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

Lisa Astor
Published: Saturday, Jan 26, 2019

“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.

“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.

BRAF-Targeted Therapy

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

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.

NTRK-Targeted Therapy

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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