MET, RET, and TRK Inhibitors Achieve Standard-of-Care Status in Lung Cancer

Alterations in MET, RET, and NTRK have become established actionable drivers of oncogenesis in lung cancer, and therapeutics targeting these aberrations have since obtained regulatory approval from the FDA and have been incorporated into treatment guidelines.

Alexander Drilon, MD, chief of Early Drug Development Service at Memorial Sloan Kettering Cancer Center in New York, discussed each of the recently approved agents used for the treatment of these tumors and presented a review of the data at the 15th Annual New York Lung Cancer Symposium, hosted by Phyisicians’ Education Resource, LLC (PERÒ).¹

MET as a Driver of Lung Tumors

Starting with alterations in MET, Drilon said it’s important to understand the role this gene plays, in particular for lung tumors, as a primary or secondary driver of oncogenesis.

As a primary driver, there are 2 genomic overlapping states that underlie pathogenesis: MET amplification, and subsequently MET exon 14 aberrations. These both lead to dependency on the MET gene and the overlapping states can be targetable.

MET can also play a role as a codriver of oncogenesis secondary to other mutations. Drilon said some cancers may acquire MET amplification in response to effects of tyrosine kinase inhibitors (TKIs), and these effects can be seen in conjunction with intrinsic mutations in EGFR, RET, and ROS1, among others.

Type I MET inhibitors actively bind to ATP pocket, such as the multikinase inhibitor crizotinib (Xalkori) and the selective inhibitor capmatinib (Tabrecta). Type II agents, such as cabozantinib (Cabometyx), engage the kinase domain in the inactive or DFG-out conformation and are useful in certain instances of resistance.

Comparing the activity of these agents, Drilon pointed out that antitumor activity of crizotinib in MET exon 14 altered non–small cell lung cancer (NSCLC) appears to be less than that of specific inhibitors capmatinib, tepotinib, and savolitinib.

For example, in the phase 1 PROFILE 1001 trial (NCT00585195) of crizotinib in lung tumors with MET exon 14 alterations, the objective response rate (ORR) was 32% in the overall population (n = 69), 25% in patients who were treatment naïve (n = 24) and 37% in those on second-line therapy (n = 41).² In the phase 2 GEOMETRY mono-1 trial (NCT02414139), ORRs in the patients who were treatment naïve (n = 28) and on second-line therapy (n = 69) were 68% and 41%, respectively.³

Although responses are promising with specific inhibitors of MET, Drilon pointed out that they have not led to the same deep and durable responses observed with other targeted TKIs.

“We’re not quite seeing what we’re seeing with osimertinib [Tagrisso] in EGFR, or alectinib [Alcensa], brigatinib [Alunbrig], and lorlatinib [Lorbrena] in ALK fusion–positive lung cancers, so there is room to improve in this arena,” Drilon said.

Reviewing resistance mechanisms to MET, Drilon said these can be in the form of on-target and off-target mechanisms.

“On-target resistance takes the form of acquired kinase domain mutations,” Drilon said, adding that these “might be more amenable to the administration of a type II MET inhibitor such as cabozanitnib.”

Off-target resistance mechanisms frequently include reliance on RAS. “Biologically, I think there’s an interaction there between the MET protein and the RAS pathway that leads to these cancers evolving down that particular route.”

Pivoting to inhibition of MET amplifications in NSCLC, which is the second major driver of MET activation, Drilon again pointed to PROFILE 1001 which showed an increase in ORR with crizotinib that correlated with the level of MET amplification. As such, ORRs were 0%, 17%, and 67% in patients with low, intermediate, and high MET amplification.⁴

“This underscores that from a diagnostic perspective, we need to do better with defining these continuous variables as predictive biomarkers, and establishing concrete cutoffs for patients, enriching them for benefit from MET inhibition,” Drilon said.

Recent data have shown that this correlation is also seen in more selective agents, with increasing kinase activity clustering with high gene copy number. Returning to the results of the GEOMETRY mono-1 trial, patients with gene copy numbers of 10 or above stood to benefit the most from capmatinib therapy.

“That highlights the fact that we should figure out the appropriate cut off for MET amplification because with the diagnostic migration that we’ve seen away from FISH [fluorescence in situ hybridization] and towards next-generation sequencing, we currently don’t have a contemporary definition of amplification that standardizes how to select patients for MET TKI therapy,” said Drilon. “Hopefully that data will emerge as we move into the future.”

Selective RET Inhibitors

Prior to 2017, inhibition of RET activity was achieved through existing multikinase inhibitors, such as vandetinib (Caprelsa) and cabozantinib, which were “repurposed” for tumors with RET mutations.

“The big leap for us in the targeted therapy field was the development of these selective RET tyrosine kinase inhibitors that hit [the] clinic in mid-2017, such as BLU-667, pralsetinib (Gavreto), or selpercatinib (Retevmo),” Drilon said. “These agents were rationally designed to optimally inhibit RET and avoid the non-RET targets that led to a high frequency of adverse effects with older drugs.”

Drilon said these strategies paid off, made evident by registrational data from the phase 1/2 LIBRETTO-001 trial (NCT03157128) for selpercatinib and the phase 1/2 ARROW trial (NCT03037385) for pralsetinib.^5,6

With both agents, patients who were treatment naïve or pretreated regardless of prior therapy had regression of the target lesion. Both agents were granted accelerated approvals for the treatment of patients with RET fusion–positive NSCLC in 2020.^7,8

“One thing to call out is that the intracranial response rates look good at 91% for selpercatinib and [are] approaching 60% for pralsetinib,” Drilon said. “This is a win for patients and it’s also a win in terms of the durability of disease control.”

Drilon also noted that median PFS and duration of response (DOR) have not been reached for pralsetinib. However, efficacy with selpercatinib appears promising with median PFS and DOR of 20.3 months and 18.4 months, respectively.

TRK Inhibition in Solid Tumors

Finally, Drilon mentioned the use of agent targeting NTRK gene fusions, namely larotrectinib (Vitrakvi) and entrectinib (Rozlytrek), both of which have pan-tumor therapy indications.

Durable disease control rates have been observed with these agents. A pooled analysis of 3 clinical trials performed on patients with NTRK fusion–positive solid tumors treated with larotrectinib following standard therapy,⁹ the ORR was 79% and the median PFS was 28.3 months. In a similar patient population, entrectinib produced an ORR of 57% and a median PFS of 11 months.¹⁰

“For NTRK fusions, we’re already developing next-generation drugs…such as LOXO-195 or repotrectinib,” Drilon concluded.

References

1. Drilon A. Targeted therapy for MET, RET, and TRK dependent lung cancer. Presented at: 15th Annual New York Lung Cancer Symposium, hosted by Physicians’ Education Resource, LLC (PERÒ). November 7, 2020. Virtual.
2. Drilon A, Clark JW, Weiss J, et al. Antitumor activity of crizotinib in lung cancers harboring a MET exon 14 alteration. Nat Med. 2020;26(1):47-51. doi:10.1038/s41591-019-0716-8
3. Wolf J, Seto T, Han JY, et al; GEOMETRY mono-1 Investigators. Capmatinib in MET Exon 14-Mutated or MET-Amplified Non-Small-Cell Lung Cancer. N Engl J Med. 2020;383(10):944-957. doi: 10.1056/NEJMoa2002787
4. Camidge DR, Ignatius Ou S-A, Shapiro G, et al. Efficacy and safety of crizotinib in patients with advanced c-MET-amplified non–small cell lung cancer (NSCLC). J Clin Oncol. 2014;32(suppl 15):8001. doi: 10.1200/jco.2014.32.15_suppl.8001
5. Drilon A, Oxnard GR, Tan DSW, et al. Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med. 2020;383(9):813-824. doi: 10.1056/NEJMoa2005653
6. Gainor JF, Curigliano G, Kim D-W, et al. Registrational dataset from the phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15):9515. doi: 10.1200/JCO.2020.38.15_suppl.9515.
7. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. May 8, 2020. Accessed November 9, 2020. https://bit.ly/2IiZxJm
8. FDA approves pralsetinib for lung cancers with RET gene fusions. FDA. September 4, 2020. Accessed November 9, 2020. https://bit.ly/38sXsp0
9. Hong DS, DuBois SG, Kummar S, et al. Larotrectinib in patients with TRK fusion-positive solid tumours: a pooled analysis of three phase 1/2 clinical trials. Lancet Oncol. 2020;21(4):531-540. doi: 10.1016/S1470-2045(19)30856-3
10. Doebele RC, Drilon A, Paz-Ares L, et al; trial investigators. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1-2 trials. Lancet Oncol. 2020;21(2):271-282. doi: 10.1016/S1470-2045(19)30691-6