Novel Agents Emerging for Lesser-Known Targets in NSCLC

Sukhmani K. Padda, MD

ROS1, NTRK, MET, and HER2 are all less common molecular targets found in non—small cell lung cancer (NSCLC), but emerging therapeutic strategies are being explored to attack these abnormalities, said Sukhmani K. Padda, MD, an assistant professor of medicine at Stanford University.

“For ROS1, newer-generation tyrosine kinase inhibitors are emerging in the first-line setting, and we are finally also seeing some drugs in the post-crizotinib setting, which also has some efficacy,” Padda explained in a presentation during the 5th Annual Miami Lung Cancer Conference.

In ROS1-rearranged NSCLC, which comprises 1% to 2% of all NSCLCs, researchers have studied agents in treatment-naïve patients as well as those who progress while on crizotinib (Xalkori), the standard and sole FDA-approved first-line treatment. The March 2016 approval of crizotinib was based on findings of the phase I PROFILE 1001 trial, in which the overall response rate (ORR) was 72% (95% CI, 58-84) for patients with advanced ROS1-rearranged disease.¹ The median progression-free survival (PFS) was 19.2 months and the median duration of response (DOR) was 17.6 months.

“These kinds of numbers are quite impressive even when you look at some of the other driver mutations, such as EGFR,” said Padda, adding that other studies have shown similar responses with crizotinib in this population.

in EUROS1, a retrospective European study, off-label use of crizotinib was associated with an 80% ORR and a median PFS of 9.1 months in patients with stage IV lung adenocarcinoma who had a ROS1 rearrangement.²

However, beyond the frontline setting, there are no approved regimens, driving the need for further research, she explained.

Ceritinib (Zykadia), which is approved for frontline and second-line therapy in ALK-rearranged NSCLC, has also shown activity in ROS1-rearranged disease. Thirty-two patients, 30 of whom were crizotinib-naïve, were treated with 750 mg of ceritinib daily in an open-label, multicenter phase II study. The ORR by blinded independent central review (BICR) was 62% (95% CI, 45-77) and the median DOR was 21 months.³

Additionally, the median PFS was 19.3 months and overall survival (OS) was 24 months. The intracranial disease-control rate was 63%.

“The advantage of ceritinib over crizotinib, based on all of our experience, is that ceritinib does a better job of crossing that blood-brain barrier,” said Padda. “This is an option I tend to think about for patients with ROS1-rearranged lung cancer who have brain metastases at diagnosis. It’s something that can be considered.”

Entrectinib (RXDX-101), which Padda described as “the new kid on the block,” is another targeted agent being explored in ROS1-rearranged NSCLC. For patients with ROS1 fusion-positive advanced disease, treatment with entrectinib induced an ORR of 68.8% by BICR, which included 2 complete responses (6.3%).⁴

Resistance mechanisms to crizotinib have been evaluated for ROS1-rearranged NSCLC, which include G2032R, WT, D2033N, and S1986F. Agents under investigation that target these mutations include cabozantinib (Cabometyx) and lorlatinib, Padda explained. Phase II data from a multicohort study with lorlatinib showed that the ORR was 36% (95% CI, 23-52) and intracranial (IC)-ORR was 56% (95% CI, 35-76) for ROS1-positive patients regardless of prior treatment.⁵

Beyond ROS1, TRK is an oncogene fusion across several tumor types that is uncommonly expressed in normal or cancerous tissues. TRK fusion drives abnormally high expression and activation of TRK kinase domain.

In a phase I/II basket trial of patients with TRK fusion—positive cancers, the novel, highly selective pan-TRK inhibitor larotrectinib (LOXO-101) led to a central-assessed ORR of 75% (95% CI, 61-85) and an 80% (95% CI, 67-90) investigator-assessed ORR.⁶ At 1 year, 71% of responses were ongoing and 55% of patients remained progression-free. The median DOR and PFS had not been reached. At a median follow-up of 9.4 months, 86% of those who responded continued treatment or had surgery that was intended to be curative.

“This response seems to be across tumor types, regardless of age and TRK gene or fusion partner, so this has made quite a splash,” Padda explained.

Entrectinib has seen encouraging activity in TRK fusion—positive NSCLC, as well in 2 phase I basket studies, ALKA-372-001 and STARTRK-1. The 1 patient enrolled with NSCLC experienced a complete IC response.⁷

MET is also a less-common target in NSCLC. Padda focused on MET exon 14 skipping mutations in her presentation, which comprise 3% of nonsquamous NSCLCs and 20% to 30% of sarcomatoid lung carcinomas. In an expansion cohort of the PROFILE 1001 trial, crizotinib had activity in these patients in addition to the ROS1-rearranged patients. Additionally, a retrospective analysis of patients who had MET exon 14 skipping mutations showed that treatment with a MET inhibitor led to an improvement in OS (HR, 0.11; 95% CI, 0.01-0.92; P = .04).⁸

“In general, the message is if a patient does have a MET exon 14 skipping mutation, they will likely benefit from a MET inhibitor,” Padda said.

Finally, HER2 mutations and amplification are also under investigation in NSCLC. In the retrospective European EUHER2 cohort, patients were treated with chemotherapy and/or HER2-directed agents, including trastuzumab (Herceptin), and ado-trastuzumab emtansine (T-DM1; Kadcyla). The ORR with trastuzumab or T-DM1 was 50.9% and the median PFS was 4.8 months.⁹

Though HER2 remains to be a difficult target, strategies are emerging, Padda concluded.

References

1. Shaw A, Rily GJ, Bang YJ, et al. Crizotinib in advanced ROS1-rearranged non-small cell lung cancer. N Eng J Med. 2014;371(21):1963-1971. doi: 10.1056/NEJMoa1406766.
2. Mazières J, Zalcman G, Crinò L, et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol. 2015;33(9):992-999. doi: 10.1200/JCO.2014.58.3302.
3. 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):263-2618. doi: 10.1200/JCO.2016.71.3701.
4. 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). Presented at: IASLC 18th World Conference on Lung Cancer; October 15-18, 2017; Yokohama, Japan. Abstract 8564.
5. 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. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract 8573.
6. 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.
7. Drilon A, Siena S, Ou SHI, et al. Safety and antitumor activity of the multi-targeted pan-TRK, ROS1, and ALK inhibitor entrectinib (RXDX-101): combined results from two phase 1 trials (ALKA-372-001 and STARTRK-1) [published online ahead of print February 9, 2017]. Cancer Discov. doi: 10.1158/2159-8290.CD-16-1237.
8. Awad MM, Leonardi GC, Kravets S, Dahlberg SE, Drilon AE, Noonan S. Impact of MET inhibitors on survival among patients (pts) with MET exon 14 mutant (METdel14) non-small cell lung cancer (NSCLC). J Clin Oncol. 2017;35(15):8511. doi: 10.1200/JCO.2017.35.15_suppl.8511.
9. Mazières J, Barlesi F, Filleron T, et al. Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort. Ann Oncol. 2016;27(2):281-286. doi: 10.1093/annonc/mdv573.