Emerging Findings Offer Hope With Less Common Genomic Drivers of Lung Cancer

Alexander Drilon, MD

Non—small cell lung cancer (NSCLC) is highly enriched for genomic drivers, and many are clinically actionable. Targeted therapies are currently available in the clinic to treat patients who harbor these mutations, with several that are FDA approved and more that are incorporated into the NCCN guidelines.

In a presentation during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Alexander Drilon, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed some of these drivers as well as the current treatment options for patients who harbor those mutations.

The frequency of ROS1 fusions is about half of what is seen in ALK-rearranged lung cancers. These are found in 1% to 2% of NSCLCs, mainly in young patients who are never or former light smokers, and largely found in lung adenocarcinomas. Similar to ALK, there are a variety of methods for identifying ROS1 fusions.

More comprehensive sequencing is being done in the field, said Drilon, and next-generation sequencing (NGS) can be used to identify ROS1 fusions. Fluorescence in situ hybridization can also be used, as well as select plasma assays. While there is not an equivalent for immunohistochemistry like in ALK, there are some data demonstrating that there is a good likelihood that a fusion will be found in tumors that express ROS1.

These patients can have very dramatic responses to targeted therapy, said Drilon. The multikinase inhibitor crizotinib (Xalkori) also inhibits ROS1, and in a multicenter phase I expansion cohort, 250 mg of crizotinib given twice daily induce an overall response rate (ORR) of 72% (95% CI, 0.58-0.84).¹ Of 50 patients who had ROS1 rearrangements, there were 33 partial responses. The median duration of response was 17.6 months, and the median progression-free survival (PFS) was 19.2 months.

Although crizotinib is the only FDA-approved therapy for the treatment of patients with ROS1-rearranged NSCLC, ceritinib (Zykadia) is another targeted approach showing promise. A phase II trial of ceritinib in this patient population showed an ORR of 62% (95% CI, 0.45-0.77), a median PFS of 9.3 months (95% CI, 0-22), and a median overall survival of 24 months (95% CI, 5-43).²

"You might now assume that anything that inhibits ALK also inhibits ROS1, but that is not true,” said Drilon. “A lesson here is to not automatically assume that every ALK inhibitor is a ROS1 inhibitor, because the profile of these agents can vary from target to target."

Other drugs that have shown activity in patients with lung cancer who have ROS1 rearrangements are entrectinib, cabozantinib (Cabometyx), and lorlatinib. Drilon said that a second TKI can work after a prior therapy, which has been seen with cabozantinib and lorlatinib.

RET-rearranged lung cancers have a similar frequency to ROS1-rearranged lung cancers, and they are also mutually exclusive with other major lung cancer drivers. The clinical features of RET-rearranged lung cancers mimic that of ROS1, as it is commonly found in younger patients who are never smokers or formerly light smokers with lung adenocarcinomas. Less than 10% of these tumors can harbor signet ring cells, which is similar to what is seen in ALK-rearranged lung cancers.

Targeted therapy can work for a subset of patients, Drilon said. A trial of cabozantinib in RET-rearranged lung cancers met its primary endpoint of overall response, reporting an ORR of 28% (95% CI, 0.12-0.49).³ Due to the activity shown by this multikinase inhibitor, cabozantinib was entered into the NCCN guidelines for the treatment of these patients.

"The efficacy of RET-directed multikinase inhibition is not quite where we expect to see it compared with other driver-positive subsets," said Drilon. "But there is hope for this subset, and I think that 2018 is going to be the year that we really see fantastic data, so stay tuned."

Following this presentation, phase I study findings for BLU-667 were presented at the 2018 AACR Annual Meeting. BLU-667, a next-generation tyrosine kinase inhibitor, appeared to be well tolerated and had broad clinical benefit among patients with advanced, RET-altered solid tumors who progressed on prior therapies.

The third gene fusion Drilon addressed was NTRK. An estimated 1500 to 5000 patients have TRK fusion—positive cancers annually in the United States. Although structurally similar to ALK and ROS1, TRK fusions are found across many solid tumors, not just lung cancer. Some of the histologies that are highly enriched for TRK occur largely in pediatric patients.

The approach to developing targeted therapy for NTRK-rearranged solid tumors followed a basket trial approach. As long as a patient had the appropriate target—in this case, NTRK—they could be enrolled onto the trial. The topline results of larotrectinib, published in the New England Journal of Medicine, showed an ORR of 80% (95% CI, 0.67-0.90).⁴

"This is groundbreaking because it was not in one particular tumor type," said Drilon. "If you give the appropriate targeted therapy for TRK, things can work very well in a histology-agnostic fashion."

The ROS1/TRK inhibitor entrectinib is also being explored, but has less data than larotrectinib. Both drugs have received breakthrough therapy designations from the FDA.

BRAF-mutant lung cancers occur in about 1% to 4% of NSCLCs, and 2% of lung adenocarcinomas. The phenotype is former and current smokers, although BRAF V600E-mutant tumors usually occur in patients who are light or never smokers.

Topline results from a phase II single-arm trial of dabrafenib (Tafinlar) plus trametinib (Mekinist) in BRAF V600E-mutant lung cancer demonstrated an ORR of 63%.⁵ In the trial, 150 mg of dabrafenib was given twice daily with 2 mg of trametinib. Of 57 patients with BRAF V600E-mutant NSCLC, there were 36 partial responses. This combination is now FDA approved and is the therapy of choice in the first-line setting, said Drilon.

One of the newer aberrations found in lung cancer is MET. MET exon 14-altered cancer has a unique biology, and when looking for these mutations, it is not as simple as with EGFR or BRAF, Drilon said. These are highly heterogeneous mutations, and support is needed from pathologists to determine whether a particular mutation may result in exon 14 skipping.

"When exon 14 is absent, you are missing that area on the MET receptor that is responsible for tagging MET for degradation or trashing in the proteasome," explained Drilon. "In the absence of that, you have less of the protein that is eliminated, and you have so much more of the MET receptor on the cell surface, that then drives oncogenic signaling."

MET exon 14 deletions are found in 3% to 4% of nonsquamous NSCLCs, and in 20% to 30% of sarcomatoid lung carcinomas. The clinicopathologic features include older patients and a lower proportion of never smokers. This backs the notion that there should be no discrimination when choosing whose tumors to send for comprehensive testing, Drilon said.

Crizotinib has also been studied in MET exon 14-altered NSCLC. In a multicenter phase I expansion cohort, 250 mg of crizotinib was given twice daily with the primary endpoint of overall response. The ORR was around 40%, and updated data is forthcoming.⁶ According to Drilon, this study was responsible for getting crizotinib into the NCCN guidelines.

Lastly, Drilon touched on HER2 mutations in lung cancers. HER2 mutations occur in about 2% of lung cancers, with the most common being insYVMA. Patients with this mutation tend to be younger with a minimal to no former history of smoking.

The use of ado-trastuzumab emtansine (T-DM1) has shown activity in this population. In a study of T-DM1 in HER2-mutant NSCLC, the ORR was 33%, and median PFS was 4 months. As a result of these findings, T-DM1 is now a part of the NCCN guidelines.⁷

Drilon said in his concluding remarks that the main message is to comprehensively sequence a patient's tumor with NGS whenever possible. Many of these drivers are highly actionable in the clinic, and beyond the FDA-approved agents, there are TKIs available to use as part of the NCCN guidelines. Beyond that, Drilon suggested enrolling patients on clinical trials.

References

1. Shaw AT, Ou SI, Bang YJ, et al. Crizotinib in ROS1-rearranged non—small-cell lung cancer. N Eng J Med. 2014;371:1963-1971. doi: 10.1056/NEJMoa1406766.
2. Lim MS, Kim RH, 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. Drilon A, Rekhtman N, Arcila M, et al. Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-center, phase 2, single-arm trial. Lancet Oncol. 2016;17(12):1653-1660. doi: 1016/S1470-2045(16)30562-9.
4. 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;378:731-739. doi: 10.1056/NEJMoa1714448.
5. 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(15):107. doi: 10.1200/JCO.2016.34.15_suppl.107.
6. Drilon A, Camidge DR, Ou SI, et al. Efficacy and safety of crizotinib in patients (pts) with advanced MET exon 14-altered non-small cell lung cancer (NSCLC). J Clin Oncol. 2016;34(15):108. doi: 10.1200/JCO.2016.34.15_suppl.108.
7. Li B, Shen R, Buonocore Z, et al. Phase 2 basket trial of ado-trastuzumab emtansine in patients with HER2 mutant or amplified lung cancers. In: Proceedings from the IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract OA 14.05.