Investigators target resistance after establishment of first-line RET inhibition in RET-impaired NSCLC

With two highly selective and active RET inhibitors approved for use in patients with metastatic non-small cell lung cancer with impaired RET, the dilemma is not determining which agent to select, but ensuring that next-generation sequencing is performed in advance and in the presence of acquired resistance.

With two highly selective and active RET inhibitors approved for use in patients with metastases RET positive-stage non-small cell lung cancer (NSCLC), the dilemma is not which agent to select, but ensuring that next-generation sequencing (NGS) is performed in advance and in the presence of an acquired resistance, according to Hossein Borghaei, MS , FAIS.

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

RET fusions are present in approximately 2% of patients with NSCLC, and selpercatinib (Retevmo) or pralsetinib (Gavreto) would be an appropriate choice for first-line use in a patient with NSCLC. RET– Impaired NSCLC, having demonstrated objective response rates (ORR) of 85% (n=39; 95% CI, 70% to 90%) and 66% (n=29; 95% CI, 46% to 82 %) in the pivotal Phase 1/2 trials LIBRETTO-001 (NCT03157128) and ARROW (NCT03037385), respectively, explained Borghaei.2.3

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

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

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

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

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

With respect to safety, the most commonly reported grade 3 or higher treatment-related adverse reactions (TRAEs) 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 recruited a similar population of patients with RET– altered solid tumors, but the only difference was that selpercatinib was given twice a day, Borghaei noted. The primary analysis of patients with RET The fusion-positive NSCLC included the first 105 patients who received platinum-based chemotherapy, in whom the agent caused an ORR of 68% (95% CI, 58% to 76%).5

The ORR was significantly higher in the treatment-naïve population (n=34), at 85% (95% CI, 69% to 95%). In addition, the agent showed durable first-line disease control, with a median DOR (95% CI, 8.3 – not evaluable [NE]) and PFS (95% CI, 9.2-NE) which was not achieved.

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

“We don’t have as much information on resistance to RET inhibitors, but we do get information from multiple analyzes that were done in patients who developed disease progression on these agents,” said Borghaei.

For example, analysis of circulating tumor DNA from the ARROW trial demonstrated that targeted resistance is rare, occurring in only about 10% of patients. The analysis also revealed that other bypass signaling pathways, including MEET amplification and BRAF V600E mutations may be more common.6

However, Borghaei pointed out that to better understand the resistance mechanisms, serial NGS will be a necessity.

“In the majority of these cases, we don’t know what the resistance mechanism is,” Borghaei said. “In a world where we struggle to get the first biopsies and molecular tests [doen for] most of our patients at the time of initial diagnosis, how will we identify these rarer alterations in those undergoing treatment and needing repeat biopsies and molecular testing? We really need to think about our approaches and find 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 new RET inhibitors are under development and data are eagerly awaited, including TPX-0046 (NCT04161391), BOS172738 (DS-5010; NCT03780517), TAS0953/HM06 (NCT04683250) and LOXO-260.


  1. Borghaei H. What’s new for the RET-rearranged NSCLC. Introduced to : 23rd Annual International Congress on Lung Cancer®; July 28-30, 2022; Huntington Beach, California. 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 English J med. 2020;383(9):813-824. doi:10.1056/NEJMoa2005653
  3. Gainor JF, Curigliano G, Kim DW, et al. Registration dataset from ARROW Phase I/II trial of pralsetinib (BLU-667) in patients (pts) with advanced RET+ fusion non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(supplement 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 non-small cell lung cancer with RET fusion: update from the ARROW trial. J Clin Oncol. 2021;39(supplement 15):9089. doi:10.1200/JCO.2021.39.15_suppl.9089
  5. A. Drilon, G. Oxnard, L. Wirth, et al. LIBRETTO-001 registration results: a phase 1/2 trial of LOXO-292 in patients with RET fusion lung cancers. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, ​​Spain. Summary PL02.08.
  6. Gainor JF, Curigliano G, Doebele RC, et al. Analysis of resistance mechanisms to pralsetinib (BLU-667) in patients 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.

Comments are closed.