Abstract
LIBRETTO-001 (ClinicalTrials.gov identifier: NCT03157128) is a registrational phase I/II, single-arm, open-label trial of selpercatinib in RET-dependent cancers. With 19 months of additional follow-up, we report the final efficacy and safety results of selpercatinib in patients with RET fusion–positive non–small cell lung cancer (NSCLC) who had previously received platinum-based chemotherapy (N = 247) or were treatment-naïve (N = 69). The objective response rate (ORR) was 62% for pretreated patients and 83% for treatment-naïve patients. Duration of response (DoR) was 31.6 months for pretreated and 20.3 months for treatment-naïve patients (median follow-up approximately 38 months). Median progression-free survival (PFS) was 26.2 months for pretreated and 22.0 months for treatment-naïve patients (median follow-up approximately 40 months). Median overall survival was 47.6 months in pretreated patients and was not reached in the treatment-naïve group (median follow-up approximately 43 months). At the 3-year landmark estimate, 57% of pretreated and 66% of treatment-naïve patients were alive. Among 26 patients with measurable CNS metastases at baseline, the CNS-ORR was 85% with a CNS-DoR of 9.4 months and CNS-PFS of 11.0 months. The safety profile of selpercatinib was consistent with previous reports. With substantial additional follow-up, selpercatinib continued to show durable responses and intracranial activity, with a manageable safety profile in patients with RET fusion–positive NSCLC.
INTRODUCTION
RET fusions are targetable alterations in non–small cell lung cancer (NSCLC). Selpercatinib, a highly selective RET kinase inhibitor with CNS penetration,1-3 was approved for the treatment of RET fusion–positive NSCLC on the basis of the results of the single-arm phase I/II trial LIBRETTO-001 (ClinicalTrials.gov identifier: NCT03157128).1,4 These results were confirmed in the recent randomized phase III trial LIBRETTO-431 (ClinicalTrials.gov identifier: NCT04194944); at an interim analysis, selpercatinib demonstrated superior progression-free survival (PFS) over platinum-based chemotherapy with or without pembrolizumab in first-line treatment.2 On the basis of these data, current treatment guidelines recommend selpercatinib as first-line treatment for RET fusion–positive NSCLC.5-7 Here, we report long-term efficacy and safety from the final analysis of selpercatinib in patients with RET fusion–positive NSCLC in the LIBRETTO-001 clinical trial, providing 3-year response outcomes, PFS and overall survival (OS), including the first reports of median OS in pretreated patients and median PFS in patients with measurable CNS metastasis at baseline. To our knowledge, this is the first mature estimation of median OS for selpercatinib and offers insights into how OS may mature in LIBRETTO-431.
METHODS
Study Design
Patients received selpercatinib in 28-day continuous cycles at doses of 20 mg once daily to 240 mg twice daily during the dose-escalation phase I. The recommended dose for phase II was 160 mg twice daily.4 Treatment continued until disease progression, death, withdrawal of consent, or unacceptable toxicity. Patients with progressive disease could continue selpercatinib if they were deriving clinical benefit according to the investigator and with sponsor approval.
Patients with RET fusion–positive, locally advanced or metastatic NSCLC were enrolled. Key exclusion criteria included symptomatic primary CNS tumor, metastases, leptomeningeal carcinomatosis, or untreated spinal cord compression. Patients with brain metastases were eligible if neurologic symptoms and CNS imaging were stable and their steroid dose was stable for 14 days before starting selpercatinib. For patients who had previous CNS radiation, intracranial lesions needed to show postradiation progression to be selected as a target lesion at baseline. Full criteria are in the protocol. This report includes treatment-naïve or previously treated patients with RET fusion–positive NSCLC. Pretreated patients could have received any number of previous therapies, including immune checkpoint inhibitors, multitargeted kinase inhibitors, and chemotherapy, but must have received previous platinum-based chemotherapy.
This trial followed the Good Clinical Practice guidelines, the Declaration of Helsinki, and all relevant regulations. The protocol was approved by the institutional review board or independent ethics committee at each site. Written informed consent was obtained from all patients or their guardians, if younger than 18 years.
Efficacy and Safety Measures
Efficacy and safety assessments were performed according to the protocol as previously described.4 The primary end point was objective response rate (ORR) assessed by an independent review committee (IRC) using RECIST version 1.1. All responses required confirmation through a follow-up scan at least 4 weeks after the initial scan indicating a response. Secondary end points included duration of response (DoR), PFS, OS, CNS-ORR, CNS-DoR, and CNS-PFS. For patients with brain metastases, CNS-ORR was assessed by IRC according to RECIST 1.1. Safety was analyzed through adverse events (AEs), graded according to the Common Terminology Criteria for Adverse Events, version 4.03.
Statistical Analysis
The data cutoff for this analysis was January 13, 2023, adding 19 months of follow-up since the previous data cutoff of August 2021.8 CIs for response rates were calculated using the Clopper-Pearson method. DoR, PFS, and OS were estimated using the Kaplan-Meier method, and median follow-up times for each efficacy end point using the reverse Kaplan-Meier method.
RESULTS
Patients
Between May 9, 2017, and January 13, 2023, 837 patients were enrolled. The RET fusion–positive NSCLC safety population included 362 patients, and the efficacy population included 356 patients, with 247 previously treated with platinum-based chemotherapy and 69 treatment-naïve (Table 1; Fig 1).
TABLE 1.
Demographic and Clinical Characteristics of Patients at Baseline
| Characteristic | Previous Platinum Chemotherapy (n = 247) | Treatment-Naïve (n = 69) |
|---|---|---|
| Age, years | ||
| Median (range) | 61.0 (23-81) | 63.0 (23-92) |
| Distribution, No. (%) | ||
| <45 | 33 (13.4) | 7 (10.1) |
| 45 to <65 | 127 (51.4) | 31 (44.9) |
| 65 to <75 | 70 (28.3) | 24 (34.8) |
| 75 to <85 | 17 (6.9) | 4 (5.8) |
| ≥85 | 0 | 3 (4.3) |
| Sex, No. (%) | ||
| Female | 140 (56.7) | 43 (62.3) |
| Male | 107 (43.3) | 26 (37.7) |
| Race, No. (%)a | ||
| White | 108 (43.7) | 48 (69.6) |
| Asian | 118 (47.8) | 13 (18.8) |
| Black | 12 (4.9) | 4 (5.8) |
| Other | 6 (2.4) | 4 (5.8) |
| Missing | 2 (0.8) | 0 |
| Smoking status, No. (%) | ||
| Never | 165 (66.8) | 48 (69.6) |
| Former | 78 (31.6) | 19 (27.5) |
| Current | 4 (1.6) | 2 (2.9) |
| ECOG performance status score, No. (%) | ||
| 0 | 90 (36.4) | 25 (36.2) |
| 1 | 150 (60.7) | 40 (58.0) |
| 2 | 7 (2.8) | 4 (5.8) |
| NSCLC histologic subtype, No. (%) | ||
| Adenocarcinoma | 221 (89.5) | 62 (89.9) |
| Large cell neuroendocrine carcinoma | 3 (1.2) | 0 |
| Squamous cell carcinoma | 1 (0.4) | 0 |
| NSCLC-NOS | 22 (8.9) | 7 (10.1) |
| Stage of disease, No. (%) | ||
| IIIB or IIIC | 7 (2.8) | 2 (2.9) |
| IV | 157 (63.6) | 50 (72.5) |
| IVA | 29 (11.7) | 4 (5.8) |
| IVB | 27 (10.9) | 8 (11.6) |
| IVC | 15 (6.1) | 1 (1.4) |
| Previous systemic lines, No. (%) | ||
| Median | 2 | 0 |
| 1-2 | 140 (56.7) | 0 |
| ≥3 | 107 (43.3) | 0 |
| Previous regimen, No. (%) | ||
| Platinum-based chemotherapy | 247 (100) | NA |
| Anti–PD-1 or anti–PD-L1 therapy | 144 (58.3) | NA |
| Multikinase inhibitor | 78 (31.6) | NA |
| Cabozantinib | 25 (10.1) | 0 |
| Vandetanib | 12 (4.9) | 0 |
| Sorafenib | 0 | 0 |
| Lenvatinib | 8 (3.2) | 0 |
| Other MKIs | 52 (21.1) | 0 |
| Otherb | 102 (41.3) | NA |
| RET fusion, No. (%)c | ||
| KIF5B-RET | 153 (61.9) | 48 (69.6) |
| CCDC6-RET | 53 (21.5) | 10 (14.5) |
| NCOA4-RET | 5 (2.0) | 1 (1.4) |
| Other | 15 (6.1) | 2 (2.9) |
| Molecular assay type, No. (%)d | ||
| NGS on tumor | 209 (84.6) | 42 (60.9) |
| NGS on plasma or blood | 23 (9.3) | 21 (30.4) |
| PCR | 4 (1.6) | 1 (1.4) |
| FISH | 10 (4.0) | 5 (7.2) |
| CNS metastases at baselinee | 77 (31.2) | 16 (23.2) |
NOTE. Percentages may not total to 100 because of rounding.
Abbreviations: ECOG, Eastern Cooperative Oncology Group; FISH, fluorescent in situ hybridization; NA, not applicable; NGS, next generation sequencing; NOS, not otherwise specified; NSCLC, non–small cell lung cancer; MKI, multikinase inhibitor; PCR, polymerase chain reaction; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.
Patients reported race.
In other, VEGF/VEGFR inhibitor was the most common (n = 80).
Unknown RET fusion partners (n = 30) are not listed.
Other molecular assays (n = 1) are not listed.
CNS metastases at baseline by investigator assessment; includes both measurable and nonmeasurable CNS metastases.
FIG 1.
Flow diagram of patient disposition. Other cohorts included 19 patients who had received systemic therapies other than platinum-based chemotherapy and 21 patients with nonmeasurable disease. In total, 50 patients (72%) discontinued treatment in the treatment-naïve group and 164 (66%) in the pretreated group. aThe safety analysis set included six patients who received previous treatment with a selective RET inhibitor; these patients were not included in the NSCLC efficacy analysis set. Patients who had received at least one dose of selpercatinib and achieved at least 6 months of potential follow-up time from the first dose of selpercatinib (or disease progression or death, whichever occurred first), as of 13 January 2023, were considered eligible for efficacy analyses. Of the 356 patients with RET fusion–positive NSCLC (independent of analysis set), 107 patients had investigator-identified CNS metastasis. Twenty-six had measurable and 81 had nonmeasurable CNS disease at baseline as assessed by an independent review committee. NSCLC, non–small cell lung cancer.
Efficacy
The ORR was 62% (95% CI, 55 to 68) in patients previously treated with platinum-based chemotherapy and 83% (95% CI, 72 to 91) in treatment-naïve patients, with 8% and 7% achieving a complete response, respectively (Table 2; Appendix Fig A1, online only). Appendix Tables A1 and A2 show efficacy summaries from previous data cutoffs. Median PFS in pretreated patients was 26.2 months (95% CI, 19.3 to 35.7) with a median follow-up of 41.2 months. In treatment-naïve patients, median PFS was 22.0 months (95% CI, 16.5 to 24.9) with a median follow-up of 38.9 months (Table 2; Fig 2).
TABLE 2.
Efficacy Results by IRC Assessment
| Outcome | Previous Platinum Chemotherapy (n = 247) | Treatment-Naïve (n = 69) |
|---|---|---|
| ORRa | ||
| No. (%) | 152 (61.5) | 57 (82.6) |
| 95% CI | 55.2 to 67.6 | 71.6 to 90.7 |
| Best overall response, No. (%) | ||
| Complete response | 20 (8.1) | 5 (7.2) |
| Partial response | 132 (53.4) | 52 (75.4) |
| Stable disease | 80 (32.4) | 7 (10.1) |
| Progressive disease | 7 (2.8) | 3 (4.3) |
| Not evaluable | 8 (3.2) | 2 (2.9) |
| Time to response, months | ||
| Median (range) | 1.9 (0.7-44.2) | 1.8 (0.7-10.8) |
| DoRb | ||
| Patients with a response, No. | 152 | 57 |
| Patients with censored data, No. (%) | 75 (49.3) | 25 (43.9) |
| DoR, months, median (95% CI) | 31.6 (20.4 to 42.3) | 20.3 (15.4 to 29.5) |
| Duration of follow-up, months, median (Q1-Q3) | 39.5 (24.6-45.0) | 37.1 (24.0-45.1) |
| 1-year DoR, % (95% CI) | 73.0 (65.0 to 79.5) | 66.7 (52.4 to 77.6) |
| 2-year DoR, % (95% CI) | 55.1 (46.4 to 62.9) | 38.1 (24.5 to 51.6) |
| 3-year DoR, % (95% CI) | 44.7 (35.7 to 53.4) | 35.4 (22.0 to 49.0) |
| PFS | ||
| Patients with censored data, No. (%) | 114 (46.2) | 31 (44.9) |
| PFS, months, median (95% CI) | 26.2 (19.3 to 35.7) | 22.0 (16.5 to 24.9) |
| Duration of follow-up, months, median (Q1-Q3) | 41.2 (24.9-46.9) | 38.9 (19.4-46.9) |
| 1-year PFS, % (95% CI) | 70.6 (64.2 to 76.1) | 70.8 (58.0 to 80.3) |
| 2-year PFS, % (95% CI) | 52.3 (45.4 to 58.7) | 44.9 (31.8 to 57.3) |
| 3-year PFS, % (95% CI) | 41.1 (34.2 to 47.9) | 34.6 (22.3 to 47.3) |
| OS | ||
| Patients with censored data, No. (%) | 137 (55.5) | 43 (62.3) |
| OS, months, median (95% CI) | 47.6 (35.9 to NE) | NE (37.8 to NE) |
| Duration of follow-up, months, median (Q1-Q3) | 44.6 (37.6-49.8) | 41.9 (34.3-47.6) |
| 1-year OS, % (95% CI) | 87.9 (83.1 to 91.5) | 94.1 (85.1 to 97.8) |
| 2-year OS, % (95% CI) | 67.9 (61.5 to 73.5) | 74.3 (61.9 to 83.1) |
| 3-year OS, % (95% CI) | 56.6 (49.8 to 62.8) | 65.6 (52.4 to 75.9) |
Abbreviations: DoR, duration of response; IRC, independent review committee; NE, not evaluable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; Q1, first quartile; Q3, third quartile.
ORR was defined as the proportion of patients with best overall response of confirmed complete response or partial response. Response was confirmed by a repeat assessment ≥28 days.
Censored patients are represented as a percentage of responders by IRC assessment, treatment-naïve (n = 57) and pretreated patients (n = 152).
FIG 2.
Long-term PFS and OS with selpercatinib. Kaplan-Meier plots show PFS on the basis of IRC assessment for patients with RET fusion–positive NSCLC who (A) received previous platinum-based chemotherapy (n = 247) or (B) were treatment-naïve (n = 69). Kaplan-Meier plots show OS for patients with RET fusion–positive NSCLC who (C) received previous platinum-based chemotherapy (n = 247) or (D) were treatment-naïve (n = 69). Tick marks indicate censored data. Eligible patients are defined as treated patients. Patients enrolled in phase II who discontinued selective RET inhibitor(s) due to intolerance are excluded. IRC, independent review committee; NSCLC, non–small cell lung cancer; OS, overall survival; PFS, progression-free survival.
Median OS was 47.6 months (95% CI, 35.9 to not evaluable [NE]) for pretreated patients with a median follow-up of 44.6 months and 56% of patients censored. In the treatment-naïve group, median OS was not reached (95% CI, 37.8 to NE) with a median follow-up of 41.9 months and 62% of patients censored. 3-year OS rates were 57% (95% CI, 50 to 63) for pretreated patients and 66% (95% CI, 52 to 76) for treatment-naïve (Table 2; Fig 2).
Among 107 of 356 (30%) patients with brain metastases at baseline as assessed by the investigator, 26 had measurable CNS disease as deemed by the IRC. These patients had on-treatment serial brain imaging, which the IRC reviewed to determine CNS-ORR, CNS-DoR, and CNS-PFS. Objective intracranial responses were observed regardless of whether patients received previous radiation therapy or the timing of the previous radiation therapy, including in 8 of 10 patients who received previous brain radiation (Appendix Tables A3-A4; Appendix Fig A2). Among the patients with measurable CNS metastasis at baseline, CNS-ORR was 85% (95% CI, 65 to 96), with 27% achieving a complete response. Median CNS-DoR was 9.4 months (95% CI, 7.4 to 15.3) with a median follow-up of 25.8 months (Appendix Fig A3). Median CNS-PFS was 11.0 months (95% CI, 9.2 to 17.1) with a median follow-up of 33.1 months (Appendix Table A4).
Safety
In the safety analysis population (N = 362; all patients with RET fusion–positive NSCLC who received at least one dose of selpercatinib, including six previously treated with a selective RET inhibitor and excluded from the efficacy analysis set), the median time on treatment was 24.6 months. The most common (≥10%) grade ≥3 treatment-emergent AEs were hypertension (19%) and aspartate and ALT elevation (10%/15%; Appendix Table A5).
Dose withholding occurred in 254 patients (70%), dose reduction in 177 (49%), and discontinuation in 40 (11%), with only 16 (4%) due to a selpercatinib-related treatment-emergent AE (Appendix Table A6). Fatal treatment-emergent AEs occurred in 26 patients (7%), none considered related to selpercatinib.
DISCUSSION
We report final efficacy and safety analyses from the LIBRETTO-001 trial in patients with RET fusion–positive NSCLC with over 3 years of follow-up. In line with previous reports, selpercatinib showed substantial and durable antitumor activity in patients who received selpercatinib as first-line therapy, in those who had received previous platinum-based chemotherapy, and in those with CNS metastases at baseline.1,2,4
With 3.5 years of follow-up, median OS was 47.6 months in pretreated patients and not reached in treatment-naïve patients. This was substantially better than the median OS in the GLORY real-world study where RET fusion–positive patients were treated with nonselective RET inhibitors,9 and better or comparable to OS benefit of other selective agents targeting driver alterations.10-12 For comparison, the median OS for pretreated patients receiving other targeted therapies has been 25.1-51.4 months.12,13 For treatment-naïve patients, the LIBRETTO-001 OS between 2 and 3 years appears comparable to that reported with selective ALK inhibitors.14 Median CNS-PFS for patients with measurable brain metastases at baseline was 11.0 months, marking the first report for RET fusion–positive NSCLC and showing comparable PFS benefit to other selective agents targeting driver alterations.15 With an additional 19 months of follow-up, the safety profile of selpercatinib continues to be characterized by toxicities that are manageable by dose modifications and standard clinical care. Although dose reductions were seen in 49% of patients to manage AEs, only 4% discontinued due to selpercatinib-related toxicity, suggesting dose reduction effectively allows patients to continue treatment. Previous exposure-response analyses have suggested no PFS detriment at lower exposures, suggesting selpercatinib dose reduction may allow ongoing clinical benefit.16,17
Recently, the randomized phase III trial LIBRETTO-431 confirmed the clinical benefit of selpercatinib, with median OS not yet reached.2 To our knowledge, the data from LIBRETTO-001 constitute the first mature estimation of median OS for selpercatinib and provide insights into OS maturation in LIBRETTO-431. Finally, these results reinforce the importance of testing for RET fusions in NSCLC to identify patients who may benefit from first-line selpercatinib treatment.
ACKNOWLEDGMENT
The authors thank the investigators and site personnel for their participation in the study, as well as the clinical study participants and their families and caregivers, without whom this work would not be possible. The authors also thank Dinorath Olvera Ramos, employee of Eli Lilly and Company, for providing critical analysis and drafting an earlier version of the manuscript.
APPENDIX
TABLE A1.
Efficacy Comparison of Previous Data Cutoffs in the Previous Platinum Chemotherapy Population
| Data Cutoff Date | December 16, 2019 | March 30, 2020 | June 15, 2021 | January 13, 2023 |
|---|---|---|---|---|
| No. | 184 | 218 | 247 | 247 |
| ORR by IRC, % (95% CI) | 57 (49 to 64) | 57 (50 to 64) | 61 (55 to 67) | 62 (55 to 68) |
| DoR | ||||
| Patients with censored data, No. (%) | 79 (76.0) | 86 (69.4) | 92 (60.9) | 75 (49.3) |
| DoR, median (95% CI), months | 17.5 (12.1 to NE) | 17.5 (12.1 to NE) | 28.6 (20.4 to NE) | 31.6 (20.4 to 42.3) |
| Duration of follow-up, months, median | 9.2 | 12.0 | 21.2 | 39.5 |
| 1-year DoR, % (95% CI) | 71.9 (58.4 to 81.7) | 69.1 (58.1 to 77.8) | 73.1 (64.9 to 79.7) | 73.0 (65.0 to 79.5) |
| 2-year DoR, % (95% CI) | NR | NR | 55.8 (46.4 to 64.2) | 55.1 (46.4 to 62.9) |
| 3-year DoR, % (95% CI) | NR | NR | NR | 44.7 (35.7 to 53.4) |
| PFS | ||||
| Patients with censored data, No. (%) | 128 (69.6) | 144 (66.1) | 138 (55.9) | 114 (46.2) |
| PFS, months, median (95% CI) | 19.3 (14 to NE) | 19.3 (16.5 to NE) | 24.9 (19.3 to NE) | 26.2 (19.3 to 35.7) |
| Duration of follow-up, months, median | 11.0 | 13.6 | 24.7 | 41.2 |
| 1-year PFS, % (95% CI) | 69.1 (60.6 to 76.1) | 69.7 (62.2 to 75.9) | 70.5 (64.1 to 76.0) | 70.6 (64.2 to 76.1) |
| 2-year PFS, % (95% CI) | NR | NR | 51.4 (44.3 to 58.1) | 52.3 (45.4 to 58.7) |
| 3-year PFS, % (95% CI) | NR | NR | NR | 41.1 (34.2 to 47.9) |
Abbreviations: DoR, duration of response; IRC, independent review committee; NE, not estimable; NR, not reached; ORR, objective response rate; PFS, progression-free survival.
TABLE A2.
Efficacy Comparison of Previous Data Cutoffs in the Treatment-Naïve Population
| Data Cutoff Date | December 16, 2019 | March 30, 2020 | June 15, 2021 | January 13, 2023 |
|---|---|---|---|---|
| No. | 39 | 48 | 69 | 69 |
| ORR by IRC, % (95% CI) | 85 (70 to 94) | 85 (72 to 94) | 84 (73 to 92) | 83 (72 to 91) |
| DoR | ||||
| Patients with censored data, No. (%) | 26 (78.8) | 31 (75.6) | 32 (55.2) | 25 (43.9) |
| DoR, months, median (95% CI) | NE (12.0 to NE) | NE (12.0 to NE) | 20.2 (13.0 to NE) | 20.3 (15.4 to 29.5) |
| Duration of follow-up, months, median | 7.4 | 9.8 | 20.3 | 37.1 |
| 1-year DoR, % (95% CI) | 63.5 (34.0 to 82.6) | 65.0 (42.8 to 80.3) | 66.1 (51.6 to 77.3) | 66.7 (52.4 to 77.6) |
| 2-year DoR, % (95% CI) | NR | NR | 41.6 (25.6 to 56.8) | 38.1 (24.5 to 51.6) |
| 3-year DoR, % (95% CI) | NR | NR | NR | 35.4 (22.0 to 49.0) |
| PFS | ||||
| Patients with censored data, No. (%) | 30 (76.9) | 34 (70.8) | 37 (53.6) | 31 (44.9) |
| PFS, months, median (95% CI) | NE (13.8 to NE) | NE (13.8 to NE) | 22.0 (13.8 to NE) | 22.0 (16.5 to 24.9) |
| Duration of follow-up, months, median | 9.2 | 10.8 | 21.9 | 38.9 |
| 1-year PFS, % (95% CI) | 75 (56 to 87) | 67.6 (49.5 to 80.3) | 70.6 (57.8 to 80.2) | 70.8 (58.0 to 80.3) |
| 2-year PFS, % (95% CI) | NR | NR | 41.6 (26.8 to 55.8) | 44.9 (31.8 to 57.3) |
| 3-year PFS, % (95% CI) | NR | NR | NR | 34.6 (22.3 to 47.3) |
Abbreviations: DoR, duration of response; IRC, independent review committee; NE, not estimable; NR, not reached; ORR, objective response rate; PFS, progression-free survival.
TABLE A3.
CNS-ORR and CNS-DoR by Previous Radiotherapy Date on the Basis of IRC Assessment in Patients With Measurable CNS Lesions
| Outcome | With Brain RT | Without Brain RT (n = 16) | All Patients With Measurable CNS Lesions (n = 26) | ||
|---|---|---|---|---|---|
| Brain RT ≤2 Months Before First Dose (n = 3) | Brain RT >2 Months Before First Dose (n = 7) | All With Previous Brain RT (n = 10) | |||
| CNS-ORR | |||||
| No. (%) | 3 (100.0) | 5 (71.4) | 8 (80.0) | 14 (87.5) | 22 (84.6) |
| 95% CI | 29.2 to 100.0 | 29.0 to 96.3 | 44.4 to 97.5 | 61.7 to 98.4 | 65.1 to 95.6 |
| CNS best overall response, No. (%) a | |||||
| Complete response | 1 (33.3) | 1 (14.3) | 2 (20.0) | 5 (31.3) | 7 (26.9) |
| Partial response | 2 (66.7) | 4 (57.1) | 6 (60.0) | 9 (56.3) | 15 (57.7) |
| Stable disease | 0 (0.0) | 2 (28.6) | 2 (20.0) | 2 (12.5) | 4 (15.4) |
| Progressive disease | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| CNS-DoR | |||||
| Patients with censored data, No. (%)a | 1 (33.3) | 2 (40.0) | 3 (37.5) | 1 (7.1) | 4 (18.2) |
| CNS-DoR, months, median (95% CI) | 8.3 (5.1 to 8.3) | 12.1 (3.7 to NE) | 8.3 (3.7 to NE) | 9.4 (6.7 to 15.3) | 9.4 (7.4 to 15.3) |
| Duration of follow-up, months, median (Q1-Q3) | NR (7.4-NE) | 24.8 (23.9-25.8) | 23.9 (23.9-25.8) | NR (NE-NE) | 25.8 (23.9-NE) |
| 1-year DoR, % (95% CI) | 0 (NE to NE) | 60.0 (12.6 to 88.2) | 45.0 (10.8 to 75.1) | 31.2 (9.7 to 55.9) | 36.1 (16.4 to 56.4) |
| 2-year DoR, % (95% CI) | 0 (NE to NE) | 40.0 (5.2 to 75.3) | 30.0 (4.4 to 62.8) | 15.6 (2.5 to 39.1) | 20.6 (6.5 to 40.2) |
NOTE. Efficacy for patients with RET fusion–positive NSCLC and measurable CNS disease at baseline (N = 26). CNS-ORR is defined as the proportion of patients with best overall response of complete response or partial response. Response was confirmed by a repeat assessment no <28 days.
Abbreviations: DoR, duration of response; NE, not estimable; NR, not reached; NSCLC, non–small cell lung cancer; ORR, objective response rate; Q1, first quartile; Q3, third quartile; RT, radiation therapy.
Percentage is calculated based on the number of patients with CNS best response of CR or PR as denominator (n = 22) per IRC using RECIST 1.1.
TABLE A4.
CNS-PFS on the Basis of IRC Assessment in Patients With Measurable CNS Lesions
| Outcome | All Patients With Measurable CNS Lesions (n = 26) |
|---|---|
| CNS-PFS | |
| Patients with censored data, No. (%) | 7 (26.9) |
| Median (95% CI), months | 11.0 (9.2 to 17.1) |
| Duration of follow-up, months, median (Q1-Q3) | 33.1 (24.6-NE) |
| 1-year CNS-PFS, % (95% CI) | 41.8 (21.5 to 60.9) |
| 2-year CNS-PFS, % (95% CI) | 23.2 (8.5 to 42.1) |
| 3-year CNS-PFS, % (95% CI) | 23.2 (8.5 to 42.1) |
Abbreviations: PFS, progression-free survival; Q1, first quartile; Q3, third quartile.
TABLE A5.
Treatment-Emergent Adverse Events in ≥20% of Patients
| Preferred or Composite Term | NSCLC Safety Population (n = 362) | |||
|---|---|---|---|---|
| Any Causality | Related to Treatment | |||
| Any Grade, No. (%) | Grade ≥3, No. (%) | Any Grade, No. (%) | Grade ≥3, No. (%) | |
| Patients with ≥1 TEAE | 362 (100.0) | 283 (78.2) | 347 (95.9) | 152 (42.0) |
| Oedema | 200 (55.2) | 4 (1.1) | 139 (38.4) | 3 (0.8) |
| Diarrhea | 197 (54.4) | 19 (5.2) | 126 (34.8) | 11 (3.0) |
| Fatigue | 167 (46.1) | 9 (2.5) | 85 (23.5) | 3 (0.8) |
| Dry mouth | 167 (46.1) | 0 | 155 (42.8) | 0 |
| Hypertension (AESI) | 149 (41.2) | 70 (19.3) | 102 (28.2) | 51 (14.1) |
| AST increased (AESI) | 155 (42.8) | 37 (10.2) | 124 (34.3) | 24 (6.6) |
| Rash | 154 (42.5) | 4 (1.1) | 99 (27.3) | 4 (1.1) |
| ALT increased (AESI) | 151 (41.7) | 54 (14.9) | 122 (33.7) | 42 (11.6) |
| Nausea | 122 (33.7) | 5 (1.4) | 45 (12.4) | 2 (0.6) |
| Constipation | 109 (30.1) | 6 (1.7) | 40 (11.0) | 3 (0.8) |
| Abdominal pain | 108 (29.8) | 4 (1.1) | 28 (7.7) | 1 (0.3) |
| Headache | 105 (29.0) | 4 (1.1) | 25 (6.9) | 0 |
| Cough | 102 (28.2) | 0 | 11 (3.0) | 0 |
| Dyspnea | 100 (27.6) | 21 (5.8) | 14 (3.9) | 0 |
| Blood creatinine increased | 97 (26.8) | 9 (2.5) | 51 (14.1) | 0 |
| Vomiting | 92 (25.4) | 7 (1.9) | 23 (6.4) | 2 (0.6) |
| Decreased appetite | 88 (24.3) | 4 (1.1) | 40 (11.0) | 1 (0.3) |
| Pyrexia | 85 (23.5) | 1 (0.3) | 23 (6.4) | 1 (0.3) |
| Thrombocytopenia | 84 (23.2) | 22 (6.1) | 57 (15.7) | 15 (4.1) |
| Dizziness | 80 (22.1) | 2 (0.6) | 29 (8.0) | 0 |
| ECG QT prolonged (AESI) | 77 (21.3) | 23 (6.4) | 59 (16.3) | 16 (4.4) |
| Back pain | 76 (21.0) | 5 (1.4) | 1 (0.3) | 0 |
| Urinary tract infection | 73 (20.2) | 9 (2.5) | 2 (0.6) | 0 |
NOTE. AEs that occurred during treatment in ≥20% of patients, regardless of causality, and treatment-related per the investigator assessment. AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) v 21.0. Composite terms are shown in italics. The most common (≥5%) grade ≥3 TEAEs were hypertension (in 19.3% of the patients) and aspartate and ALT elevation (10.2%/14.9%), hyponatremia (9.9%), prolonged ECG QT interval (6.4%), thrombocytopenia (6.1%), pleural effusion (5.8%), dyspnea (5.8%), pneumonia (5.5%), and diarrhea (5.2%).
Abbreviations: AESI, adverse event of special interest; NSCLC, non–small cell lung cancer.
TABLE A6.
Summary of Safety
| Variable | NSCLC Safety Population (n = 362) | |
|---|---|---|
| Any Causality | Related to Treatment | |
| Any grade TEAE, No. (%) | 362 (100.0) | 347 (95.9) |
| Grade ≥3 TEAE, No. (%) | 283 (78.2) | 152 (42.0) |
| Serious TEAE, No. (%) | 199 (55.0) | 59 (16.3) |
| TEAE leading to dose withheld, No. (%) | 254 (70.2) | 189 (52.2) |
| TEAE leading to dose reduction, No. (%)a | 177 (48.9) | 166 (45.9) |
| TEAE leading to permanent treatment discontinuation, No. (%)b | 40 (11.0) | 16 (4.4) |
| Fatal TEAE, No. (%)c | 26 (7.2) | 0 (0.0) |
Abbreviations: NSCLC, non–small cell lung cancer; TEAE, treatment-emergent adverse event.
When related to treatment, most commonly because of elevation of AST (n = 29 patients [8.0%]) and ALT (n = 38 patients [10.5%]) and drug hypersensitivity (5.0%).
When related to treatment, most commonly because of AST/ALT elevation, fatigue, drug hypersensitivity, proteinuria, and thrombocytopenia (each occurring in two patients [0.6%]).
Most commonly because of respiratory failure (n = 6 patients [1.7%]) and cardiac arrest (n = 4 patients [1.1]).
FIG A1.
Long-term DoR with selpercatinib. Kaplan-Meier plots show DoR for patients with RET fusion–positive NSCLC who (A) received previous platinum-based chemotherapy (n = 247) or (B) were treatment-naïve (n = 69). Tick marks indicate censored data. DoR, duration of response; NSCLC, non–small cell lung cancer.
FIG A2.
Best change in CNS tumor burden by previous therapy on the basis of IRC assessment in patients with measurable CNS Disease. Waterfall plot shows maximum change in tumor size on the basis of IRC assessment for patients with RET fusion–positive NSCLC with measurable CNS disease at baseline (n = 26). Vertical bars represent the best percent change from baseline in the sum of diameters for all target CNS lesions. Dashed lines indicate progressive disease (+20%) and partial response (−30%). SRS includes all patients reported to receive SRT, SBRT, GKS, and/or SRS. WBRT includes all patients reported to receive radiation of any kind to the whole brain, including conventional external beam, IMRT, and 3DCRT. DCRT, definitive chemoradiotherapy; EGFR, epidermal growth factor receptor; GKS, gamma knife surgery; IMRT, intensity modulated radiotherapy; IRC, Independent Review Committee; MKI, multikinase inhibitor; NSCLC, non–small cell lung cancer; SBRT, stereotactic body radiotherapy; SRS, stereotactic radiosurgery; SRT, stereotactic radiotherapy; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; WBRT, whole brain radiotherapy.
FIG A3.
CNS DoR on the basis of IRC assessments in patients with measurable CNS disease. Kaplan-Meier plot shows DoR based on IRC assessment for patients with RET fusion–positive NSCLC with measurable CNS disease at baseline (n = 26). Tick marks indicate censored data. DoR, duration of response; IRC, independent review committee; NSCLC, non–small cell lung cancer.
Oliver Gautschi
Other Relationship: AstraZeneca (Inst), Amgen (Inst)
Keunchil Park
Honoraria: INCYTE, BeiGene
Consulting or Advisory Role: AstraZeneca, Daiichi Sankyo, JNJ, IMBdx, Geninus, ABION
Speakers' Bureau: Boehringer Ingelheim
Benjamin J. Solomon
Honoraria: AstraZeneca, Merck Sharp & Dohme (Inst), Roche/Genentech, Pfizer (Inst), Amgen (Inst)
Consulting or Advisory Role: Bristol Myers Squibb (Inst), Merck Sharp & Dohme, AstraZeneca (Inst), Pfizer (Inst), Roche/Genentech (Inst), Amgen, Lilly, BeiGene, Takeda, GlaxoSmithKline (Inst), Janssen (Inst), GlaxoSmithKline
Research Funding: Sanofi (Inst)
Patents, Royalties, Other Intellectual Property: UpToDate
Pascale Tomasini
Consulting or Advisory Role: AstraZeneca, Roche, Bristol Myers Squibb Foundation, Takeda, Amgen, Janssen, Daiichi Sankyo Europe GmbH
Travel, Accommodations, Expenses: Bristol Myers Squibb/Pfizer, AstraZeneca, Takeda, Daiichi Sankyo Europe GmbH
Herbert H. Loong
Consulting or Advisory Role: GlaxoSmithKline, Roche/Genentech, Novartis, Boehringer Ingelheim, Celgene, Lilly, Illumina, Guardant Health, Eisai, Takeda
Speakers' Bureau: Ignyta, Novartis, Guardant Health, Bayer
Research Funding: MSD Oncology (Inst)
Travel, Accommodations, Expenses: Roche, MSD Oncology, Bayer, Pfizer
Filippo De Braud
Honoraria: BMS, Pierre Fabre, Mattioli 1885, MCCann Health, MSD, IQVIA, Taiho Oncology, Incyte, Indena, Menarini
Consulting or Advisory Role: Incyte, Bristol Myers Squibb, Sanofi, Pierre Fabre, Taiho Oncology
Speakers' Bureau: Nadirex International, Dephaforum, Ambrosetti, BMS, Novartis
Research Funding: AstraZeneca, BMS, AnHeart Therapeutics, Apollomics
Travel, Accommodations, Expenses: Sanofi
Koichi Goto
Honoraria: Amgen, Amoy Diagnostics, AstraZeneca Japan, Bristol Myers Squibb K.K, Chugai Pharma, Daiichi Sankyo Co, Ltd, Eisai, Lilly Japan, Guardant Health, Janssen, Merck, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific, Nippon Kayaku, Riken Genesis Co, Ltd, Sysmex
Consulting or Advisory Role: Lilly Japan, Amgen, Janssen, Amgen, Bristol Myers Squibb K.K, Daiichi Sankyo Co, Ltd, Syneos Health, GlaxoSmithKline K.K, Haihe Biopharma Co., Ltd, Bayer HealthCare Pharmaceuticals Inc, Guardant Health Japan Corp, iTeos Therapeutics Inc, Novartis, Pharma Mar, S.A
Research Funding: Medical & Biological Laboratories Co, Ltd (Inst), Kyowa Kirin Co., Ltd (Inst), Merck (Inst), Merus (Inst), Spectrum Pharmaceuticals (Inst), MSD K.K (Inst), AstraZeneca Japan (Inst), Taiho Pharmaceutical (Inst), Chugai Pharma (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), Takeda (Inst), Eisai (Inst), Lilly Japan (Inst), Bristol Myers Squibb K.K (Inst), Ignyta (Inst), Janssen (Inst), Loxo (Inst), Sysmex (Inst), Amgen (Inst), Daiichi Sankyo Co, Ltd (Inst), Turning Point Therapeutics (Inst), Novartis (Inst), Blueprint Medicines (Inst), Bayer Yakuhin (Inst), Amgen (Inst), HaiHe Biopharma Co, Ltd (Inst), Sumitomo Pharma Co., Ltd (Inst), Pfizer (Inst), Life Technologies (Inst), CRAIF Inc (Inst), Precision Medicine Asia Co., Ltd (Inst), Riken Genesis Co, Ltd (Inst), AbbVie (Inst), AnHeart Therapeutics Inc (Inst), Guardant Health Asia, Middle East & Africa, Inc (Inst), Lunit (Inst)
Patrick Peterson
Employment: Lilly
Stock and Other Ownership Interests: Lilly
Scott Barker
Employment: Lilly
Stock and Other Ownership Interests: Lilly
Katherine Liming
Employment: Lilly
Stock and Other Ownership Interests: Lilly
Geoffrey R. Oxnard
Employment: Foundation Medicine, LOXO at Lilly
Stock and Other Ownership Interests: Roche, Lilly
Bente Frimodt-Moller
Stock and Other Ownership Interests: Lilly
Alexander Drilon
Stock and Other Ownership Interests: Treeline Biosciences, mBrace
Honoraria: Pfizer, Loxo/Bayer/Lilly, IASLC, Helsinn Therapeutics, BeiGene, Remedica, Remedica, TP Therapeutics, Verastem, Ignyta/Genentech/Roche, AstraZeneca, Liberum, Lungevity, NIH, PER, OncLive/MJH Life Sciences, Clinical Care Options/NCCN, Lung Cancer Research Foundation, Associazione Italiana Oncologia Toracica (AIOT), Chugai Pharma, Sirio Libanes Hospital, Answers in CME, Research to Practice, i3 Health, RV Mais
Consulting or Advisory Role: Ignyta, Loxo, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Repare Therapeutics, Melendi, Archer, Nuvalent, Inc, Janssen, Amgen, Merus, Axis Pharma, Medscape, Liberum, Med Learning, PeerView, EPG Health, Journal of the National Comprehensive Cancer Network, Ology Medical Education, Ology Medical Education, Clinical Care Options, Clinical Care Options, touchIME, Entos, Prelude Therapeutics, Applied Pharmaceutical Science, Treeline Biosciences, Monte Rosa Therapeutics, EcoR1 Capital
Research Funding: Foundation Medicine
Patents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology), Osimertinib Selpercatinib
Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology, Pfizer, Merus, Boehringer Ingelheim
No other potential conflicts of interest were reported.
PRIOR PRESENTATION
Presented at the European Lung Cancer Congress, Prague, Czech Republic, March 20-23, 2024.
SUPPORT
Supported by Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company. A.D. was supported by grants from the National Cancer Institute/National Institutes of Health (P30CA008748, 1R01CA251591001A1, and 1R01CA273224-01) and Lungevity.
CLINICAL TRIAL INFORMATION
DATA SHARING STATEMENT
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-24-02076. Eli Lilly and Company provides access to all individual data collected during the trial, after anonymization, with the exception of pharmacokinetic, genomic, or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and the European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.
AUTHOR CONTRIBUTIONS
Conception and design: Keunchil Park, Koichi Goto, Alexander Drilon
Administrative support: Koichi Goto
Provision of study materials or patients: Oliver Gautschi, Benjamin J. Solomon, Pascale Tomasini, Koichi Goto, Alexander Drilon
Collection and assembly of data: Oliver Gautschi, Keunchil Park, Benjamin J. Solomon, Pascale Tomasini, Filippo De Braud, Koichi Goto, Geoffrey R. Oxnard, Alexander Drilon
Data analysis and interpretation: Oliver Gautschi, Keunchil Park, Benjamin J. Solomon, Pascale Tomasini, Herbert H. Loong, Filippo De Braud, Koichi Goto, Patrick Peterson, Scott Barker, Katherine Liming, Geoffrey R. Oxnard, Bente Frimodt-Moller, Alexander Drilon
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Selpercatinib in RET Fusion–Positive Non–Small Cell Lung Cancer: Final Safety and Efficacy, Including Overall Survival, From the LIBRETTO-001 Phase I/II Trial
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.
Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).
Oliver Gautschi
Other Relationship: AstraZeneca (Inst), Amgen (Inst)
Keunchil Park
Honoraria: INCYTE, BeiGene
Consulting or Advisory Role: AstraZeneca, Daiichi Sankyo, JNJ, IMBdx, Geninus, ABION
Speakers' Bureau: Boehringer Ingelheim
Benjamin J. Solomon
Honoraria: AstraZeneca, Merck Sharp & Dohme (Inst), Roche/Genentech, Pfizer (Inst), Amgen (Inst)
Consulting or Advisory Role: Bristol Myers Squibb (Inst), Merck Sharp & Dohme, AstraZeneca (Inst), Pfizer (Inst), Roche/Genentech (Inst), Amgen, Lilly, BeiGene, Takeda, GlaxoSmithKline (Inst), Janssen (Inst), GlaxoSmithKline
Research Funding: Sanofi (Inst)
Patents, Royalties, Other Intellectual Property: UpToDate
Pascale Tomasini
Consulting or Advisory Role: AstraZeneca, Roche, Bristol Myers Squibb Foundation, Takeda, Amgen, Janssen, Daiichi Sankyo Europe GmbH
Travel, Accommodations, Expenses: Bristol Myers Squibb/Pfizer, AstraZeneca, Takeda, Daiichi Sankyo Europe GmbH
Herbert H. Loong
Consulting or Advisory Role: GlaxoSmithKline, Roche/Genentech, Novartis, Boehringer Ingelheim, Celgene, Lilly, Illumina, Guardant Health, Eisai, Takeda
Speakers' Bureau: Ignyta, Novartis, Guardant Health, Bayer
Research Funding: MSD Oncology (Inst)
Travel, Accommodations, Expenses: Roche, MSD Oncology, Bayer, Pfizer
Filippo De Braud
Honoraria: BMS, Pierre Fabre, Mattioli 1885, MCCann Health, MSD, IQVIA, Taiho Oncology, Incyte, Indena, Menarini
Consulting or Advisory Role: Incyte, Bristol Myers Squibb, Sanofi, Pierre Fabre, Taiho Oncology
Speakers' Bureau: Nadirex International, Dephaforum, Ambrosetti, BMS, Novartis
Research Funding: AstraZeneca, BMS, AnHeart Therapeutics, Apollomics
Travel, Accommodations, Expenses: Sanofi
Koichi Goto
Honoraria: Amgen, Amoy Diagnostics, AstraZeneca Japan, Bristol Myers Squibb K.K, Chugai Pharma, Daiichi Sankyo Co, Ltd, Eisai, Lilly Japan, Guardant Health, Janssen, Merck, Novartis, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Thermo Fisher Scientific, Nippon Kayaku, Riken Genesis Co, Ltd, Sysmex
Consulting or Advisory Role: Lilly Japan, Amgen, Janssen, Amgen, Bristol Myers Squibb K.K, Daiichi Sankyo Co, Ltd, Syneos Health, GlaxoSmithKline K.K, Haihe Biopharma Co., Ltd, Bayer HealthCare Pharmaceuticals Inc, Guardant Health Japan Corp, iTeos Therapeutics Inc, Novartis, Pharma Mar, S.A
Research Funding: Medical & Biological Laboratories Co, Ltd (Inst), Kyowa Kirin Co., Ltd (Inst), Merck (Inst), Merus (Inst), Spectrum Pharmaceuticals (Inst), MSD K.K (Inst), AstraZeneca Japan (Inst), Taiho Pharmaceutical (Inst), Chugai Pharma (Inst), Boehringer Ingelheim (Inst), Ono Pharmaceutical (Inst), Takeda (Inst), Eisai (Inst), Lilly Japan (Inst), Bristol Myers Squibb K.K (Inst), Ignyta (Inst), Janssen (Inst), Loxo (Inst), Sysmex (Inst), Amgen (Inst), Daiichi Sankyo Co, Ltd (Inst), Turning Point Therapeutics (Inst), Novartis (Inst), Blueprint Medicines (Inst), Bayer Yakuhin (Inst), Amgen (Inst), HaiHe Biopharma Co, Ltd (Inst), Sumitomo Pharma Co., Ltd (Inst), Pfizer (Inst), Life Technologies (Inst), CRAIF Inc (Inst), Precision Medicine Asia Co., Ltd (Inst), Riken Genesis Co, Ltd (Inst), AbbVie (Inst), AnHeart Therapeutics Inc (Inst), Guardant Health Asia, Middle East & Africa, Inc (Inst), Lunit (Inst)
Patrick Peterson
Employment: Lilly
Stock and Other Ownership Interests: Lilly
Scott Barker
Employment: Lilly
Stock and Other Ownership Interests: Lilly
Katherine Liming
Employment: Lilly
Stock and Other Ownership Interests: Lilly
Geoffrey R. Oxnard
Employment: Foundation Medicine, LOXO at Lilly
Stock and Other Ownership Interests: Roche, Lilly
Bente Frimodt-Moller
Stock and Other Ownership Interests: Lilly
Alexander Drilon
Stock and Other Ownership Interests: Treeline Biosciences, mBrace
Honoraria: Pfizer, Loxo/Bayer/Lilly, IASLC, Helsinn Therapeutics, BeiGene, Remedica, Remedica, TP Therapeutics, Verastem, Ignyta/Genentech/Roche, AstraZeneca, Liberum, Lungevity, NIH, PER, OncLive/MJH Life Sciences, Clinical Care Options/NCCN, Lung Cancer Research Foundation, Associazione Italiana Oncologia Toracica (AIOT), Chugai Pharma, Sirio Libanes Hospital, Answers in CME, Research to Practice, i3 Health, RV Mais
Consulting or Advisory Role: Ignyta, Loxo, AstraZeneca, Pfizer, Blueprint Medicines, Genentech/Roche, BeiGene, Hengrui Therapeutics, Exelixis, Bayer, Tyra Biosciences, Takeda/Millennium, BerGenBio, MORE Health, Lilly, AbbVie, 14ner Oncology/Elevation Oncology, Monopteros Therapeutics, Novartis, EMD Serono/Merck, Repare Therapeutics, Melendi, Archer, Nuvalent, Inc, Janssen, Amgen, Merus, Axis Pharma, Medscape, Liberum, Med Learning, PeerView, EPG Health, Journal of the National Comprehensive Cancer Network, Ology Medical Education, Ology Medical Education, Clinical Care Options, Clinical Care Options, touchIME, Entos, Prelude Therapeutics, Applied Pharmaceutical Science, Treeline Biosciences, Monte Rosa Therapeutics, EcoR1 Capital
Research Funding: Foundation Medicine
Patents, Royalties, Other Intellectual Property: Wolters Kluwer (Royalties for Pocket Oncology), Osimertinib Selpercatinib
Other Relationship: Merck, GlaxoSmithKline, Teva, Taiho Pharmaceutical, Pfizer, PharmaMar, Puma Biotechnology, Pfizer, Merus, Boehringer Ingelheim
No other potential conflicts of interest were reported.
REFERENCES
- 1.Subbiah V, Gainor JF, Oxnard GR, et al. : Intracranial efficacy of selpercatinib in RET fusion-positive non-small cell lung cancers on the LIBRETTO-001 trial. Clin Cancer Res 27:4160-4167, 2021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Zhou C, Solomon B, Loong HH, et al. : First-line selpercatinib or chemotherapy and pembrolizumab in RET fusion–positive NSCLC. N Engl J Med 389:1839-1850, 2023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Pérol M, Solomon BJ, Goto K, et al. : CNS protective effect of selpercatinib in first-line RET fusion-positive advanced non–small cell lung cancer. J Clin Oncol 42:2500-2505, 2024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Drilon A, Oxnard GR, Tan DSW, et al. : Efficacy of selpercatinib in RET fusion-positive non-small-cell lung cancer. N Engl J Med 383:813-824, 2020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Ettinger DS, Wood DE, Aisner DL, et al. : Non–small cell lung cancer, version 3.2022, NCCN clinical practice guidelines in Oncology. J Natl Compr Cancer Netw 20:497-530, 2022 [DOI] [PubMed] [Google Scholar]
- 6.Hendriks LE, Kerr KM, Menis J, et al. : Oncogene-addicted metastatic non-small-cell lung cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up☆. Ann Oncol 34:339-357, 2023 [DOI] [PubMed] [Google Scholar]
- 7.Jaiyesimi IA, Leighl NB, Ismaila N, et al. : Therapy for stage IV non–small cell lung cancer with driver alterations: ASCO living guideline, version 2023.3. J Clin Oncol 42:e1-e22, 2024 [DOI] [PubMed] [Google Scholar]
- 8.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 41:385-394, 2023 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Gautschi O, Wolf J, Milia J, et al. : Targeting RET in patients with RET-rearranged lung cancers: Results from a global registry. J Clin Oncol 34, 2016. (suppl 15; abstr 9014) [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Mok T, Camidge DR, Gadgeel SM, et al. : Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study. Ann Oncol 31:1056-1064, 2020 [DOI] [PubMed] [Google Scholar]
- 11.Ramalingam SS, Vansteenkiste J, Planchard D, et al. : Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC. N Engl J Med 382:41-50, 2020 [DOI] [PubMed] [Google Scholar]
- 12.Drilon A, Camidge DR, Lin JJ, et al. : Repotrectinib in ROS1 fusion-positive non-small-cell lung cancer. N Engl J Med 390:118-131, 2024 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Shaw AT, Riely GJ, Bang YJ, et al. : Crizotinib in ROS1-rearranged advanced non-small-cell lung cancer (NSCLC): Updated results, including overall survival, from PROFILE 1001. Ann Oncol 30:1121-1126, 2019 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Shaw AT, Bauer TM, de Marinis F, et al. : First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer. N Engl J Med 383:2018-2029, 2020 [DOI] [PubMed] [Google Scholar]
- 15.Planchard D, Jänne PA, Cheng Y, et al. : Osimertinib with or without chemotherapy in EGFR-mutated advanced NSCLC. N Engl J Med 389:1935-1948, 2023 [DOI] [PubMed] [Google Scholar]
- 16.Park K, Arriola E, Pérol M, et al. : P1 12B.10 dose adjustments and exposure-response associated with selpercatinib in patients with advanced NSCLC. J Thorac Oncol 19:S205, 2024 [Google Scholar]
- 17.Regular Call Oral Abstracts . Thyroid 34:A-1-A-145, 2024 [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
A data sharing statement provided by the authors is available with this article at DOI https://doi.org/10.1200/JCO-24-02076. Eli Lilly and Company provides access to all individual data collected during the trial, after anonymization, with the exception of pharmacokinetic, genomic, or genetic data. Data are available to request 6 months after the indication studied has been approved in the United States and the European Union and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, and blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.