Josephine L. Feliciano, MD
Clinical familiarity with driver mutations, including BRAF V600
, 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,
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-
-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.
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.
OncLive: What therapies are available for some of these uncommon mutations?
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.
Are therapies in melanoma also successful in NSCLC?
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.
What options are available for those with ROS1 fusions?
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