Patient-Reported Outcomes in a Phase 2 Study Comparing Atezolizumab Alone or With Bevacizumab Versus Sunitinib in Previously Untreated Metastatic Renal Cell Carcinoma

Abstract

Objective:

To evaluate patient-reported outcome (PRO) data from IMmotion150. The phase 2 IMmotion150 study showed improved progression-free survival with atezolizumab plus bevacizumab versus sunitinib in patients with PD-L1+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC).

Patients and methods:

Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (IV) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg IV every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. TTD was the first ≥ 2-point score increase over baseline. Absolute effect size ≥ 0.2 suggested a clinically important difference with checkpoint inhibitor therapy versus sunitinib.

Results:

Completion rates were > 90% at baseline and ≥ 80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) versus sunitinib. Improved TTD (HR [95% CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22–0.71); RCC symptoms, 0.22 (0.12–0.41); and symptom interference, 0.36 (0.22–0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy versus sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions.

Conclusion:

PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone versus sunitinib. (IMmotion150; NCT01984242.)

Introduction

Vascular endothelial growth factor (VEGF) inhibition with VEGF monoclonal antibodies, such as bevacizumab, or receptor tyrosine kinase inhibitors (VEGFR-TKIs), such as sunitinib or pazopanib, has been a first-line standard for over a decade in metastatic renal cell carcinoma (mRCC) due to the angiogenic nature of the tumour [1]. This paradigm has changed, however, on the basis of multiple studies assessing innovative combinations of either dual checkpoint inhibitor (CPI) therapy or VEGF-directed agents with CPI. The programmed cell death 1 protein (PD-1) inhibitor nivolumab, when combined with the cytotoxic T-lymphocyte–associated protein 4 inhibitor ipilimumab, has demonstrated improved survival and response rate relative to sunitinib in patients with mRCC and intermediate- or poor-risk prognostic features [2]. The VEGFR-TKI axitinib has been combined with pembrolizumab (a PD-1 inhibitor) and avelumab (a programmed cell death 1 ligand 1 [PD-L1] inhibitor), with improved clinical outcomes over sunitinib with both combinations [3,4]. The VEGF monoclonal antibody bevacizumab combined with the PD-L1 inhibitor atezolizumab has similarly shown clinical benefit and demonstrated prolonged progression-free survival (PFS) relative to sunitinib in a phase 3 study [5].

The efficacy of CPI combinations in mRCC gives rise to the question of whether CPI monotherapy could also represent an up-front approach. To this end, the nonrandomised, prospective KEYNOTE-427 study examined 110 patients with metastatic clear cell RCC receiving first-line pembrolizumab [6]. A response rate of 36.4% (95% CI, 27.4%−46.1%) was seen in 110 evaluable patients, and the median PFS was 7.1 months (95% CI, 5.6–11.0 months). We further evaluated CPI monotherapy in the IMmotion150 study, a randomised phase 2 study, to assess the safety and efficacy of atezolizumab monotherapy or atezolizumab plus bevacizumab versus sunitinib in 305 patients with treatment-naive mRCC [5]. Objective response rates were 25%, 32%, and 29% with atezolizumab monotherapy, atezolizumab plus bevacizumab, and sunitinib, respectively, in the intention-to-treat (ITT) population, and 28%, 46%, and 27%, respectively, in the PD-L1+ population [7].

The results of the IMmotion150 study have been further examined in the IMmotion151 study. The IMmotion151 study is a randomised, open-label, phase 3 study comparing atezolizumab plus bevacizumab versus sunitinib in previously untreated mRCC. The median PFS was 11.2 months with atezolizumab plus bevacizumab versus 7.7 months with sunitinib in the PD-L1+ patient population (hazard ratio [HR], 0.74 [95% CI, 0.57–0.96]; P = .0217) [5]. Patient-reported outcome (PRO) data from the IMmotion151 study favoured atezolizumab plus bevacizumab versus sunitinib. The median time to clinically relevant deterioration of daily functioning due to treatment- and disease-related symptoms was notably longer in patients receiving atezolizumab plus bevacizumab (11.3 months) than in patients receiving sunitinib (4.3 months) in the ITT population (stratified HR, 0.56 [95% CI, 0.46–0.68]).

IMmotion150 presents a rare opportunity to juxtapose CPI monotherapy simultaneously against VEGFR-TKI and combination strategies. Because patients with cancer are burdened by both disease- and treatment-related symptoms, the assessment and lessening of these symptoms is important in therapeutic decision making. In the current manuscript, we compare PRO data for patients randomly assigned to one of these three distinct treatment approaches.

Patients and methods

Study design and eligibility

IMmotion150 (NCT01984242) is a multicentre, prospective, randomised, open-label, phase 2 study conducted at 96 institutions. This hypothesis-generating study was designed to evaluate the safety and preliminary activity of atezolizumab plus bevacizumab versus sunitinib and atezolizumab monotherapy versus sunitinib. The study was designed to enrol approximately 100 patients per arm regardless of PD-L1 status to enable adequate subset analysis. Patients eligible for the study had mRCC with clear cell and/or sarcomatoid components. No prior systemic therapy was allowed. Patients with active central nervous system disease were excluded, and patients had to have adequate haematology and laboratory parameters [7].

Patients completed PRO assessments before initiating treatment (ie, at baseline), on days 1 and 22 of each 6-week treatment cycle, and at the end of treatment. Given the two different dosing schedules, patients in the sunitinib arm were off treatment for 2 weeks at day 1 assessment visits and were receiving their 28-day treatment at day 22 assessment visits.

Treatment regimen

Patients were randomised to atezolizumab 1200 mg intravenously (IV) every 3 weeks alone or with bevacizumab 15 mg/kg IV every 3 weeks, or sunitinib 50 mg oral daily (4 weeks on, 2 weeks off). Stratification factors included Memorial Sloan Kettering Cancer Center (MSKCC) risk category (low, intermediate, or high), prior nephrectomy (yes or no), and PD-L1 status (≥ 5% or < 5%). Patients were treated until disease progression or unacceptable toxicity. Notably, patients who derived clinical benefit despite disease progression were allowed to continue study treatment with atezolizumab. The study allowed for crossover from sunitinib and atezolizumab monotherapy to combination therapy. However, crossover following atezolizumab therapy was not allowed in the European centres due to local regulatory guidance.

PRO instruments

MD Anderson Symptom Inventory

MD Anderson Symptom Inventory (MDASI) has been validated among patients diagnosed with a variety of cancer types and undergoing different forms of treatment [8]. It comprises 13 core items that assess severity of disease and treatment-related symptoms [6–8]. An additional three items were used to assess RCC-specific symptom severity (mouth/throat sores, rash/skin change, and headache). Patients were asked to rate each symptom at its worst in the past 24 hours on a scale from 0 to 10, with 10 representing the worst imaginable severity. A further six items assessed symptom interference with daily life on the same 11-point scale, with 10 representing complete interference with daily life. The six dimensions of daily life include general activity, walking, work, mood, relations with other people, and enjoyment of life.

Brief Fatigue Inventory

Brief Fatigue Inventory (BFI) is a nine-item instrument designed to assess patient-reported cancer-related fatigue [9]. BFI has been found to be unidimensional and to be a valid and reliable measure [9]. A single item, instead of three items, was used to assess the severity of fatigue at its worst in the past 24 hours on a scale from 0 to 10, with 10 indicating the worst severity. Further questions assessed fatigue-related interference across the six dimensions of daily life noted in the previous section.

Statistical analysis

The clinical data cutoff date was 19 April 2017. PROs were prespecified to evaluate disease- and treatment-related symptom severity (including fatigue) and their interference with patients’ daily functioning. Analyses included PRO data collected up to crossover for patients randomised to the atezolizumab monotherapy or sunitinib arms, and up to the end of treatment for patients randomised to the atezolizumab plus bevacizumab arm or patients randomised to the atezolizumab monotherapy arm in Europe. PROs were analysed without type I error control. Completion rates were calculated as the number of patients who completed assessments divided by the number of patients expected to complete assessments at each visit. Per developers’ user manuals, for PRO scales with > 50% of the constituent items completed, a prorated score was computed. For scales with ≤ 50% of the items completed, the scale was considered missing.

Longitudinal analysis of change in each PRO score from baseline included scheduled on-study visits among all randomised patients with a nonmissing baseline score and ≥ one postbaseline score. The primary longitudinal analysis was based on repeated-measures models including baseline PRO score, stratification factors, treatment, visit, and treatment-by-visit interaction. Supportive analysis based on linear mixed-effects models included baseline PRO score, stratification factors, treatment, and time (continuous) as fixed effects as well as random effects of intercept and slope (for time). Least-squares mean (LSM) change from baseline within each treatment arm and the difference in LSM change between treatment arms were estimated at each visit (repeated-measures models) or over the first-line treatment period (linear models). Repeated-measures model estimates are reported up to the last consecutive visit when ≥ 20% of patients were still on study. Effect size (ES) supported interpretation of differences between treatment arms, where absolute ES ≥ 0.20 likely represented a clinically important difference [10]. ES was calculated as the difference in score change divided by the pooled standard deviation at each visit. Negative ES values favoured atezolizumab alone or atezolizumab plus bevacizumab versus sunitinib, whereas positive ES values favoured sunitinib.

Time-to-event analyses were evaluated as the time to clinically meaningful deterioration, defined as the time from randomisation date to a patient’s first ≥ 2-point score increase above baseline. HRs and 95% CIs by treatment arm were estimated using a stratified Cox regression model. Kaplan-Meier methodology was used to estimate the probability of deterioration. Analyses were performed on all randomised patients. Patients without a deterioration event were censored at the last nonmissing PRO assessment date, whereas patients with no baseline or postbaseline PRO assessment were censored at randomisation.

Results

Patient characteristics

The IMmotion150 trial enrolled 305 patients between 8 January 2014 and 16 March 2015. Of those enrolled, 101 patients were randomised to the atezolizumab plus bevacizumab arm, 103 to the atezolizumab monotherapy arm, and 101 to the sunitinib arm. As previously reported, baseline patient and tumour characteristics were generally well balanced across treatment arms (Supplemental Table 1) [7].

PRO scores

Completion rates for MDASI and BFI were > 90% at baseline and ≥ 80% at most visits across arms. Baseline PRO scores indicating mild symptoms and interference were similar across arms (Supplemental Table 2). A markedly improved time to deterioration in MDASI core symptom severity, RCC symptom severity, and symptom interference was observed with atezolizumab monotherapy versus sunitinib: core symptoms, HR (95% CI), 0.39 (0.22–0.71); RCC symptoms, 0.22 (0.12–0.41); and symptom interference, 0.36 (0.22–0.58) (Figure 1a–c). Similar trends were observed with the combination of atezolizumab plus bevacizumab versus sunitinib, although the differences were less pronounced: core symptoms, HR (95% CI), 0.74 (0.45–1.20); RCC symptoms, 0.60 (0.38–0.94); and symptom interference, 0.70 (0.47–1.04). Atezolizumab monotherapy also compared favourably to sunitinib in deterioration-free rate using BFI fatigue severity and fatigue-related interference scales; the results also showed a trend in favour of atezolizumab plus bevacizumab versus sunitinib (Figure 1d, e).

Figure 1.

Time to deterioration based on (a) MDASI core symptom severity, (b) MDASI RCC symptom severity, (c) MDASI symptom interference, (d) BFI fatigue severity, and (e) BFI fatigue interference.

Atezo, atezolizumab; bev, bevacizumab; BFI, Brief Fatigue Inventory; HR, hazard ratio; MDASI, MD Anderson Symptom Inventory; NE, not evaluable; RCC, renal cell carcinoma.

Differences in core symptom severity, RCC symptom severity, and symptom interference were generally clinically relevant, favouring atezolizumab monotherapy versus sunitinib (Figure 2a–c). Linear mixed-effects model estimates were generally consistent with repeated-measures model estimates, suggesting that patients also reported a lesser degree of symptom severity and symptom interference with atezolizumab monotherapy versus sunitinib over the first-line treatment period. Differences in LSM change (95% CI) and corresponding ES for atezolizumab monotherapy versus sunitinib were as follows: core symptoms, −0.47 (−0.76 to −0.17) and −0.33; RCC symptoms, −0.64 (−0.94 to −0.33) and −0.70; and symptom interference, −0.80 (−1.24 to −0.36) and −0.36. For atezolizumab plus bevacizumab versus sunitinib, changes in core symptom severity, RCC symptom severity, and symptom interference were similar. Differences in LSM change (95% CI) during first-line treatment and corresponding ES for atezolizumab plus bevacizumab versus sunitinib were as follows: core symptoms, −0.07 (−0.36 to 0.22) and −0.05; RCC symptoms, −0.15 (−0.45 to 0.16) and −0.20; and symptom interference, −0.28 (−0.71 to 0.15) and −0.13.

Figure 2.

Change from baseline by visit based on MDASI scales assessing (a) core symptom severity, (b) RCC symptom severity, and (c) symptom interference.

Atezo, atezolizumab; bev, bevacizumab; ES, effect size; MDASI, MD Anderson Symptom Inventory; RCC, renal cell carcinoma.

All 16 symptoms assessed for severity were milder with atezolizumab versus sunitinib during first-line treatment (Figure 3). The five symptoms with the largest increase in severity from baseline (dry mouth, fatigue, rash, drowsiness, and lack of appetite) were more prominently changed in the sunitinib arm relative to atezolizumab monotherapy or atezolizumab plus bevacizumab. LSM change from baseline estimates by visit and over the first-line treatment period for BFI scales suggest nominally milder fatigue and less fatigue-related interference with atezolizumab monotherapy versus sunitinib, and similar changes in fatigue and fatigue-related interference with daily life with atezolizumab plus bevacizumab versus sunitinib.

Figure 3.

Change in individual symptom severity during first-line treatment based on MDASI.

Atezo, atezolizumab; bev, bevacizumab; ES, effect size; MDASI, MD Anderson Symptom Inventory.

^a ES ≤ −0.20 favouring atezolizumab alone versus sunitinib.

^b ES ≤ −0.20 favouring atezolizumab plus bevacizumab versus sunitinib.

Discussion

The results reported herein represent the first randomised PRO data directly comparing VEGFR-TKI therapy to CPI monotherapy in the frontline setting. Patients receiving atezolizumab monotherapy reported milder disease- and treatment-related symptoms (including fatigue), delayed symptom deterioration, and less interference of symptoms with daily life. The collective results imply that characterising the subset of patients who benefit from atezolizumab monotherapy is of paramount importance, as this strategy could confer superior quality of life (QOL) relative to therapeutic alternatives. Of note, a less pronounced difference in QOL between atezolizumab plus bevacizumab and sunitinib was observed in the current study compared with the phase 3 IMmotion151 trial (previously reported) [11]. These differences could be owing to a larger sample size in the phase 3 experience or to experiential gain with this novel doublet (or other anti-VEGF/CPI combinations) in the transition from the phase 2 to the phase 3 study.

With consistency across studies and disease states, monotherapy with PD-1/PD-L1–directed therapies has been associated with improved QOL relative to previous standards. Atezolizumab has been compared with docetaxel in patients with non-small cell lung cancer receiving second-line treatment [12]. Compared with docetaxel, atezolizumab delayed time to deterioration in physical function and led to a numerical improvement in health-related QOL (HR-QOL). In mRCC, the only published randomised experience in which QOL was assessed with CPI monotherapy versus standard treatment is the CheckMate 025 trial [13]. In this trial, patients with prior VEGF-directed therapy were randomised to receive either nivolumab or the mechanistic target of rapamycin inhibitor everolimus. HR-QOL was assessed using the Functional Assessment of Cancer Therapy-Kidney Symptom Index-Disease Related Symptoms questionnaire. A clinically meaningful improvement in HR-QOL was seen with nivolumab versus everolimus. Indeed, meta-analytic data pooling QOL data from randomised trials evaluating PD-1/PD-L1–directed therapies showed a global trend favouring these agents [14]. In mRCC, dual CPI therapy represents a current frontline standard based on the phase 3 CheckMate 214 trial [2]. This study demonstrated a significant improvement in survival in intermediate- and poor-risk patients with mRCC, and PRO data suggested improved HR-QOL relative to sunitinib in this population [15]. With all of the caveats of cross-trial comparisons, a monotherapy approach may still have merit on the basis of multiple factors, including relatively similar efficacy and reduced clinical toxicity. A phase 3 study is planned comparing nivolumab plus ipilimumab to nivolumab plus placebo to address both the efficacy and toxicity impacts of a combination CPI versus a single agent.

CPI monotherapy is of particular interest in the adjuvant setting, where maintenance of QOL is essential. In melanoma, approvals exist for ipilimumab, nivolumab, and pembrolizumab in the adjuvant setting on the basis of separate, randomised, phase 3 trials [16–18]. Durvalumab is approved for patients with stage 3 non-small cell lung cancer as consolidation treatment following combined chemoradiotherapy [19]. Following suit, several trials have been launched in patients with high-risk, localised RCC evaluating CPIs either prior to or following surgical resection. The IMmotion010 trial comparing atezolizumab to placebo in this setting has recently completed accrual, and a similar trial comparing pembrolizumab to placebo is currently underway [20, 21]. An Eastern Cooperative Oncology Group-ACRIN–led study, PROSPER, is evaluating perioperative nivolumab therapy against observation [22]. Trials are evaluating dual CPIs in this setting as well (eg, CheckMate-914, comparing nivolumab/ipilimumab to placebo). As all adjuvant studies use observation/placebo as the comparator arm, our current study may help to inform the treatment decision between sunitinib (currently approved as adjuvant therapy based on the phase 3 S-TRAC trial by the US Food and Drug Administration) and any emerging immunotherapy option in this setting [23]. Considerations around efficacy notwithstanding, our data implied superior QOL with CPI monotherapy versus VEGFR-TKI.

Although PRO questionnaire completion rates were high throughout the study, results from this hypothesis-generating phase 2 study should be interpreted in the context of the relatively small sample sizes. While PRO data did accompany the phase 3 IMmotion151 study, a much larger experience, our study offers the unique and perhaps sole opportunity to juxtapose QOL with VEGFR-TKI and CPI monotherapy [11].

During first-line treatment in IMmotion150, patients with mRCC treated with atezolizumab alone reported milder disease- and treatment-related symptoms (including fatigue), delayed symptom deterioration, and lesser impact of symptoms on their daily life compared with those treated with sunitinib. Clinically relevant differences were most pronounced when comparing atezolizumab monotherapy with sunitinib. Although not statistically significant, a trend towards improved QOL was observed in patients treated with atezolizumab plus bevacizumab versus sunitinib. Patients treated with the combination reported similar symptom burden versus sunitinib. QOL results were more compelling with atezolizumab monotherapy, suggesting that monotherapy should be explored in selected settings (eg, biomarker-selected populations in a metastatic setting, or as adjuvant treatment where immunotherapy is under investigation and use of sunitinib is controversial due to its low risk-benefit ratio).