Investigators Set Sights on Resistance Following Establishment of Frontline RET Inhibition in RET-Altered NSCLC

Hossein Borghaei, MS, DO

With two highly selective and active RET inhibitors approved for use in patients with metastatic RET alteration–positive non–small cell lung cancer (NSCLC), the dilemma is not determining which agent to select but ensuring that next-generation sequencing (NGS) is done up front and in the presence of acquired resistance, according to Hossein Borghaei, MS, DO.

“In the treatment-naïve patient population, these drugs work better, so my preference is to use the targeted therapy first instead of chemotherapy if I find someone with a RET alteration,” Borghaei, professor and chief of Thoracic Oncology and The Gloria Edmund M. Dunn Chair in Thoracic Oncology, at Fox Chase Cancer Center, said in a presentation delivered during the 23rd Annual International Lung Cancer Congress^®.¹

RET fusions are present in approximately 2% of patients with NSCLC, and either selpercatinib (Retevmo) or pralsetinib (Gavreto) would be an appropriate choice for frontline use in a patient with RET-altered NSCLC, having demonstrated objective response rates (ORRs) of 85% (n =39; 95% CI, 70%-90%) and 66% (n = 29; 95% CI, 46%-82%) in the pivotal phase 1/2 LIBRETTO-001 (NCT03157128) and ARROW (NCT03037385) trials, respectively, Borghaei explained.^2,3

Although both agents also have reported central nervous activity (CNS), with intracranial ORRs of 91% (n = 11; 95% CI, 59%-100%) and 56% (n = 4), respectively, Borghaei stated that more data are needed to determine the true CNS activity of each agent.

Pralsetinib’s entry into the clinical arena resulted from the ARROW trial, which enrolled patients who were at least 18 years of age and who had advanced or metastatic, RET-altered solid tumors. Within the RET fusion–positive NSCLC cohort, patients received pralsetinib at a dose of 400 mg once daily.

“Like many other phase 1/2 studies, the primary objective of [ARROW] was to look at the response rate,” Borghaei noted.

Among patients with treatment-naïve and pretreated disease (n = 216), the ORR per blinded independent central review was 69% (95% CI, 62%-75%) with pralsetinib; the ORR was higher in the treatment-naïve population (n = 68), at 79% (95% CI, 68%-88%).⁴

Patients who received pralsetinib in the first line also experienced a disease control rate of 93% (95% CI, 84%-98%), a clinical benefit rate of 82% (95% CI, 71%-91%), and a median progression-free survival (PFS) of 13.0 months (95% CI, 9.1–not reached [NR]). Moreover, responses were durable, with a median duration of response (DOR) that was not yet reached (95% CI, 9.0-NR) as of November 6, 2020, which was the data cutoff.

Regarding safety, the most common grade 3 or greater treatment-related adverse effects (TRAEs) reported with pralsetinib are neutropenia (any grade, 42%; grade ≥3, 20%) and anemia (any grade, 38%; grade ≥3, 13%) followed by hypertension (any grade, 25%; grade ≥3, 12%).

The LIBRETTO-001 trial enrolled a similar population of patients with RET-altered solid tumors, but the one difference was that selpercatinib was dosed twice daily, Borghaei noted. The primary analysis of patients with RET fusion–positive NSCLC featured the first 105 patients who received prior platinum chemotherapy, in whom the agent elicited an ORR of 68% (95% CI, 58%-76%).⁵

The ORR was notably higher in the treatment-naïve population (n = 34), at 85% (95% CI, 69%-95%). Moreover, the agent displayed durable disease control in the first line, with a median DOR (95% CI, 8.3–not evaluable [NE]) and PFS (95% CI, 9.2-NE) that was not reached.

Regarding TRAEs, Borghaei noted that some hypertension is reported with the agent, although this is mostly grade 1 and 2 in severity, as well as peripheral edema, although that toxicity is not significantly observed.

“We do not have as much information on resistance to RET inhibitors, but we are gaining some insights from multiple analyses that have been done in patients who have developed disease progression on these agents,” Borghaei said.

For example, a circulating tumor DNA analysis from the ARROW trial demonstrated that on-target resistance is uncommon, occurring in only approximately 10% of patients. The analysis also revealed that other bypass signaling pathways, including MET amplification and BRAF V600E mutations, may be more common.⁶

However, Borghaei emphasized that to better understand mechanisms of resistance, serial NGS will be a necessity.

“In the majority of these cases, we do not know what the resistance mechanism is,” Borghaei said. “In a world where we are having a hard time getting initial biopsies and molecular testing [doen for] most of our patients by the time of initial diagnosis, how are we going to identify these rarer alterations in those who are on treatment and who need repeat biopsies and repeat molecular testing? We really need to consider our approaches and come up with a way to serve more patients who are on these targeted therapies and who [develop] resistance mechanisms.”

Looking to the future, Borghaei concluded by stating that several novel RET inhibitors are under development, and data are eagerly anticipated, including TPX-0046 (NCT04161391), BOS172738 (DS-5010; NCT03780517), TAS0953/HM06 (NCT04683250), and LOXO-260.

References

1. Borghaei H. What’s new for RET-rearranged NSCLC. Presented at: 23rd Annual International Lung Cancer Congress^®; July 28-30, 2022; Huntington Beach, CA. Accessed July 29, 2022.
2. 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
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. Curigliano G, Gainor JF, Griesinger F, et al. Safety and efficacy of pralsetinib in patients with advanced RET fusion-positive non-small cell lung cancer: update from the ARROW trial. J Clin Oncol. 2021;39(suppl 15):9089. doi:10.1200/JCO.2021.39.15_suppl.9089
5. A. Drilon, G. Oxnard, L. Wirth, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of LOXO-292 in patients with RET fusion-positive lung cancers. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract PL02.08.
6. Gainor JF, Curigliano G, Doebele RC, et al. Analysis of resistance mechanisms to pralsetinib (BLU-667) in patients with RET fusion–positive non-small cell lung cancer (NSCLC) from the ARROW study. Presented at: 2020 North American Conference on Lung Cancer. October 16-17, 2022. Accessed July 29, 2022. https://bit.ly/3oYi9QV