Selective Kinase Inhibitors Push the Envelope in RET or NTRK Fusion–Positive NSCLC

Selective kinase inhibitors have resulted in dramatic improvements in efficacy with improved safety vs historical approaches in patients with non–small cell lung cancer (NSCLC) whose tumors harbor RET or NTRK fusions, according to Jose Pacheco, MD. Now, research efforts are focused on better understanding resistance mechanisms to these agents and developing options that can overcome them.

“For patients with RET and NTRK fusions, we have highly effective, selective kinase inhibitors that are much more effective than chemotherapy and immunotherapy for these patients. The durations of benefit, and the central nervous system [CNS] response rates that we are seeing with these drugs are improvements over any other therapy we have [used] for this particular population,” Pacheco said. “[However], these are not alterations that some providers may have been routinely testing for. We need to ensure that the panels we are using are looking for these fusions. We need to be cognizant of testing both DNA and RNA as far as next-generation sequencing goes.”

In the realm of RET fusion–positive disease, selpercatinib (LOXO-292; Retevmo) was granted accelerated approval from the FDA in May 2020 based on data from the phase 1/2 LIBRETTO-001 trial (NCT03157128), which showed that the agent elicited an objective response rate (ORR) of 64% in the NSCLC cohort.¹ This was followed by the September 2020 approval of pralsetinib (Gavreto) based on findings from the phase 1/2 ARROW trial (NCT03037385), which demonstrated that the agent induced an ORR of 57% in this patient population.²

For patients with NTRK fusion–positive disease, larotrectinib (Vitrakvi), approved in November 2018, has been shown to elicit an ORR ranging from 75% to 80% in this population,³ while entrectinib (Rozlytrek), approved in August 2019, has been shown to have an ORR of 57%.⁴ Now, repotrectinib (TPX-0005) and LOXO-195 are under development to overcome resistance mutations, according to Pacheco.

In an interview with OncLive^® during a 2021 Institutional Perspectives in Cancer webinar on lung cancer, Pacheco, an assistant professor of medicine/medical oncology at the Colorado University School of Medicine, discussed key agents that have significantly improved the care of patients with NSCLC harboring RET or NTRK fusions and efforts being made to address resistance challenges.

OncLive®: How have the FDA approvals of selpercatinib and pralsetinib impacted the treatment landscape for RET fusion–positive NSCLC?

Pacheco: Prior to these therapies, patients would generally be treated with a platinum-based doublet as initial treatment, and the time to progression would be approximately 5 months. Then, patients would receive either docetaxel or gemcitabine in the second line, and time to progression would be approximately 3 months. After that, patients would either [be enrolled to a] clinical trial or [receive] a multikinase inhibitor, such as cabozantinib (Cabometyx) or vandetanib. These multikinase inhibitors had response rates of roughly 20% to 30% and short durations of benefit; they did not tremendously impact overall survival in these patients.

Selpercatinib and pralsetinib, in contrast, have response rates of 60% to 70% in previously treated patients; [these rates are] much better than [what we saw with the] multikinase inhibitors we used to give, and much better than what we would expect to see with any of the chemotherapies. [Additionally], the duration of benefit with these agents is very long. In the pralsetinib trial, the median duration of response [DOR] was not reached. With selpercatinib, the median DOR was about 17 to 18 months in previously treated patients. As such, these drugs are a significant improvement over what we previously had.

Could you speak to the CNS activity observed with these agents?

Based on limited datasets, they appear to get into the CNS and elicit responses in [those with] previously untreated brain metastases, depending on the drug and the limited cohorts. Pralsetinib had a response rate of approximately 60% in a cohort of 9 patients with evaluable brain metastases, and selpercatinib had a response rate of approximately 90% in a cohort of about 11 patients with untreated brain metastases, and those are intracranial response rates.

What efforts are being made to overcome resistance to highly-selective RET inhibitors?

We still don't know a lot about the resistance mechanisms to these drugs. Some small retrospective studies have looked at resistance patterns to these agents. Acquired RET kinase mutations have been reported in about one-fifth of patients, and in some of the retrospective series, MET alterations have also been reported. However, there are still many cases where we have not been able, in small datasets, to identify what the resistance mechanism is. Ongoing trials with different drugs are looking at resistance populations; these are drugs that preclinically are supposed to work on acquired RET kinase mutations, which appear to cause resistance to selpercatinib and pralsetinib. We eagerly await results [from those trials].

Shifting gears, how do you navigate among larotrectinib and entrectinib in the treatment of your patients with NTRK fusions?

This is a similar story to what we saw in patients with RET fusions. Patients with NTRK fusions were initially treated with platinum doublet-based chemotherapy in the first line. In the second-line setting, patients with NTRK fusions were generally treated with docetaxel or gemcitabine upon progression. The median duration of benefit was approximately 5 months in the first-line setting with platinum doublets, and again, roughly 3 months in the second-line setting with docetaxel or gemcitabine.

Larotrectinib and entrectinib have been reported to elicit response rates of around 70%, which is much better than what we would expect to see with platinum-based doublets or single-agent gemcitabine or docetaxel. Additionally, larotrectinib and entrectinib have a much longer duration of benefit than what we would expect to see with either first-line platinum-based doublets, or second-line single-agent chemotherapy. They [also] have the additional benefit of being able to elicit CNS responses, which we do not often see with chemotherapy. Larotrectinib and entrectinib, overall, are also much better tolerated than chemotherapy.

What emerging agents are you excited about?

The targeted agent repotrectinib is currently in clinical trials; [this drug] may overcome some NTRK resistance mutations. The results of that particular drug for patients who have developed resistance to entrectinib or larotrectinib will be worthwhile to see. We’re awaiting those results. Another drug in early clinical development, [LOXO-195], is targeting some NTRK resistance alterations. We eagerly await the data from that study.

References

1. FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. News release. FDA. May 8, 2020. Accessed May 6, 2021. https://bit.ly/2QYbB7a
2. Genentech announces FDA approval of Gavreto (pralsetinib) for the treatment of adults with metastatic RET fusion-positive non-small cell lung cancer. News release. Genentech. September 4, 2020. Accessed May 6, 2021. https://bwnews.pr/2QWJ4LM.
3. 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
4. Demetri GD, Paz-Ares L, Farago AF, et al. Efficacy and safety of entrectinib in patients with NTRK fusion-positive tumors: pooled analysis of STARTRK-2, STARTRK-1 and ALKA-372-001. Ann Oncol. 2018;29(suppl 9):IX175. doi:10.1093/annonc/mdy483.003