ASH 2019: Patient-Reported Outcomes, From MOST to FDA Clinical Reviews

During oral abstract sessions at the 61st American Society of Hematology Annual Meeting & Exposition in Orlando, Florida, results from the MOST and CLL14 trials were presented on older patients being treated for essential thrombocythemia (ET)/myelofi brosis and chronic lymphocytic leukemia (CLL), respectively. Results showed signifi cant symptom burden, particularly from fatigue.

Both studies covered older patients, with a median age of 70 years (range, 19-93) for patients in MOST (80% were at least 60 years of age)¹ and at least 71˜years for patients in CLL14.² They both also used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30) to evaluate health-related quality of life (QOL) (functional ability), with MOST also using the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) for symptom burden and CLL14, the MD Anderson Symptom Inventory (MDASI). Patients were asked to report on symptom burden, functional status, and QOL at regular intervals throughout their treatment using provided questionnaires. These patient-reported outcomes (PROs) are meant to inform a greater understanding of how to improve QOL aff ected by treatment.

In MOST,¹ patients on ET-directed therapy were observed for 36 months, and their data (also known as a score) were collected every 6 months. High scores indicated good results for functional status and QOL, but a signifi cant symptom burden. The mean (SD) TSS score (range, 0-100 overall; 0-10 per symptom) was 17.1 (15.6), with women faring worse than men (18.5 [15.8] vs 14.2 [14.9]). Fatigue had the highest individual mean symptom score (3.4 [2.7]), topping also the EORTC QLQ-C30 scale for severity, at 29.6 (25.8). The mean global health status/QOL score was 72.7 (21.9) (Figure 1). Men had overall higher functioning scores and less symptom

burden than women.

In CLL14,² 432 patients received chlorambucil/obinutuzumab (Gazyva) (CIbG) or venetoclax/obinutuzumab (VenG). They were observed for a median 28.1 months, and their data (score) were collected every 3 months during follow-up. Again, high scores indicated good functional status and QOL, but a great symptom burden. EORTC physical and role function scores were a mean (SD) 75.9 (± 20.1) and 76.9 (± 19.4) in the CIbG and VenG arms (216 patients each), respectively, when treatment started, whereas QOL was 63.6 (± 21.0) and 60.3 (± 20.5), respectively. The VenG treatment group fared better more quickly, however, with meaningful improvement in QOL seen by cycle 3 of treatment compared with cycle 8 for the CIbG group (Figure 2).³ For MDASI, CLL (1.5 [± 1.2] and 1.6 [± 1.3]) and core cancer (1.5 [± 1.4] and 1.8 [± 1.7]) symptoms and symptom interference (2.1 [± 2.3] and (2.3 [± 2.3]) remained low and similar from baseline through follow-up for the VenG and CIbG groups, respectively (Figure 3).3 Overall, functional status and QOL did not worsen and symptom severity remained low among both groups, with dyspnea being the most severe symptom at baseline (24.8 [± 27.76]), compared with during treatment and follow-up.

Investigators from the MOST trial believe that “future analyses from this trial will continue to increase understanding of the symptom burden and its impact on QOL in patients with ET,” whereas CLL14 investigators note, “As elderly patients with CLL typically experience impairment of QOL, particularly when suff ering from various other conditions, such improvement should be considered a main therapeutic goal.”

References

1. Ritchie EK, Al-Janadi A, Colucci P, Kalafut P, Paranagama D, Mesa RA. Patient-reported outcomes (PRO) data from patients (pts) with essential thrombocythemia (ET) enrolled in the MOST study. Presented at: 61st American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 1665. ash.confex.com/ash/2019/webprogram/Paper124527.html. Accessed December 21, 2019.

2. A Study to Compare the Efficacy and Safety of Obinutuzumab + Venetoclax (GDC-0199) Versus Obinutuzumab + Chlorambucil in Participants With Chronic Lymphocytic Leukemia. clinicaltrials.gov/ct2/show/results/NCT02242942. Updated October 1, 2019. Accessed December 6, 2019.

3. Al-Sawaf O, Gentile B, Devine J, et al. Rapid improvement of patient-reported outcomes with venetoclax plus obinutuzumab in patients with

previously untreated CLL and coexisting conditions: a prospective analysis from the CLL14 trial. Presented at: 61st American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 4305. ash.confex.com/ash/2019/webprogram/Paper126542.html. Accessed December 21, 2019.

Patient-Reported Outcomes Are Considered During FDA Clinical Reviews

Disease symptoms, symptomatic adverse events, and physical function top the list of patient-reported outcomes (PROs) from cancer clinical trials of interest to the FDA during application reviews for both new products and new indications for existing medications.¹ During the recent 61st American Society of Hematology Annual Meeting & Exposition in Orlando, Florida, for benign and malignant hematology indications, data were presented that show just how often the FDA consider s PROs during clinical review, when PROs are included in product labels, and what the PROs referenced.

Investigators from the FDA and the Center for Biologics Evaluation and Research (CBER) gathered PRO data for approvals between 2017 and 2018 from the Center for Drug Evaluation and Research in the Office of Hematology and Oncology Products and CBER, as well as determined the frequency with which those data were included on clinical study reports (CSRs)², final FDA review, and drug labels. The FDA handed down 64 approvals during the study period (31 new molecular entity [NME]³ and 33 supplemental applications).

The investigators determined that PRO data were included on 30% (3/10) of the CSRs for benign hematology NMEs and biologics license applications (BLAs) and 47% (7/15) of CSRs for malignancy applications. However, the FDA subsequently included that data in its clinical review for 9 submissions (3 benign; 6 malignant), and labels for Hemlibra (emicizumab; Chugai) and Rituxan Hycela (rituximab/hyaluronidase human; Genentech/Biogen) ultimately incorporated the data. Hemlibra⁴ treats hemophilia A, and Rituxan Hycela5®treats relapsed or refractory follicular lymphoma (FL), previously untreated FL, nonprogressing FL, previously untreated diffuse large B-cell lymphoma, and previously untreated and treated chronic lymphocytic leukemia (CLL).

PRO data were also included on 38% (3/8) of the CSRs for supplemental benign hematology indications and 65% (13/20) for malignant indications. The FDA went on to include that data in its clinical review for 15 submissions (3, benign; 12, malignant), and labels for Feraheme (ferumoxytol; AMAG)⁶ and Imbruvica⁷ (ibrutinib; Pharmacyclics/Janssen Biotech) include the data. Feraheme treats iron deficiency anemia, and Imbruvica treats mantle cell lymphoma, CLL, CLL/small lymphocytic leukemia with 17p deletion, Waldenström’s macroglobulinemia, marginal zone lymphoma and chronic graft versus host disease.

Overall, more labels for benign indications (33% [1/3], NMEs and BLAs; 33% [1/3], supplemental) included PROs data than did those for malignant indications (16% [1/6] and 8% [1/12], respectively), and these data covered disease symptoms and physical function.⁸

The FDA is currently developing guidelines for the use of PROs in cancer clinical trials.

References

1. Patient-centered initiatives at the FDA: a conversation with Vishal Bhatnagar, MD, Bellinda King-Kallimanis, PhD, Janice Kim, PharmD, and Paul G. Kluetz, MD. The ASCO Post. ascopost.com/issues/september-25-2019/patient-centered-initiativesat-the-fda/. Published September 25, 2019. Accessed December 12, 2019.

2. Navigating the four types of clinical study reports. MMS Holdings website. mmsholdings.com/navigating-the-four-types-of-clinical-studyreports/. Accessed December 12, 2019.

3. Chemicool Dictionary. Definition of molecular entity. chemicool.com/definition/molecular_entity.html. Accessed December 12, 2019.

4. Hemlibra (emicizumab-kxwh) injection, for subcutaneous use [package insert]. South San Francisco, CA: Genentech, Inc; 2018.

5. Rituxan Hycela (rituximab and hyaluronidase human) injection, for subcutaneous use [package insert]. South San Francisco, CA: Genetech,

Inc; 2017.

6. Feraheme (ferumoxytol injection). [package insert]. Waltham, MA: AMAG Pharmaceuticals; 2018.

7. Imbruvia (ibrutinib) capsules, for oral use; Imbruvica (ibrutinib) tablets, for oral use [package insert]. Sunnyvale, CA, and Horsham, PA:

Pharmacyclics and Janssen; 2019.

8. Kim J, Kanapuru B, Roydhouse JK, et al. 2017-2018 hematology drug approvals at the Food and Drug Administration (FDA): communication of patient-reported outcomes (PRO) information in FDA clinical reviews and prescribing information. Presented at: 61st American Society of Hematology Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL. Abstract 3450. ash.confex.com/ash/2019/webprogram/Paper125798.html. Accessed December 6, 2019.

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