Retevmo was evaluated in a phase I/II trial: the largest trial ever reported in patients with RET-driven cancer1
702 patients with certain RET-altered advanced solid tumors were included in LIBRETTO-001, an open-label, single-arm, multicenter, phase I/II, multicohort trial.1-3*
Phase 1 dose escalation: Retevmo dosed at 20 mg QD–240 mg BID. Intra-patient dose escalation was allowed by protocol.4
Phase 2 dose: Retevmo dosed at 160 mg BID.4
See full Prescribing Information for dosing instructions.
Objective response rate (ORR) was defined as complete response (CR) + partial response (PR) and was assessed by independent review committee (IRC) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.1
The intent-to-treat (ITT) population was analyzed in the LIBRETTO-001 trial because this type of analysis avoids the selective exclusion of patients, which can lead to a biased assessment of an intervention's effectiveness.5-8
*Patients with RET-mutant NSCLC and RET-mutant thyroid cancer (non-medullary thyroid cancer (non-MTC)) were not enrolled in the trial since RET is not the driver of tumor growth in these cancers.1,9
†Patients with advanced or metastatic RET fusion-positive NSCLC who had progressed on platinum-based chemotherapy and those without prior systemic therapy were enrolled in separate cohorts.1
‡Non-medullary thyroid cancers (non-MTC) by histology included papillary (n=31), poorly differentiated (n=4), anaplastic (n=2), and Hurthle cell (n=1).1,3
§Other tumors included pancreatic cancer (n=7), colon cancer (n=5), and adrenal gland carcinoma (n=3).3
‖Number of patients included in the initial efficacy analysis. Efficacy was based on patients who had at least 6 months of follow-up.1
¶Efficacy was evaluated in 105 adult patients with metastatic RET fusion-positive NSCLC who were previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. All 105 patients received systemic therapy (with a median of 3 prior systemic regimens). 58 of the 105 patients received prior anti-PD-1/PD-L1 therapy, and 50 of the 105 patients received a prior multikinase inhibitor (MKI).1,3
#Patients in this cohort received no prior systemic therapy other than radioactive iodine (RAI).1
**Patients in this cohort received a prior systemic therapy (including sorafenib, lenvatinib, or both) other than RAI.1
††The efficacy of Retevmo was evaluated in 55 patients with RET-mutant advanced MTC who were previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001.1
BID=twice daily; CNS=central nervous system; DoR=duration of response; MTC=medullary thyroid cancer; NSCLC=non-small cell lung cancer; OS=overall survival; PFS=progression-free survival; QD=once daily; RET=rearranged during transfection.
See efficacy results in patients with certain RET-driven NSCLC and thyroid cancer
Response in patients with metastatic RET fusion-positive NSCLC1
Treatment-naive patients (n=39)1,10
Median DoR not yet reached
(95% CI: 12, NE)
Median follow-up: 7.4 months1,11
The major efficacy outcome measures in LIBRETTO-001 were objective response rate (ORR) and duration of response (DoR). Disease control rate (DCR) was not a prespecified endpoint and is a post-hoc calculation. DCR is defined as ORR (CR + PR) + SD.
Stable disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. In the setting of a single-arm trial without the ability to compare with a control arm provided by a randomized trial, the interpretation and clinical relevance of a best overall response of SD are not clear, and it is not possible to determine if SD is a result of natural disease progression or treatment with Retevmo.1,12
For treatment-naive patients who responded (n=33) to treatment, the median time to objective response was 1.8 months (range: 0.7, 3.7)13‡‡
Time to any and best response was a prespecified secondary endpoint.13
Time-to-event endpoints are not interpretable in a single-arm study.
Previously treated§§ patients (n=105)1,10
Median DoR
17.5
months
(95% CI: 12, NE)
Median follow-up: 12.1 months1,11
For previously treated§§ patients who responded (n=67) to treatment, the median time to objective response was 1.9 months (range: 0.7, 13.7)13‡‡
Time to any and best response was a prespecified secondary endpoint.13
Time-to-event endpoints are not interpretable in a single-arm study.
All results reviewed by an IRC.1,10,11,13
Due to rounding, numbers presented may not add up to the totals indicated and percentages may not reflect the absolute figures for the same reason.
‡‡According to the protocol, scans were to be performed every 8 weeks (±7 days). The protocol allowed investigators to conduct an initial scan at 4 weeks (±7 days).14
§§Efficacy was evaluated in 105 adult patients with metastatic RET fusion-positive NSCLC who were previously treated with platinum chemotherapy enrolled into a cohort of LIBRETTO-001. All 105 patients received systemic therapy (with a median of 3 prior systemic regimens).1
Retevmo has CNS activity in patients with measurable brain metastases (n=11). CNS ORR was observed in the LIBRETTO-001 trial1‖‖
No patients received radiation therapy (RT) to the brain within 2 months prior to study entry.1
CNS DoR was ≥6 months in all responders with measurable brain metastases1‖‖
‖‖Patients previously treated with platinum-based chemotherapy and with measurable CNS lesions at baseline according to IRC assessment.1
CNS ORR and CNS DoR were prespecified secondary endpoints in the LIBRETTO-001 trial that were evaluated and confirmed by an IRC.1,3
Additional CNS analysis
In a prespecified analysis which included both treatment-naive and treatment-experienced patients with metastatic RET fusion-positive NSCLC, an additional 11 patients with measurable brain metastases were included (n=22). Intracranial responses were seen in 18 of these 22 patients (82% CNS ORR) (95% CI: 60, 95), with a 9.4-month median CNS DoR (95% CI: 7.4, NE) in the LIBRETTO-001 trial.15
The initial CNS data analysis included 11 patients with measurable brain metastases who completed prior RT >2 months prior to Retevmo and were previously treated with platinum-based chemotherapy. An additional CNS analysis included 11 more measurable patients who could have received prior RT ≤2 months of Retevmo; 9 were previously treated with or without platinum-based chemotherapy and 2 were treatment naive. In total, 20 out of 22 were previously treated with: platinum chemotherapy (n=16), anti-PD-1/PD-L1 therapy (n=12), and/or a multi-targeted kinase inhibitor (MKI) (n=11). 8 out of 22 received prior brain RT; 6 of the 8 completed brain RT >2 months prior to Retevmo.1,15
Select Important Safety Information
Hypertension occurred in 35% of patients, including Grade 3 hypertension in 17% and Grade 4 in one (0.1%) patient. Overall, 4.6% had their dose interrupted and 1.3% had their dose reduced for hypertension. Treatment-emergent hypertension was most commonly managed with anti-hypertension medications. Do not initiate Retevmo in patients with uncontrolled hypertension. Optimize blood pressure prior to initiating Retevmo. Monitor blood pressure after 1 week, at least monthly thereafter, and as clinically indicated. Initiate or adjust anti-hypertensive therapy as appropriate. Withhold, reduce dose, or permanently discontinue Retevmo based on the severity.
Response in patients with advanced or metastatic RET fusion-positive thyroid cancer (non-MTC)1¶¶
Systemic therapy-naive## patients (n=8)1,16
Median DoR not yet reached
(95% CI: NE, NE)
Median follow-up: 8.8 months1,11
The major efficacy outcome measures in LIBRETTO-001 were ORR and DoR. DCR was not a prespecified endpoint and is a post-hoc calculation. DCR is defined as ORR (CR + PR) + SD.
SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, per RECIST v1.1. In the setting of a single-arm trial without the ability to compare with a control arm provided by a randomized trial, the interpretation and clinical relevance of a best overall response of SD are not clear, and it is not possible to determine if SD is a result of natural disease progression or treatment with Retevmo.1,12
Previously treated*** patients (n=19)1,16
Median DoR
18.4
months
(95% CI: 7.6, NE)
Median follow-up: 17.5 months1,11
All results reviewed by an IRC.1,11,16
¶¶Primary tumor histologies included papillary thyroid cancer, poorly differentiated thyroid cancer, anaplastic thyroid cancer, and Hurthle cell thyroid cancer.1
##Patients received no prior systemic therapy other than RAI.1
***Patients received a prior systemic therapy (including sorafenib, lenvatinib, or both) other than RAI.1
Response in patients with advanced or metastatic RET-mutant MTC1
Cabozantinib/vandetanib-naive patients (n=88)1,17
Median DoR
22.0
months
(95% CI: NE, NE)
Median follow-up: 7.8 months1,11
The major efficacy outcome measures in LIBRETTO-001 were ORR and DoR. DCR was not a prespecified endpoint and is a post-hoc calculation. DCR is defined as ORR (CR + PR) + SD.
SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, per RECIST v1.1. In the setting of a single-arm trial without the ability to compare with a control arm provided by a randomized trial, the interpretation and clinical relevance of a best overall response of SD are not clear, and it is not possible to determine if SD is a result of natural disease progression or treatment with Retevmo.1,12
Patients previously treated††† with cabozantinib and/or vandetanib (n=55)1,17
Median DoR not yet reached
(95% CI: 19.1, NE)
Median follow-up: 14.1 months1,11
All results reviewed by an IRC.1,11,17
†††The efficacy of Retevmo was evaluated in 55 patients with RET-mutant advanced MTC who were previously treated with cabozantinib or vandetanib enrolled into a cohort of LIBRETTO-001.1
Because Retevmo is approved across all lines of therapy, including first line in certain RET-driven cancers, consider waiting for genomic test results, including RET alteration results, before making therapeutic decisions1
An FDA-approved test for the detection of RET gene fusions and RET gene mutations is not currently available for Retevmo.1
Select Important Safety Information
Retevmo can cause concentration-dependent QT interval prolongation. An increase in QTcF interval to >500 ms was measured in 6% of patients and an increase in the QTcF interval of at least 60 ms over baseline was measured in 15% of patients. Retevmo has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. Monitor patients who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, and severe or uncontrolled heart failure. Assess QT interval, electrolytes and TSH at baseline and periodically during treatment, adjusting frequency based upon risk factors including diarrhea. Correct hypokalemia, hypomagnesemia and hypocalcemia prior to initiating Retevmo and during treatment. Monitor the QT interval more frequently when Retevmo is concomitantly administered with strong and moderate CYP3A inhibitors or drugs known to prolong QTc interval. Withhold and dose reduce or permanently discontinue Retevmo based on the severity.
National Comprehensive Cancer Network® (NCCN®) NSCLC Panel recommends selpercatinib (Retevmo) as a first-line or subsequent‡‡‡ therapy option for patients with metastatic NSCLC who are positive for RET rearrangements18
NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommendations for RET alteration-positive thyroid cancer19:
Selpercatinib is a recommended systemic therapy option (category 2A§§§) in RET fusion-positive:
- Structurally persistent/recurrent locoregional or distant metastatic (including bone or CNS metastases) papillary carcinoma, follicular carcinoma, or Hurthle carcinoma, that is not amenable to RAI therapy
Selpercatinib is a preferred systemic therapy option (category 2A§§§) in RET fusion-positive:
- Metastatic anaplastic carcinoma‖‖‖
Selpercatinib is a preferred systemic therapy option (category 2A§§§) in RET mutation-positive medullary carcinoma¶¶¶:
- Locoregional, unresectable carcinoma that is symptomatic or progressing by RECIST criteria
- Distant metastatic, asymptomatic carcinoma that is unresectable and progressing by RECIST criteria
- Distant metastatic, symptomatic or progressive carcinoma
‡‡‡If not previously used.
§§§Category 2A: Based upon lower-level evidence, and there is uniform NCCN consensus that the intervention is appropriate.
ǁǁǁMolecular testing should include BRAF, NTRK, ALK, RET, and tumor mutational burden.
¶¶¶RET somatic genotyping in patients who are germline wild-type or germline unknown.
CI=confidence interval; NE=not estimable.
References: 1. Retevmo (selpercatinib) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021. 2. Phase 1/2 study of LOXO-292 in patients with advanced solid tumors, RET fusion-positive solid tumors, and medullary thyroid cancer (LIBRETTO-001). https://clinicaltrials.gov/ct2/show/NCT03157128. Updated July 2, 2020. Accessed July 16, 2020. 3. Data on File, Lilly USA, LLC, DOF-SE-US-0033. 4. Drilon A, Oxnard G, Wirth L, et al. Registrational results of LIBRETTO-001: a phase 1/2 trial of selpercatinib (LOXO-292) in patients with RET fusion-positive lung cancers. Presented at: 2019 World Conference on Lung Cancer; September 7–10, 2019; Barcelona, Spain. 5. 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. 6. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. 7. McCoy CE. Understanding the intention-to-treat principle in randomized controlled trials. West J Emerg Med. 2017;18(6):1075-1078. 8. Gupta SK. Intention-to-treat concept: a review. Perspect Clin Res. 2011;2(3):109-112. 9. Mulligan LM. GDNF and the RET receptor in cancer: new insights and therapeutic potential. Front Physiol. 2019;9:1873. 10. Data on File, Lilly USA, LLC, DOF-SE-US-0023. 11. Data on File, Lilly USA, LLC, DOF-SE-US-0032. 12. Villaruz LC, Socinski MA. The clinical viewpoint: definitions, limitations of RECIST, practical considerations of measurement. Clin Cancer Res. 2013;19(10):2629-2636. 13. Data on File, Lilly USA, LLC, DOF-SE-US-0028. 14. Data on File, Lilly USA, LLC, DOF-SE-US-0013. 15. Subbiah V, Gainor JF, Oxnard GR, et al. Intracranial activity of selpercatinib (LOXO-292) in RET fusion-positive non-small cell lung cancer (NSCLC) patients on the LIBRETTO-001 trial. Poster presented at: 2020 ASCO Annual Meeting; May 29–June 2, 2020; Virtual Meeting. Abstract 9516. 16. Data on File, Lilly USA, LLC, DOF-SE-US-0031. 17. Data on File, Lilly USA, LLC, DOF-SE-US-0024. 18. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.8.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed September 15, 2020. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org. 19. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Thyroid Carcinoma V.2.2020. © National Comprehensive Cancer Network, Inc. 2020. All rights reserved. Accessed July 15, 2020. To view the most recent and complete version of the guidelines, go online to https://www.nccn.org.