, Ahn M, Siena S, et al. Efficacy and safety of entrectinib in locally advanced or metastatic ROS1-positive non-small cell lung cancer. Presented at: 2018 World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract OA02.01.
4. Ou S, Shaw A, Riely G, et al. Clinical activity of lorlatinib in patients with ROS1+ advanced non-small cell lung cancer: phase 2 study cohort EXP-6. Presented at: 2018 World Conference on Lung Cancer; September 23-26, 2018; Toronto, Canada. Abstract OA02.03.
5. Planchard D, Kim TM, Mazieres J, et al. Dabrafenib in patients with BRAF(V600E)-positive advanced non-small-cell lung cancer: a single-arm, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(5):642-650. doi: 10.1016/S1470-2045(16)00077-2.
6. Planchard D, Smit EF, Groen HJM, et al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017;18(10):1307-1316. doi: 10.1016/S1470-2045(17)30679-4.
7. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi: 10.1056/NEJMoa1714448.

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