CLINICAL CANCER RESEARCH | CLINICAL TRIALS: TARGETED THERAPY Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor–Mutated Non–Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial Margarita Majem1, Jonathan W. Goldman2, Thomas John3, Christian Grohe4, Konstantin Laktionov5, Sang-We Kim6, Terufumi Kato7, Huu Vinh Vu8, Shun Lu9, Shanqing Li10, Kye Young Lee11, Charuwan Akewanlop12, Chong-Jen Yu13, Filippo de Marinis14, Laura Bonanno15, Manuel Domine16, Frances A. Shepherd17, Shinji Atagi18, Lingmin Zeng19, Dakshayini Kulkarni20, Nenad Medic21, Masahiro Tsuboi22, Roy S. Herbst23, and Yi-Long Wu24 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 ABSTRACT ◥ Purpose: In the phase III ADAURA trial, adjuvant treatment with Results: Baseline physical/mental component summary (PCS/ osimertinib versus placebo, with/without prior adjuvant chemotherapy, MCS) scores were comparable between osimertinib and placebo resulted in a statistically significant and clinically meaningful disease- (range, 46–47) and maintained to Week 96, with no clinically free survival benefit in completely resected stage IB–IIIA EGFR- meaningful differences between arms; difference in adjusted least mutated (EGFRm) non–small cell lung cancer (NSCLC). We report squares (LS) mean [95% confidence intervals (CI), 1.18 (2.02 to health-related quality of life (HRQoL) outcomes from ADAURA. 0.34) and 1.34 (2.40 to 0.28), for PCS and MCS, respectively. Patients and Methods: Patients randomized 1:1 received oral There were no differences between arms for TTD of PCS and MCS; osimertinib 80 mg or placebo for 3 years or until recurrence/ HR, 1.17 (95% CI, 0.82–1.67) and HR, 0.98 (95% CI, 0.70–1.39), discontinuation. HRQoL (secondary endpoint) was measured using respectively. the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, Conclusions: HRQoL was maintained with adjuvant osimertinib then every 24 weeks until recurrence or treatment completion/ in patients with stage IB–IIIA EGFRm NSCLC, who were disease- discontinuation. Exploratory analyses of SF-36 score changes from free after complete resection, with no clinically meaningful differ- baseline until week 96 and time to deterioration (TTD) were ences versus placebo, further supporting adjuvant osimertinib as a performed in the overall population (stage IB–IIIA; N ¼ 682). new treatment in this setting. Clinically meaningful changes were defined using the SF-36 manual. See related commentary by Patil and Bunn, p. 2204 select patients with stage IB disease, adjuvant cisplatin-based chemo- Introduction therapy is recommended (4). For patients with NSCLC, approximately 30% will present with However, clinical outcomes remain poor across disease stages. resectable disease, for which the primary treatment is surgery with A pooled analysis of data from patients with resected stage I–III curative intent (1–4). For patients with stage II–IIIA NSCLC, and NSCLC receiving adjuvant chemotherapy showed rates of disease 1 18 Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Department of Thoracic Oncology, National Hospital Organization Kinki-Chuo Barcelona, Spain. 2David Geffen School of Medicine at University of California Chest Medical Center, Osaka, Japan. 19Late Oncology Statistics, AstraZeneca, Los Angeles, Los Angeles, California. 3Department of Medical Oncology, Austin Gaithersburg, Maryland. 20Late Oncology R&D, AstraZeneca, Cambridge, United €r Pneumologie—Evangelische Health, Melbourne, Victoria, Australia. 4Klinik fu Kingdom. 21AstraZeneca Oncology Business Unit, Academy House, Cambridge, Lungenklinik Berlin Buch, Berlin, Germany. 5Federal State Budgetary Institution United Kingdom. 22Department of Thoracic Surgery and Oncology, National “N.N.Blokhin National Medical Research Center of Oncology” of the Ministry of Cancer Center Hospital East, Kashiwa, Japan. 23Medical Oncology, Yale School of Health of the Russian Federation (N.N. Blokhin NMRCO), Moscow, Russia. Medicine and Yale Cancer Center, New Haven, Connecticut. 24Guangdong Lung 6 Department of Oncology, Asan Medical Center, Seoul, South Korea. 7Depart- Cancer Institute, Guangdong Provincial People’s Hospital and Guangdong ment of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan. Academy of Medical Sciences, Guangzhou, China. 8 Department of Thoracic Surgery, Choray Hospital, Ho Chi Minh City, Vietnam. 9 Note: Supplementary data for this article are available at Clinical Cancer Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Research Online (http://clincancerres.aacrjournals.org/). Shanghai, China. 10Department of Thoracic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China. 11Pre- Corresponding Author: Yi-Long Wu, Guangdong Lung Cancer Institute, Guang- cision Medicine Lung Cancer Center, Konkuk University Medical Center, Seoul, dong Provincial People’s Hospital and Guangdong Academy of Medical Republic of Korea. 12Division of Medical Oncology, Faculty of Medicine, Siriraj Sciences, 106 Zhongshan 2nd Road, Guangzhou 510080, China. Hospital, Bangkok, Thailand. 13Department of Internal Medicine, National Taiwan Phone: 86 20 8387 7855, Fax: 86-20-8382-7712, E-mail: syylwu@live.cn University Hospital Hsinchu Branch and National Taiwan University College of Clin Cancer Res 2022;28:2286–96 Medicine, Taipei, Taiwan. 14Thoracic Oncology Division, European Institute of Oncology (IEO), IRCCS, Milan, Italy. 15Medical Oncology 2, Istituto Oncologico doi: 10.1158/1078-0432.CCR-21-3530 Veneto (IOV), IRCCS, Padua, Italy. 16Department of Oncology, Hospital Uni- This open access article is distributed under Creative Commons Attribution- n Jime versitario Fundacio nez Díaz (IIS-FJD), Madrid, Spain. 17Department of NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND). Medical Oncology and Hematology, University Health Network, Princess Mar- garet Cancer Center and the University of Toronto, Toronto, Ontario, Canada. 2022 The Authors; Published by the American Association for Cancer Research AACRJournals.org | 2286 HRQoL with Adjuvant Osimertinib in Resected EGFRm NSCLC Here, we report HRQoL outcomes from ADAURA, which is the first Translational Relevance global, randomized, phase III trial in the adjuvant, resected EGFRm In the phase III ADAURA trial, health-related quality of life NSCLC setting to evaluate HRQoL with an EGFR-TKI versus placebo, (HRQoL), as assessed by the Short Form-36 (SF-36) health survey, with or without prior adjuvant chemotherapy (13, 26–28). was maintained during adjuvant osimertinib treatment, with or without prior adjuvant chemotherapy, in patients with completely resected stage IB–IIIA EGFR-mutated non–small cell lung cancer Patients and Methods (NSCLC). No clinically meaningful differences with adjuvant Patients, trial design, and treatment osimertinib versus placebo were observed for the SF-36 component Details of the ADAURA trial design (NCT02511106) have been summaries or health domains. In addition to improving efficacy previously published (13, 29). Briefly, the phase III double-blind, outcomes, a key goal of adjuvant treatment is to also maintain randomized, placebo-controlled, global ADAURA trial enrolled adult HRQoL as patients will be disease-free after surgery and may patients (≥18 years; ≥20 years in Japan and Taiwan) with histologically receive long-term treatment. Together with the previously reported confirmed primary non-squamous NSCLC of post-surgical patholog- significant disease-free survival (DFS) benefit with adjuvant osi- ical stage IB, II, or IIIA [American Joint Committee on Cancer (AJCC) mertinib versus placebo and favorable safety profile of osimertinib, 7th edition; ref. 30], central confirmation of EGFR mutation [exon 19 these HRQoL data provide further support for the use of adjuvant deletions (Ex19Del) or exon 21 codon p.Leu858Arg (L858R) point Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 osimertinib as a new treatment strategy in this patient population. mutations], and a World Health Organization performance status of 0 or 1. Complete surgical resection of the primary NSCLC (with negative margins) was required, and postoperative adjuvant chemotherapy before randomization was allowed, but not mandatory, per physician recurrence following surgery ranging from 45% for stage IB to and patient choice. Patients were stratified according to disease stage 76% for stage III disease, irrespective of postoperative chemother- (IB, II, or IIIA), EGFR mutational status (Ex19Del or L858R), and race apy use. The analysis also reported an overall HR for overall (Asian or non-Asian), and randomized 1:1 to oral osimertinib 80 mg survival (OS) of 0.89 [95% confidence interval (CI), 0.82–0.96], once daily or placebo following complete resection and adjuvant corresponding to a 5-year absolute benefit of 5.4% with chemo- chemotherapy, if indicated. Treatment continued for 3 years or until therapy versus no chemotherapy, after a median follow-up time of disease recurrence or other discontinuation criteria were fulfilled. 5.2 years (5). The primary endpoint was investigator-assessed DFS in patients In the advanced NSCLC setting, EGFR-tyrosine kinase inhibitors with stage II–IIIA disease and secondary endpoints included DFS in (EGFR-TKI) are standard of care in patients with EGFR mutations the overall population (stage IB–IIIA disease), OS, HRQoL, and safety. (refs. 6, 7; EGFRm). Osimertinib, a third-generation, irreversible, oral An interim analysis of the primary and key secondary endpoints has EGFR-TKI that potently and selectively inhibits EGFR-TKI sensitizing been reported previously (13). The data cutoff value (DCO) for the and EGFR T790M resistance mutations with proven efficacy in central previously reported primary analysis and this HRQoL analysis was nervous system metastases (8–12), is now considered the preferred January 17, 2020. first-line option for patients with EGFRm advanced NSCLC (6, 7). The study was approved by the institutional review board or Because of this benefit in the advanced setting, adjuvant osimertinib independent ethics committee associated with each study center. The was assessed in patients with resectable stage IB–IIIA EGFRm NSCLC trial was conducted in accordance with the provisions of the Decla- in the phase III ADAURA trial and demonstrated a highly statistically ration of Helsinki, Good Clinical Practice guidelines (as defined by the significant and clinically meaningful improvement in DFS versus International Conference for Harmonization), applicable regulatory placebo (HR, 0.20; 99.12% CI, 0.14–0.30; P < 0.001; ref. 13). The data requirements, and policy of the trial sponsor, AstraZeneca, on bio- also demonstrated a safety profile consistent with that known for ethics and human biologic samples. All patients provided written osimertinib, with a low frequency of dose modifications and disconti- informed consent. nuations and no new safety signals reported (13), with or without chemotherapy (14). Subsequently, osimertinib has been approved in HRQoL endpoints and data collection the US, China, the EU, the UK, and multiple countries worldwide, for HRQoL was assessed using the SF-36 health survey version 2 (31), use as an adjuvant treatment in patients with resectable EGFRm which measures a patient’s general health status with a recall period of (Ex19Del/L858R) NSCLC (15–18). 4 weeks. The SF-36 collects scores from 36 items across eight health As established in other adjuvant cancer settings, the effect of domains [Physical Functioning (PF), Role Limitations–Physical (RP), adjuvant treatment on HRQoL is an important clinical consideration Vitality (VT), General Health Perceptions (GH), Bodily Pain (BP), for patients who, following surgery with curative intent, are disease- Social Function (SF), Role Limitations- Emotional (RE), and Mental free and require long-term treatment to reduce the risk of disease Health (MH)] and produces two weighted aggregate scores, the recurrence (4, 19–22). The goal of treatment in the adjuvant setting is physical component summary (PCS) and the mental component therefore to improve efficacy outcomes while also maintaining summary (MCS). All eight health domains contribute to the PCS and HRQoL (19). However, in the adjuvant NSCLC setting, HRQoL data MCS, but the PF, RP, BP, and GH domains contribute most strongly to are limited, and comprise of two studies showing a transient, modest the PCS, and the VT, SF, RE, and MH domains contribute most worsening or no impact on HRQoL with different chemotherapy strongly to the MCS. SF-36 data were collected at randomization (pre- regimens in patients with resected stage IB–III NSCLC (23, 24), and dose), weeks 12 and 24 after randomization, and then every 24 weeks one study reporting significantly improved HRQoL with the EGFR- until disease recurrence, treatment completion (at 3 years), or treat- TKI gefitinib versus chemotherapy in patients with resected stage II– ment discontinuation, whichever occurred first. At treatment discon- IIIA EGFRm NSCLC (25), although comparison between studies is tinuation due to disease recurrence or other discontinuation criteria, limited because of the application of different QoL instruments and HRQoL data were collected at the treatment discontinuation visit; treatments evaluated. however, no further HRQoL data were collected afterwards. To AACRJournals.org Clin Cancer Res; 28(11) June 1, 2022 2287 Majem et al. minimize bias, SF-36 surveys were completed before any investigations the values defined in the most recent 3rd edition of the SF-36 or discussions with the clinical staff or physicians on the day of the scoring manual (31). Values of clinically meaningful differences for patient visit, so patients would not have been aware of any changes in MMRM and TTD analyses defined in the 2nd and 3rd editions of their disease status, such as disease progression, before completing the the SF-scoring manual are reported in Supplementary Table S1. survey. Changes from baseline were only calculated until Week 96 to ensure SF-36 scores were calculated as follows, using a norm-based scoring balanced comparison between the treatment arms, as earlier dis- method. Briefly, 0–100 scores for each of the health domain scales and continuations in completing the SF-36 survey were observed in the component summary measures (PCS and MCS) were transformed to placebo arm compared with the osimertinib arm due to earlier T-scores using standard score formulas based on the 2009 US general disease recurrence. population’s mean values (normative mean): The mean T-score in the 2009 US population is 50, with an SD of 10 (31). Higher T–scores Statistical analysis indicate better health (31). T-scores above and below 50 are above and The SF-36 compliance over time was calculated for each visit, below the average, respectively, of the 2009 US population. With the including baseline, as the number of patients with an evaluable SD being 10, each 1-point change in T-scores is interpreted as one- questionnaire (a questionnaire with a completion date and at least tenth of an SD and has an effect size of 0.1 (31). Missing responses in one health domain that was non-missing) at that visit, divided by the the SF-36 health survey were imputed using the SF-36 Full Missing number of patients still expected to complete the questionnaire. Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 Score Estimation procedure, which uses a combination of the respon- The MMRM analysis was performed on the change from base- dent’s available health domain scale and component summary mea- line in SF-36 PCS, MCS, and health domain scores at each visit sure scores (31). up to Week 96, which was averaged across visits over 96 weeks The Full Missing Score Estimation procedure was used for imputing for the osimertinib and placebo arms. The MMRM analysis missing responses in the SF-36 health survey (31). A given health included patient (as a random effect), treatment and visit (as a domain score [except for physical functioning (PF)] can be estimated fixed effect and repeated measure), and treatment-by-visit inter- when the patient provides a response to at least one item in that scale action as explanatory variables, as well as baseline score and and regression methods are used to estimate component summary baseline score-by-visit interaction as covariates, using an unstruc- measure scores based on the available scales (31). The model assumes tured covariance structure. that the missing item response(s) in one scale are the same as the TTD was defined as the time from randomization to the first response to the scale’s single answered item, or the average of all clinically important worsening, confirmed at the subsequent assess- responses, if more than one item has been answered (31). For the PF ment, or death by any cause in the absence of a clinically important scale, which comprises items that vary greatly in difficulty across the worsening, providing that death occurred within two assessment scale, estimates of missing values were obtained using the item visits from the last HRQoL assessment, and regardless of whether response theory (IRT) method. At least one item within the scale the patient withdrew from study treatment or received another needs to be answered to be able to compute the scale’s score. An IRT anticancer therapy before symptom deterioration. TTD was ana- model generates values that indicate the probability of a respondent lyzed using a log-rank test stratified by stage (II vs. IIIA, for analyses selecting a specific response to a given item, based on their responses to conducted in patients with stage II–IIIA disease; IB vs. II vs. IIIA, previously answered items in the PF scale (31). for analyses conducted in the overall population), EGFR mutation The PCS and MCS scores were estimated for a patient who had data type (Ex19Del vs. L858R), and race (Asian vs. non-Asian). Sum- for at least seven of the eight health domain scales and was not missing mary statistics for TTD of SF-36 PCS, MCS, and health domain the following required scale scores: PF for calculation of the PCS score scores were calculated using the Kaplan–Meier method. The HR and MH for calculation of the MCS score. If a patient had a fully and CI were obtained directly from the U and V statistics, as completed MCS (with no domain scales missing from the calculation), previously described (13, 33, 34). Patients with two missed visits then the PCS score was also calculated completely with no missing before confirmed deterioration were censored at the last evaluable domains and vice versa, because all eight health domain scales assessment before the two missed visits. contribute to the scoring of both MCS and PCS with different weighting. If the MCS score was calculated (and it was missing the Data availability statement PF domain only), then the PCS score was not calculated. Vice versa, if Data underlying the findings described previously in this article may the PCS score was calculated (and it was missing the MH domain only), be obtained in accordance with AstraZeneca’s data sharing policy then the MCS score was not calculated. Among 682 randomized described previously at https://astrazenecagrouptrials.pharmacm. patients, only one patient had MCS score but missing PCS score (due com/ST/Submission/Disclosure. to missing PF domain score) at the Week 156 visit. Both pre-specified and exploratory analyses of HRQoL were con- ducted. The pre-specified, per-protocol HRQoL analyses included a Results time to deterioration (TTD) analysis of the SF-36 PCS and MCS in Patients and treatment patients with stage II–IIIA disease, using values for clinically mean- A total of 682 patients with stage IB–IIIA EGFRm NSCLC were ingful differences defined in the 2nd edition of the SF-36 scoring randomized with 339 receiving osimertinib and 343 receiving place- manual (32). bo (13). Baseline demographics and clinical characteristics for these The exploratory, post hoc HRQoL analyses included a mixed model patients have been previously published by Wu and colleagues (13) of repeated measures (MMRM) of change from baseline up to Week 96 and were balanced between treatment arms. At DCO (January 17, in SF-36 PCS, MCS, and health domain scores, and a TTD analysis of 2020) in the osimertinib and placebo arms, respectively, the median the SF-36 PCS, MCS, and health domain scores. Both MMRM and (range) duration of treatment exposure was 22.5 (0–38) months and TTD analyses were conducted in the overall population (stage IB–IIIA 18.7 (0–36) months, and 12% and 10% of patients had completed the disease) using clinically meaningful differences assigned on the basis of 3-year study treatment (13). 2288 Clin Cancer Res; 28(11) June 1, 2022 CLINICAL CANCER RESEARCH HRQoL with Adjuvant Osimertinib in Resected EGFRm NSCLC (completed/expected forms x 100 90 80 Compliance rate 70 60 100; %) Osimertinib 50 40 Placebo 30 20 10 0 Baseline Week 12 Week 24 Week 48 Week 72 Week 96 Week 120 Week 144 Week 156 N Visit Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 Osimertinib 338 316 298 284 236 180 118 61 39 Placebo 341 329 301 241 189 136 81 49 33 Figure 1. Compliance rates with the SF-36 survey in the overall population. Compliance rates were calculated as the number of evaluable forms (n) divided by the number of expected forms (N), multiplied by 100, at 12- or 24-week intervals from baseline to week 156. The expected number of SF-36 forms is shown under each timepoint. SF-36, Short Form-36 health survey. SF-36 compliance tion. However, greater impairment was observed for the role-physical, Compliance with the SF-36 survey ranged from 85% to 99% for the social functioning, and role-emotional domains with T-scores 0.5–0.8 overall population from baseline through to Week 156 (Fig. 1). During SD below the normative mean (Fig. 2). this period, SF-36 compliance rates were similar with osimertinib (87%–99%) and placebo (85%–99%; Fig. 1). Change in SF-36 scores (MMRM analyses) In patients receiving osimertinib in the overall population, SF-36 Baseline SF-36 scores PCS and MCS were maintained from baseline up to Week 96, with no In the overall population, baseline mean (SD) SF-36 PCS and MCS clinically meaningful differences observed compared with the placebo T-scores were comparable between the osimertinib and placebo arms: arm (Fig. 3). In the osimertinib and placebo arms, from baseline to PCS, 47.09 (7.4) and 46.61 (7.4); MCS, 46.37 (10.4), and 46.82 (10.8), Week 96, the adjusted least squares (LS) mean for PCS score numer- respectively (Fig. 2). These T-scores were slightly lower (0.3–0.4 SD ically increased by 1.13 (95% CI, 0.54–1.72) and 2.31 (95% CI, 1.70– below the normative mean) than those in the general population. 2.91), respectively, and the adjusted LS mean for MCS score numer- Individual SF-36 health domain T-scores were also similar between the ically increased by 1.34 (95% CI, 0.60–2.08) and 2.68 (95% CI, 1.92– two treatment arms with the majority being within 0.3 SD of the 3.44), respectively (Table 1). The resulting treatment difference for the normative mean and therefore comparable with the general popula- adjusted LS mean change was 1.18 (95% CI, 2.02 to 0.34) for the 70 Mean baseline SF-36 60 Normative mean +1SD Normative mean = mean T-scores (SD) 50 T-score in the general population 40 Normative mean −1SD 30 48.4 48.7 47.9 47.5 51.0 51.0 47.1 46.6 46.4 46.8 47.3 47.2 45.3 45.0 47.4 47.8 Osimertinib 42.9 43.4 20 42.1 41.5 Placebo 10 0 PCS MCS Physical Role- Bodily General Vitality Social Role- Mental N functioning Physical pain health functioning Emotional health Osimertinib 311 311 313 312 311 314 311 312 312 312 Placebo 314 314 315 316 315 316 315 315 316 315 Figure 2. Baseline T-scores of the SF-36 component summaries and health domains in the overall population. The red dashed line shows the mean 2009 U.S. population SF-36 normative mean calculated from a sample of adults aged ≥18 years, including healthy individuals, and those with chronic conditions (31); normative data are not age- adjusted. The gray dashed lines show this normative mean  1SD. The number of patients with data available at each visit is shown below each component summary and health domain. MCS, mental component summary; PCS, physical component summary; SF-36, Short Form-36 health survey. AACRJournals.org Clin Cancer Res; 28(11) June 1, 2022 2289 Majem et al. A 20 15 10 Mean (SD) change from baseline in 5 SF-36 PCS 0 –5 –10 –15 –20 12 24 48 72 96 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 Time (wk) N Osimertinib 291 274 261 212 165 Placebo 301 275 219 172 124 Osimertinib Placebo B 20 15 10 Mean (SD) change from baseline in SF-36 MCS 5 0 –5 –10 –15 –20 12 24 48 72 96 Time (wk) N Osimertinib 291 274 261 212 165 Placebo 301 275 219 172 124 Figure 3. Change in SF-36 (A) PCS and (B) MCS T-scores from baseline to week 96 in the overall population. The data shown are mean change from baseline in T-scores with error bars representing the SDs. The number of patients with data available at each visit is shown below each timepoint. MCS, mental component summary; PCS, physical component summary; SF-36, Short Form-36 health survey. PCS score and 1.34 (95% CI, 2.40 to 0.28) for the MSC score, TTD in SF-36 score analyses neither of which represented a clinically meaningful difference In the overall population during the treatment period, 81% and 84% between treatment arms, according to the definitions from the 3rd of patients in the osimertinib and placebo arms, respectively, did not edition of the SF-36 scoring manual (Table 1; ref. 31). Similarly, SF-36 experience a clinically meaningful deterioration in the PCS or death, health domains T-scores were maintained from baseline to Week 96 and 81% in both treatment arms did not experience a clinically with osimertinib treatment, with numerical increases across the meaningful deterioration in the MCS or death; definitions for clinically majority of domains in both arms (Table 1). On the basis of the 3rd meaningful differences were based on the 3rd edition of the SF-36 edition of the SF-36 scoring manual definitions (31), no clinically scoring manual (31). In patients who did experience deterioration, meaningful differences were observed for any health domain with there were no differences in TTD of the PCS (HR, 1.17; 95% CI, 0.82– osimertinib compared with placebo (Table 1). 1.67) or MCS (HR, 0.98; 95% CI, 0.70–1.39) between the osimertinib 2290 Clin Cancer Res; 28(11) June 1, 2022 CLINICAL CANCER RESEARCH HRQoL with Adjuvant Osimertinib in Resected EGFRm NSCLC Table 1. MMRM adjusted LS mean change from baseline up to week 96 in SF-36 component summaries and health domain T-scores in the overall population. SF-36 component summary MMRM adjusted LS mean change from baseline (95% CI) Clinically meaningful or health domain Osimertinib Placebo Osimertinib–placebo differencea PCS 1.13 (0.54–1.72) 2.31 (1.70–2.91) 1.18 (2.02 to 0.34) 2 n ¼ 293 n ¼ 303 MCS 1.34 (0.60–2.08) 2.68 (1.92–3.44) 1.34 (2.40 to 0.28) 3 n ¼ 293 n ¼ 303 Physical functioning 0.53 (0.10 to 1.16) 1.38 (0.74–2.03) 0.86 (1.76 to 0.04) 3 n ¼ 295 n ¼ 303 Role-physical 2.67 (1.91–3.43) 4.47 (3.69–5.25) 1.80 (2.90 to 0.71) 3 n ¼ 294 n ¼ 304 Bodily pain 1.66 (0.91–2.40) 2.22 (1.45–2.99) 0.57 (1.64 to 0.50) 3 n ¼ 293 n ¼ 303 General health 0.41 (1.12 to 0.31) 1.09 (0.36–1.83) 1.50 (2.53 to 0.47) 2 n ¼ 296 n ¼ 304 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 Vitality 0.98 (0.22–1.74) 2.91 (2.13–3.69) 1.93 (3.02 to 0.84) 2 n ¼ 293 n ¼ 304 Social functioning 2.77 (2.06–3.49) 3.88 (3.14–4.62) 1.11 (2.13 to 0.08) 3 n ¼ 294 n ¼ 303 Role-emotional 1.05 (0.22–1.87) 2.51 (1.66–3.36) 1.46 (2.65 to 0.28) 4 n ¼ 294 n ¼ 304 Mental health 1.17 (0.44–1.90) 2.05 (1.30–2.80) 0.88 (1.92 to 0.17) 3 n ¼ 294 n ¼ 304 Abbreviations: CI, confidence interval; LS, least squares; MCS, mental component summary; MMRM, mixed model of repeated measures; PCS, physical component summary; SF-36, Short Form-36 health survey. a Clinically meaningful difference based on definitions from the 3rd edition of the SF-36 scoring manual (31). and placebo arms (Fig. 4). There were also no differences between the received (31). At the time of designing the ADAURA trial, the SF-36 osimertinib and placebo arms in the TTD for all SF-36 health domains had been translated into 10 languages, making it an accessible tool, and with HRs ranging from 0.68 to 1.19 (Fig. 5). has been used in other adjuvant cancer settings, such as breast and Comparable results were obtained when using clinically meaningful gastric cancers (21, 22, 35–37). A generic survey, rather than a cancer- differences as defined by the 2nd edition of the SF-36 scoring man- specific one, was chosen as patients were considered cancer-free before ual (31) in the overall patient population and in the pre-specified receiving osimertinib/placebo, as per the trial inclusion criteria. Fur- analysis in patients with stage II–IIIA disease; the pre-specified thermore, SF-36 assessments were performed only until disease recur- analysis is presented in Supplementary Figs. S1 and S2. In the overall rence, a period during which patients were considered not to have patient population, the HRs for TTD of the PCS and MCS were 1.25 physical symptoms of cancer, although were recovering from surgery (95% CI, 0.90–1.73) and 0.95 (95% CI, 0.69–1.30), respectively (Sup- and could potentially suffer from emotional and psychological effects plementary Fig. S3), and the HRs for TTD of the eight health domains of, for example, chemotherapy or their recent lung cancer diagnosis, ranged from 0.93 to 1.19 (Supplementary Fig. S4). which could affect their general HRQoL. SF-36 provides a compre- hensive measure of global HRQoL and comprises 36 items assessing patients’ general health on 8 multi-item dimensions (38). As such, it is Discussion a sensitive tool for measuring general HRQoL: It can capture the Previous results from the primary analysis of the ADAURA trial impact of any general health event on HRQoL, and provide useful showed a statistically significant improvement in DFS with adjuvant insights into the effects of adjuvant osimertinib treatment on overall osimertinib versus placebo in patients with completely resected stage HRQoL, including social and emotional functioning, in patients who IB–IIIA EGFRm NSCLC (13). At the time of this analysis, the OS data are disease-free. were immature and the follow-up for OS continues. The ADAURA HRQoL was a pre-specified endpoint in ADAURA. Pre-specified, analysis reported here assessed the effect of adjuvant osimertinib per-protocol analyses included a TTD analysis of PCS and MCS in versus placebo on HRQoL in patients who were disease-free following patients with stage II–IIIA disease (primary analysis population; surgery, with or without prior adjuvant chemotherapy. Overall, the ref. 13) using values for clinically meaningful differences defined in data demonstrated that HRQoL was maintained with adjuvant osi- the 2nd edition of the SF-36 scoring manual (32). The main HRQoL mertinib treatment, with no clinically meaningful differences versus results presented here were exploratory, post hoc analyses, as they were placebo in the SF-36 component summaries and individual health based on the most recent (3rd) edition of the SF-36 scoring manual (31) domain scores. and used data from the overall population (stage IB–IIIA disease), HRQoL was measured in ADAURA using the SF-36 health survey, which includes more patients than the primary analysis population which is a widely used and validated international non–cancer-specific (stage II–IIIA disease) used in the prespecified analysis. The use of the questionnaire that comprehensively measures patients’ general func- overall population in these exploratory HRQoL analyses was deemed tional status and well-being, regardless of age, disease, or treatment reasonable as the results from the primary endpoint, DFS, in patients AACRJournals.org Clin Cancer Res; 28(11) June 1, 2022 2291 Majem et al. A 1.0 0.9 being deterioration-free in Probability of patients 0.8 the SF-36 PCS 0.7 0.6 0.5 TTD events in PCS or death (n/N ) 0.4 Osimertinib 66/339 0.3 0.2 Placebo 55/343 Osimertinib 0.1 Placebo HR, 1.17; 95% CI, 0.82–1.67 0.0 0 6 12 18 24 30 36 42 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 Time from randomization (mo) No. of patients at risk Osimertinib 339 245 201 145 93 50 8 0 Placebo 343 249 167 117 67 40 8 0 B 1.0 0.9 being deterioration-free in 0.8 Probability of patients 0.7 the SF-36 MCS 0.6 0.5 TTD events in MCS or death (n/N) 0.4 Osimertinib 66/339 0.3 0.2 Placebo 64/343 Osimertinib 0.1 Placebo HR, 0.98; 95% CI, 0.70–1.39 0.0 0 6 12 18 24 30 36 42 Time from randomization (mo) No. of patients at risk Osimertinib 339 245 200 143 89 43 8 0 Placebo 343 239 164 116 66 37 7 0 Figure 4. TTD of the SF-36 (A) PCS and (B) MCS in the overall population. Kaplan–Meier plots are shown for the TTD analysis using clinically meaningful differences defined in the 3rd edition of the SF-36 scoring manual (31). The number of TTD events in MCS/PCS or death (n) in the overall population (N) are shown along with the HRs and 95% CIs comparing the treatment arms. The analysis was performed using an unstratified log-rank test due to low event counts. Crosses indicate censored patients, and the number of patients at risk is shown below each timepoint. CI, confidence interval; MCS, mental component summary; PCS, physical component summary; SF-36, Short Form-36 health survey; TTD, time to deterioration. with stage II–IIIA disease (HR, 0.17; 99.06% CI, 0.11–0.26; P < 0.001), sions from these HRQoL analyses remained the same irrespective of were similar to those reported for the overall population (HR, 0.20; the SF-36 manual edition used. 99.12% CI, 0.14–0.30; P < 0.001; ref. 13). Indeed the results from the It should be noted that no HRQoL data were collected after TTD analyses of SF-36 PCS and MCS were similar when using the treatment discontinuation, due to disease recurrence or other discon- definition of clinically meaningful difference from either the 2nd or 3rd tinuation criteria, as the objective of these analyses was to assess edition of the SF-36 scoring manual (31, 32) and the overall conclu- patients’ HRQoL while they were receiving randomized treatment. 2292 Clin Cancer Res; 28(11) June 1, 2022 CLINICAL CANCER RESEARCH HRQoL with Adjuvant Osimertinib in Resected EGFRm NSCLC HR (95% CI) Osimertinib Placebo n/N (%) n/N (%) Bodily pain 0.92 (0.63–1.35) 53/339 (15.6%) 55/343 (16.0%) General health 1.15 (0.81–1.63) 68/339 (20.1%) 58/343 (16.9%) Mental health 1.14 (0.77–1.69) 57/339 (16.8%) 46/343 (13.4%) Physical functioning 1.18 (0.78–1.77) 52/339 (15.3%) 42/343 (12.2%) Role-emotional 1.02 (0.74–1.43) 73/339 (21.5%) 69/343 (20.1%) Role-physical 1.19 (0.85–1.66) 75/339 (22.1%) 62/343 (18.1%) Social functioning 0.68 (0.43–1.08) 32/339 (9.4%) 42/343 (12.2%) Vitality 1.18 (0.76–1.81) 47/339 (13.9%) 37/343 (10.8%) Favors osimertinib Favors placebo 0.25 0.5 0.75 1 1.5 2 2.5 3 Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 HR (osimertinib: placebo) Figure 5. Forest plot of the TTD of the SF-36 health domains in the overall population. The TTD analysis used clinically meaningful differences defined in the 3rd edition of the SF-36 scoring manual (31) and was performed using an unstratified log-rank test due to low event counts. HRs and corresponding 95% CIs are shown for each health domain along with the number of events (n) in the overall population (N). An HR <1 favors osimertinib treatment. CI, confidence interval; SF-36, Short Form-36 health survey; TTD, time to deterioration. In addition, interpretation of post-recurrence HRQoL data may have the SF-36 PCS and MCS and, for those patients who had deterioration, been confounded by subsequent treatments, so it would have been there were no differences in TTD for these summaries and the difficult to isolate the effect of adjuvant osimertinib on HRQoL after individual health domains between osimertinib and placebo. disease recurrence. However, as recurrence rates were higher in the Only a few other studies have reported the effect of adjuvant placebo arm versus the osimertinib arm in ADAURA, and with chemotherapy or EGFR-TKIs on HRQoL in patients with resected HRQoL outcomes predicted to decrease upon disease recurrence (36), stage IB–IIIA NSCLC and have used cancer-specific questionnaires to the overall between-arm difference in HRQoL would likely be favoring assess HRQoL (23–25). In the JBR.10 study, adjuvant cisplatin and osimertinib. This will not be explored further in the ongoing ADAURA vinorelbine was associated with a modest and temporary worsening of trial, but analysis of long-term HRQoL data following disease recur- the European Organization for the Research and Treatment of Cancer rence will be important in future studies. (EORTC) Quality of Life Questionnaire (QLQ-C30) in patients with In patients who were disease-free following surgery, with or without resected stage IB–II NSCLC, with return to baseline function by prior adjuvant chemotherapy, baseline SF-36 PCS and MCS T-scores 9 months in most patients (23). Other chemotherapy regimens, such were comparable in the osimertinib and placebo arms, and only as gemcitabine plus cisplatin and docetaxel plus cisplatin, do not slightly lower than the mean T-scores in the general population. The appear to have any significant negative impact on EORTC QLQ-C30 in majority of health domain scores were comparable with the general patients with stage IB–III NSCLC (24). In the ADJUVANT/CTONG population; exceptions to this were for role-physical, social function- 1104 study, the EGFR-TKI gefitinib compared with cisplatin plus ing, and role-emotional, which were lower than the general population. vinorelbine showed significantly improved scores across three HRQoL This may have been due to the impact of surgery, chemotherapy, or the instruments (functional assessment of cancer therapy-lung cancer, patients’ recent lung cancer diagnosis on these aspects of QoL, lung cancer symptom scale, and trial outcome index) and was asso- although patients were randomized once they had sufficiently recov- ciated with longer TTD in these HRQoL scores in Chinese patients ered from surgery and completed adjuvant chemotherapy. Overall, the with resected stage II–IIIA EGFRm NSCLC (25). Several phase III trials data indicated that patients enrolled in ADAURA were highly func- of adjuvant immunotherapy, with or without adjuvant chemotherapy, tioning in terms of HRQoL. versus placebo/observation/best supportive care are currently ongoing Both the MMRM and TTD analyses presented here were chosen to in the resected stage IB–IIIA NSCLC setting (42–45); however, HRQoL provide a comprehensive assessment of HRQoL with adjuvant osi- data are only anticipated from one randomized phase III trial of mertinib. Although the TTD analysis as presented here is an accepted adjuvant durvalumab (NCT02273375; ref. 45). method for assessing HRQoL in cancer studies (39–41), including Several limitations should be considered when analyzing these NSCLC studies, it does not capture what happens to the patient after results. First, the data presented are from exploratory analyses (stage they experience deterioration in HRQoL. The MMRM analysis is, IB–IIIA disease, 3rd edition of the SF-36 scoring manual); however, the therefore, complementary to the TTD as it evaluates HRQoL scores results of these analyses are in line with the pre-specified analyses in a continuous manner across visits and assesses change from (stage II–IIIA disease, 2nd edition of the SF-36 scoring manual). baseline (39, 40). In the MMRM analysis, the SF-36 PCS, MCS, and Because of the earlier than planned DCO, the proportion of patients individual health domains were maintained from baseline up to Week who completed the 3-year study treatment period at DCO was low 96 during osimertinib treatment in patients who were disease-free (12% vs. 10% of patients receiving osimertinib vs. placebo), although following complete resection, with no clinically meaningful differences the compliance rates were high (≥85% across both arms). As the observed compared with placebo. More than 80% of patients across analysis was designed to assess the impact on QoL of adjuvant both arms did not experience a clinically meaningful deterioration in treatment, data were not collected beyond recurrence, so provided AACRJournals.org Clin Cancer Res; 28(11) June 1, 2022 2293 Majem et al. limited understanding on how a delay in recurrence with adjuvant mitsu, MSD, Chugai, Kyowa Hakko Kirin, Merck, Novartis Pharma, and Thermo osimertinib versus placebo impacts HRQoL in the longer term. Fisher Scientific and research grants from AstraZeneca, Eli Lilly, Ono, Taiho Pharmaceutical Co Ltd, Boehringer Ingelheim, Pfizer, Bristol-Myers Squibb, Collection of long-term HRQoL data after disease recurrence could MSD, Chugai, Merck, and F. Hoffmann-La Roche. L. Zeng reports ownership have provided useful information for payers, cost-effectiveness assess- of stock interest and is an employee of AstraZeneca. N. Medic is an employee of ments, and regulatory bodies. On the other hand, interpretation of AstraZeneca. D. Kulkarni reports ownership of stock interest and is an employee post-recurrence HRQoL data could be confounded by subsequent of AstraZeneca. M. Tsuboi reports advisory board fees from AstraZeneca, MSD, treatments and crossover to open-label osimertinib. Finally, the num- and Novartis and honoraria from Johnson & Johnson Japan, AstraZeneca KK, Eli ber of patients included in the analysis decreased over the course of the Lilly Japan, Chugai Pharmaceutical Co., Ltd, Taiho Pharmaceutical, Medtronic Japan, Ono Pharmaceutical Co., Ltd, MSD, Bristol-Myers Squibb KK, and Teijin study with 40%–53% of patients included in the analysis at Week 96 Pharma outside the submitted work. R.S. Herbst reports personal fees from compared with baseline. AbbVie Inc., ARMO Biosciences, Biodesix, Bolt Biotherapeutics, Bristol-Myers Squibb, EMD Serono, Genmab, Halozyme, Heat Biologics, IMAB Biopharma, Conclusions Immunocore, Infinity Pharmaceuticals, Loxo Oncology, Mirati Therapeutics, In summary, HRQoL via the SF-36 survey was maintained during Nektar, Neon Therapeutics, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, Symphogen, Takeda Pharmaceutical, adjuvant osimertinib treatment in patients with stage IB–IIIA EGFRm Tesaro, Tocagen, Cybrexa, and Oncternal Therapeutics; personal fees and NSCLC, who were disease-free following complete resection and prior research grants from AstraZeneca, Eli Lilly & Co., Genentech/Roche, and Merck adjuvant chemotherapy, if indicated. These results are in line with the & Co.; and advisory board fees from Junshi Pharmaceuticals outside the submitted Downloaded from http://aacrjournals.org/clincancerres/article-pdf/28/11/2286/3186837/2286.pdf by guest on 03 November 2023 overarching goal of adjuvant treatment, which is to treat with curative work. Y.-L. Wu reports personal fees and research grants from AstraZeneca, intent, while maintaining patients’ HRQoL (19). Coupled with the Bristol-Myers Squibb, Pfizer Inc., and Roche AG and personal fees from Boeh- significant DFS benefit and long-term safety profile observed with ringer-Ingelheim, Eli Lilly & Co., MSD, and Sanofi outside the submitted work. No disclosures were reported by the other authors. adjuvant osimertinib versus placebo in this patient population (13), these HRQoL data further support adjuvant osimertinib as an effective new treatment strategy in this setting. Authors’ Contributions M. Majem: Data curation, formal analysis, writing–original draft, writing–review and editing. J.W. Goldman: Writing–original draft, writing–review and editing. Authors’ Disclosures T. John: Writing–original draft, writing–review and editing. C. Grohe: Writing– M. Majem reports speakers bureau and advisory board fees from Sanofi, Pfizer, original draft, writing–review and editing. K. Laktionov: Writing–original draft, Janssen, Bristol-Myers Squibb, MSD, Boehringer-Ingelheim, AstraZeneca, Roche, writing–review and editing. S.-W. Kim: Writing–original draft, writing–review and Kyowa Kyrin, Pierre Fabre, Takeda Pharmaceutical, and Bayer AG and has editing. T. Kato: Writing–original draft, writing–review and editing. H.V. Vu: received a research grant from Bristol-Myers Squibb outside the submitted work. Writing–original draft, writing–review and editing. S. Lu: Writing–original draft, J.W. Goldman reports research grants from AbbVie Inc., Merck & Co., Bristol- writing–review and editing. S. Li: Conceptualization, writing–original draft, writing– Myers Squibb, and AstraZeneca; speakers bureau fees from Merck & Co.; and review and editing. K.Y. Lee: Writing–original draft, writing–review and editing. honoraria from AstraZeneca outside the submitted work. T. John reports advisory C. Akewanlop: Writing–original draft, writing–review and editing. C.-J. Yu: board and consultancy fees from Roche AG, Bristol-Myers Squibb, Merck & Co., Writing–original draft, writing–review and editing. F. de Marinis: Conceptualization, Ignyta, AstraZeneca, Takeda Pharmaceutical, MSD, Specialised Therapeutics, and data curation, formal analysis, writing–original draft, writing–review and editing. Pfizer Inc. outside the submitted work. C. Grohe reports speakers bureau fees, L. Bonanno: Writing–original draft, writing–review and editing. M. Domine: advisory board fees, and honoraria from AstraZeneca, Boehringer-Ingelheim, and Writing–original draft, writing–review and editing. F.A. Shepherd: Writing– MSD and travel and accommodation fees from Boehringer-Ingelheim outside the original draft, writing–review and editing. S. Atagi: Writing–original draft, submitted work. K. Laktionov reports speakers bureau fees, advisory board fees, writing–review and editing. L. Zeng: Writing–original draft, writing–review and and honoraria from AstraZeneca, Bristol-Myers Squibb, MSD, Roche, and Biocad; editing. D. Kulkarni: Data curation, formal analysis, writing–original draft, advisory board fees from Pfizer; and research grants from AstraZeneca outside the writing–review and editing. N. Medic: Writing–original draft, writing–review submitted work. S.-W. Kim reports speakers bureau and advisory board fees from and editing. M. Tsuboi: Writing–original draft, writing–review and editing. Boehringer-Ingelheim; advisory board fees from AstraZeneca, Bristol-Myers R.S. Herbst: Writing–original draft, writing–review and editing. Y.-L. Wu: Squibb, Eli Lilly & Co., and Novartis; and financial support from AstraZeneca Writing–original draft, writing–review and editing. outside the submitted work. T. Kato reports speakers bureau fees, advisory board fees, and research grants from AstraZeneca, Amgen Inc., Chugai Pharmaceutical Acknowledgments Co., Ltd, Eli Lilly & Co., Merck Biopharma, MSD, and Pfizer Inc.; speakers bureau This trial (NCT02511106) was funded and sponsored by AstraZeneca https://doi. fees from Bristol-Myers Squibb, Novartis, Taiho Pharmaceutical, Boehringer- org/10.13039/100004325, the manufacturer of osimertinib. The funder contributed to Ingelheim, and Roche AG; advisory board fees from Daiichi-Sankyo; speakers the conception and design of the trial; preparation, review, or approval of the article; bureau and research grants from Novartis; and research grants from AbbVie Inc. and decision to submit the manuscript for publication and as such is included in the outside the submitted work, as well as employment with Regeneron (spouse) and author list and acknowledgments. Thanks to all the patients and their families. The Eli Lilly & Co. S. Lu reports speakers bureau fees, advisory board fees, and research authors would like to acknowledge Laila Cancian, of Ashfield MedComms, Maccles- grants from AstraZeneca and Roche; speakers bureau fees from Hansoh; advisory field, UK, an Ashfield Health Company, part of UDG Healthcare, and Clare board fees and research grants from Hutchison MediPharma; advisory board fees McCleverty, contracted to Ashfield MedComms, for medical writing support that from Boehringer-Ingelheim, Simcere, ZaiLab, and GenomiCare; and research was funded by AstraZeneca in accordance with Good Publications Practice (GPP3) grants from Bristol-Myers Squibb, Heng, and Rui outside the submitted work. F. guidelines (http://www.ismpp.org/gpp3). de Marinis reports advisory board and consultancy fees from Roche AG, Bristol- Myers Squibb, AstraZeneca, and MSD outside the submitted work. L. Bonanno The costs of publication of this article were defrayed in part by the reports speakers bureau fees from Roche, Bristol-Myers Squibb, and MSD and payment of page charges. This article must therefore be hereby marked advisory board fees and a research grant from AstraZeneca. M. Domine reports advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate speakers bureau, advisory board, and consultancy fees from AstraZeneca, Bristol- this fact. Myers Squibb, Boehringer-Ingelheim, MSD, Pfizer Inc., and Roche AG outside the submitted work. F.A. Shepherd reports ownership of stock interest in AstraZe- neca. S. 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