Frontline Selpercatinib Doubles PFS in RET Fusion-Positive NSCLC

Herbert H. Loong, MBBS

Selpercatinib (Retevmo) showcased superior efficacy, with improved progression-free survival (PFS), vs chemotherapy with or without pembrolizumab (Keytruda) in the first-line treatment of patients with RET fusion–positive non–small cell lung cancer (NSCLC), according to data from the phase 3 LIBRETTO-431 trial (NCT04194944) presented at the 2023 European Society of Medical Oncology Congress.¹

Key Findings

At a median follow-up of approximately 19 months in the intention-to-treat (ITT)/pembrolizumab population, the median PFS in the selpercatinib arm (n = 129) was 24.8 months (95% CI, 16.9-not evaluable [NE]) by blinded independent central review (BICR) vs 11.2 months (95% CI, 8.8-16.8) in the control arm (n = 83; HR, 0.465; 95% CI, 0.309-0.699; P < .001).

In the ITT population, and with a median follow-up of approximately 18 months, the median PFS in the selpercatinib and control arms was 24.8 months (95% CI, 17.3-NE) and 11.2 months (95% CI, 8.8-16.8), respectively (HR, 0.482; 95% CI, 0.331-0.700; P < .001).

With these improvements, the primary end points of the trial were met, Herbert H. Loong, MBBS, who is a clinical associate professor in the Department of Clinical Oncology and deputy medical director of the Phase I Clinical Trials Centre at The Chinese University of Hong Kong, said in a presentation of the data.

“Selpercatinib should be considered as a first-line standard of care [SOC] in RET fusion–positive, advanced NSCLC,” he said. “These results reinforce the importance of genetic testing to identify RET fusions at the time of diagnosis, to inform initial therapy.”

Significance

The highly selective and potent RET inhibitor, selpercatinib, is indicated for adult patients with locally advanced or metastatic NSCLC harboring a RET gene fusion with the regulatory decision based on data from the phase 1/2 LIBRETTO-001 trial (NCT03157128).2 The agent induced an overall response rate (ORR) of 84% (95% CI, 73%-92%). The median PFS was 22.0 months (95% CI, 13.8-NE).³

“The prevailing SOC of treatment for patients in first-line NSCLC is platinum plus pemetrexed plus pembrolizumab. This combination, of course, is established in the first-line treatment setting based on the KEYNOTE-189 study [NCT02578680],” Loong said. Data from the trial showed that the combination elicited an ORR of 47.6% (95% CI, 42.6%-52.5%) and resulted in a median PFS of 8.8 months (95% CI, 7.6-9.2).⁴

LIBRETTO-431 Trial Design

With LIBRETTO-431, investigators set out to define the optimal frontline regimen for this patient population.1 The trial was enrolled in patients with stage IIIB to IIIC or stage IV nonsquamous NSCLC harboring RET fusions. Patients needed to have an ECOG performance status of 0 to 2 who have not previously received systemic treatment for metastatic disease. Those with symptomatic central nervous system (CNS) metastases were excluded.

Key stratification factors included geography (East Asian vs non-East Asian), brain metastases (present vs absent/unknown), and investigator’s choice of treatment with pembrolizumab.

“The prevailing treatment of choice such as these included in the study as mentioned previously is platinum plus pemetrexed plus pembrolizumab. We also understand that it is sometimes of difficulty to obtain pembrolizumab in some of these patients as well as suitability to use pembrolizumab. So, within this particular clinical trial, we did allow for patients an investigator’s choice of whether or not they should be treated with pembrolizumab if they were to be randomized into the control arm,” Loong explained. “Within the protocol, this is specified to include at least 80% of the patients with the intention to be treated with pembrolizumab in the control arm, and this is known as the ITT/pembrolizumab population.”

Patients were initially randomized in a 1:1 fashion, according to Loong; however, with a protocol amendment, this has changed to a 2:1 randomization “based on the promising results that we saw on LIBRETTO-001 study.” Participants received either selpercatinib at a twice-daily dose of 160 mg (n = 159) or carboplatin at area under the curve of 5 or cisplatin at 75 mg/m² plus pemetrexed at 500 mg/m² with or without pembrolizumab at 200 mg (n = 102).

Notably, those in the control arm had the option to cross over to receive selpercatinib upon disease progression confirmed by BICR.

PFS by BICR in the ITT/pembrolizumab and ITT populations served as the primary end points of the trial. Secondary end points included overall survival, ORR, and duration of response (DOR), as well as CNS ORR, DOR, and time to progression. Other key end points include safety and patient-reported outcomes.

Patients were enrolled in the trial between March 2020 and August 2022. At the time of the data cutoff date of May 1, 2023, a total of 261 patients underwent randomization at 103 centers spanning 23 countries. A protocol-specified interim analysis was performed following 98 BICR PFS events were reported in the ITT/pembrolizumab population.

“Of note is that in the control group, out of the 68 patients who discontinued treatment, 42 actually subsequently crossed over to selpercatinib as per what was allowed in the study protocol,” Loong said.

Key baseline characteristics were noted to be well balanced between the treatment arms.

The median patient age across the selpercatinib and control arms was 61 years (range, 31-84), with slightly more than half of patients being female (50.4% vs 57.8%, respectively) and most being never smokers (65.9% vs 71.1%). More than half of patients were Asian (58.9% vs 51.9%). In the selpercatinib arm, 58.1% of patients were enrolled in the trial in an East Asian region and 41.9% were enrolled in a Non-East Asia region; in the control arm, these rates were 49.4% and 50.6%, respectively.

Most patients had stage IV disease (94.6% vs 91.6%) and an ECOG performance status of 1 (62.8% vs 62.7%). Regarding PD-L1 expression in the selpercatinib arm, 42.6% of patients were PD-L1 positive, 24.0% were negative, and 33.3% had this information missing; in the control arm, these rates were 47.0%, 14.5%, and 38.6%, respectively.

“What I would specifically like to highlight is that about 20%—again, well balanced in both arms of patients—had brain metastases at baseline,” Loong said.

Data from the preplanned subgroup analysis showed consistent PFS benefit with selpercatinib vs the control regimen in all subsets. The HR for PFS in those enrolled to the trial in the East Asia region was 0.422 (95% CI, 0.241-0.741) and 0.554 (95% CI, 0.314-0.978) in those enrolled in a Non-East Asia region. In those with brain metastases at baseline, the HR for PFS was 0.508 (95% CI, 0.234-1.105); in patients without those metastases, the HR was 0.478 (95% CI, 0.299-0.762).

“Of note is also the fact that the positivity or negativity of PD-L1 expression in tumors did not seem to have any effect on whether patients favored selpercatinib or the control, and all these patients seemed to favor selpercatinib,” Loong said.

Additional Findings

Additional findings showed that the ORR by RECIST v1.1 criteria proved to be higher with selpercatinib vs the control regimen, at 83.7% and 65.1%, respectively. Responses also proved to be more durable with the RET inhibitor vs the control regimen, with a median DOR of 24.2 months (95% CI, 17.9-NE) and 11.5 months (95% CI, 9.7-23.3), respectively.

“OS data [are] currently immature, with a censoring rate of [approximately] 80%; it is also kind of confounded by the fact that within the protocol, there were 61% of patients who crossed over. There were also patients who are able to access select RET inhibitors out of protocol, which brings the overall effective crossover rate to 75% within this clinical trial. The currently reported HR is 0.961, but the data are still immature.”

In those with measurable CNS disease at baseline, selpercatinib (n = 17) improved intracranial ORR by RECIST v1.1 criteria vs the control regimen (n = 12), at 82.4% and 58.3%, respectively; the intracranial complete response rates were 35.3% and 16.7%, respectively. The 12-month intracranial DOR rates were 76.0% (95% CI, 42.2%-91.6%) and 62.5% (95% CI, 14.2%-89.3%), respectively. Additionally, the median intracranial PFS in the selpercatinib arm was 16.1 months (95% CI, 8.8-NE) vs 10.4 months (95% CI, 3.8-NE) in the control arm.

Notably, the time to CNS progression was delayed with selpercatinib vs the control regimen. In those without baseline CNS metastases, the 12-month cumulative incidence rates (CIRs) in the selpercatinib (n = 99) and control (n = 51) arms were 1.1% (95% CI, 0.1%-5.2%) and 14.7% (95% CI, 5.7%-27.6%), respectively (cause-specific HR, 0.17; 95% CI, 0.04-0.69). In those with baseline CNS metastases, the CIRs at 12 months in the selpercatinib (n = 21) and control (n = 21) arms were 25.7% (95% CI, 8.8%-46.7%) and 33.3% (95% CI, 14.3%-53.8%), respectively (cause-specific HR, 0.61; 95% CI, 0.19-1.92).

The median time on the RET inhibitor was approximately 70% longer than the control regimen, at 16.7 months vs 9.8 months, respectively.

Safety Analysis

Any-grade adverse effects (AEs) occurred in all patients on the selpercatinib arm (n = 158) vs 99% of those in the control arm (n = 98); these AEs were grade 3 or higher for 70.3% and 57.1% of patients, respectively. In the selpercatinib arm, AEs led to dose adjustments and reductions in 77.8% and 51.3% of patients, respectively; in the control arm, these rates were 75.5% and 28.6%, respectively. Toxicities resulted in treatment discontinuation for 10.1% vs 2.0% of patients, respectively.

“In terms of the safety profile, the most common [AEs] that were seen in patients treated with selpercatinib, included AST increase, ALT increase, hypertension, diarrhea, and edema and these were consistent with what we’ve seen in prior clinical trials, including LIBRETTO-001, as well as in our clinical practice,” Loong said. “Most of the [AEs] were essentially well managed with dose modifications and dose reductions in the patients who were treated.”

Specifically, the most common any-grade toxicities experienced with selpercatinib and the control regimen included increased aspartate aminotransferase (AST; 49% vs 39%), increased alanine aminotransferase (ALT; 38% vs 37%), hypertension (28% vs 4%), diarrhea (43% vs 23%), edema (39% vs 28%), dry mouth (39% vs 6%), increased blood bilirubin (36% vs 1%), rash (31% vs 29%), fatigue (29% vs 45%), thrombocytopenia (23% vs 22%), leukopenia (24% vs 26%), abdominal pain (25% vs 17%), increased blood creatinine (23% vs 16%), neutropenia (21% vs 17%), constipation (22% vs 39%), QT prolongation (11% vs 1%), reduced appetite (17% vs 32%), pyrexia (13% vs 24%), vomiting (13% vs 23%), nausea (13% vs 43%), anemia (10% vs 48%), and pruritus (10% vs 22%).

Selpercatinib was also found to delay time to deterioration of pulmonary symptoms (HR, 0.34; 95% CI, 0.20-0.55%) and overall physical function (HR, 0.60; 95% CI, 0.40-0.90).

Disclosures: Dr Loong disclosed advisory roles for Boehringer-Ingelheim, Celgene, Daiichi-Sankyo, Eli Lilly, Illumina, Novartis, Merck Sereno, Takeda, and George Clinical, and speaker engagements with AbbVie, Bayer, Daiichi-Sankyo, Eisai, Eli Lilly, Guardant Health, Novartis. He also disclosed receiving travel support from Bayer, Boehringer-Ingelheim, MSD, Novartis, and Pfizer; research funding from MSD, Mundipharma, and Novartis; and having membership with Pharmacy and Poisons Committee and Pharmacy & Poisons Board of Hong Kong.

References

1. Loong HHF, Goto K, Solomon BJ, et al. Randomized phase II study of first-line selpercatinib versus chemotherapy and pembrolizumab in RET fusion-positive NSCLC. Ann Oncol. 2023;34(suppl 2):S1303. doi:10.1016/j.annonc.2023.10.059
2. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive non-small cell lung cancer. FDA. September 21, 2022. Accessed October 21, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-selpercatinib-locally-advanced-or-metastatic-ret-fusion-positive-non-small-cell-lung
3. Drilon A, Subbiah V, Gautschi O, et al. Selpercatinib in patients with RET fusion-positive non-small-cell lung cancer: updated safety and efficacy from the registrational LIBRETTO-001 phase I/II trial. J Clin Oncol. 2023;41(2):385-394. doi:10.1200/JCO.22.00393
4. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. N Engl J Med. 2018;378(22):2078-2092. doi:10.1056/NEJMoa1801005