New Strategies for RET Inhibition May Expand Their Role in NSCLC

Karen L. Reckamp, MD

RET inhibitors displayed promising efficacy and a tolerable safety profile in patients with non–small cell lung cancer (NSCLC) harboring RET alterations, according to a presentation by Karen L. Reckamp, MD, during the 22nd Annual International Lung Cancer Congress.¹ The future, she noted, will depend on a deeper understanding of acquired mutations and the development of strategies to circumvent bypass resistance.

“RET is a protein that heterodimerizes and has a key role in organ development and homeostasis in the normal state,” explained Reckamp, a professor of medicine and the director of the Division of Medical Oncology at Cedars-Sinai Medical Center in Los Angeles, California. “RET alterations are found mainly in thyroid cancers and lung cancers. In thyroid cancers we see mostly mutations, while in lung cancers we see RET fusions. These occur in about 1% to 2% of NSCLCs, generally nonsquamous cell.”

Fusions may be best detected via RNA next-generation sequencing panels, according to Reckamp. FISH and IHC are still used for initial evaluation, but these methods can lead to a significant amount of false-negative and false-positive results.

Investigators have identified multiple resistance mutations in preclinical studies including the gatekeeper mutation V804L, and solvent front mutations G810A and G810S. Agents such as cabozantinib (Cabometyx) have demonstrated efficacy in patients with V804L mutations.

Next-generation RET inhibitors are under investigation, including the novel RET and SRC kinase inhibitor, TPX-0046. Reckamp said that the inhibitor is structurally differentiated from other inhibitors and is potent against a broad range of mutations, including solvent front mutations, through targeting of the RET active conformation.

“We’re still in the early phases of understanding resistance [to selective RET inhibition],” said Reckamp. “We know from the multi-targeted kinases and some early data from specific RET inhibitors that we get gatekeeper mutations and solvent front mutations. There is development of new-generation RET inhibitors to try and overcome this resistance.”

The agent is currently under investigation in a phase 1/2 trial (NCT04161391) of patients with RET inhibitor–resistant and naïve RET-driven cancers.

Additionally, other RET inhibitors may make their way into the treatment landscape. Reckamp provided an overview of the ongoing clinical trial landscape including phase 3 LIBRETTO-431 (NCT04194944), AcceleRET trial (NCT04222972), and LIBRETTO-531 (NCT04211337) trials, as well as a phase 1/2 trial (NCT04161391) and a phase 1 trial (NCT03780517).

LIBRETTO-431 is examining approximately 250 patients with RET fusion–positive advanced NSCLC and no prior systemic therapies. The trial is comparing selpercatinib (Retevmo) with standard of care platinum-based chemotherapy and pembrolizumab (Keytruda). The primary end point of the study is progression-free survival (PFS) by blinded independent review committee (BICR).

AcceleRET will enroll about 250 patients with RET fusion–positive advanced NSCLC and no prior systemic therapies. Study participants will receive either pralsetinib (Gavreto) or standard of care platinum-based chemotherapy plus pembrolizumab. The primary end point of the study is PFS.

LIBRETTO-531 is a study of approximately 400 patients with RET-mutant advanced medullary thyroid cancer and no prior kinase inhibitor therapy. The study is examining selpercatinib vs cabozantinib or vandetanib. The primary end point is target failure-free survival by BICR.

NCT04161391 is a single-arm trial examining the RET/SRC inhibitor TPX-0046 in approximately 362 patients with advanced solid tumors with RET mutations or fusions. The primary end points of the trial are overall response rate (ORR), dose-limiting toxicity, and determining the recommended phase 2 dose (RP2D).

NCT03780517 is a single-arm study of BOS172738. The trial will examine approximately 114 patients with advanced solid tumors with RET alterations. The primary end points of the trial are safety, finding the RP2D, and determining the maximum tolerated dose.

“There are also multiple trials ongoing looking at combinations with selpercatinib and pralsetinib vs standard of care and vs multitargeted TKIs, as well as [trials] looking at TPX-0046 and BOS172738,” Reckamp said. “There is more to come for resistance, [and we’ll know more] at the next [American Society of Clinical Oncology] meeting.”

In the meantime, there are 2 approved agents for RET altered cancers: selpercatinib and pralsetinib. Reckamp discussed the trials that led to their approval and set the stage for what these new trials will need to surpass in terms of efficacy and safety.

The phase 1/2 LIBRETTO-001 trial (NCT03157128) examined the first-in-class, highly selective, and potent RET-inhibitor selpercatinib. The trial enrolled a total of 531 patients with locally advanced or metastatic solid tumors and a documented RET alteration who were at least 12 years, intolerant or refractory to standard therapy, and have an ECOG performance status of 2 or less. The primary end point of the phase 1 portion was maximum-tolerated dose (MTD) and RP2D, and was overall response rate (ORR) in the phase 2 part.

In the completed phase 1, dose-escalation portion of the trial, participants received selpercatinib at a dose of 20 mg orally once a day and at a dose of 20 mg, 40 mg, 60 mg, 80 mg 12 mg, 160 mg, and 240 mg twice daily. In the ongoing phase 2, dose expansion, patients are being given 160 mg of selpercatinib orally twice per day.

In the cohort of patients with RET fusion–positive NSCLC previously treated with platinum-based chemotherapy (n = 105), most patients (56%) had disease with a KIF5B-RET fusion. Prior PD-L1 inhibitor therapy was received by 55% of patients and adenocarcinoma made up 86% of the population.

In the previously untreated arm of patients with RET fusion-positive NSCLC (n = 39), 67% were patients with a KIF5B-RET fusion and 87% had adenocarcinoma.

Patients who were previously treated with platinum-based chemotherapy had an ORR of 64% (95% CI, 54%-73%), including 2 complete responses (CRs). The median duration of response (DOR) was 17.5 months (95% CI, 12.1-not evaluable) and the median progression-free survival (PFS) was 19.3 months (95% CI, 13.9-not evaluable). Antitumor activity was observed regardless of prior therapy, including prior multitargeted TKIs, Reckamp said.²

In the treatment-naïve cohort (n = 48), the ORR was 85% (95% CI, 72%-94%) with 2 CRs and 8 patients achieving stable disease (SD). Median DOR and median PFS were not reached, and the reported 1-year PFS rate was 68% (95% CI, 50%-80%).²

The ARROW trial (NCT03037385) was a phase 1/2 study of pralsetinib in a total of 647 adult patients with locally advanced or metastatic solid tumors and a documented RET fusion or mutation. Eligible patients had an ECOG performance status of 0 to 1 and previously received or were not candidates for standard therapy. The primary end points of the study were MTD and RP2D (phase 1), and ORR by BICR and safety (phase 2).

In phase 1, participants were given the RET inhibitor pralsetinib at doses ranging from 30 to 600 mg orally once or twice daily. In the ongoing phase 2 portion, pralsetinib is being administered at a dose of 400 mg daily.

Among all patients with NSCLC (n = 132), 36% were previously treated with a PD-L1 inhibitor, 71% had prior chemotherapy, and 31% were previously treated with a combination of the 2. Patients with KIF5B-RET fusion–positive NSCLC made up a majority of both the cohort of patients previously treated with chemotherapy (n = 92) and those who were treatment naïve (n = 29), at 74% and 69%, respectively.

For all efficacy-evaluable patients (n = 116), the ORR was 65% (95% CI, 55%-73%) and the disease control rate (DCR) was 93% (95% CI, 87%-97%). The ORR in the patients receiving prior chemotherapy (n = 80) was 61% (95% CI, 50%-72%) compared with 73% (95% CI, 52%-88%) in patients without any prior therapies (n = 26).³

“In the treatment-naïve population, all patients had some tumor reduction,” said Reckamp. “We see this across fusion partners, and we also see significant activity in intracranial metastases, both with selpercatinib and pralsetinib.”

Patients treated with previously treated RET fusion–positive NSCLC who were subsequently treated with selpercatinib had a central nervous system ORR of 91% (95% CI, 59%-100%) across an 11-patient sample size. Patients with RET fusion–positive NSCLC treated with pralsetinib experienced an intracranial response of 56%, including 3 CRs, in a subgroup of 9 patients.

In terms of safety in LIBRETTO-001, the most common treatment-related adverse events (TRAEs) among all patients (N=531) were dry mouth (33%), increased AST (26%), and increased ALT (25%). Grade 3 TRAEs included hypertension (11%) and increased ALT (7%). Grade 4 events were rare, the most common of which were increased ALT and AST, both occurring 1% of the time.²

In the 354-patient safety population of ARROW, commonly occurring TRAEs of any grade included increased AST (31%), anemia (22%), and constipation (21%). Events of at least grade 3 severity included hypertension (10%), neutropenia (10%), and anemia (8%).³

The FDA has approved both selpercatinib (May 2020) and pralsetinib (September 2020) for the treatment of adult patients with metastatic RET fusion-positive NSCLC. Selpercatinib was approved at a dose of 120 mg orally, twice daily for patients weighing less than 50 kg and at 160 mg orally, twice daily for patients who weigh at least 50 kg. The recommended dose of pralsetinib is 400 mg orally once per day to be taken on an empty stomach.¹

References

1. Reckamp KL. What’s new with RET inhibitors? Paper presented at: 22nd Annual International Lung Cancer Congress; July 29-31, 2021; Huntington Beach, CA. Accessed July 29, 2021.
2. Besse B, Drilon AE, Solomon BJ, et al. Updated overall efficacy and safety of selpercatinib in patients (pts) with RET fusion+ non-small cell lung cancer (NSCLC). J Clin Oncol. 2021;39(suppl 15):9065. doi: 10.1200/JCO.2021.39.15_suppl.9065
3. Gainor JF, Curigliano G, Kim DW, 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
4. Schoffski P, Cho BC, Italiano A, et al. BOS172738, a highly potent and selective RET inhibitor, for the treatment of RET-altered tumors including RET-fusion+ NSCLC and RET-mutant MTC: Phase 1 study results. J Clin Oncol. 2021;39(suppl 15):3008. doi: 10.1200/JCO.2021.39.15_suppl.3008