Key Takeaways
- FDA officials and others reflected on the past decade’s boom in the number and types of patient reported outcome information in cancer labeling.
- Regulatory acceptance of the Lee Symptom Scale to measure patient-reported symptom bother in chronic graft vs host disease has produced has enabled PRO labeling for AbbVie/J&J’s Imbruvica, Incyte’s Jakafi, Kadmon’s Rezurock and Incyte’s Niktimvo.
- Lilly’s Retevmo and Genentech’s Itovebi labeling included detailed tolerability assessment and a multi-dimensional concept.
Patient-reported outcomes are increasingly found in cancer drug labeling, but standout examples come from a limited set of use cases in Graft-vs-host disease, myelofibrosis and Genentech’s suite of IV-to-subcutaneous antibody conversions, according to data presented to the FDA’s recent Clinical Outcome Assessment in Cancer Clinical Trials Workshop.
The Oct. 8 meeting marked the 10th annual convening of the workshop, prompting reflection on the progress of COAs, especially PROs, in the oncology space.
“The development of PROs has evolved significantly from ad hoc measurements to a sophisticated, standardized and patient-centered discipline,” said Selena Daniels, deputy director of the FDA Center for Drug Evaluation and Research’s Division of Clinical Outcome Assessment.
“The past decade has seen a boom in the number and types of PRO information included in product labeling,” said Vishal Bhatnagar, Oncology Center of Excellence Associate Director for Patient Outcomes. “That’s no accident.”
Bhatnagar highlighted the influence of the FDA’s “Core Patient-Reported Outcomes in Cancer Clinical Trials” guidance, which was finalized in October 2024, and Project Patient Voice, a web-based, public source of PRO data describing patient-reported side effects.
The FDA established the Patient-Focused Drug Development (PFDD) initiative in 2012, beginning a broad effort that would encompass clinical outcome assessments, PROs and other patient experience data.
Oncology has seen slower PRO uptake than some other therapy areas.
Trial design features reflecting high need, like open-label or single arm trials, have allowed cancer drugs to speed to market, but the same features raise risks of bias. But using PROs in oncology labeling lagged.
“We were really grappling with how to systematically evaluate PRO data in every single oncology or most oncology applications,” Bhatnagar recalled.
The FDA’s December 2009 PRO guidance was “groundbreaking,” he said, but “implementation specific to oncology trials was, I think, particularly challenging.”
Primary endpoints in oncology “are usually survival based,” he added.
Daniels said “measuring disease-related symptoms in cancer trials” is another challenge, “just due to the overlap of treatment-related symptoms.”
For sponsors “who do attempt to measure this concept, we have seen that there are limited fit-for-purpose disease-specific instruments for the intended context of use,” she said.
Now, “we see an increasing number of well collected, clinically relevant PROs included in oncology product labeling,” Bhatnagar said.
Twenty-one oncologic applications have been approved with PRO information in labeling. The approvals started sporadically nearly 15 years ago and become more common, and more varied, around 2017.
“From a regulatory standpoint, we’re still working on best ways to integrate PRO data alongside the traditional efficacy and safety information that we receive,” he said. “We’re also seeing how PRO data can serve as the basis for secondary endpoints to support those primary efficacy endpoints.”
From Jakafi …
“We saw the success of this shift with the approval and labeling of ruxolitinib back in 2011, in which a fit-for-purpose PRO multi-symptom questionnaire played an important role in its approval,” said Ethan Basch, University of North Carolina Distinguished Professor and Physician in Chief of the North Carolina Cancer Hospital.
Incyte’s Jakafi (ruxolitinib) was approved for intermediate or high-risk myelofibrosis on Nov. 16, 2011, and credited as the first oncology label cleared under the FDA’s December 2009 PRO guidance.
The primary efficacy endpoint focused on spleen shrinkage, but the clinical studies section of labeling includes data on a secondary endpoint, the modified Myelofibrosis Symptom Assessment Form (MFSAF) 2.0 diary, a PRO metric developed by Incyte following FDA advice. MFSAF addresses six MF symptoms: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on the left side and bone or muscle pain.
Bhatnagar said the Jakafi approval “showed us that thoughtful incorporation of a disease-specific measure that incorporated specific symptoms relevant to those patients that are undergoing treatment, a robust methodology, [and a] specific PRO measure, not a generic measure, can be really helpful to move the field forward.”
MFSAF addresses six MF symptoms: night sweats, pruritus, abdominal discomfort, early satiety, pain under ribs on the left side and bone or muscle pain.
The scale later was used as a secondary endpoint in Bristol Myers Squibb’s Inrebic (fedratinib) trials, earning labeling based on the MFSAF v.2.0 upon its approval Aug. 16, 2019.
Incyte returned with fatigue-specific PRO data in myelofibrosis, which the FDA added to Jakafi labeling on Oct. 10, 2017 as an exploratory analysis showing improvement in fatigue-related symptoms and impacts on daily activities using the PROMIS Fatigue 7-item short form total score.
… To Romvimza
Bhatnagar also highlighted the FDA’s Feb. 14 approval of Deciphera’s Romvimza (vimseltinib) for tenosynovial giant cell tumor.
While overall response rate (ORR) can “measure the reduction in tumor burden over time,” the agency said that “due to the slow growing nature of the tumor and the symptomatic and functional impacts of the tumor location, supportive evidence of clinical benefit based on clinical outcome assessments (COAs) that can evaluate improvement in pain, range of motion, and physical function is useful to understand the drug effect.”
The FDA and Deciphera agreed on COA parameters ahead of the Phase III MOTION study. In 2020, the agency determined that the concepts of interest identified by the company, range of motion, physical function, pain, stiffness, swelling and joint instability, were “important and relevant to the experience of patients with TGCT.”
The FDA then agreed on PRO instruments to assess relevant core concepts, including the Patient-Reported Outcomes Measurement Information System-Physical Function (PROMIS-PF) 15-item score, which includes upper and lower extremity items, along with response on the mean Brief Pain Inventory (BPI) Worst Pain numeric rating scale (NRS) score (at least a 30% improvement without a 30% or greater increase in narcotic analgesic use).
Approved Romvimza labeling included PROMIS-PF and BPI-30 response at Week 25 analyses as key secondary efficacy results of MOTION. The data are presented as a table as in the Clinical Trials section.
Symptom Bother In cGVHD
Bhatnagar discussed five chronic graft-versus-host disease approvals since 2017 with patient-reported symptom bother language in labeling, a profusion that rests on the acceptance of the Lee Symptom Scale in that setting.
Labeling for AbbVie/J&J’s Imbruvica (ibrutinib), Incyte’s Jakafi, Kadmon’s Rezurock (belumosidil), and Incyte’s Niktimvo included statements that “ORR results were supported by exploratory analyses of patient-reported symptom bother which showed at least a seven-point decrease in Lee Symptom Scale overall summary score.”
“The manifestation of graft versus host disease can vary quite significantly,” Bhatnagar said. The Lee Symptom Score “can be useful to cover many different types of concepts.”
The Lee Symptom Score questionnaire has “really been very useful because it’s capturing symptom burden, but from the patient perspective,” said Melanie Calvert, professor of outcomes methodology and director of the Center for Patient Reported Outcomes Research at the University of Birmingham (UK).
“It complements the clinical assessments, the objective clinical assessments, which sit alongside that,” Calvert said. “And I think it’s really useful because it captures things like the bother of symptoms like skin rashes, mouth sores, pain, fatigue, which are all really important to patients taking these therapies.”
Standardization Yields Benefits
Repeated experience with particular PRO measures, like the Lee Symptom Scale or the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) item library, helps set parameters for use and interpretation that encourages other sponsors to adopt them.
“Standardization has had a profound positive impact in my opinion,” Basch said. “Having these standards provides clarity on best practices, and as a result, I think we’ll be seeing greater and greater alignment across the industry and how PROs are used.”
“There’s now widespread use of this tool in global clinical trials, and we’re now starting to see inclusion of PRO-CTCAE in drug labels,” he added.
PRO-CTCAE, and its later pediatric version, have broad applicability. Sponsors can use its item library to select the most important symptomatic adverse events expected to occur.
But disease-related symptom measures remain a challenge for cancer trials, Daniels said. The overlap of cancer symptoms and drug-related AEs makes analysis challenging.
“For those who do attempt to measure this concept, we have seen that there are limited fit-for-purpose disease-specific instruments for the intended context of use,” which is “preventing sponsors from fully leveraging these guidances,” she said.
“We’ve already made really meaningful practice or progress towards standardization, but we still have a little ways to go,” said Amylou Dueck, a biostatistics professor at Mayo Clinic Arizona.
“I think we’re still in the middle of settling on that standard set of analyses and visualizations on the core outcomes,” she added. “I think that’s still got a little bit of evolution to go, but I expect in five years, we should have kind of a settled set of standard visualizations and analysis for those core outcomes.”
Increasing Tolerability Assessment
“I think increasing the amount of patient generated data that we’re looking at has really helped us move toward a more accurate and comprehensive tolerability assessment,” said Gita Thanarajasingam, Mayo Clinic associate professor of medicine.
She uses the tolerability definition published by the Friends of Cancer Research, which considers it to be “the degree to which symptomatic and non-symptomatic adverse events of the treatment affect the ability or desire of a patient to adhere to the dose or intensity of therapy.”
Two FDA approvals in 2024 are examples that “really reflect this definition of tolerability as being related to but not the same thing as the concept of safety,” she said.
Lilly’s Retevmo (selpercatinib) was approved Sept. 27, 2024 for a RET-mutant medullary thyroid cancer indication. The Clinical Trials section of labeling reports patient-reported overall side effect impact in the pivotal LIBRETTO-531 study, based on weekly administration of the Functional Assessment of Cancer Therapy item GP5 (FACT GP5). Overall side effect impact was defined as a proportion of time on treatment with high side effect bother.
“Patient-reported overall side effect impact results were supported by a lower incidence of treatment discontinuation due to adverse reactions” for Retevmo vs. the comparator, the label states.
Genentech’s Itovebi (inavolisib) was approved Oct. 10, 2024, for use in combination therapy for a targeted breast cancer indication. The tolerability analysis is included in the Adverse Reactions section of labeling, using PRO-CTCAE results.
Genentech evaluated expected symptomatic AEs for the combination of inavolisib, palbociclib, and fulvestrant from the PRO-CTCAE item library, selecting diarrhea, nausea, vomiting, fatigue, mouth sores, decreased appetite, and rash, along with a single item assessing bother due to side-effects of treatment.
“In general, these patient-reported symptoms were observed to be worse in the inavolisib arm,” FDA review documents state. “Although the PRO data collection was considered exploratory, these symptoms were considered supportive of the clinician reported safety information and informative for labeling.”
Genentech’s PRO Preference
Bhatnagar gave four approvals of Genentech products with PROs assessing patient preference described in a Patient Experience subsection of the Clinical Studies section. They used Halozyme’s recombinant hyaluronidase technology to allow subcutaneous injection of antibodies that previously required IV administration:
- Tecentriq Hybreza (atezolizumab and hyaluronidase-tqjs) was approved Sept. 12, 2024, with a summary of the IMscin002 study of patient-reported preference for IV or subcutaneous administration
- Phesgo (pertuzumab, trastuzumab, and hyaluronidase-zzxf) was approved June 29, 2020, with labeling describing the PHranceSCa patient preference study
- Herceptin Hylecta (trastuzumab and hyaluronidase-oysk) was approved Feb. 28, 2019 with the PrefHER preference study summarized in the Patient Experience section
- Rituxan Hycela (rituximab and hyaluronidase human) received Genentech’s first patient preference labeling June 22, 2017, describing results of one PRO measure, the patient preference questionnaire (PPQ), but not the Rheumatoid Arthritis Symptom Questionnaire (RASQ) or the Cancer Therapy Satisfaction Questionnaire (CTSQ).
Merck had less success with PRO data in the labeling for subcutaneous Keytruda Qlex (pembrolizumab and berahyaluronidase alfa-pmph), which was approved Sept. 19. FDA review documents show that Merck assessed health-related quality of life measures, but the agency “did not perform independent analysis of the PRO endpoint results given the descriptive and exploratory nature of this data.”
“FDA agrees with the applicant that there were no observed differences between arms on core PRO outcomes such as physical and role functioning,” the review states. “FDA does not agree with the applicant regarding conclusions made on PRO domains outside of core outcomes, such as social function, emotional function, and global health score as these are subject to non-disease and non-treatment related factors.”