In all, 156 patients were accrued. However, one patient was deemed ineligible after enrollment and eight patients withdrew during the study. The remaining 147 were included in this analysis, of which 145 provided follow-up PRO data.

Figure 1 shows the screening process which led to the final sample of 147 patients participating in the study, with 145 providing PRO information. Of 782 patients with a diagnosis of NSCLC, the largest number excluded was 336 due to excluded treatment regimens. Other key exclusions included 49 due to patients already having received first line therapy, 65 due to performance status impairment or other health issues, 36 refused, and 140 for other reasons. One patient was removed from the study after it was discovered the patient was not actually eligible; eight patients who were consented provided no follow up data. Of the 147, 66 (44.9%) received Regimen A, 25 (17.0%) Regimen B, and 56 (38.1%) Regimen C (see Table 1). With a mean age of 64.8 years old, patients were 58.5% male, 86.4% white race. Race and geographic region varied across treatment groups, (p = 0.005, p = 0.028, respectively), with fewer white patients in Regimen B and fewer patients from the South in Arm C. At the start of first-line treatment, a small proportion of the overall sample (13.6%) had impaired performance status. Stage at initial diagnosis, performance status, rates of baseline brain, bone, and liver metastasis, weighted Comorbidity Index and rate of any comorbid condition did not differ across groups, though there was some nonsignificant variability at the level of individual comorbidities. More than half of patients (55.1%) had at least one comorbidity at the start of first-line treatment. The most common comorbidity was chronic obstructive pulmonary disease (33.3%). The rate at which patients received radiation therapy in the advanced setting varied significantly among treatment groups (p = 0.0006), appearing higher in Regimen C (41.1%) compared with A and B (12.1 and 16.0%, respectively). More than 90% of patients had a smoking history.

Fig. 1 Diagram of Screening and Reasons for Non-Participation in Study Full size image

Table 1 Demographic and Clinical Characteristics by Regimen Group Full size table

Effectiveness outcomes

Median PFS in first line was 5.59 months overall, with 141 events in 147 patients. Unadjusted median PFS varied significantly by treatment group (Regimen A: 7.36 months, Regimen B: 4.18, Regimen C: 4.96, p = 0.0013) (see Fig. 2a). Cox regression analysis of PFS, controlling for demographic and clinical covariates, showed significant variability in PFS by treatment regimen, p = 0.0115 (see Table 2). Pairwise comparisons showed that Regimen A was associated with significantly longer PFS than Regimen B (HR = 0.456, p = 0.0035), and Regimen A tended to be associated with longer PFS than Regimen C (HR = 0.701, p = 0.1070). Impaired performance status was associated with shorter PFS (HR = 2.463, p = 0.0011). Other covariates were nonsignificant in predicting PFS.

Fig. 2 a Progression Free Survival in First-Line NSCLC, by Treatment Regimen. b Overall Survival in First-Line NSCLC, by Treatment Regimen Full size image

Table 2 Cox Regression of PFS and OS from Start of First-Line Treatment by Treatment Regimen Group Full size table

As measured from the start of first-line treatment, median OS was 9.67 months overall, with 102 events observed. Unadjusted OS varied significantly by treatment group (Regimen A: 12.30 months, Regimen B: 5.88, Regimen C: 7.92), p < 0.0001 (see Fig. 2b). Cox regression analysis of OS, controlling for demographic and clinical covariates, showed significant variability in OS by treatment regimen, p = 0.0040 (see Table 2). Pairwise comparisons showed that Regimen A was associated with significantly longer OS than Regimen B (HR = 0.341, p = 0.0012), and Regimen A was also associated with significantly longer OS than Regimen C (HR = 0.602, p = 0.0354). Male gender, stage IV at diagnosis, impaired performance status, and higher comorbid disease burden were associated with shorter OS.

Treatment regimen effects on adverse events and patient reported outcomes

Ninety-three patients (63.3%) had at least one adverse event, with no significant differences between regimen groups in the rate at which patients had an adverse event (Regimen A: 71.2%, Regimen B: 56.0%, Regimen C: 57.1%), p = 0.1955. Regimen groups did not differ in AE rates at the level of system organ class, except for musculoskeletal events (Regimen A: 0%, Regimen B: 8%, Regimen C: 5.4%, p = 0.042).

PRO analysis was based on 145 patients, with 1100 individual PRO surveys. Fifty-nine patients provided PRO data on or after the date of disease progression, though it should be noted that only 75 patients total received therapy beyond first line. The number of patients providing PRO data by Arm included Regimen A: 64 patients (495 surveys) before progression, 27 patients (97 surveys) after; Regimen B: 24 patients (105 surveys) before, 7 patients (14 surveys) after; and Regimen C: 56 patients (313 surveys) before, 25 patients (76 surveys) after. Differences in survey number by group were a function of group sample size and treatment duration, with surveys administered on average every 27 to 29 days during first line. Results from the linear mixed models generally showed no differences in PROs at baseline or over time between treatment regimen groups.

Disease progression and patient reported outcomes

Disease progression had a significant effect on PROs. In particular, many of the PRO endpoints showed deterioration at the time of and generally following disease progression. Modeled as a time varying covariate, disease progression was a statistically significant (p < 0.05) or near significant (p < 0.10) predictor of adverse impact for 18 of 32 PRO endpoints. Fig. 3 lists each of the PRO endpoints and the percentage deterioration attributable to disease progression for each. Controlling for patient characteristics, treatment regimen, and the passage of time, disease progression had a statistically significant effect on 12 PRO measures (Sore Mouth, Constipation, Dyspnea, Pain in Chest, Fatigue, Pain in Other Parts, Alopecia, RALS Activity Level, Physical Functioning, Social Functioning, Role Functioning, Dysphagia). The average associated deterioration was 5.7% of the instrument range, where changes of 5 to 10% of scale range were considered clinically meaningful, and represented 0.2 to 0.5 standard deviations across the measures. This range of values would be considered to reflect small to moderate clinically meaningful effects if they were between-group differences, but here, as representing longitudinal (within-subject) effects, some of these would be viewed as moderate to large clinically meaningful levels of change [25]. The largest negative effects associated with disease progression were for QLQ-LC13: Sore Mouth (8.0%), QLQ-C30: Constipation (7.6%), and QLQ-LC13: Dyspnea (7.3%). The adverse impact of disease progression on the QLQ-C30: Global Health Status scale was 4.7% (p = 0.047), and on QLQ-C30: Physical Functioning scale was 5.3%.

Fig. 3 Linear Mixed Model-Implied Effects of Disease Progression and Other Key Predictors Full size image

As illustrated in Fig. 4a–d, the combined impact of time and disease progression varied for different PRO measures. Disease progression within the figures is depicted at the median value for patients in the study sample. Models controlled for patient characteristics, treatment regimen, and the timing of each survey during first or second-line treatment. For Dyspnea, a discrete adverse impact of disease progression was observed at the time of the event, but scores were stable before and after progression (Fig. 4a). For Role Functioning (QLQ-C30) and Activity-Related Interference (MDASI), scores were stable pre-progression, with loss of functioning occurring at progression. Further gradual deterioration following progression was also observed (Fig. 4b and c). For Global Health Status (QLQ-C30), patients’ health status appeared to decline gradually over time, punctuated by the effect of the progression event (Fig. 4d). The figures therefore illustrate the different patterns in which cumulative deterioration may occur over time and at disease progression. In contrast, the deterioration due to disease progression as shown in Fig. 3 does not include effects of deterioration that occurred over time either before or after the progression event itself.

Fig. 4 Selected Patient Reported Outcomes from Start of First-Line Therapy, with Model-Implied Impact of Disease Progression Full size image

Effects of treatment regimen group on PROs were also examined. However, PRO outcomes did not vary significantly by treatment regimen group.

Patient level predictors of patient reported outcomes

Linear mixed model analyses that included patient level covariates showed that impaired performance status was strongly associated with poorer HRQOL. The largest adverse effects were for RALS (19.4% of instrument range), MDASI-LC Mood-Related Interference (16.7%), and QLQ-C30: Social Functioning (16.0%). In contrast, having private insurance was associated with relative advantage at a level that was significant on 16 measures. The largest positive effects were for QLQ-C30: Perceived Financial Impact (17.9% of instrument range), MDASI-LC Activity-Related Interference (12.3%), and QLQ-C30: Dyspnea (12.1%). The beneficial effect of having private insurance on QLQ-C30: Global Health Status was 10.4% of the instrument range (p = 0.0003).