Nivolumab is a programmed death-1 inhibitor that has shown demonstrable clinical benefits in various types of tumors. It is globally approved for intravenous (IV) administration, both as a monotherapy and in combination with other immuno-oncology therapies. These therapies have revolutionized the cancer treatment landscape (Bristol-Myers Squibb Company; Lonardi et al., 2021; Anderson et al., 2019). Subcutaneous (SC) delivery decreases the burden associated with IV administration for patients, healthcare providers, and healthcare systems related to time and resources. SC administration can reduce the time spent waiting for and receiving treatment as it shortens injection times, removes the need for IV infusion ports, decreases time spent on infusions, reduces provider and facility time to deliver cancer care, and offers cost-saving advantage compared to IV (Anderson et al., 2019).

A better understanding of patient preference for the route of administration of immuno-oncology therapies by IV or SC is fundamental in providing optimal medical therapies and may result in better outcomes for patients with cancer (Shingler et al., 2014). Measuring patient-reported experience of the route of treatment administration in controlled studies has been more common in chronic conditions (Overton et al., 2021) and, with many commonly including de novo questionnaires, or single item numeric or visual rating scales (Stoner et al., 2014; Callis Duffin et al., 2016; Schiff et al., 2016; Stauffer et al., 2018), the preference for the route of administration of oncology therapies is not readily comparable to routes of administration of therapies for patients with chronic disorders, given oncology patients often are on treatment for a limited period of time and are administered treatments typically during hospital visits, by a health professional.

To better understand experiences with and preferences for routes of administration, existing patient-reported outcome (PRO) questionnaires assessing treatment satisfaction were examined. No suitable PRO questionnaire that included patient experience and preference for routes of medication administration was identified or publicly available at the time of the CA209-8KX trial. Existing questionnaires like the European Organization for Research and Treatment of Cancer in patient satisfaction questionnaire (EORTC QLQ-SAT32) were considered to be more focused on general aspects of patient treatment satisfaction rather than satisfaction with the route of treatment administration (Brédart et al., 2010). Thus, the de novo Patient Experience and Preference Questionnaire (PEPQ) was developed by a team of PRO and clinical experts through a combination of a targeted literature review and clinical considerations about potentially relevant item concepts for inclusion for measuring satisfaction of the route of treatment administration (Abetz et al., 2005; Stoner et al., 2014). The PEPQ includes questions on patient experience of the treatment, and acceptability and satisfaction with the route of treatment administration.

A phase I/II multi-tumor clinical trial of an SC formulation of nivolumab monotherapy (CA209-8KX) was conducted to evaluate its safety and tolerability with and without recombinant human hyaluronidase PH20 (rHuPH20) (NCT03656718) (Lonardi et al., 2021; Lonardi et al., 2022; ClinicalTrials, 2023). Results from this trial have been used to establish the SC dose of nivolumab for current and potential future studies. The target population for this clinical trial included patients with advanced or metastatic tumors approved for the treatment with nivolumab IV monotherapy: non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC), unresectable or metastatic melanoma, hepatocellular carcinoma (HCC), and microsatellite instability-high or mismatch repair-deficient colorectal cancer (CRC).

An exploratory objective of the trial was to administer the PEPQ and obtain patient-centric data to understand patient experience and IV and SC administration of nivolumab to capture concepts relevant to the experience and satisfaction with the route of medication administration.

To obtain patient feedback, an embedded qualitative interview sub-study was conducted with a subset of CA209-8KX clinical trial participants to examine the experience with IV/SC treatment to support a deeper understanding of patients’ experience of the route of study medication administration. The study did not aim to compare or contrast SC or IV, but included both participants as was possible to make sure the concepts of satisfaction with treatment and route of medication administration could be captured. An exploratory objective of the qualitative interview study was to confirm concepts captured in the PEPQ. Embedded interviews during clinical trials are a recommended method for obtaining more detail on patients’ perspective on treatment benefits and clinical outcome assessment development within the context of a clinical study (Food and Drug Administration, 2022a).

All CA209-8KX trial participants enrolled in the randomized controlled trial were 18 years or older and had histologic or cytologic confirmation of advanced (metastatic and/or unresectable) solid tumors. CA209-8KX clinical trial participants with NSCLC, RCC, melanoma, HCC, or CRC from three treatment cohorts (parts C, D, and E) were eligible for the optional interview sub-study. Participants in cohort parts A and B crossed over from nivolumab IV dosing (4 weeks after last IV dose) to part C; nivolumab 1200 mg was administered SC with rHuPH20 (manually using a syringe every 4 weeks). Participants in parts D (1200 mg SC nivolumab with rHuPH20 every 4 weeks) and E (600 mg SC nivolumab with rHuPH20 every 2 weeks) only had experience with SC treatment (Ascierto et al., 2022; Jackson et al., 2022; Lonardi et al., 2022).

The PEPQ version 1.0 (v1.0) is an eight-question interview-administered questionnaire capturing the current assessment of patient experience and preferences regarding the acceptability of the route of administration, treatment-related symptoms, and satisfaction with the treatment. The PEPQ v1.0 included questions to assess experience during injection or infusion, including a pain rating, a symptom checklist, time to administer study medication, impact of the study medication administration on patient’s time, impact of the study medication administration on patient’s time to speak to a nurse or doctor and socialize, level of patient disturbance with the time to administer the study medication, overall satisfaction with the treatment, and preference for IV or SC treatment (Figure 1). The PEPQ v1.0 was envisioned as interviewer-administered primarily due to the symptom checklist. The PEPQ v1.0 was available in native languages specific to clinical trial sites. Each item is scored and interpreted individually, with no summation for the total score. The questionnaire was administered by site staff immediately following completion of the injection or infusion on day 1 of treatment cycles 1 (IV) and 2 (SC) in parts A and B, and on day 1 of cycle 1 (SC) for participants in parts C, D, and E.

Figure 1. Conceptual framework PEPQ version 2.0.

A coding framework was developed based on the interview guide and study objectives. During the coding of transcripts, new codes were added to the coding framework as needed to capture emerging information. Eight coders were trained by a qualitative data manager (JC) and instructed on using the coding framework. Qualitative data from participants’ open-ended responses were coded from the interview transcripts. Coders identified concepts mentioned by participants during the interview and assigned codes based on the coding framework. ATLAS.ti v9 software was used to support the coding process and organize the codes based on similarity of content (Friese, 2019). To demonstrate consistency of the coded data, the inter-coder agreement was evaluated in a random sample of 10% of the final interview transcripts. These selected transcripts were independently dual-coded (each selected transcript coded by two separate coders). Each dual-coded pair of coders was compared for percent agreement in code assignment. The agreement was determined as the percentage of concepts that were given the same code across two coders with a minimum threshold of 90% agreement (Patrick et al., 2011a).

Coded concepts were exported from ATLAS.ti to allow for code counts specific to the PEPQ and related quotations. Coded data were organized to present participant feedback on PEPQ concepts. Saturation of concept was evaluated by grouping transcripts chronologically and breaking into smaller transcript groups for the comparison of elicitation of symptom and impact concepts. Each subsequent transcript group was compared to the prior group to identify the appearance of new codes (representing new information). If new concepts appeared in the last transcript group, saturation was considered incomplete for those emergent concepts (Rothman et al., 2009; Patrick et al., 2011a; Patrick et al., 2011b).

Relevance of the PEPQ item concepts was evaluated by comparing the concepts elicited during the interview with the question concepts in the PEPQ. The interview results from participants in cohort parts C, D, and E were analyzed together, focusing on the relevance of the patient experience with the route of treatment administration and the content of the PEPQ. The denominator for participant feedback is noted throughout and may not sum to the total sample size due to the semi-structured nature of the interview.

The sub-study sample composed of 43 completed interviews: 11 part C participants, 15 part D participants, and 17 part E participants. Tumor types of interview participants were 33% RCC (n = 13), 23% CRC (n = 10), 19% NSCLC (n = 8), 16% HCC (n = 7), and 16% MM (n = 5). The mean age of participants was 66 years old ±11.3 standard deviation (range 24–80 years), and 67.4% (N = 29) were male. Participants reported time since diagnosis (with various tumor types) ranged between a half year to 18 years, with an average of 5 years. All but one participant (97.7%) reported receiving SC treatment in the belly. Out of the eligible CA209-8KX clinical sites from 11 countries, sub-study interviews were conducted in the following six countries: Argentina, France, the Netherlands, Poland, Spain, and New Zealand. Not all clinical sites chose to participate in the opt-in qualitative interview sub-study due to staffing, low patient numbers, or other reasons. New Zealand had the largest number of interview participants (n = 23), followed by seven participants from Poland, six participants from France, three participants from the Netherlands, and two participants from Argentina and Spain each. Participant characteristics are provided in Table 1.

Table 1. Participant characteristics.

On average, interviews were 30 min in length. Inter-coder agreement was at least 90%, demonstrating consistency in the coded data. Saturation was assessed using symptom and impacts reported by participants. Saturation findings identified that approximately 40% of the symptom and impact concepts mentioned by participants were elicited in the first transcript group (interviews 1–6, part C), followed by 11% in the second (interviews 7–12, parts C and D), and 16% in the third transcript group (interviews 13–18, parts C and D). Ten percent of concepts arose in the fourth group (interviews 19–24, part D), 19% in the fifth transcript group (interviews 25–30, parts D and E), and 3% in the sixth transcript group (interviews 31–36, part E). Only two new concepts appeared in the seventh and final transcript group (interviews 37–43, part E): pinching pain (additional pain description) and bone pain (additional pain location). Pain as a larger conceptual sub-domain had previously arisen in the first and second transcript groups.

The most frequently reported symptoms or signs occurring immediately after infusion or injection were injection-related redness (n = 12/43, 27.9%), itching (n = 6/43, 14.0%), pricking pain (of needle), and stinging or tingling (n = 5/43, 11.0% each). Participants considered their pain experience during or after the injection broadly as pain from either the needle or from drug administration. Pain/discomfort symptoms and tiredness after infusion or injection were rated (on a 0–10 numeric rating scale) as the most severe symptoms (mean values 5.5 and 5.4, respectively).

During interviews, participants were asked about the overall experience of the IV or SC medication administration, specifically probing on symptoms experienced, the time burden of the IV infusion or SC injection, and their level of satisfaction of the injection or infusion. The focus of interviews was to assess the concepts in the PEPQ of in relation to the specific route of treatment medication administration. Participant feedback on treatment experiences were mapped to the PEPQ question content to demonstrate concept relevance as outlined in Table 2 and described further below.

Table 2. Participant feedback confirming concepts of the Patient Experience Preference Questionnaire.

Severity of pain (relevance of PEPQ Q1 concept) was a common response when participants were asked to describe symptoms related to the IV infusion or SC injection. Many participants (n = 26/43, 60.5%) did not experience pain and described the IV infusion or SC injection as “pain-less,” “not painful,” or “no pain.” More than one-third of participants (n = 17/43, 39.5%), however, reported a range of pain severity experiences related to the IV infusion or SC injection, notably “pricking,” “stinging” (n = 5/43, 11.6%, each), “burning” or “tenderness” (n = 3/43, 7.0%, each), “ache or dull sensation” or “pain” (n = 2/43, 4.7%), and “discomfort” or “pinching” (n = 2/43, 2.3%, each) (Table 3).

Table 3. Symptom experience immediatiely after infusion/injection.

Table 4 shows a summary of the satisfaction ratings and responses to the final preference question in the interview guide. Ratings of treatment satisfaction were reported by participants using an 11-point (0–10) numerical rating scale (NRS). The results for the overall satisfaction rating of the route of administration of treatment were rated very high across parts C, D, and E participants. The total group mean for “satisfaction with SC treatment experience” was 9.4 on the NRS.

Table 4. Satisfaction with treatment experience and preference for the route of medication administration.

After the piloting of the PEPQ during the CA209-8KX trial, the PRO development team decided to remove question 2 “feelings or sensations during the injection or infusion” and revise the instrument from interviewer-administered to self-report PRO instrument (see Supplemental Table S1). The rationale to remove question 2 was multi-fold. One strong rationale was due to the perceived burden of administering this questionnaire from clinical site staff. A second compelling rationale was the potential for missing data, given dependence on the interviewer to accurately record responses. A third rationale for removing question 2 was that question 1 (IV/injection pain) captures key symptom experience related to routes of administration, whereas other symptoms may be more related to the treatment itself.

The sub-study interview feedback supported this decision to remove question 2 as the key symptoms reported by participants related to IV infusion or SC injection were primarily specific to pain which is captured in PEPQ question 1. Removing question 2 would simplify for patient completion rather than interviewer-administration and allow for easier scoring and interpretation of the PEPQ. The revised PEPQ v2.0 includes seven questions, and the instructions have been revised for self-report.

A 2021 review of published studies describing preferences for IV or SC treatment in patients with chronic disorders assessed concepts such as time requirement, convenience, side effects, and fear of injections (Overton et al., 2021). Research on cancer patient satisfaction has focused on satisfaction with care which focuses on the context of the treatment, rather than on homing in on the route of medication administration (Brédart et al., 2010). SC administration can reduce time spent waiting for and receiving treatment as it shortens injection times, removes the need for IV infusion ports, decreases the time spent, reduces provider and facility time to deliver cancer care, and offers cost-saving advantage compared to IV.

The PEPQ provides a 7-item tool for use in oncology clinical trials that can provide valuable information on patient satisfaction for the route of medication administration. Future studies may focus on further validation of the PEPQ, assessing the incidence of adverse events between routes of administration, and evaluating the humanistic and economic impact of SC versus IV administration.

When interpreting the current content validity study, some limitations should be considered. The PEPQ v1.0 was developed from a targeted literature review of satisfaction measures and consultation with clinical experts as an interviewer-administered measure to assure the completion of the symptom checklist and open-ended responses. Ideally, de novo PRO development should begin with patient input and follow the Food and Drug Administration (FDA) guidance (Food and Drug Administration, 2022a; Food and Drug Administration, 2022b).

The PEPQ was not evaluated directly through cognitive interviews but examined by mapping question concepts from the PEPQ to the participant feedback and experiences on topics in the interview guide. No direct feedback or assessment of the PEPQ was obtained. However, the sub-study probed on PEPQ concepts, and support was found for all questions in the PEPQ from the range of topics that participants brought up as relevant to their experience of the treatment and route of administration. There was no evidence of missing concepts for assessing the experience during or directly after IV infusion or SC injection.

Additional limitations should be considered when reviewing these results. Only part C participants (n = 28) were administered the entire PEPQ v1.0 as a part of their study assessments. Part C participants were the only group that had direct experience receiving the treatment via both IV and SC routes of administration. Parts D and E participants received an SC injection during the trial; however, they may not have had exposure to IV in prior treatment before enrolling into this study. From the clinical trial findings (Lonardi et al., 2022), 21 part C participants (n = 21/28, 75.0%) responded on the PEPQ, of which 15 (n = 15/21, 71.4%) indicated a preference for the SC route of medication administration. In comparison, 10 (n = 10/11, 90.9%) of the part C participants in the qualitative interview sample indicated a preference for SC treatment. There are several potential explanations for this difference. One explanation for the difference preference for SC treatment between the part C trial and interview sub-sample might be self-selection bias with those who agreed to interview also being participants who preferred SC injection over IV infusion. A second possibility could be a result of the difference in what participants might divulge to clinical site staff in a study visit versus a lengthy conversation with a qualitative interviewer. Another potential explanation might be that the interview is a retrospective discussion of overall clinical trial benefits and not a single point of time during a clinic visit. A fourth possibility might be that the difference is the result of a response shift due to time lapse (days or weeks) between when the interview participants completed the PEPQ and the interview. Regardless of these limitations, the qualitative interview results and the PEPQ trial results indicate the highest predominance of preference being for the SC route of administration.

Sub-study interviewers were trained on the semi-structured interview guide and asked to cover every probe included in the guide as much as reasonably possible for each telephone interview in the allotted interview time. However, due to the conversational nature of qualitative research, some probes may have been missed due to the natural flow of the discussion and dynamics with the participant and sometimes due to time restraints.

Further limitations of this study resulted from the questionnaire mode of administration of PEPQ v1.0, which was an interviewer-administered instrument. The clinical sites were responsible for administering the instrument to each trial participant. However, due to clinical sites’ other commitments and the additional burden of administering the PEPQ, missing data were noted. It is recommended that in future studies, the self-complete version of the PEPQ, PEPQ v2.0, be used to minimize clinical site staff administration burden and reduce the chances of missing data.

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2024.1310546/full#supplementary-material

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