Exploratory Analyses of Patient Preferences for Atezolizumab Subcutaneous Versus Intravenous from the IMscin002 Study in Patients with Non-Small Cell Lung Cancer.

Key Summary Points

Introduction
Atezolizumab is a programmed cell death 1 ligand 1 (PD-L1) inhibitor that is approved for the treatment of various solid tumors, including non-small cell lung cancer (NSCLC) [1, 2]. Two different formulations of atezolizumab have been approved for use: atezolizumab intravenous (IV) and atezolizumab subcutaneous (SC; a co-formulation containing atezolizumab and recombinant human hyaluronidase [rHuPH20]). Since 2023, atezolizumab SC formulation has been approved for use in over 50 countries [3].
IMscin001 (NCT03735121) is a two-part phase 1b/3 randomized, open-label, multicenter study comparing atezolizumab SC and IV administrations in patients with locally advanced/metastatic NSCLC following progression on chemotherapy. The primary objectives of part 2 of the study were met: atezolizumab SC demonstrated non-inferior drug exposure at cycle 1 compared with IV (co-primary endpoints were Ctrough and model-predicted area under the curve0–21d at cycle 1) [4]. Efficacy (including overall survival), immunogenicity, and safety were also similar between SC and IV arms [4, 5]. Importantly, patient perspectives on atezolizumab SC were positive overall; patient-reported outcomes revealed that global health status, physical functioning, and role functioning over time were similar between treatment arms [5].
IMscin002 (NCT05171777) is a phase 2, randomized, multicenter study designed to evaluate patient preferences for atezolizumab SC and IV [6]. Data from the primary analysis (data cutoff November 9, 2023) of the study showed that most patients (70.7%; n = 87/123; 95% confidence interval [CI] 61.9–78.6) preferred atezolizumab SC over IV, and 79.4% (n = 85/107) of patients chose atezolizumab SC for the continuation period [6]. Rates of patient satisfaction were high with atezolizumab SC: 85.8% (n = 109/127) of patients were satisfied or very satisfied with the SC formulation [6]. Furthermore, the preparation time of atezolizumab SC was approximately three times faster when prepared by nurses on the ward compared with pharmacists in the pharmacy [6]. We showed that time saving, including shorter administration time and reduced time in the clinic, was the main reason patients preferred atezolizumab SC over IV [6].
Patient characteristics, such as a low body weight, female sex, and older age, may make an individual more susceptible to experience injection-site pain [7–9] and, therefore, influence a patient’s preference for atezolizumab SC or IV. Additionally, as a result of the novelty of large-volume SC administrations, the level of experience of the healthcare professional (HCP) administering the injection may also play a role in patient preference for SC formulations [10]. A HCP’s approach to addressing a patient’s psychological hurdles may also differ, including the ability to communicate effectively with a patient in order to support his or her needs. Appropriate training and education to improve injection technique can reduce injection pain and, therefore, influence patient preference [10]. Previous studies have shown that patients prefer to receive anticancer treatments via SC injections rather than IV infusions because SC administration is associated with reduced pain and discomfort [11–14]. This prior research provides a rationale for exploring how patient characteristics, SC injection duration, and number of SC injections administered at each study center may affect patient preference for SC administration.
The primary analysis of IMscin002 showed that most patients preferred atezolizumab SC versus IV. Here, we present additional analyses on patient preference for atezolizumab SC or IV according to patient characteristics (including body mass index [BMI], sex, disease stage, Eastern Cooperative Oncology Group performance status [ECOG PS], and age), mean injection time of atezolizumab SC, and cumulative number of SC injections administered at each center from the IMscin002 study.

Methods
The methodology for the IMscin002 study has been reported previously and the study design can be seen in Supplementary Material Fig. S1 [6]. Enrollment and the primary analysis for this study have been completed; information on the institution review boards can be found in Supplementary Material Table S1. Details relating to the preparation and administration of atezolizumab SC have also been published previously by Burotto et al. (see Supplementary Material in Burotto, et al) [5].
Eligible patients were ≥ 18 years old, with EGFR/ALK wild-type tumors, and had either PD-L1+ (≥ 1%) resected NSCLC (stage 2, 3a, or selected 3b; AJCC 8th edition) with prior chemotherapy and no evidence of recurrence, or untreated PD-L1-high [≥ 50%] stage 4 NSCLC [6]. Patients were randomized 1:1 to receive atezolizumab SC or atezolizumab IV every 3 weeks for three cycles before switching to the alternative formulation for another three cycles. After cycle 6, patients chose atezolizumab SC or IV for the continuation period.
The primary endpoint of this study was the proportion of patients who preferred atezolizumab SC or IV, as assessed using question 1 of the patient preference questionnaire (PPQ) which all patients still receiving study treatment were asked to complete on day 1 of cycle 6. Thus, patients who completed the crossover period received a total of three SC and three IV administrations of atezolizumab before stating their preference. Patients who discontinued treatment prior to day 1 of cycle 6 were eligible to state their preferred route of administration at the time of discontinuation if they had received ≥ 2 consecutive doses of each atezolizumab formulation (SC and IV). Question 1 of the PPQ asked patients which route of administration they preferred (SC, IV, or no preference) and question 2 asked patients about the strength of their preference for atezolizumab SC or IV (very strong, fairly strong, or not very strong). A third question on the PPQ asked patients to state reasons for their preference. Full details on the PPQ have been published previously [6].
The exploratory, post hoc analyses presented in this paper assessed the strength of patients’ preference for atezolizumab SC or IV, as well as patient preference for atezolizumab SC or IV according to baseline characteristics (BMI, sex, disease stage, ECOG PS, and age), mean injection duration of atezolizumab SC, and cumulative number of injections at each center prior to the patient completing the questionnaire. A patient’s age and BMI, as well as the injection duration and the cumulative number of injections at each center, were categorized into four quartiles based on the distribution of the variable (e.g., dividing age into four categories based on the ages of the patients enrolled), and calculated from the intent-to-treat population (Supplementary Material Table S2).
This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all patients. Protocols were approved by the relevant institutional review boards at each study site.

Results

Patient Characteristics
At the time of primary analysis (data cutoff November 9, 2023), 179 patients had been enrolled in the overall intent-to-treat population of IMscin002 (Fig. 1). Demographics and baseline characteristics for patients enrolled into IMscin002 have been reported previously [6]. Key baseline characteristics considered for these analyses can be found in Table 1. Most patients were male (66.5%; n = 119) and had an ECOG PS of 1 (54.7%; n = 98). Median age was 67.0 years and mean BMI was 26.1. Most patients were of white race (83.2%; n = 149).

Overall Strength of Patients’ Preference
In IMscin002, most patients who expressed a preference had completed all six cycles of treatment. Overall, 126 patients were eligible to complete the PPQ as they had received ≥ 2 consecutive doses of atezolizumab SC and IV; 123 patients completed question 1 of the PPQ. As previously reported, 87 patients (70.7%; 95% CI 61.9–78.6) preferred atezolizumab SC, 26 patients (21.1.%) preferred atezolizumab IV, and 10 patients (8.1%) had no preference [6]. Of the patients who initially received atezolizumab IV, 20.0% preferred atezolizumab IV (71.7% preferred SC and 8.3% had no preference), and of the patients who initially received atezolizumab SC, 69.8% preferred SC (22.2% preferred IV and 7.9% had no preference). Patients chose up to two reasons for their preference; the main reasons for the 87 patients preferring atezolizumab SC were that it reduced time in the clinic (64.4%), patients felt more comfortable during administration (46.0%), and administration felt less emotionally distressing (29.9%). Of the 87 patients who preferred atezolizumab SC, 86.2% (n = 75) had a very or fairly strong preference for SC and, of the 26 patients who preferred atezolizumab IV, 69.2% (n = 18) had a very or fairly strong preference for IV (Fig. 2).

Patient Preference According to Baseline Characteristics
Preference for atezolizumab SC or IV was analyzed according to different patient baseline characteristics to identify factors influencing patient preference for one formulation of atezolizumab. Regardless of baseline or disease characteristics, the proportion of patients who preferred atezolizumab SC over IV was consistent (Fig. 3). In total, 72.6% (n = 61/84) of male patients and 66.7% (n = 26/39) of female patients preferred atezolizumab SC versus IV (Fig. 3a). When patient preference was analyzed according to disease stage (stage 2–3 versus stage 4 NSCLC), 64.6% (n = 31/48) and 74.7% (n = 56/75), respectively, preferred atezolizumab SC versus IV (Fig. 3b). Furthermore, 68.3% (n = 41/60) and 73.0% (n = 46/63) of patients with an ECOG PS of 0 and 1, respectively, preferred atezolizumab SC versus IV (Fig. 3c). A higher preference for atezolizumab SC over IV was also seen irrespective of BMI, with no obvious trend for patients with a higher or lower BMI (Fig. 3d), and patients across all age groups preferred atezolizumab SC. In total, 76.5% and 65.6% of patients aged ≤ 60 years and > 60 to ≤ 67 years, respectively, preferred atezolizumab SC; whereas 23.5% and 21.9% of patients, respectively, preferred atezolizumab IV. Of the patients aged > 67–≤ 74 years, 57.6% preferred atezolizumab SC and 27.3% preferred IV (Fig. 3e). It is worth noting that the highest proportion of preference for atezolizumab SC was seen amongst patients aged > 74 years old (SC 87.5% [n = 21/24]; IV 8.3% [n = 2/24]) (Fig. 3e). The reasons for preferring atezolizumab SC in this age group were consistent with those reported by the general patient population (data not shown).

Patient Preference According to Mean Atezolizumab Injection Duration
No obvious relationship was observed between mean injection duration and patient preference for IV or SC. Regardless of the mean injection duration with the SC formulation, patient preference was higher for atezolizumab SC compared with atezolizumab IV (Fig. 4a).

Patient Preference According to Cumulative Number of Injections per Study Center
Patient preference was evaluated across subgroups based on the cumulative number of atezolizumab SC injections administered (to any patient) at a center before the patient was asked for their preferred administration route (Fig. 4b). Across the three lowest quartiles for number of injections, patient preference for atezolizumab SC remained relatively high and stable, with values ranging from 62.1% to 67.7% for this formulation. However, for patients receiving treatment at centers where the highest cumulative number of atezolizumab SC injections had been administered before the patient was asked for their preferred administration route (> 47 to ≤ 164), preference for the SC formulation increased to 90.0% (n = 27/30) compared with 6.7% (n = 2/30) for atezolizumab IV. The reasons patients gave for their preference for SC were aligned with those of the overall patient population (data not shown).

Discussion
Primary results from the IMscin002 study demonstrated that more patients preferred atezolizumab SC than atezolizumab IV (70.7% versus 21.1%, respectively) [6]. This analysis showed that preference for the SC formulation was high and similar regardless of the mode of action they received first. In addition, of the patients who preferred atezolizumab SC, a higher proportion of patients had a very/fairly strong preference for SC compared with patients who preferred atezolizumab IV and indicated a very/fairly strong preference for the IV formulation.
The exploratory subgroup analyses in this study demonstrated no meaningful differences in patient preference for atezolizumab SC or IV according to baseline characteristics (BMI, sex, disease stage, ECOG PS, or age). For example, whilst the difference of SC preference between male and female patients was modest (approx. 6%), the 95% CI (− 26%, 12%) was wide and crossed zero. However, it was interesting to note that the highest proportion of preference for atezolizumab SC was seen in patients > 74 years old. This suggests that availability of a SC formulation may be of importance especially in older patients. Tsiantou et al. found that patients’ ages seemed to be important in shaping patient preferences [15]. However, there are currently limited data available to help understand why there is a greater preference for atezolizumab SC in older patients compared with other age groups. Further research is needed to explore this.
Studies evaluating the effect of injection speed on injection site pain have reported inconsistent findings [16–19]. In this study, no noticeable trend was observed between mean duration of injection and patient preference for IV or SC; suggesting that speed of administration in a rHuPH20 co-formulated product may not be related to patient discomfort, and that patients are more comfortable and less emotionally distressed during SC administration. Tangen et al. saw no differences in pain sensation between three SC injection speeds [20] and Heise et al. identified no differences in perceived injection pain in patients with diabetes who received saline at different injection speeds [19]. It is worth noting that these publications are based on the administration of solutions without rHuPH20, the co-formulated enzyme which transiently hydrolyses hyaluronic acid, allowing for administration of larger SC volumes, easier administration, and increased bioavailability [21]. At the time of writing this manuscript, no publications were found comparing administration speeds and patient pain or discomfort following treatment with rHuPH20-containing formulations.
A HCP more experienced in administering SC or IV formulations may better manage patient expectations and additional training may improve injection technique [10]. Our analysis indicated a higher cumulative number of previous injections administered at a center (> 47 to ≤ 164) resulted in a trend for a greater number of patients preferring atezolizumab SC over IV. This suggests that the administrator’s experience could be an important factor influencing patient preference.
A limitation of these exploratory analyses is that the IMscin002 study was designed to assess overall patient preference for atezolizumab SC or IV, and as such, these subgroup analyses on patient preference should be interpreted with caution. Secondly, subgroup analyses can have several limitations, such as not accounting for interactions between baseline characteristics or adjusting for potential confounding factors, which can influence medical practice [22]. In addition, all subgroup analyses in this study were descriptive, with no formal statistical hypothesis testing to evaluate the difference in preference across subgroups. In this analysis, the numbers of patients in the different subgroups, including within each quartile of the subgroup, were low, so any results from these analyses may be unreliable and not representative of the real world. Notably, the number of patients aged > 74 years (n = 24) was lower than the other quartiles (n > 30), and so results from this subgroup should be interpreted with caution. Thirdly, the cumulative number of injections of atezolizumab SC at a center before the patient was asked their preferred route of administration is used as a proxy for HCP experience, the latter of which is affected by multiple factors such as the size of the cancer treatment unit, the number of patients enrolled in the study at each center, or staff turnover. Lastly, information on which HCP was administering each treatment was not collected; therefore, the data could be biased if one HCP was more likely to administer the treatment. Despite the limitations noted for this analysis, the results of this exploratory analysis are consistent with the total population [6].

Conclusions
Regardless of baseline and disease characteristics, mean duration of injection with atezolizumab SC, and cumulative number of injections at the center, most patients preferred atezolizumab SC over atezolizumab IV. Preference for the SC formulation was numerically higher in older patients (> 74 years). This was also the case for patients at centers where the highest cumulative number of atezolizumab SC injections performed, which may suggest that HCP experience (and thus, in-center training) could be an important factor to maximize the potential benefits of high-volume SC formulations. These results continue to support the findings that atezolizumab SC is a preferred option for patients that could reduce the treatment burden for patients who are eligible for SC treatment.

Supplementary Information
Below is the link to the electronic supplementary material.