Introduction

For patients with advanced or metastatic non-small cell lung cancer (NSCLC), the prognosis is poor, and their well-being and functioning can be substantially affected throughout treatment [1]. The most common symptoms of NSCLC include cough, chest pain, and dyspnea, all of which have a considerable influence on health-related quality of life (HRQoL) [2]. Dyspnea, fatigue, insomnia, and pain have been reported to be the most severe patient-reported symptoms among those diagnosed with NSCLC as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) [3, 4]. As NSCLC progresses, patients generally experience greater symptom burden and lower HRQoL [4, 5].

Rearranged during transfection (RET) proto-oncogene gene fusions are rare oncogenic drivers in NSCLCs and account for about 1% to 2% of cases [6-8]. Selpercatinib, a first-in-class highly selective and potent RET inhibitor with central nervous system activity, has demonstrated clinically meaningful and durable antitumor activity with a favorable safety profile in patients with advanced or metastatic RET fusion–positive NSCLC in the ongoing phase I/II LIBRETTO-001 trial (NCT03157128) [9]. The primary endpoint of objective response rate (ORR), assessed by independent review committee, was 64% (95 confidence interval [CI], 54–73) in heavily pretreated patients (n = 105), with a median duration of response of 17.5 months (95 CI, 12–not evaluable) and 63% of responses ongoing at median follow-up of 12.1 months. The ORR in patients who were treatment-naïve (n = 39) was 85% (95 CI, 70%–94%) with 90% of responses ongoing at 6 months. Based on these findings, selpercatinib is approved in multiple countries for the treatment of RET fusion–positive NSCLC [10, 11]. A phase III trial (LIBRETTO-431; NCT04194944) is ongoing to compare selpercatinib against chemotherapy with or without immunotherapy in patients with advanced or metastatic RET fusion–positive NSCLC in the first-line setting.

An exploratory objective of the LIBRETTO-001 trial was to describe patient-reported outcomes (PROs) during selpercatinib treatment and to describe changes from baseline among patients enrolled to the trial. This interim PRO analysis descriptively summarizes findings in patients with RET fusion–positive NSCLC.

Materials and Methods

LIBRETTO-001 is an ongoing, global, multicenter, open-label, phase I/II study, which began enrollment of patients with advanced or metastatic solid tumors, including RET fusion–positive NSCLC, in May 2017 [9]. The phase II recommended dose of selpercatinib, 160 mg orally twice daily, was administered in consecutive 28-day cycles until disease progression, death, unacceptable toxicity, or withdrawal of consent. Patients who derived clinical benefit from selpercatinib despite disease progression were allowed to continue treatment at the discretion of the investigator. Eligible patients were 18 years of age or older (or as young as 12 years of age for countries and sites where approved) and had an Eastern Cooperative Oncology Group performance status score of 0–2. Prior systemic treatments were permitted with no restriction on the number of previous lines of therapy received, which included immune checkpoint inhibitors, multikinase inhibitors, and chemotherapy. The primary endpoint was ORR assessed by an independent review committee using RECIST version 1.1. Secondary endpoints included duration of response and safety. A descriptive summary of PROs was an exploratory endpoint of the trial.

Patients with RET fusion–positive NSCLC in the LIBRETTO-001 trial completed the EORTC QLQ-C30 version 3.0 at baseline (cycle 1, day 1), approximately every 8 weeks until cycle 13 (approximately every other cycle), and every 12 weeks after cycle 13 until end of treatment (approximately every third cycle). The QLQ-C30 questionnaire is a commonly used scale in clinical trial research worldwide and has been extensively validated [13]. It includes an overall health status/quality of life (QoL) subscale, five functional subscales (physical, role, cognitive, emotional, and social), and nine symptom subscales (fatigue, pain, nausea and vomiting, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties).

All QLQ-C30 subscales are scored from 0 to 100. Higher scores on the global health status/QoL and functional subscales represent better functionality, whereas higher scores on the symptom subscales represent greater symptom burden. Published thresholds for clinical importance were used to interpret the QLQ-C30 scores in terms of clinically meaningful values. Scores lower than the thresholds of 83 (physical function), 71 (emotional function), 58 (role function, social function), or 75 (cognitive function) on the functional subscales represent a clinically meaningful problem for patients, whereas scores higher than 8 (nausea/vomiting), 39 (fatigue), 25 (pain), 17 (diarrhea, dyspnea, financial difficulties), or higher than 50 (appetite loss, insomnia, constipation) represent clinically meaningful problems on the symptom subscales [14].

A change of at least 10 points from baseline was considered a clinically meaningful difference based on validated parameters [15]. Data were evaluated through cycle 13 at this interim analysis because of the small number patients who had yet reached later cycles of therapy. Each patient was evaluated at each odd-numbered cycle in comparison with their baseline score. Patients were categorized as “improved” or “worsened” if the 10-point threshold had been met. Time to worsening and time to improvement were calculated as the time from baseline to the first 10-point or greater change in each subscale, measured using the Kaplan-Meier method among patients with at least 6 months of follow-up. Patients with events prior to the 6-month time period were included in the analysis. Patients were censored at the last time point when they completed the instrument, if the individual patient's score did not vary by 10 points from their baseline value at any subsequent assessment. All analyses were conducted using SAS 9.2 (SAS Institute, Cary, NC).

Results

As of the time of this interim database lock, 253 patients with RET fusion–positive NSCLC received selpercatinib. Among these patients, 239 were categorized into prespecified treatment-naïve and previously treated cohorts, in which 39 were naïve to systemic treatment, 64 had received one prior line of therapy, and 136 had received two or more prior lines of therapy at study enrollment (Table 1). Overall, the median age was 61 years; most patients were female (57.3%), White (51.4%), and never smokers (69.6%). Adherence to completion of the QLQ-C30 was greater than 85% at each scheduled assessment (corresponding to the odd-numbered cycles of study treatment).

Table 1. Baseline characteristics of patients with RET fusion–positive non-small cell lung cancer by prior treatment status at enrollment to LIBRETTO-001 Characteristic All patients (n = 253)a Treatment-naïve (n = 39)b One prior line of therapy (n = 64)b Two or more prior lines of therapy (n = 136)b Age, median (range), years 61.0 (44–86) 61.0 (23–86) 61.5 (35–80) 61.0 (23–81) Sex, n (%) Female 145 (57.3) 10 (62.5) 37 (57.8) 78 (57.4) Male 108 (42.7) 17 (37.5) 27 (42.2) 58 (42.6) Race, n (%) White 130 (51.4) 28 (71.8) 31 (48.4) 66 (48.5) Asian 103 (40.7) 7 (17.9) 25 (39.1) 62 (45.6) Black 12 (4.7) 3 (7.7) 6 (9.4) 3 (2.2) Other/missing 8 (3.2) 0 2 (3.1) 5 (3.7) ECOG PS, n (%) 0 94 (37.2) 19 (48.7) 23 (35.9) 46 (33.8) 1 154 (60.9) 20 (51.3) 39 (60.9) 87 (64.0) 2 5 (2.0) 0 2 (3.1) 3 (2.2) Smoking history, n (%) Never smoker 176 (69.6) 29 (74.4) 40 (62.5) 96 (70.6) Former smoker 72 (28.5) 9 (23.1) 23 (35.9) 37 (27.2) Current smoker 5 (2.0) 1 (2.6) 1 (1.6) 3 (2.2) a The overall non-small cell lung cancer (NSCLC) population includes an additional 14 patients with nonmeasurable disease at baseline who were not categorized in the NSCLC subgroups. All of these patients had at least one prior line of therapy. b Data are from prespecified cohorts. All patients in each NSCLC subgroup had measurable disease with the exception of one patient with nonmeasurable disease who received at least one prior line of therapy. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; RET, rearranged during transfection. Global Health Status and Physical Function

Mean ± SD baseline global health status/QoL overall was 61.5 ± 23.6 (supplemental online Table 1). For patients who were treatment-naïve (n = 39) or had one line of prior therapy (n = 64), mean ± SD global health status/QoL score at baseline was 60.2 ± 23.4 and 65.2 ± 23.5, respectively. Patients with two or more lines of therapy (n = 53) at enrollment had a baseline global health status/QoL score of 60.4 ± 22.6. The proportion of patients with improvement or worsening from baseline are summarized in Figure 1 by treatment cycle. Among those included in the time-to-event analyses, improvements in global health status/QoL were observed among 66.7% (18/27) of patients who were treatment-naïve, 64.1% (25/39) of patients with one prior line of therapy, and among 61.1% (33/54) of patients who had received two or more prior lines of therapy at study enrollment. Median time to first improvement in global health status/QoL was 1.9 (95 CI, 1.9–not reached), 3.7 (95 CI, 1.9–5.6), and 2.1 (95 CI, 1.9–not reached) months among patients who were treatment-naïve, had one prior line of therapy, and had two or more prior lines of therapy at study enrollment, respectively.

Change in global health status/quality of life from baseline by cycle of study treatment as measured by the Quality of Life Questionnaire (QLQ-C30) in patients with RET fusion–positive NSCLC. For each respective cycle, the percentage of patients whose status improved (blue bar), remained stable (orange bar), or worsened (gray bar) from baseline was calculated using the number of patients with both baseline and corresponding postbaseline assessment as the denominator. Abbreviations: NSCLC, non-small cell lung cancer; Tx, treatment.

Overall, baseline mean ± SD physical function was 75.9 ± 22.2 (supplemental online Table 1). Patients who were treatment-naïve at enrollment had a mean ± SD baseline score of 72.6 ± 24.1 on the physical function subscale, while patients with one prior line of therapy had a mean ± SD baseline score of 79.8 ± 21.0, and those with two or more lines of therapy had a mean ± SD baseline score of 76.1 ± 18.8. All groups, therefore, had clinically important impairments in physical function, with mean baseline values each below the threshold of 83 [14]. The proportion of patients experiencing improvements in physical function ranged from 23.3% (two or more prior lines of therapy, cycle 5) to 58.3% (treatment-naïve, cycle 11) (Fig. 2). Improvement (≥10-point increase) in physical function was observed beginning at cycle 3 by 43.5%, 28.1%, and 29.8% of patients who were treatment-naïve, had one prior line of therapy, and had two or more lines of previous therapy, respectively.

Change in physical function from baseline by cycle of study treatment as measured by the Quality of Life Questionnaire (QLQ-C30) in patients with RET fusion–positive NSCLC. For each respective cycle, the percentage of patients whose status improved (blue bar), remained stable (orange bar), or worsened (gray bar) from baseline was calculated using the number of patients with both baseline and corresponding postbaseline assessment as the denominator. Abbreviations: NSCLC, non-small cell lung cancer; Tx, treatment.

Among patients included in the time-to-event analyses, improvements in physical function were observed in 55.6% (15/27), 41.0% (16/39), and 48.2% (26/54) of patients who were treatment-naïve, had one prior line of therapy, or had two or more prior lines of therapy, respectively. Median time to first improvement in physical function was 3.7 months (95 CI, 1.9–not reached) among patients who were treatment-naïve and was 5.6 months (95 CI, 3.7–not reached) among patients with two or more prior lines of therapy. Median time to first improvement was not reached among those who had only one prior line of therapy.

Other Functional Subscales

None of the other functional subscales met a clinically meaningful threshold at baseline. Mean scores for all functional subscales are included in supplemental online Table 1 for each treatment cycle and by line of therapy.

Symptom Subscales

Mean ± SD baseline dyspnea exceeded the clinically meaningful threshold of 17 points overall and in each subgroup (overall, 31.3 ± 30.3; treatment-naïve, 28.4 ± 33.0; one prior line of therapy, 23.1 ± 27.7; , 37.7 ± 28.3). The proportion of patients experiencing improvements and worsening in dyspnea by cycle are presented in Figure 3. Among patients included in the time-to-event analyses, improvements in dyspnea (≥10-point decrease) were observed in 48.1% (13/27), 33.3% (13/39), and 61.1% (33/54) of patients who were treatment-naïve, had one prior line of therapy, or had two or more prior lines of therapy, respectively. Median time to first improvement in dyspnea was not reached in either the treatment-naïve or in those with one prior line of therapy but was 3.4 months (95 CI, 1.9–5.8) among those with two or more prior lines of therapy at study enrollment. Median time to first worsening was not evaluable because of too few events and the median not being reached in all subgroups with RET fusion–positive NSCLC.

Change in dyspnea from baseline by cycle of study treatment as measured by the Quality of Life Questionnaire (QLQ-C30) in patients with RET fusion–positive NSCLC. For each respective cycle, the percentage of patients whose status improved (blue bar), remained stable (orange bar), or worsened (gray bar) from baseline was calculated using the number of patients with both baseline and corresponding postbaseline assessment as the denominator. Abbreviations: NSCLC, non-small cell lung cancer; Tx, treatment.

Baseline insomnia did not meet a clinically meaningful threshold in any group of patients with RET fusion–positive NSCLC. The proportion of patients experiencing improvements and worsening of insomnia by cycle is presented in Figure 4. Among patients included in the time-to-event analyses, improvements in insomnia (≥10-point decrease) were observed in 55.6% (15/27), 38.5% (15/39), and 50.0% (27/54) of patients who were treatment-naïve, had one prior line of therapy, or had two or more prior lines of therapy, respectively. Median time to first improvement of insomnia was 4.1 (95 CI, 1.9–not reached), 13.8 (95 CI, 3.7–not reached), and 7.2 (95 CI, 3.9–not reached) months among patients who were treatment-naïve, had one prior line of therapy, or had two or more prior lines of therapy, respectively.

Change in insomnia from baseline by cycle of study treatment as measured by the Quality of Life Questionnaire (QLQ-C30) in patients with RET fusion–positive NSCLC. For each respective cycle, the percentage of patients whose status improved (blue bar), remained stable (orange bar), or worsened (gray bar) from baseline was calculated using the number of patients with both baseline and corresponding postbaseline assessment as the denominator. Abbreviations: NSCLC, non-small cell lung cancer; Tx, treatment.

Baseline fatigue did not meet a clinically meaningful threshold overall (mean ± SD, 37.9 ± 26.0); however, the 39-point threshold was exceeded among patients who were treatment-naïve at enrollment (baseline mean ± SD, 41.6 ± 27.7) and those with two or more prior lines of therapy (baseline mean ± SD, 41.8 ± 26.3) but did not meet the threshold for patients with one prior line of therapy at enrollment. Among patients included in the time-to-event analyses, improvements in fatigue (≥10-point decrease) were observed in 77.8% (21/27), 56.4% (22/39), and 66.7% (36/54) of patients who were treatment-naïve, had one prior line of therapy, or had two or more prior lines of therapy, respectively. Median time to first improvement in fatigue was 1.9 (95 CI, 1.8–3.7), 3.7 (95 CI, 2.1–not reached), and 2.1 (95 CI, 1.9–5.6), months, respectively.

Baseline pain met a clinically meaningful threshold of 25 points overall (mean ± SD, 29.4 ± 28.5) and in all subgroups. Among patients included in the time-to-event analyses, improvements in pain (≥10-point decrease) were observed among 63.0% (17/27), 46.2% (18/39), and 50.0% (27/54) of those who were treatment-naïve, had one prior line of therapy, or had two or more prior lines of therapy, respectively. Median time to first improvement in pain was 1.9 (95 CI, 1.8–not reached), median not reached, and 9.3 (95 CI, 1.9–not reached), months, respectively.

All line of therapy subgroups exceeded the clinically meaningful threshold of 8 points for nausea and vomiting; no other subscales met the threshold reflecting a clinically meaningful problem. Mean scores for all symptom subscales are presented in supplemental online Table 2 for each treatment cycle and by line of therapy subgroup.

Discussion

Patient-reported outcomes are increasingly recognized as an important outcome in clinical trials to capture the patient experience of symptoms and toxicities not fully captured in physician-assessed outcome measures [16, 17]. The PROs were successfully incorporated in LIBRETTO-001 with high adherence to the QLQ-C30 (>85%) at all visits. The PRO data show that the majority of patients with RET fusion–positive NSCLC maintained or improved in all HRQoL domains as measured by the QLQ-C30 during treatment with selpercatinib.

Dyspnea is a common distressing symptom of lung cancers, and the recalcitrant nature of the symptom is demonstrated by the high patient-reported symptom burden at study enrollment. This is consistent with other studies that have shown dyspnea to be a major component of symptom burden reported by patients with NSCLC [3, 4]. However, prior research has generally been limited to evaluating time to deterioration of dyspnea [18]. In this study, median time to deterioration was not reached. Approximately half of all patients enrolled to LIBRETTO-001 who were included in the time-to-event analyses demonstrated a clinically meaningful improvement in dyspnea during study participation, with a 3.4-month median time to first improvement among patients with two or more prior lines of therapy. The majority of patients reported improvements or stable dyspnea at each postbaseline study visit.

Other symptoms that are relevant for patients with NSCLC include insomnia, fatigue, and pain [3, 4]. In this study cohort, only pain was considered clinically meaningful at baseline in all groups of patients with RET fusion–positive NSCLC. At the first postbaseline evaluation (cycle 3), nearly half of all patients improved, with 45.9% of patients reporting a ≥ 10-point reduction in pain. The proportion of patients remaining stable or improved was very consistent at each subsequent study assessment of pain. Fatigue was a particular concern at baseline among patients who were more heavily treated prior to enrollment to LIBRETTO-001. These heavily pretreated patients were also those who had the highest rate of improvement at postbaseline assessments. In all subscales, however, data during the later cycles of therapy should be interpreted with caution because of the decreasing sample size over time, as patients continue to be treated on LIBRETTO-001 and few had reached the later cycles of therapy at the time of this interim analysis.

The interpretation of the PRO data recorded in this trial has limitations, primarily the lack of a control arm, which limits the ability to infer the magnitude of causality for these outcomes to treatment with selpercatinib. In addition, time-to-event analyses demonstrate the immaturity of data, as medians were not reached, particularly with regard to time to worsening, which is likely due to the low rate of worsening across all QLQ-C30 subscales. Subsequent analyses are planned as data mature and patients have longer duration of follow-up.

Conclusion

In this preliminary analysis of PRO data, the majority of patients with RET fusion–positive NSCLC remained stable or improved on all QLQ-C30 subscales at each study visit during study participation, demonstrating the favorable HRQoL as measured by the QLQ-C30 during treatment with selpercatinib. Further analyses will be conducted as data mature and more patients are enrolled in this ongoing trial and as part of the subsequent phase III trial, LIBRETTO-431.

Acknowledgments

We thank the patients, their caregivers, and the trial teams at the participating centers, and we thank Karen Paulsrud, R.Ph. (Eli Lilly & Co.) for copyediting, editorial, and production assistance. Funding for this work was supported by Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly & Co.

Author Contributions

Conception/design: Vivek Subbiah, Bruce Robinson, Min-Hua Jen, Elizabeth Olek

Provision of study material or patients: Anna Minchom, Aaron C. Tan, Erminia Massarelli, Vivek Subbiah, Valentina Boni, Bruce Robinson, Lori J. Wirth, Caroline E. McCoach

Collection and/or assembly of data: Aaron C. Tan, Erminia Massarelli, Valentina Boni, Bruce Robinson, Lori J. Wirth, Elizabeth Olek, Caroline E. McCoach

Data analysis and interpretation: Anna Minchom, Aaron C. Tan, Erminia Massarelli, Vivek Subbiah, Valentina Boni, Lori J. Wirth, Min-Hua Jen, Jennifer Kherani, Caroline E. McCoach

Manuscript writing: Anna Minchom, Aaron C. Tan, Erminia Massarelli, Vivek Subbiah, Valentina Boni, Bruce Robinson, Lori J. Wirth, Lisa M. Hess, Min-Hua Jen, Jennifer Kherani, Elizabeth Olek, Caroline E. McCoach

Final approval of manuscript: Anna Minchom, Aaron C. Tan, Erminia Massarelli, Vivek Subbiah, Valentina Boni, Bruce Robinson, Lori J. Wirth, Lisa M. Hess, Min-Hua Jen, Jennifer Kherani, Elizabeth Olek, Caroline E. McCoach

Disclosures

Anna Minchom: Chugai Pharmaceuticals, Novartis Oncology, Bayer Pharmaceuticals, Amgen Pharmaceuticals, Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly & Co. (H); Faron Pharmaceuticals, Janssen Pharmaceuticals, Merck Pharmaceuticals (C/A); Aaron C. Tan: Amgen (C/A); Erminia Massarelli: Merck, Janssen (C/A), Merck, AstraZeneca, Eli Lilly & Co. (H); Vivek Subbiah: Loxo Oncology, Inc., a wholly owned subsidiary of Eli Lilly & Co. (RF, C/A), Roche/Genentech, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, D3, Pfizer, Multivir, Amgen, Abbvie, Alfasigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint Medicines, Altum, Dragonfly Therapeutics, Takeda, National Comprehensive Cancer Network, NCICTEP, UT MD Anderson Cancer Center, Turning Point Therapeutics, Boston Pharmaceuticals, Novartis, Pharmamar, Medimmune (RF), Helsinn, Incyte, QED Pharma, Daiichi-Sankyo, Signant Health, Novartis, Medimmune (C/A), Pharmamar, Incyte, ASCO (other—travel); Valentina Boni: Puma Biotechnology, Ideaya Biosciences, Loxo Therapeutics, CytomX Therapeutics, Guidepoint, Oncoart (C/A), Eli Lilly & Co. (H), Abbvie, ACEO, Adaptaimmune, Amcure, Amgen, AstraZeneca, Bristol-Myers Squibb, Cytomx, GlaxoSmithKline, Genentech/Roche, H3, Incyte, Janssen, Kura, Eli Lilly & Co., Loxo, Nektar, Macrogenics, Menarini, Merck, Merus, Nanobiotix, Novartis, Pfizer, PharmaMar, Principia, PUMA, Sanofi, Taiho, Tesaro, BeiGene, Transgene, Takeda, Incyte, Innovio, Merck Sharp & Dohme, PsiOxus, Seattle Genetics, Mersana, Daiichi, Nektar, Astellas, ORCA, Boston Therapeutics, Dynavax, DebioPharm, Boehringer Ingelheim, Regeneron, Millennium, Synthon, Spectrum, Rigontec, Zenith (RF—institution); Lori J. Wirth: Eli Lilly & Co., Blueprint Medicines, Eisai, Exelixis (C/A), Eli Lilly & Co. (E); Lisa M. Hess: Eli Lilly & Co. (E); Min-Hua Jen: Eli Lilly & Co. (E); Jennifer Kherani: Eli Lilly & Co. (E); Elizabeth Olek: Eli Lilly & Co. (E); Caroline E. McCoach: Genentech (E), Genentech, AstraZeneca (C/A), Novartis, Guardant Health (H), Novartis, Revolution Medicines (RF). The other author indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board

See http://www.TheOncologist.com for supplemental material available online.

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Appendix S1. Supporting Information

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